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"abstract": "Though there is ample evidence for the association between selective serotonin reuptake inhibitors and hyponatremia, evidence for the relationship between mirtazapine and hyponatremia is scarce. We present a case of mirtazapine-induced hyponatremia in an adult patient, which was dose related.",
"affiliations": "Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Ghosh|Abhishek|A|;Hegde|Aditya|A|;Grover|Sandeep|S|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D007552:Isotonic Solutions; D008803:Mianserin; D012965:Sodium Chloride; D012964:Sodium; D000078785:Mirtazapine",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.135964",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-46-44810.4103/0253-7613.135964Drug WatchMirtazapine-associated hyponatremia presenting as delirium Ghosh Abhishek Hegde Aditya Grover Sandeep Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, IndiaCorrespondence to: Dr. Sandeep Grover, E-mail: drsandeepg2002@yahoo.comJul-Aug 2014 46 4 448 449 24 12 2013 31 1 2014 01 5 2014 Copyright: © Indian Journal of Pharmacology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Though there is ample evidence for the association between selective serotonin reuptake inhibitors and hyponatremia, evidence for the relationship between mirtazapine and hyponatremia is scarce. We present a case of mirtazapine-induced hyponatremia in an adult patient, which was dose related.\n\nKEY WORDS\nHyponatremiamirtazapinedelirium\n==== Body\nIntroduction\nVarious antidepressants especially selective serotonin reuptake inhibitors (SSRIs) are known to cause hyponatremia, especially in elderly and those with medical comorbidities or on polypharmacy. Hyponatremia is also reported with other antidepressants, few antipsychotics and with mood stabilizers like carbamazepine and oxcarbazepine.[123] However, among various antidepressants, there is limited literature to suggest association of mirtazapine and hyponatremia. In our review of literature (done in early September 2013 by using PUBMED), we could find only five cases of mirtazapine-induced hyponatremia.[456] A review of these cases suggests that all these patients were elderly who had multiple physical comorbidities which by themselves predispose to hyponatremia. In this report, we present a case of mirtazapine-induced severe hyponatremia, which was seen in an adult patient, was related to the dose of mirtazapine and appeared within few hours of intake of increased dose of mirtazapine.\n\nCase Report\nA 46-year-old widow female, low socioeconomic status, with poor social support, who was premorbidly well adjusted, presented to psychiatric outpatient clinic with an acute onset illness, precipitated by family stress in the form of her son marrying against her wishes, of 4 months duration, progressive in nature, characterized by persistent sadness, bodyaches, lethargy, anhedonia, depressive cognition, anxiety spells, decreased sleep, and decreased appetite. Her past history did not reveal any significant medical or psychiatric history and there was no family history of mental illness. Her body weight was 54 kg, body mass index was 22.5 kg/m2, and her blood pressure was in the normal range. She was diagnosed with moderate depressive episode without somatic syndrome (ICD-10). Because of marked sleep disturbance, mirtazapine was preferred and she was started on Tab. mirtazapine 7.5 mg/day, which was increased to 15 mg/day after 4 days along with Tab. Clonazepam 0.5 mg/day. In the meanwhile, routine investigations in the form of hemogram, serum electrolytes, renal function test, liver function test, fasting blood sugar levels, lipid profile were done, which did not reveal any abnormality. Over the period of 4 weeks, her sleep and anxiety improved marginally, with overall 30% improvement in symptomatology (Score on Hamilton depression rating decreased from 18 to 13), following which Tab. mirtazapine was increased to 22.5 mg/day. However, immediately after the increase in the dose of mirtazapine, her difficulty in falling asleep reappeared along with intermittent awakening. Next morning, she was noticed to be restless, appeared confused and agitated. As the day progressed, she became disoriented to time, place and person, irritable, had labile affect, and her speech became incomprehensible. Later by the evening, she became restless and started to wander around aimlessly. Following this, she was brought to medical emergency. On evaluation she was found to have disorientation to time, place and person, poor attention and concentration, impairment in short-term memory, labile affect, and incomprehensible speech. Physical examination did not reveal any evidence of dehydration, hypervolumia, and her pulse rate and blood pressure were in the normal physiological limits. History did not reveal any evidence of head injury, taking over the counter medications or any overdose, restriction of diet, drug or alcohol abuse, and excessive intake of water. Her mini-mental state scale score was 6 and her Revised Delirium Rating Scale (DRS-98) score was 21. She was investigated including a computerised tomography of brain, X-ray chest, ultrasound abdomen, liver function test, serum urea and creatinine, serum electrolytes, and random blood sugar levels. No abnormality was noted except for evidence of hyponatremia (serum sodium level 123 meq/l). Tab. mirtazapine was stopped. She was managed with water restriction and intravenous sodium replacement with isotonic saline slow intravenous drip. Over the next 2 days, her mental state improved, along with normalization of serum sodium (138 meq/l). Her mini–mental state examination (MMSE) improved to 30 and her DRS-R-98 score reduced to 7. After a weeks time, serum sodium levels were repeated, which was in the normal range (138 meq/l), following which she was started on Tab. milnacipran with close monitoring of serum sodium levels. She was able to tolerate Tab. milnacipran 100 mg/day, with which her depression remitted and she has been maintaining well with milnacipran for the last 5 months.\n\nDiscussion\nIndex case exemplifies an association of hyponatremia with mirtazapine. On the Naranjo Adverse Drug Reaction Probability Scale,[7] the score of index case was 7, suggesting a probable association of hyponatremia and mirtazapine.\n\nIn contrast to the most of literature, which suggests association of mirtazapine and hyponatremia in the presence of risk factors like advance age, hypertension, diabetes mellitus, concomitant prescription of medications known to cause hyponatremia,[45] in the index case hyponatremia was noted in an adult patient who had no medical comorbidity and was not on any concomitant medications. Studies which have found association of hyponatremia and other antidepressants have also reported low body weight and renal dysfunction[8] to be other risk factors for development of hyponatremia. No such risk factors existed in the index case.\n\nAnother interesting observation noted in the patient was emergence of hyponatremia, immediately after increasing the dose of mirtazapine from 15 to 22.5 mg/day. Studies in literature have not focused much on the relationship of dosage of psychotropics and development of hyponatremia.\n\nThough a few case reports of relatively later onset of hyponatremia has also been documented in the literature,[910] this is contrary to the usual notion that antidepressant-induced hyponatremia occurs within a month of initiation and is unrelated to the dose of medication.[11]\n\nMirtazapine is a serotonin receptor blocker which also effects norepinephrine through blockade of alpha-2 adrenergic receptor. The hyponatremia noted in patients with mirtazapine may possibly be mediated by the same syndrome of inappropriate anti-diuretic hormone secretion (SIADH) mechanism mediated by its effect on serotonin. Effect of antidepressants on 5-HT and 5-HT1c receptors has been thought to responsible for relapse of anti-diuretic hormone (ADH). However, the exact mechanism which can explain mirtazapine-induced or SSRI-induced hyponatremia is not known.[11] The case suggests that there is merit in monitoring serum sodium levels while increasing the dose of mirtazapine in apparently physically healthy subjects.\n\nSource of Support: Nil\n\nConflict of Interest: No\n==== Refs\n1 Mannesse CK van Puijenbroek EP Jansen PA van Marum RJ Souverein PC Egberts TC Hyponatraemia as an adverse drug reaction of antipsychotic drugs: A case-control study in VigiBase Drug Saf 2010 33 569 78 20553058 \n2 Giorlando F Teister J Dodd S Udina M Berk M Hyponatraemia: An audit of aged psychiatry patients taking SSRIs and SNRIs Curr Drug Saf 2013 8 175 80 23841535 \n3 Letmaier M Painold A Holl AK Vergin H Engel R Konstantinidis A Hyponatraemia during psychopharmacological treatment: Results of a drug surveillance programme Int J Neuropsychopharmacol 2012 15 739 48 21777511 \n4 Famularo G Gasbarrone L De Virgilio A Minisola G Mirtazapine-associated hyponatremia in an elderly patient Ann Pharmacother 2009 43 1144 5 19435965 \n5 Cheah CY Ladhams B Fegan PG Mirtazapine associated with profound hyponatremia: Two case reports Am J Geriatr Pharmacother 2008 6 91 5 18675767 \n6 Roxanas MG Mirtazapine-induced hyponatraemia Med J Aust 2003 179 453 4 14558878 \n7 Naranjo C Busto U Sellers E Sandor P Ruiz I Roberts E Empiric delineation of the probability spectrum of adverse drug reactions Clin Pharmacol Ther 1981 29 267 8 \n8 Jacob S Spinler SA Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults Ann Pharmacother 2006 40 1618 22 16896026 \n9 Arinzon ZH Lehman YA Fidelman ZG Krasnyansky II Delayed recurrent SIADH associated with SSRIs Ann Pharmacother 2002 36 1175 7 12086550 \n10 Bavbek N Kargili A Akcay A Kaya A Recurrent hyponatremia associated with citalopram and mirtazapine Am J Kidney Dis 2006 48 e61 2 16997047 \n11 Liu BA Mittmann N Knowles SR Shear NH Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: A review of spontaneous reports CMAJ 1996 155 519 27 8804257\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "46(4)",
"journal": "Indian journal of pharmacology",
"keywords": "Hyponatremia; delirium; mirtazapine",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000929:Antidepressive Agents, Tricyclic; D003693:Delirium; D003866:Depressive Disorder; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007552:Isotonic Solutions; D008803:Mianserin; D008875:Middle Aged; D000078785:Mirtazapine; D012964:Sodium; D012965:Sodium Chloride; D016896:Treatment Outcome",
"nlm_unique_id": "7902477",
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"pages": "448-9",
"pmc": null,
"pmid": "25097290",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16896026;14558878;18675767;8804257;23841535;20553058;12086550;16997047;21777511;19435965",
"title": "Mirtazapine-associated hyponatremia presenting as delirium.",
"title_normalized": "mirtazapine associated hyponatremia presenting as delirium"
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"abstract": "Mantle cell lymphomas (MCLs) are the prototypic B-cell non-Hodgkin lymphomas defined by cyclin D1 gene (CCND1; or other cyclin D family gene) rearrangements. However, extremely rare cases of diffuse large B-cell lymphomas (DLBCLs) harboring CCND1 rearrangements, resulting in cyclin D1 protein expression, have also been reported. In this report, we describe an unusual primary large B-cell lymphoma of non-germinal center immunophenotype of the central nervous system (CNS) in an elderly male patient, which was negative for CD5 and SOX11, and exhibited cyclin D1 expression. Fluorescence in situ hybridization analysis detected IGH-CCND1 and BCL6 rearrangements. This case may represent the first report of a primary CNS DLBCL with IGH-CCND1 rearrangement. The clinico-pathologic features that can help differentiate primary CNS MCL from primary DLBCL of the CNS with IGH-CCND1 rearrangement are discussed.",
"affiliations": "Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.;Department of Neurology & Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.;Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.;Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.;Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.",
"authors": "Parrott|Andrew M|AM|https://orcid.org/0000-0002-7845-7479;Haggiagi|Aya M|AM|;Murty|Vundavalli V|VV|;Bhagat|Govind|G|;Alobeid|Bachir|B|",
"chemical_list": "D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C529133:IGH-CCND1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D019938:Cyclin D1",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2779",
"fulltext": null,
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"issn_linking": "0278-0232",
"issue": "38(5)",
"journal": "Hematological oncology",
"keywords": "cyclin D1; diffuse large B-cell lymphoma; mantle cell lymphoma; pleomorphic/blastoid; primary CNS; t(11;14)",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001706:Biopsy; D016543:Central Nervous System Neoplasms; D019938:Cyclin D1; D015870:Gene Expression; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse; D020522:Lymphoma, Mantle-Cell; D008279:Magnetic Resonance Imaging; D008297:Male; D015514:Oncogene Proteins, Fusion",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "817-822",
"pmc": null,
"pmid": "32639587",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Primary large B-cell lymphoma of the central nervous system with cyclin D1 expression and t(11;14) (IGH-CCND1): Diffuse large B-cell lymphoma with CCND1 rearrangement or mantle cell lymphoma?",
"title_normalized": "primary large b cell lymphoma of the central nervous system with cyclin d1 expression and t 11 14 igh ccnd1 diffuse large b cell lymphoma with ccnd1 rearrangement or mantle cell lymphoma"
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"activesubstancename": "TEMOZOLOMIDE"
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"abstract": "Hepatitis C virus-associated porphyria cutanea tarda can result from viral-induced inhibition of uroporphyrinogen decarboxylase and the subsequent accumulation of uroporphyrins and associated metabolites in urine.",
"affiliations": "is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.;is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.;is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.;is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.;is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.;is a Dermatology Resident Physician, is a Physician Assistant Student, is a Dermatology Attending Physician, is a Gastroenterology and Hepatology Attending Physician, and is a Dermatology Attending Physician, all at the University of Tennessee Health Science Center in Memphis. is a Medical Student at College of Osteopathic Medicine, Lincoln Memorial University DeBusk College of Osteopathic Medicine in Harrogate, Tennessee. Bradford Waters is a Gastroenterology and Hepatology Attending Physician and Robert Skinner is a Dermatology Attending Physician, both at the Memphis Veterans Affairs Medical Center in Tennessee.",
"authors": "Cash|Joshua|J|;Skinner|Ashley|A|;Cash|Susannah|S|;Jones|Allison|A|;Waters|Bradford|B|;Skinner|Robert B|RB|",
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"issue": "36(Suppl 2)",
"journal": "Federal practitioner : for the health care professionals of the VA, DoD, and PHS",
"keywords": null,
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"nlm_unique_id": "9500574",
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"pages": "S11-S13",
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"pubdate": "2019-03",
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"references": "18855993;22510500;24470839;26924097;26967675;27732687;28369802;29404508",
"title": "Blistering Disease During the Treatment of Chronic Hepatitis C With Ledipasvir/Sofosbuvir.",
"title_normalized": "blistering disease during the treatment of chronic hepatitis c with ledipasvir sofosbuvir"
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"abstract": "Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis-related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty-three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression-free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high-risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo-HSCT.",
"affiliations": "Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Lymphoma-Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.",
"authors": "Jeon|Young-Woo|YW|0000-0003-3362-8200;Yoon|Seugyun|S|;Min|Gi June|GJ|;Park|Sung-Soo|SS|;Park|Silvia|S|;Yoon|Jae-Ho|JH|0000-0002-2145-9131;Lee|Sung-Eun|SE|0000-0002-9810-2050;Cho|Byung-Sik|BS|0000-0002-4524-6616;Eom|Ki-Seong|KS|;Kim|Yoo-Jin|YJ|;Kim|Hee-Je|HJ|;Lee|Seok|S|;Min|Chang-Ki|CK|;Lee|Jong Wook|JW|0000-0003-2949-4166;Cho|Seok-Goo|SG|",
"chemical_list": "D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.2565",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 3156016510.1002/cam4.2565CAM42565Original ResearchClinical Cancer ResearchOriginal ResearchClinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real‐world experience JEON et al.Jeon Young‐Woo https://orcid.org/0000-0003-3362-8200\n1\n\n2\n\n3\nYoon Seugyun \n1\nMin Gi June \n1\nPark Sung‐Soo \n1\nPark Silvia \n1\nYoon Jae‐Ho https://orcid.org/0000-0002-2145-9131\n1\nLee Sung‐Eun https://orcid.org/0000-0002-9810-2050\n1\nCho Byung‐Sik https://orcid.org/0000-0002-4524-6616\n1\nEom Ki‐Seong \n1\nKim Yoo‐Jin \n1\nKim Hee‐Je \n1\nLee Seok \n1\nMin Chang‐Ki \n1\nLee Jong Wook https://orcid.org/0000-0003-2949-4166\n1\nCho Seok‐Goo \n1\n\n2\n\n3\nchosg@catholic.ac.kr \n1 \nDivision of Lymphoma‐Myeloma\nCatholic Hematology Hospital\nSeoul St. Mary's Hospital\nCollege of Medicine\nThe Catholic University of Korea\nSeoul\nKorea\n\n2 \nInstitute for Translational Research and Molecular Imaging\nCatholic Institutes of Medical Science\nSeoul\nKorea\n\n3 \nLaboratory of Immune Regulation\nConvergent Research Consortium for Immunologic Disease\nSeoul St. Mary's Hospital\nSeoul\nKorea\n* Correspondence\n\nSeok‐Goo Cho, Division of Lymphoma‐Myeloma, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, #505, Banpo‐Dong, Seocho‐Ku, Seoul 06591, Republic of Korea.\n\nEmail: chosg@catholic.ac.kr\n27 9 2019 11 2019 8 16 10.1002/cam4.v8.166860 6870 30 3 2019 24 7 2019 04 9 2019 © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nIbrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT.\n\nAlthough ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies.\n\n\nallogeneic stem transplantationbendamustineibrutinibmantle cell lymphomanonresponderNational Research Foundation of Korea(NRF) grant funded by the Korea governmentNRF‐2016R1A2B4007282The Korean Association of Internal Medicine grant2016-144 source-schema-version-number2.0cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019\n\n\nJeon \nY‐W \n, \nYoon \nS \n, \nMin \nGJ \n, et al. Clinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real‐world experience . Cancer Med . 2019 ;8 :6860 –6870 . 10.1002/cam4.2565 \n31560165\n==== Body\n1 INTRODUCTION\nMantle cell lymphoma (MCL) is a rare form of B‐cell non‐Hodgkin lymphoma (NHL) that accounts for 6%‐8% of all NHLs.1 It affects more males than females (3:1 ratio), with a median age ranging between 65 and 68 years at initial diagnosis.1, 2 Although many patients with MCL initially respond well to therapy, most ultimately relapse and progress to disseminated refractory lymphoma with a remission duration as short as up to 3 years with median overall survival (OS) of 4‐5 years.3, 4 Given the nature of these disease characteristics, maximizing the effect of salvage therapy for patients with relapsed MCL is an important therapeutic strategy.\n\nIn the relapsed or refractory setting, advanced understanding of basic MCL‐related biology has identified potential novel therapeutic agents. Among them, ibrutinib, a first‐in‐class Bruton's tyrosine kinase (BTK) inhibitor, inhibits B‐cell receptor signaling within malignant B cells to mitigate downstream cell growth, proliferation, survival, adhesion, and migration.5, 6\n\n\nThree representative ibrutinib studies enrolled patients with relapsed or refractory MCL. A phase 2 trial by Wang et al (PCYC‐1104) is the primary research that definitively influenced the general use of this drug in patients with relapsed or refractory MCL. Oral ibrutinib at a daily dose of 560 mg had durable efficacy in 111 patients with relapsed or refractory MCL (median progression‐free survival [PFS], 13.9 months; overall response rate [ORR], 68%).7 In updated long‐term follow‐up data, the study showed a continued duration of response (DOR) (17.5 months at 2 years).8 Also, recent long‐term follow‐up data from the RAY study, which is a randomized, open‐label study comparing ibrutinib and temsirolimus, confirmed significantly improved ORR and PFS in the ibrutinib therapy group compared with temsirolimus.9, 10\n\n\nBased on these novel clinical studies and increasing amounts of positive objective evidence indicating the efficiency and safety of ibrutinib, it is emerging as the preferred standard therapeutic strategy in current clinical guidelines for relapsed or refractory disease.11 Despite these significant advances, approximately one‐third of all ibrutinib‐treated patients are nonresponders. Also, primary resistance or loss of response to ibrutinib has been sporadically reported in real‐world practice.12, 13, 14 Several studies have investigated ibrutinib resistance, and various resistance mechanisms have been hypothesized, including BTK binding site mutations.15, 16\n\n\nHowever, these multicenter prospective studies generally had focused on the therapeutic response of ibrutinib, so there is less interest in the survival outcome such as OS or PFS in clinical practice. In addition, the limited data are available regarding the impact of therapeutic strategy and prognostic factors on predicting the ibrutinib response. Therefore, we conducted the current study to understand the clinical outcomes of ibrutinib therapy in the salvage setting with the same therapeutic protocol in a single center, and to identify the most appropriate therapeutic strategy for patients with relapsed or refractory MCL in the ibrutinib era.\n\n2 PATIENTS AND METHODS\n2.1 Patients\nA retrospective observational cohort study was planned to assess the effectiveness and prognostic implications of ibrutinib salvage monotherapy. Consecutive adult patients who were diagnosed with histopathologically confirmed CD20‐positive, cyclin D1‐positive MCL according to the current World Health Organization classification17 were screened from January 2013 to August 2018 at a single center (Lymphoma‐Myeloma division, Catholic Hematology Hospital, Seoul). Among them, individuals with a relapsed or refractory disease status who received salvage therapy with ibrutinib monotherapy were included in the study. Patients who were undergoing non‐ibrutinib therapies followed by ibrutinib maintenance were excluded. A “consistent responder” was defined as achieving complete remission (CR) or a partial response (PR) from the start of ibrutinib monotherapy until the last follow‐up, an “inconsistent responder” had a loss of therapeutic response (progressive disease [PD] after achieving CR or PR with ibrutinib), and a “primary nonresponder” had stable disease (SD) or PD after the first three cycles of beginning ibrutinib. Based on the response status to ibrutinib therapy, we considered “inconsistent responders” and “primary nonresponders” to be ibrutinib failures. Clinical data, including demographic information, initial or salvage chemotherapy, and response to initial or salvage chemotherapy, were extracted retrospectively from electronic medical records. The study protocol was approved by the institutional review board of Seoul St. Mary's Hospital of The Catholic University of Korea and was in accordance with the Declaration of Helsinki.\n\n2.2 Therapeutic strategy and clinical therapeutic response evaluation\nPatients were administered fixed continuous doses of oral ibrutinib 560 mg per day until disease progression or unacceptable toxicity. Ibrutinib therapeutic dosing was withheld for any grade ≥3 nonhematologic toxicity, and then treatment was restarted after complete resolution or improvement within two weeks. Response to therapy was assessed after every three or four cycles of ibrutinib monotherapy. Assessments included a physical examination, blood counts, a serum chemistry profile, and computed tomography (CT) scans. Ki‐67 index was determined according to consensus criteria.18 While bone marrow (BM) aspiration with biopsy was performed mandatorily at initial diagnosis, repeated BM aspirations were performed on selected patients with persistent pancytopenia or peripheral blast cells in a refractory or relapsed setting. When SD or PD was confirmed, ibrutinib administration was discontinued. Response criteria were defined according to the Lugano Classification19, 20: CR was defined as the absence of a palpable mass, a normalized size on CT scan, and a negative FDG‐PET scan, without the appearance of new lesions for at least 4 weeks. PR required at least a 50% reduction in the size of the measurable lymphoma mass on CT without the appearance of a new lesion for at least 4 weeks. SD was defined as no reduction in assessable lymphoma. PD was defined as the appearance of new lesions or a ≥25% increase in tumor volume. Relapse was defined as a new disease in patients with CR or PR. We conducted a response evaluation using CT every 3 months and a response assessment using PET CT every 6 months.\n\n2.3 Statistical analysis\nPFS was defined as the day from ibrutinib monotherapy to the time of documented disease progression, disease recurrence, or death. OS was calculated from the time of initiation of ibrutinib administration to any cause of death. Patients with documented disease progression or death or who were lost to follow‐up were censored from further analysis.\n\nSurviving patients were censored on the last day of follow‐up. All ibrutinib monotherapy‐related categorical variables are expressed as proportions and were compared using chi‐squared and Fisher's exact tests. Continuous variables are expressed as medians with ranges, and two groups were compared using Mann‐Whitney U‐tests. All patients were classified into one of four types of Mantle Cell Lymphoma International Prognostic Index (MIPI) scores using the International Prognostic Index (IPI) as follows: standard MIPI, simplified MIPI, biologic MIPI, and combined MIPI.21 PFS and OS were calculated using the Kaplan‐Meier survival method with log‐rank analysis. Cox regression was used to perform univariate and multivariate analyses to assess the independent impact of various factors on PFS and OS. Cumulative incidence estimates of relapse were calculated according to relapse or death from other causes defined as competitive events using Gray tests for univariate analysis and the Fine‐Gray method for proportional hazards regressions. All statistical analyses were performed using R version 3.2.0 (Comprehensive R Archive Network project, http://cran.us.r-project.org) with EZR graphical user interface by Kanda (Saitama Medical Center, Jichi Medical University).22\n\n\n3 RESULTS\n3.1 Clinical characteristics of all ibrutinib‐treated patients\nThirty‐three consecutive patients were treated with ibrutinib monotherapy in a relapsed or refractory setting. Among them, 20 consistent responders were still receiving treatment, but one patient had electively stopped ibrutinib due to remission after receiving allo‐HSCT. Six inconsistent responders and six primary nonresponders had discontinued ibrutinib therapy. The clinical baseline characteristics before the start of ibrutinib, including staging and the MCL‐specific risk classification system are provided in Table 1, and the therapeutic sequences and results are shown in Figure 1. The median age at diagnosis was 65 years (range, 40‐79 years) and most patients had a tolerable Eastern Cooperative Oncology Group (ECOG) performance status (score 0‐1; n = 29, 87.9%); the population was predominantly male (male:female ratio, 4:1). Approximately half of the patients (57.6%) were diagnosed with BM involvement with malignant cells. According to the MCL‐related scoring system, most patients had advanced disease (84.9%, Ann Arbor stage III–IV; 57.6%, standard or simplified MIPI, intermediate to high risk; 81.8% biologic MIPI intermediate to high risk; 36.4% biologic MIPI high‐intermediate to high risk). Ibrutinib monotherapy was administered early to the patients during the MCL therapy; 69.7% of patients received one or two different types of chemotherapy before treatment with ibrutinib. All of the patients were treated with R‐CHOP regimen as first‐line chemotherapy. Among them, only six patients were treated with upfront auto‐HSCT, and seven patients were treated with Bendamustine and Rituximab combination chemotherapy (BR). There were no patients receiving Rituximab maintenance monotherapy after conventional chemotherapy.\n\nTable 1 Patient characteristics and demographics at baseline\n\nFactors\tIbrutinib responder (n = 21), No. (%)\tIbrutinib failure (n = 12), No. (%)\tTotal (n = 33), No. (%)\t\nP‐value\t\nGender\t\t\t\t.522\t\nMale\t16 (76.2)\t11 (91.7)\t27 (81.8)\t\t\nFemale\t5 (23.8)\t1 (8.3)\t6 (18.2)\t\t\nAge at diagnosis, median (range)\t65 (40‐78)\t67 (46‐79)\t65 (40‐79)\t.587\t\nLDH, U/L (range)\t387 (255‐928)\t452 (277‐980)\t417 (255‐980)\t.340\t\nWBC /109 (range)\t6.2 (2.3‐13.7)\t7.8 (4.6‐10.8)\t6.9 (2.3‐13.7)\t.096\t\nBeta2 microglobulin, µg/mL\t2.4 (1.4‐22.4)\t4.1 (2.2‐6.5)\t2.9 (1.4‐22.4)\t.002\t\nB symptom, yes\t9 (42.9)\t5 (41.7)\t14 (42.4)\t1.000\t\nNo. of extranodal nodes involved\t\t\t.363\t\n0‐2\t10 (47.6)\t3 (25.0)\t13 (39.4)\t\t\n≥3\t11 (52.4)\t9 (75.0)\t20 (60.6)\t\t\nBulky mass (≥7 cm), yes\t1 (4.8)\t2 (16.7)\t3 (9.1)\t.607\t\nKi‐67 index, elevated (≥30%)\t6 (28.6)\t5 (41.7)\t11 (33.3)\t.701\t\nBM involvement, yes\t11 (52.4)\t8 (66.7)\t19 (57.6)\t.665\t\nChromosomal abnormality, yes\t2 (9.5)\t2 (16.7)\t4 (12.1)\t.960\t\nECOG performance\t\t\t\t.003\t\n0‐1\t21 (100)\t8 (66.7)\t29 (87.9)\t\t\n2‐3\t0\t4 (33.3)\t4 (12.1)\t\t\nStaging system at initial diagnosis\t\nAnn‐Arbor stage\t\t\t\t.979\t\nII\t3 (14.3)\t2 (16.7)\t5 (15.2)\t\t\nIII\t2 (9.5)\t1 (8.3)\t3 (9.1)\t\t\nIV\t16 (76.2)\t9 (75.0)\t25 (75.8)\t\t\nStandard MIPI\t\t\t\t.242\t\nLow\t11 (52.4)\t3 (25.0)\t14 (42.4)\t\t\nIntermediate\t6 (28.6)\t4 (33.3)\t10 (30.3)\t\t\nHigh\t4 (19.0)\t5 (41.7)\t9 (27.3)\t\t\nSimplified MIPI\t\t\t\t.087\t\nLow\t13 (61.9)\t1 (8.3)\t14 (42.4)\t\t\nIntermediate\t6 (28.6)\t6 (50.0)\t12 (36.4)\t\t\nHigh\t2 (9.5)\t5 (41.7)\t7 (21.2)\t\t\nBiologic MIPI\t\t\t\t.461\t\nLow\t5 (23.8)\t1 (8.3)\t6 (18.2)\t\t\nIntermediate\t6 (28.6)\t3 (25.0)\t9 (27.3)\t\t\nHigh\t10 (47.6)\t8 (66.7)\t18 (54.5)\t\t\nCombined MIPI\t\t\t\t.125\t\nLow\t6 (28.6)\t2 (16.7)\t8 (24.2)\t\t\nLow‐intermediate\t10 (47.6)\t3 (25.0)\t13 (39.4)\t\t\nHigh‐intermediate\t5 (23.8)\t5 (41.7)\t10 (30.3)\t\t\nHigh\t0\t2 (16.7)\t2 (6.1)\t\t\nLines of previous chemotherapy\t\t\t\t.474\t\n1\t8 (38.1)\t3 (25.0)\t11 (33.3)\t\t\n2\t6 (28.6)\t6 (50.0)\t12 (36.4)\t\t\n3\t5 (23.8)\t3 (25.0)\t8 (24.2)\t\t\n4\t2 (9.5)\t0\t2 (6.1)\t\t\nPrior auto‐HSCT\t3 (14.3)\t3 (25.0)\t6 (18.2)\t.691\t\nPrior allo‐HSCT\t0\t0\t0\t\t\nPrior bendamustine exposure\t2 (9.5)\t5 (41.7)\t7 (21.2)\t.059\t\nResponse to ibrutinib\t\t\t\t.002\t\nCR\t18 (85.7)\t3 (25.0)\t21 (63.6)\t\t\nPR\t3 (14.3)\t3 (25.0)\t6 (18.2)\t\t\nSD\t0\t1 (8.3)\t1 (3.0)\t\t\nPD\t0\t5 (41.7)\t5 (15.2)\t\t\nMedian duration of ibrutinib therapy, months\t15 (3‐69)\t17 (3‐34)\t16 (3‐69)\t.272\t\nJohn Wiley & Sons, LtdFigure 1 Therapeutic scheme of 33 mantle cell lymphoma (MCL) patients treated with ibrutinib\n\nPatients were classified into two groups according to ibrutinib response patterns: ibrutinib responders (consistent responders to ibrutinib, n = 21) or ibrutinib failure (inconsistent responders or primary nonresponders to ibrutinib, n = 12). There were no differences in clinical characteristics such as MCL‐specific risk classification system and duration of ibrutinib therapy between the two groups, except for β2‐microglobulin levels (2.4 vs 4.1 µg/mL, P = .002) and poor ECOG performance status (ECOG score 2‐3, 0% vs 33%, P = .003).\n\n3.2 General clinical outcomes after salvage ibrutinib monotherapy\nFor all patients included in the analysis, the ORR after the first three cycles of ibrutinib therapy was 82% (n = 27), which consisted of 18% CR (n = 6) and 64% PR (n = 21). However, the final ORR was 64% (n = 21) which consisted of 15% CR (n = 5) and 48% PR (n = 16); six patients (18%) lost their initial response to ibrutinib (three with initial CR and three with initial PR). The remaining six patients (18%) did not respond to ibrutinib after three cycles (one patient had stable disease [3%] and five patients had progressive disease [15%]). Therefore, six patients (18%) were primarily refractory to ibrutinib.\n\nThe median OS, PFS, and DOR after initiation of ibrutinib were 35.1, 27.4, and 33.4 months, respectively (Figure 2). The median duration of ibrutinib therapy was 16 months (range, 3‐69 months) for the entire cohort. The main cause of ibrutinib discontinuation was disease progression upon treatment (and one elective discontinuation for allo‐HSCT), documented in 12 patients (36.4%), with primary refractoriness to ibrutinib in six patients (18.2%) and disease progression after initial CR or PR in six patients (18.2%). Three patients discontinued ibrutinib owing to drug‐related complications, community‐acquired pneumonia with septic shock (n = 2, 6.1%), and acute myocardial infarction (n = 1, 3.0%). Also, two patients had ibrutinib‐related atrial fibrillation (n = 2, 6.1%); one of the two was withheld from ibrutinib therapy due to the progression of acute myocardial infarction finally (this patient was progressed to acute myocardial infarction in the above mentioned), and the other one was manageable with cardiac medications and kept ibrutinib therapy without interruption. Of the patients who discontinued ibrutinib due to drug‐associated toxicities, all subsequently experienced disease progression and died. There were no discontinuations due to medication compliance problems and no bleeding‐related adverse events.\n\nFigure 2 Overall survival of patients receiving ibrutinib therapy for refractory or relapsed MCL. The median overall survival (OS), progression‐free survival (PFS), and duration of response (DOR) were 35.1, 27.4, and 33.4 months after the start of ibrutinib treatment, respectively\n\n3.3 Prognostic factor analysis for survival outcomes during ibrutinib therapy\nPrognostic factor analysis for OS or PFS showed that an advanced MCL‐related classification system rating (high‐intermediate‐ to high‐risk IPI, high‐risk standard MIPI, high‐risk simplified MIPI, high‐risk biologic MIPI, and high‐intermediate‐ to high‐risk combined MIPI) nonresponse to ibrutinib at the first three cycles and nonresponse to ibrutinib during ongoing treatment were significantly adversely prognostic according to univariate analysis (Table S1).\n\nEach MCL‐associated classification system was a significant independent factor in the univariate analysis. However, to exclude the effects of interference between these factors, only biologic MIPI system, which had the highest statistical significance among the MCL‐associated classification systems, was used for multivariate analysis. As a result, high‐risk biologic MIPI (hazard ratio [HR], 12.74; 95% confidence interval [CI], 1.58‐102.5; P = .017) and nonresponse to ibrutinib at the first three cycles (HR, 5.57; 95% CI, 1.20‐25.92; P = .029) were significantly associated with inferior OS (Figure 3A,B). Poor PFS was associated with high‐risk biologic MIPI (HR, 5.47; 95% CI,1.24‐24.22; P = .025), prior bendamustine exposure (HR, 6.65; 95% CI, 1.36‐32.56, P = .019), and nonresponse to ibrutinib at the first three cycles (HR, 29.97; 95% CI, 4.80‐197.2; P < .0001) (Table 2, Figure 3A‐C).\n\nFigure 3 Survival outcomes according to prognostic factors. Overall survival (OS) and progression‐free survival (PFS) according to therapeutic response at first three cycles of ibrutinib (A), biologic MIPI (B), and status of bendamustine exposure (C)\n\nTable 2 Multivariate analysis of predictive prognostic factors affecting ibrutinib response\n\nFactors\tOS\tPFS\t\nHR (95% CI)\t\nP‐value\tHR (95% CI)\t\nP‐value\t\nPrior bendamustine‐based therapy\t—\t—\t\t\t\nNo\t\t\t1\t1.36‐32.56\t\nYes\t\t\t6.65\t.019\t\nBiologic MIPI\t\t\t\t\t\nLow to intermediate\t1\t1.58‐102.5\t1\t1.24‐24.22\t\nHigh\t12.74\t.017\t5.47\t.025\t\nResponse to ibrutinib at first three cycles\t\t\t\t\t\nSensitive (CR or PR)\t1\t1.20‐25.92\t1\t4.80‐187.2\t\nRefractory (SD or PD)\t5.57\t.029\t29.97\t<.0001\t\nOngoing (overall) response to ibrutinib\t\t\t—\t—\t\nSensitive (CR or PR)\t1\t.40‐8.72\t\t\t\nRefractory (SD or PD)\t1.87\t.424\t\t\t\nJohn Wiley & Sons, Ltd3.4 Clinical outcomes and post‐ibrutinib therapy in the ibrutinib‐failure group\nIn the subgroup analysis of the ibrutinib failure group (n = 12), the median duration of ibrutinib treatment was 17 months (range, 3‐34 months). Seven patients (58%) died after ibrutinib refractoriness. The median OS after the start of ibrutinib (Figure 4A) and the median OS after the time at ibrutinib resistance were 21 months and 4.6 months (range, 1.8‐30.4 months), respectively. The median PFS after ibrutinib therapy was 8.3 months in the ibrutinib failure group (Figure 4C). In addition, the median PFS in subgroup analysis according to primary refractory group and loss of response was 0.4 months and 19.2 months, respectively (Figure 4D). Unlike the ibrutinib failure group, only three patients in the ibrutinib responder group died due to nondisease‐related causes (14%), and ibrutinib‐related median OS and PFS were not reached (Figure 4A,B).\n\nFigure 4 Survival outcomes according to subgroup classification for responsiveness to ibrutinib (A) Overall survival (OS) differed between ibrutinib responders and nonresponders. (B) After stratification by responsiveness to ibrutinib, primary nonresponders had an inferior OS compared with loss‐of‐response or consistent responders. (C) Progression‐free survival (PFS) differed between responders and treatment failures. (D) Subgroup analysis by responsiveness to ibrutinib showed that primary nonresponders had more inferior PFS than loss‐of‐response or consistent responders\n\nAmong the 12 ibrutinib failure cases, only six patients (50%) received salvage chemotherapy after ibrutinib resistance. Six patients (three inconsistent responders and three primary nonresponders) were not treated with subsequent chemotherapy as they all died shortly after disease progression. The salvage chemotherapies were mainly conventional regimens, including BR (n = 3); etoposide, methylprednisolone, high‐dose Ara‐C, and Platinol (ESHAP) (n = 2); and dexamethasone, high‐dose Ara‐C, and Platinol (DHAP) (n = 1). The ORR for the first salvage chemotherapy after ibrutinib failure was 33% (two of six patients) with a median DOR of 3.2 months (range, 1.8‐6.1 months). Three patients underwent allo‐HSCT (two after achieving a response to salvage chemotherapy and one at refractory disease status), and all remained alive and in remission for at least 12 months after transplant.\n\nAmong the risk factors related to therapeutic strategy, prior bendamustine‐based therapy exhibited inferior PFS (HR, 2.507; 95% CI, 0.75‐8.41; P = .048) on univariate analysis (Table S1) and the survival curve for PFS (Figure 4A), although useful independent significance disappeared with multivariate analysis (HR, 3.24; 95% CI, 0.93‐11.31; P = .066). However, there was no significant difference in OS between patients with and without prior bendamustine exposure (HR, 1.64; 95% CI 0.73‐3.67; P = .228) (Table S1).\n\n3.5 HSCT and ibrutinib\nIn MCL patients undergoing ibrutinib therapy, six patients received upfront auto‐HSCT (18.2%) before ibrutinib therapy, and no patients had auto‐HSCT after becoming refractory to ibrutinib. In cases receiving allo‐HSCT, three underwent allo‐HSCT after ibrutinib treatment failed and one patient received allo‐HSCT as a bridging therapy with ibrutinib; all of these patients were in the auto‐HSCT failure group. No patients received allo‐HSCT before ibrutinib treatment. Three patients who underwent allo‐HSCT survived and maintained a disease‐free status for at least 12 months.\n\n4 DISCUSSION\nAlthough large cohort studies in MCL patients treated with ibrutinib are rare, the prognosis of patients with refractoriness to ibrutinib is very poor.23, 24, 25 In this retrospective study performed at a single center, we evaluated relapsed or refractory MCL patients treated with ibrutinib monotherapy in routine clinical practice. This report confirms that MCL patients with ibrutinib refractoriness had very poor survival prognoses in the salvage setting. First, approximately 80% of ibrutinib‐treated patients had favorable responses during early ibrutinib administration. However, roughly 20% of early responders had a response duration that was not prolonged, and the patients with a loss of response had a similar dismal prognosis to primary nonresponders. In our cohort, no baseline biological factors predicted the survival outcomes associated with ibrutinib responses in multivariate analysis. However, some overall risk factors were linked with significant survival outcomes: inferior OS was related to a high risk of biologic MIPI at initial diagnosis and a lack of response to ibrutinib during the first three cycles. Also, poor PFS was associated with high‐risk biologic MIPI, early refractoriness to ibrutinib, and prior bendamustine exposure.\n\nIn an analysis of survival outcomes, previous reference trials reported similar results: PCYC‐11047 and RAY9 reported ORRs of 68% and 72%, a median OS of 22.5 months and not reached, and a median PFS of 13.9 months and 14.6 months with 27 months and 20 months of median follow‐up duration, respectively. In our analysis of 33 patients, the ORR at the early period (82%) was higher than in previous studies, but was similar to the aforementioned studies when only patients with a consistent response were analyzed (ORR, 64% [21/33 patients]). Risk factor analyses to predict survival outcomes with ibrutinib therapy were performed in several studies. Although the results may vary, the major poor prognostic factors were a higher risk of MIPI and ibrutinib failure.23 As expected, multivariate analysis revealed that high risk of biologic MIPI and primary refractoriness to ibrutinib were poor prognostic factors. Inconsistent responders had improved survival outcomes initially, but eventually had poor survival outcomes. This is an indirect reminder that therapeutic strategies to maximize the efficacy of ibrutinib are needed in the salvage setting.\n\nConsidering that the treatment options might change depending on the patient's age and conditions and the administration stages of ibrutinib could be different, subgroup analysis was performed by younger‐unfit (n = 10), elderly‐fit (n = 14), and frail patient group (n = 9). In younger‐unfit and frail group, there were no survival differences between ibrutinib‐responder and ibrutinib‐failure statistically (P = .300 of OS and P = .115 of PFS in younger‐unfit subgroup; P = .747 of OS and P = .805 of PFS in frail subgroup, Figure 5A,C). However, in the elderly fit subgroup, OS and PFS showed a favorable result with statistical significance in ibrutinib responder (P = .021 of OS and P = .0003 of PFS, Figure 5B). Although this finding was limited with less meaningful statistical interpretation due to the very few number of patients in each subgroup, in the elderly group, because the conventional salvage chemotherapy could not be adopted to this group easily, it might be suggested that responsiveness of ibrutinib had a significant impact on survival outcomes.\n\nFigure 5 Survival outcomes according to subgroup of young, elderly, and frail patient. Divide each group by (A) younger‐unfit group, (B) elderly‐fit group, and (C) frail group, and then analyzed overall survival (OS) and progression‐free survival (PFS) respectively according to ibrutinib‐responsiveness\n\nFailure after ibrutinib treatment leads to a dismal prognosis; thus, effective therapy is an unmet need for these patients. Although the number of patients was very small, the current results revealed an ORR of 33% (2/6) for the first salvage chemotherapy after ibrutinib failure, with a median DOR of 3.2 months (range, 1.8‐6.1 months). These results are consistent with previous reports describing survival outcomes after ibrutinib refractoriness: an ORR of 30% (18/61) with a median OS of 2.9 months by Martin et al,12 and an ORR of 35% (6/17) and median OS of 4 months by Cheah et al.25 Several studies of large numbers of patients have revealed no uniquely successful therapies, including allo‐HSCT, in the post‐ibrutinib setting.12 Similarly, the current data showed that neither MIPI score nor the choice of salvage chemotherapy predicted survival after ibrutinib failure (data not shown). It is unclear why MIPI score and prior bendamustine exposure status were not statistically significant factors influencing survival in our cohort, but this may be explained by the limited number of patients in the post‐ibrutinib group. There was also limited statistical power to evaluate all possible predictors of survival, such as pre‐ibrutinib therapies. Nevertheless, although a much larger cohort and extended long‐term survival analysis are needed, the difference from previous reports is that allo‐HSCT improved survival outcomes without treatment‐related mortality after ibrutinib failure in the current study.\n\nCurrently, upfront auto‐HSCT is generally recommended for younger and fit patients in MCL treatment.11, 26 However, auto‐HSCT is often not available due to disease characteristics of MCL. Therefore, since this study included that all patients were treated with R‐CHOP as frontline chemotherapy and only six patients were treated with upfront auto‐HSCT, it is considered to be meaningful as an indirectly identifying the therapeutic response and prognosis of ibrutinib in the group of the elderly or auto‐HSCT unfit.\n\nOur study had several limitations. First, it had a retrospective designed study, so it was possible to include biases in these data. Most of all, the smaller sample size is the main problem of this study; statistical results for each factor analysis should be interpreted with caution regarding the small number of patients. In addition, our data identified to much higher ORR than previously reported large prospective studies, it suggested that response evaluation might have differed from rigorous evaluations performed in the context of clinical trials as well as small size cohort.\n\nTo summarize the results of our analysis, we must ensure that the therapeutic effects of ibrutinib are maintained for as long as possible to improve the survival outcomes in patients with relapsed or refractory MCL. Interestingly, although the number of patients was too small to draw any definitive conclusions, prior bendamustine exposure was associated with inferior survival outcomes. This needs to warrant further verification in a larger number of patients in future studies. Moreover, allo‐HSCT is currently a possible salvage therapeutic strategy option after ibrutinib failure. A previous report recommended continuing a once‐daily dose of ibrutinib, unlike other conventional chemotherapies, until disease progression or unacceptable toxicity is noted.7 It is inevitable that patients will experience a loss of response while maintaining ibrutinib therapy. Therefore, inconsistent responders should have a therapeutic strategy that includes preparation for allo‐HSCT in advance.\n\nIn conclusion, the current study confirmed favorable ORR and DOR for ibrutinib‐treated patients with relapsed or refractory MCL. Unlike ibrutinib responders, ibrutinib failure patients with a high risk of biologic MIPI had very poor survival outcomes, and there was no promising salvage treatment after refractoriness to ibrutinib. We confirm again the recent observations of Martin et al12 and Cheah et al25 that ibrutinib failures have inferior survival outcomes, and these findings are not surprising or novel. Despite the potential bias of the retrospective observational study design and the limited number of patients, this study represents a real‐world population in daily clinical practice, and our research might have been meaningful in that it also raised a premature question about a sequential relationship with ibrutinib and other salvage chemotherapy such as bendamustine.\n\nSupporting information\n \n\nClick here for additional data file.\n\n DATA AVAILABILITY STATEMENT\nThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\n==== Refs\nREFERENCES\n1 \n\nCortelazzo \nS \n, \nPonzoni \nM \n, \nFerreri \nAJ \n, \nDreyling \nM \n. Mantle cell lymphoma . Crit Rev Oncol Hematol . 2012 ;82 (1 ):78 ‐101 .21658968 \n2 \n\nZhou \nY \n, \nWang \nH \n, \nFang \nW \n, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004 . Cancer . 2008 ;113 (4 ):791 ‐798 .18615506 \n3 \n\nBacher \nU \n, \nKlyuchnikov \nE \n, \nLe‐Rademacher \nJ \n, et al. Conditioning regimens for allotransplants for diffuse large B‐cell lymphoma: myeloablative or reduced intensity? \nBlood . 2012 ;120 (20 ):4256 ‐4262 .23007405 \n4 \n\nCheah \nCY \n, \nFowler \nNH \n, \nWang \nML \n. Breakthrough therapies in B‐cell non‐Hodgkin lymphoma . Ann Oncol . 2016 ;27 (5 ):778 ‐787 .26802148 \n5 \n\nHonigberg \nLA \n, \nSmith \nAM \n, \nSirisawad \nM \n, et al. The Bruton tyrosine kinase inhibitor PCI‐32765 blocks B‐cell activation and is efficacious in models of autoimmune disease and B‐cell malignancy . Proc Natl Acad Sci U S A . 2010 ;107 (29 ):13075 ‐13080 .20615965 \n6 \n\nHerrmann \nA \n, \nHoster \nE \n, \nZwingers \nT \n, et al. Improvement of overall survival in advanced stage mantle cell lymphoma . J Clin Oncol . 2009 ;27 (4 ):511 ‐518 .19075279 \n7 \n\nWang \nML \n, \nRule \nS \n, \nMartin \nP \n, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle‐cell lymphoma . N Engl J Med . 2013 ;369 (6 ):507 ‐516 .23782157 \n8 \n\nWang \nML \n, \nBlum \nKA \n, \nMartin \nP \n, et al. Long‐term follow‐up of MCL patients treated with single‐agent ibrutinib: updated safety and efficacy results . Blood . 2015 ;126 (6 ):739 ‐745 .26059948 \n9 \n\nDreyling \nM \n, \nJurczak \nW \n, \nJerkeman \nM \n, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle‐cell lymphoma: an international, randomised, open‐label, phase 3 study . Lancet . 2016 ;387 (10020 ):770 ‐778 .26673811 \n10 \n\nRule \nS \n, \nJurczak \nW \n, \nJerkeman \nM \n, et al. Ibrutinib versus temsirolimus: 3‐year follow‐up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open‐label RAY study . Leukemia . 2018 ;32 (8 ):1799 ‐1803 .29572505 \n11 \n\nDreyling \nM \n, \nCampo \nE \n, \nHermine \nO \n, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up . Annals Oncol . 2017 (suppl_4 ):iv62 ‐iv71 .\n12 \n\nMartin \nP \n, \nMaddocks \nK \n, \nLeonard \nJP \n, et al. Postibrutinib outcomes in patients with mantle cell lymphoma . Blood . 2016 ;127 (12 ):1559 ‐1563 .26764355 \n13 \n\nBroccoli \nA \n, \nCasadei \nB \n, \nMorigi \nA \n, et al. Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma . Oncotarget . 2018 ;9 (34 ):23443 ‐23450 .29805746 \n14 \n\nSmith \nA \n, \nRoman \nE \n, \nAppleton \nS \n, et al. Impact of novel therapies for mantle cell lymphoma in the real world setting: a report from the UK's Haematological Malignancy Research Network (HMRN) . Br J Haematol . 2018 ;181 (2 ):215 ‐228 .29532919 \n15 \n\nChiron \nD \n, \nDi Liberto \nM \n, \nMartin \nP \n, et al. Cell‐cycle reprogramming for PI3K inhibition overrides a relapse‐specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma . Cancer Discov . 2014 ;4 (9 ):1022 ‐1035 .25082755 \n16 \n\nRahal \nR \n, \nFrick \nM \n, \nRomero \nR \n, et al. Pharmacological and genomic profiling identifies NF‐kappaB‐targeted treatment strategies for mantle cell lymphoma . Nat Med . 2014 ;20 (1 ):87 ‐92 .24362935 \n17 \n\nSabattini \nE \n, \nBacci \nF \n, \nSagramoso \nC \n, \nPileri \nSA \n. WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview . Pathologica . 2010 ;102 (3 ):83 ‐87 .21171509 \n18 \n\nKlapper \nW \n, \nHoster \nE \n, \nDetermann \nO \n, et al. Ki‐67 as a prognostic marker in mantle cell lymphoma‐consensus guidelines of the pathology panel of the European MCL Network . J Hematop . 2009 ;2 (2 ):103 ‐111 .19669190 \n19 \n\nCheson \nBD \n, \nFisher \nRI \n, \nBarrington \nSF \n, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non‐Hodgkin lymphoma: the Lugano classification . J Clin Oncol . 2014 ;32 (27 ):3059 ‐3068 .25113753 \n20 \n\nBarrington \nSF \n, \nMikhaeel \nNG \n, \nKostakoglu \nL \n, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the international conference on malignant lymphomas imaging working group . J Clin Oncol . 2014 ;32 (27 ):3048 ‐3058 .25113771 \n21 \n\nHoster \nE \n, \nDreyling \nM \n, \nKlapper \nW \n, et al. A new prognostic index (MIPI) for patients with advanced‐stage mantle cell lymphoma . Blood . 2008 ;111 (2 ):558 ‐565 .17962512 \n22 \n\nKanda \nY \n. Investigation of the freely available easy‐to‐use software 'EZR' for medical statistics . Bone Marrow Transplant . 2013 ;48 (3 ):452 ‐458 .23208313 \n23 \n\nRule \nS \n, \nDreyling \nM \n, \nGoy \nA \n, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open‐label studies . Br J Haematol . 2017 ;179 (3 ):430 ‐438 .28832957 \n24 \n\nHershkovitz‐Rokah \nO \n, \nPulver \nD \n, \nLenz \nG \n, \nShpilberg \nO \n. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects . Br J Haematol . 2018 ;181 (3 ):306 ‐319 .29359797 \n25 \n\nCheah \nCY \n, \nChihara \nD \n, \nRomaguera \nJE \n, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes . Ann Oncol . 2015 ;26 (6 ):1175 ‐1179 .25712454 \n26 \n\nDreyling \nM \n, \nFerrero \nS \n, \nHermine \nO \n. How to manage mantle cell lymphoma . Leukemia . 2014 ;28 (11 ):2117 ‐2130 .24854989\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "8(16)",
"journal": "Cancer medicine",
"keywords": "allogeneic stem transplantation; bendamustine; ibrutinib; mantle cell lymphoma; nonresponder",
"medline_ta": "Cancer Med",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
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"pages": "6860-6870",
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"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "31560165;26673811;29532919;19075279;23782157;17962512;20615965;21171509;25113753;26764355;18615506;24854989;26802148;25712454;19669190;26059948;23208313;29572505;25113771;29359797;28832957;25082755;28881919;29805746;21658968;24362935;23007405",
"title": "Clinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real-world experience.",
"title_normalized": "clinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real world experience"
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"abstract": "Electronic cigarettes are becoming increasingly popular and therefore psychiatrists are being confronted more and more frequently by this relatively new phenomenon. We discuss the case of a patient who switched from traditional cigarettes to electronic cigarettes and thereupon had a significant increase in the clozapine serum level. The increased level led to considerable side-effects and, as a result, the patients clozapine dosage had to be reduced. In theory, a rise in the clozapine serum level is to be expected after such a switch. However, since electronic cigarettes have not been on the market for very long, psychiatrists need to be aware of the risks and dangers that can arise as a result of exceptionally high clozapine levels.",
"affiliations": null,
"authors": "Nonner|T S E|TS|;Timmer|S J|SJ|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
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"mesh_terms": "D014150:Antipsychotic Agents; D003024:Clozapine; D004305:Dose-Response Relationship, Drug; D066300:Electronic Nicotine Delivery Systems; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders; D012907:Smoking; D016540:Smoking Cessation",
"nlm_unique_id": "0423731",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clozapine and the electronic cigarette; a case study.",
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"abstract": "About half of idiopathic retroperitoneal fibrosis might be classified as a IgG4-related disease, a newly characterized disease that is especially known to be sensitive to steroid therapy. We developed a new protocol for diagnosis and treatment of retroperitoneal fibrosis, which included aggressive diagnosis of IgG4- related disease. We retrospectively reviewed 22 cases with idiopathic retroperitoneal fibrosis that were diagnosed and treated according to our protocol. Of them, 10 patients (45.5%) had no evidence of IgG4- related disease (non-IgG4RD group), whereas 12 patients (54.5%) were diagnosed with IgG4-related disease (IgG4RD group). All patients received steroid therapy, and 13 patients (59.1%) underwent ureteral stenting or received prednisolone (PNS). There was no severe adverse event and planned steroid therapy was completed in all patients. In principle, maintenance steroid therapy was continued after induction therapy in the IgG4RD group, whereas steroid therapy was discontinued in the non-IgG4RD group. Regression of retroperitoneal plaque was achieved in all 22 patients. Four (57.1%) out of 7 patients and 3 (50.0%) out of 6 patients achieved freedom from ureteral stent or PNS in the non-IgG4RD group and IgG4RD group, respectively. All 3 patients with PNS became catheter-free after treatment, whereas only 4 (40.0%) of the 10 patients withureteral stent could become stent-free. Steroid therapy could be discontinued in 7 patients (70.0%) in the non-IgG4RD group. The results of this study suggest that similar efficacy of steroid therapy can be expected in the non-IgG4RD group and IgG4RD group.",
"affiliations": "The Department of Urology, Sapporo Medical University School of Medicine.;The Department of Urology, Sapporo Medical University School of Medicine.;The Department of Urology, Sapporo Medical University School of Medicine.;The Department of Clinical Immunology and Rheumatology, Sapporo Medical University School of Medicine.;The Department of Clinical Immunology and Rheumatology, Sapporo Medical University School of Medicine.;The Department of Urology, Sapporo Medical University School of Medicine.",
"authors": "Iyoki|Takaya|T|;Maehana|Takeshi|T|;Tanaka|Toshiaki|T|;Yamamoto|Motohisa|M|;Takahashi|Hiroki|H|;Masumori|Naoya|N|",
"chemical_list": "D007074:Immunoglobulin G",
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"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": "Idiopathic retroperitoneal fibrosis; IgG4 related disease",
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D012185:Retroperitoneal Fibrosis",
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"title": "Clinical Evaluation of Diagnostic and Treatment Protocol of Idiopathic Retroperitoneal Fibrosis Incorporating Consideration of Possible IgG4-Related Disease.",
"title_normalized": "clinical evaluation of diagnostic and treatment protocol of idiopathic retroperitoneal fibrosis incorporating consideration of possible igg4 related disease"
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"abstract": "The clinical presentation of repetitive choreiform involuntary movements of the anterior abdominal wall was first introduced as \"belly dancer's dyskinesia.\" Etiologies of this rare condition include idiopathic causes, medication inducement, or post-abdominal surgery. We report a case of orobuccal stereotypic movements and abdominal wall dyskinesia secondary to prochlorperazine intake. The movements began 2 weeks after cessation of prochlorperazine. The patient took this dopamine receptor-blocking medication for 6 months to treat nausea due to chemotherapy. To our knowledge, abdominal wall dyskinesia as a tardive syndrome of prochlorperazine has not been previously reported.",
"affiliations": "Department of Neurology, New York Medical College, Valhalla, New York, USA.;Department of Neurology, New York Medical College, Valhalla, New York, USA.;Department of Neurology, New York Medical College, Valhalla, New York, USA.;Department of Neurology, New York Medical College, Valhalla, New York, USA.",
"authors": "Cavdar|Leyla|L|;Ajasin|Solomon|S|;Woolf|Scott|S|;Fekete|Robert|R|",
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"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504336",
"fulltext": "\n==== Front\nCase Rep Neurol\nCase Rep Neurol\nCRN\nCase Reports in Neurology\n1662-680X S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000504336\ncrn-0012-0069\nSingle Case − General Neurology\nAbdominal Wall Dyskinesia: Case Report\nCavdar Leyla Ajasin Solomon Woolf Scott Fekete Robert * Department of Neurology, New York Medical College, Valhalla, New York, USA\n*Dr. Robert Fekete, Department of Neurology, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595 (USA), robertfekete@hotmail.com\nJan-Apr 2020 \n14 2 2020 \n14 2 2020 \n12 1 69 72\n18 10 2019 22 10 2019 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The clinical presentation of repetitive choreiform involuntary movements of the anterior abdominal wall was first introduced as “belly dancer's dyskinesia.” Etiologies of this rare condition include idiopathic causes, medication inducement, or post-abdominal surgery. We report a case of orobuccal stereotypic movements and abdominal wall dyskinesia secondary to prochlorperazine intake. The movements began 2 weeks after cessation of prochlorperazine. The patient took this dopamine receptor-blocking medication for 6 months to treat nausea due to chemotherapy. To our knowledge, abdominal wall dyskinesia as a tardive syndrome of prochlorperazine has not been previously reported.\n\nKeywords\nExtrapyramidal symptomProchlorperazineTardive dyskinesia\n==== Body\nBackground\nThe clinical presentation of repetitive, dyskinetic, and involuntary motions of the anterior abdominal wall was first introduced as “belly dancer's dyskinesia” in 1990 [1, 2]. Tardive dyskinesia, trauma, or pain of the affected region may be causative factors [3]. We report a case of abdominal wall dyskinesia secondary to prochlorperazine intake.\n\nCase Presentation\nThe patient was a 68-year-old male who presented to the hospital for evaluation of sudden onset of involuntary abdominal wall movement. These movements had been going on for the past 2 weeks with a constant time course. The patient reported no associated prodrome or any obvious triggers. The movement was observed as bilateral, writhing, and continuous (online suppl. Video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000504336). Furthermore, the patient showed classic orobuccolingual stereotypic movements of tardive dyskinesia, also shown in online supplementary Video 1. The neurological examination was otherwise normal.\n\nThe patient denied any similar episodes in the past. He also denied any shortness of breath, chest pain, or abdominal pain. There was no reported family history. The patient worked as a technical engineer before retirement and had a medical history of cardiac amyloidosis for which he began chemotherapy in January 2019. Chemotherapeutic agents included cyclophosphamide, daratumumab, elotuzumab, and bortezomib. Due to the side effects of nausea and vomiting, the patient was prescribed prochlorperazine (Compro) 5-mg tablets in February 2019.\n\nThe patient was a somewhat poor historian, as he initially reported that he occasionally would take 20 tablets in 1 day, but later reported that he would take 4–6 tablets per day. After chemotherapy had concluded in May 2019, the patient reported he would still take prochlorperazine as needed for prophylaxis against nausea. Pharmacy records showed that the patient obtained prochlorperazine from two different providers at two different pharmacies, which summed up to 1,620 obtained tablets over the course of 6 months.\n\nThe patient reported discontinuing prochlorperazine altogether about 1 month ago in August 2019, and the abdominal movements beginning a few weeks afterward. We suspect the abdominal wall dyskinesia to be an unusual and rare extrapyramidal manifestation of prochlorperazine.\n\nDiscussion\nWe report a case of a patient with bilateral, writhing, and continuous abdominal wall movement, accompanied by orobuccolingual stereotypies. Medical history and medication review revealed a likely prochlorperazine-induced etiology. The patient's extrapyramidal symptoms were not present when he was taking this medication, but first began 2 weeks after cessation. The patient's involuntary movements with onset after cessation of dopamine receptor-blocking medication are consistent with the diagnosis of tardive dyskinesia [4].\n\nProchlorperazine is a first-generation antipsychotic that acts as by blocking dopaminergic receptors in the brain. It is commonly used in the treatment of positive symptoms of schizophrenia as well as in managing post-chemotherapy nausea and vomiting [5]. Abdominal wall dyskinesia has a variety of etiologies, including idiopathic causes, drug inducement, post-abdominal surgery, pontine or extrapontine myelinolysis, or local trauma [2, 6].\n\nBelly dancer's dyskinesia secondary to prochlorperazine was suspected once other potential causes had been ruled out. The patient's bloodwork, imaging, physical examination, and medical history were unremarkable and did not reveal a cause of dyskinesia. Furthermore, the temporal relationship of drug cessation and symptom onset further raised suspicion of this disorder. Dyskinesia of the abdominal wall has been previously reported with levodopa [7], paroxetine [8], clebopride [9], and even galantamine [10] but, to our knowledge, has not been previously reported with prochlorperazine use.\n\nThe diagnosis of belly dancer's dyskinesia is a clinical one, but fluoroscopy and electromyography can be done in addition, and brain and spinal cord imaging can be done to exclude other diagnoses [2]. Different case reports have demonstrated the effectiveness of diphenhydramine and diazepam [11], transcutaneous electrical nerve stimulation [9], or phrenic nerve block when symptoms are resistant [2]. Acutely, the patient responded with improvement on clonazepam 1 mg t.i.d. Vesicular monoamine transporter type 2 inhibitors may be considered for the treatment of tardive dyskinesia [12].\n\nStatement of Ethics\nWritten informed consent to publish case report and video was obtained from the patient.\n\nDisclosure Statement\nL.C., S.A., and S.W. have nothing to disclose. R.F. served on advisory boards of and as a consultant for Teva Neuroscience, Inc., Lundbeck, LLC, and Neurocrine Biosciences, Inc.\n\nFunding Sources\nThe authors did not receive any funding.\n\nAuthor Contributions\nL.C. led the genesis of the paper, wrote the first draft, and obtained the video. S.A. and S.W. revised the paper and reviewed the literature. R.F. edited the video, managed the project, reviewed the literature, and revised the manuscript.\n\nSupplementary Material\nSupplementary data\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Iliceto G Thompson PD Day BL Rothwell JC Lees AJ Marsden CD Diaphragmatic flutter, the moving umbilicus syndrome, and “belly dancer's” dyskinesia Mov Disord 1990 5 (1) 15 22 2136930 \n2 Gupta A Kushwaha S. Belly Dancer's Dyskinesia: A Glimpse of a Rare Phenomenon Cureus 2017 9 (7) e1457 29104832 \n3 Aggarwal A Thompson PD Unusual focal dyskinesias Handb Clin Neurol 2011 100 617 28 21496611 \n4 Burkhard PR Acute and subacute drug-induced movement disorders Parkinsonism Relat Disord 2014 1 20 Suppl 1 S108 12 24262159 \n5 Din L Preuss CV Prochlorperazine StatPearls 2019 Jan. Treasure Island (FL) StatPearls Publishing Available from https://www.ncbi.nlm.nih.gov/books/NBK537083/ \n6 Yeh JY Tu KY Tseng PT Lee Y Lin PY Acute onset of abdominal muscle dyskinesia (“Belly Dancer Syndrome”) from quetiapine exposure: a case report Clin Neuropharmacol 2018 Mar-Apr 41 (2) 73 4 29474193 \n7 Carecchio M Collini A Comi C Cantello R Bhatia KP Monaco F Levodopa-induced belly dancer's dyskinesias in Parkinson's disease: report of one case Mov Disord 2010 8 25 (11) 1760 2 20645401 \n8 Inghilleri M Conte A Frasca V Vaudano AE Meco G Belly dance syndrome due to spinal myoclonus Mov Disord 2006 3 21 (3) 394 6 16211614 \n9 Linazasoro G Van Blercom N Lasa A Fernández JM Aranzábal I Etiological and therapeutical observations in a case of belly dancer's dyskinesia Mov Disord 2005 2 20 (2) 251 3 15455446 \n10 Hernández-Fernández F Pardal-Fernández JM García-Martínez E Segura T Respiratory myoclonus, a side effect of galantamine Farm Hosp 2011 Mar-Apr 35 (2) 97 9 21106426 \n11 Amin OS Abdulkarim QH Shaikhani M Intermittent bursts of abdominal wall jerky movements: belly dancer's syndrome? BMJ Case Rep 2012 12 2012 dec23 1 bcr2012007393 \n12 Scorr LM Factor SA VMAT2 inhibitors for the treatment of tardive dyskinesia J Neurol Sci 2018 6 389 43 7 29433808\n\n",
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"issn_linking": "1662-680X",
"issue": "12(1)",
"journal": "Case reports in neurology",
"keywords": "Extrapyramidal symptom; Prochlorperazine; Tardive dyskinesia",
"medline_ta": "Case Rep Neurol",
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"pages": "69-72",
"pmc": null,
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"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29433808;2136930;23266778;29104832;15455446;16211614;24262159;20645401;21496611;29474193;21106426",
"title": "Abdominal Wall Dyskinesia: Case Report.",
"title_normalized": "abdominal wall dyskinesia case report"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-083802",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ELOTUZUMAB"
},
"drugadd... |
{
"abstract": "Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon-based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)-coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir-sofosbuvir (LDV-SOF). A 56-year-old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV-SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9-1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV-SOF and TDF were discontinued, and the patient's serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV-SOF is commonly prescribed in patients with HIV-HCV coinfection, as patients who received LDV-SOF- and TDF-containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV-SOF and TDF. Clinicians prescribing LDV-SOF to HCV-HIV-coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF.",
"affiliations": "College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.;Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois. svibhakar@cookcountyhhs.org.;College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.;Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois.;John H. Stroger Jr. Hospital, Cook County Health and Hospitals System, Chicago, Illinois.;Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois.",
"authors": "Bunnell|Kristen L|KL|;Vibhakar|Sonia|S|;Glowacki|Robert C|RC|;Gallagher|Maureen A|MA|;Osei|Albert M|AM|;Huhn|Gregory|G|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C586541:ledipasvir; D000068698:Tenofovir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1803",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "36(9)",
"journal": "Pharmacotherapy",
"keywords": "adverse drug reaction; antiretrovirals; hepatitis C; nephrotoxicity",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000998:Antiviral Agents; D001562:Benzimidazoles; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D007668:Kidney; D008875:Middle Aged; D000069474:Sofosbuvir; D000068698:Tenofovir",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e148-53",
"pmc": null,
"pmid": "27459733",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Nephrotoxicity Associated with Concomitant Use of Ledipasvir-Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection.",
"title_normalized": "nephrotoxicity associated with concomitant use of ledipasvir sofosbuvir and tenofovir in a patient with hepatitis c virus and human immunodeficiency virus coinfection"
} | [
{
"companynumb": "US-MYLANLABS-2016M1050140",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Acute and chronic graft-versus-host disease (GVHD) remain major barriers to successful hematopoietic stem cell transplantation (SCT). TNF-alpha has been implicated in the pathogenesis of GVHD and TNF-alpha blockade has been explored for treatment of GVHD. The development of a chimeric mouse/human monoclonal antibody (infliximab) which binds to cells producing TNF-alpha, allowing for not only the neutralization of TNF-alpha but also lysis of the cells producing the TNF-alpha, makes this an attractive drug to explore in GVHD. We report on 11 patients with acute GVHD who were treated with infliximab after failing other therapies. The survival was very poor, in keeping with previously published reports of steroid-refractory acute GVHD. Two patients with severe diarrhea from acute GI GVHD resolved their symptoms after treatment with infliximab. Only these two patients survived. It appears that of all acute GVHD manifestations, gastrointestinal GVHD may be more responsive to treatment with infliximab than others. Caution is recommended when using this agent since it may exacerbate active infections, particularly aspergillosis. Furthermore, we do not know the correct dose or schedule to use with this drug. Given these data, controlled studies assessing dose and timing of administration may be warranted to study infliximab in acute GVHD.",
"affiliations": "Department of Pediatrics, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. djacobsohn@childrensmemorial.org",
"authors": "Jacobsohn|David A|DA|;Hallick|Jason|J|;Anders|Viki|V|;McMillan|Stephanie|S|;Morris|Lawrence|L|;Vogelsang|Georgia B|GB|",
"chemical_list": "D000911:Antibodies, Monoclonal; D013256:Steroids; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.10392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "74(2)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D002675:Child, Preschool; D003967:Diarrhea; D004351:Drug Resistance; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D019233:Retreatment; D013256:Steroids",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "119-24",
"pmc": null,
"pmid": "14508798",
"pubdate": "2003-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infliximab for steroid-refractory acute GVHD: a case series.",
"title_normalized": "infliximab for steroid refractory acute gvhd a case series"
} | [
{
"companynumb": "US-PFIZER INC-2017299500",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null... |
{
"abstract": "In 5 patients, 3 women aged 30, 32 and 41 years and 2 men aged 36 and 56 years, serious side effects developed after starting aripiprazole, a new antipsychotic drug. 2 patients had not been treated with antipsychotic drugs before, while in 3 there was a switch in antipsychotic treatment. The side effects consisted primarily oftroubling feelings ofagitation, akathisia, insomnia and dysphoria. 3 of the patients made a suicide attempt and 2 developed suicidal thoughts. The patients had not previously attempted suicide and the suicidal thoughts disappeared after discontinuation ofaripiprazole. Suicidal tendencies have not been reported before as a side effect ofaripiprazole.",
"affiliations": "Universitair Medisch Centrum Utrecht, Rudolf Magnus Instituut voor Neurowetenschappen, afd. Psychiatrie, Postbus 85.500, 3508 GA Utrecht. m.r.m.scholten@cs.com",
"authors": "Scholten|M R M|MR|;Selten|J P|JP|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "149(41)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011618:Psychotic Disorders; D015363:Quinolones; D013406:Suicide, Attempted; D013850:Thinking",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "2296-8",
"pmc": null,
"pmid": "16240856",
"pubdate": "2005-10-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Suicidal ideations and suicide attempts after starting on aripiprazole, a new antipsychotic drug.",
"title_normalized": "suicidal ideations and suicide attempts after starting on aripiprazole a new antipsychotic drug"
} | [
{
"companynumb": "NL-MACLEODS PHARMACEUTICALS US LTD-MAC2022036248",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drug... |
{
"abstract": "Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.",
"affiliations": "Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA; Clinical Translational Science Center, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: dldinwiddie@salud.unm.edu.;Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; Division of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: jmbracken@cmh.edu.;Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; Division of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: jabass@cmh.edu.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Division of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: kchristenson@cmh.edu.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA. Electronic address: ssoden@cmh.edu.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA. Electronic address: csaunders@cmh.edu.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: nmiller@cmh.edu.;Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA. Electronic address: vsingh@cmh.edu.;Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA. Electronic address: dzwick@cmh.edu.;Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; Division of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: croberts@cmh.edu.;Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; Division of Hematology Oncology, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: jddalal@cmh.edu.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology, Children's Mercy Hospital, Kansas City, MO 64108, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA. Electronic address: sfkingsmore@cmh.edu.",
"authors": "Dinwiddie|Darrell L|DL|;Bracken|Julia M|JM|;Bass|Julie A|JA|;Christenson|Kathy|K|;Soden|Sarah E|SE|;Saunders|Carol J|CJ|;Miller|Neil A|NA|;Singh|Vivekanand|V|;Zwick|David L|DL|;Roberts|Charles C|CC|;Dalal|Jignesh|J|;Kingsmore|Stephen F|SF|",
"chemical_list": "D053709:Interleukin-10 Receptor alpha Subunit",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-7543",
"issue": "102(5-6)",
"journal": "Genomics",
"keywords": "Colitis; Crohn's disease; Exome sequencing; Hematopoietic stem cell transplantation; IL10; IL10RA; Inflammatory bowel disease",
"medline_ta": "Genomics",
"mesh_terms": "D002648:Child; D059472:Exome; D005820:Genetic Testing; D014644:Genetic Variation; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases; D053709:Interleukin-10 Receptor alpha Subunit; D008297:Male; D025202:Molecular Diagnostic Techniques; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome",
"nlm_unique_id": "8800135",
"other_id": null,
"pages": "442-7",
"pmc": null,
"pmid": "24001973",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23128226;12824425;22550014;11125122;22566844;22549091;21519361;21560194;22205512;23631824;20562413;20354512;22086963;22086951;22495306;22022947;22495309;18414213;23158016;23128233;23035047;16247296;19923578;20038494;19890111;21478889;21228398;20147302;22476154;21173700;19253307;21677747;21937992;20934598",
"title": "Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing.",
"title_normalized": "molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing"
} | [
{
"companynumb": "US-JNJFOC-20140107631",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report 3 patients with minocycline-induced autoimmunity resulting in peripheral nerve vasculitis.\n\n\nMETHODS\nWe report 3 patients who, during minocycline treatment for acne vulgaris, developed subacute onset of pain and weakness caused by vasculitis in single and multiple mononeuropathy patterns.\n\n\nRESULTS\nEach patient underwent either a nerve or muscle biopsy that confirmed vasculitis. One patient additionally developed systemic symptoms (including fever, fatigue, and night sweats) and another had a posterior circulation stroke. Symptoms developed with either early or prolonged use of minocycline. Despite withdrawal of minocycline, patients needed long-term immunotherapy to gain neurologic improvement.\n\n\nCONCLUSIONS\nOur findings suggest that the typical neuropathy associated with minocycline use is painful single or multiple mononeuropathy due to peripheral nerve vasculitis, which may also be accompanied by presumed CNS vasculitis (presenting as stroke).",
"affiliations": "Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.;Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.",
"authors": "Baratta|John M|JM|;Dyck|P James B|PJ|;Brand|Patricio|P|;Thaisetthawatkul|Pariwat|P|;Dyck|Peter J|PJ|;Engelstad|JaNean K|JK|;Goodman|Brent|B|;Karam|Chafic|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000180",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201500672610.1212/NXI.0000000000000180213131132134ArticleVasculitic neuropathy following exposure to minocycline Baratta John M. MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDyck P. James B. MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nI am an associate editor on the Journal of Neurology, Neurosurgery and Psychiatry editorial board as of 2013.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBrand Patricio MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nThaisetthawatkul Pariwat MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDyck Peter J. MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\n(1) Diabetes, Associate Editor, April 5, 2011 to March 30, 2014.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nReceives research support from Pfizer Inc, Isis Pharmaceuticals, Inc., Anylam Pharmaceuticals\n\n\n\nResearch Support, Government Entities:\nNIH, Principal Investigator, NINDS 36797, 2004 to 2009. NIH, Principal Investigator, R01 NS 51306-05, 2005 to 2013. FDA, Principal Investigator, FD FD-R-002532-3, 2004 to 2008. NCRR, Co-Investigator, U54 RR 24150-2, 2006 to 2011.\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nEngelstad JaNean K. HTScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nRoyalties from the book: Companion to Peripheral Neuropathy: Illustrated Cases and New Developments, 1st Ed., Saunders, 2010.\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nGoodman Brent MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKaram Chafic MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nI have received speaker honoraria from Nufactor.\n\n\n\nEditorial Boards:\nI served on the editorial board of the Neurology Resident and Fellow section. I currently serve as Deputy Editor, Neurology Write Click.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nI have received consulting honoraria from Lundbeck.\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Departments of Physical Medicine & Rehabilitation (J.M.B.) and Neurology (C.K.), The University of North Carolina, Chapel Hill; the Department of Neurology (P.J.B.D., P.B., P.J.D., J.K.E.), Mayo Clinic, Rochester, MN; the Department of Neurological Sciences (P.T.), University of Nebraska Medical Center, Omaha; and the Department of Neurology (B.G.), Mayo Clinic, Scottsdale, AZ.Correspondence to Dr. Karam: chafickaram@gmail.comFunding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by UNC Neurology.\n\n12 11 2015 2 2016 12 11 2015 3 1 e18019 6 2015 06 10 2015 © 2015 American Academy of Neurology2015American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.Objective:\nTo report 3 patients with minocycline-induced autoimmunity resulting in peripheral nerve vasculitis.\n\nMethods:\nWe report 3 patients who, during minocycline treatment for acne vulgaris, developed subacute onset of pain and weakness caused by vasculitis in single and multiple mononeuropathy patterns.\n\nResults:\nEach patient underwent either a nerve or muscle biopsy that confirmed vasculitis. One patient additionally developed systemic symptoms (including fever, fatigue, and night sweats) and another had a posterior circulation stroke. Symptoms developed with either early or prolonged use of minocycline. Despite withdrawal of minocycline, patients needed long-term immunotherapy to gain neurologic improvement.\n\nConclusions:\nOur findings suggest that the typical neuropathy associated with minocycline use is painful single or multiple mononeuropathy due to peripheral nerve vasculitis, which may also be accompanied by presumed CNS vasculitis (presenting as stroke).\n\nOPEN-ACCESSTRUE\n==== Body\nMinocycline is a synthetic tetracycline derivative commonly used for its broad-spectrum antibiotic properties, such as in the treatment of acne vulgaris. Prior reports have demonstrated an association between minocycline exposure and development of autoimmune syndromes, such as serum sickness, drug-induced lupus, autoimmune hepatitis, and systemic vasculitis.1 There are additionally several previously reported cases of minocycline-associated vasculitic neuropathy as part of a systemic, drug-induced, lupus-like,2 or polyarteritis nodosa–like syndrome.3 In this case series, we describe 3 patients, 1 previously reported,4 who developed a stereotypical syndrome of painful single or multiple mononeuropathy following minocycline exposure. These conditions were sometimes associated with systemic symptoms (such as fevers and night sweats) and with posterior circulation strokes.\n\nCASE REPORTS\nPatient 1.\nA 17-year-old otherwise healthy girl awoke with new-onset arm pain, numbness, and weakness in the left ulnar nerve distribution. She had a history of acne for which she had taken minocycline for 3 years. Eleven days after development of the left arm symptoms, she developed numbness over the lateral aspects of the bilateral feet and thighs.\n\nShe was seen by an orthopedist who believed she had a compressive left ulnar neuropathy at the elbow and, on day 31 after symptom onset, she underwent a left ulnar nerve transposition. Left arm pain and weakness worsened postoperatively. A month later, the patient developed acute left leg weakness, nausea, and vertigo, which prevented her from walking. On examination, she demonstrated left arm and bilateral ankle dorsiflexion weakness and reduced sensation in the left hand and bilateral feet.\n\nSubsequent brain MRI showed an acute right medial medullary ischemic stroke. Extensive evaluation did not reveal a hypercoagulable state, embolic source, or large artery abnormality. Nerve conduction studies and needle EMG showed diffuse abnormalities within all limbs, which were asymmetric and suggestive of an axonal multiple mononeuropathy or asymmetrical polyradiculoneuropathy. Left upper extremity findings localized to the brachial plexus or multiple peripheral nerves. A brachial plexus MRI showed generalized increased T2 signal intensity throughout the course the left brachial plexus. Antinuclear antibody (ANA) was mildly positive (1:160) and C-reactive protein was elevated (18.4). CSF analysis was normal. Autoimmune and infectious workups were otherwise negative. A left superficial radial nerve biopsy was consistent with necrotizing vasculitis (figure 1).\n\nFigure 1 Patient 1 radial nerve biopsy\n(A) Hematoxylin & eosin stain of radial nerve demonstrates epineurial nerve large arteriole necrotizing vasculitis. Note the prominent inflammatory cell infiltrate infiltrating and disrupting all layers of the arteriolar wall and the fibrinoid necrosis (arrows). (B) Methylene blue stain of radial nerve demonstrates myelinated fiber degeneration in the center of the fascicle that is typical of ischemic changes (outlined).\n\nFollowing diagnosis, minocycline was discontinued. The patient was started on IV methylprednisolone and azathioprine. On follow-up several months after discharge, she demonstrated good clinical improvement with regard to pain, strength, and sensation.\n\nPatient 2.\nA 33-year-old man was seen in consultation for evaluation of left foot pain and weakness. The patient had a several month history of recurrent episodes of generalized muscle soreness, joint pain, and fatigue. Episodes would last up to several days at a time. The most severe episode occurred in conjunction with a fever (103°F), chills, cold sweats, low back pain radiating to the right testicle, and acute left leg and foot pain and paresthesias. He had been taking minocycline for acne for 2 years. Strength examination was normal apart from mild left foot inversion, ankle plantarflexion, and toe weakness. There was reduced sensation to vibration at the left toe and reduced pinprick at the sole of the left foot.\n\nAn ANA was mildly positive (1:160) and a thyroid peroxidase antibody level was elevated (19.34). Autoimmune and infectious workups were otherwise negative. No imaging was performed. Electrophysiology studies demonstrated an isolated left, subacute, primarily axonal, tibial mononeuropathy. A left gastrocnemius muscle biopsy was consistent with necrotizing vasculitis (figure 2).\n\nFigure 2 Patient 2 gastrocnemius muscle biopsy10\nGomori trichrome stain of gastrocnemius muscle biopsy shows large arteriole necrotizing vasculitis.\n\nFollowing diagnosis, the minocycline was discontinued. The patient was initiated on high-dose oral prednisone and IV cyclophosphamide. At 3-month follow-up after diagnosis, he demonstrated clinical improvement of strength and pain. His constitutional symptoms had fully resolved.\n\nPatient 3 (previously reported).\nA 28-year-old woman presented for evaluation of weakness, pain, and paresthesia in the left foot.4 She was previously healthy other than starting minocycline 2 weeks prior for treatment of acne vulgaris. Minocycline was discontinued shortly after symptom onset.\n\nOn examination, there was distal left foot weakness involving both peroneal and tibial distributions and diminished sensation in the left sciatic territory. Electrophysiology studies demonstrated a left sciatic mononeuropathy with active denervation in both peroneal and tibial innervated muscles. Serologic testing demonstrated positive ANA and SSA. The remainder of autoimmune and infectious workups was negative. A lumbosacral plexus MRI demonstrated mild increased T2 hyperintensity of the bilateral L4-S1 nerve roots with extension into the femoral and sciatic nerves. A left sural nerve biopsy was consistent with necrotizing vasculitis, with multifocal myelinated fiber loss as well as large and small perivascular inflammatory cell collections in both the endoneurium and epineurium.\n\nAfter cessation of minocycline, the patient was started on a 1 g per week 12-week IV methylprednisolone treatment session. She was seen in follow-up at 3 months, by which time her strength and gait had returned to normal.\n\nDISCUSSION\nMinocycline exposure has recently been associated with the development of several types of systemic autoimmune syndromes.1–3 Our 3 cases further demonstrate an association between minocycline exposure and development of both systemic (patient 2, who presented with constitutional symptoms) and possible nonsystemic (patients 1 and 3) vasculitic neuropathies. In each of the 3 cases presented above, minocycline had been initiated for treatment of acne vulgaris before the onset of the neuropathy. The diagnosis of single or multiple vasculitic mononeuropathy in each case was confirmed by nerve or muscle biopsy.\n\nThere have also been reports of 2 cases of posterior circulation stroke5,6 and one case of cervical myelopathy in association with vertebral artery vasculitis7 secondary to polyarteritis nodosa–like syndrome related to minocycline use. Patient 1, who sustained an acute right medial medullary ischemic stroke, had no traditional cerebrovascular risk factors and extensive evaluation did not reveal any embolic source or large artery abnormality. Given that the rest of her illness was due to peripheral nerve vasculitis, this patient's stroke was likely due to CNS vasculitis.\n\nThe current understanding of minocycline-induced autoimmunity suggests that haptens, which invoke the immune response, may be the product of minocycline processing by neutrophils or hepatocytes.8 Haptens may further bind to degrading enzymes inducing an immune response against those enzymes, such as anti-myeloperoxidase antibodies. Of note, antihistone antibody, which is present in more than 95% of traditional drug-induced lupus, is frequently absent in minocycline-induced autoimmune syndromes.8 The reason for this is unclear.\n\nThe timing of minocycline initiation and development of symptoms was variable, ranging from acute (2 weeks in patient 4) to chronic exposures (2–4 years in patients 1–3). Prior reports of systemic minocycline-induced lupus suggest that autoimmunity typically develops after chronic administration of the drug, with Schlienger et al.9 suggesting a median time to onset of 19 months.\n\nPatients who develop a minocycline-induced autoimmune condition typically respond to cessation of the minocycline with administration of oral or IV corticosteroids.8 A steroid-sparing agent, such as cyclophosphamide or azathioprine, may also be added. All 3 of our patients demonstrated clinical improvement following cessation of minocycline and initiation of glucocorticoids with a steroid-sparing agent.\n\nThis case series adds to the growing body of literature regarding minocycline-induced autoimmunity. Each of our cases presented in a stereotypical way with the development of pain and weakness in the distribution of single or multiple individual nerves and showed evidence of ischemic injury and vasculitis on nerve and muscle biopsy. One of the patients had a simultaneous posterior circulation stroke. Physicians treating those with neuromuscular conditions should be aware of the possible association between minocycline exposure and the development of both nonsystemic and systemic vasculitic neuropathies and cerebral posterior circulation strokes.\n\nAUTHOR CONTRIBUTIONS\nJohn M. Baratta: conceptualization, data interpretation, manuscript drafting and revision. P. James B. Dyck: conceptualization, data interpretation, manuscript drafting and revision. Patricio Brand: conceptualization, data interpretation. Pariwat Thaisetthawatkul: conceptualization, data interpretation, manuscript drafting and revision. Peter J. Dyck: conceptualization, data interpretation, manuscript drafting and revision. JaNean K. Engelstad: data interpretation. Brent Goodman: conceptualization, data interpretation. Chafic Karam: conceptualization, data interpretation, manuscript drafting and revision.\n\nSTUDY FUNDING\nNo targeted funding.\n\nDISCLOSURE\nJ.M. Baratta reports no disclosures. P.J.B. Dyck is an associate editor for Journal of Neurology, Neurosurgery and Psychiatry. P. Brand and P. Thiasetthawatkul report no disclosures. P.J. Dyck was an associate editor for Diabetes, and received research support from Pfizer, Isis Pharmaceuticals, Anylam Pharmaceuticals, NIH, FDA, and NCRR. JaNean Englestad received royalties from Saunders. B.P. Goodman reports no disclosures. C. Karam serves as Neurology® WriteClick® deputy editor, was on the editorial board for Neurology Resident and Fellow Section, received speaker honoraria from NuFACTOR, and has consulted for Lundbeck. Go to Neurology.org/nn for full disclosure forms.\n\nGLOSSARY\nANAantinuclear antibody\n==== Refs\nREFERENCES\n1. Elkayam O Yaron M Caspi D \nMinocycline-induced autoimmune syndromes: an overview . Semin Arthritis Rheum \n1999 ;28 :392 –397 .10406406 \n2. Graham L Bell A \nMinocycline-associated lupus-like syndrome with ulnar neuropathy and antiphospholipid antibody . Clin Rheumatol \n2001 ;20 :67 –69 .11254246 \n3. Ogawa N Kawai H Yamakawa I Sanada M Sugimoto T Maeda K \nCase of minocycline-induced vasculitic neuropathy [in Japanese] . Rinsho Shinkeigaku \n2010 ;50 :301 –305 .20535977 \n4. Thaisetthawatkul P Sundell R Robertson CE Dyck PJ \nVasculitic neuropathy associated with minocycline use . J Clin Neuromuscul Dis \n2011 ;12 :231 –234 .22361522 \n5. Kermani TA Ham EK Camilleri MJ Warrington KJ \nPolyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series . Semin Arthritis Rheum \n2012 ;42 :213 –221 .22704357 \n6. Klaas JP Matzke T Makol A Fulgham JR \nMinocycline-induced polyarteritis nodosa-like vasculitis presenting as brainstem stroke . J Clin Neurosci \n2015 ;22 :904 –907 .25778384 \n7. Garg N Altowaijri GH Nesbit GM Gultekin SH Bourdette DN \nMinocycline-associated vasculitis of extracranial branches of vertebral arteries presenting as myelopathy . Neurol Neuroimmunol Neuroinflamm \n2014 ;1 :e7 .25340063 \n8. Schaffer JV Davidson DM McNiff JM Bolognia JL \nPerinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris . J Am Acad Dermatol \n2001 ;44 :198 –206 .11174376 \n9. Schlienger RG Bircher AJ Meier CR \nMinocycline-induced lupus. A systematic review . Dermatology \n2000 ;200 :223 –231 .10828631 \n10. Karam C \nEye of the storm . Neurology \n2015 ;84 :1180 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2332-7812",
"issue": "3(1)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": null,
"nlm_unique_id": "101636388",
"other_id": null,
"pages": "e180",
"pmc": null,
"pmid": "26601119",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "11254246;10828631;11174376;25778384;25340063;22361522;20535977;22704357;10406406",
"title": "Vasculitic neuropathy following exposure to minocycline.",
"title_normalized": "vasculitic neuropathy following exposure to minocycline"
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"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2016-04834",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
... |
{
"abstract": "Although a 7-day (d) regimen of azacitidine (AZA) is the standard treatment of high-risk myelodysplastic syndromes (MDS), AZA is difficult to administer during weekends in an outpatient setting. We retrospectively investigated the outcome of a 5-d regimen of AZA in patients with high-risk MDS. High-risk MDS was defined as MDS with intermediate-2- or high-risk MDS according to the International Prognostic Scoring System. Every months AZA was given at 75 mg/m(2) per day for 5-7 d in hospital for first cycle and 5 d in outpatient for second cycle and later. Between April 2011 and December 2013, AZA treatment was initiated in 25 patients (men, 22; women, 3; median age, 75 yr; age range, 59-86 yr). The median number of AZA cycles was 10 (range, 1-24). Twenty patients received more than three cycles of AZA and 13 (52%) achieved any hematological improvement (HI). The median time to first response was two cycles (1-3). The most common non-hematological adverse events were neutropenia in 21 patients and thrombocytopenia in 17 patients. Nineteen patients died. The main cause of death was disease progression (five patients) and infectious complications (11 patients). The median overall survival was 13.2 months. The 5-d AZA regimen showed a good continuation rate of more than three cycles and an equivalent HI with the 7-d regimen.",
"affiliations": "Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan.;Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan.;Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan.;Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.",
"authors": "Fujimaki|Katsumichi|K|;Miyashita|Kazuho|K|;Kawasaki|Rika|R|;Tomita|Naoto|N|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12709",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "97(3)",
"journal": "European journal of haematology",
"keywords": "5-day regimen; azacitidine; high-risk myelodysplastic syndromes",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "228-31",
"pmc": null,
"pmid": "26613362",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of a 5-day regimen of azacitidine for patients with high-risk myelodysplastic syndromes.",
"title_normalized": "efficacy and safety of a 5 day regimen of azacitidine for patients with high risk myelodysplastic syndromes"
} | [
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"companynumb": "JP-CELGENEUS-JPN-2016086416",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": "3",
... |
{
"abstract": "A patient presented with agitation, paranoia, and psychosis following ingestion of dextromethorphan, propoxyphene, and hydrocodone, a previously unreported combination. Symptoms resolved with antipsychotics and cessation of offending drugs. The pharmacodynamics of dextromethorphan and the opioids, including drug interactions are discussed, and several potential mechanisms for the production of the patient's symptoms are proposed.",
"affiliations": "Carilion Clinic, Roanoke, Virginia, USA. sjamison@carilion.com",
"authors": "Jamison|S C|SC|;Vasudeva|S|S|",
"chemical_list": "D000701:Analgesics, Opioid; D003915:Dextromethorphan",
"country": "United States",
"delete": false,
"doi": "10.1177/0269881108092125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-8811",
"issue": "23(8)",
"journal": "Journal of psychopharmacology (Oxford, England)",
"keywords": null,
"medline_ta": "J Psychopharmacol",
"mesh_terms": "D000701:Analgesics, Opioid; D003915:Dextromethorphan; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D011595:Psychomotor Agitation; D011618:Psychotic Disorders",
"nlm_unique_id": "8907828",
"other_id": null,
"pages": "989-91",
"pmc": null,
"pmid": "18583439",
"pubdate": "2009-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 60-year-old woman with agitation and psychosis following ingestion of dextromethorphan and opioid analgesics.",
"title_normalized": "a 60 year old woman with agitation and psychosis following ingestion of dextromethorphan and opioid analgesics"
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"companynumb": "US-ASTRAZENECA-2017SF00522",
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"abstract": "Pseudo-pulmonary embolism (PPE) superimposed on heparin-induced thrombocytopenia (HIT) is an important complication in patients undergoing hemodialysis (HD) treatment. We report the clinical profile of an HD patient with acute respiratory distress induced by PPE and HIT. A 67-year-old man with diabetic nephropathy and end-stage renal failure developed congestive heart failure. He was admitted to Kitasato University Hospital. He was introduced to HD treatment using low-molecular-weight heparin as an anticoagulant for an HD session on day 1 of admission. On day 11 after admission, he suddenly developed respiratory distress and hypoxia at 30 min after the start of the fifth HD session. The HD session was immediately discontinued, and oxygen inhalation improved his complaints and hypoxia. The platelet count decreased from 220 x 10(9)/L at the start of the HD session to 80 x 10(9)/L at the end of the HD session. We suspected HIT when blood clotting occurred in his hemodialyzer and blood circuit for HD during the HD session on day 12. Chest X-ray, electrocardiogram, echocardiography, and pulmonary microcirculation scintigraphy were normal. Serum analysis was positive for heparin-platelet factor 4 (PF4) antibody. We then diagnosed him with PPE superimposed on HIT. After the anticoagulant agent for HD was changed from low-molecular-weight heparin to nafamostat mesilate, his clinical symptoms and thrombocytopenia disappeared. PPE superimposed on HIT appeared approximately 7-10 days after the initial use of heparin for the HD session. PPE also led to acute respiratory distress, blood coagulation in the hemodialyzer and blood circuit for HD, as well as thrombocytopenia with less than a 50% decrease in platelet counts. The prognosis of PEE and HIT is good after discontinuing the use of heparin.",
"affiliations": null,
"authors": "Watarai|Risako|R|;Aoyama|Togo|T|;Kamata|Mariko|M|;Miyazawa|Masako|M|;Ogawa|Miyuki|M|;Okina|Chikako|C|;Murano|Junya|J|;Tanaka|Kei|K|;Aoyama|Masanori|M|;Nakano|Motoko|M|;Sano|Takashi|T|;Kamata|Kouju|K|",
"chemical_list": "D000906:Antibodies; D000925:Anticoagulants; D006493:Heparin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2385",
"issue": "57(7)",
"journal": "Nihon Jinzo Gakkai shi",
"keywords": null,
"medline_ta": "Nihon Jinzo Gakkai Shi",
"mesh_terms": "D000368:Aged; D000906:Antibodies; D000925:Anticoagulants; D003937:Diagnosis, Differential; D006493:Heparin; D006801:Humans; D008297:Male; D011655:Pulmonary Embolism; D006435:Renal Dialysis; D013921:Thrombocytopenia",
"nlm_unique_id": "7505731",
"other_id": null,
"pages": "1248-52",
"pmc": null,
"pmid": "26665617",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Heparin-induced thrombocytopenia with pseudo-pulmonary embolism in a patient who was newly introduced to hemodialysis treatment.",
"title_normalized": "heparin induced thrombocytopenia with pseudo pulmonary embolism in a patient who was newly introduced to hemodialysis treatment"
} | [
{
"companynumb": "JP-WATSON-2015-28122",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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"drugadditional": null,
... |
{
"abstract": "Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.\n\n\n\nEighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.\n\n\n\nA total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).\n\n\n\nThe success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.",
"affiliations": "Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey",
"authors": "Demiroğlu|Haluk|H|0000-0002-6790-8748;Çiftçiler|Rafiye|R|0000-0001-5687-8531;Büyükaşık|Yahya|Y|0000-0002-4764-2348;Göker|Hakan|H|0000-0002-1039-7756",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjh.galenos.2020.2020.0409",
"fulltext": "\n==== Front\nTurk J Haematol\nTurk J Haematol\nTJH\nTurkish Journal of Hematology\n1300-7777\n1308-5263\nGalenos Publishing\n\n33161684\n10.4274/tjh.galenos.2020.2020.0409\n48677\nResearch Article\nPrediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma\nHodgkin ve Non-Hodgkin Lenfomalı Hastalarda Kök Hücre Mobilizasyon Başarısızlığının ÖngörüsüDemiroğlu Haluk 1https://orcid.org/0000-0002-6790-8748\n\nÇiftçiler Rafiye 1https://orcid.org/0000-0001-5687-8531\n\nBüyükaşık Yahya 1https://orcid.org/0000-0002-4764-2348\n\nGöker Hakan 1*https://orcid.org/0000-0002-1039-7756\n\n1 Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey\n* Address for Correspondence: Hacettepe University Faculty of Medicine, Departments of Hematology, Ankara, Turkey Phone: +90 312 305 30 50 E-mail:hgoker1@gmail.com\n9 2021\n25 8 2021\n38 3 204210\n16 7 2020\n4 11 2020\n© Copyright 2021 by Turkish Society of Hematology / Turkish Journal of Hematology, Published by Galenos Publishing House.\n2021\nhttps://creativecommons.org/licenses/by/2.5/ 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 work is properly cited.\nObjective:\n\nAutologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.\n\nMaterials and Methods:\n\nEighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.\n\nResults:\n\nA total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).\n\nConclusion:\n\nThe success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.\n\nAmaç:\n\nOtolog kök hücre transplantasyonu (OKHT), relaps/refrakter lenfoma hastaları için önemli ve potansiyel olarak küratif bir tedavi yöntemidir. Yetersiz mobilizasyon ve periferik kök hücrelerin toplanması OKHT’nin gerçekleştirilmesi için büyük bir engel olabilir. Bu çalışmanın amacı lenfoma hastalarında mobilizasyon başarısızlığını etkileyebilecek faktörleri değerlendirmektir.\n\nGereç ve Yöntemler:\n\nHacettepe Üniversitesi Tıp Fakültesi Kemik İliği Nakil Merkezi’nde 2000-2018 yılları arasında Hodgkin ve non-Hodgkin lenfoma tanısı alan ve sonrasında kök hücre mobilizasyonu yapılan 87 hasta değerlendirildi.\n\nBulgular:\n\nBu çalışmaya toplam 87 hasta dahil edildi. Seksen yedi hastanın 66’sında (%75,9) ilk mobilizasyon denemesi başarılı oldu. 66 hastada (9,5±8,1) ilk aferezde yeterli (≥2x106/kg) CD34+ hücre toplandı. Seksen yedi kişiden 21’i (%24,1) için ilk mobilizasyon denemesi başarısız oldu. Bu nedenle bu hastalara pleriksafor ile (5,5±3,3) ikinci bir mobilizasyon denemesi yapıldı. İlk mobilizasyonda başarılı olan hastalarda CD34+ hücre sayısı anlamlı olarak yüksekti (p=0,002).\n\nSonuç:\n\nMobilizasyon öncesi trombosit sayısı yüksek olan hastalarda ve kemoterapi bazlı mobilizasyon protokolleri alan hastalarda ilk mobilizasyon denemesinin başarı oranı daha yüksek bulundu. İlk denemede mobilizasyon başarısızlığı olan hastalarda daha sonraki mobilizasyonda pleriksafor kullanılmış ve bu hastalarda OKHT için yeterli miktarda kök hücre mevcuttu. Mobilizasyon başarısızlığını öngören parametreler, ilk mobilizasyon girişimi sırasında bu tür ajanların önleyici, daha uygun maliyetli kullanımına izin verecektir; ancak, mobilizasyon başarısızlığı için risk faktörleri hala net değildir.\n\nHodgkin lymphoma\nNon-Hodgkin lymphoma\nStem cell mobilization\nMobilization failure\n==== Body\nIntroduction\n\nAutologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].\n\nWe have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.\n\nMaterials and Methods\n\nStudy Design and Data Collection\n\nThis study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.\n\nPatients and Disease Characteristics\n\nEighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.\n\nMedian age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.\n\nStatistical Analysis\n\nStatistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.\n\nResults\n\nPatient Characteristics\n\nA total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.\n\nBetween the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.\n\nPost-transplant Outcomes\n\nAll of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).\n\nOverall Survival\n\nThe overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.\n\nThe disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.\n\nDiscussion\n\nStem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.\n\nFor successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.\n\nRecent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].\n\nIt is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.\n\nConclusion\n\nIn this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.\n\nTable 1 Baseline clinical and demographic characteristics of patients.\n\nTable 2 Post-transplantation outcomes.\n\nFigure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).\n\nFigure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).\n\nEthics\n\nEthics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.\n\nInformed Consent: Obtained.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n==== Refs\nReferences\n\n1 Sheppard D Bredeson C Allan D Tay J Systematic review of randomized controlled trials of hematopoietic stem cell mobilization strategies for autologous transplantation for hematologic malignancies Biol Blood Marrow Transplant 2012 18 1191 1203 22261379\n2 Van Gorkom G Finel H Giebel S Pohlreich D Shimoni A Ringhoffer M Sucak G Schaap N Dreger P Sureda A Schouten HC Prospective noninterventional study on peripheral blood stem cell mobilization in patients with relapsed lymphomas J Clin Apher 2017 32 295 301 27614935\n3 Siena S Schiavo R Pedrazzoli P Carlo-Stella C Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy J Clin Oncol 2000 18 1360 1377 10715309\n4 To LB Levesque JP Herbert KE How I treat patients who mobilize hematopoietic stem cells poorly Blood 2011 118 4530 4540 21832280\n5 Allan DS Keeney M Howson-Jan K Popma J Weir K Bhatia M Sutherland DR Chin-Yee IH Number of viable CD34+ cells reinfused predicts engraftment in autologous hematopoietic stem cell transplantation Bone Marrow Transplant 2002 29 967 972 12098064\n6 Mendrone A Jr Arrais CA Saboya R de Alencar Fischer Chamone D Dulley FL Factors affecting hematopoietic progenitor cell mobilization: an analysis of 307 patients Transfus Apher Sci 2008 39 187 192 19036640\n7 Kuittinen T Nousiainen T Halonen P Mahlamäki E Jantunen E Prediction of mobilisation failure in patients with non-Hodgkin’s lymphoma Bone Marrow Transplant 2004 33 907 912 15034543\n8 Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Carbone PP Toxicity and response criteria of the Eastern Cooperative Oncology Group Am J Clin Oncol1982 5 649 656\n9 Cheson BD Fisher RI Barrington SF Cavalli F Schwartz LH Zucca E Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification J Clin Oncol 2014 32 3059 3068 25113753\n10 Ford C Chan K Reilly W Petersen F An evaluation of predictive factors for CD34+ cell harvest yields from patients mobilized with chemotherapy and growth factors Transfusion 2003 43 622 625 12702184\n11 Milone G Tripepi G Martino M Ancora F Bartolozzi B Spadaro A Nozzoli C La Fauci A Amico I Leotta S Poidomani M Irrera G Iacopino P Saccardi R Guidi S Bosi A Early measurement of CD34+ cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding “on demand” use of plerixafor Blood Transfus 2013 11 94 101 23114516\n12 Hosing C Saliba RM Ahlawat S Körbling M Kebriaei P Alousi A De Lima M Okoroji JG McMannis J Qazilbash M Anderlini P Giralt S Champlin RE Khouri I Popat U Poor hematopoietic stem cell mobilizers: a single institution study of incidence and risk factors in patients with recurrent or relapsed lymphoma Am J Hematol 2009 84 335 337 19384931\n13 Rossi G Skert C Morello E Almici C Arcaini L Basilico C Cavalli L Botto B Castelli A Pica G Ripamonti F Salvi F Carella AM Gaidano G Levis A Nosari A Russo D Vitolo U PBSC mobilization in lymphoma patients: analysis of risk factors for collection failure and development of a predictive score based on the kinetics of circulating CD34+ cells and WBC after chemotherapy and G-CSF mobilization Hematol Oncol 2015 33 125 132 24890497\n14 Wuchter P Ran D Bruckner T Schmitt T Witzens-Harig M Neben K Goldschmidt H Ho AD Poor mobilization of hematopoietic stem cells—definitions, incidence, risk factors, and impact on outcome of autologous transplantation Biol Blood Marrow Transplant 2010 16 490 499 19925876\n15 Tarella C Di Nicola M Caracciolo D Zallio F Cuttica A Omede P Bondesan P Magni M Matteucci P Gallamini A Pileri A Gianni AM High-dose ara-C with autologous peripheral blood progenitor cell support induces a marked progenitor cell mobilization: an indication for patients at risk for low mobilization Bone Marrow Transplant 2002 30 725 732 12439694\n16 Özkurt ZN Yeğin ZA Suyanı E Akı ŞZ Acar K Yağcı M Türköz Sucak G Factors affecting stem cell mobilization for autologous hematopoietic stem cell transplantation J Clin Apher 2010 25 280 286 20623783\n17 Pusic I Jiang SY Landua S Uy GL Rettig MP Cashen AF Westervelt P Vij R Abboud CN Stockerl-Goldstein KE Sempek DS Smith AL DiPersio JF Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation Biol Blood Marrow Transplant 2008 14 1045 1056 18721768\n18 Fruehauf S Seggewiss R It’s moving day: factors affecting peripheral blood stem mobilization and strategies for improvement Br J Haematol 2003 122 360 375 12877663\n19 André M Baudoux E Bron D Canon JL D’Hondt V Fassotte MF D’Hondt L Fillet G Humblet Y Jerusalem G Vermeulen P Symann M Beguin Y Phase III randomized study comparing 5 or 10 μg per kg per day of filgrastim for mobilization of peripheral blood progenitor cells with chemotherapy, followed by intensification and autologous transplantation in patients with nonmyeloid malignancies Transfusion 2003 43 50 57 12519430\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "38(3)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": "Hodgkin lymphoma; Non-Hodgkin lymphoma; Stem cell mobilization; Mobilization failure",
"medline_ta": "Turk J Haematol",
"mesh_terms": null,
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "204-210",
"pmc": null,
"pmid": "33161684",
"pubdate": "2021-08-25",
"publication_types": "D016428:Journal Article",
"references": "12519430;7165009;20623783;10715309;27614935;21832280;12439694;18721768;24890497;12098064;12702184;19036640;19925876;23114516;22261379;15034543;25113753;19384931;12877663",
"title": "Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma",
"title_normalized": "prediction of stem cell mobilization failure in patients with hodgkin and non hodgkin lymphoma"
} | [
{
"companynumb": "TR-AMGEN-TURSP2021143142",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo increase awareness of oxalate nephropathy as a cause of acute kidney injury (AKI) among systemic sclerosis patients with small intestinal dysmotility and malabsorption, and to prompt consideration of dietary modification and early treatment of predisposing causes of oxalate nephropathy in this population.\n\n\nMETHODS\nTwo cases of biopsy-proven oxalate nephropathy were identified among systemic sclerosis patients in the course of direct clinical care. Subsequently, a retrospective search of the Johns Hopkins Pathology databases identified a third patient with systemic sclerosis who developed oxalate nephropathy.\n\n\nRESULTS\nAmong the three patients with qualifying biopsies, all three had systemic sclerosis with lower gastrointestinal involvement. All three presented with diarrhea, malabsorption, and AKI. In two of the three patients, diarrhea was present for at least 2 years before the development of AKI; in the third, incidental oxalate nephropathy was noted 3 years before she developed AKI and extensive oxalate nephropathy in the setting of a prolonged mycobacterium avium-intracellulare enteritis. In the first case, oxalate crystals were present by urinalysis months before diagnosis by biopsy; in the second, hyperoxaluria was diagnosed by urine collection immediately after; and in the third, oxalate crystals had been noted incidentally on post-transplant renal biopsy 3 years before the development of fulminant oxalate nephropathy. All three patients died within a year after diagnosis.\n\n\nCONCLUSIONS\nPatients with systemic sclerosis and bowel dysmotility associated with chronic diarrhea and malabsorption may be at risk for an associated oxalate nephropathy. Regular screening of systemic sclerosis patients with small bowel malabsorption syndromes through routine urinalysis or 24-h urine oxalate collection, should be considered. Further studies defining the prevalence of this complication in systemic sclerosis, the benefit of dietary modification on hyperoxaluria, the effect of treating small intestinal bowel overgrowth with antibiotics, and the effectiveness of probiotics, calcium supplements, or magnesium supplements to prevent hyperoxaluria-associated renal disease in these patients, are warranted.",
"affiliations": "Department of Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Ave, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224.;Department of Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Ave, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224.;Department of Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Ave, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224. Electronic address: zmcmaha1@jhmi.edu.",
"authors": "Ligon|Colin B|CB|;Hummers|Laura K|LK|;McMahan|Zsuzsanna H|ZH|",
"chemical_list": "D019815:Oxalic Acid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "45(3)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Acute kidney injury; Calcium oxalate; Chronic kidney disease; Gastrointestinal disease; Malabsorption; Oxalate nephropathy; Scleroderma; Scleroderma renal crisis; Small intestinal bacterial overgrowth; Systemic sclerosis",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D005260:Female; D006801:Humans; D006959:Hyperoxaluria; D008875:Middle Aged; D019815:Oxalic Acid; D012595:Scleroderma, Systemic",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "315-20",
"pmc": null,
"pmid": "26239907",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "12839097;15370283;14644848;16556171;16925274;16832842;17222634;17215441;17377509;17601770;18322162;18523430;18701613;19013593;19193409;19696066;20224931;20647294;21381959;21737848;21607878;22402440;21874572;22366809;22955019;23639091;23666469;23953730;24889779;24999029;25500295;4693896;4808710;641156;705253;500316;6624448;6088813;3358801;2775321;2231959;1747716;1433562;7966716;9519420;9931109;10523373;15610315;15801020;15812215;12853784;831127;11380833;11834767;12105264;12352456;12474641;12631089;15064109;15268737;15879804",
"title": "Oxalate nephropathy in systemic sclerosis: Case series and review of the literature.",
"title_normalized": "oxalate nephropathy in systemic sclerosis case series and review of the literature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-282380",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Rasburicase is indicated for the prevention and treatment of tumor lysis syndrome which can be a potentially life-threatening emergency. The drug has oxidizing potential and as an adverse effect, it can convert the ferrous form of iron in erythrocytes to its ferric form resulting in the formation of methemoglobin which makes the heme component incapable of carrying oxygen. Patients with glucose-6-phosphate dehydrogenase enzyme deficiency are at high risk of methemoglobinemia from oxidizing agents. Symptoms of methemoglobinemia range from none to life-threatening hypoxemia, cyanosis and respiratory compromise. Treatment is indicated at levels above 20% and at lower levels if the patient is significantly anemic. We present a case of a 60-year-old male with diffuse large B cell lymphoma at high risk of tumor lysis syndrome. Rasburicase was administered to prevent renal failure and further rise in uric acid. Twenty-four hours later, a bedside pulse oximetry showed an oxygen saturation ranging from 60 to 65% with minimal cyanosis. Co-oximetry revealed a methemoglobin level of 9.8%. Methylene blue was administered and the methemoglobin level decreased to 2.6%. However, the patient developed hemolysis several hours later, likely secondary to rasburicase and methylene blue, requiring transfusion support. We discuss this potentially fatal and initially asymptomatic adverse effect of rasburicase along with diagnostic and treatment considerations, and review the cases described in the current literature.",
"affiliations": "1 Department of Hematology/Oncology, Staten Island University Hospital, Staten Island, NY, USA.;2 Department of Pulmonary/Critical Care, Staten Island University Hospital, Staten Island, NY, USA.;2 Department of Pulmonary/Critical Care, Staten Island University Hospital, Staten Island, NY, USA.;2 Department of Pulmonary/Critical Care, Staten Island University Hospital, Staten Island, NY, USA.;2 Department of Pulmonary/Critical Care, Staten Island University Hospital, Staten Island, NY, USA.",
"authors": "Ibrahim|Uroosa|U|;Saqib|Amina|A|;Mohammad|Farhan|F|;Atallah|Jean Paul|JP|;Odaimi|Marcel|M|",
"chemical_list": "D006074:Gout Suppressants; D011994:Recombinant Proteins; C469709:rasburicase; D014503:Urate Oxidase",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217701295",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "24(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Methemoglobinemia; hemolysis; methylene blue; rasburicase; tumor lysis syndrome",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D006074:Gout Suppressants; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008708:Methemoglobinemia; D008875:Middle Aged; D011994:Recombinant Proteins; D015275:Tumor Lysis Syndrome; D014503:Urate Oxidase",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "309-313",
"pmc": null,
"pmid": "28345492",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rasburicase-induced methemoglobinemia: The eyes do not see what the mind does not know.",
"title_normalized": "rasburicase induced methemoglobinemia the eyes do not see what the mind does not know"
} | [
{
"companynumb": "US-REGULIS-1065088",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Chronic HCV liver infection is considered one of the main causes of liver cirrhosis and hepatocellular carcinoma (HCC). For a selected group of patients, orthotopic liver transplantation (OLTx) is the most effective option to cure both liver diseases. After liver transplantation, patients may be at risk of viral infection reactivation and HCC recurrence. HCV recurrence on the transplanted organ can lead to graft cirrhosis and therefore the clearance of virus with antiviral therapies has a pivotal role on the prevention of graft damage. Nowadays, direct antiviral agents (DAAs) represent the choice treatment for HCV recurrence in liver transplanted patients, ensuring high eradication rates. We present the case of a liver transplant recipient who developed, 7 years after OLTx and immediately after a DAAs treatment, a subcutaneous abdominal mass with histological characteristics of HCC.",
"affiliations": "Liver Unit, Internal Medicine, Department of Medicine (DAME), University School of Medicine of Udine, Piazzale S. M. Misericordia 1, 33100, Udine, Italy.;Liver Unit, Internal Medicine, Department of Medicine (DAME), University School of Medicine of Udine, Piazzale S. M. Misericordia 1, 33100, Udine, Italy.;Liver Unit, Internal Medicine, Department of Medicine (DAME), University School of Medicine of Udine, Piazzale S. M. Misericordia 1, 33100, Udine, Italy.;Department of Laboratory Medicine, Institute of Pathological Anatomy, University School of Medicine of Udine, Udine, Italy.;Liver Unit, Internal Medicine, Department of Medicine (DAME), University School of Medicine of Udine, Piazzale S. M. Misericordia 1, 33100, Udine, Italy.;Liver Unit, Internal Medicine, Department of Medicine (DAME), University School of Medicine of Udine, Piazzale S. M. Misericordia 1, 33100, Udine, Italy. giorgio.soardo@asuiud.sanita.fvg.it.",
"authors": "Maier|Silvia|S|;Donnini|Debora|D|;De Luca|Laura|L|;Avellini|Claudio|C|;Sechi|Leonardo Alberto|LA|;Soardo|Giorgio|G|http://orcid.org/0000-0003-3181-5651",
"chemical_list": "D000998:Antiviral Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-01031-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Direct antiviral agents; Hepatitis C infection; Hepatocellular carcinoma metastasis; Orthotopic liver transplantation",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D019698:Hepatitis C, Chronic; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011183:Postoperative Complications; D012008:Recurrence",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "260-266",
"pmc": null,
"pmid": "31410743",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10966697;27288051;22047762;29102521;19524573;17446127;22424438;26494973;25755615;28867970;27296288;28544691;10518312;28052619;28408907;28070200;28130846;28480063;19058754;27084592;27392425;19790142;21975686;28388736;26584407;25709503",
"title": "Hepatocellular metastasis recurrence in liver transplant after treatment with direct antiviral agents.",
"title_normalized": "hepatocellular metastasis recurrence in liver transplant after treatment with direct antiviral agents"
} | [
{
"companynumb": "IT-ACCORD-182088",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHemorrhagic complications are quite common in the rare cases where thrombolysis is performed. Ischemic stroke in the aftermath of thrombolysis for a ST elevation myocardial infarction is a very rare and paradoxical complication. With these observations in mind we report two interesting cases of ischemic stroke which occurred after fibrinolytic therapy with tenecteplase for a ST elevation myocardial infarction.\n\n\nMETHODS\nThe first case was a 56-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 6 hours after chest pain onset. Thrombolysis with tenecteplase was performed and few minutes later an ischemic stroke occurred. The second patient was a 65-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 5 hours after chest pain onset. Thrombolysis was performed and 10 hours later an ischemic stroke occurred.\n\n\nCONCLUSIONS\nHemorrhagic stroke is not the only complication of thrombolysis, ischemic stroke can occur even if it is an extremely rare complication. The two cases on which we report shed light on the association between fibrinolytic therapy and ischemic stroke, the pathophysiology of which is not well understood.",
"affiliations": "Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco. Arous.salim@hotmail.fr.;Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco.;Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco.;Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco.;Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco.",
"authors": "Arous|Salim|S|;Haboub|Meryem|M|;El Ghali Benouna|Mohamed|M|;Bentaoune|Tarik|T|;Habbal|Rachida|R|",
"chemical_list": "D005343:Fibrinolytic Agents; D006493:Heparin; D000077144:Clopidogrel; D010959:Tissue Plasminogen Activator; D013988:Ticlopidine; D001241:Aspirin; D000077785:Tenecteplase",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1322-3",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 132210.1186/s13256-017-1322-3Case ReportIschemic stroke complicating thrombolytic therapy with tenecteplase for ST elevation myocardial infarction: two case reports Arous Salim Arous.salim@hotmail.fr Haboub Meryem hmeryem@gmail.com El Ghali Benouna Mohamed benounam@hotmail.fr Bentaoune Tarik bentarik@gmail.com Habbal Rachida hrachida@hotmail.fr Department of Cardiology, Ibn Rushd University Hospital, Casablanca, Morocco 11 6 2017 11 6 2017 2017 11 15412 3 2017 12 5 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHemorrhagic complications are quite common in the rare cases where thrombolysis is performed. Ischemic stroke in the aftermath of thrombolysis for a ST elevation myocardial infarction is a very rare and paradoxical complication. With these observations in mind we report two interesting cases of ischemic stroke which occurred after fibrinolytic therapy with tenecteplase for a ST elevation myocardial infarction.\n\nCase presentation\nThe first case was a 56-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 6 hours after chest pain onset. Thrombolysis with tenecteplase was performed and few minutes later an ischemic stroke occurred. The second patient was a 65-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 5 hours after chest pain onset. Thrombolysis was performed and 10 hours later an ischemic stroke occurred.\n\nConclusions\nHemorrhagic stroke is not the only complication of thrombolysis, ischemic stroke can occur even if it is an extremely rare complication. The two cases on which we report shed light on the association between fibrinolytic therapy and ischemic stroke, the pathophysiology of which is not well understood.\n\nKeywords\nIschemic strokeThrombolysisMyocardial infarctionissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nST elevation myocardial infarction (STEMI) is due to complete occlusion of the coronary artery. The gold standard therapy for STEMI is recanalization of the infarct-related coronary artery as soon as possible by pharmacological or mechanical means. The indication for this is STEMI presenting within 12 hours of symptom onset.\n\nPrimary percutaneous coronary intervention (PCI) is superior to thrombolytic therapy (TT), but there are many limitations to PCI such as the absence of a nearby angioplasty center. TT is therefore an effective treatment of choice in STEMI, as it is easy to perform anywhere and at any time [1].\n\nThe efficacy and safety of various thrombolytic agents have been well documented in large clinical trials. The most feared complication of TT is intracranial hemorrhage which is well documented in the literature. Ischemic stroke in the aftermath of TT for STEMI worsens the patient’s prognosis; it is a paradoxical, very rare complication, the pathophysiology of which is not well understood [2]. Hence, we report two interesting cases of ischemic stroke after TT for STEMI to shed light on the association between TT and ischemic stroke.\n\nCase presentation\nCase report 1\nA 56-year-old African man presented to our emergency department 6 hours after severe chest pain onset. He was a tobacco smoker, diabetes status unknown, neither hypertensive nor dyslipidemic, and had no history of stroke. He had no personal or family medical history, including heart disease or heart rhythm disorder, and was not under any treatment prior to diagnosis. He was from a low socio-economic level. An electrocardiogram (EKG) showed a sinus rhythm with ST-segment elevation in inferior and posterior leads (Fig. 1).Fig. 1 Electrocardiogram showing ST-segment elevation in inferior leads\n\n\n\n\nAt admission he was conscious, Glasgow Coma Scale (GCS) of 15/15, without motor deficit or sensory disorder; his chest pain was constrictive irradiating to his two upper limbs without syncope. Blood pressure (BP) on admission was 140/85 mmHg symmetrical, regular rhythm at 60 beats per minute (bpm), heart sounds clearly auscultated with no heart or carotid murmur, there was no murmur of mitral insufficiency or ventricular septal defect, no signs of heart failure including no crackles, and he was without edema of his lower limbs or turgor of his jugular veins leading to a right ventricular infarction. His peripheral pulses were perceived symmetrically. The rest of the examination was strictly normal. Acute inferior and posterior STEMI was diagnosed and intravenously administered TT using tenecteplase (intravenous bolus of 30 mg considering a weight of 54 kg) was performed with adjuvant antithrombotic medication (aspirin, clopidogrel, and enoxaparin).\n\nA few minutes later, he developed motor aphasia and right hemiplegia with altered level of consciousness: GCS of 12/15. The first cerebral computed tomography (CT) performed 1 hour later was normal and the second one performed 12 hours later showed a frontal, temporal, and parietal left ischemic stroke with a hemorrhagic infarct (Fig. 2). On an EKG, the ST-segment elevation regressed more than 50% at 60 minutes after TT. An echocardiographic examination (Vivid 6S) was performed following the therapy. It revealed a left ventricle ejection fraction (LVEF) at 50%, no mitral insufficiency, pulmonary artery pressure at 36 mmHg, no thrombus was detected in any cavity, no ventricular septal defect, and no pericardial effusion. An echo-Doppler of the supra-aortic trunks was not performed. The laboratory findings were as follows: troponin Ic, 18 ng/ml; normal liver function tests; glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) method at 85 ml/1.73 m2 body surface area (BSA) per minute; hemoglobin, 13.5 g/dl; platelets count, 500,000/mm3; plasmatic fibrinogen level, 2.49 g/l before TT and 5.89 g/l 12 hours after; white blood cells count (WBC), 15,000 mm3; and C-reactive protein (CRP), 72 mg/l. Antithrombotic medication was discontinued. His neurological condition worsened progressively and, after 1 week, he died.Fig. 2 Cerebral computed tomography showing frontal, temporal, and parietal left ischemic stroke\n\n\n\n\nCase report 2\nA 65-year-old African man presented to our emergency department 5 hours after severe chest pain onset. He is a tobacco smoker, diabetes status unknown, neither hypertensive nor dyslipidemic, and had no history of stroke. He had no personal or family medical history, including heart disease or heart rhythm disorder, and he was not under any treatment prior to diagnosis. He was from a low socio-economic level. An EKG showed a sinus rhythm with ST-segment elevation in inferior and posterior leads (Fig. 3). At admission he was conscious, GCS of 15/15, without motor deficit or sensory disorder; his chest pain was constrictive irradiating to his two upper limbs without syncope. BP on admission was at 190/120 mmHg symmetrical, pulse rate at 122 bpm, heart sounds clearly auscultated, no heart or carotid murmur, there was no murmur of mitral insufficiency or ventricular septal defect, no signs of heart failure including no crackles, and he was without edema of his lower limbs or turgor of his jugular veins leading to a right ventricular infarction. His peripheral pulses were perceived symmetrically. The rest of the examination was strictly normal. Acute inferior and posterior STEMI was diagnosed and intravenously administered TT using tenecteplase (intravenous bolus of 35 mg considering a weight of 65 kg) was performed after lowering BP at 150/90 mmHg, associated with aspirin 300 mg administered orally and clopidogrel 300 mg administered orally. It is important to note that the first dose of heparin was missed. Echocardiographic examination (Vivid 6S) was performed following the therapy. It revealed segmental wall motion abnormalities, LVEF at 50%, no mitral valve insufficiency, pulmonary artery pressure at 29 mmHg, and no thrombus or any mechanical complication was detected. One hour after TT, his chest pain and more than 50% of ST-segment elevation resolved with no hemorrhagic complications. The laboratory findings were as follows: troponin Ic, 9 ng/ml; normal liver function tests; serum creatinine level, 14.9 mg/l; estimating a GFR at 50.5 ml/1.73 m2 BSA per minute using MDRD; hemoglobin, 16.3 g/dL; hematocrit, 49.5%; platelets count, 281,000/mm3; plasmatic fibrinogen level, 7.4 g/l; WBC, 14,900/mm3; and CRP, 62 mg/l.Fig. 3 Electrocardiogram showing ST-segment elevation in inferior leads and a mirror aspect in V1 to V4\n\n\n\n\nTen hours later, he developed a left hemiparesis with motor aphasia without sensory disturbance and drowsiness: GCS of 14/15. The first cerebral CT performed 3 hours later was normal and the one performed 24 hours later showed right internal capsule ischemic stroke without hemorrhagic infarct (Fig. 4). An echo-Doppler of the supra-aortic trunks was normal. The case was discussed with neurologists and aspirin 75 mg administered orally once daily, clopidogrel 75 mg administered orally once daily, and unfractionated heparin, which was monitored by partial thromboplastin time (PTT), were continued. His neurological condition improved (level of consciousness and motor deficit). He was discharged after 12 days of hospitalization; physiotherapy and neurological follow-up were planned. One month after discharge, PCI using a bare-metal stent (BMS) was performed on a circumflex coronary artery lesion.Fig. 4 Cerebral computed tomography showing a right internal capsule ischemic stroke\n\n\n\n\nHe was followed-up regularly after discharge every 2 months. At 1 year of follow-up, clinically he no longer presents a deficit, he is without recurrence of chest pain, and the ischemic image at a cerebral control scan disappeared. No hemorrhagic complications were developed under dual antiplatelet therapies (DAPT). Clopidogrel was stopped after 6 months.\n\nDiscussion\nSTEMI, caused by acute occlusion of the infarct-related coronary artery, is an emergency condition. The primary therapy is restoration of full antegrade flow by either PCI or TT in patients presenting within 12 hours of symptom onset. Although primary PCI is superior to TT in patients with STEMI, there are many limitations in clinical practice. TT is therefore an effective treatment of choice in STEMI as it is easy to perform anywhere and at any time.\n\nAll thrombolytic agents share a common mechanism of activating plasminogen into plasmin, which in turn activates the fibrin degradation pathway. The efficacy and safety of various thrombolytic agents have been well documented in large clinical trials [2]. TT decreases mortality in patients with STEMI, but as experience with thrombolytic agents grows, the potential risk of serious side effects becomes more apparent. The most feared complication is bleeding (global incidence of bleeding is 10%), especially intracranial hemorrhage which occurs in 0.9% of patients treated with tissue plasminogen activator (tPA), and it is well documented [3, 4].\n\nBleeding after fibrinolytic treatment is due to the depletion of clotting factors and lysis of recently formed hemostatic plugs [5]. However, embolic cerebral infarction after TT is not well documented in the literature, which is the reason why we have reported our cases.\n\nBefore the era of TT, the incidence of stroke during a hospital stay after acute coronary syndrome (ACS) ranged from 0.7 to 2.2% with a mortality rate at 46%. Hachet and colleagues reported that typical cases occurred during the first week and 33% during the first 24 hours [6]. These rates can be confirmed by the observational studies of American and Swedish patient registries which show the results of representative patient populations. The evaluation of the American Nationwide Inpatient Sample revealed a rate of neurologic complications of 2% (ischemic stroke 1.5%, transient ischemic attack 0.3%, and hemorrhagic stroke 0.2%) [7]. Predictive factors of stroke after acute myocardial infarction (AMI) were: anterior or apical wall motion abnormalities, atrial arrhythmias, cardiogenic shock, and history of stroke. Most cases were attributed to cerebral embolization [8].\n\nIschemic stroke after TT for STEMI is paradoxical and rare. A multivariate analysis showed a significantly low risk after TT performed within 15 minutes and a low but not significant risk after primary PCI performed within 90 minutes of first medical contact. Despite the use of fibrinolytics and primary PCI, the incidence of left ventricular thrombus formation seems to be lower but remains substantial [9].\n\nThe Trial of ORG 10172 in Acute Stroke Treatment (TOAST trial) studied ischemic strokes during hospital stay at the acute phase of myocardial infarction: 60% was of cardioembolic origin and 36% were of undetermined pathogenesis [6].\n\nThe underlying pathophysiological processes of ischemic strokes after AMI are multifactorial. Ischemia itself induces a systemic procoagulant effect, facilitating cardiac thrombus formation and embolization. Furthermore, ischemia results in the release of inflammatory cytokines; this might trigger the destabilization and rupture of plaques in the cerebral circulation. Therefore, complex and unstable carotid plaques are common in patients with AMI (42% versus 8% in patients with stable angina) [10]. These processes explain the beneficial effect of a fast restoration of coronary flow with respect to the risk of ischemic strokes following AMI [11].\n\nCardioembolic strokes after AMI are mainly caused by atrial fibrillation and left ventricular thrombi [9]. Cardiac embolic ischemic stroke after fibrinolytic treatment for ACS with ST-segment elevation is rare. Some cases are reported in the literature, explained by a paroxysmal atrial fibrillation or by thrombophilia by protein C deficiency and mutation C677T in methylenetetrahydrofolate reductase (MTHFR) [2, 7].\n\nThere is also a procoagulant state of thrombolytic treatment which can explain the occurrence of a stroke after thrombolysis, hence the interest in systematically giving heparin, unfortunately that was not done with our second patient.\n\nLeft ventricle thrombi formation is mainly caused by an akinetic segment of the left ventricular myocardium which can fragment and migrate to the brain after thrombolysis. It is a common complication in large anterior and apical myocardial infarction with a low LVEF (less than 40%) and the thrombotic risk increases with decrease in LVEF. The thrombi usually occur within 2 weeks after AMI; a median of 5 days after the acute event. In the prethrombolytic era, ischemic stroke after STEMI was a common complication and the incidence of thrombus formation was reported to range from 20 to 55% in patients with an anterior STEMI [9].\n\nCrenshaw et al. showed a significant risk of ischemic stroke after AMI with atrial fibrillation treated with TT [11]. Another strong predictor of an increased stroke risk following AMI is the presence or new onset of atrial fibrillation. Data from the Framingham Study show that a myocardial infarction, or even ischemia, is a risk factor for new onset of atrial fibrillation [12]. Following stent implantation, patients with atrial fibrillation are at risk of both stroke and stent thrombosis and, therefore, have an indication for triple therapy [11].\n\nIn total, several mechanisms may explain the occurrence of an ischemic stroke in the course of a thrombolysis of a STEMI. In some cases it has been explained by the procoagulant effect of thrombolytics. Embolization of microthrombi formed at the left ventricle or from carotid plaques following thrombolysis has also been reported. Some cases were explained by a paroxysmal atrial fibrillation or by thrombophilia by protein C deficiency and mutation C677T in MTHFR.\n\nIn our two cases, patients were in sinus rhythm, the STEMI was inferior and posterior, LVEF was 40% or more, and no intracavitary thrombus was detected. The ischemic stroke could be explained by inflammatory reaction due to ischemia causing left ventricle microthrombi and it is presumed that TT induced lysis, fragmentation, and embolization of microthrombi in the cerebral circulation. Inflammatory reaction due to ischemia could also explain destabilization of carotid plaques. In addition, our second patient missed the first dose of heparin.\n\nConclusions\nHemorrhagic stroke is not the only complication of thrombolysis, ischemic stroke can occur even if it is an extremely rare complication. Those cases represent an extremely rare clinical condition on which we report to shed light on the association between fibrinolytic therapy and ischemic stroke.\n\nPatients receiving TT for the treatment of STEMI should receive immediate antithrombotic co-therapies, have constant neurological re-evaluation, and clinicians must be prepared to handle such complications in a timely manner.\n\nAdditional studies are needed to clarify the benefice of thrombolysis in high risk patients, especially the elderly or ones with a history of stroke.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors have no funding to declare.\n\nAvailability of data and materials\nThe published information is available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nSA participated in the design of the study, acquired data, performed a literature review, and drafted the manuscript. MH conceived the study, participated in its design and coordination, acquired data, and helped to draft and edit the manuscript. MEB participated in the design of the study and edited the manuscript. TB participated in the design of the study and edited the manuscript. RH acquired data, participated in the design of the study, and edited the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nThe need for ethics approval was waived.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Tarín-Vicente N Ischemic stroke after fibrinolytic therapy myocardial infarction in a patient with hypercoagulability Rev Esp Cardiol 2006 59 5 515 8 10.1157/13087906 16750151 \n2. Bostan M Cerebral embolism following thrombolytic therapy for acute myocardial infarction: the second reported case Cardiovasc J Afr 2010 21 3 155 7 20532455 \n3. Gore JM Sloan M Price TR Randall AMY Bovill E Collen D Forman S Knatterud GL Sopko G Terrin ML and the TIMI Investigators Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study: Thrombolysis in Myocardial Infarction, Phase II, Pilot and Clinical Trial Circulation 1991 83 448 59 10.1161/01.CIR.83.2.448 1899364 \n4. The international tPA/SK Mortality Trial study group In hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between tissue plasminogen activator or streptokinase with or without heparin Lancet 1990 336 71 5 10.1016/0140-6736(90)91590-7 1975322 \n5. Maggioni AP Franzosi MG Santoro E White H Van de Werf F Tognini G the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico II (GISSI-II) and the International Study Group The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment N Engl J Med 1992 327 1 6 10.1056/NEJM199207023270101 1598096 \n6. Hachet O Guenancia C Stamboul K Frequency and predictors of stroke after acute myocardial infarction: specific aspects of in-hospital and postdischarge events Stroke 2014 45 12 3514 20 10.1161/STROKEAHA.114.006707 25370585 \n7. Naderi N Masoomi H Mozaffar T Patient characteristics and comorbidities associated with cerebrovascular accident following acute myocardial infarction in the United States Int J Cardiol 2014 175 2 323 7 10.1016/j.ijcard.2014.05.024 24874908 \n8. Sloan MA Price TR Terrin ML Forman S Gore JM Chaitman BR Hodges M Mueller H Rogers WJ Knatterud GL Braunwald E Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction. The TIMI-II pilot and randomized clinical trial combined experience Stroke 1997 28 6 1107 14 10.1161/01.STR.28.6.1107 9183334 \n9. Shacham Y Leshem-Rubinow E Ben Assa E Frequency and correlates of early left ventricular thrombus formation following anterior wall myocardial infarction treated with primary percutaneous coronary intervention Am J Cardiol 2013 111 5 667 70 10.1016/j.amjcard.2012.11.016 23261006 \n10. Lombardo A Biasucci LM Lanza GA Inflammation as a possible link between coronary and carotid plaque instability Circulation 2004 190 25 3158 63 10.1161/01.CIR.0000130786.28008.56 \n11. Crenshaw BS Ward SR Granger CB Stebbins AL Topol EJ Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries J Am Coll Cardiol 1997 30 2 406 13 10.1016/S0735-1097(97)00194-0 9247512 \n12. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population based cohort. The Framingham Heart Study. JAMA. 1994;271(11):840–4.\n\n",
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"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Ischemic stroke; Myocardial infarction; Thrombolysis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D001241:Aspirin; D000077144:Clopidogrel; D004562:Electrocardiography; D005343:Fibrinolytic Agents; D006493:Heparin; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D000072657:ST Elevation Myocardial Infarction; D015607:Stents; D020521:Stroke; D000077785:Tenecteplase; D013988:Ticlopidine; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"title": "Ischemic stroke complicating thrombolytic therapy with tenecteplase for ST elevation myocardial infarction: two case reports.",
"title_normalized": "ischemic stroke complicating thrombolytic therapy with tenecteplase for st elevation myocardial infarction two case reports"
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"abstract": "BACKGROUND\nIntrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) has routinely been used to assess infants exposed to antidepressants in utero.\n\n\nOBJECTIVE\nThe purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero.\n\n\nMETHODS\nRetrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized.\n\n\nRESULTS\n220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%).\n\n\nCONCLUSIONS\nSevere abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described.",
"affiliations": "Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.;Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.;Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden.;Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.",
"authors": "Forsberg|Lisa|L|;Navér|Lars|L|;Gustafsson|Lars L|LL|;Wide|Katarina|K|",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors",
"country": "United States",
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"doi": "10.1371/journal.pone.0111327",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 25365553PONE-D-14-2211410.1371/journal.pone.0111327Research ArticleMedicine and Health SciencesMental Health and PsychiatryNeurologyDevelopmental and Pediatric NeurologyPediatricsNeonatologyPharmacologyClinical PharmacologyPsychopharmacologyWomen's HealthMaternal HealthPregnancyPregnancy ComplicationsObstetrics and GynecologyNeonatal Adaptation in Infants Prenatally Exposed to Antidepressants- Clinical Monitoring Using Neonatal Abstinence Score Antidepressants and Pregnancy- Neonatal AdaptationForsberg Lisa \n1\n\n2\n\n*\nNavér Lars \n1\n\n2\nGustafsson Lars L. \n3\nWide Katarina \n1\n\n2\n\n1 \nDepartment of Pediatrics, Karolinska University Hospital, Stockholm, Sweden\n\n2 \nDepartment of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden\n\n3 \nDepartment of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden\nFischer Gabriele Editor\nMedical University of Vienna, Austria\n* E-mail: lisa.forsberg.1@ki.seCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: LF LN LLG KW. Performed the experiments: LF LN KW. Analyzed the data: LF LN LLG KW. Contributed reagents/materials/analysis tools: LF KW LN. Wrote the paper: LF LN LLG KW.\n\n2014 3 11 2014 9 11 e11132726 5 2014 29 9 2014 © 2014 Forsberg et al2014Forsberg et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nIntrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) has routinely been used to assess infants exposed to antidepressants in utero.\n\nAim\nThe purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero.\n\nMethod\nRetrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized.\n\nResults\n220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%).\n\nConclusion\nSevere abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described.\n\nFunding provided by Swedish Research Council, grant number 2011-3440 www.vr.se to LLG, Swedish Research Council, grant number 2012-3466, www.vr.se to KW, The Mayflower Foundation, www.majblomman.se to KW LF and The Samariten Foundation, www.stiftelsensamariten.se to LF KW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityThe authors confirm that all data underlying the findings are fully available without restriction. The data cannot be made available in the manuscript, the supplemental files or in a public repository due to ethical restrictions from the Regional Ethical Review Board in Stockholm. Data files will be made available after completion of a supplementary application to the Regional Ethical Review Board in Stockholm. To request data, contact Lisa Forsberg (first author) and the Regional Ethical Review Board in Stockholm, phone number +46 8 524 870 00 or +468 524 800 00, www.epn.se.Data Availability\nThe authors confirm that all data underlying the findings are fully available without restriction. The data cannot be made available in the manuscript, the supplemental files or in a public repository due to ethical restrictions from the Regional Ethical Review Board in Stockholm. Data files will be made available after completion of a supplementary application to the Regional Ethical Review Board in Stockholm. To request data, contact Lisa Forsberg (first author) and the Regional Ethical Review Board in Stockholm, phone number +46 8 524 870 00 or +468 524 800 00, www.epn.se.\n==== Body\nBackground\nPsychiatric conditions are common during and after pregnancy. A large US study showed a prevalence of 13% for both mood and for anxiety disorders in pregnant or postpartum women [1]. Antidepressants are commonly used to treat major depressive disorders as well as other psychiatric conditions such as anxiety and obsessive compulsive disorders. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed group of antidepressants, also in pregnant women [2]. Serotonin norepinephrine reuptake inhibitors (SNRIs) are also used during pregnancy with similar effects on prenatally exposed children as SSRIs [3]. A population based register study showed that 3% of all pregnant women in Sweden used antidepressants, mainly SSRIs, three months prior to conception, whereas the numbers decreased during pregnancy, down to 1% in the third trimester [2]. In Denmark, there has been an increase in antidepressant use in pregnancy. In 1997, 0.2% of all pregnant women had at some point during pregnancy been using antidepressants, in 2010 this figure had increased to 3.2% [4].\n\nUse of paroxetine during early pregnancy has been linked to an increased risk of heart malformations, OR 1.66 (95% CI 1.09 to 2.53) and hypospadias, OR 2.45 (95% CI 1.12 to 4.64) [5]. A Canadian study found a significantly increased risk of heart malformations only in infants exposed to paroxetine daily doses higher than 25 mg [6]. A neonatal maladaptation syndrome in infants exposed to SSRIs during late pregnancy is well known. It includes symptoms such as jitteriness, feeding problems, respiratory distress, hypoglycemia [5], [7], [8]. The relative risk of persistent pulmonary hypertension, a potentially life threatening condition, is increased in infants prenatally exposed to SSRI, from 1.2 per 1000 live births in unexposed infants to 3 per 1000 live births in SSRI exposed neonates [9]. Maternal illness (depression, anxiety) may also contribute to milder neonatal symptoms usually resolving within a week [10]. The mode of action for neonatal maladaptation after SSRI/SNRI exposure is largely unknown. ‘Abstinence’ due to the discontinued distribution of the pharmacological substance at delivery as well as serotonergic overstimulation has been suggested [8].\n\nFinnegan score, or Neonatal Abstinence Score sheet (NAS) was originally developed to diagnose abstinence in infants prenatally exposed to opioids [11], but has also been used to assess neonatal symptoms in SSRI exposed infants [12].\n\nAs stated above, antidepressants during pregnancy is a common clinical problem, of growing significance. Conducting clinical research in the field of perinatal pharmacological exposure is complicated due to many ethical considerations and an abundance of potential confounders. This study was initiated to shed light on the occurrence of neonatal abstinence/maladaptation after SSRI/SNRI exposure in utero and its prevalence, timing, severity and clinical features of this known but inadequately described condition.\n\nMethods\nThe study design was a retrospective cohort study. The study patients were identified in the integrated electronic health record used in the delivery and prenatal care units as well as for outpatient maternal visits (ObstetrixR 2.12.01.100, Siemens AG, Munich, Germany). Patients with diagnostic codes for psychiatric illness during pregnancy and exposure to fetus of pharmacological substances were selected as the study population.\n\nWomen fulfilling these criteria and who had been giving birth at the Karolinska University Hospital Huddinge between 1 January, 2007 and 30 June, 2009 were included. Patients with reported substance abuse (alcohol or drugs) or use of certain kinds of neurotropic medication (antiepileptic drugs, lithium, opioids) were excluded. Information about substance abuse was reported in the patient records but not systematically confirmed through urine toxicology or breathalyser. Patients where substantial parts of the prenatal care records could not be retrieved were also excluded.\n\nInformation regarding social situation, prenatal medication (antidepressants and other pharmacological substances), health status and pregnancy related complications were retrieved from the prenatal part of the electronic health record (ObstetrixR). The information on use of antidepressants, bensodiazepines and other pharmacological substances was based on self-report or stated by the prescribing physician in the patient records. ObstetrixR was also used to extract clinical information about the delivery, infant health including health problems in the maternal ward and admission to the neonatal ward. During the study period, all infants where the mother had reported antidepressant use during late pregnancy were routinely observed at the maternal ward for at least 72 hours and modified Finnegan score used regularly to detect signs of abstinence. The assessments were extracted from the electronic health record system and analyzed.\n\nA modified Finnegan score or Neonatal Abstinence Score (NAS) in Swedish was used in this study [13]. A version re-translated into English from Swedish is showed in Fig. 1. The assessment includes four categories: central nervous system (CNS), respiratory, gastrointestinal and ‘other symptoms’. The maximum score for each scoring occasion is 40 points, of which 21 are related to CNS items. Neonatal abstinence was in this study classified as either mild (score 4 and above on at least two occasions) or severe (score 8 and above on at least two occasions). A similar classification has been used previously [12].\n\n10.1371/journal.pone.0111327.g001Figure 1 Neonatal Abstinance Score.\nModified from Finnegan to Swedish, (Sarman 2000) here re-translated.\n\nPopulation data regarding rates of neonatal admission, rates of smoking in early pregnancy, caesarian section and maternal age with regard to the Stockholm county area and Karolinska University Hospital Huddinge were obtained from the Swedish Neonatal Quality Register (SNQ) and from the statistical unit at National Swedish Board of Health and Welfare. These data were obtained as processed data [14].\n\nStatistical analyses were performed with StatisticaR 64, version 12 (StatSoft Scandinavia AB, Uppsala, Sweden). In the comparison between groups, chi square Pearson's test, ANOVA (Analysis of Variance) or Kruskal Wallis was used. Ordinal regression was used in the comparison of different levels of abstinence. Logistic regression or linear regression was used in the multiple regression models.\n\nThe study was a retrospective evaluation, based on patient records and conducted several years after the delivery of the infants. Neither written nor verbal informed consent was obtained. Data from patient records were extracted by one researcher and only relevant parts of the records were entered. The data was recorded in a data file with the confidentiality that is applied to patient records. Every individual was given a code number to strengthen the protection of confidentiality. No individual is possible to identify from the report. The study design was approved by the Regional Ethical Review Board in Stockholm (no. 2010/686-31).\n\nResults\nDuring the study period of 2.5 years between January 1, 2007 and June 30, 2009, 365 patients with diagnostic code for pharmacological exposure to fetus and psychiatric illness during pregnancy delivered at Karolinska University Hospital Huddinge. Use of SSRI/SNRI was confirmed in 277 patients. Thirty-four were excluded due to confirmed (or strongly suspected) substance abuse, opioid use or use of other psychotropic medication such as lithium or antipsychotics. Twenty patients could not be included due to missing data. One pair of twins was excluded. Two hundred and twenty patients remained; 54 gave birth in 2007, 103 in 2008 and 63 during the first six months of 2009. During 2007, 2008 and 2009 a total of 13755 infants were born at Karolinska University Hospital Huddinge [14].\n\n\nTable 1 describes the women in the cohort with regard to social factors, health status and reported medication during pregnancy (antidepressants and other); divided by reported third trimester antidepressant use. The most common exposures were citalopram, sertraline and fluoxetine (Table 1). The remaining patients, in all 33 (15%), were exposed to escitalopram (13 patients), venlafaxine (11 patients), paroxetine (8 patients) and duloxetine (one patient). Depression and anxiety disorders were the most common reasons for antidepressant use.\n\n10.1371/journal.pone.0111327.t001Table 1 Characteristics of study population, women with antidepressant treatment and delivery at Karolinska University Hospital Huddinge Jan 2007 to June 2009.\n\tAll antidepressants\tCitalopram\tSertraline\tFluoxetine\tOther antidepressants**\n\t\n\tn = 220\tn = 77 (35%)\tn = 76 (35%)\tn = 34 (15%)\tn = 33 (15%)\t\n\nAge of mother at delivery mean (years)\t31.2\t31.2\t32.1\t29.4\t31.0\t\n\nMaternal psychiatric diagnosis\n≠ (n)\t\nDepression\t168\t59\t58\t29\t22\t\nAnxiety disorder\t80\t29\t27\t8\t16\t\nOther psychiatric diagnoses≠≠\n\t34\t7\t12\t10\t5\t\n\nTobacco in early pregnancy\n* (n [%])\t\nNo smoking\t189 (86%)\t69 (90%)\t62 (82%)\t29 (85%)\t29 (88%)\t\n<10 cigarettes per day\t25 (11%)\t7 (9%)\t11 (14%)\t4 (12%)\t3 (9%)\t\n>10 cigarettes per day\t4 (2%)\t1 (1%)\t2 (3%)\t1 (3%)\t\t\nSnuff\t2 (1%)\t\t1 (1%)\t\t1 (3%)\t\n\nEmployment status\n* (n [%])\t\nFull time employed\t87 (40%)\t32 (42%)\t33 (43%)\t9 (26%)\t13 (39%)\t\nPart time employed\t54 (25%)\t19 (25%)\t18 (24%)\t5 (15%)\t12 (36%)\t\nUnemployed\t72 (33%)\t23 (30%)\t23 (30%)\t18 (53%)\t8 (24%)\t\nMissing data\t7 (3%)\t3 (4%)\t2 (3%)\t2 (6%)\t\t\n\nBody mass index\n* mean (kg/m2)\t24.4\t24.0\t24.7\t24.9\t24.1\t\n\nOther illnesses\n* (n [%])\t106 (48%)\t33 (43%)\t42 (55%)\t12 (35%)\t19 (58%)\t\n\nAntidepressant dose in third trimester\n*** median (range) (mg)\tNA\t20 (5–80)\t50 (5–200)\t30 (10–80)\tNA\t\n\nUse of benzodiazepine during pregnancy (n [%])\t14 (6%)\t4 (5%)\t5 (7%)\t3 (9%)\t2 (6%)\t\n\nUse of other medications during pregnancy (n [%])\t136 (62%)\t43 (56%)\t44 (58%)\t27 (79%)\t22 (67%)\t\n\nMode of delivery (n [%])\t\nVaginal delivery\t155 (70%)\t57 (74%)\t48 (63%)\t25 (74%)\t25 (76%)\t\nCesarean section (planned)\t24 (11%)\t7 (9%)\t11 (14%)\t2 (6%)\t4 (12%)\t\nCesarian section (acute)\t20 (9%)\t5 (6%)\t9 (12%)\t4 (12%)\t2 (6%)\t\nVacuum extraction\t21 (10%)\t8 (10%)\t8 (11%)\t3 (9%)\t2 (6%)\t\n≠ one patient can have more than one diagnosis.\n\n≠≠ other psychiatric diagnoses, all antidepressants (n): Phobia (4), Post-traumatic stress disorder (4), Eating disorder (9), Personality disorder (6), Obsessive compulsive disorder (7), Bipolar disorder type II (1), Attention deficit hyperactivity disorder (3).\n\n *stated by mother at interview with midwife in prenatal care center, gestational week 10–14.\n\n **other antidepressants (n = 33): escitalopram (13 patients), venlafaxine (11), paroxetine (8) and duloxetine (1).\n\n ***Highest dose in maternal care records during third trimester.\n\n NA = not applicable.\n\nCigarette smoking in early pregnancy in the cohort was 13% (for all 2.5 years) as compared to 5.4% in 2007, 4.9% in 2008 and 4.7% in 2009 for women in early pregnancy in the whole Stockholm area. BMI was higher in the cohort, 24.4 kg/m2, compared to all women who gave birth in the Stockholm area 2007 (23.9), 2008 (23.9) and 2009 (23.8).\n\nA total of 48% of the women had ‘other illnesses’ documented in the prenatal care records. Most of these illnesses were mild and manageable, such as musculoskeletal problems, asthma, migraine, thyroid diseases or gastrointestinal reflux disease. Some were potentially serious such as obesity or chronic hepatitis. Eleven patients had more severe conditions such as diabetes mellitus, inflammatory bowel disease, serious or potentially serious pulmonary, rheumatic or neurological diseases.\n\nBirth weight and head circumference did not differ between the four different exposure groups (Table 2). Linear regression adjusting for maternal age, maternal smoking in early pregnancy, gestational age and infant sex showed no statistical significance regarding birth weight (p = 0.75). A model adjusting for only maternal smoking did not reach statistical significance. For head circumference the corresponding result was p = 0.56. A model adjusting for maternal smoking only did not show any statistically significant differences between the four antidepressant exposure groups. Prematurity (gestational age of 36 weeks and 6 days or less) was seen in 13% of the infants exposed to citalopram (Table 2). In a logistic regression model adjusting for maternal age, maternal tobacco use in early pregnancy and infant sex there were no statistically significant differences regarding prematurity between citalopram exposed infants (13%) and infants exposed to sertraline (7%, p = 0.85), fluoxetine (9%, p = 0.67) or other antidepressants (3%, p = 0.30).\n\n10.1371/journal.pone.0111327.t002Table 2 Neonatal characteristics of infants exposed to antidepressants in utero, born 1 Jan 2007 to 30 June 2009 at Karolinska University Hospital.\n\tAll antidepressants\tCitalopram\tSertraline\tFluoxetine\tOther antidepressants**\n\t\n\tn = 220\tn = 77\tn = 76\tn = 34\tn = 33\t\n\nSex (male:female) (n[%])\t106∶114 [48∶52]\t38∶39 [49∶51]\t36∶40 [47∶53]\t16∶18 [47∶53]\t16∶17 [48∶52]\t\n\nGestational age (weeks)\t\nmean [95% CI]\t38.5 [38.3 to 38.7]\t38.2 [37.8 to 38.5]\t38.8 [38.4 to 39.1]\t38.6 [38.1 to 39.1]\t38.5 [38.0 to 39.1]\t\nrange\t31–42\t31–41\t32–41\t35–42\t34–42\t\n\nPrematurity (n [%]) *\n\t19 [9]\n\t10 [13]\n\t5 [7]\n\t3 [9]\n\t1 [3]\n\t\n\nBirth weight (gram)\t\nmean [95% CI]\t3386 [3314 to 3458]\t3302 [3177 to 3425]\t3476 [3352 to 3600]\t3385 [3217 to 3553]\t3377 [3167 to 3588]\t\nrange\t1790–5015\t1790–4315\t1905–5015\t2110–4670\t2305–4615\t\n\nHead circumference (cm)\t\nn\t217\t75\t75\t34\t33\t\nmean [95% CI]\t34.3 [34.1 to 34.5]\t34.0 [33.6 to 34.4]\t34.4 [34.1 to 34.8]\t34.3 [33.7 to 34.8]\t34.5 [33.9 to 35.1]\t\nrange\t28–38\t28–37.5\t31–38\t30–37\t31–37.5\t\n\nHypoglycemia (n [%])\t42 [19]\n†\n\t8 [11]\n\t15 [20]\n\t12 [35]\t7 [21]\n\t\n\nRespiratory diagnosis (n [%])\t14 [6]\n\t5 [6]\n\t5 [7]\n\t2 [6]\n\t2 [6]\n\t\n\nJaundice (n [%])\t10 [5]\n\t5 [6]\n\t3 [4]\n\t1 [3]\n\t1 [3]\n\t\n\nNeonatal care (n [%])\t29 [13]\n\t10 [13]\n\t9 [12]\n\t6 [18]\n\t4 [12]\n\t\n *gestational age <37+0.\n\n **other antidepressants (n = 33): escitalopram (13 patients), venlafaxine (11), paroxetine (8) and duloxetine (1).\n\n† p 0.02, statistical test (logistic regression, adjusting for gestational age, maternal tobacco use, infant sex and 5 min Apgar).\n\nHypoglycemia in the neonate was defined as a blood glucose level <2.6 mmol/L. Hypoglycemia was diagnosed in 42 (19%) of all study infants. A logistic regression model (adjusting for 5 min Apgar, gestational age, tobacco use in early pregnancy and infant sex) showed significantly more infants with at least one hypoglycemic episode in the fluoxetine group, 12 (35%), compared to 8 (10%) in the citalopram group, p = 0.01. There were no significant differences between citalopram exposed infants and infants exposed to sertraline (p = 0.74) or other antidepressants (p = 0.70). A model adjusting for only 5 min Apgar and gestational age did not add further information.\n\nThe blood glucose values of all hypoglycemic infants (n = 42) ranged from 1.0 to 2.5 mmol/L (mean 2.0 mmol/L). In hypoglycemic infants exposed to citalopram (n = 8) the mean blood glucose was 2.0 (range 1.4 to 2.3). These numbers for hypoglycemic infants exposed to sertraline, fluoxetine and other antidepressants were 1.9 (range 1.0 to 2.5), 1.9 (range 1.0 to 2.5) and 2.1 (range 1.1 to 2.5) respectively. There were no significant differences between the groups, p = 0.6 (Kruskal Wallis).\n\nRespiratory disorders included ‘respiratory distress syndrome of newborn’, ‘transient tachypnea of newborn’, ‘other respiratory distress of newborn’, pneumothorax, persistent fetal circulation and ‘condition originating in the perinatal period’, the latter an apneoic event. There were 14 cases (6.3%) of respiratory disorders and 4 of them were in prematurely born infants. No significant correlation was seen between occurrence of respiratory disorders and type of antidepressant exposure in third trimester, in logistic regression adjusting for 5 min Apgar score and gestational age (in weeks), p = 1.0.\n\nThere were five children with Apgar score <7 at five minutes of age.\n\nJaundice was diagnosed in 10 children (4 born prematurely). There were no significant differences between groups for antidepressant exposure, in a logistic regression model adjusting for 5 min Apgar and gestational age, p = 1.0.\n\nOne hundred and fifty-eight infants (71%), received the diagnostic code Z001A ‘healthy infant born in hospital’.\n\nTwenty-nine (13%) of the infants exposed to antidepressants were admitted to the neonatal ward. During 2007, 2008 and 2009, 13755 infants were born at Karolinska University Hospital Huddinge [14] and 1418 (10.3%) of them admitted to the neonatal ward (data from Swedish Neonatal Quality Register). A univariate analysis showed no statistical difference between exposed and unexposed infants (born at Karolinska University Huddinge) regarding probability for neonatal admission (p = 0.16). Multivariate analysis (logistic regression adjusting for 5 min Apgar and gestational age) did not reveal any differences in admittance rates between the four exposure groups (p = 0.67).\n\nNo specific treatment for neonatal maladaptation syndrome was performed. The patients were treated with supportive care. Respiratory disorders were treated with CPAP (continuous positive airway pressure) if needed (8 cases) and hypoglycemia with intensified oral feeding, in some instances with i.v glucose, depending on the severity of the condition.\n\nA total of 205 infants (93%) were scored with Neonatal Abstinence Score sheet (table 3). The mean time at ‘peak score’ i e highest recorded score in patients who had a score of four or higher at any time, was for infants exposed to citalopram 31.6 hours (range 2–90; SD 21.4), for sertraline exposure 37.4 (1–84; 21.7), fluoxetine exposure 37.1 (4–74; 21.3) and other antidepressants exposure 22.1 hours (3–64; 17.6). There were no statistically significant differences between the groups (Kruskal Wallis, p = 0.07).\n\n10.1371/journal.pone.0111327.t003Table 3 Analyses of Neonatal Abstinence Score in infants exposed to antidepressants in utero, born at Karolinska University Hospital Huddinge 1 Jan 2007 to 30 June 2009.\n\tAll antidepressants\tcitalopram\tsertraline\tfluoxetine\tOther antidepressants≠\n\tp\t\n\nScoring performed (n[%])\t205 [93%]\t71 [92%]\t71 [93%]\t33 [97%]\t30 [91%]\t0.5†\n\t\n\nNumber of scoring occasions\n\t\t\t\t\t\t\t\n(mean [SD] [range])\t8.4 [3.0] [2–27]\t8.5 [2.7] [3]–[18]\n\t8.4 [2.9] [2]–[20]\n\t8.4 [4.4] [2–27]\t8.3 [2.2] [5]–[13]\n\t0.66††\n\t\n\nNeonatal abstinence (n[%])\t\t\t\t\t\t\t\n\nNo abstinence\n\t152 [74%]\t51 [72%]\t53 [75%]\t24 [73%]\t24 [80%]\t\t\n\nMild abstinence\n*\n\t46 [22%]\t18 [25%]\t16 [23%]\t7 [21%]\t5 [17%]\t\t\n\nSevere abstinence\n**\n\t7 [3%]\t2 [3%]\t2 [3%]\t2 [6%]\t1 [3%]\t0.85***\n\t\n *two or more scorings of 4–7.\n\n **two or more scorings of 8 or above.\n\n ***Multiple ordinal regression, adjusted for infant sex and 5 min Apgar.\n\n† Chi square test.\n\n†† Kruskal Wallis.\n\n≠ other antidepressants (n = 33): escitalopram (13 patients), venlafaxine (11), paroxetine (8) and duloxetine (1).\n\nCNS symptoms contributed with on average 67% of the points in the group with severe abstinence (two or more scores of eight or higher) and 58% in the group with mild abstinence (two or more scores of four or higher). Infants exposed to citalopram had mild abstinence in 18 cases (25%), severe abstinence in two cases. Comparing citalopram to sertraline exposure in ordinal regression, adjusting for 5 min Apgar and infant sex, infants exposed to sertraline had an odds ratio of 1.08 (95% confidence interval, 0.64 to 1.82). Odds ratio for fluoxetine compared to citalopram was 0.86 (95% CI, 0.45 to 1.63) and for other antidepressants compared to citalopram 1.3 (95% CI, 0.61 to 2.61). There were no significant differences in the occurrence of mild or severe abstinence between the different types of antidepressant exposure, adjusting for 5 min Apgar and infant sex, p = 0.85.\n\nThere were no significant differences in mean maternal SSRI dose in third trimester (analysis made for citalopram [p = 0.20], sertraline [p = 0.83] and fluoxetine [p = 0.18]) between infants with or without abstinence (Mann Whitney U test).\n\nTwenty-nine infants in the study were admitted to the neonatal ward. Twenty four percent of them were not scored with NAS compared to 4% of the infants who remained in the maternity ward (p = 0.0007).\n\nDiscussion\nThis study shows that a majority of all infants born to mothers with SSRI or SNRI treatment during pregnancy are healthy in the neonatal period. Only 3% developed a severe abstinence syndrome and 22% signs of mild abstinence, the symptoms mainly arising from the central nervous system. Our results are in accordance with other studies with similar or slightly higher prevalence of the neonatal abstinence/maladaptation syndrome in infants with intrauterine SSRI/SNRI exposure. A study that used Finnegan score and similar definitions of severe and mild neonatal maladaptation syndrome found mild or severe neonatal maladaptation syndrome in 18/60 (30%) infants exposed to SSRI, compared to 0/60 control infants [12]. A slightly different definition of severe maladaptation (NAS score >12 or 3 scores >8) reported a prevalence of 4% in infants exposed to SSRI and 9% in infants exposed to venlafaxine [15]. Oberlander et al described symptoms of transient poor neonatal adaptation in 30% of a group of infants exposed to SSRI with or without the addition of clonazepam [16]. The reasons behind the differences in prevalence may be found in the different definitions of neonatal maladaptation syndrome as well as differences in study population (maternal age, socioeconomic status, health care, concomitant pharmacological treatment, use of tobacco and alcohol).\n\nHypoglycemia was common, 19% of all infants had blood glucose of 2.6 mmol/L or lower. Most of them were treated with intensified oral feeding. Other studies have found an association between prenatal antidepressant exposure and hypoglycemia [7]. The etiology behind this may be increased demands of energy in babies with abstinence. The prevalence reported in other studies have been lower, 1.4% in a register based cohort study [17] or 3/60 exposed infants in an Israeli cohort [12]. These large differences between studies may be explained by different definitions of hypoglycemia (the ICD-10 diagnosis of neonatal hypoglycemia, P70.4, requires blood glucose 2.2 mmol/L or lower) as well as differences in study protocols or in clinical practice. Hypoglycemia is also fairly common in all infants. In a clinical study of healthy term and preterm infants, 12% of the term and 14% of the preterm infants had a blood glucose of below 2.6 mmol/L during the first week of life [18]. In observational studies such as this one, the high rates of hypoglycemia may also be due to the fact that jitteriness and tremor can be perceived as symptoms of hypoglycemia leading to the measurement of blood glucose, increasing the chance of diagnosing a low blood glucose value. Hypoglycemia in infants is however a potentially serious condition [19], [20] and needs to be further investigated, preferably in a randomized controlled study. Until then, screening of blood glucose in neonates prenatally exposed to antidepressants should be considered.\n\nThe mothers in this study had a more unfavorable health status than the average pregnant Stockholm County population with regard to higher proportion of smokers and higher BMI. This may also affect neonatal outcome. The catchment area of Karolinska University Hospital Huddinge includes many socioeconomically constrained areas, often associated with higher BMI and a higher proportion of smokers. Any comparison between this catchment area and the rest of Stockholm County must be done with caution. Studies on infants to mothers with opioid use during pregnancy have shown increased risk of neonatal abstinence as well as other negative neonatal outcomes in opioid exposed infants where there was a concomitant heavy cigarette consumption [21]. Smoking cessation and control of weight gain during pregnancy may be an important method in this patient group to improve infant (and maternal) health.\n\nSeveral other studies report a high incidence of respiratory symptoms in infants exposed to SSRIs [5], [22]. However, some experts argue that the increased risk of neonatal complications that have been attributed to SSRI exposure may be due to confounding factors [23]. Fourteen neonates in this study had a respiratory diagnosis but the study design did not allow a comparison to an unexposed population.\n\nDifferent antidepressants have different pharmacokinetic properties. This may, in theory, influence the timing of symptoms of abstinence or serotonergic overstimulation in exposed neonates. Time to peak value (NAS) was therefore analyzed but failed to show any significant differences between the groups. Individual factors such as metabolic and transporter capacity of SSRI/SNRI in mother and child as well as placenta may be of greater influence on the occurrence of maladaptation and timing of symptoms [15], [24]–[26]. Time to peak value ranged between 2 and 90 hours suggesting that infants exposed to antidepressants may have a relatively late onset of peak abstinence symptoms. With today's extremely short duration of hospital stay for newborns, the symptoms may even occur after discharge from hospital. Karolinska University Hospital Huddinge, as well as several other hospitals, has abandoned the policy of advising parents of infants prenatally exposed to antidepressants to stay at least 72 hours. In uneventful deliveries, the mother and infant usually leave the maternity ward within 48 hours.\n\nSeven percent of the infants in the study were not subject to abstinence scoring. This may be due to the fact that the midwife nurse was not aware of the guidelines, that the infant was perceived to be healthy or that the scoring sheet was not properly stored. Also, NAS is often used as a screening tool and may therefore be considered unnecessary in sick infants in the neonatal ward who are subjected to more sophisticated surveillance methods. This may explain why scoring was not performed in a larger proportion of the infants admitted to the neonatal ward compared to the maternity care units.\n\nThe causal relationship between SSRI or SNRI exposure and high scoring values in the NAS is of course not established in each infant included in this study. Other illnesses or prenatal risk factors, unrelated to pharmacological exposure or maternal illness, may contribute. This study could not investigate an increased risk of neonatal symptoms in infants prenatally exposed to antidepressants compared to unexposed ones.\n\nIt can be argued that we recruited a too small study population. There may have been differences between the exposure groups had they been larger. The retrospective design of the study and the changed policy of the hospital (Neonatal Abstinence Score and increased surveillance of all infants prenatally exposed to SSRIs were abandoned in July 2009) made it impossible to perform this study on a larger cohort. The retrospective design is of course an important limitation to this study. A prospective design would have allowed us to for example confirm antidepressant use and exposure in mother and infant.\n\nMonitoring neonates with prenatal exposure to drugs and abuse substances is a delicate task. There is a risk that health care professionals are being too interventional, introducing unnecessary concern regarding the infant's health. There is also a risk, with antidepressants becoming increasingly common in the pregnant population- and considered ‘safe’- that knowledge about potentially serious complications is lost. A modified Neonatal Abstinence Score could be useful in detecting abstinence/maladaptation in this group. The CNS and respiratory categories are probably more useful than the gastrointestinal category. Most important is however knowledge among care givers regarding the possible symptoms that can arise after prenatal exposure to antidepressants.\n\nConclusions\nSevere abstinence in a cohort of infants exposed to SSRI/SNRI in late pregnancy was rare since it occurred in only 3% of the cases. Neonatal hypoglycemia was observed in 19% of the infants which is higher than previously reported. Admission to the neonatal ward was seen in 13% of the infants and did not differ significantly from the admittance rate in other infants born in the same hospital during the studied period.\n==== Refs\nReferences\n1 \nVesga-Lopez O , Blanco C , Keyes K , Olfson M , Grant BF , et al (2008 ) Psychiatric disorders in pregnant and postpartum women in the United States . Arch Gen Psychiatry \n65 : 805 –815 .18606953 \n2 \nStephansson O , Granath F , Svensson T , Haglund B , Ekbom A , et al (2011 ) Drug use during pregnancy in Sweden - assessed by the Prescribed Drug Register and the Medical Birth Register . Clin Epidemiol \n3 : 43 –50 .21386973 \n3 \nLennestal R , Kallen B (2007 ) Delivery outcome in relation to maternal use of some recently introduced antidepressants . 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J Pediatr \n134 : 492 –498 .10190926 \n21 \nWinklbaur B , Baewert A , Jagsch R , Rohrmeister K , Metz V , et al (2009 ) Association between prenatal tobacco exposure and outcome of neonates born to opioid-maintained mothers. Implications for treatment . Eur Addict Res \n15 : 150 –156 .19420947 \n22 \nLeibovitch L , Rymer-Haskel N , Schushan-Eisen I , Kuint J , Strauss T , et al (2013 ) Short-Term Neonatal Outcome among Term Infants after in utero Exposure to Serotonin Reuptake Inhibitors . Neonatology \n104 : 65 –70 .23711579 \n23 \nWarburton W , Hertzman C , Oberlander TF (2010 ) A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health . Acta Psychiatr Scand \n121 : 471 –479 .19878137 \n24 \nHilli J , Heikkinen T , Rontu R , Lehtimaki T , Kishida I , et al (2009 ) MAO-A and COMT genotypes as possible regulators of perinatal serotonergic symptoms after in utero exposure to SSRIs . Eur Neuropsychopharmacol \n19 : 363 –370 .19223155 \n25 \nOberlander TF , Bonaguro RJ , Misri S , Papsdorf M , Ross CJ , et al (2008 ) Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications . Mol Psychiatry \n13 : 65 –73 .17519929 \n26 \nTer Horst PG , Jansman FG , van Lingen RA , Smit JP , de Jong-van den Berg LT , et al (2008 ) Pharmacological aspects of neonatal antidepressant withdrawal . Obstet Gynecol Surv \n63 : 267 –279 .18348740\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "9(11)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000220:Adaptation, Biological; D000328:Adult; D000928:Antidepressive Agents; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D012307:Risk Factors; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e111327",
"pmc": null,
"pmid": "25365553",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15066868;23711579;1163358;16461873;18606953;15003078;15633850;23638179;21386973;22240235;17187388;15900008;18348740;19452377;19223155;1586171;12860776;17519929;19878137;19420947;23086597;20047705;10190926;18004128;10850047",
"title": "Neonatal adaptation in infants prenatally exposed to antidepressants--clinical monitoring using Neonatal Abstinence Score.",
"title_normalized": "neonatal adaptation in infants prenatally exposed to antidepressants clinical monitoring using neonatal abstinence score"
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"activesubstancename": "SERTRALINE HYDROCHLORIDE"
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"abstract": "The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations.\n\n\n\nTS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms.\n\n\n\nPatients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients' electrophysiologists.\n\n\n\nSeventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia.\n\n\n\nThis study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.",
"affiliations": "Department of Pediatrics, Division of Pediatric Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah.;Department of Cardiovascular Diseases, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota; Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.;Department of Pediatrics, Division of Pediatric Cardiology, Naval Medical Center San Diego, San Diego, California.;Department of Pediatrics, Division of Pediatric Cardiology, Royal Children's Hospital, MCRI, and University of Melbourne, Melbourne, Australia.;Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah.;Department of Pediatrics, Division of Pediatric Cardiology, Rady Children's Hospital/UC San Diego, San Diego, California.;Department of Medicine, Division of Pediatric Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Medicine, Division of Pediatric Cardiology, Academic Medical Center, Amsterdam, the Netherlands.;Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.;Cardiology Care for Children, Lancaster, Pennsylvania.;Department of Pediatrics, Division of Pediatric Cardiology, Starship Children's Hospital, Auckland, New Zealand.;University of Louisville, Louisville, Kentucky.;Pediatric and Adult Congenital Cardiology, Kapi'olani Medical Specialists, Honolulu, Hawaii.;Department of Cardiovascular Diseases, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota; Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.;Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address: shahm@email.chop.edu.",
"authors": "Dufendach|Keith A|KA|;Timothy|Katherine|K|;Ackerman|Michael J|MJ|;Blevins|Benjamin|B|;Pflaumer|Andreas|A|;Etheridge|Susan|S|;Perry|James|J|;Blom|Nico A|NA|;Temple|Joel|J|;Chowdhury|Devyani|D|;Skinner|Jonathan R|JR|;Johnsrude|Christopher|C|;Bratincsak|Andras|A|;Bos|J Martijn|JM|;Shah|Maully|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacep.2017.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2405-500X",
"issue": "4(4)",
"journal": "JACC. Clinical electrophysiology",
"keywords": "T-wave alternans; Timothy syndrome; hypoglycemia; sudden cardiac death; syndactyly; ventricular fibrillation",
"medline_ta": "JACC Clin Electrophysiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D001321:Autistic Disorder; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D007231:Infant, Newborn; D008133:Long QT Syndrome; D008297:Male; D012189:Retrospective Studies; D013576:Syndactyly; D014693:Ventricular Fibrillation; D055815:Young Adult",
"nlm_unique_id": "101656995",
"other_id": null,
"pages": "459-466",
"pmc": null,
"pmid": "30067485",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter International Study of a Rare Disorder.",
"title_normalized": "clinical outcomes and modes of death in timothy syndrome a multicenter international study of a rare disorder"
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"abstract": "Maintaining mechanical circulatory support (MCS) device patients in a specified therapeutic range for anticoagulation remains challenging. Subtherapeutic international normalized ratios (INRs) occur frequently while on warfarin therapy. An effective anticoagulant bridge strategy may improve the care of these patients. This retrospective review of MCS patients with subtherapeutic INRs compared an intravenous unfractionated heparin (UFH) strategy with a subcutaneous enoxaparin or fondaparinux strategy. Native thromboelastography (n-TEG) was used to evaluate anticoagulant effect with coagulation index (CI) as the primary outcome measure. Enoxaparin 0.5 mg/kg subcutaneously (SC) every 12 hours or fondaparinux 2.5-5 mg SC daily were compared with an initial UFH rate of 5 units/kg/hr and titrated to stated n-TEG goal range. The anticoagulant groups UFH, enoxaparin, and fondaparinux were found to be statistically similar with regard to frequency in n-TEG goal range, above range (hypercoagulability), or below range (hypocoagulability). Clinical outcomes were similar among groups with three gastrointestinal bleeds in UFH, one in enoxaparin, and one in fondaparinux groups. Device thrombosis occurred in one UFH patient, while UFH and fondaparinux groups had one ischemic cerebrovascular accident event each. These strategies provided comparable n-TEG results and clinical outcomes when compared with intravenous UFH. Low-dose enoxaparin or fondaparinux may provide an alternative anticoagulant bridging option in MCS patients presenting with subtherapeutic INR.",
"affiliations": "From the Department of Pharmacy, Banner University Medical Center Tucson, Tucson, Arizona.;From the Department of Pharmacy, Banner University Medical Center Tucson, Tucson, Arizona.;Artificial Heart Department, Banner University Medical Center Tucson, Tucson, Arizona.;Department of Epidemiology and biostatistics, University of Arizona, Tucson, Arizona.;Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.;From the Department of Pharmacy, Banner University Medical Center Tucson, Tucson, Arizona.;Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.;Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.;Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.;Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.",
"authors": "Cosgrove|Richard H|RH|;Basken|Robyn L|RL|;Smith|Richard G|RG|;Hsu|Chiu-Hsieh|CH|;Kazui|Toshinobu|T|;Martinez|Brandon K|BK|;Burt|Richard W|RW|;Crawford|Eric S|ES|;Lick|Scott D|SD|;Khalpey|Zain|Z|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D000077425:Fondaparinux",
"country": "United States",
"delete": false,
"doi": "10.1097/MAT.0000000000000747",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "65(1)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000925:Anticoagulants; D017984:Enoxaparin; D005260:Female; D000077425:Fondaparinux; D006353:Heart-Assist Devices; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013927:Thrombosis",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "54-58",
"pmc": null,
"pmid": "29324514",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anticoagulant Bridge Comparison in Mechanical Circulatory Support Patients.",
"title_normalized": "anticoagulant bridge comparison in mechanical circulatory support patients"
} | [
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"activesubstancename": "HEPARIN SODIUM"
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"drugadditional": "3",
... |
{
"abstract": "Staphylococcus simulans is a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness.",
"affiliations": "Department of Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA.;Department of Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA.;Department of Medicine, Division of Pulmonology and Critical Care Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA.;Department of Medicine, Chief of Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA.",
"authors": "Lal|Amos|A|0000-0002-0021-2033;Akhtar|Jamal|J|;Ullah|Ashfaq|A|;Abraham|George M|GM|0000-0003-4296-8362",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2018/7831284",
"fulltext": "\n==== Front\nCase Rep Infect DisCase Rep Infect DisCRIIDCase Reports in Infectious Diseases2090-66252090-6633Hindawi 10.1155/2018/7831284Case ReportFirst Case of Pleural Empyema Caused by Staphylococcus simulans: Review of the Literature http://orcid.org/0000-0002-0021-2033Lal Amos manavamos@gmail.com\n1\nAkhtar Jamal \n1\nUllah Ashfaq \n2\nhttp://orcid.org/0000-0003-4296-8362Abraham George M. \n3\n\n4\n\n5\n\n6\n\n7\n\n8\n\n1Department of Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA\n2Department of Medicine, Division of Pulmonology and Critical Care Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA\n3Department of Medicine, Chief of Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA\n4Professor of Medicine, University of Massachusetts Medical School, Worcester, MA, USA\n5Governor, MA Chapter, and Regent, American College of Physicians (ACP), Philadelphia, PA, USA\n6Chair-Elect, Board of Governors (ACP), Philadelphia, PA, USA\n7Chair, Infectious Disease Board, American Board of Internal Medicine (ABIM), Philadelphia, PA, USA\n8Vice Chair, Board of Registration in Medicine (BORIM), Commonwealth of Massachusetts, Wakefield, MA, USAAcademic Editor: Paola Di Carlo\n\n2018 11 10 2018 2018 783128410 5 2018 16 9 2018 23 9 2018 Copyright © 2018 Amos Lal 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.\nStaphylococcus simulans is a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness.\n==== Body\n1. Introduction\n\nStaphylococcus simulans is a coagulase-negative staphylococcus. It is mainly an animal pathogen and has been found to cause bovine mastitis. It can occasionally colonize the human skin. Human infections with Staphylococcus simulans have rarely been reported, mainly in patients who have repeated contact with animals. We report the first case of pleural empyema caused by S. simulans.\n\n1.1. Case Report\nAn 80-year-old woman was admitted to the hospital after a fall. Her prior history was notable for coronary artery disease status post percutaneous intervention, poorly controlled type 2 diabetes mellitus, congestive heart failure, hypothyroidism, and atrial fibrillation. She had had multiple mechanical falls in the past with cervical spine and right-sided rib fractures. She had no recent hospitalization in the last 90 days and has been living at home prior to presentation. There was no history of exposure to the farm animals. During this hospitalization, she developed progressive dyspnea and hypoxia. Computed tomography (CT) revealed a bilateral pleural effusion, right more than left, with diffuse interlobular septal thickening. Note was also made of a diffuse, mosaic-like attenuation of the lung parenchyma, likely related to air trapping or obstructive small airway disease. There was no pleural enhancement, septations, or air noted within the pleural space (Figure 1(a)). She was noted to have new fracture of right posterior seventh, eighth, and ninth ribs. Laboratory data at admission revealed a white blood cell (WBC) count of 9.7 × 1000/µL (with 83% neutrophils and 1% eosinophils). Her hemoglobin was 11.09 g/dL, hematocrit 40.6%, platelets 143 × 1000/µL, total protein 5.1 g/dL, blood urea nitrogen (BUN) 31 mg/dL, serum creatinine 1.51 mg/dL, serum sodium (Na) 145 mEq/L, chloride (Cl) 102 mEq/L, potassium (K) 3.6 mEq/L, aspartate aminotransferase (AST) 24 IU/L, and lactate dehydrogenase (LDH) 472 IU/L. Serum procalcitonin levels were elevated to 0.59 ng/mL (normal 0.00 – 0.08 ng/mL) and hemoglobin A1C (HbA1C) to 8.9%.\n\nBlood cultures prior to initiation of antimicrobial therapy returned negative. Sputum culture was negative for bacteria, including acid-fast bacilli. Transthoracic echocardiography was unremarkable.\n\nThe patient was treated initially with levofloxacin and ampicillin/sulbactam for a pneumonia and parapneumonic pleural effusion. Despite antimicrobial therapy, her respiratory status continued to deteriorate and within 48 hours of hospitalization required endotracheal intubation and ventilatory support. A thoracentesis yielded 250 ml of pus (WBCs more than 50,000 with 95% neutrophils, elevated protein 3.6 g/dL (normal 0.0–2.4 g/dL), LDH 13461 IU/L, glucose 6 mg/dL, and pH 6.94). A right-sided thoracostomy was performed to facilitate evacuation of the empyema using a 32 French (F) thoracostomy tube. Postprocedure chest X-ray confirmed the optimal placement of the tube (Figure 2). Gram stains obtained from the pleural fluid collected under sterile conditions revealed gram-positive cocci, and her antibiotics were changed to vancomycin. The final isolate on culture and sensitivity was identified as S. simulans with heavy growth, susceptible to vancomycin and clindamycin only. A repeat CT scan of the chest revealed a persistent collection of right-sided empyema (Figure 1(b)). Ultrasound imaging of the pleural collections did not demonstrate any septations or loculated pockets on either side. Second attempt was made to evacuate the pleural collection with the use of intrapleural fibrinolytic tissue plasminogen activator (t-PA) with little success. The patient was considered a high-risk candidate for surgical intervention considering her frailty and other medical comorbidities. Her course was further complicated by circulatory shock requiring vasopressor supports and atrial fibrillation with rapid ventricular response requiring multiple rate-controlling drugs. After about 3 weeks of a tenuous course, her family elected to withdraw care and she passed away very shortly thereafter.\n\n2. Discussion\nCoagulase-negative staphylococcus (CoNS) has become an important cause of nosocomial infections. Common human isolates are Staphylococcus epidermidis, Staphylococcus capitis, Staphylococcus hominis, Staphylococcus haemolyticus, Staphylococcus warneri, Staphylococcus caprae, Staphylococcus saccharolyticus, Staphylococcus pasteuri, Staphylococcus saprophyticus, and Staphylococcus lugdunensis [1].\n\n\nS. simulans commonly affects cows, sheep, goats, and horses. Human infections are rare, and the literature has commonly reported soft tissue infection, osteomyelitis, bacteremia, urinary tract infection, prosthetic joint infection, and native valve endocarditis [1–8] (Table 1). A case of pneumonia was reported by de Jesus et al. which revealed S. simulans in blood culture and CoNS in sputum culture [2]. de Jesus et al. also reported a case of acute respiratory failure, ARDS with blood culture growing S. simulans [2]. To the best of our knowledge, this is the first case of pleural empyema caused by S. simulans. In our patient, there was no history of contact with animals. Mode of acquisition of infection in our patient remained unclear.\n\n\nS. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters [8]. S. simulans has also been shown to share virulence factors with S. aureus in infectious animal isolates, including staphylococcal enterotoxins, tissue necrosis cytotoxin Panton–Valentine leukocidin, and the methicillin-resistance gene, mecA [5]. The encapsulated forms of S. simulans (i.e., slime layer or biofilm) have an antiphagocytic effect on human polymorphonuclear leucocytes as compared to unencapsulated forms of the pathogen [8]. Sequencing of the tuf gene has been shown to be the most accurate for the species identification of CoNS [9].\n\nThe critical event in the establishing the pathogenicity includes formation of multilayered biofilm, especially in foreign body-associated infections caused by CoNS. Members of the genus Staphylococcus produce various proteinaceous and nonproteinaceous adhesins, to mediate attachment to host surfaces, such as plasma extracellular and matrix proteins or even host cells [10, 11].\n\nThere are limited data available about how CoNS which are usually common pathogens in veterinary medicine are gaining pathogenicity in human hosts. There are some shared virulence factors with Staphylococcus aureus which are documented in Table 2 [5, 12–14]. Of note, mecA-positive CoNS are capable to horizontally transfer their genes inside the staphylococcal genus with the prospective to contribute increase in new methicillin-resistant strains [12].\n\nThe challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. The major diagnostic question remains as to whether the CoNS isolate represents a contamination of the specimen, physiological colonization of the skin or mucus membranes, or a clinically significant infection. In our case, the absence of other microbiological data and the confidence in the sterile process of procuring the sample from pleural fluid warranted consideration of S. simulans in the pleural fluid as pathogenic. Important considerations include isolation of a strain in pure culture from the site of infection and repeated isolation of the same strain over the course of infection [11, 15].\n\nWhile treating the pleural infections, clinicians need to be cognizant of the choice of antimicrobial therapy and relevant pharmacokinetics. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself; acute inflammation is proven to be a supporting factor due to vasodilation [16, 17]. Teixeira et al. demonstrated that penicillin has the best penetration for the treatment of pleural pathologies, followed by metronidazole; gentamicin was found to have poor penetration and considered a poor choice for treatment of empyemas [16].\n\n\nS. simulans is known to demonstrate resistance to multiple antibiotics including vancomycin [2]. In our case, the organism was resistant to ampicillin/sulbactam, cefazolin, ciprofloxacin, oxacillin, and tetracycline, but it was susceptible to vancomycin in vitro. The use of vancomycin in pleural infections has long been debated due to its suboptimal penetration; however, in our case, the multidrug-resistant nature of the isolate required its use. It is debatable in retrospect if continuation of a broader antimicrobial coverage would have changed the outcome for the patient, considering poor biochemical and clinical response with the chosen antibiotic regimen.\n\nSource control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. The MIST-2 study reiterated the fact where use of t-PA and DNase combination therapy in patients with pleural infection improved drainage of pleural empyema, resulting in reduction in hospital stay and need for thoracic surgery intervention [18].\n\n3. Conclusion\n\nStaphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate.\n\nConflicts of Interest\nAll authors claim no conflicts of interest.\n\nAuthors' Contributions\nAL conceived the study, drafted the manuscript, collected data, and reviewed and revised the study. JA collected the data, drafted the manuscript, and reviewed the study. AU collected the data, drafted the manuscript, and reviewed the study. GMA conceived the study, drafted the manuscript, and reviewed the study.\n\nFigure 1 (a) CT chest showing bilateral empyema (right more than left). (b) CT chest showing persistent bilateral empyema after attempted drainage through chest drains.\n\nFigure 2 Chest X-ray showing the right-sided chest tube (green arrows), positioned in the most dependent area.\n\nTable 1 Author\tAge/sex\tDiagnosis\tTissue culture for S. simulans\tBlood culture for S. simulans\tAntibiotic resistance\tOutcome\tAnimal exposure\t\nShields et al. [5]\t80/M\tRight great toe cellulitis\tPositive\tNot specified\tTetracycline resistance\tResolution with TMP-SMX\tNot specified\t\nTous Romero et al. [6]\t60/M\tPyoderma left hand\tPositive\tNot specified\tNot specified\tResolution with azithromycin\tPositive\t\nAl Kline et al. [8]\t65/M\tAbscess, osteomyelitis right foot\tPositive bone culture\tPositive\tAmpicillin, ciprofloxacin, clindamycin, oxacillin, penicillin, ceftriaxone\tResolution with IV vancomycin\tPositive\t\nVallianou et al. [3]\t46/M\tVertebral osteomyelitis, native valve, endocarditis\tNot specified\tPositive\tMethicillin\tResolution with IV vancomycin, teicoplanin, oral clindamycin\tPositive\t\nSturgess et al. [7]\t77/F\tRight pubic osteomyelitis\tNot specified\tPositive\tPan-sensitive\tResolution with flucloxacillin, fusidic acid\tNot specified\t\nde Jesus et al. [2]\t84/M\tSepticemia, colon cancer\tNot specified\tPositive\tMethicillin-sensitive\tDied\tNot specified\t\nde Jesus et al. [2]\t41/M\tAcute respiratory failure, ARDS, H/O HIV, IV drug abuse\tNot specified\tPositive\tMethicillin-sensitive\tDied\tNot specified\t\nde Jesus et al. [2]\t63/M\tPneumonia\tCN staph in sputum\tPositive for S. simulans\tNot specified\tResolved with erythromycin, cefuroxime\tNot specified\t\nde Jesus et al. [2]\t58/M\tColon cancer, septicemia\tNot specified\tPositive\tMethicillin-resistant\tResolved with vancomycin\tNot specified\t\nMales et al. [1]\t39/M\tRight ankle, osteomyelitis, septic, arthritis\tPositive\tPositive\tPan-sensitive\tPenicillin\tNot specified\t\nTable 2 Staphylococcal species\tCommon virulence factors\tClinical manifestations\t\n\nS. aureus and S. simulans\n\tStaphylococcal enterotoxins (se)\tGastrointestinal manifestations of diarrhea, nausea, vomiting, and enterocolitis.\t\nTissue necrosis cytotoxin Panton–Valentine leukocidin (pvl)\tHospital-acquired pneumonia, infective endocarditis, and tissue necrosis\t\nMethicillin-resistance gene (mecA)\tMajor contributing factor for increase in new methicillin-resistant strains\t\nExfoliative toxins (eta, etb)\tCutaneous manifestations of cellulitis\t\nToxic shock syndrome toxin-1 (tst)\tSeptic shock and disseminated blood stream infections\n==== Refs\n1 Males B. M. Bartholomew W. R. Amsterdam D. \nStaphylococcus simulans septicemia in a patient with chronic osteomyelitis and pyarthrosis Journal of Clinical Microbiology 1985 21 2 255 257 3972995 \n2 de Jesus L. Caruso G. de Caprariis P. Ditchek A. Visconti E. \nStaphylococcus simulans septicemia Infectious Diseases in Clinical Practice 1993 2 5 351 352 10.1097/00019048-199309000-00008 \n3 Vallianou N. Evangelopoulos A. Makri P. Vertebral osteomyelitis and native valve endocarditis due to Staphylococcus simulans : a case report Journal of Medical Case Reports 2008 2 1 p. 183 10.1186/1752-1947-2-183 2-s2.0-45549095062 \n4 Razonable R. R. Lewallen D. G. Patel R. Osmon D. R. Vertebral osteomyelitis and prosthetic joint infection due to Staphylococcus simulans Mayo Clinic Proceedings 2001 76 10 1067 1070 10.4065/76.10.1067 2-s2.0-0034774789 11605694 \n5 Shields B. E. Tschetter A. J. Wanat K. A. \nStaphylococcus simulans : an emerging cutaneous pathogen JAAD Case Reports 2016 2 6 428 429 10.1016/j.jdcr.2016.08.015 2-s2.0-85000366377 27957522 \n6 Tous Romero F. Gutierrez Garcia-Rodrigo C. Velasco Tamariz V. Llamas Martin R. Acute infection by Staphylococcus simulans in the hand of a man JAMA Dermatology 2016 152 9 p. 1060 10.1001/jamadermatol.2016.0959 2-s2.0-84999040150 \n7 Sturgess I. Martin F. C. Eykyn S. Pubic osteomyelitis caused by Staphylococcus simulans Postgraduate Medical Journal 1993 69 818 927 929 10.1136/pgmj.69.818.927 2-s2.0-0027748187 8121867 \n8 Al Kline D. \nStaphylococcus simulans osteomyelitis of the foot: a case report Foot and Ankle Online Journal 2010 3 1 \n9 Carpaij N. Willems R. J. Bonten M. J. Fluit A. C. Comparison of the identification of coagulase-negative staphylococci by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and tuf sequencing European Journal of Clinical Microbiology and Infectious Diseases: Official Publication of the European Society of Clinical Microbiology 2011 30 10 1169 1172 10.1007/s10096-011-1204-3 2-s2.0-80054719135 \n10 Heilmann C. Adhesion mechanisms of staphylococci Advances in Experimental Medicine and Biology 2011 Basel, Switzerland Springer Nature 105 123 10.1007/978-94-007-0940-9_7 2-s2.0-79960119861 \n11 Becker K. von Eiff C. Staphylococcus, micrococcus, and other catalase-positive cocci Manual of Clinical Microbiology 2011 Washington, DC, USA American Society of Microbiology 308 330 \n12 Unal N. Cinar O. D. Detection of stapylococcal enterotoxin, methicillin-resistant and panton-valentine leukocidin genes in coagulase-negative staphylococci isolated from cows and ewes with subclinical mastitis Tropical Animal Health and Production 2012 44 2 369 375 10.1007/s11250-011-0032-x 2-s2.0-84855211247 22160510 \n13 Davis M. F. Cain C. L. Brazil A. M. Rankin S. C. Two coagulase-negative staphylococci emerging as potential zoonotic pathogens: wolves in sheep’s clothing? Frontiers in Microbiology 2013 4 p. 123 10.3389/fmicb.2013.00123 2-s2.0-84884227178 \n14 Lina G. Piemont Y. Godail-Gamot F. Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 1999 29 5 1128 1132 10.1086/313461 2-s2.0-0033496604 10524952 \n15 Chatzika K. Manika K. Kontou P. Moxifloxacin pharmacokinetics and pleural fluid penetration in patients with pleural effusion Antimicrobial Agents and Chemotherapy 2014 58 3 1315 1319 10.1128/aac.02291-13 2-s2.0-84896828042 24323477 \n16 Teixeira L. R. Sasse S. A. Villarino M. A. Nguyen T. Mulligan M. E. Light R. W. Antibiotic levels in empyemic pleural fluid Chest 2000 117 6 1734 1739 10.1378/chest.117.6.1734 2-s2.0-0034087865 10858410 \n17 Valcke Y. Pauwels R. Van der Straeten M. Pharmacokinetics of antibiotics in the lungs European Respiratory Journal 1990 3 6 715 722 2199210 \n18 Rahman N. M. Maskell N. A. West A. Intrapleural use of tissue plasminogen activator and DNase in pleural infection New England Journal of Medicine 2011 365 6 518 526 10.1056/nejmoa1012740 2-s2.0-80051618075 21830966\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
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"nlm_unique_id": "101573243",
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"pages": "7831284",
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"pmid": "30405924",
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"references": "11605694;21557060;21359622;27957522;10524952;21830966;27144675;22160510;10858410;8121867;3972995;24323477;18510763;23720657;2199210",
"title": "First Case of Pleural Empyema Caused by Staphylococcus simulans: Review of the Literature.",
"title_normalized": "first case of pleural empyema caused by staphylococcus simulans review of the literature"
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"abstract": "Topiramate is a sulfa-derivative antiepileptic drug which is also used for other indications such as essential tremor. A 79-year-old male was admitted to our center due to acute bilateral painless decline of vision. One month before admission, he had experienced essential tremor and treatment with topiramate 50 mg/day and propranolol 40 mg/day. Best-corrected visual acuity was 20/800 OD and 20/600 OS. Both eyes had normal anterior chamber depths and irides. Intraocular pressure was 10 mm Hg in the right eye and 11 mm Hg in the left eye. Retinal examination showed notable choroidal detachments in all quadrants of the periphery, which were confirmed by ultrasonography. Refraction showed no myopic shift. The administration of topiramate was discontinued as a potential causative agent for this condition. During follow-up, choroidal detachment and visual acuity gradually resolved. In this study, we described the first case of isolated massive choroidal detachment induced by topiramate.",
"affiliations": "Medical School, Feiz Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.",
"authors": "Dehghani|Alireza|A|;Abtahi|Mohammad-Ali|MA|;Abtahi|Seyed-Hossein|SH|;Peyman|Alireza|A|;Etemadifar|Masoud|M|;Ghanbari|Heshmatollah|H|;Mohammadi|Zahra|Z|",
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"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. 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 2194150110.1159/000330860cop0002-0251Published: August 2011Massive Bilateral Choroidal Detachment Induced by Administration of Topiramate Dehghani Alireza abAbtahi Mohammad-Ali abdAbtahi Seyed-Hossein ad*Peyman Alireza abEtemadifar Masoud acGhanbari Heshmatollah abMohammadi Zahra abaMedical School, Feiz Hospital, Isfahan University of Medical Sciences, Isfahan, IranbOphthalmology Ward, Feiz Hospital, Isfahan University of Medical Sciences, Isfahan, IrancDepartment of Neurology, Medical School, Isfahan University of Medical Sciences, Isfahan, IrandIsfahan Medical Students Research Committee (IMSRC), Isfahan, Iran*Seyed-Hossein Abtahi, S.H.A. Official Research Center of Neurological-Ophthalmological Sciences (SHARNOS Co.), No. 9, Boroomand, Seyed-Alikhan, Chaharbagh Abbasi, Isfahan 81448-14581 (Iran), Tel. +98 913 409 8036, E-Mail shf.Abtahi@yahoo.comMay-Aug 2011 9 8 2011 9 8 2011 2 2 251 255 Copyright © 2011 by S. Karger AG, Basel2011This 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.Topiramate is a sulfa-derivative antiepileptic drug which is also used for other indications such as essential tremor. A 79-year-old male was admitted to our center due to acute bilateral painless decline of vision. One month before admission, he had experienced essential tremor and treatment with topiramate 50 mg/day and propranolol 40 mg/day. Best-corrected visual acuity was 20/800 OD and 20/600 OS. Both eyes had normal anterior chamber depths and irides. Intraocular pressure was 10 mm Hg in the right eye and 11 mm Hg in the left eye. Retinal examination showed notable choroidal detachments in all quadrants of the periphery, which were confirmed by ultrasonography. Refraction showed no myopic shift. The administration of topiramate was discontinued as a potential causative agent for this condition. During follow-up, choroidal detachment and visual acuity gradually resolved. In this study, we described the first case of isolated massive choroidal detachment induced by topiramate.\n\nKey Words\nTopiramateChoroidal detachmentSide effectSulfa derivative\n==== Body\nIntroduction\nTopiramate is a sulfa-derivative antiepileptic drug which is also used for other indications such as migraine, personality disorders, weight loss, neuropathic pain and, recently, essential tremor [1, 2]. The pharmacodynamic picture of this drug generally reflects the modulation of voltage-gated sodium and calcium channels, increase of GABAergic inhibition, blockage of glutamate receptors and mild carbonic anhydrase inhibition [3]. To date, several side effects of this drug are reported, of which ophthalmic manifestations are of special importance. The most clinically significant ophthalmic side effects are angle-closure glaucoma, myopic shift, diplopia and nystagmus. The precise mechanisms responsible for such adverse effects are, however, not completely understood [4].\n\nSerous choroidal detachment (transudation of fluid into the suprachoroidal space) may be due to globe hypotony of any etiology or exudation of serum caused by inflammation or other causes [5]. Choroidal detachment is generally known as a probable complication of sensitized eyes following surgery. Typically, these cases are concurrently treated with ocular hypotensive drugs [6]. Moreover, there are some instances in which the occurrence of choroidal detachment is not explainable by common mechanisms [5].\n\nTo our knowledge, massive choroidal detachment following the administration of topiramate has never been described in previous case reports. The purpose of this report was to illustrate the clinical and paraclinical features of a patient who experienced the above-mentioned adverse event. We also aimed to discuss the possible pathogenic links of topiramate by comparing the features of our case with those of cases previously reported in the literature.\n\nCase Report\nA 79-year-old male was admitted to our center for further evaluation of acute bilateral painless decline of vision. The patient's past clinical history included 80 mg/day aspirin intake due to unstable angina for 11 years. He denied any past history of smoking or addiction.\n\nOn neurological examination, mental status was found to be normal. The patient had no significant neurological disorder until 1 month before admission, when he experienced essential tremor. As a result, treatment with topiramate 50 mg/day and propranolol 40 mg/day was started 2 weeks before his admission due to ophthalmic symptoms. This treatment was prescribed by a neurologist.\n\nHe underwent uncomplicated cataract surgery 11 years ago for the right eye and 9 years ago for the left eye, and both eyes had intraocular lenses. He had no clinical history of glaucoma surgery or anti-glaucoma medications.\n\nOn ophthalmologic examination, best-corrected visual acuity was 20/800 OD and 20/600 OS. The eyelids showed meibomian gland dysfunction. Both eyes showed mild hyperemia and had normal anterior chamber depths and irides. Pupillary reactions to light and near stimuli were normal, and no pupillary afferent defect was present. Ocular motility was normal. Intraocular pressure was 10 mm Hg in the right and 11 mm Hg in the left eye. Anterior vitreous examination showed no abnormality. Retinal examination revealed posterior pole drusen compatible with mild dry age-related macular degeneration and notable choroidal detachments in all quadrants of the periphery (fig.\n1), which were confirmed by ultrasonography (fig.\n2). Refraction showed no myopic shift.\n\nThe administration of topiramate was discontinued as a potential causative agent for this condition; however, we did not reduce the dosage of propranolol. We continued monitoring the patient's status daily. Within 3 days, visual acuity improved to 20/200 OD and 20/60 OS. This improvement continued until day 7, when visual acuity gradually exceeded to 20/25 OD and 20/30 OS. By the end of day 7, choroidal detachment resolved as well.\n\nDiscussion\nWe described the first case of isolated massive choroidal detachment induced by topiramate. However, it is worth noting that in a study by the National Registry of Drug-Induced Ocular Side Effects, 9 cases of suprachoroidal effusion were concisely mentioned regardless of the severity of their complication. The data on these subjects were extracted from the records of the World Health Organization or other related/similar organizations [4]. Nevertheless, to the best of our knowledge, neither precise features of these cases, e.g. the severity of effusion, were published elsewhere, nor any of them were specified to present massive choroidal detachment.\n\nA review of the ophthalmology literature reveals that, to date, there are several reports describing bilateral angle closure following topiramate intake [4, 7, 8, 9]. Our patient did not exhibit myopic changes or a shallow anterior chamber, although such side effects have been frequently observed with the use of this drug.\n\nThe term ‘ciliochoroidal effusion syndrome’ was first proposed by Ikeda et al. [10] to describe the phenomena induced by topiramate and other sulfa derivatives. This syndrome represents a category of symptoms including ciliochoroidal effusion, forward displacement of the lens-iris diaphragm and, consequently, angle narrowing and myopic shift. Accordingly, in our case choroidal effusion without development of angle closure or myopic shift could be due to lack of crystalline lens.\n\nAs mentioned previously, the main cause of choroidal detachment is generally believed to be ocular hypotony following surgical procedures [6]. In our literature review, we could identify an interesting case by Doherty et al. [11] that shares decisive common features with ours. This patient was reported to manifest bilateral choroidal detachment after administration of topical dorzolamide. Taking together, four main similarities are worth noting: (1) both patients had a past history of uncomplicated cataract surgery; (2) intraocular pressure was within normal limits in both patients; (3) dorzolamide and topiramate are both sulfa-derivative drugs, and (4) similar to dorzolamide which is a carbonic anhydrase antagonist, topiramate is also suggested to be ‘a mild carbonic anhydrase inhibitor’ [3]. Accordingly, the authors concluded that the cause of choroidal detachment is not always hypotony and postulated that it may also be due to hypersensitivity to dorzolamide. Our case provides further evidence in favor of this hypothesis, and this raises the question whether the cause of choroidal detachment in our case was hypersensitivity to topiramate as this is a sulfa-derivative drug as well. From another point of view, it is well known that carbonic anhydrase antagonists can cause choroidal detachment [12], and this may explain why the administration of dorzolamide and topiramate results in this adverse effect.\n\nAs a conclusion, we propose that the administration of topiramate and perhaps other sulfa-derivative drugs might be eligible to be added as a differential diagnosis of choroidal detachment.\n\nDisclosure Statement\nThe authors have no conflicts of interest.\n\nFig. 1 Fundus photographies of both eyes showing massive choroidal detachment. a Right eye. b, c Left eye.\n\nFig. 2 B scan ultrasonography confirming massive choroidal detachment in both eyes.\n==== Refs\nReferences\n1 Mirza N Marson AG Pirmohamed M Effect of topiramate on acid-base balance: extent, mechanism and effects Br J Clin Pharmacol 2009 68 655 661 19916989 \n2 Sadeghi R Ondo WG Pharmacological management of essential tremor Drugs 2010 70 2215 2228 21080739 \n3 Kjellström S Bruun A Isaksson B Eriksson T Andréasson S Ponjavic V Retinal function and histopathology in rabbits treated with Topiramate Doc Ophthalmol 2006 113 179 186 17111186 \n4 Fraunfelder FW Fraunfelder FT Keates EU Topiramate-associated acute, bilateral, secondary angle-closure glaucoma Ophthalmology 2004 111 109 111 14711721 \n5 Elagouz M Stanescu-Segall D Jackson TL Uveal effusion syndrome Surv Ophthalmol 2010 55 134 145 20159229 \n6 Alexander P Ramirez-Florez S Hypotony and choroidal detachment as a complication of travoprost after trabeculectomy surgery Eye (Lond) 2008 22 736 737 18327156 \n7 Banta JT Hoffman K Budenz DL Ceballos E Greenfield DS Presumed topiramate-induced bilateral acute angle-closure glaucoma Am J Ophthalmol 2001 132 112 114 11438067 \n8 Rhee DJ Goldberg MJ Parrish RK Bilateral angle-closure glaucoma and ciliary body swelling from topiramate Arch Ophthalmol 2001 119 1721 1723 11709030 \n9 Dehghani A Rezaei L Peyman A Acute myopia and angle closure glaucoma associate with topiramate use: a case series Am J Case Rep 2010 11 271 273 \n10 Ikeda N Ikeda T Nagata M Mimura O Ciliochoroidal effusion syndrome induced by sulfa derivatives Arch Ophthalmol 2002 120 1775 12470170 \n11 Doherty MD Wride NK Birch MK Figueiredo FC Choroidal detachment in association with topical dorzolamide: is hypotony always the cause? Clin Experiment Ophthalmol 2009 37 750 752 19788679 \n12 Goldberg S Gallily R Bishara S Blumenthal EZ Dorzolamide-induced choroidal detachment in a surgically untreated eye Am J Ophthalmol 2004 138 285 286 15289139\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1663-2699",
"issue": "2(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Choroidal detachment; Side effect; Sulfa derivative; Topiramate",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "251-5",
"pmc": null,
"pmid": "21941501",
"pubdate": "2011-05",
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"title": "Massive bilateral choroidal detachment induced by administration of topiramate.",
"title_normalized": "massive bilateral choroidal detachment induced by administration of topiramate"
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"abstract": "BACKGROUND\nChronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection.\n\n\nMETHODS\nA 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV-1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up.\n\n\nCONCLUSIONS\nChronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes.",
"affiliations": "Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO, 63104, USA. claohath@slu.edu.;Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO, 63104, USA.;Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO, 63104, USA.;Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO, 63104, USA.",
"authors": "Laohathai|Christopher|C|;Weber|Daniel J|DJ|;Hayat|Ghazala|G|;Thomas|Florian P|FP|",
"chemical_list": "D004279:DNA, Viral",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-015-0822-6",
"fulltext": null,
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"issn_linking": "0300-8126",
"issue": "44(1)",
"journal": "Infection",
"keywords": "Cyclosporine; Encephalitis; Epilepsy; Herpes simplex; Immunosuppression; Seizure",
"medline_ta": "Infection",
"mesh_terms": "D001921:Brain; D002555:Cerebrospinal Fluid; D002908:Chronic Disease; D004279:DNA, Viral; D000069279:Drug Resistant Epilepsy; D020803:Encephalitis, Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D066027:Transplant Recipients",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "121-5",
"pmc": null,
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"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2096245;19819030;12531966;21961549;9706620;15581185;9548334;22919528;17005102;9701483;8736603;12122186;20179002;12748669",
"title": "Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient.",
"title_normalized": "chronic herpes simplex type 1 encephalitis with intractable epilepsy in an immunosuppressed patient"
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"abstract": "Chemotherapy is the main treatment strategy for gestational trophoblastic neoplasia (GTN). Surgical resection is crucial to deal with chemoresistance and recurrence following chemotherapy. The aim of this study was to explore if high-intensity focused ultrasound (HIFU) can be used as a complementary technique to surgical procedures in the management of GTN.\n\n\n\nThis case report described two females who previously developed chemoresistance or recurrence during chemotherapy and then underwent HIFU as an adjuvant surgical salvage procedure. For high-risk GTN patients with chemoresistance, HIFU treatment decreased the risk of chemoresistance and shortened the course of chemotherapy. It also reduced the dosage of chemotherapeutic agents used for the patient who suffered a recurrence.\n\n\n\nFor patients with GTN who desire to preserve their uterus, HIFU may be used as a complementary technique to surgical resection in the management of GTN.",
"affiliations": "Department of Laboratory Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi City, China.;Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi City, China.;Department of Clinical Medicine, Zunyi Medical and Pharmaceutical College, Zunyi City, China.;Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi City, China.;Department of Gynecology, Chongqing Haifu Hospital, Chongqing, China.;Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi City, China.",
"authors": "She|Chaokun|C|;Li|Sha|S|;Wang|Xiaojun|X|;Lu|Xianghui|X|;Liang|Hao|H|;Liu|Xiaoyun|X|0000-0002-7497-580X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02656736.2021.1998659",
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"issn_linking": "0265-6736",
"issue": "38(1)",
"journal": "International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group",
"keywords": "Chemoresistance; chemotherapy; gestational trophoblastic neoplasia; high intensity focused ultrasound (HIFU); recurrence",
"medline_ta": "Int J Hyperthermia",
"mesh_terms": "D019008:Drug Resistance, Neoplasm; D005260:Female; D031901:Gestational Trophoblastic Disease; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D009364:Neoplasm Recurrence, Local; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "8508395",
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"pages": "1584-1589",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-intensity focused ultrasound ablation as an adjuvant surgical salvage procedure in gestational trophoblastic neoplasia chemotherapy with chemoresistance or recurrence: two case reports.",
"title_normalized": "high intensity focused ultrasound ablation as an adjuvant surgical salvage procedure in gestational trophoblastic neoplasia chemotherapy with chemoresistance or recurrence two case reports"
} | [
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"abstract": "Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.\n\n\n\nIn patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed.\n\n\n\nThis investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m2 on day 1) every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.\n\n\n\nFrom September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated.\n\n\n\nBevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.",
"affiliations": "Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.;Department of Abdominal Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.",
"authors": "Chen|Ye|Y|;Zhou|Yu-Wen|YW|;Cheng|Ke|K|;Li|Zhi-Ping|ZP|;Luo|De-Yun|DY|;Qiu|Meng|M|;Li|Qiu|Q|;Wang|Xin|X|;Shen|Ya-Li|YL|;Cao|Dan|D|;Yang|Yu|Y|;Bi|Feng|F|;Liu|Ji-Yan|JY|;Gou|Hong-Feng|HF|",
"chemical_list": "D011799:Quinazolines; D013876:Thiophenes; D000068258:Bevacizumab; C068874:raltitrexed; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13778",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(8)",
"journal": "The oncologist",
"keywords": "Bevacizumab; Drug resistance; Raltitrexed; Refractory metastatic colorectal cancer; S-1",
"medline_ta": "Oncologist",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D011799:Quinazolines; D013876:Thiophenes",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e1320-e1326",
"pmc": null,
"pmid": "33830591",
"pubdate": "2021-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "31999946;31631858;32162797;23177514;18259091;25600568;18650835;29946728;29459325;23168366;30651398;32536012;29215955;19483736;10645207;25981818;30422156;23313143;29021377;25982297;25970050;25717219",
"title": "Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study.",
"title_normalized": "bevacizumab combined with s 1 and raltitrexed for patients with metastatic colorectal cancer refractory to standard therapies a phase ii study"
} | [
{
"companynumb": "CN-ROCHE-2684523",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The emergence of drug-resistant tuberculosis (DRTB) has continued to pose a threat to public health in sub-Saharan Africa and globally. Despite the high burden of tuberculosis (TB) in Nigeria, there are paucity of data on the safety and efficacy of newer agents and repurposed drugs used in the treatment of DRTB.\n\n\n\nThis prospective cohort study was conducted at a regional DRTB treatment center in Kano, Northwestern Nigeria. Descriptive statistics, Mann-Whitney U-test, and Chi-square or Fisher's exact test were used to analyze the data as appropriate.\n\n\n\nThe median age of the patients was 32 years (interquartile range 26-42 years). Of the 39 patients, 34 (87.18%) were males. The majority of the patients came from the rural areas 25 (64.10%). By 10 months of initiation of combination therapy, 25 (64.10%) of the patients were alive, culture negative and on treatment while 14 (35.90%) of the patients have died. Out of the 39 patients in the cohort, 26 (66.67%) patients had at least one serious adverse event. The most common serious adverse events were hematological disorders (13 [35.14%] of 37 events) and neurological disorders (11 [29.73%] of 37 events). Peripheral neuropathy (P < 0.0001), anemia (P = 0.029), and skin reaction (P = 0.021) occurred more frequently among linezolid interrupters.\n\n\n\nIn conclusion linezolid-based combination therapy, with linezolid at a dose of 600mg daily is associated with satisfactory culture conversion rate by 10 months of therapy. However, linezolid may be associated with peripheral neuropathy that may warrant interruption of the drug.",
"affiliations": "Multidrug-Resistant Tuberculosis Unit, Infectious Disease Hospital, Kano, Kano State, Nigeria.;Department of Medicine, College of Health Sciences, Bayero University, Kano, Kano State, Nigeria.;Department of Medicine, Muhammad Abdullahi Wase Teaching Hospital, Kano, Kano State, Nigeria.;Department of Medicine, College of Health Sciences, Bayero University, Kano, Kano State, Nigeria.",
"authors": "Dayyab|Farouq Muhammad|FM|;Iliyasu|Garba|G|;Ahmad|Bashir Garba|BG|;Habib|Abdulrazaq Garba|AG|",
"chemical_list": "D000995:Antitubercular Agents; D000069349:Linezolid",
"country": "Netherlands",
"delete": false,
"doi": "10.4103/ijmy.ijmy_57_21",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5531",
"issue": "10(2)",
"journal": "International journal of mycobacteriology",
"keywords": "Drug efficacy; Nigeria; drug resistance; drug safety; drug treatment; individualized regimen; linezolid",
"medline_ta": "Int J Mycobacteriol",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D004359:Drug Therapy, Combination; D006801:Humans; D000069349:Linezolid; D008297:Male; D009549:Nigeria; D011446:Prospective Studies; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "101615660",
"other_id": null,
"pages": "129-135",
"pmc": null,
"pmid": "34558463",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Early safety and efficacy of linezolid-based combination therapy among patients with drug-resistant tuberculosis in North-western Nigeria.",
"title_normalized": "early safety and efficacy of linezolid based combination therapy among patients with drug resistant tuberculosis in north western nigeria"
} | [
{
"companynumb": "NG-BAYER-2021-176472",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BEDAQUILINE"
},
"drugadditional": null,
... |
{
"abstract": "IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.",
"affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: nasr.samih@mayo.edu.;Arkana Laboratories, Little Rock, Arkansas, USA.;Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.;Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Department of Nephrology, Paris, France; INSERM UMRS1138, Research Center Cordeliers, Paris Descartes Sorbonne Paris-Cité University, Paris, France.;Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.;Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Ambroise Paré Hospital, Boulogne-Billancourt, France; Inserm U1018 Team5 UVSQ, University Paris Saclay, Villejuif, France.;Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Ambroise Paré Hospital, Boulogne-Billancourt, France; Inserm U1018 Team5 UVSQ, University Paris Saclay, Villejuif, France.;Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Hôpital Tenon, Paris Sorbonne University, Paris, France.;Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Tenon, Paris Sorbonne University, Paris, France.;Department of Nephrology, Bourg-en-Bresse General Hospital, Bourg-en-Bresse, France.;Department of Nephrology, Roubaix General Hospital, Roubaix, France.;Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.",
"authors": "Nasr|Samih H|SH|;Larsen|Christopher P|CP|;Sirac|Christophe|C|;Theis|Jason D|JD|;Domenger|Camille|C|;Chauvet|Sophie|S|;Javaugue|Vincent|V|;Hogan|Jonathan J|JJ|;Said|Samar M|SM|;Dasari|Surendra|S|;Vrana|Julie A|JA|;McPhail|Ellen D|ED|;Cornell|Lynn D|LD|;Vilaine|Eve|E|;Massy|Ziad A|ZA|;Boffa|Jean-Jacques|JJ|;Buob|David|D|;Toussaint|Stéphanie|S|;Guincestre|Thomas|T|;Touchard|Guy|G|;D'Agati|Vivette D|VD|;Leung|Nelson|N|;Bridoux|Frank|F|",
"chemical_list": "D000911:Antibodies, Monoclonal",
"country": "United States",
"delete": false,
"doi": "10.1016/j.kint.2019.10.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0085-2538",
"issue": "97(3)",
"journal": "Kidney international",
"keywords": "MGRS; complement alternative pathway; membranoproliferative glomerulonephritis; monoclonal gammopathy; myeloma",
"medline_ta": "Kidney Int",
"mesh_terms": "D000911:Antibodies, Monoclonal; D002999:Clone Cells; D005921:Glomerulonephritis; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D010265:Paraproteinemias; D010950:Plasma Cells; D040901:Proteomics",
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "589-601",
"pmc": null,
"pmid": "32001067",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.",
"title_normalized": "light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-241577",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "OBJECTIVE\nThe long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years.\n\n\nMETHODS\nSubjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit.\n\n\nRESULTS\nAmongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) or an alkaline phosphatase >ULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs. 43.7 years, P=0.01) and more likely to have a cholestatic lab profile at DILI onset (54 vs. 20%, P<0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 physical summary scores at DILI onset and throughout follow-up compared with the resolvers (P<0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis.\n\n\nCONCLUSIONS\nIn all, 75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression.",
"affiliations": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.;University of North Carolina, Chapel Hill, North Carolina, USA.;Duke Clinical Research Institute, Durham, North Carolina, USA.;National Cancer Institute, Bethesda, Maryland, USA.;Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennysylvania, USA.;Department of Medicine, Indiana University, Indianapolis, Indiana, USA.;Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;University of Southern California, Los Angeles, California, USA.;Duke Clinical Research Institute, Durham, North Carolina, USA.;Liver Disease Research Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, USA.;University of North Carolina, Chapel Hill, North Carolina, USA.",
"authors": "Fontana|Robert J|RJ|;Hayashi|Paul H|PH|;Barnhart|Huiman|H|;Kleiner|David E|DE|;Reddy|K Rajender|KR|;Chalasani|Naga|N|;Lee|William M|WM|;Stolz|Andrew|A|;Phillips|Thomas|T|;Serrano|Jose|J|;Watkins|Paul B|PB|;|||",
"chemical_list": "D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2015.283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "110(10)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001219:Aspartate Aminotransferases; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D015331:Cohort Studies; D018450:Disease Progression; D005234:Fatty Liver; D005260:Female; D006505:Hepatitis; D006801:Humans; D008099:Liver; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1450-9",
"pmc": null,
"pmid": "26346867",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "19132805;19155082;17555424;17133470;16539636;15565570;10421667;10205214;7982642;8201211;12879986;12484709;12395370;11172349;10869294;18955056;20512999;25039930;24681128;24037963;23081825;22911653;22577093;21983984;20858492",
"title": "Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.",
"title_normalized": "persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury"
} | [
{
"companynumb": "US-TAKEDA-2015TJP022747",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Within the recent years, RNA interference (RNAi) has become an almost standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential therapeutic use. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. This chapter describes the in vivo application of targeted non-virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation. A remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells was found. In vivo siRNA application was well tolerated without any clinically adverse events. The current findings imply that the clinical application of synthetic siRNA is feasible and safe and has real potential for genetic-based therapies using synthetic non-viral carriers.",
"affiliations": "Faculty of Medicine, Department of Bone Marrow Transplantation, West German Cancer Center, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany, michael.koldehoff@uk-essen.de.",
"authors": "Koldehoff|Michael|M|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D005229:Fatty Acids, Monounsaturated; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane",
"country": "United States",
"delete": false,
"doi": "10.1007/978-1-4939-1538-5_17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-3745",
"issue": "1218()",
"journal": "Methods in molecular biology (Clifton, N.J.)",
"keywords": null,
"medline_ta": "Methods Mol Biol",
"mesh_terms": "D000970:Antineoplastic Agents; D017209:Apoptosis; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D005229:Fatty Acids, Monounsaturated; D005260:Female; D016044:Fusion Proteins, bcr-abl; D015973:Gene Expression Regulation, Leukemic; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; D034622:RNA Interference; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016896:Treatment Outcome",
"nlm_unique_id": "9214969",
"other_id": null,
"pages": "277-92",
"pmc": null,
"pmid": "25319658",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions.",
"title_normalized": "targeting bcr abl transcripts with sirnas in an imatinib resistant chronic myeloid leukemia patient challenges and future directions"
} | [
{
"companynumb": "DE-AUROBINDO-AUR-APL-2021-011154",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional"... |
{
"abstract": "We present three cases of autoimmune pancreatitis (AIP) complicated by gastric varices. Case 1: A 57-year-old man was diagnosed with AIP complicated by gastric varices and splenic vein obstruction. Splenomegaly was not detected at the time of the diagnosis. The AIP improved using steroid therapy, the splenic vein was reperfused, and the gastric varices disappeared; case 2: A 55-year-old man was diagnosed with AIP complicated by gastric varices, splenic vein obstruction, and splenomegaly. Although the AIP improved using steroid therapy, the gastric varices and splenic vein obstruction did not resolve; case 3: A 68-year-old man was diagnosed with AIP complicated by gastric varices, splenic vein obstruction, and splenomegaly. The gastric varices, splenic vein obstruction, and AIP did not improve using steroid therapy. These three cases suggest that gastric varices or splenic vein obstruction without splenomegaly may be an indication for steroid therapy in patients with AIP because the complications will likely become irreversible over time.",
"affiliations": "Department of Gastroenterology, Nishi-Kobe Medical Center, Hyogo 651-2273, Japan. marshall_prs@nmc-kobe.org",
"authors": "Goto|Norihiro|N|;Mimura|Jun|J|;Itani|Toshinao|T|;Hayashi|Motohito|M|;Shimada|Yukari|Y|;Matsumori|Tomoaki|T|",
"chemical_list": "D013256:Steroids",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v18.i31.4228",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "18(31)",
"journal": "World journal of gastroenterology",
"keywords": "Autoimmune; Gastric varices; Pancreatitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D004932:Esophageal and Gastric Varices; D006801:Humans; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D013162:Splenic Vein; D013163:Splenomegaly; D013256:Steroids; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4228-32",
"pmc": null,
"pmid": "22919259",
"pubdate": "2012-08-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15855821;18499030;15128363;20213336;1735356;9462408;12077078;3500243;10636062;7628283;16682257;17541445;15632697",
"title": "Autoimmune pancreatitis complicated by gastric varices: a report of 3 cases.",
"title_normalized": "autoimmune pancreatitis complicated by gastric varices a report of 3 cases"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1019283",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"abstract": "Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET.\n\n\n\nA 37-year-old male with lower abdominal pain and weight loss was referred to our hospital. Abdominal ultrasound and computed tomography (CT) showed diffuse peritoneal implants. Surgical specimen histology showed a GIST with c-KIT exon 11 deletion (c.1708_1728del) and treatment with imatinib 400 mg/day was initiated. Due to disease progression illustrated on baseline versus follow-up 18F-FDG-PET/CT scans therapy was switched to imatinib 800 mg/day and later to sunitinib 50 mg/day. Upon further disease progression 10 months later, third line treatment with regorafenib 160 mg/day was initiated. 18F-FDG-PET/CT showed the metabolic responses after 4 months regorafenib treatment ranging from complete response to the appearance of a new lesion in the liver. The new hypermetabolic lesion was only seen on the non-attenuation-corrected images because of breathing motion artifact.\n\n\n\nThis case illustrates that metabolic response can occur in GIST lesions without morphological response after third line regorafinib treatment. Furthermore this is the first case in literature to show regorafinib response on PET.",
"affiliations": "Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. Donatienne.vanweehaeghe@uzleuven.be.;Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Radiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.",
"authors": "Van Weehaeghe|Donatienne|D|0000-0001-6646-106X;Gheysens|Olivier|O|;Vandecaveye|Vincent|V|;Schöffski|Patrick|P|;Van Laere|Koen|K|;Deroose|Christophe M|CM|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 415410.1186/s12885-018-4154-7Case ReportMixed response on regorafenib treatment for GIST (gastro-intestinal stromal tumor) according to 18F–FDG-PET/CT http://orcid.org/0000-0001-6646-106XVan Weehaeghe Donatienne +32 16 34 20 59Donatienne.vanweehaeghe@uzleuven.be 1Gheysens Olivier olivier.gheysens@uzleuven.be 1Vandecaveye Vincent Vincent.vandecaveye@uzleuven.be 2Schöffski Patrick Patrick.schoffski@uzleuven.be 3Van Laere Koen koen.vanlaere@uzleuven.be 1Deroose Christophe M. christophe.deroose@uzleuven.be 11 0000 0004 0626 3338grid.410569.fNuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 2 0000 0004 0626 3338grid.410569.fRadiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 3 0000 0004 0626 3338grid.410569.fDepartment of oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 5 3 2018 5 3 2018 2018 18 25323 10 2017 20 2 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nGastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET.\n\nCase presentation\nA 37-year-old male with lower abdominal pain and weight loss was referred to our hospital. Abdominal ultrasound and computed tomography (CT) showed diffuse peritoneal implants. Surgical specimen histology showed a GIST with c-KIT exon 11 deletion (c.1708_1728del) and treatment with imatinib 400 mg/day was initiated. Due to disease progression illustrated on baseline versus follow-up 18F–FDG-PET/CT scans therapy was switched to imatinib 800 mg/day and later to sunitinib 50 mg/day. Upon further disease progression 10 months later, third line treatment with regorafenib 160 mg/day was initiated. 18F–FDG-PET/CT showed the metabolic responses after 4 months regorafenib treatment ranging from complete response to the appearance of a new lesion in the liver. The new hypermetabolic lesion was only seen on the non-attenuation-corrected images because of breathing motion artifact.\n\nConclusion\nThis case illustrates that metabolic response can occur in GIST lesions without morphological response after third line regorafinib treatment. Furthermore this is the first case in literature to show regorafinib response on PET.\n\nKeywords\nGIST18F–FDG-PET/CT RegorafenibFollow-upAttenuation-artefactRespiratory motionCase reportissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nGastro-intestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastro-intestinal tract. However they are very rare, accounting for about 1% of the tumors of the gastro-intestinal tract. These tumors originate from the interstitial cells of Cajal or other common cell precursors which express tyrosine kinase receptors (type III). They are sometimes called the pacemaker cells of the gut. Treatment consists of surgical resection with or without adjuvant/neo-adjuvant therapy with an oral multi-kinase inhibitor like regorafinib [1–3].\n\nRegorafenib is an oral multi-kinase inhibitor used to treat metastatic GISTs after progression on standard treatment. It significantly improve progression-free survival compared with placebo in patients [3]. To our knowledge this is the first case in literature to show the response of regorafenib on 18F–FDG PET/CT.\n\nCase presentation\nA 37-year-old male complaining about lower abdominal pain and weight loss was referred to our hospital. He reported a weight loss of 5 kg in the last 3 months. An abdominal ultrasound and computed tomography (CT) were performed as work-up. Both examinations showed diffuse peritoneal implants.\n\nDiscussion\nSurgical exploration and debulking was performed to obtain a tumor specimen for histopathological examination. Histological examination of this specimen showed a GIST with c-KIT exon 11 deletion (c.1708_1728del). As 18F–FDG PET has been shown of significant value in evaluating treatment response in GISTs, high dose contrast-enhanced 18F–FDG PET/CT scans (374.9 ± 17.2 MBq; approximately 60 min after tracer injection) were performed both before treatment and after every therapy switch to evaluate treatment response [4]. 18FDG-PET/CT performed for tumor staging showed multiple tumor localizations in the small bowel, the sigmoid and mesenterium without signs of extra-abdominal disease. Treatment with imatinib 400 mg daily was started with follow-up 18F–FDG PET/CT 2 months later showing disease progression. The dose was increased to 800 mg daily but follow-up 18F–FDG PET/CT 3 months later again revealed disease progression. A switch to sunitinib 50 mg once a day was performed. Upon further disease progression on the 18F–FDG PET/CT 10 months later, third line treatment with regorafenib 160 mg/day was initiated with a mixed response on 18F–FDG-PET/CT 4 months after treatment initiation with regorafinib (Fig. 1). There was one lesion with a complete metabolic response (CR), one with a partial metabolic response (PMR) and one with stable disease (SD) according to the EORTC criteria for 18F–FDG-PET response [5].Fig. 1 Maximal intensity projection (MIP) images of the 18F–FDG-PET scan at baseline and after regorafenib treatment. CR = complete response; SD = stable disease; Deep PMR = deep partial metabolic response\n\n\n\nPre- and post-therapy with regorafinib fused PET/CT and CT images with the differences in maximal standardized uptake value (ΔSUVmax) and differences in maximal diameter (Δdiammax) are shown in Figs. 2 and 3. The lesion with complete metabolic response had a ΔSUVmax of − 91% and a Δdiammax of − 1.7%. The lesion with the partial metabolic response had a ΔSUVmax of − 56% and a Δdiammax of − 21%. Both lesions were stable disease on CT scan according to the RECIST1.1 criteria. [6]. The lesion with stable disease on PET had a ΔSUVmax of − 8.0% and a Δdiammax of − 3.3%. The total volume of the lesion with complete metabolic response was 19.9 cm3 pretherapy and 17.6 cm3 posttherapy. The lesions with partial metabolic response and stable disease did not change in volume and were respectively 4.1 cm3 and 3.6 cm3. The volume of the new lesion was 3.2 cm3. No histological confirmation of this new lesion was obtained due to the general condition of the patient. However, this lesion increased both in volume and metabolism on follow-up scans, compatible with a true positive new tumoral lesion.Fig. 2 Pre- and post-therapy fused PET/CT and CT images of the different lesions. NAC = non-attenuation-corrected images\n\nFig. 3 Pre- and post-therapy fused PET/CT and CT images of the different lesions\n\n\n\nBesides these previously known lesions, a new hypermetabolic lesion was seen on the non-attenuation-corrected (NAC) 18F–FDG-PET images. It corresponded to a new hypodense liver lesion on CT, implying a new liver metastasis. However, the lesion was not visible on the attenuation-corrected (AC) and MIP images because of breathing motion-induced misregistration and subsequent lung density attenuation correction, which strongly reduces the apparent uptake in the lesion. This lesion has important consequences for the patient with regard to further treatment options (switch to another tyrosine kinase inhibitor) and illustrates the importance to look at NAC images on all oncological scans, in particular not to miss liver lesions within the liver dome [7, 8].\n\nConclusion\nThis case illustrates that metabolic response to third line regorafinib treatment can occur in GIST lesions without morphological response. Therefore, even though it did not affect treatment decision in this case, this finding highlights the importance of 18F–FDG PET scans in the evaluation of treatment response in future GIST tumors cases.\n\nAbbreviations\n18F-FDG PET[18]Fluor-Fluorodeoxyglucose Positron Emission Tomography\n\nACAttenuation-corrected\n\nc.1708_1728delc-KIT exon 11 deletion\n\nCRComplete metabolic response\n\nCTComputed tomography\n\nGISTsGastro-intestinal stromal tumors\n\nMIPMaximal intensity projection\n\nNACNon-attenuation-corrected\n\nPMRPartial metabolic response\n\nRECISTRespons Evaluation Criteria in Solid Tumours\n\nSDStable disease\n\nΔdiammaxMaximal diameter\n\nΔSUVmaxMaximal standardized uptake value\n\nAcknowledgements\nWe have no acknowledgments to be made.\n\nFunding\nNo funding for this case report was received.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors contributed to the manuscript in order of publication. DVW contributed to the conception, design, acquisition, analysis and interpretation of data, drafted the manuscript, gave final approve and agreed to be accountable for all aspects of the work. OG: contributed to the conception, design, acquisition, gave final approve and agreed to be accountable for all aspects of the work. VV: contributed to the acquisition, gave final approve and agreed to be accountable for all aspects of the work. PS: contributed to the acquisition, gave final approve and agreed to be accountable for all aspects of the work. KVL: contributed to the acquisition, gave final approve and agreed to be accountable for all aspects of the work. CMD: contributed to the conception, design, acquisition, analysis and interpretation of data, has been involved in drafting the manuscript, gave final approve and agreed to be accountable for all aspects of the work.\n\nEthics approval and consent to participate\nThis study was approved by the Ethics Committee UZ Leuven. Informed written consent from the patient was received.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Maki RG Blay JY Demetri GD Fletcher JA Joensuu H Martin-Broto J Key issues in the clinical Management of Gastrointestinal Stromal Tumors: an expert discussion Oncologist 2015 20 823 830 10.1634/theoncologist.2014-0471 26070915 \n2. Valsangkar N Sehdev A Misra S Zimmers TA O'Neil BH Koniaris LG Current management of gastrointestinal stromal tumors: surgery, current biomarkers, mutations, and therapy Surgery 2015 158 1149 1164 10.1016/j.surg.2015.06.027 26243346 \n3. Demetri GD Reichardt P Kang YK Blay JY Rutkowski P Gelderblom H Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 295 302 10.1016/S0140-6736(12)61857-1 23177515 \n4. Hassanzadeh-Rad A Yousefifard M Katal S Asady H Fard-Esfahani A Moghadas Jafari A The value of (18) F-fluorodeoxyglucose positron emission tomography for prediction of treatment response in gastrointestinal stromal tumors: a systematic review and meta-analysis J Gastroenterol Hepatol 2016 31 929 935 10.1111/jgh.13247 26642423 \n5. Young H Baum R Cremerius U Herholz K Hoekstra O Lammertsma AA Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of cancer (EORTC) PET study group Eur J Cancer 1999 35 1773 1782 10.1016/S0959-8049(99)00229-4 10673991 \n6. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \n7. Papathanassiou D Liehn JC Bourgeot B Amir R Marcus C Cesium attenuation correction of the liver dome revealing hepatic lesion missed with computed tomography attenuation correction because of the respiratory motion artifact Clin Nucl Med 2005 30 120 121 10.1097/00003072-200502000-00015 15647684 \n8. Sarikaya I Yeung HW Erdi Y Larson SM Respiratory artefact causing malpositioning of liver dome lesion in right lower lung Clin Nucl Med 2003 28 943 944 10.1097/01.rlu.0000093095.28642.2b 14578720\n\n",
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"keywords": "18F–FDG-PET/CT; Attenuation-artefact; Case report; Follow-up; GIST; Regorafenib; Respiratory motion",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D019788:Fluorodeoxyglucose F18; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds; D000072078:Positron Emission Tomography Computed Tomography; D011379:Prognosis; D011725:Pyridines; D019275:Radiopharmaceuticals",
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"title": "Mixed response on regorafenib treatment for GIST (gastro-intestinal stromal tumor) according to 18F-FDG-PET/CT.",
"title_normalized": "mixed response on regorafenib treatment for gist gastro intestinal stromal tumor according to 18f fdg pet ct"
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"abstract": "BACKGROUND\nCerebral aspergillosis (CA) is a rare manifestation of invasive aspergillosis. It usually affects seriously immunocompromised hosts. Pancreatic bacterial or/and fungal infection is common in patients with severe acute pancreatitis.\nWe report the first case of an immunocompetent woman with infected necrotizing pancreatitis due to multidrug resistant Acinetobacter baumannii who, in the course of treatment, developed isolated CA.\nMagnetic resonance imaging, rather than computed tomography, revealed latent homolateral sinus disease-the possible source of the Aspergillus infection.\n\n\nMETHODS\nThe pancreatic infection was controlled by open necrosectomy, and the CA was disappeared after neuronavigation-guided drainage and voriconazole antifungal therapy.\n\n\nRESULTS\nThe patient was discharged without complications. Our report revealed that persistent hyperglycemia, sepsisassociated immunoparalysis, and prolonged antibiotic use could impair severe patient's immunocompetence, making them more susceptible to opportunistic cerebral Aspergillus infection; the risk may be especially high in patients with paranasal sinus diseases.\n\n\nCONCLUSIONS\nTimely neurosurgical intervention combined with voriconazole antifungal therapy can provide a favorable outcome.",
"affiliations": "Department of SICU The Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, China.",
"authors": "Zhang|Shaoyang|S|;Fu|Qinghui|Q|;Chen|Qi|Q|;Liang|Ting-Bo|TB|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-17-0621410.1097/MD.0000000000008908089084900Research ArticleClinical Case ReportIsolated cerebral aspergillosis in an immunocompetent woman on treatment for bacterial infected necrotizing pancreatitis A case reportZhang Shaoyang MDaFu Qinghui MDaChen Qi MDaLiang Ting-bo MD, PhDb∗NA. a Department of SICUb The Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, China.∗ Correspondence: Ting-bo Liang, The Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine. 310000, Zhejiang Province, China (e-mail: liangtingbo@zju.edu.com).12 2017 01 12 2017 96 48 e89088 10 2017 30 10 2017 6 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0Abstract\nRationale:\nCerebral aspergillosis (CA) is a rare manifestation of invasive aspergillosis. It usually affects seriously immunocompromised hosts. Pancreatic bacterial or/and fungal infection is common in patients with severe acute pancreatitis.\n\nPatient concerns:\nWe report the first case of an immunocompetent woman with infected necrotizing pancreatitis due to multidrug resistant Acinetobacter baumannii who, in the course of treatment, developed isolated CA.\n\nDiagnoses:\nMagnetic resonance imaging, rather than computed tomography, revealed latent homolateral sinus disease—the possible source of the Aspergillus infection.\n\nInterventions:\nThe pancreatic infection was controlled by open necrosectomy, and the CA was disappeared after neuronavigation-guided drainage and voriconazole antifungal therapy.\n\nOutcome:\nThe patient was discharged without complications. Our report revealed that persistent hyperglycemia, sepsisassociated immunoparalysis, and prolonged antibiotic use could impair severe patient's immunocompetence, making them more susceptible to opportunistic cerebral Aspergillus infection; the risk may be especially high in patients with paranasal sinus diseases.\n\nLessons:\nTimely neurosurgical intervention combined with voriconazole antifungal therapy can provide a favorable outcome\n\nKeywords\ncerebral aspergillosisimmunocompetenceinfected necrotizing pancreatitissepsisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCerebral aspergillosis (CA) is an opportunistic fungal infection that usually affects seriously immunocompromised hosts, typically patients on cytotoxic chemotherapy or immunosuppressive therapy, those receiving long-term corticosteroids, or those with neutropenia or immunodeficient states such as AIDS.[1] However, there is an increasing number of reports of CA in immunocompetent patients, especially in the intensive care unit (ICU).[2–4] Without effective management, CA has a poor prognosis. Often, the outcome depends on the immune status of the host. The mortality rate is 10% to 20% in immunocompetent patients without systemic involvement versus 90% to 100% in immunocompromised patients.[2,3]\n\nPancreatic bacterial or/and fungal infection is common in patients with severe acute pancreatitis. We describe a previously immunocompetent woman with infected necrotizing pancreatitis (INP) due to multidrug resistant Acinetobacter baumannii who, in the course of treatment, developed CA. To our knowledge this is the first report of CA in patients with pancreatitis. The possible causes and treatment of CA following INP are discussed.\n\n2 Case report\nA 72-year-old female with history of hypertension and secondary hypothyroidism was admitted to a regional hospital for an attack of acute pancreatitis. She had no other disease and no apparent immune deficiency. On the third day, she developed circulatory collapse with acute respiratory distress syndrome. She was transferred to the ICU, intubated, and started on mechanical ventilation. Supportive therapy with fluid resuscitation, pain relievers, oxygen administration, and antiemetics was provided as necessary. The circulatory failure responded to vasopressors and fluid resuscitation and was stabilized after 3 days. However, she developed high-grade fever, and empirical antibiotic therapy was started (first, with ceftriaxone and then a carbapenem). Small doses of corticosteroids were also administered intermittently to control her hyperpyrexia, but the fever persisted. Her blood glucose levels were also persistently high (>10 mmol/L). As she had severe abdominal distention, she was on total parenteral nutrition. On day 18, because of persistent severe abdominal distention and hyperpyrexia, she was transferred to our institution.\n\nAt our hospital, symptomatic treatment and close monitoring were continued. Partial enteral nutrition was started. Because of persistent systemic inflammatory response syndrome (SIRS) and suspected of sepsis, broad-spectrum antibiotics were continued (initially imipenem, with vancomycin added later). The hyperglycemia was reduced with insulin, but there were wide swings in blood sugar levels. On day 22, contrast-enhanced computed tomography (CECT) revealed extensive parenchymal necrosis of the body and head regions of the pancreas. Despite full doses of broad-spectrum antibiotics, the patient continued to spike fevers. Infected pancreatic necrosis was suspected and percutaneous catheter drainage of the necrotic collections was performed on day 27. Cultures of peripancreatic drainage fluid grew multidrug resistant A baumannii, and antibiotic treatment with tigecycline and imipenem was started. Since she showed no response, open necrosectomy was done on day 31. Tigecycline and imipenem were administered postoperatively for 2 weeks, after which tigecycline was withdrawn and only imipenem was continued. The infection was controlled, and the clinical symptoms and laboratory data showed obvious improvement after surgical debridement. The temperature and blood sugar level returned to normal. Two weeks after operation, total enteral nutrition was achieved. The tracheostomy tube was removed 3 weeks after the abdominal operation.\n\nFour weeks after the abdominal surgery, however, the patient suddenly developed chills and fever, altered mental status, and seizures. Magnetic resonance imaging (MRI) of the head revealed a solitary 3-cm size oval mass in the right frontal lobe (Fig. 1A), with the right sphenoid sinus wall showing hyperintense signal on T2-weighted MR images (Fig. 2A). CECT of the head done 4 days later showed a ring-enhancing lesion with perifocal edema in the right frontal lobe (Fig. 1B). Contrast-enhanced MRI confirmed the right sphenoid sinus disease (Fig. 2B) and the homolateral frontal lobe mass with edge enhancement (Fig. 1C). Infection workup confirmed the diagnosis of cerebral abscess, and neuronavigation-guided aspiration and drainage was performed. Cytopathology and culture of surgically aspirated specimens revealed hyphae and confirmed that the brain abscess was due to Aspergillus. The serum was also positive for galactomannan antigen. CT scan and respiratory culture ruled out invasive pulmonary aspergillosis. Intravenous voriconazole (6 mg/kg twice a day on day 1, followed by 4 mg/kg twice daily) was initiated as soon as the diagnosis was established. After 4 weeks of treatment with voriconazole, her symptoms were improved and the brain lesion had almost disappeared on CECT (Fig. 1D). Then, she was discharged without complications.\n\nFigure 1 Contrast-enhanced computed tomography (CECT) and magnetic resonance imaging (MRI) of the brain lesion: (A) On day 59, a single mass is seen, with a thin, slightly irregular, hypointense ring on T2-weighted MR images (arrow marked). (B) On day 63, CECT scan shows a ring-enhancing lesion with perifocal edema in the right frontal lobe (arrow marked) (C) On day 64, an isolated abscess in the frontal lobe, with edge enhancement on contrast-enhanced MRI (arrow marked). (D) On day 87 (3 weeks after head surgery), the brain lesion has almost disappeared on CECT. CECT = contrast-enhanced computed tomography, MRI = magnetic resonance imaging\n\nFigure 2 Sphenoid sinus display in MRI and CT: (A) On day 59, the right sphenoid sinus wall shows hyperintense signal on T2-weighted MR images (arrow marked). (B) On day 64, contrast-enhanced MR images shows abnormally enhancing soft tissue in the right sphenoid sinus (arrow marked). CECT on day 63 (C) and CT on day 76 (D) does not reveal the sphenoid sinus disease. CECT = contrast-enhanced computed tomography, CT = computed tomography, MRI = magnetic resonance imaging.\n\nAfter discharge, the patient could not afford to continue voriconazole therapy and did not take any other antifungal treatment; she refused further intervention, and died 6 months after discharge.\n\n3 Discussion\nAspergillus is a ubiquitous saprophytic fungus found in soil, growing as a mold on decaying vegetable matter. Aspergillus fungal spores can be inhaled into the upper respiratory tract and survive as a commensal of the paranasal sinuses; it can also colonize the external auditory canal.[5] Depending on the host's immune status, a variety of diseases can be caused by Aspergillus spp., ranging from allergies and superficial infections to life-threatening invasive mycoses. Inhalation of Aspergillus spp. conidia by immunocompetent individuals rarely causes disease as they are efficiently eliminated by immune mechanisms.[6] However, individuals with compromised immune systems are at high risk of developing a fatal fungal infection. The continuing advances in medical care, with many patients surviving with chemotherapy and immunosuppressive therapies (following transplants), has contributed to the steadily increasing number of patients with impaired immune systems.[7] Rarely, infection may occur in apparently immunocompetent patients. Our patient, for instance, can be considered to have been immunocompetent. The well-encapsulated lesion seen on her MRI and CECT was evidence of competent host defense mechanisms attempting to isolate or encapsulate the infecting organism. However, the course of severe acute pancreatitis and the extended stay in the ICU, with multiple invasive procedures, poorly controlled hyperglycemia, sepsis-associated immunoparalysis, prolonged antibiotic and intermittently corticosteroid use, all contributed to the development of invasive aspergillosis (IA) in our patient. Existing researches show that extended ICU stay, hemodialysis, advanced liver disease, antibiotics, low-dose steroids, congestive heart failure, chronic obstructive pulmonary disease, mechanical ventilation, and diabetes are known risk factors for IA in ICU patients without classical immunosuppression.[4,8]\n\nSevere acute pancreatitis results in marked metabolic stress, and causes a state of hyperglycemia. Alterations in glucose and insulin regulation adversely affect the function of the cellular components of the innate immune system.[9] In combination with inadequate systemic insulin levels and insulin resistance, long-term exposure to stress-induced hyperglycemia is linked to increased incidence of infections and sepsis, multiorgan failure, and mortality.[10] During the course of INP, sepsis-associated immunoregulatory disturbances, such as macrophage deactivation and altered cellular immune response, can induce a state of immunoparalysis, hampering host response to fungal infection.[11] Treatment with broad-spectrum antibiotics is at the cost of increased risk of infection with multidrug-resistant bacteria or opportunistic microorganisms. Administration of broad-spectrum antibiotics over a 3-month period has been shown to predispose to central nervous system aspergillosis.[12] Our patient had been on broad-spectrum antibiotics for 8 weeks, consequently, developed multidrug-resistant A baumannii infection and concomitantly with CA. The elevated blood sugar also likely promoted the development CA.[13] A high prevalence of diabetes mellitus has reported in immune-competent patients with CA.[14] Diabetes is known to have an immunosuppressive effect, but the relationship between persistent hyperglycemia and CA has not been studied. In our case, depressed phagocyte activity induced by persistent hyperglycemia and insulin resistance might promote survival of Aspergillus in mucosal surfaces through a decrease in mucosal clearance of the fungus.\n\nAspergillus can reach the brain by 3 different routes: by hematogenous spread from a remote extracranial focus; by extension from a contiguous extracranial location; and by direct introduction consequent to mechanical breakdown of the blood–brain barrier due to surgery or trauma.[15] Our patient had not undergone any neurosurgical procedure previously and had no evidence of invasive pulmonary aspergillosis. She did, however, have homolateral sinus disease, and the location of the cerebral abscess suggested that the source of infection may have been a small focus in the paranasal sinuses, with infection reaching the brain via direct extension or the hematogenous route. In the literature, CT scan has been mentioned as the modality of choice for identifying paranasal sinus disease. In our patient, CT scan could not identify the focus of infection in the paranasal sinus (Fig. 2C and D), but, MRI readily revealed the tiny sinus lesions (Fig. 2A and B).\n\nThe gold standard of systemic antifungal treatment is voriconazole; it is significantly superior to amphotericin B and its use has led to a profound improvement in the survival rates of patients with CA.[16] Liposomal amphotericin B appears to be an alternative for primary treatment, while caspofungin, amphotericin B lipid complex, or posaconazole are capable of inducing partial or complete response in patients refractory to, or intolerant of, primary antifungal therapy. Generally, antifungal therapy should be continued until the manifestations of IA have been completely resolved or until residual scarring is demonstrated with imaging, which may take up to 12 weeks. Our patient only administered with voricanazole antifungal therapy for 4 weeks, and failed to continue antifungal therapy maybe give rise to her death 6 months later.\n\nSurgical drainage or excision, tailored to the location and size of the lesion, is an important adjunct to antifungal therapy and may be life saving. Surgery can decrease the fungal load, allow better antifungal penetration, relieve mass effect, and decrease the local neurotoxic and inflammatory effects of the fungal infection.[17] Neurosurgical intervention combined with antifungal therapy has provided better survival rates than pharmacologic treatment alone.[2,18,19]\n\nIn conclusion, CA may occur in immunocompetent patients. MRI precedes CT on identify the latent sinus disease—the possible source of the Aspergillus infection. Persistent hyperglycemia, sepsis-associated immunoparalysis, and prolonged antibiotic use could impair severe patient's immunocompetence, making them more susceptible to opportunistic cerebral Aspergillus infection; the risk may be especially high in patients with paranasal sinus diseases. The combination of timely neurosurgical intervention and voriconazole antifungal therapy appears to have a favorable outcome.\n\nAbbreviations: AIDS = acquired immunodeficiency syndrome, CA = cerebral aspergillosis, CECT = contrast-enhanced computed tomography, ICU = intensive care unit, INP = infected necrotizing pancreatitis, MRI = magnetic resonance imaging, SIRS = systemic inflammatory response syndrome.\n\nConsent: Written informed consent was obtained from the patient's family members for publication of this case report and any accompanying images.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Hohl TM \nImmune responses to invasive aspergillosis: new understanding and therapeutic opportunities . Curr Opin Infect Dis \n2017 ;30 :364 –71 .28509673 \n[2] Bokhari R Baeesa S Al-Maghrabi J \nIsolated cerebral aspergillosis in immunocompetent patients . World Neurosurg \n2014 ;82 :e325 –33 .24076053 \n[3] Spapen H Spapen J Taccone FS \nCerebral aspergillosis in adult critically ill patients: a descriptive report of 10 patients from the AspICU cohort . Int J Antimicrob Agents \n2014 ;43 :165 –9 .24315314 \n[4] Taccone FS Van den Abeele AM Bulpa P \nEpidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes . Crit Care \n2015 ;19 :7 .25928694 \n[5] McCarthy MW Aguilar-Zapata D Petraitis V \nDiagnosis, classification, and therapeutic interventions for sinopulmonary aspergillosis . Expert Rev Respir Med \n2017 ;11 :229 –38 .28095078 \n[6] Krappmann S \nHow to invade a susceptible host: cellular aspects of aspergillosis . Curr Opin Microbiol \n2016 ;34 :136 –46 .27816786 \n[7] Brown GD Denning DW Gow NA \nHidden killers: human fungal infections . Sci Transl Med \n2012 ;4 :165rv13 .\n[8] Stevens DA Melikian GL \nAspergillosis in the ’nonimmunocompromised’ host . Immunol Invest \n2011 ;40 :751 –66 .21985304 \n[9] Xiu F Stanojcic M Diao L \nStress hyperglycemia, insulin treatment, and innate immune cells . Int J Endocrinol \n2014 ;2014 :486403 .24899891 \n[10] Kerby JD Griffin RL MacLennan P \nStress-induced hyperglycemia, not diabetic hyperglycemia, is associated with higher mortality in trauma . Ann Surg \n2012 ;256 :446 –52 .22868366 \n[11] Hartemink KJ Paul MA Spijkstra JJ \nImmunoparalysis as a cause for invasive aspergillosis? \nIntensive Care Med \n2003 ;29 :2068 –71 .12768234 \n[12] Chen S Pu JL Yu J \nMultiple Aspergillus cerebellar abscesses in a middle-aged female: case report and literature review . Int J Med Sci \n2011 ;8 :635 –9 .22022217 \n[13] Pellacchia V Terenzi V Moricca LM \nBrain abscess by mycotic and bacterial infection in a diabetic patient: clinical report and review of literature . J Craniofac Surg \n2006 ;17 :578 –84 .16770203 \n[14] Hodgson KA Morris JL Feterl ML \nAltered macrophage function is associated with severe Burkholderia pseudomallei infection in a murine model of type 2 diabetes . Microbes Infect \n2011 ;13 :1177 –84 .21835260 \n[15] Wang RX Zhang JT Chen Y \nCerebral aspergillosis: a retrospective analysis of eight cases . Int J Neurosci \n2017 ;127 :339 –43 .26978276 \n[16] Patterson TF Thompson GR 3rdDenning DW \nPractice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America . Clin Infect Dis \n2016 ;63 :e1 –60 .27365388 \n[17] Ellenbogen JR Waqar M Cooke RP \nManagement of granulomatous cerebral aspergillosis in immunocompetent adult patients: a review . Br J Neurosurg \n2016 ;30 :280 –5 .26853515 \n[18] Kourkoumpetis TK Desalermos A Muhammed M \nCentral nervous system aspergillosis: a series of 14 cases from a general hospital and review of 123 cases from the literature . Medicine (Baltimore) \n2012 ;91 :328 –36 .23117848 \n[19] Panda PK Mavidi SK Wig N \nIntracranial aspergillosis in an immunocompetent young woman . Mycopathologia \n2017 ;182 :527 –38 .28054219\n\n",
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"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000368:Aged; D001228:Aspergillosis; D002494:Central Nervous System Infections; D005260:Female; D006801:Humans; D007121:Immunocompetence; D008279:Magnetic Resonance Imaging; D019283:Pancreatitis, Acute Necrotizing",
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"title": "Isolated cerebral aspergillosis in an immunocompetent woman on treatment for bacterial infected necrotizing pancreatitis: A case report.",
"title_normalized": "isolated cerebral aspergillosis in an immunocompetent woman on treatment for bacterial infected necrotizing pancreatitis a case report"
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"abstract": "BACKGROUND\nAnemia is the most frequent hematological disturbance in cancer patients, with prevalence between 30% and 90%, depending on the type of tumor, the antitumor treatment, and other factors (infection, malnutrition, bleeding, tumor infiltration of the bone marrow). A number of erythropoietic agents have shown to be effective in increasing the hemoglobin (Hb) levels, reducing the requirements for transfusion, and improving quality of life. The objective of this study is to compare darbepoetin alfa and epoetin alfa when used to correct anemia in cancer patients who are receiving radiotherapy or radiochemotherapy.\n\n\nMETHODS\nA prospective study of 125 consecutive patients with anemia (Hb <13 g/dL in males or <12 g/dL in females) who were undergoing treatment with radiotherapy (RT) or radiochemotherapy (RCT) in our department were enrolled between March 2003 and March 2005. The treatment for the anemia was either darbepoetin alfa 150 mcg/week (62 patients, group 1) or epoetin alfa 40,000 IU/week (63 patients, group 2). Patients received iron supplements in both groups. Treatment was administered in a consecutive manner depending on tumor type. If the increase in Hb was <1 g/dL after 4 weeks of treatment, the dose was increased to 300 mcg/week in group 1 or to 60,000 IU/week in group 2. The treatment was terminated when a Hb value of ≥15 g/dL was reached during RT treatment, a Hb value of ≥14 g/dL was reached if the RT had been completed, or after 16 weeks of treatment whatever the Hb value. The mean age of patients was 63.36 ± 11.27 years, 67% were male. No significant differences were observed between the 2 groups in tumor type or stage, previous treatments, or intent to treat with RT or RCT.\n\n\nRESULTS\nComparing group 1 and group 2 by intent to treat, the mean Hb at the start of treatment with the study drug was 12.1 g/dL vs 11.8 g/dL, the proportion of patients whose dose was increased was 19.7% vs 24.6%, the need for transfusion was 3.2% in each group, the duration of erythropoietic treatment was 6.5 weeks in both groups, and 2 patients in group 2 restarted treatment with epoetin alfa. The percentage of patients who responded (defined as an increase in the Hb ≥ 2 g/dL in the absence of transfusions) was of 72.6% and 66.7%, respectively. Four vascular adverse events were observed, 2 in each group. No significant differences were observed with respect to the baseline, week 4, and week 12 levels of endogenous erythropoietin, serum iron,% saturation, and ferritin. The increase in Hb 1 month after the final administration of the study drug was 2.21 g/dL in group 1 and 2.46 g/dL in group 2 (p = ns).\n\n\nCONCLUSIONS\nThe results of our study demonstrate that both treatments are equally effective in correcting anemia in cancer patients undergoing RT or RCT.",
"affiliations": "Department of Oncological Radiotherapy Hospital Central de la Defensa, Madrid, Spain.",
"authors": "Ots|Pilar Ma Samper|PM|;Carrizosa|Concepción López|CL|;Pérez|Aurora Rodríguez|AR|;de Dios Saez Garrido|Juan|J|;Pérez|José Ma Delgado|JM|",
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"fulltext": "\n==== Front\nClin Med Oncol101467911Clinical Medicine. Oncology1177-9314Libertas Academica cmo-2-2008-393Original ResearchDarbepoetin Versus Epoetin Alfa for the Correction of Anemia in Cancer Patients Receiving Radiotherapy or Chemoradiotherapy Treatment Ots Pilar Ma Samper Carrizosa Concepción López Pérez Aurora Rodríguez de Dios Saez Garrido Juan Pérez José Ma Delgado Department of Oncological Radiotherapy Hospital Central de la Defensa, Madrid, SpainCorrespondence: Dr. Pilar Ma Samper Ots, Department of Oncological Radiotherapy, Hospital Central de la Defensa, Glorieta del Ejercito s/n, 28047 Madrid. Fax: 91 422 86 55; Email: psampero@hotmail.com2008 19 5 2008 2 393 399 © 2008 the author(s), publisher and licensee Libertas Academica Ltd.2008This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http://creativecommons.org/licenses/by/3.0/).Introduction\nAnemia is the most frequent hematological disturbance in cancer patients, with prevalence between 30% and 90%, depending on the type of tumor, the antitumor treatment, and other factors (infection, malnutrition, bleeding, tumor infiltration of the bone marrow). A number of erythropoietic agents have shown to be effective in increasing the hemoglobin (Hb) levels, reducing the requirements for transfusion, and improving quality of life. The objective of this study is to compare darbepoetin alfa and epoetin alfa when used to correct anemia in cancer patients who are receiving radiotherapy or radiochemotherapy.\n\nMaterial and methods\nA prospective study of 125 consecutive patients with anemia (Hb <13 g/dL in males or <12 g/dL in females) who were undergoing treatment with radiotherapy (RT) or radiochemotherapy (RCT) in our department were enrolled between March 2003 and March 2005. The treatment for the anemia was either darbepoetin alfa 150 mcg/week (62 patients, group 1) or epoetin alfa 40,000 IU/week (63 patients, group 2). Patients received iron supplements in both groups. Treatment was administered in a consecutive manner depending on tumor type. If the increase in Hb was <1 g/dL after 4 weeks of treatment, the dose was increased to 300 mcg/week in group 1 or to 60,000 IU/week in group 2. The treatment was terminated when a Hb value of ≥15 g/dL was reached during RT treatment, a Hb value of ≥14 g/dL was reached if the RT had been completed, or after 16 weeks of treatment whatever the Hb value. The mean age of patients was 63.36 ± 11.27 years, 67% were male. No significant differences were observed between the 2 groups in tumor type or stage, previous treatments, or intent to treat with RT or RCT.\n\nResults\nComparing group 1 and group 2 by intent to treat, the mean Hb at the start of treatment with the study drug was 12.1 g/dL vs 11.8 g/dL, the proportion of patients whose dose was increased was 19.7% vs 24.6%, the need for transfusion was 3.2% in each group, the duration of erythropoietic treatment was 6.5 weeks in both groups, and 2 patients in group 2 restarted treatment with epoetin alfa. The percentage of patients who responded (defined as an increase in the Hb ≥ 2 g/dL in the absence of transfusions) was of 72.6% and 66.7%, respectively. Four vascular adverse events were observed, 2 in each group. No significant differences were observed with respect to the baseline, week 4, and week 12 levels of endogenous erythropoietin, serum iron,% saturation, and ferritin. The increase in Hb 1 month after the final administration of the study drug was 2.21 g/dL in group 1 and 2.46 g/dL in group 2 (p = ns).\n\nConclusions\nThe results of our study demonstrate that both treatments are equally effective in correcting anemia in cancer patients undergoing RT or RCT.\n\ndarbepoetin alfaepoetin alfaanemiaradiotherapyradiochemotherapy\n==== Body\nIntroduction\nAnemia is present in 30% to 90% of cancer patients, depending on the type of tumor and on the definition of anemia used (1). Its origin is multifactorial: chronic inflammation, blood loss, nutritional deficits, hemolysis, bone marrow infiltration by malignant cells, low erythropoietin levels, and a reduction in the response to erythropoietin (2). Furthermore, most oncological treatments cause anemia (3). Anemia increases tumor hypoxia, which is common in patients with anemia, may increase the aggressive behavior of the tumor and reduce the efficacy of radiotherapy (4–6), and is therefore a prognostic factor for local control and survival (7–11).\n\nThe current treatment of anemia in cancer patients is the administration of erythropoiesis-stimulating factors. In cases of severe anemia, red blood cell (RBC) transfusions may also be used. Transfusions provide a rapid correction of anemia but are associated with a series of risks such as acute transfusion reactions and possible infections (12).\n\nRecombinant human erythropoietin (rHuEPO) is a protein that stimulates erythropoiesis and is effective in the prevention and reversal of anemia in patients with cancer (13). Darbepoetin alfa also stimulates erythropoiesis and has a longer serum half-life than rHuEPO. Darbepoetin alfa can be used in various doses and regimens including administration every 1, 2, or 3 weeks. It is well tolerated and effective for the treatment of anemia in cancer patients (14,15).\n\nThe objective of this study was to compare darbepoetin alfa with epoetin alfa, both administered weekly, for the correction of anemia in cancer patients undergoing radiotherapy (RT) or radiochemotherapy (RCT) treatment.\n\nMaterial and Methods\nWe performed a prospective study, between March 2003 and March 2004, that included 125 consecutive patients with anemia, defined as a Hb <13 g/dL in males or <12 g/dL in females. These patients were undergoing either RT or RCT in our department. Basal endogenous erythropoietin (EPO) levels and iron metabolism were measured at baseline and during the 4th and 12th weeks; and a weekly blood count was measured during RT or RCT treatment and one month after the final dose of the study drug. Two treatment groups were established: group 1, darbepoetin alfa 150 mcg/week; and group 2, epoetin alfa 40.000 IU/week. Oral iron supplements were given to patients in both groups. If the Hb increase was <1 g/dL after 4 weeks of treatment, the dose was increased to 300 mcg/week in group 1 or to 60.000 IU/week in group 2. The treatment was suspended if Hb values ≥15 g/dL were reached during RT or RCT treatment, if values ≥14 g/dL were reached after completing the RT or RCT, or after 16 weeks of treatment regardless of the Hb level. RBC transfusion was indicated if the Hb value fell below 8 g/dL. Assignment to treatment groups was made in a consecutive manner according to the tumor type: 62 patients were assigned to group 1 and 63 patients to group 2. The mean age overall was 63.36 ± 11.27 years, and 67% were males. The descriptive characteristics of the sample are presented in Table 1. Both groups well are balanced and not statistically significant differences were observed between the groups with respect to age, tumor type or stage, previous oncological treatment, or current oncological treatment: RT or RCT and intent to treat with RT.\n\nThe following variables were analyzed:\n\nthe changes in Hb levels,\n\nthe proportion of patients who doses were increased,\n\nthe percentage of patients who responded (defined as an increase in Hb of ≥2 g/dL in the absence of RBC transfusions),\n\nthe duration of treatment with the study drug,\n\nthe transfusion requirements,\n\nthe changes in iron metabolism, and\n\nthe onset of adverse events.\n\nThe SPSS version 12.0 program was used for the statistical analysis. The results are presented by intent to treat. The descriptive statistic of the sample has been made as well as comparison of the groups by means of the ANOVA test, X2 de Pearson, and univariante analysis to determine the factors that influence in the response to the treatment. The p meaning level has been considered ≤ to 0.05.\n\nResults\nThe mean levels of endogenous EPO were of 45.03 ± 44.02 mU/mL (95% confidence interval of the mean: 37.04 to 53.02 mU/mL). No statistically significant differences were observed between treatment groups (p = 0.076). The mean Hb level at the start of treatment with the study drug was 11.85 ± 1.12 g/dL in group 1 and 11.76 ± 1.13 g/dL in group 2 (p = 0.651). After 4 weeks of treatment, the Hb levels had increased in both groups: 13.16 ± 1.7 g/dL in group 1 and 13.02 ± 1.93 g/dL in group 2 (p = 0.320). The weekly changes in the Hb levels are shown in Figure 1. In group 1, the darbepoetin alfa dose was doubled in 12 patients (19.4%). The epoetin alfa dose was doubled in 15 patients (23.8%) in group 2 (p = 0.667). During the study, 2 patients (3.2%) from group 2 restarted treatment with epoetin alfa. The percentage of patients who responded was 72.6% (45 patients) in group 1 and 66.7% (42 patients) in group 2 (p = 0.3).\n\nThe mean treatment duration with the study drug was 6.47 ± 4.09 weeks in group 1 and 6.5 ± 4.1 weeks in group 2 (p = 0.923). The erythropoietic agent total average dose administered in each group was of 970.5 mcg for darbopoetin alpha and 260,000 UI for epoetin alpha respectively. The reason for termination of treatment with the study drug are presented in Table 2.\n\nOne month after the final dose of the epoetin alfa or darbepoetin alfa, the mean Hb levels were 14.25 ± 1.08 g/dL, an increase of 2.21 g/dL over baseline, in group 1 and 14.3 ± 1.35 g/dL, an increase of 2.46 g/dL over baseline, in group 2 (p = 0.440).\n\nThe Hb levels at the start of RT or RCT treatment was 13.01 ± 1.43 g/dL in group 1 and 12.7 ± 1.77 g/dL in group 2 (p = 0.461) and at the end of RT or RCT were 13.47 ± 1.69 g/dL and 13.2 ± 1.89 g/dL, respectively (p = 0.415).\n\nThirty-four adverse events (27,4% in group 1 and 27% in group 2, p = 0.558) were observed. Most adverse events were related to the tumor progression or the oncological treatment. However, 4 adverse events (2 in each treatment group) were vascular and may have been related to the administration of the study drug: 1 thrombophlebitis event, 2 acute myocardial infarction events, and 1 aortic aneurysm rupture. All events except thrombophlebitis resulted in death. Blood pressure was controlled weekly during the study and showed no marked changes.\n\nThe mean levels of serum iron, ferritin, and % saturation are shown in Table 3.\n\nDiscussion\nRecombinant HuEPO is useful in the treatment of anemia, increasing the hemoglobin levels and reducing the need for transfusion in patients with chronic anemia due to cancer. It also improves the quality of life and the performance status and is well tolerated (16,17). The best results have been obtained by subcutaneous administration (18). The standard dose of epoetin alfa in cancer patients is 150 IU/kg, 3 times per week, doubling the dose if the Hb levels have not increased at least 1 g/dL after 4 weeks of treatment. However, pharmacokinetic and pharmacodynamic studies have demonstrated equivalence between a weekly regimen of 40,000 IU and a thrice weekly regimen of 150 IU (19). In 2001, Gabrilove et al. (20), published the results from 3012 non-hematologic cancer patients undergoing chemotherapy treatment who were also receiving epoetin alfa at doses of 40,000 IU/week. The dose was increased to 60,000 IU/week if no response was obtained after 4 weeks. This once weekly regimen increased the Hb levels, reduced the transfusion requirements, and improved the quality of life in patients with cancer and anemia who were receiving chemotherapy. The results were similar to those seen when a three times a week regimen was used.\n\nDarbepoetin alfa, with its higher concentration of sialic acid, has a longer mean half-life than other epoetins. Several randomized studies have demonstrated its efficacy and tolerance in the control of anemia induced by chemotherapy in patients with lymphoproliferative diseases (21) and in those with solid tumors (15) when given weekly or three times a week (22).\n\nIn our study, we have used the guideline of administration of weekly erythropoietic agent, since the obtained results are equal to the obtained ones with regimes of three days per week and the quality of life of the patient is improved. Oral iron was administered to all the patients since the correction of the anemia is faster when the erythrpoietic agents goes along with iron administration.\n\nAlthough a number of publications discuss the efficacy and safety of the 2 erythropoietic agents, few publications compare the two. We have found only 2 retrospective studies comparing epoetin alfa and darbepoetin alfa.\n\nThe study by Reeves et al. (23,24) provides a retrospective analysis of 512 patients with chemotherapy-induced anemia who received treatment with erythropoietic agents: 196 patients received darbepoetin alfa, 212 patients received epoetin alfa, and 104 patients received both agents. Darbepoetin alfa was most frequently given in doses of 100 mcg/week and 200 mcg/2 weeks (49% and 36%, respectively, 300 patients) and 86% of the 212 patients on epoetin alfa received 40,000 IU/week. The mean baseline Hb was 10.1 g/dL for the darbepoetin alfa group and 9.6 g/dL for the epoetin alfa group. Reeves et al. analyzed the results from 350 patients (a separate analysis); 97 patients were treated with darbepoetin alfa 100 mcg/week, 70 patients were treated with darbepoetin alfa 200 mcg/2 weeks, and 183 patients were treated with epoetin alfa 40,000 IU/week. The respective increases in the Hb at 5 weeks were 0.8 g/dL, 0.8 g/dL and 0.6 g/dL and, at 8 weeks, the increases were 1.1 g/dL, 1.3 g/dL, and 0.9 g/dL. The incidence of transfusions was 4%, 11%, and 14%, respectively. The conclusion of the study was that darbepoetin alfa and epoetin alfa have a comparable efficacy in the treatment of chemotherapy-induced anemia.\n\nThe second study, published by Herrington, et al. (25), retrospectively reviewed 3123 medical histories from 65 oncology hospitals and selected 1444 patients who were treated with darbepoetin alfa and 1341 who were given epoetin alfa over 12 weeks. In 61% of the patients who received darbepoetin alfa, the dose used was 200 mcg/2 weeks, and in 72% of the patients who received epoetin alfa the dose was 40,000 IU/week. Baseline Hb was 10.3 g/dL in both groups. The dose was increased in 22% of the patients treated with darbepoetin alfa and in 23% of those treated with epoetin alfa after a mean period of 6 weeks in each group. The transfusion requirements were also similar in the 2 groups: 11% in the darbepoetin alfa group and 12% in the epoetin alfa group. After 12 weeks of treatment, the increase in Hb was 1.0 g/dL in the darbepoetin group and 1.1 g/dL in the epoetin alfa group. Harrington et al. concluded that at the doses used (darbepoetin alfa 200 mcg/2 weeks and epoetin alfa 40,000 IU/week) the efficacy is clinically comparable.\n\nIn our series, the Hb at the beginning of the treatment with erythropoietic agent is 11.85 + 1.125 for group 1 and 11.76 + 1.138 for group 2; superior to the one of the studies commented previously; nevertheless our results, with respect to the increase and maintenance of the levels of Hb, are superposable to the obtained ones by them.\n\nSchwartzberg et al. (26) published the results of a randomized study in 312 patients with breast, lung and gynecological cancer who had chemotherapy-induced anemia; 157 patients received darbepoetin alfa 200 mcg/2 weeks and 155 patients received epoetin alfa 40,000 IU/week. Overall, no significant differences were observed in the analysis of:\n\nmean baseline Hb (10.4 g/dL in both groups),\n\nthe percentage of patients who reached Hb levels ≥11 g/dL (82% vs 86%),\n\nthe mean time in which Hb ≥ 11 g/dL was achieved (5 vs 4 weeks),\n\nthe duration of treatment with the erythropoietic treatment (9.3 vs 10.1 weeks),\n\nthe Hb level achieved during the study (12.1 vs 12.2 g/dL),\n\nthe increase in Hb (1.8 vs 1.6 g/dL),\n\nthe transfusion requirements (16% vs 17%), or\n\nor the adverse effects related to the treatment.\n\nThis study concluded that darbepoetin alfa (200 mcg/2 weeks) and epoetin alfa (40,000 IU/week) have comparable clinical efficacy.\n\nAt the American Society of Clinical Oncology (ASCO) 41st Annual Meeting in 2005, the final results of 2 randomized studies comparing darbepoetin alfa (200 mcg/2 weeks) and epoetin alfa (40,000 IU/week) in patients with chemotherapy induced anemia, with contradictory results, were presented. In the study conducted by Waltzman et al. (27), 180 patients receiving darbepoetin alfa and 178 patients receiving epoetin alfa had a baseline Hb of 10.1 and 10.2 g/dL, respectively. The Hb increase at the end of the study was significantly higher in the epoetin alfa group (0.8 vs 1.2 g/dL), the mean time to increase the Hb level by 1 g/dL was significantly lower in the epoetin group (48 vs 35 days), and the percentage of patients with an increase in Hb ≥2 g/dL was significantly higher in the epoetin alfa group (26% vs 44% at 9 weeks and 41% vs 57%) at the end of the study. It was concluded that the index of response is greater and the time to achieve an increase in Hb of 1 g/dL is shorter in the group treated with epoetin alfa 40,000 IU/week compared with darbepoetin alfa 200 mcg/2 weeks. In the second study, Glaspy et al. (28) randomized 1220 patients, 1209 of which received more than one dose of study drug (606 patients received darbepoetin alfa 200 mcg/2 weeks and 603 received epoetin alfa 40,000 IU/week). The mean levels of baseline Hb were 10.2 g/dL in both groups. No significant differences were found in:\n\nthe mean Hb at the end of the study (11.8 and 11.9 g/dL),\n\nthe percentage of patients who achieved a Hb level between 11 and 13 g/dL (76% vs 81%),\n\nthe mean time to achieve a Hb level between 11 to 13 g/dL (6 vs 5 weeks),\n\nthe percentage of patients who maintained a Hb level between 11 to 13 g/dL (74% vs 80%), and\n\nthe transfusion requirements (21% vs 16%).\n\nThe authors concluded the adverse effects were also similar between the groups and that both agents present similar clinical efficacy.\n\nIn Europe, the usual administration of darbepoetin alfa is 150 mcg/week, although the optimal dose of darbepoetin alfa given weekly and its therapeutically equivalent dose with epoetin alfa (29) are not yet clearly defined.\n\nWe have not found any published study comparing the efficacy of both drugs in weekly administration. In our study, we prospectively included 125 consecutive patients receiving RT or RCT with anemia, defined as Hb < 13 g/dL in males and <12 g/dL in females. The mean Hb level at study drug initiation was 11.85 g/dL in the darbepoetin alfa group and 11.76 g/dL in the epoetin alfa group (p = ns). After 4 weeks of treatment, the Hb levels increased in both groups to 13.16 g/dL in the darbepoetin alfa group and to 13.02 g/dL in the epoetin alfa group (p = ns). Of the patients treated with darbepoetin alfa, 19.4% doubled the dose compared with 23.8% in the epoetin alfa group (p = ns). The increases in the mean levels of Hb over the baseline values one month after the final dose were 2.21 g/dL and 2.46 g/dL, respectively (p = ns). The transfusion requirements were similar in the 2 groups. These dates demonstrate the efficacy of darbepoetin alpha and epoetin alpha in increasing Hb levels and agree with Reeves et al. (24) and Herrington et al. (25), in demonstrating a similar clinical effectiveness for both erythropoietic agents. Changes regarding Hb intervention values have been published as guidelines (30) for the last few years; this study stands for march 2003 standards and does not match with actual clinical practice.\n\nConclusions\nThe results of our study demonstrate that the 2 treatments, darbepoetin alfa 150 mcg/week and epoetin alfa 40,000 IU/week, are equally effective in correcting anemia in cancer patients receiving RT or RCT treatment.\n\nFigure 1 Changes in the Hb over the course of the study.\n\nTable 1 Descriptive characteristics of the sample.\n\nTreatment group\nNumber of patients\t\tGroup 1\nN = 62\tGroup 2\nN = 63\tP\t\nAge (mean ± SD)\t\t67.89 ± 11.8\t66.84 ± 10.78\t0.606\t\nSex\tmales\t45 (72.6%)\t39 (61.9%)\t0.140\t\n\tfemales\t17 (27.4%)\t24 (38.1%)\t\t\nTumor\tH&N\t15 (24.2%)\t19 (30.2%)\tns\t\n\tBreast\t5 (8.1%)\t4 (6.3%)\t\t\n\tRectum\t11 (17.7%)\t10 (15.9%)\t\t\n\tGenitourinary\t15 (24.2%)\t14 (23.8%)\t\t\n\tLung\t4 (6.5%)\t4 (6.5%)\t\t\n\tGynecologic\t5 (8.1%)\t5 (8.1%)\t\t\n\tEsophagogastric\t3 (4.8%)\t3 (4.8%)\t\t\n\tOther\t4 (6.5%)\t3 (4.8%)\t\t\nStage\tI\t3 (4.8%)\t10 (15.9%)\t0.124\t\n\tII\t24 (38.7%)\t15 (23.8%)\t\t\n\tIII\t27 (43.5%)\t31 (49.2%)\t\t\n\tIV\t4 (6.5%)\t5 (7.9%)\t\t\n\tTumor recurrence\t3 (98.4%)\t1 (1.6%)\t\t\n\tNot stated\t1 (1.6%)\t1 (1.6%)\t\t\nPrevious oncological treatment\tNeoadjuvant CTX\t8 (12.9%)\t8 (12.7%)\t0.592\t\n\tSurgery\t26 (41.9%)\t29 (46%)\t0.359\t\n\tAdjuvant CTX\t5 (8.1%)\t8 (12.7%)\t0.280\t\n\tHT\t9 (14.5%)\t7 (11.1%)\t0.408\t\nCurrent oncological treatment\tRT + CTX\t20 (32.3%)\t24 (38.1%)\t0.664\t\n\tRT only\t42 (67.7%)\t39 (61.9%)\t\t\nIntention to treat with RT\tRadical\t35 (56.5%)\t32 (50.8%)\t0.850\t\n\tAdjuvant\t19 (30.6%)\t24 (38.1%)\t\t\n\tNeoadjuvant\t6 (9.7%)\t5 (7.9%)\t\t\n\tPalliative\t2 (3.2%)\t2 (3.2%)\t\t\nTable 2 Reason for the termination of treatment with the study drug.\n\nReason for termination, n (%)\tGroup 1 (Darbepoetin alfa)\tGroup 2 (Epoetin alfa)\t\nAchieved a Hb > 15 g/dL during RT or RCT\t20 (65.6%)\t20 (65.6%)\t\nHb 14 g/dL after RCT treatment\t23 (38.3%)\t17 (27.4%)\t\nCompleted 16 weeks of study drug\t4 (6.7%)\t1 (1.6%)\t\nStudy drug related or unrelated adverse event\t12 (19.7%)\t18 (29.0%)\t\nPatient request\t4 (6.8%)\t7 (11.3%)\t\n2 patients in each group required RBC transfusions.\n\nTable 3 Mean serum iron, ferritin, and % saturation levels.\n\nLevel\tGroup 1 (Darbepoetin alfa)\tGroup 2 (Epoetin alfa)\tP\t\nSerum Iron, mcg/dL (mean ± SD)\t\n Baseline\t75.71 ± 45.56\t82.16 ± 49.23\t0.456\t\n Week 4\t65.35 ± 57.87\t67.73 ± 48.11\t0.831\t\n Week 12\t34.09 ± 8.74\t67.30 ± 64.05\t0.104\t\n 1 month after final dose of study drug\t99.15 ± 41.28\t113.04 ± 45.43\t0.186\t\nFerritin, ng/mL (mean ± SD)\t\n Baseline\t255.10 ± 250.86\t245.12 ± 324.88\t0.851\t\n Week 4\t149.66 ± 212.08\t144.41 ± 233.54\t0.911\t\n Week 12\t192.18 ± 413.35\t97.0 ± 199.16\t0.517\t\n 1 month after final dose of study drug\t246.55 ± 280.76\t291.90 ± 285.28\t0.510\t\nSaturation,% (mean ± SD)\t\n Baseline\t31.98 ± 25.05\t34.37 ± 27.93\t0.618\t\n Week 4\t27.44 ± 32.76\t25.93 ± 23.32\t0.800\t\n Week 12\t13.54 ± 5.3\t24.9 ± 32.12\t0.261\t\n 1 month after final dose of study drug\t41.65 ± 27.87\t44.64 ± 22.43\t0.631\n==== Refs\nReferences\n1 Knight K Wade S Balducci L 2004 Prevalence and outcomes of anemia in cancer: a systematic review of the literature Am. J. Med. 116 7A 11S 26S 15050883 \n2 Coiffier B 2000 The impact and management of anaemia in haematological malignancies Med. Oncol. 17 Suppl 1 S2 10 11188782 \n3 Mercadante S Gebbia V Marrazzo A Filosto S 2000 Anaemia in cancer: pathophysiology and treatment Cancer Treat. Rev. 26 4 303 11 10913385 \n4 Hawliezek R Oismuller R 1999 The effect of systematic rHu-EPO treatment before and during radiotherapy (radio-chemotherapy) in unselected anemic cancer patients. Preliminary results of an Austrian multicenter observation study (meeting abstract) Proc. Annu. Meet Am. Soc. Clin. Oncol. 18 A2310 \n5 Henke M Bechtold C Momm F Dorr W Guttenberg R 2000 Blood hemoglobin level may affect radiosensitivity-preliminary results on acutely reacting normal tissues Int J Rad Oncol Biol Phys 48 339 45 \n6 Vaupel P Thews O Hoeckel M Höckel M 2001 Treatment resistance of solid tumors: role of hypoxia and anemia Med Oncol 18 243 59 11918451 \n7 Frommhold H Guttenberger R Henke M 1998 The impact of blood hemoglobin content on the outcome of radiotherapy. The Freiburg experience Strahlenther Onkol. 174 Suppl IV 31 4 9879345 \n8 Kumar P 2000 Impact of anemia in patiens with head and neck cancer Oncologist 5 Suppl 2 13 8 \n9 Jazieh AR Hussain M Howington JA Spencer HJ Husain M Grismer JT Read RC 2000 Prognostic factors inpatients with surgically resected stages I and II non-small cell lung cancer Annals of Thoracic Surgery 70 1168 71 11081863 \n10 Dunst J 2000 Hemoglobin level and anemia in radiation oncology: prognostic impact and therapeutic implications Sem Oncol 27 4 8 \n11 Harrison LB Chadha M Hill RJ Shasha D 2002 Impact of tumor hypoxia and anemia on radiation therapy outcomes Oncologist 7 492 508 12490737 \n12 Walker R 1987 Award lectures and especial reports: Transfusion risks Am J Clin Pathol 88 374 8 3630978 \n13 Maraveyas A Pettengell R 1998 What is the role of erythropoietin in patients with solid tumors Ann Oncol 9 255 60 9602258 \n14 Glaspy JA Jadeja JS Justice G 2002 Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated wiyh cancer chemotherapy Br J Cancer 87 268 76 12177793 \n15 Vansteenkiste J Pirker R Massuti B 2002 Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy J Natl Cancer Inst 94 1211 20 12189224 \n16 Ardizzoni A Cafferata MA Rosso R 1998 Epoietin alfa in lung cancer Tumori 84 Suppl 1 S20 6 10083891 \n17 Quirt I Kovacs M Burdette-Radoux S Dolan S McKenzie M Tang SC 1999 Epoetin Alfa reduces transfusion requirements, increases hemoglobin (Hb) and improves quality of life (QofL) in cancer patients with anemia who are not receiving concomitant chemotherapy (Meeting abstract) Proc. Annu. Meet Am. Soc. Clin. Oncol. 18 A2295 \n18 Henke M Guttenberger R Barke A Pajonk F Pötter R Frommhold H 1999 Erythropoietin for patients undergoing radio-therapy: a pilot study Radiother Oncol 50 185 90 10368042 \n19 Beguin Y 1998 Prediction of response to treatment with recombinant human erythropoietin in anaemia associated with cancer Med. Oncol. 15 Suppl 1 S38 46 9785336 \n20 Gabrilove JL Cleeland CS Livingston RB 2001 Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing J Clin Oncol 19 2875 82 11387360 \n21 Hedenus M Adriansson M San Miguel J 2003 Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study Br J Haematol 122 394 403 12877666 \n22 Kotasek D Steger G Faught W 2003 Dabepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study Eur J Cancer 39 2026 34 12957457 \n23 Reeves TJ Wallace JF Patton JF 2004 Darbepoetin alfa is comparable to Epoetin alfa for chemotherapy-induced anaemia in clinical practice www.supportiveoncology.net 2 Suppl 2 \n24 Patton JF Reeves TJ Wallace JF 2004 Effectiveness of Darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice The Oncologist 9 451 8 15266098 \n25 Herrington JD Davidson SL Tomita DK 2005 Utilization of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia Am J Health-Syst Pharm 62 54 62 15658073 \n26 Schwartzberg LS Yee LK Senecal FM Charu V Tomita D Wallace J Rossi G 2004 A randomized comparison of every-2-week Darbepoetin alfa and weekly Epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynaecologic cancer The Oncologist 9 696 707 15561813 \n27 Waltzman RJ Croot C Williams D 2005 Final hematologic results: epoetin alfa (EPO) 40,000 U QW vs darbepoetin alfa (DARB.) 200 μg Q2W in anemic cancer patients (pts) receiving chemotherapy (CT) ASCO Annual Meeting Abstract 8030 \n28 Glaspy J Berg R Tomita D Rossi G Vadhan-Raj S 2005 on behalf of the 20030125 Study Group Final results of a phase 3, randomized, open-label study of darbepoetin alfa 200 μg every 2 weeks (Q2W) versus epoetin alfa 40,000 U weekly (QW) in patients withchemotherapy-induced anemia (CIA) ASCO Annual Meeting Abstract 8125 \n29 Pujade-Lauraine E Topham C 2005 Once -weekly treatment of anemia in patients with cancer: a comparative review of epoetins Oncology 68 122 9 \n30 Rodgers GM Cella D Chanan-Khan A 2007 Cancer- and treatment-related anemia NCCN. Clinical Practice Guidelines in Oncology 1 www.nccn.org\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1177-9314",
"issue": "2()",
"journal": "Clinical medicine. Oncology",
"keywords": "anemia; darbepoetin alfa; epoetin alfa; radiochemotherapy; radiotherapy",
"medline_ta": "Clin Med Oncol",
"mesh_terms": null,
"nlm_unique_id": "101467911",
"other_id": null,
"pages": "393-9",
"pmc": null,
"pmid": "21892305",
"pubdate": "2008",
"publication_types": "D016428:Journal Article",
"references": "9602254;11188782;10913385;15561813;10896324;16015034;15266098;10847301;12957457;9785336;15658073;15050883;10368042;9879345;11081863;11918451;10083891;3630978;12490737;10974446;12177793;12877666;12189224;11387360",
"title": "Darbepoetin versus epoetin alfa for the correction of anemia in cancer patients receiving radiotherapy or chemoradiotherapy treatment.",
"title_normalized": "darbepoetin versus epoetin alfa for the correction of anemia in cancer patients receiving radiotherapy or chemoradiotherapy treatment"
} | [
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"companynumb": "ES-AMGEN-UK125742",
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"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study was to investigate the rate of carbapenem-resistant gram-negative bacilli (CRGNB) colonization and to analyze the risk factors associated with CRGNB colonization.\n\n\nMETHODS\nThis prospective study was conducted in adult patients hospitalized in hematopoietic stem cell transplantation (HSCT) units over a period of 8 months. Rectal swab samples were obtained from each participant every Monday, and patients CRGNB positive on admission were excluded.\n\n\nRESULTS\nOf 185 participants, the median age was 47 years, and 59.5% were men. CRGNB colonization was detected in 21 (11.4%) patients. The most commonly isolated CRGNB were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Multivariate analysis revealed that busulfan use (11.9 times), fludarabine use (6.4 times), transfer from another hospital (7.8 times), transfer between units (9.3 times), and central venous catheterization (5.1 times) were risk factors for CRGNB colonization. During the study period, febrile neutropenia (FN) developed in 9 (56.2%) of the 21 colonized patients, and 1 patient died.\n\n\nCONCLUSIONS\nScreening of patients for CRGNB colonization may have a role in preventing the spread of CRGNB. However, the empirical antimicrobial treatment for FN in patients with CRGNB colonization did not change, and their mortality rates were similar.",
"affiliations": "Department of Infectious Diseases and Clinical Microbiology, Erciyes University, Melikgazi, Kayseri, Turkey. Electronic address: tigin68@hotmail.com.;Infection Control Committee, Erciyes University, Kayseri, Turkey.;Department of Medical Microbiology, Erciyes University, Kayseri, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Hacettepe University, Ankara, Turkey.;Department of Hematology, Erciyes University, Kayseri, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Erciyes University, Melikgazi, Kayseri, Turkey; Infection Control Committee, Erciyes University, Kayseri, Turkey.",
"authors": "Demiraslan|Hayati|H|;Cevahir|Fatma|F|;Berk|Elife|E|;Metan|Gokhan|G|;Cetin|Mustafa|M|;Alp|Emine|E|",
"chemical_list": "D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajic.2017.01.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-6553",
"issue": "45(7)",
"journal": "American journal of infection control",
"keywords": "Carbapenem resistance; Gram-negative bacterial colonization; HSCT; Hematopoietic stem cell transplantation; Risk factors; Surveillance",
"medline_ta": "Am J Infect Control",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001426:Bacterial Proteins; D016026:Bone Marrow Transplantation; D002353:Carrier State; D003428:Cross Infection; D062665:Epidemiological Monitoring; D005260:Female; D006090:Gram-Negative Bacteria; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D017053:Infection Control; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult; D001618:beta-Lactamases",
"nlm_unique_id": "8004854",
"other_id": null,
"pages": "735-739",
"pmc": null,
"pmid": "28214159",
"pubdate": "2017-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Is surveillance for colonization of carbapenem-resistant gram-negative bacteria important in adult bone marrow transplantation units?",
"title_normalized": "is surveillance for colonization of carbapenem resistant gram negative bacteria important in adult bone marrow transplantation units"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK201711103",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
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{
"abstract": "This article presents a case of unsuccessful pharmaceutical and invasive pain treatment for 6 years without any adequate diagnostics in a female suffering from unilateral thoracic radiculopathy (Th8, right) leading to severe disability and unemployment. The origin was an undetected Tarlov cyst. After resection of the cyst the pain and other complaints disappeared (follow up: 8 months) without need for further pain medication. This case underlines the necessity of adequate diagnostics ahead of long-term pain treatment. Thoracic Tarlov cysts are very uncommon but should be included in the differential diagnosis because curative treatment may be possible.",
"affiliations": "Abteilung für Schmerzmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland. Christoph.Maier@rub.de.;Abteilung für Schmerzmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland.;Abteilung für Schmerzmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland.;Institut für Diagnostische Radiologie, Interventionelle Radiologie und Nuklearmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland.;Abteilung für Neurochirurgie und Neurotraumatologie, , Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland.",
"authors": "Maier|C|C|;Eitner|L|L|;Altenscheidt|J|J|;Nicolas|V|V|;Martinez|R|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00482-017-0262-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-433X",
"issue": "32(1)",
"journal": "Schmerz (Berlin, Germany)",
"keywords": "Pain diagnostics; Radiculopathy; Tarlov cyst",
"medline_ta": "Schmerz",
"mesh_terms": "D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D010146:Pain; D059408:Pain Management; D011843:Radiculopathy; D052958:Tarlov Cysts",
"nlm_unique_id": "8906258",
"other_id": null,
"pages": "56-60",
"pmc": null,
"pmid": "29270852",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23936511;28327939;21818717;16697110;20800797;27035580;28523386;28610610;11453427;27154168;28631151;15687849;27759681;21562735;18628699",
"title": "Unsuccessful pain treatment over 6 years of a thoracic radiculopathy caused by an unrecognized Tarlov cyst.",
"title_normalized": "unsuccessful pain treatment over 6 years of a thoracic radiculopathy caused by an unrecognized tarlov cyst"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1066571",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
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"drugadditional": null,
... |
{
"abstract": "Cladophialophora bantiana is a neurotropic mould and primary cause of cerebral phaeohyphomycoses, which presents with brain abscesses in both immunocompromised and immunocompetent individuals. It is associated with high mortality due to delay in diagnosis and absence of standardised therapy. We present a case of fatal cerebral phaeohyphomycosis in a 67-year-old Caucasian man. Diagnosis was achieved by histopathological examination of brain tissue followed by conventional culture and molecular identification. We highlight diagnostic and treatment challenges involved.",
"affiliations": "Department of Neurology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK.;Department of Medical Microbiology, North West London Pathology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.;Department of Medical Microbiology, North West London Pathology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.;National Mycology Reference Laboratory, Public Health England, Bristol BS10 5NB, UK.;National Mycology Reference Laboratory, Public Health England, Bristol BS10 5NB, UK.;Department of Histopathology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK.;Department of Neurology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK.;Department of Medical Microbiology, North West London Pathology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.;Department of Medical Microbiology, North West London Pathology, Imperial College Healthcare NHS Trust, London W6 8RF, UK.;Department of Neurology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK.;Department of Neurology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK.",
"authors": "Howlett|Sarah|S|;Sullivan|Tadhg|T|;Abdolrasouli|Alireza|A|;Borman|Andrew M|AM|;Johnson|Elizabeth M|EM|;Lewis|Paul|P|;Baheerathan|Aravindhan|A|;Davies|Frances|F|;Sanderson|Frances|F|;Davies|Nicholas|N|;Singh-Curry|Victoria|V|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2019.02.004",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30013-210.1016/j.mmcr.2019.02.004Case ReportA black mould death: A case of fatal cerebral phaeohyphomycosis caused by Cladophialophora bantiana Howlett Sarah sarah.howlett5@nhs.neta∗Sullivan Tadhg bAbdolrasouli Alireza bcBorman Andrew M. dJohnson Elizabeth M. dLewis Paul eBaheerathan Aravindhan aDavies Frances bSanderson Frances bDavies Nicholas aSingh-Curry Victoria aa Department of Neurology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UKb Department of Medical Microbiology, North West London Pathology, Imperial College Healthcare NHS Trust, London W6 8RF, UKc Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College, London W6 8RF, UKd National Mycology Reference Laboratory, Public Health England, Bristol BS10 5NB, UKe Department of Histopathology, Charing Cross Hospital, Imperial College NHS Trust, London W6 8RF, UK∗ Corresponding author. Department of Neurology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. sarah.howlett5@nhs.net28 2 2019 6 2019 28 2 2019 24 23 26 4 2 2019 25 2 2019 © 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cladophialophora bantiana is a neurotropic mould and primary cause of cerebral phaeohyphomycoses, which presents with brain abscesses in both immunocompromised and immunocompetent individuals. It is associated with high mortality due to delay in diagnosis and absence of standardised therapy. We present a case of fatal cerebral phaeohyphomycosis in a 67-year-old Caucasian man. Diagnosis was achieved by histopathological examination of brain tissue followed by conventional culture and molecular identification. We highlight diagnostic and treatment challenges involved.\n\nKeywords\nCerebral phaeohyphomycosesDematiaceous fungiGene sequencingCladophialophora bantiana\n==== Body\n1 Introduction\nCladophialophora bantiana is a melanised mould and is the commonest cause of cerebral phaeohyphomycosis. Among human fungal pathogens, it is recognised for its neurotropism and ability to cause infections in immunocompetent hosts. Most reported cases are from the Indian subcontinent [1,2]. Mammalian cases acquired in the UK are extremely rare [3], although imported cases are referred to the National Mycology Reference Laboratory (MRL) Public Health England.\n\n2 Case\nA 67-year-old Caucasian man was admitted to a District General Hospital in June 2017, having suffered a generalised tonic-clonic seizure on a flight from the Philippines. Past medical history included hypertension, asthma, coronary artery bypass and untreated quiescent sarcoidosis. Further investigation revealed a two-month history of headache, dizziness, weight loss and diplopia, which was initially investigated at his local hospital with a CT head, which was reportedly normal. Following this, he visited his partner in a rural area of the Philippines, which he did regularly. While overseas his symptoms worsened. A CT head performed in the Philippines showed multifocal lesions in the left cerebral hemisphere. He was given a provisional diagnosis of glioblastoma multiforme and returned to the UK for further investigation and treatment.\n\nHe was initially treated with levetiracetam and dexamethasone for seizure control, and co-amoxiclav for presumed aspiration pneumonia. His admission CT head revealed multiple ring enhancing intra-axial lesions within the left frontal lobe, left cerebellar hemisphere and pons with surrounding vasogenic oedema. An MRI confirmed the presence of a chain of well-defined round lesions within the left frontal lobe corona radiata, of low T1 and high T2 signal intensity up to 15mm in axial dimension demonstrating rim enhancement (Fig. 1a, b). Further areas of enhancement were demonstrated in the left cerebellar peduncle and pons with surrounding meningeal enhancement. Surrounding parenchymal oedema was noted with surrounding mass effect with approximately 5mm of midline shift (Fig. 1 c, d). He was transferred to our centre for further treatment (day 0).Fig. 1 (a and b) Post-contrast images demonstrated marginal enhancement highlighting multiple lobulated lesions with low T1 centre, (c) T2 weighted MRI revealed multifocal intra-axial abnormalities in the left pons, extending through the pontocerebellar junction to the left cerebellar hemisphere, (d) cerebral hemispheres associated with parenchymal oedema and mass effect, (e) DWI - lesions showed restricted diffusion, (f) short septate melanised hyphae and occasional holoblastic conidia in histology section of brain biopsy consistent with cerebral phaeohyphomycosis, (g) growth of C. bantiana on Sabouraud desxtrose agar slopes at 30 °C (left) and 37 °C (right) after two weeks incubation showed darkly pigmented colonies that were heaped in centre, (h) truncated and elongated conidia in long, non-fragile and rarely-ranched chains were seen in direct microscopic examination of fungal cultures.\n\nFig. 1\n\nOn admission, he was febrile (38.6 °C) with a Glasgow Coma Score (GCS) of 10/15 (E3V2M5), deteriorating to 8/15 (E1V2M5), requiring emergency intubation and transfer to the intensive therapy Unit (ITU). A repeat CT head showed no radiological deterioration. A CT thorax demonstrated bilateral upper lobe consolidation. High dose meropenem (2g TDS) and anti-tuberculous therapy (rifampicin 600mg BD, moxifloxacin 400mg BD, isoniazid 300mg OD and pyrazinamide 2g OD with dexamethasone) were initiated to cover potential intracranial bacterial abscesses and disseminated tuberculosis respectively (Table 1).Table 1 Summary of investigation results and anti-infective treatment timeline.\n\nTable 1Legend of abbreviations: ALT – Alanaine Aminotransferase; BAL – Bronchoalevolar Lavage; CRP – C-reactive protein; CT CAP – Computerised Tomography Chest Abdomen Pelvis; CTH – Computerised Tomography Head; GCS – Glasgow Coma Score; HIV – Human Immunodeficiency Virus; PCR – Polymerase Chain Reaction; TB - Tuberculosis; WCC – White Cell Count.\n\n\n\nHe was extubated on day 3 but GCS remained 11/15. He had brisk reflexes bilaterally and an absent vestibulo-ocular reflex. Due to fever spikes, gentamicin was added for 48 hours on day 4 to cover Gram-negative bacteria. Given the diagnostic uncertainty a left frontal lobe biopsy was performed on day 6. His GCS deteriorated post-operatively and he required re-intubation. Despite negative TB PCR from bronchoscopy samples, anti-TB medications were continued given high clinical suspicion. He remained febrile and on day 10, vancomycin was added to cover resistant staphylococci. Moxifloxacin was changed to ethambutol owing to concern regarding lowering of the seizure threshold. Liposomal Amphotericin B (5mg/kg) was added to cover possible fungal infection.\n\nOn day 11 post admission, histopathological exam showed branched septate hyphae (Fig. 1f), with surrounding necrotising granulomatous tissue suggestive of cerebral mycoses. On day 14 anti-tuberculous drugs were discontinued, as both pulmonary and cerebral samples were negative for Mycobacterium tuberculosis. Fungal cultures confirmed growth of a dematiaceous mould. Voriconazole (5mg/kg) and caspofungin (70mg OD) were added on day 15 to provide further antifungal cover. A percutaneous tracheostomy was formed on day 15 to facilitate extubation. A CT head on day 18 showed increasing mass effect and enlargement of the lesions into the midbrain. The lesions were deemed too extensive for surgical resection.\n\nFollowing a delay due to national shortage, flucytosine 2.5g QDS IV was initiated in place of caspofungin on day 21. There was difficulty achieving therapeutic voriconazole levels likely related to the rifampicin and phenytoin received earlier in admission. Voriconazole levels remained sub-therapeutic despite increasing the dose to 400mg BD on day 22. On day 22, GCS continued to fluctuate between 6 and 10/15. Despite a moderate transaminitis (peak ALT of 203 iu/L) he was able to tolerate triple antifungal therapy.\n\nOn day 24 identification of C. bantiana was confirmed. Molecular identification was performed by PCR amplification and sequencing of internal transcribed spacer region ITS-1 and the D1-2 fragment of the 28S rDNA gene [4]. The sequence of the D1-2 portion of the 28S rRNA gene was 100% identical over the entire 355 nt amplicon length with sequences from isolates of C. bantiana present in the synchronised public databases (EMBL accession numbers AM168525, AB363799 and KU928133). Antifungal susceptibility testing was performed using E-test method. Minimum inhibitory concentrations (MIC) of 6 antifungal agents were determined as: amphotericin B (1 mg/L), flucytosine (2 mg/L), isavuconazole (0.06 mg/L), itraconazole (0.06 mg/L), posaconazole (0.06 mg/L), and voriconazole (0.06 mg/L).\n\nHis subsequent clinical course was complicated by recurrent aspiration pneumonias requiring broad-spectrum antibiotics. Given the lack of neurological improvement and after discussions with his family the decision was made to continue medical management but not to attempt re-intubation or cardiopulmonary resuscitation should he deteriorate. On day 39 of admission the patient had a respiratory arrest and passed away. The patient was referred for post-mortem. Autopsy showed infection was confined to the brain. No granulomata were identified in the thoracic lymph nodes or lung therefore pre-existing diagnosis of sarcoidosis was not confirmed.\n\n3 Discussion\nC. bantiana is found in decaying plant matter in soil worldwide. The pathogenesis of phaeohyphomycosis due to C. bantiana infection is uncertain. While a minority of infections follows traumatic inoculation [1], it has been hypothesised that a subclinical pulmonary infection followed by haematogenous spread might seed infection to the CNS [5].\n\nAccording to a recent systematic review [1] this is only the fifth published case of this infection in the UK, although MRL regularly receives isolates from cases acquired overseas (unpublished data). There are only two cases described of cerebral C. bantiana in the UK; both of these were in patients whom were significantly immunosuppressed – one due to an underlying immunodeficiency (Duncan's syndrome) and one on chemotherapy for lymphoma [6,7]. This is in contrast to the immunocompetence of our patient. In both cases patients were treated with amphotericin B, flucytosine and voriconazole. Despite this treatment strategy both patients died.\n\nThe diagnosis of C. bantiana infection presented a significant challenge. Its clinical presentation and radiological findings could not be distinguished from bacterial abscesses, primary CNS neoplastic lesions and cerebral metastatic disease. A fungal infection was considered initially unlikely compared to TB by the clinical teams. On admission it had been advised by the microbiology team to test for fungal biomarkers including β-D-glucan and galactomannan, however this was not done until later in admission. It can be postulated that this delayed the decision to cover for fungal infection.\n\nNeuroimaging with CT or MRI confirms the presence of ring enhancing lesions with associated perilesional oedema and meningeal involvement may yield abnormalities in cerebrospinal fluid (CSF) such as raised white cell count and protein [8]. However in this case concerns about risk of coning meant lumbar puncture was not performed. Definitive diagnosis requires tissue biopsy for fungal culture, histology and panfungal polymerase chain reaction (PCR). In our patient, brain biopsy did not take place until day 6 as it was hoped that the bronchoalveolar lavage (BAL) would confirm tuberculous infection. Despite the relatively low invasiveness of BAL, extra-cerebral disease is rare, as in our case, so brain biopsy should be considered early.\n\nOnce a diagnosis is established, there is no defined treatment for cerebral phaeohyphomycosis due to C. bantiana and various strategies have been employed in the literature. The joint ESCMID/ECMM guidelines for management of systemic phaeohyphomycosis recommend complete excision of brain abscesses wherever possible along with combination antifungal therapy [9]. The efficacy of antifungal therapy is limited by both sensitivity of the organism and the relatively poor CNS penetration of many antifungals. In the systematic reviews of intracranial C bantiana, no treatment strategy was associated with improved survival except for regimens containing itraconazole [1]. Our patient did not receive this at any point. The selection of an antifungal regimen in this case was complicated by low serum levels of voriconazole, likely due to cytochrome P450 induction from his rifampicin treatment.\n\nAlthough surgical resection is desirable, in our case brainstem disease at presentation meant that it was not possible. The autopsy report hypothesised that the patient's final respiratory demise resulted from fungal infection directly affecting his respiratory centres in the brainstem or cerebral oedema causing the same. Had the disease been detected prior to the brainstem being affected it is possible that resection may have impacted on outcome.\n\nOverall, this case demonstrates extensive CNS disease secondary to C. bantiana in an immunocompetent host. It highlights the potential diagnostic difficulties and the importance of astute clinical suspicion. Whilst there is currently no optimal therapeutic regimen, a combination of anti-fungal therapy and complete excision of brain abscesses should be employed.\n\nConflict of interest\nThe authors have no conflicts of interest to declare.\n\nAcknowledgements\nThe authors acknowledge the help of Public Health England Mycology laboratory with gene sequencing.\n==== Refs\nReferences\n1 Kantarcioglu A.S. Guarro J. De Hoog S. An updated comprehensive systematic review of Cladophialophora bantiana and analysis of epidemiology, clinical characteristics, and outcome of cerebral cases Med. Mycol. 55 2017 579 604 28007938 \n2 Chakrabati A. Kaur H. Rudramurthy S.M. Appannanavar S.B. Patel A. Mukherjee K.K. Brain abscess due to Cladophialophora bantiana : a review of 124 cases Med. Mycol. 54 2016 111 119 26483430 \n3 Coldrick O. Brannon C.L. Kydd D.M. Pierce-Roberts G. Borman A.M. Torrance A.G. Fungal pyelonephritis due to Cladophialophora bantiana in a cat Vet. Rec. 161 21 2007 724 727 18037696 \n4 Borman A.M. Linton C.J. Miles S.-J. Johnson E.M. Molecular identification of pathogenic fungi J. Antimicrob. Chemother. 61 Suppl 1 2008 i7 12 18063605 \n5 Gandham P. Cladophialophora bantiana Int. J. Res. Med. Sci. 2 2014 38 41 \n6 Roche M. Mac Redmond R. O'Neill S. Smyth E. A case of multiple cerebral abscesses due to infection with Cladophialophora Bantiana J. Infect. 51 2005 e285 e288 15908005 \n7 Hemmaway C. Laverse E. Nicholas M. Nagy Z. Cerebellar Cladophialophora bantiana infection in a patient with marginal zone lymphoma treated with immunochemotherapy including rituximab Br. J. Haematol. 154 2011 423 21506941 \n8 Revankar S. Sutton D. Rinaldi M. Primary central nervous system phaeohyphomycosis: a review of 101 cases Clin. Infect. Dis. 38 2 2004 206 216 14699452 \n9 Chowdhary A. Meis J.F. Guarro J. de Hoog G.S. Kathuria S. Arendrup M.C. European society of clinical microbiology and infectious diseases fungal infection study group; European confederation of medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi Clin. Microbiol. Infect. 20 2014 47 75 24483780\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "24()",
"journal": "Medical mycology case reports",
"keywords": "Cerebral phaeohyphomycoses; Cladophialophora bantiana; Dematiaceous fungi; Gene sequencing",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "23-26",
"pmc": null,
"pmid": "30886820",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "14699452;15908005;18037696;18063605;21506941;24483780;26483430;28007938",
"title": "A black mould death: A case of fatal cerebral phaeohyphomycosis caused by Cladophialophora bantiana.",
"title_normalized": "a black mould death a case of fatal cerebral phaeohyphomycosis caused by cladophialophora bantiana"
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"abstract": "Pulmonary embolism is a leading cause of maternal death in the United States, contributing to the death of approximately 2 women per 100,000 live births each year. Thrombosis during pregnancy traditionally is treated conservatively with unfractionated heparin or low-molecular-weight heparin; however, cardiovascular collapse associated with a large pulmonary embolus may require immediate aggressive intervention to save the mother and fetus. We report the use of catheter infusion thrombolysis in the successful management of a third-trimester pregnant patient with a hemodynamically significant saddle pulmonary embolus.",
"affiliations": "From the Departments of *Anesthesiology, †Medicine, and ‡Radiology, New York Presbyterian Medical Center, Weill Medical College of Cornell University, New York, New York.",
"authors": "Pick|Jeremy|J|;Berlin|David|D|;Horowitz|James|J|;Winokur|Ron|R|;Sista|Akhilesh K|AK|;Lichtman|Adam D|AD|",
"chemical_list": "D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D010959:Tissue Plasminogen Activator",
"country": "United States",
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"mesh_terms": "D000328:Adult; D005260:Female; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D011263:Pregnancy Trimester, Third; D011655:Pulmonary Embolism; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D062666:Vascular Access Devices",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "91-4",
"pmc": null,
"pmid": "25827861",
"pubdate": "2015-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive pulmonary embolism in pregnancy treated with catheter-directed tissue plasminogen activator.",
"title_normalized": "massive pulmonary embolism in pregnancy treated with catheter directed tissue plasminogen activator"
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"companynumb": "US-ROCHE-1643617",
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"activesubstancename": "ENOXAPARIN"
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"abstract": "In order to avoid adverse drug reactions (ADRs), pharmacists are reconstructing ADR-related information based on various types of data gathered from patients, and then providing this information to patients. Among the data provided to patients is the time-to-onset of ADRs after starting the medication (i.e., ADR onset timing information). However, a quantitative evaluation of the effect of onset timing information offered by pharmacists on the probability of ADRs occurring in patients receiving this information has not been reported to date. In this study, we extracted 40 ADR-drug combinations from the data in the Japanese Adverse Drug Event Report database. By applying Bayes' theorem to these combinations, we quantitatively evaluated the usefulness of onset timing information as an ADR detection predictor. As a result, when information on days after taking medication was added, 54 ADR-drug combinations showed a likelihood ratio (LR) in excess of 2. In particular, when considering the ADR-drug combination of anaphylactic shock with levofloxacin or loxoprofen, the number of days elapsed between start of medication and the onset of the ADR was 0, which corresponded to increased likelihood ratios (LRs) of 138.7301 or 58.4516, respectively. When information from 1-7 d after starting medication was added to the combination of liver disorder and acetaminophen, the LR was 11.1775. The results of this study indicate the clinical usefulness of offering information on ADR onset timing.",
"affiliations": "Department of Analytical Pharmaceutics and Informatics, Faculty of Pharmaceutical Sciences, Josai University.;Department of Analytical Pharmaceutics and Informatics, Faculty of Pharmaceutical Sciences, Josai University.;Department of Analytical Pharmaceutics and Informatics, Faculty of Pharmaceutical Sciences, Josai University.;Department of Analytical Pharmaceutics and Informatics, Faculty of Pharmaceutical Sciences, Josai University.;Laboratory of Drug Metabolism, Faculty of Pharmaceutical Sciences, Josai International University.;Josai University Pharmacy.;Laboratory of Pharmacy Management, Faculty of Pharmaceutical Sciences, Josai University.;Laboratory of Pharmacy Management, Faculty of Pharmaceutical Sciences, Josai University.;Laboratory of Pharmacy Management, Faculty of Pharmaceutical Sciences, Josai University.;Laboratory of Biostatistics, Faculty of Pharmaceutical Sciences, Josai University.;Department of Analytical Pharmaceutics and Informatics, Faculty of Pharmaceutical Sciences, Josai University.",
"authors": "Oshima|Shinji|S|;Enjuji|Takako|T|;Negishi|Akio|A|;Akimoto|Hayato|H|;Ohara|Kousuke|K|;Okita|Mitsuyoshi|M|;Numajiri|Sachihiko|S|;Inoue|Naoko|N|;Ohshima|Shigeru|S|;Terao|Akira|A|;Kobayashi|Daisuke|D|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1248/bpb.b17-00165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-6158",
"issue": "40(9)",
"journal": "Biological & pharmaceutical bulletin",
"keywords": "Bayes’ theorem; adverse drug reaction; adverse event reporting system; likelihood ratio; onset timing information; patient adherence instruction",
"medline_ta": "Biol Pharm Bull",
"mesh_terms": "D022126:Access to Information; D016907:Adverse Drug Reaction Reporting Systems; D001499:Bayes Theorem; D003625:Data Collection; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D033181:Information Dissemination; D007564:Japan; D010595:Pharmacists; D024382:Professional Role; D018570:Risk Assessment; D013997:Time Factors",
"nlm_unique_id": "9311984",
"other_id": null,
"pages": "1389-1398",
"pmc": null,
"pmid": "28579595",
"pubdate": "2017-09-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Study on the Increased Probability of Detecting Adverse Drug Reactions Based on Bayes' Theorem: Evaluation of the Usefulness of Information on the Onset Timing of Adverse Drug Reactions.",
"title_normalized": "study on the increased probability of detecting adverse drug reactions based on bayes theorem evaluation of the usefulness of information on the onset timing of adverse drug reactions"
} | [
{
"companynumb": "JP-JNJFOC-20171001481",
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"actiondrug": "5",
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"activesubstancename": "LEVOFLOXACIN"
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... |
{
"abstract": "BACKGROUND\nAlthough anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.\nA 55-year-old woman with no history of smoking presented to our hospital with a swelling on the left neck. Clinical imaging and histopathological examination revealed a tumor of adenocarcinoma histology in the left upper lung with no CNS metastasis.\nThe patient was diagnosed with ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA).\n\n\nMETHODS\nShe received the second-generation ALK inhibitors, alectinib and brigatinib, in the first and second-line settings, respectively. However, she developed meningeal carcinomatosis. Hence, treatment with lorlatinib was initiated in the third-line setting.\n\n\nRESULTS\nThe symptoms associated with meningeal carcinomatosis, such as disturbance of consciousness and diplopia, improved dramatically. At 8 months from the initiation of lorlatinib, the patient remained well without disease progression.\n\n\nCONCLUSIONS\nLorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis.",
"affiliations": "Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan.;Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Eiheiji-cho, Matsuoka-gun, Fukui-ken, Japan.",
"authors": "Nakashima|Koki|K|0000-0002-2818-6703;Demura|Yoshiki|Y|;Kurokawa|Kosuke|K|;Takeda|Toshihiro|T|;Jikuya|Norihiro|N|;Oi|Masahiro|M|;Tada|Toshihiko|T|;Akai|Masaya|M|;Ishizuka|Tamotsu|T|",
"chemical_list": "D000631:Aminopyridines; D002227:Carbazoles; D007769:Lactams; D009943:Organophosphorus Compounds; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; C000598580:brigatinib; C582670:alectinib; C000590786:lorlatinib",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027385",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-04922\n10.1097/MD.0000000000027385\n27385\n5700\nResearch Article\nClinical Case Report\nSuccessful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib\nA case report\nhttp://orcid.org/0000-0002-2818-6703\nNakashima Koki MD a b ∗\nDemura Yoshiki MD, PhD a\nKurokawa Kosuke MD a\nTakeda Toshihiro MD a\nJikuya Norihiro MD a\nOi Masahiro MD a\nTada Toshihiko MD a\nAkai Masaya MD, PhD a\nIshizuka Tamotsu MD, PhD b\nSaranathan. Maya\na Depertment of Respiratory Medicine, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui-shi, Fukui-ken, Japan\nb Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Eiheiji-cho, Matsuoka-gun, Fukui-ken, Japan.\n∗ Correspondence: Koki Nakashima, Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Eiheiji-cho, Matsuoka-gun 910-1193, Fukui-ken, Japan (e-mail: kouk0527@yahoo.co.jp).\n01 10 2021\n01 10 2021\n100 39 e2738514 7 2021\n25 8 2021\n15 9 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nAlthough anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.\n\nPatients concerns:\n\nA 55-year-old woman with no history of smoking presented to our hospital with a swelling on the left neck. Clinical imaging and histopathological examination revealed a tumor of adenocarcinoma histology in the left upper lung with no CNS metastasis.\n\nDiagnoses:\n\nThe patient was diagnosed with ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA).\n\nInterventions:\n\nShe received the second-generation ALK inhibitors, alectinib and brigatinib, in the first and second-line settings, respectively. However, she developed meningeal carcinomatosis. Hence, treatment with lorlatinib was initiated in the third-line setting.\n\nOutcomes:\n\nThe symptoms associated with meningeal carcinomatosis, such as disturbance of consciousness and diplopia, improved dramatically. At 8 months from the initiation of lorlatinib, the patient remained well without disease progression.\n\nLessons:\n\nLorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis.\n\nKeywords\n\nanaplastic lymphoma kinase\ncase report\nlorlatinib\nmeningeal carcinomatosis\nnon-small cell lung cancer\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nMeningeal carcinomatosis is a severe condition associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Based on previous studies, patients without driver oncogenes have demonstrated a median overall survival of about 1.4 to 5.9 months from diagnosis.[1,2] Contrarily, for patients with NSCLC harboring driver oncogenes who develop meningeal carcinomatosis, molecularly targeted drugs, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors, have been shown to be effective treatment options.[1–4] However, achieving long-term survival in patients with meningeal carcinomatosis resistant to these drugs is difficult.\n\nLorlatinib, a third-generation ALK inhibitor, was designed for selective central nervous system (CNS) penetration.[5,6] Lorlatinib exerts potent antitumor activity against tumors that are resistant to first- and/or second-generation ALK inhibitors.[7,8] Therefore, lorlatinib could be an effective treatment option for patients with ALK-positive NSCLC with CNS metastasis, who have been previously treated with ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis.\n\nWe report a patient with ALK-positive lung adenocarcinoma who developed meningeal carcinomatosis after treatment with alectinib and brigatinib.\n\n2 Case presentation\n\nThe patient gave his informed consent for the publication of the details concerning his case, including images.\n\nA 55-year-old woman without a history of smoking presented to our hospital with a swelling in the left neck. Computed tomography revealed a tumor in the left upper lung, swelling of the left supraclavicular lymph nodes, multiple mediastinal lymph nodes, and liver metastasis. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed no CNS metastasis. Pathological examination of the endobronchial ultrasound-guided transbronchial needle aspiration of lymph node #7 revealed adenocarcinoma histology. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor was positive for ALK. Based on these findings, a diagnosis of ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA) was establihed.\n\nAlectinib (600 mg/day) was initiated as first-line treatment, and it resulted in a partial response. There were no adverse effects associated with the use of alectinib. However, tumor progression was observed 20 months after the initiation of alectinib. Therefore, brigatinib (180 mg/day) was initiated as second-line treatment, resulting in a partial response. There were no adverse effects associated with the use of brigatinib. However, disturbance of consciousness and diplopia occurred 30 months after the initiation of brigatinib. Contrast-enhanced MRI of the brain revealed a diffuse and linear enhancement along the cerebellar folia (Fig. 1). Examination of the cerebrospinal fluid showed 34 white blood cells /μL (mononuclear cells 95%, polynuclear cells 1%, others 4%), a protein value of 105 mg/dL, and a glucose level of 44 mg/dL. Adenocarcinoma was confirmed by cerebrospinal fluid examination. Based on these findings, a diagnosis of meningeal carcinomatosis was established, and the disturbance of consciousness and diplopia were considered to be its associated symptoms.\n\nFigure 1 Brain contrast-enhanced magnetic resonance imaging when a disturbance of consciousness and diplopia occurred, shows diffuse, and linear enhancement along the cerebellar folia (arrows).\n\nTreatment with lorlatinib (100 mg/day) was initiated in the third-line setting, and the patient's disturbance of consciousness and diplopia improved dramatically. Contrast-enhanced MRI of the brain revealed that the diffuse and linear enhancement along the cerebellar folia had disappeared (Fig. 2). There were no adverse effects associated with the use of lorlatinib. At 8 months from the initiation of treatment with lorlatinib, the patient remained well without disease progression.\n\nFigure 2 Brain contrast-enhanced magnetic resonance imaging after 3 months after the initiation of lorlatinib shows improvement of the diffuse and linear enhancement along the cerebellar folia.\n\n3 Discussion\n\nThe prognosis of patients with NSCLC who develop meningeal carcinomatosis without driver oncogenes remains poor.[1,2]ALK inhibitors are an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis.[4] However, the successful treatment of ALK-positive NSCLC with ALK-inhibitor-resistant meningeal carcinomatosis has not yet been reported in the literature. To the best our knowledge, this is the first report of successful treatment with lorlatinib in a patient who responded poorly to alectinib and brigatinib.\n\nThe efficacy of lorlatinib in the present case was influenced by 2 factors. First, lorlatinib is highly effective for treating patients with CNS metastasis since it was designed to cross the blood-brain barrier to achieve high CNS exposure.[5] Chen et al[6] have shown that the brain tissue partition coefficient of lorlatinib is 0.7, indicating high CNS exposure. Wang et al[9] reported that lorlatinib was clinically the most effective ALK inhibitor against CNS metastasis among lorlatinib, alectinib, brigatinib, and crizotinib. In patients with EGFR mutation-positive NSCLC who develop meningeal carcinomatosis, osimertinib has been reported to be the most beneficial treatment option.[3] Several studies have also shown that osimertinib has greater CNS penetration and higher brain exposure than other EGFR-TKIs.[10] These results indicate that CNS penetration is an important factor in the treatment of meningeal carcinomatosis with molecularly targeted drugs. In the present case, the high intracranial penetration of lorlatinib likely affected the intracranial metastasis, even though the tumor progressed with brigatinib.\n\nSecond, lorlatinib is effective against tumors that are resistant to first-, and second-generation ALK inhibitors. Lorlatinib acts against all known ALK resistance mutations.[11,12] Several clinical trials have shown that lorlatinib is effective in ALK-positive NSCLC patients with secondary ALK resistance mutations.[8,13] As seen in the present case, lorlatinib is effective for tumors that are resistant to second-generation ALK inhibitors, such as alectinib and brigatinib.\n\nThe present report indicates that lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors.\n\n4 Conclusion\n\nHere we have reported the successful treatment with lorlatinib of a patient with ALK-positive NSCLC who develop meningeal carcinomatosis. Our results suggest that lorlatinib could be considered in patients with meningeal carcinomatosis resistant to second-generation ALK inhibitors, even when they exhibit serious symptoms associated with meningeal carcinomatosis.\n\nAcknowledgments\n\nWe would like to thank Editage (www.editage.com) for providing English language editing assistance.\n\nAuthor contributions\n\nConceptualization: Koki Nakashima, Yoshiki Demura.\n\nData curation: Yoshiki Demura.\n\nResources: Yoshiki Demura.\n\nSupervision: Tamotsu Ishizuka.\n\nValidation: Koki Nakashima.\n\nVisualization: Koki Nakashima, Yoshiki Demura.\n\nWriting – original draft: Koki Nakashima, Yoshiki Demura.\n\nWriting – review & editing: Kosuke Kurokawa, Toshihiro Takeda, Norihiro Jikuya, Masahiro Oi, Toshihiko Tada, Masaya Akai, Tamotsu Ishizuka.\n\nAbbreviations: ALK = anaplastic lymphoma kinase, CNS = central nervous system, EGFR = epidermal growth factor receptor, MRI = magnetic resonance imaging, NSCLC = non-small cell lung cancer, TKI = tyrosine kinase inhibitor.\n\nHow to cite this article: Nakashima K, Demura Y, Kurokawa K, Takeda T, Jikuya N, Oi M, Tada T, Akai M, Ishizuka T. Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib: a case report. Medicine. 2021;100:39(e27385).\n\nThe authors have no conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Umemura S Tsubouchi K Yoshioka H . Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012;77 :134–9.22487432\n[2] Xu Y Hu M Zhang M . Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy. Lung Cancer 2018;125 :142–9.30429013\n[3] Yang JCH Kim SW Kim DW . Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the BLOOM study. J Clin Oncol 2020;38 :538–47.31809241\n[4] Gaye E Geier M Bore P . Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis. Lung Cancer 2019;133 :01–3.\n[5] Johnson TW Richardson PF Bailey S . Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem 2014;57 :4720–44.24819116\n[6] Chen W Jin D Shi Y Zhang Y Zhou H Li G . The underlying mechanisms of lorlatinib penetration across the blood-brain barrier and the distribution characteristics of lorlatinib in the brain. Cancer Med 2020;9 :4350–9.32347012\n[7] Shaw AT Felip E Bauer TM . Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017;18 :1590–9.29074098\n[8] Solomon BJ Besse B Bauer TM . Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19 :1654–67.30413378\n[9] Wang L Sheng Z Zhang J . Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor-naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis. J Chemother 2021;01–10. Online ahead of print.\n[10] Ballard P Yates JW Yang Z . Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-Mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22 :5130–40.27435396\n[11] Gainor JF Dardaei L Yoda S . Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016;6 :1118–33.27432227\n[12] Horn L Whisenant JG Wakelee H . Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer. J Thorac Oncol 2019;14 :1901–11.31446141\n[13] Shaw AT Solomon BJ Besse B . ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol 2019;37 :1370–9.30892989\n\n",
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"mesh_terms": "D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles; D002289:Carcinoma, Non-Small-Cell Lung; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007769:Lactams; D008175:Lung Neoplasms; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D009943:Organophosphorus Compounds; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines",
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"title": "Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib: A case report.",
"title_normalized": "successful treatment with lorlatinib in a patient with meningeal carcinomatosis of alk positive non small cell lung cancer resistant to alectinib and brigatinib a case report"
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"abstract": "Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplant. Although living donor liver transplant (LDLT) has been increasingly performed, PTLD after LDLT has not been well investigated. We aimed to determine the clinical characteristics of PTLD after LDLT. We investigated 323 consecutive patients undergoing adult-to-adult LDLT and identified three patients who developed biopsy-proven PTLD. All of them were seropositive for Epstein-Barr virus (EBV) and had hepatitis C virus-related cirrhosis at transplant. All three patients developed late-onset and monomorphic PTLD, including one diffuse large B-cell lymphoma and two Burkitt lymphomas with c-myc rearrangement. Two of them were EBV negative. The initial therapy included chemotherapy, rituximab, and immunosuppression withdrawal. One patient died of sepsis during treatment and two patients achieved complete responses. We showed a relatively low incidence and distinct clinicopathological features of PTLD after adult-to-adult LDLT, which might reflect the unique nature of LDLT.",
"affiliations": "Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.",
"authors": "Kataoka|Keisuke|K|;Seo|Sachiko|S|;Sugawara|Yasuhiko|Y|;Ota|Satoshi|S|;Imai|Yoichi|Y|;Takahashi|Tsuyoshi|T|;Fukayama|Masashi|M|;Kokudo|Norihiro|N|;Kurokawa|Mineo|M|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016031:Liver Transplantation; D019520:Living Donors; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D012189:Retrospective Studies; D012196:Review Literature as Topic; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Post-transplant lymphoproliferative disorder after adult-to-adult living donor liver transplant: case series and review of literature.",
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"abstract": "Chronic use of hydroxychloroquine can result in cardiomyopathy and conduction disturbances. Here, we describe a case of hydroxychloroquine cardiotoxicity in a patient with heart failure with preserved ejection fraction and severe chronotropic incompetence. (Level of Difficulty: Intermediate.).",
"affiliations": "Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.",
"authors": "Ezzeddine|Fatima M|FM|;Giudicessi|John R|JR|;Maleszewski|Joseph J|JJ|;Lin|Peter T|PT|;Borlaug|Barry A|BA|;Geske|Jeffrey B|JB|",
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"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00232-1\n10.1016/j.jaccas.2021.03.003\nCase Report\nClinical Case\nUnmasking Hydroxychloroquine Cardiotoxicity in a Patient With Heart Failure and Chronotropic Incompetence\nEzzeddine Fatima M. MD a\nGiudicessi John R. MD a\nMaleszewski Joseph J. MD b\nLin Peter T. MD b\nBorlaug Barry A. MD a\nGeske Jeffrey B. MD geske.jeffrey@mayo.edu\na∗\na Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA\nb Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA\n∗ Address for correspondence: Dr. Jeffrey B. Geske, Mayo Clinic, Cardiovascular Diseases, 200 1st Street SW, Rochester, Minnesota 55905, USA. geske.jeffrey@mayo.edu\n26 5 2021\n07 7 2021\n26 5 2021\n3 7 9971001\n6 11 2020\n12 2 2021\n11 3 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/).\nChronic use of hydroxychloroquine can result in cardiomyopathy and conduction disturbances. Here, we describe a case of hydroxychloroquine cardiotoxicity in a patient with heart failure with preserved ejection fraction and severe chronotropic incompetence. (Level of Difficulty: Intermediate.)\n\nCentral Illustration\n\nKey Words\n\ncardiomyopathy\nchronotropic incompetence\nexercise\nheart failure\nhydroxychloroquine\nAbbreviations and Acronyms\n\nHCQ, hydroxychloroquine\nLVH, left ventricular hypertrophy\nOSA, obstructive sleep apnea\n==== Body\nHistory of Presentation\n\nA 69-year-old female patient presented with progressive exertional dyspnea of 1 year in duration, associated with fatigue and lightheadedness, which now limited her active lifestyle inclusive of hiking. She had been diagnosed with decreased central hypoxic drive and had been using supplemental oxygen with some improvement of her dyspnea.Learning Objectives\n\n• To recognize the cardiotoxic effects of hydroxychloroquine use.\n\n• To highlight the importance of endomyocardial biopsy in establishing the diagnosis of hydroxychloroquine-induced cardiomyopathy.\n\nPast Medical History\n\nThe patient’s past medical history was significant for hypertension, asthma, obstructive sleep apnea (OSA), hypothyroidism, and discoid lupus erythematous. She had been treated previously for hypertension with valsartan for approximately 20 years but had not required antihypertensive therapy for approximately 9 years. The patient’s discoid lupus erythematous was diagnosed in her 30s, and it had been well controlled on hydroxychloroquine (HCQ) 200 mg daily since that time. The diagnoses of asthma and OSA were made after the initiation of HCQ therapy. Asthma was well controlled with albuterol and mometasone/formoterol inhalers. The patient was compliant with continuous positive airway pressure therapy for treatment of her OSA.\n\nDifferential Diagnosis\n\nThe differential diagnosis of dyspnea in this case is broad and includes cardiac and pulmonary etiologies (coronary artery disease, cardiomyopathy, conduction abnormalities, arrhythmias, valvular heart disease, asthma, chronic obstructive pulmonary disease, and interstitial lung disease).\n\nInvestigations\n\nPhysical examination was remarkable for bradycardia with a heart rate of 49 beats/min. Body mass index was 23.72 kg/m2. No cardiac murmurs were noted. The electrocardiogram showed sinus bradycardia and left ventricular hypertrophy (LVH) (Figure 1). Plasma N-terminal pro-B-type natriuretic peptide was modestly elevated, at 966 pg/ml (normal range: ≤202 pg/ml). Initial transthoracic echocardiogram revealed a left ventricular ejection fraction of 60% to 65%, mild concentric LVH, elevated filling pressures with medial mitral E/e′ of 28, moderate left atrial enlargement by visual assessment, and absence of hemodynamically significant valvular disease or dynamic left ventricular obstruction. Repeat transthoracic echocardiography 5 months after HCQ discontinuation revealed a left ventricular ejection fraction of 66%, mild to moderate concentric LVH with an indexed left ventricular mass measurement of 123 g/m2, grade 2/4 left ventricular diastolic dysfunction with medial mitral E/e′ ratio 16, biatrial enlargement with an indexed left atrial volume of 48 ml/m2, estimated right ventricular systolic pressure of 32 mm Hg, and absence of hemodynamically significant valvular disease or dynamic left ventricular obstruction (Figure 2, Videos 1 and 2). Cardiac magnetic resonance imaging showed nonspecific mild concentric LVH (maximal wall thickness: 16 mm) and very mild late gadolinium myocardial enhancement without other evidence to suggest myocardial infarction, infiltrative process, or myocarditis (Figure 3). Cardiopulmonary exercise testing revealed a peak oxygen consumption of 22.2 ml/kg/min (91% predicted), with a peak heart rate of 111 beats/min and blunted chronotropic response in the absence of atrioventricular nodal blocking agents. Findings of pulmonary studies, including pulmonary function testing and chest computed tomography scan, were unremarkable. The H2FPEF score (1) was 2, suggesting low likelihood of heart failure with preserved ejection fraction based on the available workup/clinical picture.Figure 1 Resting Electrocardiogram Showing Sinus Bradycardia, Left Ventricular Hypertrophy, and a Premature Atrial Contraction Beat\n\nFigure 2 2-Dimensional Echocardiography Showing Mild Left Ventricular Hypertrophy, Biatrial Enlargement, and Diastolic Dysfunction\n\n(A) Parasternal long-axis view. (B) 4-chamber view. (C) Mitral inflow view. (D) Mitral medial tissue Doppler measurements.\n\nFigure 3 Cardiac Magnetic Resonance Images Showing Mild Left Ventricular Hypertrophy and Biatrial Enlargement\n\nCardiac magnetic resonance 4-chamber steady state free precession (A) and late gadolinium enhancement (B) sequences. Late gadolinium enhancement was absent, reducing the likelihood of an underlying infiltrative process, myocarditis, or sequelae of myocardial infarction.\n\nIn light of the patient’s unexplained exertional dyspnea, she subsequently underwent invasive hemodynamic cardiopulmonary exercise testing. Furthermore, given a nearly 30-year history of chronic HCQ use and documented chronotropic incompetence, the patient also underwent right ventricular endomyocardial biopsy to rule out HCQ-related cardiotoxicity. Hemodynamic catheterization was diagnostic of heart failure with preserved ejection fraction with severe chronotropic incompetence. Baseline right atrial pressure and pulmonary capillary wedge pressure were mildly elevated, at 7 mm Hg and 18 mm Hg, respectively (Figure 4A), with a resting heart rate of 38 beats/min. With exercise, there was severe elevation in biventricular filling pressures and severe exercise-induced pulmonary hypertension (Figure 4B). Peak exercise capacity was depressed because of chronotropic incompetence. Peak oxygen consumption (Vo2) was 948 ml/min (13.35 ml/kg/min), peak heart rate was 95 beats/min, peak cardiac output was 7.5 l/min, and peak cardiac index was 3.54 l/min/m2 (26% of the predicted increase based on metabolic demand).Figure 4 Hemodynamic Catheterization\n\n(A) Baseline right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP). (B) Severe elevation in biventricular filling pressures with exercise. LVP = left ventricular pressure.\n\nRight ventricular endomyocardial biopsy findings were consistent with HCQ cardiotoxicity, and hematoxylin and eosin staining showed myocytes with mild sarcoplasmic vacuolization (Figure 5A). Furthermore, transmission electron microscopy showed the presence of myelinoid bodies within myocytes (Figure 5B).Figure 5 Right Ventricular Endomyocardial Biopsy\n\n(A) Light microscopy (hematoxylin and eosin stain; original magnification: ×40) showing myocytes with mild sarcoplasmic vacuolization. (B) Transmission electron microscopy showing the presence of myelinoid bodies within myocytes.\n\nManagement\n\nAfter the initial evaluation, HCQ was discontinued because of a high clinical suspicion that it may be contributing to the patient’s symptoms. After completion of the hemodynamic study, the patient underwent permanent pacemaker implantation because of the persistence of severe symptomatic chronotropic incompetence despite HCQ discontinuation for 5 months.\n\nDiscussion\n\nChronic HCQ use can cause lysosomal dysfunction, which results in restrictive or hypertrophic cardiomyopathy with or without dilatation and/or conduction abnormalities, including atrioventricular blocks and bundle branch blocks (2). A high index of suspicion is needed to make the diagnosis of HCQ cardiotoxicity. The echocardiographic features of HCQ cardiotoxicity include diffusely thickened ventricular walls, biatrial enlargement, and diastolic dysfunction (2,3) Restrictive physiology is also frequently seen (3). Cardiac magnetic resonance imaging is usually helpful in biventricular structural and functional assessment, ruling out infiltrative cardiomyopathies and defining the myocardial substrate in restrictive cardiomyopathy (4). Endomyocardial biopsy remains the standard diagnostic test of HCQ cardiotoxicity. The pathological findings include enlarged and vacuolated cells on light microscopy and the presence of myelinoid and curvilinear bodies on transmission electron microscopy, which are due to the accumulation of metabolic products, such as glycogen and phospholipids (2, 3, 4, 5). Curvilinear bodies are more specific for HCQ cardiotoxicity, but they are not always seen (2). Therefore, in the proper clinical context, myelinoid bodies alone would be considered sufficient for making the diagnosis of HCQ cardiotoxicity. Enlarged mitochondria may also be seen (6).\n\nRisk factors for HCQ cardiotoxicity include older age, female sex, longer duration of therapy (>10 years), pre-existing cardiac disease, and renal insufficiency (2). Prognosis of HCQ cardiotoxicity can vary from complete reversibility to lack of reversibility requiring cardiac transplantation (2). Early recognition of HCQ cardiotoxicity is crucial to prevent late irreversible stages of the drug toxicity.\n\nFollow-Up\n\nSeveral months after the cessation of HCQ, the patient noticed a substantial improvement in her dyspnea. This symptomatic improvement continued after the pacemaker implantation. Two weeks after pacemaker implantation, she was found to have atrial fibrillation on cardiac device interrogation and was then started on anticoagulation with apixaban.\n\nConclusions\n\nThe present case underlines the importance of endomyocardial biopsy in confirming the diagnosis of HCQ-induced cardiomyopathy. It is unclear in this case the extent of diastolic dysfunction and chronotropic incompetence that were solely due to the cytopathic effects of HCQ, as opposed to overlap with unrelated heart failure with preserved ejection fraction. Regardless, HCQ cessation is indicated to treat a potentially reversible contributor to the patient’s symptoms.\n\nFunding Support and Author Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nTwo dimensional echocardiography (parasternal long axis view).\n\nSupplemental Video 2\n\nTwo dimensional echocardiography (4-chamber view).\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Reddy Y.N. Carter R.E. Obokata M. Redfield M.M. Borlaug B.A. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction Circulation 138 2018 861 870 29792299\n2 Joyce E. Fabre A. Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review Eur Heart J Acute Cardiovasc Care 2 2013 77 83 24062937\n3 Cotroneo J. Sleik K.M. Rodriguez E.R. Klein A.L. Hydroxychloroquine-induced restrictive cardiomyopathy: correlation between clinical, echocardiographic and pathologic findings Eur J Echocardiogr 8 2007 247 251 16600690\n4 Yogasundaram H. Putko B.N. Tien J. Paterson D.I. Cujec B. Ringrose J. Oudit G.Y. Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment Can J Cardiol 30 2014 1706 1715 25475472\n5 Ratliff N.B. Estes M.L. Myles J.L. Shirey E.K. McMahon J.T. Diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy N Engl J Med 316 1987 191 193 3796692\n6 Soong T.R. Barouch L.A. Champion H.C. Wigley F.M. Halushka M.K. New clinical and ultrastructural findings in hydroxychloroquine-induced cardiomyopathy—a report of 2 cases Hum Pathol 38 2007 1858 1863 18061791\n\n",
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"keywords": "HCQ, hydroxychloroquine; LVH, left ventricular hypertrophy; OSA, obstructive sleep apnea; cardiomyopathy; chronotropic incompetence; exercise; heart failure; hydroxychloroquine",
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"title": "Unmasking Hydroxychloroquine Cardiotoxicity in a Patient With Heart Failure and Chronotropic Incompetence.",
"title_normalized": "unmasking hydroxychloroquine cardiotoxicity in a patient with heart failure and chronotropic incompetence"
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"abstract": "Lymphoblastic lymphoma is a malignant neoplasia that originates from B or T lymphocyte precursors and rarely occurs in the mouth. The authors report a rare case of B-cell lymphoblastic lymphoma in the maxilla of a child. Clinical examination revealed facial asymmetry with a swelling of the right maxilla, covered by healthy mucosa and painful to palpation. Radiographic examination revealed a poorly defined radiolucent lesion. Based on the hypothesis of malignant neoplasia of hematopoietic origin, an incisional biopsy was performed. Histological examination revealed malignant neoplasia with proliferation of monomorphic, lymphoid cells. Immunohistochemical staining was positive for leucocyte common antigen (LCA), CD10, CD20, CD79, and terminal deoxynucleotidyl transferase (TdT). After the diagnosis of B-cell lymphoblastic lymphoma, the patient underwent chemotherapy, but died of leukoencephalopathy and demyelinization caused by high doses of methotrexate.",
"affiliations": "Department of Bioscience and Oral Diagnosis, School of Dentistry of São José dos Campos, São Paulo State University, São José dos Campos, São Paulo, Brazil. anasueli@fosjc.unesp.br",
"authors": "Cavalcante|A S R|AS|;Anbinder|A L|AL|;Pontes|E M|EM|;Carvalho|Y R|YR|",
"chemical_list": "D018951:Antigens, CD20; D014408:Biomarkers, Tumor; D051925:CD79 Antigens; D004253:DNA Nucleotidylexotransferase; D017493:Leukocyte Common Antigens; D015260:Neprilysin",
"country": "Denmark",
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"doi": "10.1016/j.ijom.2009.07.010",
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"issn_linking": "0901-5027",
"issue": "38(12)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": null,
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D018951:Antigens, CD20; D014408:Biomarkers, Tumor; D001706:Biopsy; D051925:CD79 Antigens; D002648:Child; D004253:DNA Nucleotidylexotransferase; D005146:Facial Asymmetry; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens; D016393:Lymphoma, B-Cell; D008441:Maxillary Neoplasms; D015260:Neprilysin; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011862:Radiography, Panoramic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "1326-30",
"pmc": null,
"pmid": "19665353",
"pubdate": "2009-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "B-cell lymphoblastic lymphoma in the maxilla of a child: a rare case report.",
"title_normalized": "b cell lymphoblastic lymphoma in the maxilla of a child a rare case report"
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"abstract": "This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92).",
"affiliations": "Hematology Department, University Hospital Hôtel-Dieu, Nantes, France;;Hematology Department, University Hospital, Reims, France;;Hematology Department, University Hospital, Toulouse, France;;Hematology Department, University Hospital, Dijon, France;;Hematology Department, University Hospital, Tours, France;;Hematology Department, University Hospital, La Roche sur Yon, France;;Hematology Department, University Hospital Hôtel-Dieu, Nantes, France;;Hematology Department, University Hospital, Lille, France;;Hematology Department, University Hospital, Toulouse, France;;Hematology Department, University Hospital, Clermont-Ferrand, France;;Hematology Department, University Hospital Hôtel-Dieu, Nantes, France;;Hematology Department, University Hospital Hôtel-Dieu, Nantes, France;;Hematology Department, University Hospital Hôtel-Dieu, Nantes, France;;Hematology Department, University Hospital, Toulouse, France;;Inserm U1153, University Hospital Saint-Louis, Paris, France; and.;Hematology Department, University Hospital, Nancy, France.;Hematology Department, University Hospital, Lille, France;",
"authors": "Moreau|Philippe|P|;Kolb|Brigitte|B|;Attal|Michel|M|;Caillot|Denis|D|;Benboubker|Lotfi|L|;Tiab|Mourad|M|;Touzeau|Cyrille|C|;Leleu|Xavier|X|;Roussel|Murielle|M|;Chaleteix|Carine|C|;Planche|Lucie|L|;Chiffoleau|Anne|A|;Fortin|June|J|;Avet-Loiseau|Hervé|H|;Mary|Jean-Yves|JY|;Hulin|Cyrille|C|;Facon|Thierry|T|",
"chemical_list": "D009842:Oligopeptides; C524865:carfilzomib; D008558:Melphalan; D011241:Prednisone",
"country": "United States",
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"doi": "10.1182/blood-2015-02-626168",
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"issn_linking": "0006-4971",
"issue": "125(20)",
"journal": "Blood",
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"medline_ta": "Blood",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D009842:Oligopeptides; D011241:Prednisone; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
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"pubdate": "2015-05-14",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma.",
"title_normalized": "phase 1 2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma"
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"abstract": "Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases.\nThe rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.\nTo the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.",
"affiliations": "Yeditepe University Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey;Diyarbakır Child Health Hospital, Clinic of Neonatology, Diyarbakır, Turkey;University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom;Diyarbakır Child Health Hospital, Clinic of Neonatology, Diyarbakır, Turkey;Diyarbakır Child Health Hospital, Clinic of Neonatology, Diyarbakır, Turkey;University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom;University of Health Sciences, Diyarbakır Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey",
"authors": "Haliloğlu|Belma|B|;Tüzün|Heybet|H|;Flanagan|Sarah E.|SE|;Çelik|Muhittin|M|;Kaya|Avni|A|;Ellard|Sian|S|;Özbek|Mehmet Nuri|MN|",
"chemical_list": "C577507:ABCC8 protein, human; D007166:Immunosuppressive Agents; D064233:Sulfonylurea Receptors; D020123:Sirolimus",
"country": "Turkey",
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"doi": "10.4274/jcrpe.5335",
"fulltext": "\n==== Front\nJ Clin Res Pediatr EndocrinolJ Clin Res Pediatr EndocrinolJCRPEJournal of Clinical Research in Pediatric Endocrinology1308-57271308-5735Galenos Publishing 2921749810.4274/jcrpe.533517030Case ReportSirolimus-Induced Hepatitis in Two Patients with Hyperinsulinemic Hypoglycemia Haliloğlu Belma 1*https://orcid.org/0000-0001-9946-235XTüzün Heybet 2https://orcid.org/0000-0002-7894-4859Flanagan Sarah E. 3https://orcid.org/Çelik Muhittin 2https://orcid.org/0000-0001-7367-0310Kaya Avni 2https://orcid.org/0000-0002-8917-8037Ellard Sian 3https://orcid.org/Özbek Mehmet Nuri 4https://orcid.org/0000-0002-3203-741X\n1 Yeditepe University Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey\n2 Diyarbakır Child Health Hospital, Clinic of Neonatology, Diyarbakır, Turkey\n3 University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom\n4 University of Health Sciences, Diyarbakır Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey* Address for Correspondence: Yeditepe University Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey Phone: +90 505 267 01 97 E-mail:belmahaliloglu26@hotmail.com9 2018 31 7 2018 10 3 279 283 15 9 2017 29 11 2017 © Copyright 2018, Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.2018This 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.Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases.\n\nThe rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.\n\nTo the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.\n\nHyperinsulinemic hypoglycemiasirolimushepatitisliver enzymes\n==== Body\nWhat is already known on this topic?\nSirolimus is an alternative for the treatment of congenital hyperinsulinism unresponsive to diazoxide and octreotide.\n\nWhat this study adds?\nThis is the first report of sirolimus-induced hepatitis in pediatric patients with hyperinsulinemic hypoglycemia.\n\nIntroduction\nCongenital hyperinsulinism (CHI) is characterized by inappropriate insulin secretion despite hypoglycemia. It is a heterogeneous disorder with the clinical manifestations ranging from severe hypoglycemia in the newborn period to mild hypoglycemia in childhood (1,2). The incidence is approximately 1:30.000 live births but is increased in populations with a high prevalence of consanguinity (3). Most cases of CHI are caused by autosomal recessive mutations in the ABCC8 and KCNJ11 genes (1).\n\nHistorically the treatment of severe, diffuse CHI, unresponsive to diazoxide and octreotide was subtotal pancreatectomy. This surgery has been associated with a high incidence of insulin-dependent diabetes, persistent hypoglycemia and exocrine pancreatic insufficiency (4). As a novel agent, the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, has been recommended for the treatment of the diffuse form of CHI, unresponsive to diazoxide and octreotide. It has been reported to be a safe agent in pediatric cases (5,6,7). Herein, we report two cases of diazoxide and octreotide unresponsive CHI, due to homozygous ABCC8 gene mutations in which sirolimus had to be discontinued because of drug related hepatotoxicity.\n\nCase Reports\nCase 1\nA female infant presented with severe hypoglycemia on the first day of life. CHI was diagnosed based on laboratory findings. She was normoglycemic with intravenous (iv) glucose, diazoxide, iv glucagon and octreotide on day 16 but the reduction in glucose requirement was not successful during the next five days (Table 1). She also had congenital hypothyroidism with normal thyroid ultasonography (TSH: >100 uIU/mL, sT4:0.7 ng/dL) and was euthyroid with L-thyroxine (12 mcg/kg/day).\n\n18F-DOPA positron emission tomography/computed tomography (PET/CT) scanning could not be performed but sequence analysis identified a novel homozygous p.H59P (c.176A>C) missense mutation in the proband’s ABCC8 gene. In silico analysis predicted the variant was likely to be pathogenic and that the affected residue was highly conserved across species (Alamut, Rouen, France). The identification of a recessively inherited ABCC8 mutation in the patient was consistent with diffuse pancreatic disease. After consent from the parents, sirolimus was started at a dose of 0.5 mg/m2/day on day 21. The serum level of sirolimus and laboratory tests (full blood count, kidney and liver function tests, lipid profile, electrolytes) were checked every five days, to maintain the serum sirolimus concentration between 5-15 ng/dL. The patient was discharged on day 72 with oral feeding, subcutaneous octreotide (40 mcg/kg/d) and oral sirolimus (3 mg/m2/day). The sirolimus level and biochemical markers were checked at monthly intervals.\n\nSince she was normoglycemic, the octreotide dose was decreased during follow-up. At the age of 10 months the patient presented with diarrhea. At this time, she was being treated with octreotide (6 mcg/kg/d) and sirolimus (3.1 mg/m2/day) and was normoglycemic. Her laboratory tests revealed elevated liver enzymes (Table 2). The coagulation tests, bilirubin levels, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and abdominal ultrasound results were all normal. Although the sirolimus level was below the therapeutic range (1.4 ng/mL), it was discontinued due to its known hepatotoxic effect. The liver enzyme levels during dose adjustments are shown in the Figure 1. After sirolimus was discontinued, the octreotide dose was increased to 45 mcg/kg/d to achieve normoglycemia and four months later the patient was switched to octreotide-long-acting release (LAR). She is currently 18 months of age with normal neuromotor development and normoglycemia, treated solely with octreotide-LAR (15 mg/monthly, 41 mcg/kg/d) and oral feedings with three hourly intervals. Her most recent HbA1c level was 4.9% (30 mmol/mol) and also, she is euthyroid on L-thyroxine treatment.\n\nCase 2\nThis female infant was referred to our clinic on day 14 of life with CHI resistant to medical therapy (Table 1) and the reduction in glucose requirement was not successful. She had also congenital hypothyroidism with normal thyroid ultrasound (TSH: >100 uIU/mL, sT4:0.9 ng/dL) and was euthyroid with L-thyroxine (8 mcg/kg/d).\n\nSequence analysis identified a previously reported homozygous missense mutation, p.A1185E (c.3554C>A), in ABCC8 (8). The presence of a homozygous mutation in the patient was in keeping with diffuse pancreatic disease. After consent from the parents was obtained, sirolimus (0.5 mg/m2/day) was added, due to no reduction in the glucose requirement by day 17. Serum levels of sirolimus were checked every five days to maintain a therapeutic serum level as before. Neither clinical nor laboratory side effects were observed. She was discharged at age 40 days with sirolimus 0.4 mg/m2/day and octreotide 23 mcg/kg/d.\n\nOne month later, routine blood tests for side effects revealed elevated liver enzymes (Table 2) without any clinical symptoms. Sirolimus level at this time was 9.9 ng/mL in the middle of the therapeutic range. All other laboratory tests (blood count, kidney function tests, ALP, GGT, bilirubin levels) and abdominal ultrasound revealed normal results. The liver enzyme levels during dose adjustments are shown in Figure 1. As sirolimus was discontinued, the dose of octreotide was increased from 10 to 45 mcg/kg/d. Although, the glucose levels were generally close to the lower limit of normal, with frequent oral feedings and applying a maximum dose of octreotide, we were able to protect the patient from severe hypoglycemia (a glucose level <50 mg/dL). Subcutaneous octreotide was switched to octreotide-LAR five months later. The patient is currently 13 months of age and normoglycemic with octreotide-LAR (15 mg/monthly, 45 mcg/kg/d) and oral feedings at 4 hours intervals. Last HbA1c is 4.2% (22 mmol/mol) and also, she is euthyroid on L-thyroxine treatment.\n\nDiscussion\nThe aim of treatment in CHI is to achieve normoglycemia and to prevent neurological damage. However, the clinical management of severe, diffuse CHI, unresponsive to medical treatment is still a vexing clinical problem (4). In a recent study, mTOR inhibitor, sirolimus, has been reported to be a novel agent for the treatment of diazoxide unresponsive CHI. Therapy with sirolimus achieved normoglycemia with no major adverse effect in four cases (5). We now report two further cases with severe CHI due to a homozygous ABCC8 mutation. Both were successfully treated with sirolimus consistent with previous reports, but sirolimus had to be discontinued because of drug-induced hepatitis.\n\nIn adult studies, various side effects of mTOR inhibitors have been reported which include bone marrow suppression, dyslipidemia, immunosuppression, elevation of liver enzymes, renal dysfunction, pneumonitis and stomatitis. These were reversible with dose reduction (9,10). In children, this drug was reported to be well tolerated in several studies with normal or high doses (1-6 mg/m2/d) (11,12,13). The main side effect reported in these studies was oral mucositis. However, in a recent study, Szymanowski et al (14) investigated the efficacy and adverse effect profile of sirolimus in the treatment of severe CHI. These authors detected adverse events such as hypertriglyceridemia, anemia, stomatitis, sepsis, varicella zoster and gut dysmotility in 80% of their patients, but also reported a 30% therapeutic success rate.\n\nHepatotoxicity is another known side effect of sirolimus, resulting in transient and mild increase in liver enzymes. Its incidence was reported to be 17% in patients with renal transplant (15). Senniappean et al (5) and Méder et al (6) reported mild, transient elevation of liver enzyme concentrations. These increases were less than double the normal range and resolved spontaneously or with reduction in sirolimus dose (5,6). Although sirolimus appears to be safe in terms of hepatotoxicity, cases with severe sirolimus-induced hepatitis have been reported. One report was that of a patient with renal transplantation who received sirolimus as an initial immunosuppressive in the post-transplant period (16). At the 16th month post-transplant, increased liver enzyme levels were detected [maximum aspartate aminotransferase (AST): 368 IU/L, alanine aminotransferase (ALT): 579 IU/L] with a serum sirolimus level of 6.3 ng/dL. After sirolimus withdrawal, quick normalization of aminotransferases was observed. Jacques et al (17) reported another case with renal transplantation. In the second month of sirolimus, biochemical tests showed acute hepatitis (AST: 861 IU/l, ALT: 609 IU/L) with signs of hepatic insufficiency. The serologic and autoimmune markers for hepatitis were normal. Despite a normal sirolimus level (10 ng/mL), it was withdrawn and transaminase levels normalized within five weeks. In our two cases, after sirolimus was discontinued in one case and decreased in the other, the normalization of transaminases was observed within a few days.\n\nWhile octreotide is usually well tolerated in most patients with CHI, octreotide induced hepatitis has been reported in a few patients (18,19,20,21). Hepatitis was found to develop even with doses within the normal range, but the withdrawal of octreotide resulted in resolution. The rapid normalization of liver enzyme levels after sirolimus withdrawal and dose reduction, in our first and second case respectively, followed by elevation of transaminases after restart or dose increase and rapid normalization after sirolimus was again withdrawn while the patient continued with octreotide treatment provides robust evidence of sirolimus-induced hepatitis.\n\nFortunately, both patients are now normoglycemic with octreotide-LAR and frequent feedings. This observation suggests that this entity may tend to become milder over time. It also suggests that a good response to octreotide-LAR may be expected as the patients get older.\n\nOctreotide may affect thyroid hormones and may cause hypothyroidism with a concomitant low TSH level. However, hypothyroidism with elevated TSH levels was also reported in two cases with octreotide treated CHI due to ABCC8 gene mutation (19,20). Similarly, our cases had elevated TSH levels with a low free thyroxine that is a characteristic finding for primary hypothyroidism. This is most probably a coincidental finding since patients on octreotide therapy usually develop central hypothyroidism marked by low TSH. Further tests will be done for the etiology of primary hypothyroidism in later years.\n\nIn conclusion, sirolimus is a promising drug for diazoxide and octreotide unresponsive CHI patients, but physicians should be vigilant for its adverse effects which may necessitate the withdrawal of the drug.\n\nEthics\n\nInformed Consent: Informed consent was taken from the patients.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Belma Haliloğlu, Muhittin Çelik, Heybet Tüzün, Mehmet Nuri Özbek, Concept: Belma Haliloğlu, Design: Belma Haliloğlu, Data Collection or Processing: Belma Haliloğlu, Heybet Tüzün, Mehmet Nuri Özbek, Avni Kaya, Analysis or Interpretation: Belma Haliloğlu, Sian Ellard, Sarah E. Flanagan, Literature Search: Belma Haliloğlu, Writing: Belma Haliloğlu, Sarah E. Flanagan.\n\nFinancial Disclosure: The genetic studies were funded by the Medical Research Council (grant number: 98144). Sarah E. Flanagan has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number: 105636/Z/14/Z).\n\nTable 1 The clinical features of the patients before sirolimus\nTable 2 The liver enzyme levels of the patients during hepatotoxic period of sirolimus\nFigure 1 Liver enzyme levels (AST: aspartate aminotransferase, ALT: alanine aminotransferase) of Case 1 and Case 2 during sirolimus treatment and immediately after cessation\n==== Refs\nReferences\n1 Flanagan SE Kapoor RR Hussain K Genetics of congenital hyperinsulinemic hypoglycemia Semin Pediatr Surg 2011 20 13 17 21185998 \n2 de Lonlay P Fournet JC Touati G Groos MS Martin D Sevin C Delagne V Mayaud C Chigot V Sempoux C Brusset MC Laborde K Bellane-Chantelot C Vassault A Rahier J Junien C Brunelle F Nihoul-Fékété C Saudubray JM Robert JJ Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases Eur J Pediatr 2002 161 37 48 11808879 \n3 Arnoux JB Verkarre V Saint-Martin C Montravers F Brassier A Valayannopoulos V Brunelle F Fournet JC Robert JJ Aigrain Y Bellanné-Chantelot C de Lonlay P Congenital hyperinsulinism: current trends in diagnosis and therapy Orphanet J Rare Dis 2011 6 63 21967988 \n4 Güemes M Hussain K Hyperinsulinemic hypoglycemia Pediatr Clin of North Am 2015 62 1017 1036 26210630 \n5 Senniappan S Alexandrescu S Tatevian N Shah P Arya V Flanagan S Ellard S Rampling D Ashworth M Brown RE Hussain K Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia N Engl J Med 2014 370 1131 1137 24645945 \n6 Méder Ü Bokodi G Balogh L Körner A Szabó M Pruhova S Szabo AJ Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy Pediatrics 2015 136 1369 1372 \n7 Abraham MB Shetty VB Price G Smith N Bock Md Siafarikas A Resnick S Whan E Ellard S Flanagan SE Davis EA Jones TW Hussain K Choong CS Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia J Pediatr Endocrinol Metab 2015 28 1391 1398 26226122 \n8 Arya VB Guemes M Nessa A Alam S Shah P Gilbert C Senniappan S Flanagan SE Ellard S Hussain K Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations Eur J Endocrinol 2014 171 685 695 25201519 \n9 Ventura-Aguiar P Campistol JM Diekmann F Safety of mTOR inhibitors in adult solid organ transplantation Expert Opin Drug Saf 2016 15 303 319 26667069 \n10 Sankhala K Mita A Kelly K Mahalingam D Giles F Mita M The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents Target Oncol 2009 4 135 142 19381454 \n11 Nadal M Giraudeau B Tavernier E Jonville-Bera AP Lorette G Maruani A Efficacy and Safety of Mammalian Target of Rapamycin Inhibitors in Vascular Anomalies: A Systematic Review Acta Derm Venereol 2016 96 448 452 26607948 \n12 Zou L Liu Y Pang L Ju J Shi Z Zhang J Chen X Su X Hu L Shi X Yang X Efficacy and safety of rapamycin in treatment of children with epilepsy complicated with tuberous sclerosis Zhonghua Er Ke Za Zhi 2014 52 812 816 25582464 \n13 Schachter AD Benfield MR Wyatt RJ Grimm PC Fennell RS Herrin JT Lirenman DS McDonald RA Munoz-Arizpe R Harmon WE Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy Pediatr Transplant 2006 10 914 919 17096757 \n14 Szymanowski M Estebanez MS Padidela R Han B Mosinska K Stevens A Damaj L Pihan-Le Bars F Lascouts E Reynaud R Ferreira C Bansept C de Lonlay P Saint-Martin C Dunne MJ Banerjee I Arnoux JB mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success J Clin Endocrinol Metab 2016 101 4719 4729 27691052 \n15 Groth CG Backman L Morales JM Calne R Kreis H Lang P Touraine JL Claesson K Campistol JM Durand D Wramner L Brattström C Charpentier B Sirolimus (rapamycine)- based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group Transplantation 1999 67 1036 1042 10221490 \n16 Niemczyk M Wyzgał J Perkowska A Porowski D Paczek L Sirolimus-associated hepatotoxicity in the kidney graft recipient Transpl Int 2005 18 1302 1303 16221163 \n17 Jacques J Dickson Z Carrier P Essig M Guillaudeau A Lacour C Bocquentin F Aldigier JC Rerolle JP Severe sirolimus-induced acute hepatitis in a renal transplant recipient Transpl Int 2010 23 967 970 20497403 \n18 Avatapalle B Padidela R Randell T Banerjee I Drug-induced hepatitis following use of octreotide for long-term treatment of congenital hyperinsulinism BMJ Case Rep 2012 2012. \n19 Levy-Khademi F Irina S Avnon-Ziv C Levmore-Tamir M Leder O Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism J Pediatr Endocrinol Metab 2015 28 449 451 25324442 \n20 Koren I Riskin A Barthlen W Gillis D Hepatitis in an infant treated with octreotide for congenital hyperinsulinism J Pediatr Endocrinol Metab 2013 26 183 185 23327817 \n21 Ben-Ari J Greenberg M Nemet D Edelstein E Eliakim A Octreotide-induced hepatitis in a child with persistent hyperinsulinemia hypoglycemia of infancy J Pediatr Endocrinol Metab 2013 26 179 182 23327813\n\n",
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"issue": "10(3)",
"journal": "Journal of clinical research in pediatric endocrinology",
"keywords": "Hyperinsulinemic hypoglycemia; sirolimus,; hepatitis,; liver enzymes",
"medline_ta": "J Clin Res Pediatr Endocrinol",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D044903:Congenital Hyperinsulinism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D020123:Sirolimus; D064233:Sulfonylurea Receptors",
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"title": "Sirolimus-Induced Hepatitis in Two Patients with Hyperinsulinemic Hypoglycemia",
"title_normalized": "sirolimus induced hepatitis in two patients with hyperinsulinemic hypoglycemia"
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"abstract": "Pseudoprogression (PP) is a diagnostic dilemma in the follow-up of brain high grade gliomas (HGG), and the introduction of new therapies has further complicated its identification in Magnetic Resonance Imaging (MRI). We report a case of pseudoprogression after intraoperative radiotherapy (ioRT) and Regorafenib therapy in a patient with anaplastic astrocytoma recurrence. A 65-year-old man, treated in August 2017 for a right frontal anaplastic astrocytoma, with surgical resection and following radiotherapy and Temozolomide, in October 2019 was again treated for peri-surgical bed recurrence with resection and ioRT followed by Regorafenib therapy, interrupted in February 2020, after the onset of adverse reactions. MRI examination showed a large irregular alteration posterior to the surgical bed, T2 weighted hypointense featuring strong diffusion restriction (low ADC values), with an irregular contrast-enhancement (CE) pattern, and surrounded by a vast vasogenic oedema; Dynamic Susceptibility Contrast (DSC) perfusion imaging (PWI) showed no increase of relative cerebral blood volume (rCBV). Particularly, lesion appeared markedly hypointense and dusty-like on susceptibility weighted images (SWI) probably due to a constant hemorrhagic diapedesis promoted by Regorafenib. Therefore, pseudoprogression was suspected. Follow-up MRI exams showed gradual reduction of SWI and CE abnormalities, but a persistent DWI restriction. Unfortunately, the last MRI control showed a secondary cerebellar localisation of the disease. New therapies are changing MRI pattern in HGG imaging and this case underlines how a multimodality approach is increasingly necessary. In particular, when using anti-VEGF drugs, SWI can have a crucial role in identifying therapy-related haemorrhagic changes.",
"affiliations": "Neuroradiology Unit, San Bortolo Hospital, AULSS 8 Berica, Vicenza, Italy.;Neuroradiology Unit, San Bortolo Hospital, AULSS 8 Berica, Vicenza, Italy.;Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.;Pathology Unit, San Bortolo Hospital, AULSS 8 Berica, Vicenza, Italy.;Oncology Unit, San Bortolo Hospital, AULSS 8 Berica, Vicenza, Italy.;Neurosurgery Unit, San Bortolo Hospital, AULSS 8 Berica, Vicenza, Italy.",
"authors": "Mansour|Mariam|M|;Vitale|Valerio|V|https://orcid.org/0000-0001-8042-3959;Lombardi|Giuseppe|G|;Riva|Giulio|G|;Pancheri|Francesca|F|;Zanusso|Mariano|M|",
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"journal": "Journal of medical imaging and radiation oncology",
"keywords": "Regorafenib; SWI; high-grade glioma; pseudoprogression",
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"title": "Modification of MRI pattern of high-grade glioma pseudoprogression in regorafenib therapy.",
"title_normalized": "modification of mri pattern of high grade glioma pseudoprogression in regorafenib therapy"
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"abstract": "Parkinsonism-hyperpyrexia syndrome (PHS) is a neurologic potentially fatal emergency that mimics neuroleptic malignant syndrome. It commonly presents as systemic inflammatory response syndrome, acute onset worsening of muscular rigidity, autonomic instability, hyperpyrexia, confusion, diaphoresis and high creatine phosphokinase. The most common trigger for PHS is reduction or withdrawal of anti-Parkinson's medications, especially levodopa. It was also reported in a few cases following deep brain stimulation of the subthalamic nucleus surgery shortly after anti-Parkinson's medications were discontinued. Rare causes of PHS include deep brain stimulator (DBS) malfunction due to battery depletion. To the best of our knowledge, PHS following DBS battery depletion was reported only in three occasions. Here, we report a case of PHS due to DBS battery depletion presented as sepsis and was successfully treated with the administration of dopamine agonists, intravenous fluids and changing the DBS battery.",
"affiliations": "Internal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA.;Internal Medicine, Hadassah Medical Center, Jerusalem, Israel.;Internal Medicine, Hadassah Medical Center, Jerusalem, Israel.;Internal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA.",
"authors": "Azar|Jehad|J|http://orcid.org/0000-0002-5966-152X;Elinav|Hila|H|;Safadi|Rifaat|R|;Soliman|Mona|M|",
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"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22912210.1136/bcr-2018-229122New Disease1506152015601374200228218Case ReportMalignant deep brain stimulator withdrawal syndrome http://orcid.org/0000-0002-5966-152XAzar Jehad 1Elinav Hila 2Safadi Rifaat 2Soliman Mona 1\n1 \nInternal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA\n\n2 \nInternal Medicine, Hadassah Medical Center, Jerusalem, Israel\nCorrespondence to Dr Jehad Azar, jehad.azar@gmail.com2019 15 5 2019 15 5 2019 12 5 e2291223 5 2019 © BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Parkinsonism-hyperpyrexia syndrome (PHS) is a neurologic potentially fatal emergency that mimics neuroleptic malignant syndrome. It commonly presents as systemic inflammatory response syndrome, acute onset worsening of muscular rigidity, autonomic instability, hyperpyrexia, confusion, diaphoresis and high creatine phosphokinase. The most common trigger for PHS is reduction or withdrawal of anti-Parkinson’s medications, especially levodopa. It was also reported in a few cases following deep brain stimulation of the subthalamic nucleus surgery shortly after anti-Parkinson’s medications were discontinued. Rare causes of PHS include deep brain stimulator (DBS) malfunction due to battery depletion. To the best of our knowledge, PHS following DBS battery depletion was reported only in three occasions. Here, we report a case of PHS due to DBS battery depletion presented as sepsis and was successfully treated with the administration of dopamine agonists, intravenous fluids and changing the DBS battery.\n\nneurology (drugs and medicines)neuroendocrinologyspecial-featureunlocked\n==== Body\nBackground\nHigh-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established modality for treating Parkinson’s disease (PD) for more than two decades. Our knowledge about the pathophysiology of PD and the clinical applications for STN DBS is rapidly evolving. Nevertheless, the exact mechanism of action of STN DBS remains an enigma.1 The common hypothesis is that DBS acts through modulation or disruption of the pattern of neural signalling within targeted regions in the brain: the STN and the internal segment of globus pallidus.2 3 The long-term efficacy and safety of DBS are promising, as reported in many recent publications.4 Parkinsonism-hyperpyrexia syndrome (PHS) is a life-threatening disorder, commonly reported following withdrawal of anti-Parkinson medications. More rarely, PHS is concomitant with DBS malfunction. In this case report, we describe a novel syndrome of PHS due to DBS battery depletion, which presented as sepsis in our hospital in May 2014.\n\nCase presentation\nA 67-year-old woman, previous medical history significant for Hashimoto hypothyroidism, essential hypertension, dementia, major depression and diabetes mellitus. She was diagnosed with PD in 1991. Over the years, her treatment included levodopa/carbidopa and pramipexole, with poor control of her symptoms. In 2007, bilateral STN DBS was implanted, resulting in significant improvement of tremors and motor deficit. Her symptoms were well controlled for the following 7 years; however, the DBS battery was never replaced.\n\nThe patient presented to the emergency room (ER) in May 2014 with a 3-day history of high-grade fever (up to 39°C) (figure 1), altered mental status, poor oral intake and low urinary output. On admission, she was febrile 38.5°C, tachycardia at 110 beats/min with elevated blood pressure 180/77 mm Hg; her respiratory rate was 18 breaths/min, with pulse oximetry of 90% in room air. Her physical examination showed a somnolent, diaphoretic and severely dehydrated patient, with mild respiratory distress; neurologic examination demonstrated somnolence with lack of response to painful stimuli. Her breath sounds were diminished in the lung bases. The rest of the physical examination was unremarkable.\n\nFigure 1 Fever chart in degrees Celsius. Day 1 is the first day of admission. Day 9 (red arrow) represents time of increasing her levodopa dose. Day 17 (blue arrow) is when her IPG Impulse Generator was replaced. On day 23, she was sent to rehabilitation.\n\nLaboratory tests were remarkable for acute prerenal failure with creatinine 123 µmol/L, hypernatraemia 157 mmol/L, elevated creatine kinase at 1015 U/L, leucocytosis 12 600/µL with a C reactive protein (CRP) of 1.6 mg/dL. A chest X-ray demonstrated atelectasis in the lung bases. Lumbar puncture ruled out central nervous system (CNS) infection, with normal cell count and negative viral PCR and cerebrospinal fluids (CSF) cultures. After blood, sputum, urinary and stool cultures were obtained, the patient was started on an antibiotics for possible pulmonary infection. Due to continued fevers and decreased consciousness, she underwent a whole-body CT that failed to localise a possible source of infection. Serology for cytomegalovirus (CMV) and Epstein-Barr Virus (EBV), respiratory viral swab and all other cultures came back negative. The patient’s Thyroid Stimulating Hormone (TSH), calcium, ammonia, liver enzymes and vitamin B12 levels were all within normal limits. She completed a course of antibiotics and thiamine with no improvement.\n\nDue to lack of a similar reported cases in the literature, unfamiliarity with this presentation among the medical team, and given no history of neuroleptics administration or withdrawal of dopaminergic medications prior to the onset of symptoms. It was not until day 9 postadmission that the diagnosis of PHS was made, after the patient continued to have non-resolving high fever, severe muscular rigidity, altered mental status, autonomic instability (hypertension up to 180/90 and tachycardia between 110 and 125 beats/min) and elevated creatine kinase (CK) to 1615 U/L. Subsequently, the patient was treated with intravenous fluids, acetaminophen and ice packs; levodopa dose was tripled, with no clinical improvement. Yet, transient resolution of fever was noted before it spiked again 2 days later (figure 1). Considering the unsatisfactory results of conservative management, lack of clinical improvement and given that the estimated DBS battery life is between 3 and 5 years, DBS withdrawal syndrome due to battery depletion was suspected. However, the Implantable Pulse Generator (IPG) replacement was not accomplished until day 17 of admission due to lack of similar reported cases and unavailability of supportive evidences in the literature. A few hours later following successful IPG replacement, clinical improvement was documented. After 1 day post IPG replacement, there was no more fever (figure 1) or autonomic instability; CK, white blood cell (WBC) count, creatinine level and CRP all normalised. The patient’s rigidity and mental status improved to full recovery until discharge.\n\nOutcome and follow-up\nDuring the course of admission, the patient continued to have non-resolving high fever, altered mental status and autonomic instability. CK level increased to 1615 U/L. After a delayed diagnosis of malignant DBS withdrawal syndrome due to battery depletion was made, she underwent successful IPG replacement with subsequent dramatic clinical improvement, as documented by rapid resolution of fever (figure 1), normalisation of CK, WBC count, creatinine and CRP levels. Full recovery with normal mental status was documented on discharge.\n\nDiscussion\nPHS is a medical emergency described in patients with PD. This syndrome was first shown in a PD patient in 1981 after discontinuation of his anti-Parkinson’s medications even though no neuroleptics were prescribed.5 It is not uncommon to misdiagnose PHS because of the overlapping symptoms with advanced PD and sepsis. The classic presentation include muscle rigidity, tremors, rapidly evolving fever, autonomic instability, reduced mental status, diaphoresis, elevated CRP, high CK due to rhabdomyolysis and increase in WBC counts.6 The exact pathogenesis behind the development of PHS remains unclear. A growing body of evidence suggests acute reduction of neurotransmission in the hypothalamus, nigrostriatal system and mesocortical dopaminergic system contributing to the development of PHS.7 Complications of PHS include aspiration pneumonia, renal failure due to rhabdomyolysis, disseminated intravascular coagulation and venous thromboembolism. In addition, patients may develop a potentially fatal CNS; hypodopaminergic crisis within hours to days. Supportive management and reinitiation of dopaminergic medications are the core stones of treatment.7 8\n\nThe most common trigger for PHS is withdrawal of anti-Parkinson’s medications, especially levodopa. Due to ultra-short half-life of levodopa, sudden withdrawal of dopaminergic medications during the perioperative period may cause PHS.9–15 Additional triggers reported in the PD patient include prescription of neuroleptic medication, infection, dehydration and excessive hot weather.16 17\n\nCases of PHS reportedly associated with acute DBS withdrawal are summarised in table 1.\n\nTable 1 Reported cases with DBS withdrawal syndrome (all patients had subthalamic nucleus DBS)\n\nReport\tA/S/YOD\tPDD/DBSD\tTreatment\tLaboratory results\tCause of DBS failure\tDBS restoration\tOutcome\t\nChyong-jy et al\n18\n\t69/M/2017\t16/9\t↑Levodopa\t↑CK (1250 IU/L)\tBattery depletion\tBattery was replaced\tRecovery\t\n\t\t\tConservative\t↑WBC (12.1 x 109/L)\t\t\t\t\n\t\t\tBromocriptine\t\t\t\t\t\n\t\t\tDantrolene\t\t\t\t\t\nArtusi et al\n19\n\t63/M/2015\t18/5\t↑Levodopa\t↑CK (2820 U/L)\tBattery depletion\tIPG was reimplanted\tRecovery\t\n\t\t\tConservative\t↑CRP (50.1 mg/L)\t\t\t\t\n\t\t\t\t↑WBC (10.0 x 109/L)\t\t\t\t\nReuter et al\n22\n\t75/M/2014\t19/9\t↑Levodopa\t–\tIPG infection\tIPG was not reimplanted\tDeath\t\n\t\t\tIV Amantadine\t\t\t\t\t\n\t\t\tConservative\t\t\t\t\t\nReuter et al\n22\n\t74/M/2014\t24/10\t↑Levodopa\t–\tIPG infection\tIPG was not reimplanted\tDeath\t\n\t\t\tIntravenous amantadine\t\t\t\t\t\n\t\t\tConservative\t\t\t\t\t\nReuter et al\n22\n\t52/M/2013\t20/8\t↑Levodopa\t–\tIPG infection\tIPG was reimplanted\tRecovery\t\n\t\t\tIntravenous amantadine\t\t\t\t\t\n\t\t\tApomorphine\t\t\t\t\t\n\t\t\tConservative\t\t\t\t\t\nNeuneier et al\n20\n\t77/M/2013\t18/5\t↑Levodopa\t↑CK (1642 U/L)\tBattery depletion\tLate IPG reimplantation\tDeath\t\n\t\t\tIntravenous amantadine\t↑CRP (50 mg/L)\t\t\t\t\n\t\t\tConservative\t\t\t\t\t\nKadowaki et al\n21\n\t60/M/–\t17/8\tConservative\t↑CK (1878 U/L)\tDBS switched off\tDBS switched on\tRecovery\t\n\t\t\t\t↑CRP (10.3 mg/L)\t\t\t\t\n\t\t\t\t↑WBC (12.6 x 109/L)\t\t\t\t\nOur case\t67/F/2014\t23/7\t↑Levodopa\t↑ CK (1615 U/L)\tBattery depletion\tBattery was replaced\tRecovery\t\n\t\t\tPramipexole\t↑ CRP (10.6 mg/L)\t\t\t\t\n\t\t\tConservative\t↑WBC (16.5 x 109/L)\t\t\t\t\nConservative treatment refers to intravenous fluids +/− (antipyretic, antibiotics, cooling measures, sedatives, eg, benzodiazepines).\n\nA, age; CK creatine kinase; CRP, C reactive protein; DBS, deep brain stimulator; DBSD, DBS duration at PHS onset; PDD, Parkinson’s disease duration; PHS, Parkinson-hyperpyrexia syndrome; S, sex; WBC, white blood cell; YOD, year of diagnosis.\n\nChyong-jy et al\n18 reported a patient with a history of PD for 16 years, who developed PHS during preoperative assessment for planned DBS battery replacement, which was consequently postponed on account of suspected sepsis. Following significant clinical deterioration despite broad-spectrum antibiotic administration, and the failure to identify a source of sepsis, PHS was suspected. Treatment of dantrolene and bromocriptine was commenced, as well as intense supportive care, and the dose of dopaminergic medications was increased. As a result of the failure of conservative management, the DBS battery was replaced with subsequent recovery. Artusi et al\n19 described a 63-year-old man with long-standing advanced PD with suspected PHS due to DBS battery depletion, showing gradual clinical and laboratory improvement after IPG replacement. Neuneier et al\n20 reported a case of fatal PHS in a patient with advanced PD, who developed withdrawal syndrome a few days after battery depletion. IPG replacement was postponed in this case, due to risk of bleeding on account of concomitant antiplatelet administration, resulting in the death of the patient with disseminated intravascular coagulation (DIC) and multiorgan failure. Kadowaki et al\n21 described a PD patient with recurrent PHS following several attempts of discontinuing STN-DBS to improve psychiatric complications (manic symptoms). Reuter et al\n22 published three cases with PHS after the removal of DBS implant, due to hardware-related infection. Fatal outcomes were reported in patients who had no IPG replacement despite an increase in the dose of levodopa. In our reported case, we came to the conclusion on account of the knowledge that battery efficiency depletes within a specific time frame and replacement is advised regularly, as is the exclusion of possible diagnosis, which would explain presenting symptoms. PHS was suspected despite a lack of previous reported cases. Initial treatment involved the increase of levodopa dose, administration of intravenous fluids, as well as pramipexole, with no clinical improvement in a patient with advanced PD and long-term STN stimulation. It was only after IPG replacement that the patient began to show signs of recovery.\n\nThe exact mechanism by which DBS influences neurotransmission in the brain has yet to be determined. As seen in other reported cases, as well as in our case, dopaminergic transmission may have been enhanced during the patient’s STN DBS stimulation; therefore, abrupt cessation of DBS results in a rebound effect with PHS development. In this scenario, patients were not responsive to conservative treatment using intravenous fluids and an increase in the dosage of dopaminergic medications. On the contrary, patients responded to the restoration of STN stimulation after replacing the IPG, suggesting possible different mechanisms of action in the nigral pathways for the DBS versus oral dopaminergics. As a result, sudden withdrawal of DBS, independent of changes in dopaminergic therapy, may induce PHS, deeming dopaminergic therapy in these cases ineffective. Possible risk factors for life-threatening DBS withdrawal syndrome may include long-standing PD (mean is 19.3 years, table 1), prolonged DBS stimulation (mean is 7.6 years, table 1) and old age (mean is 67.1 years, table 1). An optimal prognosis can be achieved with high index of suspicion and immediate DBS restoration, while delayed restoration or failure to restore DBS activity can result in fatal outcomes.\n\nLearning points\nMalignant deep brain stimulation (DBS) withdrawal syndrome is a rare disease, which happens exclusively in patients with advanced Parkinson’s disease as a result of abrupt cession of DBS activity.\n\nIt has a hypothesised different mechanism of action, in comparison with dopaminergic medication.\n\nTreatment by augmenting the dopaminergic medications should be considered temporary, while immediate DBS restoration is considered the definitive treatment, preventing an otherwise fatal outcome.\n\nI would like to express my deep and sincere gratitude to my research supervisors; Professor Arie Ben Yehuda, Chairman of Internal Medicine at Hadassah Medical Center, and Dr Keyvan Ravakhah, Chairman of Internal Medicine at St. Vincent Charity Medical Center. Both have provided insight and expertise that greatly assisted the research.\n\nContributors: JA is the first author, HE and RS were involved in the patient care and helped in reviewing the case. MS had reviewed the case report.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPatient consent for publication: Obtained.\n==== Refs\nReferences\n1 \nBenabid AL , Chabardes S , Mitrofanis J , et al \nDeep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease . Lancet Neurol \n2009 ;8 :67 –81 .19081516 \n2 \nBronstein JM , Tagliati M , Alterman RL , et al \nDeep brain stimulation for Parkinson disease: an expert consensus and review of key issues . Arch Neurol \n2011 ;68 :165 .20937936 \n3 \nKleiner-Fisman G , Herzog J , Fisman DN , et al \nSubthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes . Mov Disord \n2006 ;21 (Suppl 14 ):S290 –S304 .16892449 \n4 \nMoro E , Lozano AM , Pollak P , et al \nLong‐term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson’s disease . Mov Disord \n2010 ;25 :578 –86 .20213817 \n5 \nToru M , Matsuda O , Makiguchi K , et al \nNeuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs . J Nerv Ment Dis \n1981 ;169 :324 –7 .6111584 \n6 \nNewman EJ , Grosset DG , Kennedy PG \nThe parkinsonism-hyperpyrexia syndrome . Neurocrit Care \n2009 ;10 :136 –40 . 10.1007/s12028-008-9125-4 \n18712508 \n7 \nMizuno Y , Takubo H , Mizuta E , et al \nMalignant syndrome in Parkinson’s disease: concept and review of the literature . Parkinsonism Relat Disord \n2003 ;9 (Suppl 1 ):S3 –S9 .12735909 \n8 \nGranner MA , Wooten GF \nNeuroleptic malignant syndrome or parkinsonism hyperpyrexia syndrome . Semin Neurol \n1991 ;11 :228 –35 .1947485 \n9 \nUrasaki E , Fukudome T , Hirose M , et al \nNeuroleptic malignant syndrome (parkinsonism-hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus . J Clin Neurosci \n2013 ;20 :740 –1 . 10.1016/j.jocn.2012.04.024 \n23465352 \n10 \nGovindappa ST , Abbas MM , Hosurkar G , et al \nParkinsonism Hyperpyrexia Syndrome following Deep Brain Stimulation . Parkinsonism Relat Disord \n2015 ;21 :1284 –5 . 10.1016/j.parkreldis.2015.08.004 \n26298388 \n11 \nAkçakaya MO , Akçakaya NH , Kasımcan MÖ , et al \nLife-threatening parkinsonism-hyperpyrexia syndrome following bilateral deep brain stimulation of the subthalamic nucleus . Neurol Neurochir Pol \n2018 ;52 :289 –92 . 10.1016/j.pjnns.2017.11.012 \n29233537 \n12 \nKim JH , Kwon TH , Koh SB , et al \nParkinsonism–hyperpyrexia syndrome after deep brain stimulation surgery: case report . Neurosurgery \n2010 ;66 :E1029\n10.1227/01.NEU.0000367799.38332.43 \n20404676 \n13 \nThemistocleous MS , Boviatsis EJ , Stavrinou LC , et al \nMalignant neuroleptic syndrome following deep brain stimulation surgery: a case report . J Med Case Rep \n2011 ;5 :255 \n10.1186/1752-1947-5-255 \n21714889 \n14 \nLinazasoro G , Van Blercom N , Castro A , et al \nSubthalamic deep brain stimulation masking possible malignant syndrome in Parkinson disease . Neurology \n2004 ;63 :589 –90 .15304607 \n15 \nFactor SA \nFatal parkinsonism–hyperpyrexia syndrome in a Parkinson’s disease while actively treated with deep brain stimulation . Mov Disord \n2007 ;22 :147 –8 .\n16 \nDouglas A , Morris J \nIt was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson’s disease . Age Ageing \n2006 ;35 :640 –1 .16943262 \n17 \nGaig C , Marti MJ , Tolosa E , et al \nParkinsonism-hyperpyrexia syndrome not related to antiparkinsonian treatment withdrawal during the 2003 summer heat wave . J Neurol \n2005 ;252 :1116 –9 .15778809 \n18 \nChyong-jy Joyce LIU , Crnkovic A , Dalfino J , et al \nWhether to proceed with Deep Brain Stimulator Battery Change in a Patient With Signs of Potential Sepsis and Parkinson Hyperpyrexia Syndrome: A Case Report . A&A Case Reports \n2017 ;8 :187 –91 .28166109 \n19 \nArtusi CA , Merola A , Espay AJ , et al \nParkinsonism-hyperpyrexia syndrome and deep brain stimulation . J Neurol \n2015 ;262 :2780 –2 . 10.1007/s00415-015-7956-4 \n26530506 \n20 \nNeuneier J , Barbe MT , Dohmen C , et al \nMalignant deep brain stimulation-withdrawal syndrome in a patient with Parkinson’s disease . Mov Disord \n2013 ;28 :1640 –1 . 10.1002/mds.25494 \n23857820 \n21 \nKadowaki T , Hashimoto K , Suzuki K , et al \nCase report: recurrent parkinsonism–hyperpyrexia syndrome following discontinuation of subthalamic deep brain stimulation . Mov Disord \n2011 ;26 :1561 –2 .21449010 \n22 \nReuter S , Deuschl G , Falk D , et al \nUncoupling of dopaminergic and subthalamic stimulation: life-threatening DBS withdrawal syndrome . Mov Disord \n2015 ;17 .\n\n",
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"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "neuroendocrinology; neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000978:Antiparkinson Agents; D046690:Deep Brain Stimulation; D005260:Female; D006801:Humans; D010300:Parkinson Disease; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31092485",
"pubdate": "2019-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12735909;15304607;15778809;16892449;16943262;17080464;18712508;19081516;1947485;20213817;20404676;20937936;21449010;21714889;23465352;23857820;26184453;26298388;26530506;28166109;29233537;6111584",
"title": "Malignant deep brain stimulator withdrawal syndrome.",
"title_normalized": "malignant deep brain stimulator withdrawal syndrome"
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-025994",
"fulfillexpeditecriteria": "2",
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"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
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... |
{
"abstract": "We report two cases of patients who were hospitalised for hypertensive emergency. In both cases, laboratory testing during admission revealed elevated normetanephrines in the range of 4-5 times the upper limit of normal using liquid chromatography with mass spectrometry. Imaging studies did not localise any phaeochromocytoma or paraganglioma (PPGL). Repeat biochemical testing after discharge was within normal limits in both cases. These observations suggest that hypertensive emergency should be recognised as a potential cause of 'false-positive' laboratory findings in the diagnostic assessment for PPGL.",
"affiliations": "Jacobi Medical Center, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.;Jacobi Medical Center, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.;Jacobi Medical Center, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.;Jacobi Medical Center, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.",
"authors": "Hulkower|Raphael|R|;Gubbi|Sriram|S|;Meholli|Mimoza|M|;Schubart|Ulrich|U|",
"chemical_list": "D009647:Normetanephrine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217628",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; hypertension",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000368:Aged; D003937:Diagnosis, Differential; D005189:False Positive Reactions; D006801:Humans; D006973:Hypertension; D008875:Middle Aged; D009647:Normetanephrine; D010235:Paraganglioma; D010673:Pheochromocytoma",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28784870",
"pubdate": "2017-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12788870;14557417;15126517;15317907;15673315;15703419;17200132;19152190;20411698;24347425;24893135;25683095;3680586;5450975;6453259;8419068",
"title": "Hypertensive emergency masquerading as phaeochromocytoma: a report of two cases.",
"title_normalized": "hypertensive emergency masquerading as phaeochromocytoma a report of two cases"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-047822",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONIDINE HYDROCHLORIDE"
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{
"abstract": "BACKGROUND\nThe vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.\n\n\nMETHODS\nOmbrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(-2) with 75 mg m(-2) docetaxel, then from 30 to 35 mg m(-2) with 100 mg m(-2) docetaxel. Recommended phase II dose cohorts were expanded.\n\n\nRESULTS\nFifty-eight patients were treated. Recommended phase II doses were 35 mg m(-2) ombrabulin with 75 mg m(-2) docetaxel (35/75 mg m(-2); 13 patients) and 30 mg m(-2) ombrabulin with 100 mg m(-2) docetaxel (30/100 mg m(-2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(-2) ombrabulin), eight lasting >3 months.\n\n\nCONCLUSIONS\nSequential administration of ombrabulin with 75 or 100 mg m(-2) docetaxel every 3 weeks is feasible.",
"affiliations": "Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.;Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.;Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.;Oncology Division and Trial Operations Department, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.;Division of Drug Disposition DSAR, Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France.;Oncology Division and Trial Operations Department, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.;Division of Biostatistics & Programming, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France.;Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France.",
"authors": "Eskens|F A L M|FA|;Tresca|P|P|;Tosi|D|D|;Van Doorn|L|L|;Fontaine|H|H|;Van der Gaast|A|A|;Veyrat-Follet|C|C|;Oprea|C|C|;Hospitel|M|M|;Dieras|V|V|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D012694:Serine; C400245:AC 7700",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2014.137",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201413710.1038/bjc.2014.13724714750Clinical StudyA phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours Phase I ombrabulin/docetaxel combinationEskens F A L M 1*Tresca P 2Tosi D 2Van Doorn L 1Fontaine H 3Van der Gaast A 1Veyrat-Follet C 4Oprea C 3Hospitel M 5Dieras V 21 Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands2 Clinical Research Unit, Institut Curie, 26, rue d'Ulm, 75231 Paris Cedex 05, France3 Oncology Division and Trial Operations Department, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France4 Division of Drug Disposition DSAR, Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France5 Division of Biostatistics & Programming, Sanofi, 13 Quai Jules Guesde, 94400 Vitry-Sur-Seine, France* E-mail: f.eskens@erasmusmc.nl29 04 2014 08 04 2014 110 9 2170 2177 30 10 2013 06 02 2014 21 02 2014 Copyright © 2014 Cancer Research UK2014Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Background:\nThe vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.\n\nMethods:\nOmbrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m−2 with 75 mg m−2 docetaxel, then from 30 to 35 mg m−2 with 100 mg m−2 docetaxel. Recommended phase II dose cohorts were expanded.\n\nResults:\nFifty-eight patients were treated. Recommended phase II doses were 35 mg m−2 ombrabulin with 75 mg m−2 docetaxel (35/75 mg m−2; 13 patients) and 30 mg m−2 ombrabulin with 100 mg m−2 docetaxel (30/100 mg m−2; 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m−2 docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m−2 ombrabulin), eight lasting >3 months.\n\nConclusions:\nSequential administration of ombrabulin with 75 or 100 mg m−2 docetaxel every 3 weeks is feasible.\n\ndocetaxelombrabulinpharmacokineticsvascular disrupting agent\n==== Body\nVascular disrupting agents (VDAs) exploit the often fragile structure of existing tumoural blood vessels via a variety of different mechanisms, ultimately resulting in vascular shutdown and tumour necrosis. Some VDAs cause increased vascular permeability of the arteriolar system by targeting rapidly proliferating and immature endothelial cells, resulting in their detachment from vessel walls (Hori and Saito, 2003). Ombrabulin (AVE8062, AC-7700), a microtubule-destabilising agent, is one such molecule currently under clinical investigation. This synthetic derivative of the water-soluble VDA combretastatin A4 phosphate (CA4P), binds at or near the colchicine site on the β-subunit of tubulin, leading to microtubule depolymerisation and cytoskeleton disorganisation (Kanthou and Tozer, 2002).\n\nIncreased anti-tumour activity is anticipated when VDAs are combined with other treatment modalities such as cytotoxic chemotherapies, anti-angiogenic agents, external-beam radiotherapy, and radioimmunotherapy (McKeage and Baguley, 2010). Encouraging results, have been observed, such as the intriguing example of the anti-VEGF antibody bevacizumab combined with CA4P (Nathan et al, 2012) or ombrabulin (Del Conte et al, 2012).\n\nPreclinical evaluation of ombrabulin with a range of chemotherapeutic agents revealed several promising combination chemotherapy candidates. Docetaxel binds to tubulin (at a different site to that of ombrabulin) and results in microtubule stabilisation causing cell cycle arrest. Combining docetaxel with ombrabulin yielded additive and sometimes synergistic activity in a range of tumour cell lines at ombrabulin doses below the highest non-toxic dose, as was demonstrated by fractional cell kill values and anti-proliferative activity on endothelial cells when ombrabulin administration preceded that of docetaxel by 24 h (Lejeune et al, 2005; Kim et al, 2007). This combination resulted in significant survival improvements in multiple murine tumour models, including breast and ovarian cancers, and was well tolerated. Docetaxel is widely used to treat advanced and metastatic solid tumours, in particular breast, hormone-refractory prostate, non-small cell lung, head and neck, gastric, and ovarian cancers, either as monotherapy or in combination with other agents.\n\nIn a phase I ombrabulin single-agent study, abdominal pain, tumour pain, and hypertension were dose-limiting and 50 mg m−2 was established as the recommended dose (Sessa et al, 2013). The current two-step phase I study was designed to determine the recommended phase II ombrabulin dose (RP2D) for use in combination with two standard docetaxel doses (75 and 100 mg m−2). Pharmacokinetic analyses were conducted to assess potential interactions between ombrabulin and docetaxel and anti-tumour activity was assessed.\n\nPatients and methods\nPatient selection\nTo be eligible, patients had to be aged 18–75 years and have a histologically or cytologically confirmed metastatic or locally advanced tumour for which docetaxel treatment was recommended. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, adequate haematological, renal, and hepatic function, and appropriate washout since prior therapy were required. In France, women with locally advanced or metastatic breast cancer without prior adjuvant chemotherapy were excluded. Patients with grade 2 or higher peripheral neuropathy or chemotherapy-related grade 3 or higher ototoxicity according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE, version 3.0) were excluded, as were patients having received prior intensive chemotherapy with autologous stem cell rescue or a high cumulative anthracycline dose (doxorubicin >400 mg m−2 or epirubicin >750 mg m−2), patients with severe hypersensitivity to taxanes or polysorbate 80, a history of cardiac conditions, left ventricular ejection fraction (LVEF) <50%, untreated hypertension (systolic blood pressure (BP) >140 mm Hg or diastolic BP >90 mm Hg), patients receiving antihypertensive medication (other than angiotensin converting enzyme inhibitors, receptor antagonists, or diuretics), with hypertension-related organ damage, Q-wave infarction or ST segment changes ⩾1 mm (12-lead electrocardiogram (ECG)), or ventricular tachycardia (Holter ECG). The study was approved by the ethics committees of the two participating centres (Tarnier-Cochin Hospital, France, and Erasmus MC Cancer Institute, The Netherlands) and was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent prior to enrolment. The study is registered at ClinicalTrials.gov (NCT01907685).\n\nStudy design and treatment\nThis phase I dose escalation study was performed between June 2006 and February 2011. Ombrabulin (Sanofi, Vitry-sur-Seine, France) was administered as a 30-min intravenous infusion on day 1, followed on day 2 by docetaxel (1-h infusion, 24 h after the end of the ombrabulin infusion), every 3 weeks. Two docetaxel doses were evaluated. Initially 75 mg m−2 docetaxel was investigated combined with ombrabulin at the starting dose of 11.5 mg m−2. This ombrabulin dose was selected based on preclinical data suggesting that a minimal dose of 6 mg m−2 was required for synergy with docetaxel, and from phase I single-agent weekly and intermittent regimens showing that 11.5 mg was safe. Once the RP2D with 75 mg m−2 docetaxel was established, 100 mg m−2 docetaxel was investigated with ombrabulin at a starting dose of 30 mg m−2. Medications metabolised by CYP2C19 were omitted for 12 h prior to and after the ombrabulin infusion. LHRH agonists administered to prostate cancer patients were maintained. Growth factor treatment for therapeutic or prophylactic intent was permitted throughout the study. Antihypertensive prophylaxis was not administered.\n\nA traditional 3+3 design was used with initially three patients per dose level and three additional patients if dose-limiting toxicity (DLT) occurred. Occurrence of DLT during the first cycle was used to determine the RP2Ds. For each docetaxel dose, ombrabulin dose escalation was stopped when two or more patients had DLT during the first cycle, and the dose level immediately below was considered the RP2Ds and expanded with 10 additional patients.\n\nDose-limiting toxicity was defined as grade 4 thrombocytopaenia, grade 4 neutropaenia lasting >5 days, grade 4 febrile neutropaenia, grade 3 or 4 neutropaenic infection, any grade 3–4 non-haematological toxicity (other than nausea, vomiting, and hypersensitivity without adequate treatment), or any of the following cardiovascular events: documented angina pectoris, arterial thromboembolism, grade 3–4 vascular events (except tumour haemorrhage or necrosis), acute impairment of a target organ (brain, heart, kidney), troponin I or creatine kinase (CK)-MB increase above myocardial necrosis limits, systolic BP ⩾180 mm Hg and/or diastolic BP ⩾120 mm Hg or grade ⩾2 hypotension and/or systolic BP <90 mm Hg (in at least two successive measurements at 30-min intervals), ST segment elevation or depression ⩾1 mm in at least two contiguous leads or Q-wave infarction on a 12-lead ECG, severe ventricular arrhythmia or ST segment elevation or depression ⩾2 mm lasting ⩾1 min on a Holter ECG, or grade 2 or higher LVEF, and any other toxicity deemed dose-limiting, regardless of grade. Patients receiving at least one combined ombrabulin-docetaxel administration with clinical and laboratory examinations during the first cycle were evaluable for DLT.\n\nAdequate laboratory values (ANC ⩾1.5 × 109/l, platelets ⩾100 × 109/l, ALT/AST/AP⩽grade 1, total bilirubin within normal limits, total creatinine <1.5 mg dl−1) and recovery from any grade 3–4 toxicity to grade 1 or baseline levels were required at the start of each cycle. A 1-week treatment delay was permitted for related toxicity. Ombrabulin treatment was stopped if a cardiovascular DLT occurred or the patient did not recover from toxicity following a 1-week delay. Ombrabulin dose reduction could be implemented following DLT or grade 2 peripheral neuropathy with recovery within 1 month or a repeat delay from the same toxicity.\n\nSafety and tumour evaluations\nPhysical and neurological examinations were performed weekly. Haematology was evaluated weekly and biochemistry weekly for the first cycle and every cycle thereafter. The following exams were performed within 4 weeks prior to the first treatment administration, before each ombrabulin infusion, and as follows: a cardiovascular exam (6–12 and 24 h post-ombrabulin), a 12-lead ECG (at 6–12 h post-ombrabulin), a 24-h Holter ECG, and CK-MB and troponin I (6–12 and 24 h post-infusion). An echocardiography, an ocular funduscopy (in hypertensive patients) and a brain MRI were performed within 4 weeks prior to treatment start. Chest X-rays were performed prior to treatment then every 3 months. Adverse events (AEs) were evaluated according to the NCI-CTCAE version 3.0. A central review of cardiovascular toxicity was performed by an assigned cardiologist. Tumour evaluation was performed every 6 weeks and response was determined according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0 (Therasse et al, 2000). Objective responses had to be confirmed a minimum of 4 weeks after the initial criteria were met and stable disease (SD) had to be derived from an evaluation a minimum of 5 weeks after the first dose. Duration of objective response was from first documented response until disease progression and duration of SD was from first study drug administration until disease progression.\n\nPharmacokinetics\nThe pharmacokinetics of ombrabulin and its active metabolite RPR258063 were assessed in all patients using 2-ml blood samples collected in heparinised tubes on day 1 of cycle 1, pre-infusion, immediately prior to the end of the 30-min infusion, and at 5, 10, 25, 45, and 60 min then 2, 4, 6, 8–10, and 24 h post-infusion. Blood samples were collected for docetaxel analysis in heparinised tubes pre-infusion (i.e., day 2 of cycle 1), 15 min before the end of infusion, 15 and 45 min, 2 and 5 h after the end of the infusion. Samples were assayed with a validated LC/MS/MS method using a limit of quantification of 2.0 ng ml−1 for ombrabulin and RPR258063 and 1.0 ng ml−1 for docetaxel. Non-compartmental analyses for ombrabulin and RPR258063 including Cmax, Tmax, AUCt, t1/2Z, CL, and Vss were performed using WinNonlin software, version 5.2.1 (Pharsight Inc., St Louis, MO, USA). For docetaxel, CL and AUC were determined by Bayesian estimation using NONMEM software, version V (Globomax, Hanover, MD, USA). A three-compartment structural model with first-order elimination was used as prior information (estimates were CL 36.8 l h−1, Vd central compartment 7.83 L, Vss 122 L, t1/2Z 10.0 h) (Bruno et al, 1996).\n\nResults\nIn total, 58 patients were treated, 39 with 75 mg m−2 docetaxel and 19 with 100 mg m−2 docetaxel. Patient and disease characteristics are summarised in Table 1. The most common tumours were breast (36%) and oesophageal (24%).\n\nDose-limiting toxicity\nDose-limiting toxicity was evaluated in the first cycle, with 29 patients assessed at 75 mg m−2 docetaxel and 9 patients at 100 mg m−2 docetaxel. Ombrabulin was escalated from 11.5 to 42 mg m−2 with 75 mg m−2 docetaxel (Table 2). One episode of DLT was seen in a patient at 25 mg m−2 ombrabulin consisting of grade 3 neutropaenic infection despite receiving prophylactic G-CSF. At 42 mg m−2 ombrabulin, DLTs were reported in two patients, one with grade 3 headache (4 days postombrabulin) and one with grade 3 fatigue. The RP2D for 75 mg m−2 docetaxel was set at 35 mg m−2 ombrabulin (35/75 mg m−2) and an additional 10 patients were treated at this dose level.\n\nIn the second step, 100 mg m−2 docetaxel was evaluated with 30 and 35 mg m−2 ombrabulin. One patient with 30 mg m−2 ombrabulin had grade 4 febrile neutropaenia 1 week after the docetaxel infusion, despite receiving prophylactic G-CSF. At 35 mg m−2 ombrabulin, DLTs were reported in two patients, one with grade 3 fatigue (2 days post-docetaxel) and one with grade 3 deep vein thrombosis (2 weeks postdocetaxel). The RP2D was set at 30 mg m−2 ombrabulin with 100 mg m−2 docetaxel (30/100 mg m−2) and an additional 10 patients were enrolled at this dose level.\n\nHaematological toxicity\nGrade 1–2 haematological toxicity was common (Table 3) however anaemia was prevalent prior to treatment (28% of patients). Grade 3–4 neutropaenia and leukopaenia were reported at all dose levels, including 36% and 21% of patients treated with 75 mg m−2 docetaxel, respectively, and 58% and 53% of patients, respectively, at 100 mg m−2. No grade 3–4 thrombocytopaenia was reported. Prophylactic use of G-CSF was permitted. During the first cycle, prophylactic G-CSF was administered in 30 patients treated with 75 mg m−2 docetaxel (77%) and 18 patients (95%) at 100 mg m−2 docetaxel. Overall G-CSF was administered in 32 (82%) and 19 (100%) patients, respectively.\n\nNon-haematological toxicity\nRelated non-haematological AEs were mainly grade 1–2 (Table 4). At 75 mg m−2 docetaxel, the most common AEs were asthaenia/fatigue (69%), nausea (64%), alopecia (56%), and vomiting (31%). Incidences were similar at 100 mg m−2 docetaxel with the exception of asthaenia/fatigue which was more frequent (95%). Additional toxicities at 100 mg m−2 docetaxel included diarrhoea (68%), peripheral sensory neuropathy/peripheral neuropathy (58%), nail disorders (58%), dysgeusia/ageusia (58%), and peripheral oedema (42%). Other cutaneous reactions were reported in 10% to 15% of patients including hand/foot syndrome, erythema, and pruritus. Grade 1–2 hepatic enzyme elevations were common at all dose levels, however baseline elevations in ALT and alkaline phosphatase were present in 31% and 36% of patients, respectively.\n\nGrade 3–4 non-haematological toxicities were reported in only one patient each with the exception of alkaline phosphatase elevations (four patients), fatigue (three patients), thrombosis, and AST/ALT elevations (two patients each). One patient (15.5/75 mg m−2) had unrelated acute renal failure with grade 4 creatinine elevation and hypernatraemia which recovered with treatment. Related grade 4 sepsis occurred in one patient (20/75 mg m−2) which did not resolve despite treatment discontinuation, developing to febrile neutropaenia and grade 3 respiratory failure resulting in death. Two other patients (35/75 mg m−2) discontinued due to related events (grade 3 thrombosis and grade 2 gastrointestinal fistula). Ombrabulin dose reductions were reported in four patients (at the two highest ombrabulin levels) following grade 3 ALT, headache, or thrombosis. Docetaxel dose reductions were implemented in 18 patients (31%), most at 30/100 mg m−2 (9 of 16 patients), and were generally due to mild to moderate oedema, fatigue/asthaenia, or skin/nail disorders. Of the 348 cycles administered, 8 were delayed and 10 were temporarily interrupted due to ombrabulin toxicity, whereas 27 docetaxel cycles were interrupted due to toxicity.\n\nRelated cardiovascular events were reported in nine patients (16%), mostly at 30 mg m−2 ombrabulin or higher. Tachycardia (atrial, sinus, or supraventricular) was reported in five patients, palpitations in three patients, and AV block and sinus arrhythmia in one patient each. Vascular events occurred in 22 patients (38%) including phlebitis in five patients at a range of dose levels, thrombosis in two and hypotension, flushing and haematoma in one patient each. All related cardiovascular events were grade 1–2 with the exception of thrombosis (two grade 3 episodes). One patient had a minimal LVEF decrease (47% compared with the lower limit of 50%) and CK-MB elevations were noted in two patients without concomitant cardiovascular events. A single case of unrelated and transient grade 3 hypertension was observed. BP abnormalities were reported in eight patients, most of which were transient. A retrospective expert cardiologic evaluation confirmed these results.\n\nAnti-tumour activity\nAll patients were evaluated for response according to RECIST 1.0 (Table 5). Ten patients (17%) had partial responses (PRs), seven with breast cancer, and one each with prostate, ovarian or oesophageal carcinoma. Seven of the responders were treated at 30/100 mg m−2 and all had a previous best response of SD or disease progression. Seven of the 33 patients who had previously received taxanes had PR with the ombrabulin/docetaxel doublet (two had a previous best response of PR and one had SD under docetaxel, and four were treated in the adjuvant setting). Eight PRs lasted for more than 3 months (range 2.7–8.5) with a median duration of 5.3 months. Stable disease was reported in 27 patients (47%) at a range of dose levels, with a median duration of 4.6 months. The rate of disease control (PR+SD) was 81% in breast cancer patients (17 out of 21), 64% in oesophageal cancer patients (9 out of 14) and 100% in the three prostate cancer patients.\n\nPharmacokinetics\nThe pharmacokinetics of ombrabulin and its active metabolite RPR258063 were evaluated in 57 patients and pharmacokinetics of docetaxel were evaluated in 56 patients. A summary of results is provided in Table 6 and concentration time profiles of ombrabulin, its active metabolite RPR258063 and docetaxel are shown in Figure 1. Exposure to ombrabulin and RPR258063 was dose proportional with mean AUC ranging from 290 ng*h ml−1 to 856 ng*h ml−1 and from 394 ng*h ml−1 to 1830 ng*h ml−1, respectively. For ombrabulin, elimination was biphasic with rapid conversion to RPR258063 (mean half-life 12 min) and high clearance of 67 l h−1 m−2, whereas steady state volume of distribution was low at 30 l m−2. For RPR258063, a biphasic or triphasic elimination profile was observed with a terminal half-life of 8 h. For docetaxel, mean clearance was 25.2±8.1 and 23.2±5.0 l h−1 m−2 after 75 and 100 mg m−2, respectively, corresponding to AUCs of 5.12±12.4 μg*h ml−1 and 4.59±1.38 μg*h ml−1. One patient receiving 75 mg m−2 docetaxel had a very high AUC (79.4 μg*h ml−1). When this value was excluded, mean AUC was 3.11±0.84 μg*h ml−1.\n\nDiscussion\nThe current study demonstrates the feasibility of integrating ombrabulin into two standard docetaxel regimens of 75 and 100 mg m−2, which are approved for use in a variety of clinical settings in different tumour types. Three DLTs were reported with each docetaxel dose. Neutropaenic complications were dose-limiting at lower ombrabulin doses (25 and 30 mg m−2) with both docetaxel doses, while headache, fatigue, and thrombosis were dose-limiting at 35 and 42 mg m−2 ombrabulin with both docetaxel doses. The recommended combination doses for further clinical studies were therefore set at 35 mg m−2 ombrabulin/75 mg m−2 docetaxel and 30 mg m−2 ombrabulin/100 mg m−2 docetaxel.\n\nThe DLTs reported are consistent with the single-agent profiles. Neutropaenic complications are associated with docetaxel, but were not reported with single-agent ombrabulin (Sessa et al, 2013). Headache and fatigue were frequent with ombrabulin, and grade 3 thrombosis occurred at the highest ombrabulin single-agent dose evaluated (50 mg m−2), although none of these toxicities were dose-limiting with ombrabulin monotherapy. The addition of ombrabulin to docetaxel at doses commonly used in standard therapeutic regimens did not compromise the safety of either agent, and there was no indication of prolonged or cumulative toxicities. As expected, prominent toxicities associated with docetaxel were dose-dependent grade 3-4 neutropaenia and leukopaenia. Common grade 1–2 non-haematological toxicities such as asthaenia, nausea, vomiting, diarrhoea, and neuropathy are coherent with the toxicity profiles of both docetaxel (75 and 100 mg m−2) and ombrabulin (Sessa et al, 2013), as was the higher frequency of diarrhoea, nail disorders, oedema, and neuropathy with 100 mg m−2 docetaxel compared with 75 mg m−2 (Extra et al, 1993; Harvey et al, 2006). Other ombrabulin-related toxicities such as headache and abdominal pain were reported but were only mild (grade 1–2). Notably, tumour pain which is considered to be VDA dose-dependent was rarely reported at the two ombrabulin combination RP2Ds (30 and 35 mg m−2). Overlapping toxicities for the two agents, notably asthaenia, digestive toxicities, abdominal pain, and neuropathy, rarely required dose reductions or delays.\n\nAn expert cardiovascular review concluded that with the absence of ischemic episodes, cardiac decompensation, ECG, and cardiac biomarker abnormalities, and no cases of related hypertension notably in the ten patients with a history of hypertension, the addition of ombrabulin to docetaxel at the proposed RP2Ds does not impose cardiovascular restrictions. This supports previous reports that cardiovascular toxicity does not present a limitation to ombrabulin use (Soria et al, 2008; Sessa et al, 2013). Nonetheless, and given the as yet limited clinical experience with ombrabulin, appropriate screening and close cardiovascular surveillance during treatment remain a recommended aspect of ombrabulin use.\n\nIt has been suggested that the strategy of combining a chemotherapeutic agent with a VDA may prevent development of a rim of viable tumour cells surrounding the necrotic core which is characteristic of advanced solid tumours (Tozer et al, 2005). This not only targets the proliferating border of tumours, but also offers a potential means of overcoming drug resistance which can impose limitations on the use of cytotoxic agents. Although intriguing preclinical evidence has urged exploration of this sequence in a clinical setting, the exact molecular explanation for how ombrabulin and docetaxel interact has not been fully elucidated. In a recent review (McKeage and Baguley, 2010), it was suggested that VDAs are able to access poorly perfused regions which are inaccessible to chemotherapy molecules (Siim et al, 2003). Another possibility is that VDAs result in decreased tumoural clearance of chemotherapy agents and increased tumoural susceptibility to chemotherapeutic agents via micro-environmental changes (Pruijn et al, 1997).\n\nPharmacokinetic analyses of ombrabulin over the 24 h following its administration showed dose proportionality and rapid conversion to its metabolite RPR258063. As expected with this analysis performed prior to docetaxel administration, the outcome was similar to that reported in the monotherapy study (Sessa et al, 2013), although volume of distribution and clearance were higher than with monotherapy. Docetaxel parameters following ombrabulin administration were also consistent with published single-agent data (Bruno et al, 1998; Harvey et al, 2006). Systemic exposure of docetaxel thus does not appear to be altered by preceding administration of ombrabulin 24 h earlier, confirming the absence of relevant drug interaction when administered according to this schedule.\n\nResponses and durable SD were seen across all dose levels. Several PRs were reported in breast cancer patients, which is coherent with reported response rates ranging from 23% to 48% with single-agent docetaxel in metastatic breast cancer patients (Bonneterre et al, 1999; Chan et al, 1999; Nabholtz et al, 1999; Sjostrom et al, 1999; Bonneterre et al, 2002; Jones et al, 2005). Activity in oesophageal cancer patients was encouraging and although only three prostate cancer patients were included, all had clinical benefit suggesting further investigation in these indications may be worthwhile.\n\nEvaluation of biomarkers indicative of sensitivity to tubulin-interacting agents, tumour vascularisation or angiogenesis and endothelial cells is an important step in the clinical development of ombrabulin in order to establish a predictive signature, with the ratio of mature to immature vessel markers potentially correlating with response outcome. An exploratory analysis performed as part of this study, unfortunately, did not show clear correlations between biomarker expression in archived tissue and outcome. It has to be emphasised that our analysis was hampered by the small sample size and very few on-study evaluations and further investigation of these parameters therefore is needed.\n\nThis study has determined the ombrabulin recommended doses for further clinical development in combination with two docetaxel doses that are frequently used in standard 3-weekly schedules. In an extension of this regimen, the addition of ombrabulin to platinum/taxane doublets has meanwhile been evaluated in a phase II study in non-small cell lung cancer patients (von Pawel et al, 2012). Further studies to assess the added value of ombrabulin to other cytotoxic regimens will be undertaken.\n\nWe thank Patricia Fernandez (Sanofi, France) for study management support, Eric Le Bras (Sanofi, France) for programming support, and Sarah MacKenzie (Medi.Axe, France, funded by Sanofi) for assistance drafting the manuscript. The study was funded by Sanofi and the institutes of FAE and VD received grant support from Sanofi for this clinical trial.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nResults were published in part at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, 2009 and the 46th Annual Meeting of the American Society of Clinical Oncology, 2010.\n\nHF, CVF, CO, and MH are employees of Sanofi. FAE and VD received institutional financial support for this study from Sanofi. All other authors have no conflict of interest.\n\nFigure 1 Concentration-time profiles of ombrabulin, its active metabolite RPR258063 and docetaxel. Plasma concentrations in cycle 1 are shown for (A) ombrabulin and (B) RPR258063 by dose level according to median concentrations (N=57), and for docetaxel (C) 75 mg m−2 (N=38) and (D) 100 mg m−2 (N=18) presenting individual results against predicted values for a patient with a body surface area of 1.76 m2 and 1.89 m2, respectively.\n\nTable 1 Patient and disease characteristics\nN patients treated\t58\t\nFemale, N (%)\t35 (60%)\t\nAge in years, median (range)\t53 (28–71)\t\nCaucasian, N (%)\t54 (93%)\t\nECOG performance status, N (%)\t\n0/1\t28 (48%)/30 (52%)\t\nPrimary tumour site, N (%)\t\nBreast\t21 (36%)\t\nOesophagus\t14 (24%)\t\nMuscle/soft tissue\t5 (9%)\t\nPancreas\t5 (9%)\t\nProstate\t3 (5%)\t\nOthera\t10 (17%)\t\nMetastatic disease, N (%)\t52 (90%)\t\nPrior therapy, N (%)\t\nChemotherapyb\t49 (84%)\t\nSurgery\t39 (67%)\t\nRadiotherapy\t31 (53%)\t\nHormone\t19 (33%)\t\nBiologics\t6 (10%)\t\nAbbreviation: ECOG=Eastern Cooperative Oncology Group.\n\na Head and neck (2), ovary (2), bladder, liver, skin (1 each), unknown (3).\n\nb Includes 33 patients (57%) with prior taxane therapy.\n\nTable 2 Treatment exposure and DLT\nDose level (mg m−2)\t \tMedian\nN\ncycles (range)\t \t\nDocetaxel\tOmbrabulin\tN\nPatients\tOmbrabulin\tDocetaxel\tCycle 1 DLT (N\npatients)\t\n75\t11.5\t3\t2 (1–3)\t2 (1–3)\t \t\n \t15.5\t5\t2 (2–14)\t2 (2–12)\t \t\n \t20\t3\t4 (4–4)\t4 (4–4)\t \t\n \t25\t6\t6.5 (2–12)\t6.5 (2–10)\tG3 neutropaenic infection (1)a\t\n \t30\t3\t8 (4–13)\t6 (4–8)\t \t\n \t35\t3+10b\t4 (1–22)\t4 (1–22)\t \t\n \t42\t6\t4 (1–8)\t4 (1–8)\tG3 headache (1)\nG3 fatigue (1)\t\n100\t30\t6+10b\t9.5 (2–16)\t8 (2–15)\tG4 febrile neutropaenia (1)a\t\n \t35\t3\t2 (2–4)\t2 (2–4)\tG3 fatigue (1)\nG3 thrombosis (1)\t\nAbbreviation: DLT=dose-limiting toxicity.\n\na Both patients with neutropaenia received prophylactic G-CSF during cycle 1 and prior to the episode.\n\nb Ten additional patients were treated at the RP2D after dose escalation was completed.\n\nTable 3 Haematological toxicity (NCI-CTCAE)\n \tN\npatients (%)\t\n \t11.5–42 mg m−2\nombrabulin/75 mg m−2\ndocetaxel (N=39)\t30–35 mg m−2\nombrabulin/100 mg m−2\ndocetaxel (N=19)\t\n \tAll grades\tG3–4\tAll grades\tG3–4\t\nLeukopaenia\t22 (56%)\t8 (21%)\t15 (79%)\t10 (53%)\t\nNeutropaeniaa\t18 (46%)\t14 (36%)\t13 (68%)\t11 (58%)\t\nLymphopaenia\t30 (77%)\t8 (21%)\t15 (79%)\t7 (37%)\t\nAnaemia\t39 (100%)\t1 (3%)\t18 (95%)\t–\t\nThrombocytopaenia\t14 (36%)\t–\t9 (47%)\t–\t\nAbbreviation: NCI-CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.\n\na Note that prophylactic G-CSF was administered at least once to 32 patients treated at 75 mg m−2 docetaxel and all 19 patients treated at 100 mg m−2 docetaxel.\n\nTable 4 Non-haematological drug-related AEs, in >20% patients or grade 3–4 (NCI-CTCAE)\n \tN\npatients (%)\t\n \t11.5–42 mg m−2\nombrabulin/75 mg m−2\ndocetaxel (N=39)\t30–35 mg m−2\nombrabulin/100 mg m−2\ndocetaxel (N=19)\t\n \tAll grades\tG3–4\tAll grades\tG3–4\t\nNausea\t25 (64%)\t–\t11 (58%)\t–\t\nAlopecia\t22 (56%)\t–\t13 (68%)\t–\t\nFatigue\t15 (38%)\t2 (5%)\t8 (42%)\t1 (5%)\t\nAsthaenia\t12 (31%)\t–\t10 (53%)\t–\t\nVomiting\t12 (31%)\t–\t7 (37%)\t–\t\nDecreased appetite\t10 (26%)\t1 (3%)\t7 (37%)\t–\t\nDiarrhoea\t9 (23%)\t–\t13 (68%)\t–\t\nDysgeusia\t9 (23%)\t–\t4 (21%)\t–\t\nPeripheral sensory neuropathya\t3 (8%)\t–\t9 (47%)\t–\t\nMyalgia\t6 (15%)\t–\t7 (37%)\t–\t\nStomatitis\t5 (13%)\t–\t5 (26%)\t–\t\nOedema (peripheral)\t4 (10%)\t–\t8 (42%)\t–\t\nHeadache\t3 (8%)\t1 (3%)\t4 (21%)\t–\t\nNail disorder\t3 (8%)\t–\t11 (58%)\t–\t\nAgeusia\t3 (8%)\t–\t9 (47%)\t–\t\nIncreased lacrimation\t2 (5%)\t–\t7 (37%)\t–\t\nArthralgia\t1 (3%)\t–\t4 (21%)\t1 (5%)\t\nThrombosis\t1 (3%)\t1 (3%)\t1 (5%)\t1 (5%)\t\nFebrile neutropaenia\t–\t–\t1 (5%)\t1 (5%)\t\nHand/foot syndrome\t2 (5%)\t–\t3 (16%)\t1 (5%)\t\nNeutropaenic infection\t2 (5%)\t1 (3%)\t1 (5%)\t–\t\nOesophageal fistula\t1 (3%)\t1 (3%)\t–\t–\t\nNail toxicity\t2 (5%)\t1 (3%)\t–\t–\t\nSepsis\t1 (3%)\t1 (3%)\t–\t–\t\nRespiratory failure\t1 (3%)\t1 (3%)\t–\t–\t\nAbbreviations: AE=adverse event; NCI-CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.\n\na Peripheral neuropathy was reported in an additional 5 (13%) patients at 75 mg m−2 and 3 (16%) at 100 mg m−2.\n\nTable 5 Tumour response according to RECIST\n \t75 mg m−2\ndocetaxel (N=39)\t100 mg m−2\ndocetaxel (N=19)\tAll (N=58)\t\nBest overall response\t\nPR\t3 (7.7%)\t7 (36.8%)\t10 (17.2%)\t\nStable disease\t18 (46.2%)\t9 (47.4%)\t27 (46.6%)\t\nDisease progression\t17 (43.6%)\t3 (15.8%)\t20 (34.5%)\t\nNot evaluable\t1 (2.6%)\t0\t1 (1.7%)\t\nAbbreviations: PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumours.\n\nTable 6 Pharmacokinetic parameters following a 30 min ombrabulin intravenous infusion in cycle 1 (mean±s.d.)\n \t \tOmbrabulin\tRPR258063\t \t\nDose (mg m−2)\tN\npatients\tAUC (ng*h ml−1)\tCL (l h−1)\tCmax(ng ml−1)\tT1/2z(h)\tTmax(h)\tVss(L)\tAUC (ng*h ml−1)\tCmax(ng ml−1)\tt1/2Z(h)\tt1max(h)\tMetabolic ratio (AUCRPR/Omb)\t\nOmbrabulin\t\n11.5\t3\t343±149\t74.6±45.8\t787±292\t0.225±0.047\t0.48 (0.47–0.48)\t22.6±12.2\t394±86.0\t113±9.07\t5.40±1.58\t0.68 (0.58–0.70)\t1.36±0.729\t\n15.5\t5\t290±94.6\t110±45.5\t652±155\t0.191±0.059\t0.50 (0.47–0.50)\t39.3±11.6\t440±147\t114±12.2\t7.83±2.30\t0.58 (0.47–0.97)\t1.67±0.868\t\n20\t3\t464±253\t85.9±39.6\t1100±650\t0.219±0.036\t0.50 (0.38–0.53)\t28.6±15.4\t686±115\t219±9.29\t7.22±1.84\t0.53 (0.53–0.67)\t1.70±0.691\t\n25\t6a\t414±135\t107±33.3\t936±287\t0.193±0.039\t0.50 (0.43–0.53)\t33.8±10.7\t1120±692\t277±108\t7.34±3.09\t0.67 (0.50–0.68)\t3.13±2.16\t\n30\t18\t470±181\t143±74.5\t1040±393\t0.199±0.026\t0.50 (0.42–0.60)\t101±167\t776±237\t259±68.4\t9.94±2.42\t0.59 (0.42–0.72)\t1.91±0.950\t\n35\t15b\t706±352\t114±52.7\t1600±742\t0.215±0.021\t0.48 (0.42–0.75)\t33.9±15.3\t918±270\t318±93.0\t8.59±1.91\t0.67 (0.42–0.98)\t1.59±0.833\t\n42\t6\t856±482\t150±174\t1970±929\t0.203±0.023\t0.49 (0.42–0.58)\t48.3±51.6\t1830±808\t433±96.2\t7.60±2.06\t0.58 (0.48–0.67)\t2.82±1.81\t\nDocetaxelc\t\nDose (mg m−2)\tN patients\tAUC (μg*h ml−1)\tCL (L h−1 m−2)\tVss(L m−2)\t \t \t \t \t \t \t \t \t\n75\t38\t5.12±12.4\t25.2±8.10\t4.34±1.42\t \t \t \t \t \t \t \t \t\n100\t18\t4.59±1.38\t23.2±4.96\t3.81±1.06\t \t \t \t \t \t \t \t \t\na Missing data for 1 patient for RPR258063 AUC.\n\nb Missing data for 1 patient for AUCt, Cmax, and Tmax.\n\nc 75 mg m−2 mean body surface area=1.76±0.23; 100 mg m−2 mean body surface area=1.89±0.19.\n==== Refs\nBonneterre J Roche H Monnier A Guastalla JP Namer M Fargeot P Assadourian S 2002 Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure Br J Cancer 87 1210 1215 12439707 \nBonneterre J Spielman M Guastalla JP Marty M Viens P Chollet P Roche H Fumoleau P Mauriac L Bourgeois H Namer M Bergerat JP Misset JL Trandafir L Mahjoubi M 1999 Efficacy and safety of docetaxel (Taxotere) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience Eur J Cancer 35 1431 1439 10673974 \nBruno R Hille D Riva A Vivier N ten Bokkel Huinnink WW van Oosterom AT Kaye SB Verweij J Fossella FV Valero V Rigas JR Seidman AD Chevallier B Fumoleau P Burris HA Ravdin PM Sheiner LB 1998 Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer J Clin Oncol 16 187 196 9440742 \nBruno R Vivier N Vergniol JC De Phillips SL Montay G Sheiner LB 1996 A population pharmacokinetic model for docetaxel (Taxotere): model building and validation J Pharmacokinet Biopharm 24 153 172 8875345 \nChan S Friedrichs K Noel D Pinter T Van Belle S Vorobiof D Duarte R Gil Gil M Bodrogi I Murray E Yelle L von Minckwitz G Korec S Simmonds P Buzzi F Gonzalez Mancha R Richardson G Walpole E Ronzoni M Murawsky M Alakl M Riva A Crown J 1999 Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer J Clin Oncol 17 2341 2354 10561296 \nDel Conte G Bahleda R Moreno V Damian S Perotti A Lassau N Farace F Ong M Stimpson S Tunariu T Micallef S Demers B Oprea C Capri G Soria J Sessa C Molife R 2012 A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors (NCT01193595) [Abstract] J Clin Oncol 30 (SupplAbstr No. 3080.\nExtra JM Rousseau F Bruno R Clavel M Le Bail N Marty M 1993 Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion Cancer Res 53 1037 1042 8094996 \nHarvey V Mouridsen H Semiglazov V Jakobsen E Voznyi E Robinson BA Groult V Murawsky M Cold S 2006 Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer J Clin Oncol 24 4963 4970 17033039 \nHori K Saito S 2003 Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis Br J Cancer 89 1334 1344 14520469 \nJones SE Erban J Overmoyer B Budd GT Hutchins L Lower E Laufman L Sundaram S Urba WJ Pritchard KI Mennel R Richards D Olsen S Meyers ML Ravdin PM 2005 Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer J Clin Oncol 23 5542 5551 16110015 \nKanthou C Tozer GM 2002 The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells Blood 99 2060 2069 11877280 \nKim TJ Ravoori M Landen CN Kamat AA Han LY Lu C Lin YG Merritt WM Jennings N Spannuth WA Langley R Gershenson DM Coleman RL Kundra V Sood AK 2007 Antitumor and antivascular effects of AVE8062 in ovarian carcinoma Cancer Res 67 9337 9345 17909042 \nLejeune P Vrignaud P Goulaouic H Nicolas S Bissery M-C 2005 In vivo synergy between docetaxel and AVE8062A, a tumor vasculature targeting agent [Abstract] Proc AACR Annual Meeting 46: Abstr No. 3425.\nMcKeage MJ Baguley BC 2010 Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer Cancer 116 1859 1871 20166210 \nNabholtz JM Senn HJ Bezwoda WR Melnychuk D Deschenes L Douma J Vandenberg TA Rapoport B Rosso R Trillet-Lenoir V Drbal J Molino A Nortier JW Richel DJ Nagykalnai T Siedlecki P Wilking N Genot JY Hupperets PS Pannuti F Skarlos D Tomiak EM Murawsky M Alakl M Aapro M 1999 Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy 304 Study Group. J Clin Oncol 17 1413 1424 \nNathan P Zweifel M Padhani AR Koh DM Ng M Collins DJ Harris A Carden C Smythe J Fisher N Taylor NJ Stirling JJ Lu SP Leach MO Rustin GJ Judson I 2012 Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer Clin Cancer Res 18 3428 3439 22645052 \nPruijn FB van Daalen M Holford NH Wilson WR 1997 Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid Cancer Chemother Pharmacol 39 541 546 9118467 \nSessa C Lorusso P Tolcher A Farace F Lassau N del Monte A Braghetti A Bahleda R Cohen P Hospitel M Veyrat-Follet C Soria JC 2013 Phase 1 safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors Clin Cancer Res 19 4832 4842 23833302 \nSiim BG Lee AE Shalal-Zwain S Pruijn FB McKeage MJ Wilson WR 2003 Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) Cancer Chemother Pharmacol 51 43 52 12497205 \nSjostrom J Blomqvist C Mouridsen H Pluzanska A Ottosson-Lonn S Bengtsson NO Ostenstad B Mjaaland I Palm-Sjovall M Wist E Valvere V Anderson H Bergh J 1999 Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group Eur J Cancer 35 1194 1201 10615229 \nSoria J Sessa C Perotti A Massard C JP A Lassau N Farace F Elsa B Gianni L 2008 A comprehensive study of translational research and safety exploration of the vascular disrupting agent (VDA) AVE8062 in combination with cisplatin administered every 3 weeks to patients with advanced solid tumors [Abstract]. Proc AACR Annual Meeting49: Abstr LB-302.\nTherasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG 2000 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 92 205 216 10655437 \nTozer GM Kanthou C Baguley BC 2005 Disrupting tumour blood vessels Nat Rev Cancer 5 423 435 15928673 \nvon Pawel J Gorbomunova V Reck M Kowalski D Allard A Chadjaa M Rey A Bennouna J Grossi F 2012 DISRUPT: a randomized phase 2 trial of ombrabulin (AVE8062) combined with a taxane-platinum regimen in the first-line treatment of metastatic non-small cell lung cancer (NSCLC) [Abstract] Ann Oncol 23 (SupplAbs.1250P 21948815\n\n",
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"journal": "British journal of cancer",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012694:Serine; D043823:Taxoids; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours.",
"title_normalized": "a phase i pharmacokinetic study of the vascular disrupting agent ombrabulin ave8062 and docetaxel in advanced solid tumours"
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"abstract": "OBJECTIVE\nThe aim of this study was to evaluate children with pulmonary arterial hypertension (PAH) regarding epidemiological characteristics, clinical status with respect to the WHO functional class (WHO-FC), prognostic factors, and efficacy of medical treatment.\n\n\nMETHODS\nA retrospective evaluation of 41 patients with PAH was made in the Pediatric Cardiology Unit, Gazi University Medical Faculty, between February 2006 and October 2015.\n\n\nRESULTS\nOf the 41 patients included in this study, 51.2% were female. The median age was 60 months at first evaluation. The median follow-up was 60 months. At the start of the treatment, 43.9% patients were receiving combined drug therapy, and this rate increased to 60.9% by the last evaluation. The median time of adding a new medication to the therapy was 20 months. The 1- and 5-year survival rates were 94% and 86%, respectively. At the time of diagnosis, only pro-brain natriuretic peptide (proBNP) levels were associated with mortality (p=0.004), but at the last evaluation, 6-min walking test, proBNP and uric acid levels, and WHO-FC were also associated with survival (p=0.02, p=0.001, p=0.002, and p=0.05, respectively).\n\n\nCONCLUSIONS\nWith current treatment choices in experienced centers, positive results are obtained with respect to the functional status and survival rates of patients with PAH. At the time of diagnosis, only proBNP had a prognostic value, whereas at the last evaluation, WHO-FC, 6-min walking test, proBNP, and uric acid were reported prognostic factors. For preventing rapid progression, determination of factors that have an effect on prognosis, in particular, is extremely important.",
"affiliations": "Department of Pediatric Cardiology, Faculty of Medicine, Gazi University; Ankara-Turkey. kula@gazi.edu.tr.",
"authors": "Kula|Serdar|S|;Canbeyli|Fatma|F|;Atasayan|Vildan|V|;Tunaoğlu|Fatma Sedef|FS|;Oğuz|Ayşe Deniz|AD|",
"chemical_list": null,
"country": "Turkey",
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"doi": "10.14744/AnatolJCardiol.2018.78370",
"fulltext": "\n==== Front\nAnatol J CardiolAnatol J CardiolAnatolian Journal of Cardiology2149-22632149-2271Kare Publishing Turkey 29952362AJC-20-4110.14744/AnatolJCardiol.2018.78370Original InvestigationA retrospective study on children with pulmonary arterial hypertension: A single-center experience Kula Serdar Canbeyli Fatma Atasayan Vildan Tunaoğlu Fatma Sedef Oğuz Ayşe Deniz Department of Pediatric Cardiology, Faculty of Medicine, Gazi University; Ankara-TurkeyAddress for correspondence: Dr. Serdar Kula, Gazi Üniversitesi Tıp Fakültesi, Çocuk Kardiyoloji Bilim Dalı, 06500 Beşevler, Ankara-Türkiye Phone: +90 312 202 56 26 E-mail: kula@gazi.edu.tr7 2018 27 6 2018 20 1 41 47 23 5 2018 Copyright: © 2018 Turkish Society of Cardiology2018This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International LicenseObjective:\nThe aim of this study was to evaluate children with pulmonary arterial hypertension (PAH) regarding epidemiological characteristics, clinical status with respect to the WHO functional class (WHO-FC), prognostic factors, and efficacy of medical treatment.\n\nMethods:\nA retrospective evaluation of 41 patients with PAH was made in the Pediatric Cardiology Unit, Gazi University Medical Faculty, between February 2006 and October 2015.\n\nResults:\nOf the 41 patients included in this study, 51.2% were female. The median age was 60 months at first evaluation. The median follow-up was 60 months. At the start of the treatment, 43.9% patients were receiving combined drug therapy, and this rate increased to 60.9% by the last evaluation. The median time of adding a new medication to the therapy was 20 months. The 1- and 5-year survival rates were 94% and 86%, respectively. At the time of diagnosis, only pro-brain natriuretic peptide (proBNP) levels were associated with mortality (p=0.004), but at the last evaluation, 6-min walking test, proBNP and uric acid levels, and WHO-FC were also associated with survival (p=0.02, p=0.001, p=0.002, and p=0.05, respectively).\n\nConclusion:\nWith current treatment choices in experienced centers, positive results are obtained with respect to the functional status and survival rates of patients with PAH. At the time of diagnosis, only proBNP had a prognostic value, whereas at the last evaluation, WHO-FC, 6-min walking test, proBNP, and uric acid were reported prognostic factors. For preventing rapid progression, determination of factors that have an effect on prognosis, in particular, is extremely important.\n\npulmonary arterial hypertensionchildrensurvivalcongenital heart disease\n==== Body\nIntroduction\nPulmonary arterial hypertension (PAH) is a chronic and progressive disease that may affect all age groups, i.e., from newborns to adults (1). However, PAH in children is different from that in adults with respect to etiology and therapeutic approach (2). Although there has been an increase in pediatric studies related to PAH, knowledge about the diagnosis and treatment of pediatric PAH is still limited.\n\nSpecific treatment protocols for adult patients are based on the results of randomized controlled studies, and the adoption of these protocols has distinctly improved the quality of life and survival of these patients (3, 4). In addition, beneficial and hazardous effects of the drugs that have been developed for PAH might considerably vary in children and adults (5). Therefore, in this study, we focus on monitoring and treating children diagnosed with PAH.\n\nIt is of great importance to determine prognostic factors that can be used to monitor children with PAH and specify the efficiency of the administered drugs. Although echocardiographic findings and hemodynamic characteristics may indicate prognosis and therapeutic efficacy, noninvasive parameters, such as WHO functional class (WHO-FC), 6-min walk test (6MWT), and pro-brain natriuretic peptide (proBNP) levels, can also be used (2, 6).\n\nThis study aims to evaluate pediatric patients with PAH regarding epidemiological characteristics, clinical status with respect to WHO-FC, prognostic factors, and efficacy of medical treatment.\n\nMethods\nThis is a retrospective review of 41 patients who were diagnosed with PAH in the Department of Pediatric Cardiology at Gazi University Medical School Hospital between February 2006 and October 2015. The inclusion criteria were age <18 years at the time of diagnosis and mean pulmonary artery pressure (mPAP) ≥25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg, and pulmonary vascular resistance index (PVRI) ≥3 WU.m2, measured by right heart catheterization (7). The exclusion criteria were (i) age ≤28 days at the time of diagnosis and (ii) withdrawal from clinical follow-up.\n\nData related to patient age, sex, underlying etiology, clinical symptoms (fatigue, exercise-induced cyanosis, and dyspnea), and medical treatment were obtained from hospital files. Serum uric acid and pro BNP levels were measured; WHO-FC categorization, cardiac catheterization findings, 6MWT results, and vasoreactivity test positivity were recorded at the time of diagnosis.\n\nCardiac catheterization was performed in 40 patients (97.6%) patients, whereas it could not be performed in one patient because of deterioration in his general status. In this patient, the diagnosis of PAH was made using Doppler echocardiography, according to the European Society of Cardiology guidelines (8). The vasoreactivity test was conducted with inhaled iloprost in 24 patients who underwent cardiac catheterization (60%), and a positive response was obtained in nine patients (37.5%), based on the criteria recommended by the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) record study (9). Moreover, 6MWT was conducted in all patients aged >7 years (n=25, 61%) according to the American Thoracic Society guidelines, with adjustment of the track distance from 30 to 8 m to prevent children from getting distracted on a long track (10).\n\nAll patients diagnosed with PAH were monitored at 3-month intervals. Serum uric acid and proBNP levels were measured, WHO-FC categorization was done, and 6MWT was performed at all follow-up visits.\n\nStatistical analysis\nCollected data were analyzed using Statistical Package for Social Sciences version 15.0 (SPSS IBM, Armonk, NY, USA). Continuous variables are expressed as median, interquartile range (IQR), or range (minimum–maximum), whereas categorical variables were denoted as numbers or percentages. Data distribution was tested by the Shapiro–Wilk test. Wilcoxon test and McNemar test were used for comparing continuous and categorical variables, respectively. The univariate Cox regression analysis was performed for determining predictors of survival, and the Kaplan–Meier curve was drawn for illustrating survival of the patients. Two-tailed p values <0.05 were considered to be statistically significant.\n\nResults\nTable 1 demonstrates demographic and clinical characteristics of pediatric patients with PAH. The most common cause of PAH was congenital heart diseases (73.2%), and ventricular septal defect (VSD) was the most frequent congenital heart disease (19.5%). The most frequently encountered clinical symptoms were fatigue (65.9%) and exercise-induced cyanosis (63.4%). There were five patients with Down’s syndrome in the study cohort (12.2%).\n\nTable 1 Characteristics of patients at the time of diagnosis\n\nAge (months)&\t60.0 (2-240)\t\nFemale/Male\t21 (51.2%)/20 (48.8%)\t\nMedian follow-up (months)&\t60.0 (4-156)\t\nUnderlying etiology\t\t\nCongenital heart diseases\t30 (73.2%)\t\n VSD\t8 (19.5%)\t\n ASD+VSD\t7 (17.0%)\t\n ASD+Agenesis of right pulmonary artery\t3 (7.3%)\t\n DORV+VSD\t1 (2.4%)\t\n TGA+VSD\t1 (2.4%)\t\n cTGA+VSD\t1 (2.4%)\t\n AVCD\t2 (4.9%)\t\n TGA\t2 (4.9%)\t\n TAPVR\t1 (2.4%)\t\n Truncus arteriosus type 1\t1 (2.4%)\t\n Tricuspid atresia+ASD+VSD+PS\t1 (2.4%)\t\n AP window\t2 (4.9%)\t\nResidual PAH\t5 (12.2%)\t\nPrimary PAH\t4 (9.8%)\t\nChronic obstructive sleep apnea\t1 (2.4%)\t\nChronic pulmonary disease\t1 (2.4%)\t\nSymptoms\t\t\nFatigue\t27 (65.9%)\t\nExercise-induced cyanosis\t26 (63.4%)\t\nDyspnea\t3 (7.3%)\t\nWHO Functional classification\t\t\nII\t7 (17.0%)\t\nIII\t29 (71.0%)\t\nIV\t5 (12.0%)\t\nHemodynamic parameters&\t\t\nmPAP (mm Hg)\t66.0 (29-98)\t\nPVRi (Wood Unit.m2)\t9.5 (1-64)\t\nRp/Rs\t0.58 (0.08-2.28)\t\nQp/Qs\t1.09 (0.48-6.40)\t\nmRAP (mm Hg)\t5.0 (2-12)\t\n& Data are presented as median (minimum-maximum).\n\nVSD - ventricular septal defect; ASD - atrial septal defect; DORV - double outlet right ventricle; TGA - transposition of the great arteries; cTGA - corrected transposition of the great arteries; AVCD - atrioventricular canal defect; TAPVR - total anomalous pulmonary venous return; PS - pulmonary stenosis; AP window - aortapulmonary window; mPAP - mean pulmonary artery pressure; PVRi - pulmonary vascular resistance index; Rp/Rs - pulmonary resistance/systemic resistance; Qp/Qs - pulmonary flow/systemic flow; mRAP - mean right atrial pressure\n\nTable 2 shows medical treatment protocols and their effects on clinical symptoms and findings during clinical follow-up. Bosentan was the most commonly administered monotherapy (48.8%), whereas bosentan+inhaled iloprost were the most frequently administered combination therapy (22.0%). The administration rate of combined therapy increased from 44% at the time of diagnosis to 73.5% at the last evaluation. Sildenafil and inhaled iloprost were the most commonly added drugs. The median time of adding a new medication to the therapy was 20 (range, 10–64) months. Compared with the time of diagnosis, fatigue and exercise-induced cyanosis were significantly less and serum proBNP level was significantly lower at the last evaluation (p=0.001, p=0.012, and p=0.037, respectively). Moreover, the 6MW distance and serum uric acid level was significantly higher at the last evaluation than at the time of diagnosis (p=0.012 and p=0.022, respectively).\n\nTable 2 Medical treatment and its effects determined during the clinical follow-up\n\n\tTime of diagnosis (n=41)\tLast evaluation (n=41)\tP\t\nTreatment\t\t\t\t\t\nNo treatment\t0 (0.0%)\t5 (12.2%)\t\t\nMonotherapy\t23 (56.0%)\t11 (26.5%)\t\t\n Bosentan\t20 (48.8%)\t10 (24.4%)\t\t\n Sildenafil\t2 (4.9%)\t1 (2.4%)\t\t\n Inhaled iloprost\t1 (2.4%)\t0 (0.0%)\t\t\nDual therapy\t18 (44.0%)\t19 (46.3%)\t\t\n Bosentan+Sildenafil\t7 (17.1%)\t11 (26.8%)\t\t\n Bosentan+Inhaled iloprost\t9 (22.0%)\t6 (14.6%)\t\t\n Sildenafil+Inhaled iloprost\t2 (4.9%)\t2 (4.9%)\t\t\nTriple therapy\t0 (0.0%)\t6 (14.6%)\t\t\n Bosentan+Sildenafil+Inhaled iloprost\t0 (0.0%)\t3 (7.3%)\t\t\n Bosentan+Tadalafil+Inhaled iloprost\t0 (0.0%)\t1 (2.4%)\t\t\n Bosentan+Sildenafil+Treprostinil\t0 (0.0%)\t2 (4.9%)\t\t\nSymptoms\t\t\t\t\n Fatigue\t27 (65.9%)\t13 (31.7%)\t0.001\t\n Exercise-induced cyanosis\t26 (63.4%)\t17 (41.5%)\t0.012\t\n6MWT (m)&\t390 (134.0)\t480 (150.0)\t0.012\t\nProBNP (pg/mL)&\t280 (848.5)\t176.5 (646.6)\t0.037\t\nUric acid (mg/dL)&\t3.9 (1.5)\t4.4 (2.4)\t0.022\t\n& Data are presented as median (IQR).\n\nFigure 1 points out that WHO-FC at the time of diagnosis significantly improved at the time of the last evaluation (p=0.007). The 6MW distance significantly increased, and the serum proBNP level significantly decreased in patients who had been undergoing monotherapy at the time of diagnosis (p=0.023 and p=0.031, respectively). However, there were no significant improvements in 6MWT and proBNP values of patients who were undergoing combined therapy at the time of diagnosis (Table 3).\n\nFigure 1 World Health Organization functional classification at the time of diagnosis and last evaluation\n\nTable 3 Effects of treatment modalities on clinical findings\n\n\tMonotherapy at the start of treatment\tCombination therapy at the start of treatment\t\n\tFirst\tLast\tP\tFirst\tLast\tP\t\n6MWT (m)\t392 (136)\t486 (206)\t0.023\t360 (204)\t441 (180)\t0.17\t\t\nProBNP (pg/mL)\t206 (783)\t151 (272)\t0.031\t683 (1021.5)\t284 (1227.4)\t0.332\t\t\n& Data are presented as median (IQR).\n\n6MWT - 6-min walk test; proBNP - pro-brain natriuretic peptide\n\nFour patients died during the clinical follow-up, while postoperative pulmonary hypertensive crisis following VSD+ASD surgery occurred in one patient and heart failure related to primary PAH affected one patient. In addition, infection developed in one patient who had PDA, and residual PAH was diagnosed in another patient. The 1- and 5-year survival rates were 94% and 86%, respectively (Fig. 2).\n\nFigure 2 The Kaplan–Meier curve of the patients\n\nUnivariate Cox regression analysis showed that lower proBNP levels at the time of diagnosis and lower WHO-FC, higher 6MW distance, and lower proBNP and uric acid levels at the last evaluation were associated with survival (Table 4).\n\nTable 4 Parameters associated with the survival of patients\n\n\tn\tDeath n (%)\tMedian survival (months)\tHR\tUnivariate analysis 95% CI\tP\t\n\t\t\t\t\t\t\nAt diagnosis\t\t\t\t\t\t\t\t\nWHO-FC\t\t\t\t\t\t\t\t\nI-II\t7\t1 (14.3)\t24\t1\t\t\t\t\nIII-IV\t34\t3 (8.8)\t60\t0.513\t0.053 - 4.955\t0.564\t\t\nTreatment\t\t\t\t\t\t\t\t\nMonotherapy\t23\t2 (8.7)\t60\t1\t\t\t\t\nCombination therapy\t18\t2 (11.2)\t60\t1.327\t0.187 - 9.428\t0.777\t\t\nmPAP\t41\t4 (9.8)\t60\t1.010\t0.960 - 1.063\t0.694\t\t\nPVRi\t41\t4 (9.8)\t60\t1.050\t0.992 - 1.110\t0.091\t\t\nRp/Rs\t41\t4 (9.8)\t60\t0.696\t0.059 - 8.194\t0.773\t\t\n6MWT\t41\t4 (9.8)\t60\t0.990\t0.979 - 1.001\t0.080\t\t\nProBNP\t41\t4 (9.8)\t60\t1.001\t1.000 - 1.001\t0.004\t\t\nUric acid\t41\t4 (9.8)\t60\t1.404\t0.794 - 2.481\t0.243\t\t\nAt last evaluation\t\t\t\t\t\t\t\t\nWHO-FC\t\t\t\t\t\t\t\t\n I-II\t32\t1 (3.1)\t60\t1\t\t\t\n III-IV\t9\t3 (33.3)\t60\t9.393\t0.975 - 90.492\t0.053\t\n6MWT\t41\t4 (9.8)\t60\t0.984\t0.969 - 0.998\t0.027\t\t\nProBNP\t41\t4 (9.8)\t60\t1.001\t1.000 - 1.001\t0.001\t\t\nUric acid\t41\t4 (9.8)\t60\t1.525\t1.045 - 2.227\t0.029\t\t\n6MWT - 6-min walk test; proBNP - pro-brain natriuretic peptide; WHO-FC - WHO functional class; mPAP - mean pulmonary artery pressure; PVRi - pulmonary vascular resistance index; Rp/Rs - pulmonary resistance/systemic resistance; Qp/Qs - pulmonary flow/systemic flow\n\nDiscussion\nPAH is a progressive disease that significantly impairs the functional status of the patient and even results in mortality. There is no scientific consensus on monitoring and prognostically assessing pediatric patients with PAH because of the limited number of related clinical studies. Similar to the management of adult patients, pediatric cardiologists dealing with PAH tend to use WHO-FC, 6MWT, and proBNP levels for the clinical follow-up of affected children (6).\n\nAt the time of diagnosis, the number of pediatric patients with WHO-FC III-IV disease was higher than expected, and this finding has been attributed to a delay in the diagnosis and rapid progression of the disease (11-14). Accordingly, at the time of diagnosis, WHO-FC III-IV was present in 83% patients reviewed in this study. As expected, shorter survival is associated with the presence of WHO-FC III-IV disease at the time of diagnosis (3, 15).\n\nBalkin et al. (16) found a close correlation between WHO-FC at final evaluation and mortality, but they were unable to detect the same correlation between WHO-FC at the time of diagnosis and mortality. Similarly, in this study, WHO-FC at the last evaluation was an indicator for survival, but WHO-FC at the time of diagnosis did not indicate survival. Therefore, deteriorating WHO-FC during the clinical follow-up might have a greater prognostic value than WHO-FC at the time of diagnosis. Medical treatment should, thus, be renewed in patients who have worsening WHO-FC.\n\nIt is well-known that 6MWT has remarkable prognostic value in adults diagnosed with PAH (4, 17), but this test cannot be performed in small children because of a lack of cooperation. Although some studies have claimed that 6MWT is not beneficial in pediatric patients with PAH (18, 19), Lammers et al. (20) determined that 6MWT was associated with clinical outcomes in these patients. In this study, a significant improvement was achieved in 6MWT results of children with PAH at the last evaluation, and this improvement was significantly marked in pediatric patients who had been undergoing monotherapy. The 6MWT result at the last evaluation was also addressed as an indicator for survival.\n\nIt has been shown that the gradual increase in serum proBNP levels would help to predict the unfavorable prognosis of children diagnosed with PAH (3, 9, 21). A significant decrease was specified in serum proBNP levels at the last evaluation of the children with PAH and this decrease was significantly more prominent in pediatric patients who had been undergoing monotherapy. ProBNP values at the time of diagnosis and last evaluation were labeled as prognostic factors related to survival in pediatric patients with PAH.\n\nMuch like proBNP, an increase in serum uric acid levels can indicate an adverse outcome in children with PAH (19, 22). In this study, medical treatment was found to successfully decrease serum uric acid levels of pediatric patients with PAH. Moreover, serum uric acid levels at the last evaluation were found to predict survival.\n\nStarting combination therapy at the time of diagnosis has been a controversial issue in the management of pediatric PAH. However, recent guidelines have suggested initiation of combined therapy in selected cases (23, 24). Therefore, the administration rate of combined therapy has increased in pediatric patients with PAH within the last decade (Table 5) (11, 13, 25).\n\nTable 5 Medical treatment in the current and previous studies\n\nDrugs\tCurrent study n (%)\tFraise et al. (11) (%)\tRoldan et al. (13) (%)\tFavilli et al. (25) (%)\t\t\nMonotherapy\t11 (26.8)\t34.0\t55.1\t72.7\t\t\nCombination therapy\t25 (60.9)\t44.0\t45.9\t27.3\t\t\nEndothelin receptor antagonist\t33 (80.4)\t78.0\t23.6\t72.7\t\t\nPhosphodiesterase inhibitor\t20 (48.7)\t34.0\t58.0\t24.2\t\t\nProstanoids\t14 (34.1)\t24.0\t18.3\t3.0\t\t\nA thorough review of literature designates the endothelin receptor antagonist as the most frequently preferred monotherapy (11, 12, 25). In addition, sildenafil add-on to bosentan monotherapy reduces the severity of PAH in children (23). On the other hand, inhaled iloprost has been described as an efficient and safe therapy for PAH in pediatric patients. Most of the affected children can tolerate the combination of an endothelin receptor antagonist and phosphodiesterase inhibitor (24).\n\nThe present study identified significant improvements in patients who underwent monotherapy at the time of diagnosis, but these improvements were not detected in those who had been undergoing combination therapy at the beginning. This finding should not be interpreted as monotherapy being superior to combined therapy, rather it reflects the widespread approach of administering monotherapy to patients with early stage PAH (WHO-FC I-II) who are more likely to exhibit signs of improvement. This finding also emphasizes the importance of making an early diagnosis and initiating the optimal treatment.\n\nThe present study identifies bosentan+inhaled iloprost as the most frequently administered combination therapy at the time of diagnosis. This regimen has been changed to bosentan+sildenafil at the time of last evaluation. Such an alteration can be explained by the probably lower patient compliance associated with the administration of inhaled iloprost treatment. That is, oral ingestion of a drug twice or three times a day may be more easily performed and, thus, more frequently preferred than inhalation of a drug 6–9 times a day.\n\nBecause of PAH-specific drugs coming into routine use, the survival span of patients with PAH has been significantly prolonged (26). Complying with literature (11, 12, 19), in this study, 1- and 5-year survival rates are computed to be 94.5% and 86%, respectively. These relatively high survival rates can be attributed to the fact that majority study cohort is made up by children with congenital heart diseases. It has been well-established that idiopathic PAH has a worse course than congenital heart disease-related PAH; therefore, 1- and 5-year survival rates were 73% and 60%, respectively, for patients with idiopathic PAH (3, 26, 27).\n\nStudy limitations\nPatients in this cohort had heterogeneous etiopathogenesis varying from primary to residual PAH.\n\nA subgroup analysis based on PAH etiology could not be made because of the insufficient number of patients in etiological groups.\n\nA subgroup analysis based on co-morbidities (i.e., Down’s syndrome) could not be made because of the relatively small cohort size.\n\nBiochemical alterations related to pharmacological side effects could not be assessed.\n\nConclusion\nBecause of the latest advances in pharmacological treatment, functional status and survival rates of patients with PAH have significantly improved. Because PAH is a progressive disease, the prevention of rapid progression in affected children is particularly important. The 6MWT, proBNP and uric acid levels, and WHO-FC are prognostic factors that can be used for preventing rapid progression of pediatric PAH. Further research is warranted for clarifying prognostic factors and long-term efficacy of medical treatment in children diagnosed with PAH.\n\nAcknowledgement\nWe thank Bülent Çelik PhD for statistical analysis.\n\nConflict of interest: None declared.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship contributions: Concept – S.K.; Design – S.K.; Supervision – F.S.T.; Fundings – S.K.; Materials – F.C.; Data collection &/or processing – F.C.; Analysis &/or interpretation – S.K.; Literature search – V.A.; Writing – F.C.; Critical review – A.D.O.\n==== Refs\nReferences\n1 Schermuly RT Ghofrani HA Wilkins MR Grimminger F Mechanisms of disease:pulmonary arterial hypertension Nat Rev Cardiol 2011 8 443 55 21691314 \n2 Ivy DD Abman SH Barst RJ Berger RM Bonnet D Fleming TR Pediatric pulmonary hypertension J Am Coll Cardiol 2013 62 25 Suppl D117 26 24355636 \n3 Zijlstra WMH Douwes JM Rosenzweig EB Schokker S Krishnan U Roofthooft MTR Survival differences in pediatric pulmonary arterial hypertension:clues to a better understanding of outcome and optimal treatment strategies J Am Coll Cardiol 2014 63 2159 69 24681143 \n4 Benza RL Miller DP Gomberg-Maitland M Frantz RP Foreman AJ Coffey CS Predicting survival in pulmonary arterial hypertension:insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) Circulation 2010 122 164 72 20585012 \n5 Nakau K Sugimoto M Oka H Kajihama A Maeda J Yamagishi H Pharmacokinetics of drugs for pediatric pulmonary hypertension Pediatr Int 2016 58 1112 7 27038140 \n6 Ploegstra MJ Zijlstra WM Douwes JM Hillege HL Berger RM Prognostic factors in pediatric pulmonary arterial hypertension:A systematic review and meta-analysis Int J Cardiol 2015 184 198 207 25706327 \n7 Hoeper MM Bogaard HJ Condliffe R Frantz R Khanna D Kurzyna M Definitions and diagnosis of pulmonary hypertension J Am Coll Cardiol 2013 62 25 Suppl D42 50 24355641 \n8 Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Recommendations for cardiac chamber quantification by echocardiography in adults:an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging Eur Heart J Cardiovasc Imaging 2015 16 233 70 25712077 \n9 Barst RJ McGoon MD Elliott CG Foreman AJ Miller DP Ivy DD Survival in childhood pulmonary arterial hypertension:insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management Circulation 2012 125 113 22 22086881 \n10 ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories ATS statement:guidelines for the six-minute walk test Am J Respir Crit Care Med 2002 166 111 7 12091180 \n11 Fraisse A Jais X Schleich JM di Filippo S Maragnes P Beghetti M Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France Arch Cardiovasc Dis 2010 103 66 74 20226425 \n12 Chung WJ Park YB Jeon CH Jung JW Ko KP Choi SJ Baseline Characteristics of the Korean Registry of Pulmonary Arterial Hypertension J Korean Med Sci 2015 30 1429 38 26425039 \n13 Roldan T Deiros L Romero JA Gutierrez-Larraya F Herrero A Del Cerro MJ Safety and tolerability of targeted therapies for pulmonary hypertension in children Pediatr Cardiol 2014 35 490 8 24141893 \n14 Ling Y Johnson MK Kiely DG Condliffe R Elliot CA Gibbs JS Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension:results from the pulmonary hypertension registry of the United Kingdom and Ireland Am J Respir Crit Care Med 2012 186 790 6 22798320 \n15 Park YM Chung WJ Choi DY Baek HJ Jung SH Choi IS Functional class and targeted therapy are related to the survival in patients with pulmonary arterial hypertension Yonsei Med J 2014 55 1526 32 25323888 \n16 Balkin EM Olson ED Robertson L Adatia I Fineman JR Keller RL Change in Pediatric Functional Classification During Treatment and Morbidity and Mortality in Children with Pulmonary Hypertension Pediatr Cardiol 2016 37 756 64 26843461 \n17 Miyamoto S Nagaya N Satoh T Kyotani S Sakamaki F Fujita M Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension Comparison with cardiopulmonary exercise testing Am J Respir Crit Care Med 2000 161 487 92 10673190 \n18 Moledina S Pandya B Bartsota M Mortensen KH McMillan M Quyam S Prognostic significance of cardiac magnetic resonance imaging in children with pulmonary hypertension Circ Cardiovasc Imaging 2013 6 407 14 23572488 \n19 Wagner BD Takatsuki S Accurso FJ Ivy DD Evaluation of circulating proteins and hemodynamics towards predicting mortality in children with pulmonary arterial hypertension PLoS One 2013 8 e80235 24278261 \n20 Lammers AE Munnery E Hislop AA Haworth SG Heart rate variability predicts outcome in children with pulmonary arterial hypertension Int J Cardiol 2010 142 159 65 19176261 \n21 Chida A Sato H Shintani M Nakayama T Kawamura Y Furutani Y Soluble ST2 and N-terminal pro-brain natriuretic peptide combination Useful biomarker for predicting outcome of childhoodpulmonary arterial hypertension Circ J 2014 78 436 42 24304538 \n22 van Loon RL Roofthooft MT Delhaas T van Osch-Gevers M ten Harkel AD Strengers JL Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies Am J Cardiol 2010 106 117 24 20609658 \n23 Abman SH Hansmann G Archer SL Ivy DD Adatia I Chung WK American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation;Council on Clinical Cardiology;Council on Cardiovascular Disease in the Young;Council on Cardiovascular Radiology and Intervention;Council on Cardiovascular Surgery and Anesthesia;and the American Thoracic Society. Pediatric Pulmonary Hypertension:Guidelines From the American Heart Association and American Thoracic Society Circulation 2015 132 2037 99 26534956 \n24 Galiè N Humbert M Vachiery JL Gibbs S Lang I Torbicki A ESC Scientific Document Group 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS):Endorsed by:Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Heart J 2016 37 67 119 26320113 \n25 Favilli S Spaziani G Ballo P Fibbi V Santoro G Chiappa E Advanced therapies in patients with congenital heart disease-related pulmonary arterial hypertension:results from a long-term, single center, real-world follow-up Intern Emerg Med 2015 10 445 50 25573622 \n26 Haworth SG Hislop AA Treatment and survival in children with pulmonary arterial hypertension:the UK Pulmonary Hypertension Service for Children 2001-2006 Heart 2009 95 312 7 18952635 \n27 van Loon RL Roofthooft MT Hillege HL ten Harkel AD van Osch-Gevers M Delhaas T Pediatric pulmonary hypertension in the Netherlands:epidemiology and characterization during the period 1991 to 2005 Circulation 2011 124 1755 64 21947294\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2149-2263",
"issue": "20(1)",
"journal": "Anatolian journal of cardiology",
"keywords": null,
"medline_ta": "Anatol J Cardiol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002662:Child Health Services; D002675:Child, Preschool; D005260:Female; D006785:Hospitals, University; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016019:Survival Analysis; D014421:Turkey; D055815:Young Adult",
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"other_id": null,
"pages": "41-47",
"pmc": null,
"pmid": "29952362",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "25706327;19176261;24278261;26425039;12091180;24355641;22798320;26534956;25323888;23572488;26843461;21691314;10673190;21947294;18952635;24304538;20585012;24681143;25573622;27038140;26320113;24355636;25712077;24141893;20226425;20609658;22086881",
"title": "A retrospective study on children with pulmonary arterial hypertension: A single-center experience.",
"title_normalized": "a retrospective study on children with pulmonary arterial hypertension a single center experience"
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"abstract": "Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.",
"affiliations": "III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor, Inselspital, Bern, Switzerland.;Klinik für Hämatologie, Universitätsspital, Basel, Switzerland.;II. Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.;Medizinische Klinik und Poliklinik III, Klinikum der Ludwig-Maximilians-Universität, München, Germany.;Medizinische Klinik 5, Universitätsklinikum, Erlangen, Germany.;Klinik für Hämatologie, Onkologie, Immunologie, Palliativmedizin, Infektiologie und Tropenmedizin, Klinikum Schwabing, München, Germany.;Medizinische Klinik IV, Uniklinik RWTH, Aachen Germany.;Zentrum für ambulante Hämatologie und Onkologie, Bonn, Germany.;Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Klinikum, Idar-Oberstein, Germany.;Klinik für Hämatologie, Onkologie und Palliativmedizin, Klinikum, Kempten, Germany.;Medizinische Klinik 2, Klinikum Mittelbaden, Standort Balg, Baden-Baden, Germany.;Klinik für Onkologie/Hämatologie, Kantonsspital, St Gallen, Switzerland.;Innere Medizin 1, Klinikum Mutterhaus der Borromäerinnen, Trier, Germany.;Mannheimer Onkologie Praxis, Mannheim, Germany.;Medizinische Klinik III, Krankenhaus, Düren, Germany.;Praxis für Innere Medizin, Nephrologie, Hämatologie und Onkologie, Trier, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany.;Klinik für Innere Medizin II, Universitätsklinikum, Jena, Germany.;Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.;III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.",
"authors": "Miranda|M B|MB|;Lauseker|M|M|;Kraus|M-P|MP|;Proetel|U|U|;Hanfstein|B|B|;Fabarius|A|A|;Baerlocher|G M|GM|;Heim|D|D|;Hossfeld|D K|DK|;Kolb|H-J|HJ|;Krause|S W|SW|;Nerl|C|C|;Brümmendorf|T H|TH|;Verbeek|W|W|;Fauser|A A|AA|;Prümmer|O|O|;Neben|K|K|;Hess|U|U|;Mahlberg|R|R|;Plöger|C|C|;Flasshove|M|M|;Rendenbach|B|B|;Hofmann|W-K|WK|;Müller|M C|MC|;Pfirrmann|M|M|;Hochhaus|A|A|;Hasford|J|J|;Hehlmann|R|R|;Saußele|S|S|",
"chemical_list": "D016898:Interferon-alpha; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "England",
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"doi": "10.1038/leu.2016.20",
"fulltext": "\n==== Front\nLeukemiaLeukemiaLeukemia0887-69241476-5551Nature Publishing Group leu20162010.1038/leu.2016.2026859076Original ArticleSecondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV Secondary malignancies in CMLMiranda M B 120Lauseker M 220Kraus M-P 1Proetel U 1Hanfstein B 1Fabarius A 1Baerlocher G M 3Heim D 4Hossfeld D K 5Kolb H-J 6Krause S W 7Nerl C 8Brümmendorf T H 9Verbeek W 10Fauser A A 11Prümmer O 12Neben K 13Hess U 14Mahlberg R 15Plöger C 16Flasshove M 17Rendenbach B 18Hofmann W-K 1Müller M C 1Pfirrmann M 2Hochhaus A 19Hasford J 2Hehlmann R 1Saußele S 1*1 III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany2 Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany3 Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor, Inselspital, Bern, Switzerland4 Klinik für Hämatologie, Universitätsspital, Basel, Switzerland5 II. Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany6 Medizinische Klinik und Poliklinik III, Klinikum der Ludwig-Maximilians-Universität, München, Germany7 Medizinische Klinik 5, Universitätsklinikum, Erlangen, Germany8 Klinik für Hämatologie, Onkologie, Immunologie, Palliativmedizin, Infektiologie und Tropenmedizin, Klinikum Schwabing, München, Germany9 Medizinische Klinik IV, Uniklinik RWTH, Aachen Germany10 Zentrum für ambulante Hämatologie und Onkologie, Bonn, Germany11 Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Klinikum, Idar-Oberstein, Germany12 Klinik für Hämatologie, Onkologie und Palliativmedizin, Klinikum, Kempten, Germany13 Medizinische Klinik 2, Klinikum Mittelbaden, Standort Balg, Baden-Baden, Germany14 Klinik für Onkologie/Hämatologie, Kantonsspital, St Gallen, Switzerland15 Innere Medizin 1, Klinikum Mutterhaus der Borromäerinnen, Trier, Germany16 Mannheimer Onkologie Praxis, Mannheim, Germany17 Medizinische Klinik III, Krankenhaus, Düren, Germany18 Praxis für Innere Medizin, Nephrologie, Hämatologie und Onkologie, Trier, Germany19 Klinik für Innere Medizin II, Universitätsklinikum, Jena, Germany* III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Pettenkoferstrasse 22, Mannheim 68169, Germany. E-mail: Susanne.Saussele@medma.uni-heidelberg.de20 These authors contributed equally to this work.\n\n06 2016 09 02 2016 26 02 2016 30 6 1255 1262 22 10 2015 14 12 2015 23 12 2015 Copyright © 2016 Macmillan Publishers Limited2016Macmillan Publishers LimitedThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63–1.20)) for men and 1.06 (95% CI 0.69–1.55) for women. SIRs were between 0.49 (95% CI 0.13–1.34) for colorectal cancer in men and 4.29 (95% CI 1.09–11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.\n==== Body\nIntroduction\nTreatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 5-and 8-year survival rate of 90% and 88%, respectively.1, 2 The life expectancy of patients who achieve complete cytogenetic remission is not different from that of the general population,3, 4 and is influenced mostly by comorbidities.5\n\nThe increased life expectancy requires closer long-term observation of potential side effects. The development of secondary malignancies is regarded as a common risk of antineoplastic therapies. An increased rate of secondary malignancies compared with the general population has been reported in patients with Hodgkin's lymphoma,6, 7 chronic lymphocytic leukemia8, 9 and other lymphoproliferative diseases,10 as well as in polycythemia vera11 and essential thrombocythemia.12, 13\n\nAn increased rate of secondary malignancies has also been described in patients who had received allogeneic stem cell transplantation14, 15, 16, 17, 18 for various hematologic diseases. Exposure to radiotherapy,19, 20 chemotherapy and immunosuppression, either disease or treatment related,21 have been suggested as risk factors for secondary malignancies.\n\nTKIs have also been discussed as risk factors for malignancies. Preclinical data demonstrated an interaction of imatinib with DNA repair mechanisms.22 In studies with rats, neoplastic changes occurred in kidneys, urinary bladder, urethra, preputial and clitoral glands, small intestine, parathyroid glands, adrenal glands and non-glandular stomach.23\n\nAnother TKI effect that may be relevant for the development of malignancies is the inhibition of T-lymphocytes and dendritic cells. It has been shown that imatinib inhibits the effector function of T-lymphocytes and impairs the differentiation of peripheral blood progenitor cells into dendritic cells.24\n\nThese effects may facilitate the development of lymphatic malignancies during long-term exposure to imatinib.\n\nIn CML, data on the incidence of secondary malignancies are contradictory (see Supplementary Table 1). An increased rate of prostate cancer was found in a French cohort of 189 CML patients treated with imatinib.25 However, data from the Novartis registries of more than 9500 patients did not confirm this observation, but they were not obtained from randomized trials.26\n\nAnalyses of patient cohorts from multiple phase I and II trials at the MD Anderson Cancer Center, who were treated with TKI for CML and other myeloproliferative neoplasms, showed a risk of secondary malignancies that was lower than expected in the general population.27 In line with this is the analysis from Poland of 221 CML patients under imatinib treatment (median of 61 months) with no increase of secondary malignancies.28\n\nIn contrast, two other studies demonstrated an higher incidence in CML patients: (1) an analysis of the US-American SEER database found a significantly higher observed/expected ratio of secondary malignancies in the imatinib era of 1.48 versus 1.06 in the pre-imatinib era;29 (2) a study that crosslinked the Swedish CML register to the Swedish Cancer registry found a standardized incidence ratio (SIR) of 1.52 for a patient cohort from the imatinib era;30 and (3) in a cohort of 1038 Czech and Slovakian CML patients treated with TKI, the age-adjusted incidence rate of secondary malignancies was found to be 1.5-fold higher than that of the general population, but the difference was not statistically significant.31\n\nHowever, CML itself has been discussed as a risk factor for solid cancers and hematologic malignancies. The acquired translocation t(9;22) at diagnosis of CML and additional chromosomal changes/mutations as a sign of clonal evolution during the course of disease show the potential of genetic instability in CML. Therefore, progenitors may already have the capacity to enforce themselves as distinct cells with enhanced malignancy resulting in solid cancers/hematologic malignancies before or later than CML.32 Two epidemiological studies that analyzed cancer registries for patients with CML in Sweden31, 33 and patients with myeloproliferative neoplasms including CML in Denmark34 showed an increased risk of secondary malignancies in CML patients.\n\nTo further elucidate the risk for the development of secondary malignancies in chronic-phase CML patients under treatment, we analyzed data from the CML Study IV after a median treatment duration of >5 years.\n\nPatients and methods\nPatients\nCML study IV is a randomized 5-arm trial that compares imatinib 400 mg vs imatinib 800 mg vs imatinib 400 mg in combination with interferon-α vs imatinib 400 mg in combination with low-dose cytarabine and vs imatinib 400 mg after interferon failure.\n\nThe study was conducted as previously published.1\n\nInclusion criteria allowed the history of primary cancer if the disease was in stable remission without impact on study procedures. A total of 102 malignancies were reported in 92 patients before the diagnosis of CML. If relapses occurred within 5 years after diagnosis of primary cancer, they were not considered for further analysis.\n\nMedian follow-up for all patients after diagnosis of CML was 67.5 months (range, 0.12–124 months). Analysis was done according to intention-to-treat principle, that is, for patients on primary imatinib and after switch of therapy based on failure or intolerance.\n\nStatistical analysis\nSIRs35 were calculated from the age-specific rates from the German reference population, obtained from the Robert Koch Institute.36 Patients <15 years of age were excluded from the study and the groups 15–19 years and >85 years of age were not considered as >30 patient years were observed. As usual, non-melanoma skin cancer was not considered.36 The 95% confidence intervals (CIs) were calculated with ‘Mid-P exact test' using the modification of Miettinen37 as previously described.38 Overall survival and progression-free survival as defined by the ELN (European LeukemiaNet) criteria39 were calculated using the Kaplan–Meier method.40 Cumulative incidences of second malignancies were estimated under the presence of the competing risk of death.41 Unless otherwise specified, date of diagnosis was considered as starting point for all time-to-event analyses. If one type of malignancy occurred more than once in a patient it was counted as one case according to the IACR (International Association of Cancer Registries).42\n\nIf not specified otherwise, all computations were done with SAS 9.2 (SAS Institute, Cary, NC, USA) or R 3.0.1.43\n\nEthics\nThe protocol followed the Declaration of Helsinki and was approved by the ethics committee of the ‘Medizinische Fakultät Mannheim der Universität Heidelberg' and by local ethics committees of participating centers. Written informed consent was obtained from all patients before they entered the study.\n\nResults\nPatient characteristics\nFrom February 2002 to March 2012, 1551 CML patients in chronic phase were randomized; 1525 were evaluable. Patient characteristics are described in Table 1 and Figure 1.\n\nSecondary malignancies\nIn total, 67 secondary malignancies in 64 (4.2%) patients were found after a median follow-up of 67.5 months. Of these patients, 26 were female (41%). The median age of these 64 patients at diagnosis of CML was 65 years (range, 30–88 years), and the median age at diagnosis of the first secondary malignancy after diagnosis of CML was 66 years (range, 31–88 years). The median time from diagnosis of CML to secondary malignancy was 2.4 years (range, 0.1–8.3 years).\n\nSo far, cumulative incidences of secondary malignancies among the five therapy arms are similar; the 5-year cumulative incidence varied between 1.9 and 6.3% (see Figure 1).\n\nTwo patients with secondary malignancy had been switched to second-generation TKIs (dasatinib: 1, nilotinib: 1) because of imatinib failure 3 days and 3 years, respectively, before the diagnosis of the secondary malignancies. In addition, one patient received allogeneic stem cell transplantation (>4 years before diagnosis of secondary malignancy).\n\nTwelve of the patients with primary cancer before CML diagnosis developed malignancies under TKI treatment. Six of these patients had metastases or recurrence of the first malignancy 5–19 years after diagnosis of the primary cancers (two patients with breast cancer and one patient with cancer of unknown origin, prostate rectal and renal cell cancer).\n\nThe types of malignancies were: prostate (n=9, 13%), colorectal (n=6, 9%), lung (n=6, 9%), non-Hodgkin's lymphoma (NHL; n=7, 10%), malignant melanoma (n=5, 7%), skin tumors (basalioma n=4 and squamous cell carcinoma n=1, 7%), breast (n=5, 7%), pancreas (n=4, 6%), kidney (n=4, 6%), chronic lymphocytic leukemia (n=3, 4%), head and neck (n=2, 3%), biliary (n=2, 3%), sarcoma (n=2, 3%), and esophagus, stomach, liver, vulva, uterus, brain and cancer of unknown origin (each n=1, 1%, see Table 2).\n\nThree patients had more than one malignancy while receiving TKI. One patient developed a leiomyosarcoma and later a liposarcoma, one patient had a NHL that recurred (recurrence after 7 years) and one patient had prostate cancer and developed a NHL.\n\nOutcome of patients with secondary malignancies\nOf the 64 patients, 8 were in complete cytogenetic remission, 31 in major molecular remission at the time of diagnosis of the secondary malignancy. Two had progression of CML before diagnosis of the secondary malignancy, and one of these regained a remission before diagnosis of secondary malignancy (Table 2).\n\nAfter diagnosis of secondary malignancies, CML treatment was continued without modification in 36 patients (56%). After a median follow-up time of 46.8 months (range 0–105 months) from time of diagnosis of the secondary malignancy, 26 patients had died. Of these patients, 22 died from the secondary malignancy, 2 from other causes (cerebellar infarction, infection) and 2 from unknown causes. Progression of CML was not a cause of death in any case. With a 4-year-survival of 57% (95% CI 43–70%, median overall survival 6.5 years), the overall survival and progression-free survival was significantly reduced in patients who developed secondary malignancies (Figures 2a and b).\n\nStatistical analysis\nCumulative incidences\nCumulative incidence of secondary malignancies in patients >50 years of age was significantly higher than in patients ⩽50 years old (P<0.001): at 6 years the cumulative incidence was 8.1% (95% CI 9.2–10.5%) and 0.8% (95% CI 0.3–1.9%), respectively (Figure 3).\n\nNo significant differences were found between males and females (cumulative incidence 4.6% (95% CI 3.2–6.5%) vs 5.2% (95% CI 3.4–7.5%)) and EUTOS (European Treatment and Outcome Study)44 high- vs low-risk patients at 6 years.\n\nSIRs for secondary malignancies (without non-melanoma skin tumors) in the CML population in comparison with the general German population were 0.88 (95% CI 0.63–1.20) in men and 1.06 (95% CI 0.69–1.55) in women (38 and 24 patients observed vs 43.0 and 22.7 patients expected in the matched German population, Figures 4a and b).\n\nCancer subtypes\nRegarding the subtypes of secondary malignancies, the numbers for prostate cancer, colorectal cancer, breast cancer, malignant melanoma, pancreas and kidney cancer in CML patients were not statistically significantly different from expected numbers of the general population. The SIRs were between 0.49 (colorectal in male) and 3.33 (kidney cancer in female) (Figure 4).\n\nThe number of cases of NHL however was significantly higher in the CML IV cohort than the expected number in the matched German population. The SIR for male was 3.33 (95% CI 1.06–8.04) and 4.29 for female (95% CI 1.09–11.66) (see Table 3 and Figure 4b).\n\nDiscussion\nOverall, our data do not support an increased risk for secondary malignancies in CML patients treated with imatinib as the SIR of men and women were similar to that of general population. However, looking at subtypes of malignancies we found a significant increase of the SIR for NHL for both sexes.\n\nThese data are in contrast to analyses of population-based registries in Denmark34 and Sweden33 that found an increased risk for secondary malignancies in CML patients. The observation timeframes for both studies were between 1970 and 2007 and between 1977 and 2008, respectively, and therefore mostly from the pre-TKI era. Both studies did not report on the specific treatment, but one can conclude that most commonly hydroxyurea and interferon-α were given to the patients during most of the time period. Knowing that BCR-ABL itself is a mutant driver of malignancy, this could explain the discrepancy of the studies.\n\nThe data from the SEER database contrast the above observations as in their study secondary malignancies in the pre-imatinib era were less common than in the imatinib era.29\n\nA recent analysis of 868 CML patients from the Swedish CML registry diagnosed between 2002 and 2011 that were crosslinked to the Swedish Cancer registry showed a 50% overall increased risk of second malignancies compared with the normal population.30 This is in line with the study by Rebora et al.33 A possible explanation of the differences to our analyses is that we have a very well-described patient population with very good remission rates under imatinib-based treatments.45 Therefore, the BCR-ABL effect as described above may play a less important role in the CML IV trial cohort and may contribute to lower incidence rates of secondary malignancies.\n\nIn line with our observation is the study by Voglova et al.31 The age-adjusted incidence rate of secondary malignancies in their cohort of 1038 Czech and Slovakian CML patients treated with TKI was 1.5-fold higher than the normal population, but the difference was not statistically significant.31\n\nSubtypes\nThere are several studies showing an increasing risk for subtypes of different cancers under TKI treatment. Verma et al.27 reported on secondary malignancies in patients with different myeloproliferative neoplasms including CML. They found a smaller number of secondary neoplasms than expected but an increased risk of melanoma, kidney and endocrine cancers.\n\nIn our study the increased rate of prostate cancer, the most common malignancy we found, was not statistically significant. This corresponds to data from the Novartis registries of clinical trials and adverse event reports of more than 9500 patients and more than 1 20 000 patient years and is in contrast to Roy et al.25\n\nThe increased frequency of NHL in our study was statistically significant. It must be considered that two of the seven cases occurred in patients who had already developed a secondary malignancy: in one case the documented NHL was a recurrence after 7 years, and the other case was a NHL in a patient with a previously documented prostate cancer. Another reason for the increased number of NHL cases may be that three of the seven cases were low-grade lymphomas that are easily missed in the general population but found in a monitored study cohort. We could not demonstrate a sex difference in appearance of NHL as this was shown by Radivoyevitch et al.46\n\nPrevalence\nIn addition, a high number of patients (92 out of 1525, 6.0%) with malignancies that were diagnosed before the CML diagnosis were randomized to our study. In an analysis of the SEER database, Brenner et al.47 found that 14% of patients with CML had a malignancy before CML was diagnosed. Usually, in official publications like from the German Robert Koch Institute, cancer prevalence is reported as a period prevalence, for example, 5-year prevalence instead of point prevalence. Thus, no number for comparison exists directly. However, the cancer prevalence in our patient population seems to be high and a potential influence on the pathogenesis of CML can be discussed.\n\nThe diagnosis of secondary malignancies had a significantly unfavorable impact on overall survival and progression-free survival compared with other study patients of our trial. Remarkably, the cause of death in all these patients was not related to CML as no progression was observed.\n\nObservation data from other disease entities, for example, Hodgkin's lymphoma, indicate a long latency time between time after start of exposure to a risk factor and risk of secondary malignancies. The relative risk increased from 2.2 after 5 years to 10.9 after 20 years.7 Peaks for the rate of secondary malignancies were 5 to 9 years after chemotherapy and remained raised for ⩾25 years.6 Therefore, longer follow-up of CML patients is warranted. In summary, there is no consistent distribution of malignancies in the different reports.25, 26, 27, 31, 33, 34 The risk of secondary malignancies is increased in population-based studies of CML patients,27, 34 but not increased in case–control studies of CML patients who are treated with TKI.27, 28, 31 So far, it is impossible to dissect patient selection in the observed patient populations from the impact of CML treatment on the risk of secondary malignancies.\n\nTherefore, it is speculative if secondary malignancies occur after long exposure to TKI. Ideally, long-term follow-up on large cohorts of CML patients under treatment is warranted. As analyses of cancer registries often do not integrate complete data on treatment, a solution could be a registry on CML trial patients after end of study.\n\nCML Study IV is supported by the Deutsche Krebshilfe (Nr. 106642), Novartis, Nürnberg, Germany, Deutsches Kompetenznetz für Akute und Chronische Leukämien (BMBF 01GI0270), Deutsche José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v, H03/01, R05/23), European LeukemiaNet (LSHC-CT-2004-503216), Roche, Grenzach-Wyhlen, Germany, and Essex Pharma, München, Germany. The contributions of Sabine Dean, Elke Matzat, Regina Pleil-Lösch, Inge Stalljann, Gabriele Bartsch, Ute Kossak, Barbara Müller, Andrea Elett, Catherine Sodan-Boyer and all CML centers (see Supplementary File) are acknowledged.\n\nSupplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)\n\nBH has received honoraria from Bristol-Myers Squibb (BMS) and research funding from Novartis; SWK honoraria and research funding by Novartis; MCM honoraria and research funding from Novartis, BMS, ARIAD and Pfizer; MP honoraria from BMS and consultancy from Novartis; AH honoraria from Novartis, BMS, ARIAD, consultancy from Novartis and research funding from Novartis, ARIAD and Pfizer; RH research funding from Novartis and BMS and SS honoraria from Novartis, BMS, Pfizer, ARIAD and research funding from Novartis and BMS. The other authors declare no conflict of interest.\n\nSupplementary Material\nSupplementary Table 1 Click here for additional data file.\n\n Figure 1 Consort statement of the CML study IV and occurrence of secondary malignancies per recruitment arm.\n\nFigure 2 Probability of survival with or without the appearance of secondary malignancies. (a) Overall survival from time of diagnosis of CML. (b) Progression-free survival from time of diagnosis of secondary malignancy.\n\nFigure 3 Cumulative incidence of all secondary malignancies according to age ⩽50 vs >50 years.\n\nFigure 4 SIRs of secondary malignancies within CML study IV for men and women compared with normal population for different tumor types. (a): SIRs of men (b) and SIRs of women.\n\nTable 1 Patient characteristics of available patients and patients with secondary malignancies\nCharacteristic\tPatients who developed secondary malignancies (n=64)\tTotal cohort (n=1525)\t\nAge at diagnosis of CML, years\t65 (30–88)\t52 (16–88)\t\nAge at diagnosis of secondary malignancy, years\t66 (31–88)\t—\t\nTime to secondary malignancy, years\t2.4 (0.1–8.3)\t—\t\nFollow-up after diagnosis of secondary malignancy, months\t46.8 (0–104.6)\t—\t\nMedian overall survival, months\tNot reached\tNot reached\t\nPatients with history of cancer, n\t12\t92\t\nMalignancy was metastases or recurrence of primary malignancy, n\t5\t—\t\nTime from primary cancer to secondary malignancy, years\tRange 5–19\t—\t\nTreatment for CML\tn (%)\tn (%)\t\nImatinib 400 mg\t22 (34)\t396 (26)\t\nImatinib+IFN\t19 (30)\t426 (28)\t\nImatinib 800 mg\t9 (14)\t417 (27)\t\nImatinib+AraC\t4 (6)\t158 (10)\t\nIFN-standard\t10 (16)\t128 (8)\t\nOf this, IFN only\t3\t15\t\nAbbreviations: AraC, Cytarabin; CML, chronic myeloid leukemia; CP, chronic phase; IFN, interferon.\n\nTable 2 Incidence, treatment and outcome of secondary malignancies in the German CML IV study (cases: n=67)\nSecondary malignancy\tCases, n\tRemission status of CML at time of secondary NPL, n\tTreatment of secondary NPL\tChange of CML therapy\tOutcome\t\n \tMale\tFemale\tTotal\t%\tn\tMMR\tMR4.0\tMR4.5\tCCyR\tLess than CCR\tOP\tRTx\tCTx\tAHT\tRituximab\tObserve\tNone\t \tDeath\tRemission\tStable disease\t\nProstate\t9\t0\t9\t13\t9\t3\t \t3\t2\t1\t6\t3\t2\t2\t \t \t \t \t3\t6\t \t\nColorectal\t3\t3\t6\t9\t6\t1\t1\t \t1\t3\t4\t2\t2\t \t \t \t \t \t2\t4\t \t\nLung\t4\t2\t6\t9\t6\t1\t \t \t2\t3\t4\t2\t2\t \t \t \t \t \t5\t1\t \t\nNon-Hodgkin‘s lymphoma\t4\t3\t7\t10\t7\t1\t1\t3\t \t2\t \t3\t1\t \t1\t2\t \t \t \t2\t5\t\nMelanoma\t2\t3\t5\t7\t5\t1\t \t2\t \t2\t5\t \t \t \t \t \t \t \t \t5\t \t\nSkin, non-melanoma\t2\t3\t5\t7\t5\t1\t \t2\t1\t1\t5\t \t \t \t \t \t \t \t \t5\t \t\nBreast\t0\t5\t5\t7\t5\t1\t \t \t \t4\t2\t3\t2\t2\t \t \t \t \t3\t2\t \t\nPancreatic\t2\t2\t4\t6\t4\t1\t \t \t \t3\t3\t \t1\t \t \t \t1\t \t3\t1\t \t\nRenal\t2\t2\t4\t6\t4\t1\t1\t1\t \t1\t2\t \t1\t \t \t \t1\t \t3\t1\t \t\nChronic lymphatic leukemia\t2\t1\t3\t4\t3\t1\t \t \t \t2\t \t \t \t \t \t \t \t \t \t \t3\t\nHead and neck\t2\t0\t2\t3\t2\t2\t \t \t \t \t2\t \t \t \t \t \t \t \t \t2\t \t\nHepatobiliary\t1\t1\t2\t3\t2\t2\t \t \t \t \t1\t \t2\t \t \t \t \t \t2\t \t \t\nSarcoma\t2\t0\t2\t3\t2\t2\t \t \t \t \t1 (2)\t \t \t \t \t \t \t \t \t2\t \t\nEsophagus\t1\t0\t1\t1\t1\t \t \t \t \t1\t \t1\t \t \t \t \t \t \t1\t \t \t\nStomach\t1\t0\t1\t1\t1\t \t \t \t \t1\t \t \t \t \t \t \t1\t \t1\t \t \t\nLiver\t1\t0\t1\t1\t1\t \t \t \t \t1\t \t \t \t \t \t \t1\t \t1\t \t \t\nVulva\t0\t1\t1\t1\t1\t \t \t \t1\t \t \t \t \t \t \t \t \t \t1\t \t \t\nUterus\t0\t1\t1\t1\t1\t \t \t \t1\t \t1\t \t \t \t \t \t \t \t \t1\t \t\nBrain\t1\t0\t1\t1\t1\t \t \t \t \t1\t1\t1\t1\t \t \t \t \t \t1\t \t \t\nCancer of unknown origin\t1\t0\t1\t1\t1\t \t1\t \t \t \t1\t1\t1\t \t \t \t \t \t1\t \t \t\nTotal\t40\t27\t67\t100\t67\t18\t4\t11\t8\t26\t37\t17\t15\t4\t1\t2\t4\t0\t27\t32\t8\t\nAbbreviations: AHT, antihormone therapy; CCyR, complete cytogenetic remission; CML, chronic myeloid leukemia; CTx, chemotherapy; MMR, major molecular remission; MR, molecular remission; none, no tumor-specific therapy; NPL, neoplasia; observe, observation; OP, operation; RTx, radiotherapy.\n\nTable 3 Standardized incidence rates of secondary malignancies (excluding non-melanoma skin cancer)\n \tMale\tFemale\t\n \tCML IV\tMatched German population\tObserved/expected (95% confidence interval)\tCML IV\tMatched German population\tObserved/ expected (95% confidence interval)\t\nOverall, n\t38\t43.0\t0.88 (0.63–1.20)\t24\t22.7\t1.06 (0.69–1.55)\t\nAge >50 years, n\t37\t40.6\t0.91 (0.65–1.24)\t20\t20.5\t1.02 (0.65–1.54)\t\nAge <50 years, n\t1\t2.4\t0.42 (0.02–2.06)\t4\t2.2\t1.82 (0.58–4.39)\t\nSecondary malignancy type (types with only one occurence were not shown)\t\n Prostate, n\t9\t11.8\t0.76 (0.37–1.40)\t \t \t \t\n Colorectal, n\t3\t6.1\t0.49 (0.13–1.34)\t3\t2.8\t1.07 (0.27–2.92)\t\n Lung, n\t4\t6.1\t0.66 (0.21–1.58)\t2\t1.7\t1.18 (0.20–3.89)\t\n NHL, n\t4\t1.2\t3.33 (1.06–8.04)\t3\t0.7\t4.29 (1.09–11.66)\t\n Breast, n\t \t \t \t5\t7.8\t0.64 (0.23–1.42)\t\n Pancreas, n\t2\t1.3\t1.54 (0.26–5.08)\t2\t0.7\t2.86 (0.48–9.44)\t\n Kidney, n\t2\t1.6\t1.25 (0.21–4.13)\t2\t0.6\t3.33 (0.56–11.01)\t\nAbbreviations: CML, chronic myeloid leukemia; NHL, non-Hodgkin's lymphoma.\n==== Refs\nHehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N et al. 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Incidence of second malignancies during treatment of chronic myeloid leukemia with tyrosine kinase inhibitors in the Czech Republic and Slovakia . Neoplasma \n2011 ; 58 : 256 –262.21395367 \nFabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C et al. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML . Ann Hematol \n2015 ; 94 : 2015 –2024.26385387 \nRebora P, Czene K, Antolini L, Gambacorti Passerini C, Reilly M, Valsecchi MG. Are chronic myeloid leukemia patients more at risk for second malignancies? A population-based study . Am J Epidemiol \n2010 ; 172 : 1028 –1033.20861143 \nFrederiksen H, Farkas DK, Christiansen CF, Hasselbalch HC, Sorensen HT. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study . Blood \n118 : 6515 –6520.22039256 \nEsteve J, Benhamou E, Raymond L. Statistical methods in cancer research. Volume IV. Descriptive epidemiology . IARC Sci Publ \n1994 , 1 –302.\nRobert Koch Institute and the Association of Population-based Cancer Registries in Germany (eds). Cancer in Germany 2007/2008 , 9th edn. Robert Koch Institute: : Berlin, Germany,, 2012 . Available from: http://www.krebsdaten.de/Krebs/EN/Content/Publications/Cancer_in_Germany/cancer_chapters_2009_2010/cancer_germany_2009_2010.pdf?__blob=publicationFile.\nMiettinen OS. Proportion of disease caused or prevented by a given exposure, trait or intervention . Am J Epidemiol \n1974 ; 99 : 325 –332.4825599 \nRothman KJ, Boice HD, Austin H. Epidemiologic Analysis with a Programmable Calculator . Epidemiology Resources, Incorporated \n1982 ; pp 197 .\nBaccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia . 2013 Blood \n2013 ; 122 : 872 –884.23803709 \nKaplan EL, Meier P. Nonparametrical estimation for incomplete observations . J Am Stat Assoc \n1958 ; 53 : 457 –481.\nGooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators . Stat Med \n1999 ; 18 : 695 –706.10204198 \nIARC/IACR. 2004. International Rules for Multiple Primary Cancers (ICD-0 Third Edition). International Agency for Research on Cancer: Lyon. ISBN. Available from: http://www.iacr.com.fr/MPrules_july2004.pdf).\nR Development Core Team R: A Language and Environment for Statistical Computing . The R Foundation for Statistical Computing: Vienna, Austria, 2011 .\nHasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score . Blood \n2011 ; 118 : 686 –692.21536864 \nKalmanti L, Saussele S, Lauseker M, Muller MC, Dietz CT, Heinrich L et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV . Leukemia \n2015 ; 29 : 1123 –1132.25676422 \nRadivoyevitch T, Sachs RK, Gale RP, Molenaar RJ, Brenner DJ, Hill BT et al. Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation . Leukemia \n2015 ; 30 : 285 –294.26460209 \nBrenner H, Gondos A, Pulte D. Long-term survival in chronic myelocytic leukemia after a first primary malignancy . Leuk Res \n2009 ; 33 : 1604 –1608.19272642\n\n",
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"abstract": "Amiodarone-induced pulmonary toxicity (AIPT) has a variety of presentations. Amiodarone use has been rarely associated with the development of acute respiratory failure. We present a patient with a history of paroxysmal atrial fibrillation who developed acute respiratory distress syndrome despite taking a low dose of amiodarone and having no risk or precipitating factors. The diagnosis of AIPT was made after drug discontinuation and exclusion of other potential causes. The development of acute respiratory failure due to AIPT is often underdiagnosed and undertreated. Better identification of risk factors and developing appropriate diagnostic tools for risk stratification of patients receiving amiodarone is mandatory.",
"affiliations": "Department of Cardiology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia.;Department of Pathology, Forensic Medicine and Cytology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia.;Department of Cardiology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia.;Department of Rheumatology and Clinical Immunology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia.",
"authors": "Meter|Mijo|M|;Prusac|Ivana Kuzmić|IK|;Glavaš|Duška|D|;Meter|Diana|D|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00162-3\n10.1016/j.rmcr.2021.101500\n101500\nCase Report\nAcute respiratory failure on a low dose of amiodarone – is it an underdiagnosed and undertreated condition?\nMeter Mijo mijometer05@gmail.com\na∗\nPrusac Ivana Kuzmić ikuzmicp@mefst.hr\nb\nGlavaš Duška duska.glavas@gmail.com\na\nMeter Diana dianabajo53@gmail.com\nc\na Department of Cardiology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia\nb Department of Pathology, Forensic Medicine and Cytology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia\nc Department of Rheumatology and Clinical Immunology, University Hospital Centre Split, Spinčićeva 1, 21000, Split, Croatia\n∗ Corresponding author. mijometer05@gmail.com\n05 9 2021\n2021\n05 9 2021\n34 1015001 7 2021\n18 8 2021\n24 8 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/).\nAmiodarone-induced pulmonary toxicity (AIPT) has a variety of presentations. Amiodarone use has been rarely associated with the development of acute respiratory failure. We present a patient with a history of paroxysmal atrial fibrillation who developed acute respiratory distress syndrome despite taking a low dose of amiodarone and having no risk or precipitating factors. The diagnosis of AIPT was made after drug discontinuation and exclusion of other potential causes. The development of acute respiratory failure due to AIPT is often underdiagnosed and undertreated. Better identification of risk factors and developing appropriate diagnostic tools for risk stratification of patients receiving amiodarone is mandatory.\n\nHighlights\n\n• Amiodarone use is rarely associated with the development of acute respiratory failure.\n\n• The most clinical presentation of AIPT is a subacute illness presented by the nonproductive cough, progressive dyspnoea, and low-grade fever\n\n• The diagnosis of AIPT is often made after drug discontinuation and exclusion of other potential causes.\n\n• Identification of risk factors and developing appropriate diagnostic tools for risk stratification of patients receiving amiodarone is mandatory\n\nKeywords\n\nAcute respiratory failure\nAmiodarone\nPulmonary toxicity\n==== Body\npmc1 Introduction\n\nAmiodarone is a class III antiarrhythmic agent used for both supraventricular and ventricular arrhythmias [1]. The toxic effects of amiodarone on the lungs are well known, but the sudden onset of those effects is not adequately recognized and treated. Amiodarone use has been rarely associated with the development of acute respiratory distress syndrome (ARDS) [2,3]. We present a patient with a history of taking low-dose amiodarone who was admitted into the intensive care unit (ICU) due to new onset of dyspnoea and acute respiratory failure.\n\n2 Case report\n\nA 70-year old man with a history of paroxysmal atrial fibrillation, diabetes mellitus, and arterial hypertension presented to the Emergency Department with the symptoms of dyspnoea, cough, and fever lasting for five days. The patient had symptomatic paroxysmal atrial fibrillation and was treated with amiodarone 200 mg daily for the previous five years. His vital signs at the arrival were as follows: blood pressure 160/110 mmHg, respiratory rate 34/min with decreased oxygen saturation (89%). Electrocardiogram (ECG) showed atrial fibrillation with a fast ventricular response rate of 110/min and no signs of ischemia. Physical examination revealed diminished pulmonary sounds with right side basal crackles. Laboratory workup revealed increased levels of white blood cell count (WBC) 13,100/ml with 83% neutrophils, creatinine (180mg/dl), C-reactive protein (CRP) 296.4 mg/dl and slite elevation of gamma-glutamyl transferase (GGT) 80 mg/dl and lactate dehydrogenase (LDH) 315 mg/dl. Chest X-ray showed diffuse bilateral perihilar nonhomogeneous infiltrates (Fig. 1). Due to the acute clinical deterioration, he was immediately admitted into the intensive care unit (ICU) and treated with high-flow oxygen. Empirical antibiotic therapy with amoxicillin-clavulanic acid and levofloxacin was started. Considering the potential toxicity, the therapy with amiodarone was discontinued. A repeated chest X-ray study one week later did not show any resolution of pulmonary infiltrates. Blood and urine cultures were taken and found to be sterile. Further investigation included a high-resolution computed tomography (HRCT) scan of the chest that showed diffuse interlobar septal thickening with the extensive ground-glass opacities in the upper lungs and consolidation in the anterior segment of the right upper lobe (Figure 2. (A and B)). The differential diagnosis considered at the time included cryptogenic organizing pneumonia (COP) but based on the imaging features, there was also a suspicion of amiodarone-induced pulmonary toxicity (AIPT). HRCT also revealed bilateral pleural effusions with paratracheal and subcarinal enlargement of lymph nodes. Transthoracic echocardiography demonstrated hypertrophic interventricular septum with normal left ventricular systolic function and no valvular abnormalities. Mitral inflow showed a pseudonormal left ventricular filling pattern consistent with elevated LV filling pressures and grade II diastolic dysfunction. Right-sided thoracocentesis was done and bacterial cultures of the pleural fluid were negative. Legionella antigen was negative. Due to the worsening of respiratory function noninvasive ventilation (NIV) was applied. After clinical stabilization, he was transferred to the Department for further investigation and treatment. After that, bronchoscopy with aspiration and transbronchial biopsy (TBB) was performed to confirm a definitive diagnosis. Bacterial cultures of the bronchial aspiration fluid were negative. Transbronchial lung tissue biopsy showed morphological findings suggestive of amiodarone exposure and indicative of its toxicity. Two small samples of lung tissue demonstrated organizing pneumonia and diffuse interstitial pneumonitis with the widening of alveolar septae infiltrated with chronic inflammatory cells and mild to moderate interstitial fibrosis. The histologic finding of hyaline membranes as seen in diffuse alveolar damage was indicative of adult respiratory distress syndrome. Reactive hyperplasia of type II pneumocytes, some of them with lipid vacuoles, were present. The intra-alveolar foamy macrophages with cytoplasmic vacuolization were characteristic of amiodarone lung toxicity (Fig. 3, Fig. 4, Fig. 5.) One week after patient's clinical condition improved and he was discharged from the hospital. A follow-up chest X-ray six weeks later showed no previously detected pulmonary infiltrates.Fig. 1 Diffuse bilateral perihilar inhomogenous infiltrates on chest X-ray.\n\nFig. 1\n\nFig. 2 (A and B) High-resolution computed tomography scan of the chest showing diffuse interlobar septal thickening with ground-glass opacities.\n\nFig. 2\n\nFig. 3 Lung tissue showing organizing pneumonia, interstitial thickening and hyaline membranes (H&E stain, 100X).\n\nFig. 3\n\nFig. 4 The alveolar septae are thickened and infiltrated by mononuclear cell infiltration, lined by hyperplastic pneumocytes type II. Organizing pneumonia is also seen. (H&E stain, 400X).\n\nFig. 4\n\nFig. 5 Small aggregates of lipid-laden macrophages in alveolar spaces. Also note aforementioned morphologic changes (H&E stain, 400X).\n\nFig. 5\n\n3 Discussion\n\nAmiodarone is a widely used antiarrhythmic agent. Acute and chronic pulmonary drug toxicity related to amiodarone is still noticed [4]. AIPT has a variety of presentations ranging from mild to very severe and includes organizing pneumonia, interstitial pneumonitis, and acute respiratory distress syndrome [5]. Amiodarone toxicity is related to several different mechanisms such as a cytotoxic effect of type II pneumocytes, an immune-mediated mechanism in genetically predisposed patients, and the activation of the angiotensin enzyme system [[6], [7], [8]]. The incidence of AIPT ranges from 0.5% and up to 17% [2]. Overall mortality rates of AIPT vary between 1% and 33% depending on the respiratory situation [9]. Risk factors associated with AIPT include a high cumulative dose (400 mg/day), duration of therapy more than two months, older age, preexisting lung disease, major surgery, and diagnostic procedure such as pulmonary angiography [10]. According to the current data it is recommended to apply 200 mg/d as a maintenance dose to keep the probability for AIPT as low as possible but in our case, acute pulmonary toxicity developed despite taking only a daily low dose of amiodarone [11]. Sweidan et al. reported a case of amiodarone induced-pulmonary toxicity in a 56- year-old male with coronary artery disease and chronic obstructive pulmonary disease after coronary artery bypass graft CABG surgery. The patient received amiodarone in a daily dose of 400 mg [12]. Abuzaid et al. also described a case of acute amiodarone pulmonary toxicity in a 57-year old patient who was treated with 400 mg daily of amiodarone for recurrent episodes of atrial fibrillation [13]. Although our patient did not have any risk or precipitating factors and despite the that he was taking a daily low dose of amiodarone (200 mg/day), he developed AIPT with signs of acute respiratory failure. All this outlines that risk factors for developing AIPT are still underrecognized and need to be investigated. Typical clinical presentation of AIPT is a subacute illness presented by the nonproductive cough, progressive dyspnoea, and low-grade fever, malaise with weight loss [14]. Our patient presented with the acute onset of respiratory symptoms which at first did not point at the amiodarone as a primary cause of respiratory failure. Nevertheless, he did not undergo any major surgery or diagnostic procedure that would explain such an acute clinical deterioration. Laboratory tests are not specific for the diagnosis of AIPT. They may show increased erythrocyte sedimentation rate and lactate dehydrogenase, leukocytosis, and rarely eosinophilia. Increased levels of BNP, which were high in our patient, do not exclude amiodarone lung toxicity, since these clinical entities may co-exist [15]. Our patient had a history of arterial hypertension, atrial fibrillation with a fast ventricular response, and signs of diastolic dysfunction confirmed on transthoracic echocardiography. Keeping that in mind, it is hard to distinguish to which extent fluid overload contributed to this condition since it is known that all of these conditions can lead to volume overload. Right-sided pleural effusion seen in our patient was the manifestation of acute decompensated heart failure precipitated with an ARDS. However, Hawatmeh, et al. reported a case of an amiodarone-induced pleural effusion without associated lung parenchymal involvement in a 73-year-old male with a history of coronary artery disease [16]. Uong et al. also reported a case of an amiodarone-induced bilateral pleural effusion without associated pneumonitis in a 70-year old female patient with a history of atrial fibrillation [17]. Our patient laboratory tests showed leukocytosis and increased levels of lactate dehydrogenase with no signs of eosinophilia. On chest X-ray images, the extent of the AIPT is very often underestimated. CT images of lungs are more relevant in the detection of early infiltrations [18]. Radiographic hallmarks of AIPT are interstitial infiltrates which can be localized or diffuse. Alveolar ground-glass opacities can also be found in AIPT, as was the case with our patient [10]. We also considered other medications associated with organizing pneumonia. Our patient was taking bisoprolol, amlodipine, rivaroxaban and amiodarone. All of these drugs, except amiodarone are not associated with the development of organizing pneumonia.\n\nBronchoalveolar lavage (BAL) may reveal an inclusion body in alveolar macrophages and type II pneumocytes of accumulated phospholipids [19]. To exclude other potential causes of acute respiratory failure we performed bronchoscopy with transbronchial biopsy (TBB) to confirm a diagnosis but also to rule out malignancy or atypical fungal, mycobacterial, and viral infections. Pathology remains the gold standard for diagnosing AIPT. The histopathologic findings suggesting AIPT include lipid-laden macrophages in airspaces, nonspecific interstitial pneumonitis, type II pneumocyte hyperplasia, interstitial edema, and fibrosis which was also found in our patient [11,20,21]. The intra-alveolar foamy macrophages with cytoplasmic vacuolization which were found in our patient may be associated with amiodarone toxicity. However, these histological findings can also correlate with chronic exposure to amiodarone and they are not specific for amiodarone toxicity [15].\n\nLung biopsy, alveolar cytogram, and foamy macrophages in BAL can help in the formulation of the diagnosis. To make a definitive diagnosis of AIPT requires the exclusion of other diagnostic possibilities, especially congestive heart failure, accompanied by an appropriate combination of symptoms or findings [22].\n\nThe first line of therapy is drug cessation. Systemic corticosteroids had been widely used, but there are currently no randomized controlled studies to confirm their benefit in terms of AIPT [10,23]. We did not administer corticosteroids because the patient clinical condition dramatically improved after one week. Additionally, we wanted to exclude some other conditions, particularly malignancy before corticosteroid administration. In our opinion, his clinical improvement was due to a combination of intensive care management, which included oxygen therapy, noninvasive ventilation, antibiotic therapy, diuretic and beta-blockers administration, pleurocentesis, and drug discontinuation. Intensive care measures, rather than amiodarone discontinuation led to clinical improvement because amiodarone is a lipophilic structure with a half-life of 25–100 days [24]. The aim of this case report was to emphasize that we should think about AIPT even in patients with no obvious risk or precipitating factors and taking only a low-dose of amiodarone. We also want to point that risk factors for developing AIPT are still underappreciated and better risk stratification of patients taking amiodarone to avoid AIPT is mandatory. Further studies are needed to investigate potential new risk factors in order to identify patients at high risk for AIPT.\n\n4 Conclusion\n\nTo conclude, amiodarone pulmonary toxicity is a rare clinical condition, and diagnosis can be very challenging. It is usually made by exclusion of other potential causes. The combination of imaging and histological findings in our patient could be associated with amidarone pulmonary toxicity. Better identification of risk factors and developing appropriate diagnostic tools for risk stratification of patients receiving amiodarone is an emergent necessity.\n\nCrediT author statement\n\nMijo Meter: Conceptualization, Validation, Writing - Original Draft preparation.\n\nIvana Kuzmić Prusac: Visualization.\n\nDuška Glavaš: Writing - Reviewing & Editing.\n\nDiana Meter: Writing - Reviewing & Editing, Supervision.\n\nAuthor contributions\n\nThe case report described here was carried out in collaboration with all authors. Mijo Meter contributed to the conception and interpretation of data for the case report, he performed the literature review and wrote the initial draft. Ivana Kuzmić Prusac prepared and presented histopathologic analysis. Duška Glavaš revised draft critically and contributed in analysing the data. Diana Meter revised the manuscript critically for important intellectual content and gave the final approval of the version to be published. All authors made an agreement to be accountable for all aspects of the case report in ensuring that all questions are appropriately investigated and resolved. All authors agree to the publication.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\n1 Vassallo P. Trohman R. Prescribing amiodarone J. Am. Med. Assoc. 298 11 2007 1312 1322\n2 Schwaiblmair M. Berghaus T. Haeckel T. Wagner T. von Scheidt W. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect? Clin. Res. Cardiol. 99 11 2010 693 700 20623129\n3 Kumar S. Bangalore S. Kumari R. Grosu H. Jean R. Amiodarone-induced acute respiratory distress syndrome masquerading as acute heart failure J. Emerg. Med. 43 5 2012 e311 e314 21459542\n4 Dharmarajan T. Shah A. Dharmarajan L. Amiodarone-induced pulmonary toxicity: potentially fatal, recognize early during life! J. Am. Geriatr. Soc. 56 7 2008 1363 1365 18774973\n5 Colby R. Geyer H. Amiodarone-induced pulmonary toxicity J. Am. Acad. Physician Assistants 30 11 2017 23 26\n6 Uhal B. Wang R. Laukka J. Zhuang J. Soledad-Conrad V. Filippatos G. Inhibition of amiodarone-induced lung fibrosis but not alveolitis by angiotensin system antagonists Pharmacol. Toxicol. 92 2 2003 81 87 12747577\n7 Uhal B. Zhang H. Abdul-Hafez A. Shu R. Li X. Amiodarone induces angiotensinogen gene expression in lung alveolar epithelial cells through activation protein-1 Basic Clin. Pharmacol. Toxicol. 100 1 2007 59 66 17214612\n8 Nikaido A. Tada T. Nakamura K. Murakami M. Banba K. Nishii N. Clinical features of and effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity Int. J. Cardiol. 140 3 2010 328 335 19106010\n9 Hughes M. Binning A. Intravenous amiodarone in intensive care Intensive Care Med. 26 12 2000 1730 1739 11271079\n10 Wolkove N. Baltzan M. Amiodarone pulmonary toxicity Can. Respir. J. J. Can. Thorac. Soc. 16 2 2009 43 48\n11 Goldschlager N. Epstein A. Naccarelli G. Olshansky B. Singh B. Collard H. A practical guide for clinicians who treat patients with amiodarone: 2007 Heart Rhythm 4 9 2007 1250 1259 17765636\n12 Sweidan A. Singh N. Dang N. Lam V. Datta J. amiodarone-induced pulmonary toxicity – a frequently missed complication Clin. Med. Insights Case Rep. 9 2016 CCRep.S39809\n13 Abuzaid A. Saad M. Ayan M. Kabach A. Haddad T. Smer A. Acute amiodarone pulmonary toxicity after drug holiday: a case report and review of the literature Case Rep. Cardiol. 2015 1 3 2015\n14 Dusman R. Stanton M. Miles W. Klein L. Zipes D. Fineberg N. Clinical features of amiodarone-induced pulmonary toxicity Circulation 82 1 1990 51 59 2364524\n15 Camus P. Martin W. Rosenow E. Amiodarone pulmonary toxicity Clin. Chest Med. 25 1 2004 65 75 15062598\n16 Hawatmeh A. Thawabi M. Jmeian A. Shaaban H. Shamoon F. Amiodarone-induced loculated pleural effusion without pulmonary parenchymal involvement: a case report and literature review J. Nat. Sci. Biol. Med. 8 1 2017 130 133 10.4103/0976-9668.198345 28250689\n17 Uong V. Nugent K. Alalawi R. Raj R. Amiodarone-induced loculated pleural effusion: case report and review of the literature Pharmacotherapy 30 2 2010 Feb 218 10.1592/phco.30.2.218 PMID: 20099996 20099996\n18 Oyama N. Oyama N. Yokoshiki H. Kamishima T. Nambu T. Tsutsui H. Detection of amiodarone-induced pulmonary toxicity in supine and prone positions-high-resolution computed tomography study Circ. J. 69 4 2005 466 470 15791044\n19 Dean P. Groshart K. Porterfield J. Iansmith D. Golden E. Amiodarone-associated pulmonary toxicity: a clinical and pathologic study of eleven cases Am. J. Clin. Pathol. 87 1 1987 7 13 3799544\n20 Camus P. Fanton A. Bonniaud P. Camus C. Foucher P. Interstitial lung disease induced by drugs and radiation Respiration 71 4 2004 301 326 15316202\n21 Bedrossian C. Warren C. Ohar J. Bhan R. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry Ann. Diagn. Pathol. 1 1 1997 47 56 9869825\n22 Terzo F. Ricci A. D'Ascanio M. Raffa S. Mariotta S. Amiodarone-induced Pulmonary toxicity with an excellent response to treatment: a case report Respir. Med. Case Rep. 29 2019 Nov 29 100974 10.1016/j.rmcr.2019.100974 31853440\n23 Nacca N. Bhamidipati C.M. Yuhico L.S. Pinnamaneni S. Szombathy T. Severe amiodarone induced pulmonary toxicity J. Thorac. Dis. 4 6 2012 667 670 23205299\n24 Essrani R. Mehershahi S. Essrani R.K. Ravi S.J.K. Bhura S. Sudhakaran A. Amiodarone-induced acute liver injury Case Rep. Gastroenterol. 14 1 2020 Feb 20 87 90 10.1159/000506184 32231507\n\n",
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"title": "Acute respiratory failure on a low dose of amiodarone - is it an underdiagnosed and undertreated condition?",
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"abstract": "A patient with a marginal zone lymphoma received RCHOP and obtained PR. He received RDHAP, autograft, and obtained CR. Three months later, he developed Kaposi's sarcoma with spontaneous regression. Two months later, he developed DLBCL treated with R-MIV with CR. Thereafter, he developed AML and died a few days later.",
"affiliations": "Department of Hematology Centre Hospitalier Le Mans France.;Department of Hematology Centre Hospitalier Le Mans France.;Department of Hematology Centre Hospitalier Le Mans France.;Department of Hematology Centre Hospitalier Le Mans France.;Department of Medicine Pôle Sante Sud Le Mans France.;Laboratory of Haematology Centre Hospitalier Le Mans France.;Clinical Research Center Centre Hospitalier Le Mans France.;Department of pharmacy Centre Hospitalier Le Mans France.",
"authors": "Laribi|Kamel|K|;Ghnaya|Habib|H|;Mention|Pierre-Jean|PJ|;Rousset|Hoel|H|;Baugier de Materre|Alix|A|;Pineau-Vincent|Fabienne|F|;Truong|Catherine|C|;Bolle|Delphine|D|",
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"country": "England",
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"doi": "10.1002/ccr3.393",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.393CCR3393Case ReportCase ReportsQuadri‐lineage disease involving nodal B‐cell marginal zone lymphoma, high‐grade B‐cell lymphoma, Kaposi's syndrome, and acute myeloid leukemia K. Laribi et al.Laribi Kamel \n1\nGhnaya Habib \n1\nMention Pierre‐Jean \n1\nRousset Hoel \n1\nBaugier de Materre Alix \n2\nPineau‐Vincent Fabienne \n3\nTruong Catherine \n4\nBolle Delphine \n5\n1 Department of HematologyCentre HospitalierLe MansFrance2 Department of MedicinePôle Sante SudLe MansFrance3 Laboratory of HaematologyCentre HospitalierLe MansFrance4 Clinical Research CenterCentre HospitalierLe MansFrance5 Department of pharmacyCentre HospitalierLe MansFrance* Correspondence\n\nKamel Laribi, Centre Hospitalier, 194 Avenue Rubillard, 72000 Le Mans, France.\n\nTel: 33 (0)2 43 43 43 61;\n\nFax: 33 (0)2 43 43 25 18;\n\nE‐mail: klaribi@ch-lemans.fr\n13 11 2015 1 2016 4 1 10.1111/ccr3.2016.4.issue-139 42 20 3 2015 30 6 2015 11 8 2015 © 2015 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‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nA patient with a marginal zone lymphoma received RCHOP and obtained PR. He received RDHAP, autograft, and obtained CR. Three months later, he developed Kaposi's sarcoma with spontaneous regression. Two months later, he developed DLBCL treated with R‐MIV with CR. Thereafter, he developed AML and died a few days later.\n\nAcute myeloid leukemiadiffuse large B‐cell lymphomaKaposi's syndromemarginal zone lymphoma source-schema-version-number2.0component-idccr3393cover-dateJanuary 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.2 mode:remove_FC converted:06.01.2016\n\nClinical Case Reports \n2016 ; 4 (1 ): 39 –42\n==== Body\nIntroduction\nMarginal zone lymphomas are usually indolent and respond well to treatment 1, 2, but the nodal form is often more severe and is associated with poor response rates and shorter survival times 3, 4, 5. Progression to high‐grade B‐cell lymphoma may occur, and has long been known 1, 6, 7.\n\nThe occurrence of acute leukemia after a high‐grade B‐cell lymphoma has also been described in various studies 8, 9, 10. The use of alkylating agents based chemotherapy and the intensification of therapy with autologous stem cell transplantation are risk factors for leukemia or myelodysplasia 11, 12, 13.\n\nKaposi's sarcoma after autologous bone marrow transplantation for non‐Hodgkin's lymphoma is rare, but cases have been published 14.\n\nThe occurrence in the same patient of nodal B‐cell marginal zone lymphoma, high‐grade B‐cell lymphoma, Kaposi's syndrome, and acute myeloid leukemia in quick succession has never been described.\n\nCase Report\nWe report an exceptional case of diseases of four lineages in a 61‐year‐old man with a history of type 2 diabetes, deep vein thrombosis of the lower limbs, syphilis, hypertension, and glaucoma. He developed a marginal zone lymphoma, revealed by alteration of his general condition, weight loss of 8 kg over the previous 3 months, and detected as a left pelvic nodal mass with a diameter of 8.5 cm. A chest and abdominal CT revealed left axillary, mediastinal, retroperitoneal, and pelvic involvement. A pelvic lymph node biopsy showed proliferation in the marginal zone with a moderate contingent of large cells and a mitotic index (Ki 67) of 40%. Blood tests showed anemia with low hemoglobin levels (9 g/dL). Lactate dehydrogenase levels were high (2 N) and the ECOG PS was 2. Up to 30% of the bone marrow was infiltrated by lymphoma cells. A PET scan was not performed. The patient was diagnosed with a high tumor burden lymphoma (FLIPI = 4, IPI adjusted to age 3).\n\nThe nodal and medullary karyotypes were normal. Bone marrow and blood cells tested positive for BCL2 by PCR.\n\nPretreatment assessment identified a syphilis infection, which was cured with penicillin. Hypogammaglobulinemia or lymphopenia were not detected during the assessment. Serological tests for hepatitis B, hepatitis C, HIV, CMV, and HTLV were negative.\n\nThe patient was treated with the standard protocol for the RCHOP regimen (rituximab–cyclophosphamide–doxorubicin–vincristin). After three courses of chemotherapy, the response was evaluated to be 50% by physical examination and tomography scans of the chest and abdomen. Bone marrow was not analyzed. The patient then received three courses of RDHAP (rituximab–cisplatin–cytosine arabinoside–dexamethasone) and obtained a complete response (chest and abdominal CT, and bone marrow biopsies were negative), and an autologous stem cell transplant conditioned by the BEAM regimen (carmustine–cytosine arabinoside–etoposid–melphalan). This treatment was followed by complete remission.\n\nThree months after the autograft, the patient developed multiple nodular lesions of the legs and the right and left forearms, the largest of which was 2‐cm long and on the left forearm. Skin biopsy revealed a typical Kaposi's sarcoma, and HHV8 serological tests were positive (Figs. 1 and 2).\n\nFigure 1 Vascular‐type CD34+ spindle cell tumor within the dermis.\n\nFigure 2 Vascular tumor with atypical cytonuclear HHV8+ staining indicating Kaposi's sarcoma.\n\nConcomitantly, the patient became severely immunosuppressed; the absolute CD4+ cell count was 220 × 106/L, with 1048 × 106/L CD8+ cells, and thus a CD4/CD8 ratio of 0.2.\n\nIt was decided not to treat. The lesions spontaneously regressed 3 months after their appearance, and had completely disappeared 6 months later; the CD4/CD8 ratio rose to 0.8, and immunity returned to normal.\n\nTwo months later, the patient developed a bilateral cervical lymphadenopathy 3 cm in diameter. Nodal biopsy showed a typical diffuse large B‐cell lymphoma. Extended assessment found Ann Arbor stage III, IPI adjusted to age 3. Bone marrow biopsy, medullary karyotype, and FISH were normal.\n\nNo sibling donor was available; given the age of the patient, the nature of the lymphoma, and the severity of the comorbidity no volunteer donor was sought. The patient was administered six sequences of the R‐MIV regimen (rituximab–ifosfamide–mitoxantone–etoposide). Physical examination, tomography scan of the chest and the abdomen, and PET scan indicated that complete remission was obtained.\n\nSix months later, the patient developed pancytopenia (PN 0.3 × 106/L, platelets 26 × 106/L, hemoglobin 83 g/L). The myelogram showed bone marrow infiltration, 90% AML type 1. Karyotyping by FISH revealed a translocation t (9, 11) with an MLL rearrangement. It was decided not to treat because of mounting concerns about the poor general condition of the patient, who had developed cellulitis of the right arm. The patient died from multiple sepsis a few days later.\n\nDiscussion\nSeveral studies have analyzed the prognostic factors affecting the survival of patients with marginal zone lymphoma. Some identified no prognostic factors 5 and others found that age (>60 years) 15 or a high follicular lymphoma international prognostic index 16 score were associated with shorter survival 17. In another study, patients expressing Ki 67 in less than 5% of tumor cells had a better prognosis 18. Recently, in a large retrospective series of 197 patients with marginal zone lymphoma, Meyer et al. 19 found that age (>60 years), elevated serum LDH, lower than normal hemoglobin, high IPI 20, high FLIPI, and a lack of PR or CR after initial therapy were independent risk factors for shorter survival.\n\nIn addition, nodal marginal zone lymphomas (NMZL) are more aggressive than extranodal marginal zone lymphomas, with lower PFS and overall survival 3, 4, 5, 21.\n\nFurthermore, several groups have reported that the risk of developing a second cancer is high in patients with marginal zone lymphoma 19, 22, 23, resulting in shorter survival rates among such patients 19.\n\nThese findings are consistent with the clinical presentation of our patient: he was older than 60, had high LDH levels, a high FLIPI score, a high IPI score, did not respond to initial treatment with RCHOP, and relapsed with an aggressive cancer within 5 months of the autograft.\n\nKaposi's sarcoma after autologous bone marrow transplantation for non‐Hodgkin's lymphoma is rare, but cases have been reported in relation to immunosuppression induced by chemotherapy 14.\n\nAlthough the use of alkylating and autologous stem cells may have influenced the onset of acute leukemia, it is surprising that the nodal karyotype appeared normal at diagnosis. No cytogenetic abnormalities were detected by in situ hybridization at the time of the occurrence of acute leukemia besides the MLL rearrangement 9, 11, which is usually associated with alkylating agents (full or partial deletions of chromosomes 5 and 7, trisomy 8). These observations, and the succession of four diseases in a short time (21 months after the diagnosis of nodal marginal zone lymphoma and 15 months after autograft), makes this a rather unusual case.\n\nAlthough standard cytogenetic analyses were normal at diagnosis, FISH provided a more detailed information and genomic DNA copy number analysis may have been informative 3, 22, 23.\n\nAlthough the findings of this particularly severe case cannot be generalized to other patients, it may not be an isolated case. Prospective studies are required to validate the different prognostic factors found in retrospective studies.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nBerger , F. \n, \nP. \nFelman \n, \nC. \nThieblemont \n, \nT. \nPradier \n, \nL. \nBaseggio \n, \nP. A. \nBryon \n, et al. 2000 \nNon‐MALT marginal zone B‐cell lymphomas: a description of clinical presentation and outcome in 124 patients . Blood \n95 :1950 –1956 .10706860 \n2 \n\nThieblemont , C., \n and \nB. \nCoiffier \n. 2006 \nManagement of marginal zone lymphomas . Curr. Treat. Options Oncol. \n7 :213 –222 . Review.16615877 \n3 \n\nTraverse‐Glehen , A. \n, \nF. \nBertoni \n, \nC. \nThieblemont \n, \nE. \nZucca \n, \nB. \nCoiffier \n, \nF. \nBerger \n, et al. 2012 \nNodal marginal zone B‐cell lymphoma: a diagnostic and therapeutic dilemma . Oncology \n26 :92 –99 , 103–104.22393802 \n4 \n\nArmitage , J. O. \n, and \nD. D. \nWeisenburger \n. 1998 \nNew approach to classifying non‐Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non‐Hodgkin's Lymphoma Classification Project . J. Clin. Oncol. \n16 :2780 –2795 .9704731 \n5 \n\nTraverse‐Glehen , A. \n, \nP. \nFelman \n, \nE. \nCallet‐Bauchu \n, \nS. \nGazzo \n, \nL. \nBaseggio \n, \nP. A. \nBryon \n, et al. 2006 \nA clinicopathological study of nodal marginal zone B‐cell lymphoma. A report on 21 cases . Histopathology \n48 :162 –173 .16405665 \n6 \n\nOh , S. Y. \n, \nB. Y. \nRyoo \n, \nW. S. \nKim \n, \nK. \nKim \n, \nJ. \nLee \n, \nH. J. \nKim \n, et al. 2006 \nNodal marginal zone B‐cell lymphoma: analysis of 36 cases. Clinical presentation and treatment outcomes of nodal marginal zone B‐cell lymphoma . Ann. Hematol. \n85 :781 –786 .16847665 \n7 \n\nCoiffier , B. \n, \nC. \nThieblemont \n, \nP. \nFelman \n, \nG. \nSalles \n, and \nF. \nBerger \n. 1999 \nIndolent non follicular lymphomas: characteristics, treatment, and outcome . Semin. Hematol. \n36 :198 –200 .10319388 \n8 \n\nPirani , M. \n, \nR. \nMarcheselli \n, \nL. \nMarcheselli \n, \nA. \nBari \n, \nM. \nFederico \n, and \nS. \nSacchi \n. 2011 \nRisk for second malignancies in non‐Hodgkin's lymphoma survivors: a meta‐analysis . Ann. Oncol. \n22 :1845 –1858 .21310758 \n9 \n\nMudie , N. Y. \n, \nA. J. \nSwerdlow \n, \nC. D. \nHiggins \n, \nP. \nSmith \n, \nZ. \nQiao \n, \nB. W. \nHancock \n, et al. 2006 \nRisk of second malignancy after non‐Hodgkin's lymphoma: a British Cohort Study . J. Clin. Oncol. \n24 :1568 –1574 .16520465 \n10 \n\nPedersen‐Bjergaard , J. \n, \nJ. \nErsbøll \n, \nH. M. \nSørensen \n, \nN. \nKeiding \n, \nS. O. \nLarsen \n, \nP. \nPhilip \n, et al. 1985 \nRisk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non‐Hodgkin's lymphomas. Comparison with results obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating agents . Ann. Intern. Med. \n103 :195 –200 .4014901 \n11 \n\nTravis , L. B. \n, \nR. E. \nCurtis \n, \nJ. D. \nJr Boice \n, \nB. F. \nHankey \n, and \nJ. F. \nJr Fraumeni \n. 1991 \nA Second cancers following non‐Hodgkin's lymphoma . Cancer \n67 :2002 –2009 .2004317 \n12 \n\nAndré , M. \n, \nN. \nMounier \n, \nX. \nLeleu \n, \nA. \nSonet \n, \nP. \nBrice \n, \nM. \nHenry‐Amar \n, et al. 2004 \nGroupe D'Etude Des Lymphomes De L'Adulte. Second cancers and late toxicities after treatment of aggressive non‐Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients . Blood \n103 :1222 –1228 .14576060 \n13 \n\nSacchi , S. \n, \nL. \nMarcheselli \n, \nA. \nBari \n, \nR. \nMarcheselli \n, \nS. \nPozzi \n, \nP. G. \nGobbi \n, et al. 2008 \nSecond malignancies after treatment of diffuse large B cell non‐Hodgkin's lymphoma: a GISL cohort study . Haematologica \n93 :1335 –1342 .18698083 \n14 \n\nPorta , F. \n, \nM. \nBongiorno \n, \nF. \nLocatelli \n, \nA. \nGibardi \n, \nA. \nLanfranchi \n, \nR. \nRosso \n, et al. 1991 \nKaposi's sarcoma in child after autologous bone marrow transplantation for non‐Hodgkin's lymphoma . Cancer \n68 :1361 –1364 .1873788 \n15 \n\nCamacho , F. I. \n, \nP. \nAlgara \n, \nM. \nMollejo \n, \nJ. F. \nGarcía \n, \nC. \nMontalbán \n, \nN. \nMartínez \n, et al. 2003 \nNodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases . Am. J. Surg. Pathol. \n27 :762 –771 .12766579 \n16 \n\nSolal‐Céligny , P. \n, \nP. \nRoy \n, \nP. \nColombat \n, \nJ. \nWhite \n, \nJ. O. \nArmitage \n, \nR. \nArranz‐Saez \n, et al. 2004 \nFollicular lymphoma international prognostic index . Blood \n104 :1258 –1265 .15126323 \n17 \n\nArcaini , L. \n, \nM. \nPaulli \n, \nS. \nBurcheri \n, \nA. \nRossi \n, \nM. \nSpina \n, \nF. \nPassamonti \n, et al. 2007 \nIntergruppo Italiano Linfomi. Primary nodal marginal zone B‐cell lymphoma: clinical features and prognostic assessment of a rare disease . Br. J. Haematol. \n136 :301 –304 .17233821 \n18 \n\nPetit , B. \n, \nM. P. \nChaury \n, \nC. \nLe Clorennec \n, \nA. \nJaccard \n, \nN. \nGachard \n, \nS. \nMoalic‐Judge \n, et al. 2005 \nIndolent lymphoplasmacytic and marginal zone B‐cell lymphomas: absence of both IRF4 and Ki67 expression identifies a better prognosis subgroup . Haematologica \n90 :200 –206 .15710572 \n19 \n\nMeyer , A. H. \n, \nA. \nStroux \n, \nK. \nLerch \n, \nJ. \nEucker \n, \nJ. \nEitle \n, \nK. \nHohloch \n, et al. 2014 \nTransformation and additional malignancies are leading risk factors for an adverse course of disease in marginal zone lymphoma . Ann. Oncol. \n25 :210 –215 .24356632 \n20 \n\nShipp , M. A. \n, and \nP. D. \nHarrington \n. 1993 \nA predictive model for aggressive non‐Hodgkin's lymphoma. The International Non‐Hodgkin's Lymphoma Prognostic Factors Project . N. Engl. J. Med. \n329 :987 –994 .8141877 \n21 \n\nAngelopoulou , M. K. \n, \nC. \nKalpadakis \n, \nG. A. \nPangalis \n, \nM. C. \nKyrtsonis \n, and \nT. P. \nVassilakopoulos \n. 2014 \nNodal marginal zone lymphoma . Leuk. Lymphoma \n55 :1240 –1250 .24004184 \n22 \n\nRinaldi , A. \n, \nM. \nMian \n, \nE. \nChigrinova \n, \nL. \nArcaini \n, \nG. \nBhagat \n, \nU. \nNovak \n, et al. 2011 \nGenome‐wide DNA profiling of marginal zone lymphomas identifies subtype‐specific lesions with an impact on the clinical outcome . Blood \n117 :1595 –1604 .21115979 \n23 \n\nNovak , U. \n, \nA. \nRinaldi \n, \nI. \nKwee \n, \nS. V. \nNandula \n, \nP. M. \nRancoita \n, \nM. \nCompagno \n, et al. 2009 \nThe NF‐κ B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas . Blood \n113 :4918 –4921 .19258598\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "4(1)",
"journal": "Clinical case reports",
"keywords": "Acute myeloid leukemia; Kaposi's syndrome; diffuse large B‐cell lymphoma; marginal zone lymphoma",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "39-42",
"pmc": null,
"pmid": "26783433",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "17233821;18698083;15710572;14576060;15126323;19258598;24004184;22393802;24356632;10319388;16520465;10706860;16615877;21310758;16847665;8141877;26783433;12766579;2004317;21115979;4014901;16405665;1873788;9704731",
"title": "Quadri-lineage disease involving nodal B-cell marginal zone lymphoma, high-grade B-cell lymphoma, Kaposi's syndrome, and acute myeloid leukemia.",
"title_normalized": "quadri lineage disease involving nodal b cell marginal zone lymphoma high grade b cell lymphoma kaposi s syndrome and acute myeloid leukemia"
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"abstract": "BACKGROUND\nThe treatment of heart failure has changed with the use of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers since the middle of the 1990s. However, the outcome in infantile dilated cardiomyopathy (DCM) when treated with them remains poorly understood.\n\n\nMETHODS\nWe reviewed the medical records of infants with DCM within 24 months old in our hospital between 1979 and 2012, and compared the outcome in the later group (1997-2012) with that in the early group (1979-1996). The survival and cardiac event (CE)-free survival rates were calculated by the Kaplan-Meier method.\n\n\nRESULTS\nThere were 20 patients in the early group and 24 patients in the later group. The median left ventricular fractional shortening at the onset of disease in the early and later groups were 11% (range 4-17%) and 12% (range 4-25%), respectively. In the later group, ACEIs and beta-blockers were administered in 22 and 21 patients, respectively. An usual low-dose induction of carvedilol therapy (0.01-0.02mg/kg/day) sometimes worsened the heart failure in 9 patients (43%) after the successful initial conventional treatment for acute heart failure. Nineteen patients died and 25 survived. The CEs were as follows: heart transplantation 4, mitral valvuloplasty 1, Batista operation with mitral valve replacement 1, and cardiac resynchronization therapy in the late period 1. The 20-year survival rate in the early and later groups were 5% (95% CI 0.7-28) and 100%, respectively (p<0.001). The 2-year CE-free survival rate in the early and later groups were 5% (95% CI 0.7-28) and 83% (95% CI 59-91), respectively (p<0.001).\n\n\nCONCLUSIONS\nThe outcome in patients with infantile DCM has significantly improved with careful acute and chronic treatments using ACEIs and beta-blockers since the 2000s. Adopting a long-term supportive treatment during a period of low ventricular function and the use of beta-blockers corresponding to each patient's condition were key to survival.",
"affiliations": "Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address: etsuda@ncvc.go.jp.;Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.",
"authors": "Tsuda|Etsuko|E|;Yamada|Osamu|O|;Kitano|Masataka|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000077261:Carvedilol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jjcc.2019.02.005",
"fulltext": null,
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"issn_linking": "0914-5087",
"issue": "74(2)",
"journal": "Journal of cardiology",
"keywords": "Beta-blockers; Brain natriuretic peptide; Dilated cardiomyopathy; Heart failure; Heart transplantation",
"medline_ta": "J Cardiol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D058406:Cardiac Resynchronization Therapy; D002311:Cardiomyopathy, Dilated; D000077261:Carvedilol; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8804703",
"other_id": null,
"pages": "189-194",
"pmc": null,
"pmid": "30876708",
"pubdate": "2019-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Improvement of the outcome in patients with infantile dilated cardiomyopathy over three decades - The usefulness of long-term gradually medical supportive care.",
"title_normalized": "improvement of the outcome in patients with infantile dilated cardiomyopathy over three decades the usefulness of long term gradually medical supportive care"
} | [
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-214752",
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"activesubstancename": "CARVEDILOL"
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"abstract": "Posterior reversible encephalopathy syndrome has been associated with hypertension, preeclampsia, cancer chemotherapy, and drugs of abuse, such as amphetamine and methamphetamine. We report a young man who suddenly developed severe headache, disorientation, and aphasia following ingestion of kratom and Adderall. Computed tomography and magnetic resonance imaging of his head revealed foci of vasogenic edema in the posterior occipital lobes, frontal lobes, and brainstem. In addition, he had a small area of hemorrhage in the left posterior occipital lobe. Lumbar puncture revealed an increased number of red blood cells but no other abnormalities. His initial blood pressure was elevated but returned to normal during hospitalization. This case suggests that kratom can cause posterior reversible encephalopathy syndrome and needs to be considered when patients present to emergency centers with headaches, confusion, and visual disturbances.",
"affiliations": "Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.",
"authors": "Castillo|Austin|A|;Payne|J Drew|JD|;Nugent|Kenneth|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2017.11929647",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "30(3)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": null,
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "355-357",
"pmc": null,
"pmid": "28670086",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "27018165;20411370;1632361;27466822;19151296;8559202;27453697;25995615;26511390",
"title": "Posterior reversible leukoencephalopathy syndrome after kratom ingestion.",
"title_normalized": "posterior reversible leukoencephalopathy syndrome after kratom ingestion"
} | [
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"companynumb": "US-ARBOR PHARMACEUTICALS, LLC-US-2019ARB000987",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
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{
"abstract": "This paper describes a patient who presented with mania with psychotic features in the context of concomitant use of S-adenosyl-L-methionine (SAMe) and selective serotonin reuptake inhibitor (SSRI). The aim of this case report is to provide medical practitioners with a greater awareness of the possibility of a psychotic episode and/or mania manifesting with concurrent use of SAMe and SSRI.",
"affiliations": "Psychiatry, Queensland Health, Cairns, Queensland, Australia.;Psychiatry, James Cook University College of Medicine and Dentistry, Cairns, Queensland, Australia.",
"authors": "Abeysundera|Hesitha|H|;Gill|Ramandeep|R|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D012436:S-Adenosylmethionine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224338",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "bipolar I disorder; depressive disorder; drugs: psychiatry; psychiatry (drugs and medicines); psychotic disorders (incl schizophrenia)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D015283:Citalopram; D003863:Depression; D004359:Drug Therapy, Combination; D005260:Female; D006212:Hallucinations; D006801:Humans; D012436:S-Adenosylmethionine; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29950497",
"pubdate": "2018-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7941964;3318447;15537554;787511;7686459;2680435;2673478;13084611;15538131;1925418;16021987;2183633;27727432;24500245;20595412;3052139",
"title": "Possible SAMe-induced mania.",
"title_normalized": "possible same induced mania"
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"abstract": "BACKGROUND While takotsubo cardiomyopathy (TC) is a rare cardiomyopathy, recurrent takotsubo cardiomyopathy (rTC) is even more so, occurring in only 4% of patients with TC. Treatment is based on expert opinion and includes standard heart failure treatment using beta blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI). We present a case of rTC demonstrating how using a selective serotonin reuptake inhibitor (SSRI) with cognitive behavioral therapy (CBT) can successfully prevent recurrence. CASE REPORT A 64-year-old woman presented with ST-elevation myocardial infarction, and coronary angiography demonstrated non-obstructive coronary artery disease. Left heart catheterization showed apical hypokinesis with preserved function of the basal segments, consistent with TC. She reported having experienced multiple emotional stressors. The patient was started on BB and ACEI, and 5 months later repeat imaging showed resolution of her TC. One month after resolution, she was re-admitted for chest pressure, and imaging demonstrated rTC. This time, in addition to continued conventional therapy, she was started on an SSRI and CBT. Nearly 6 months later, her rTC had resolved. CONCLUSIONS Anxiety and depression are more common in patients with TC than in patients with STEMI, but there is little in the literature about the roles of SSRI and CBT in TC treatment. In fact, SSRIs are controversial since they can increase catecholamine concentration, which some experts believe contributes to TC. The positive response of our patient to combination SSRI-CBT therapy suggests that additional research is needed on the use of this approach for prevention and treatment of rTC.",
"affiliations": "Department of Internal Medicine, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX, USA.;Department of Cardiology, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX, USA.;Department of Cardiology, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX, USA.;Department of Cardiology, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX, USA.",
"authors": "Tunzi|Matthew A|MA|;Dinkha|Laith|L|;Sharp|Alec J|AJ|;Gore|Rosco S|RS|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.923067",
"fulltext": null,
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"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D015928:Cognitive Behavioral Therapy; D003131:Combined Modality Therapy; D017023:Coronary Angiography; D004452:Echocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D017367:Serotonin Uptake Inhibitors; D013315:Stress, Psychological; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101489566",
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"pages": "e923067",
"pmc": null,
"pmid": "32507847",
"pubdate": "2020-06-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent Takotsubo Cardiomyopathy: Getting to the Root of the Problem.",
"title_normalized": "recurrent takotsubo cardiomyopathy getting to the root of the problem"
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"abstract": "BACKGROUND\nPontocerebellar hypoplasia (PCH) involves a diverse range of etiologies including a group of single gene disorders. Mutations in the tRNA splicing endonuclease complex (TSEN) 54 gene can be responsible for PCH type 2, 4 and 5. The more common and less severe PCH 2 phenotype is caused by homozygosity for the common missense mutation A307S, while the severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with a nonsense or splice site mutation.\n\n\nMETHODS\nWe report a 4- month-old girl who presented with epileptic spasms that remained intractable to several antiepileptic medications. Magnetic Resonance Imaging (MRI) brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem with prominent extra-axial fluid spaces. Extensive metabolic testing was negative. Commercial testing for PCH via TSEN54 gene revealed missense mutation of Ala307Ser. A novel sequence variant, designated c.17_40 del, was also found and was predictive of an in-frame deletion of eight amino acids. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis.\n\n\nCONCLUSIONS\nThis case report describes a rare case of PCH with overlapping features of the less severe PCH2 and the more severe PCH4/5 phenotype. It also adds another new entity in the list of genetic conditions where West syndrome and pontocerebellar hypoplasia can be seen together, emphasizing the need for further investigations of the genotype-phenotype correlation of mutations in order to advance our understanding of the pathophysiologic mechanism in these rare conditions.",
"affiliations": "Division of Child Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Division of Child Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.",
"authors": "Samanta|Debopam|D|;Willis|Erin|E|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-2327.168629",
"fulltext": "\n==== Front\nAnn Indian Acad NeurolAnn Indian Acad NeurolAIANAnnals of Indian Academy of Neurology0972-23271998-3549Medknow Publications & Media Pvt Ltd India AIAN-19-38510.4103/0972-2327.168629Case ReportIntractable epileptic spasms in a patient with Pontocerebellar hypoplasia: Severe phenotype of type 2 or another subtype? Samanta Debopam Willis Erin Division of Child Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USAFor correspondence: Dr. Debopam Samanta, 1 Children's Way, Little Rock, Arkansas-72202, USA. E-mail: dsamanta@uams.eduJul-Sep 2016 19 3 385 387 30 3 2015 20 4 2015 06 5 2015 Copyright: © Annals of Indian Academy of Neurology2016This 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.Introduction:\nPontocerebellar hypoplasia (PCH) involves a diverse range of etiologies including a group of single gene disorders. Mutations in the tRNA splicing endonuclease complex (TSEN) 54 gene can be responsible for PCH type 2, 4 and 5. The more common and less severe PCH 2 phenotype is caused by homozygosity for the common missense mutation A307S, while the severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with a nonsense or splice site mutation.\n\nReport:\nWe report a 4- month-old girl who presented with epileptic spasms that remained intractable to several antiepileptic medications. Magnetic Resonance Imaging (MRI) brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem with prominent extra-axial fluid spaces. Extensive metabolic testing was negative. Commercial testing for PCH via TSEN54 gene revealed missense mutation of Ala307Ser. A novel sequence variant, designated c.17_40 del, was also found and was predictive of an in-frame deletion of eight amino acids. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis.\n\nConclusion:\nThis case report describes a rare case of PCH with overlapping features of the less severe PCH2 and the more severe PCH4/5 phenotype. It also adds another new entity in the list of genetic conditions where West syndrome and pontocerebellar hypoplasia can be seen together, emphasizing the need for further investigations of the genotype-phenotype correlation of mutations in order to advance our understanding of the pathophysiologic mechanism in these rare conditions.\n\nEpileptic spasminfantile spasmpontocerebellar hypoplasiaTSENWest syndrome\n==== Body\nIntroduction\nA group of single gene disorders, among diverse range of etiologies, can cause pontocerebellar hypoplasia (PCH).[1] There are several subtypes of PCH, and the correct molecular identification of the type is important for counseling and prognostication. One particular gene- TSEN (tRNA splicing endonuclease complex) 54 mutation- can be responsible for PCH type 2, 4, and 5. The more common PCH 2 phenotype is caused by homozygosity for the common missense mutation -A307S and manifests with less severe phenotype. On the contrary, severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with additional nonsense or splice site mutation of TSEN54 gene. We report a confirmed case of TSEN54 mutation associated PCH who presented with epileptic spasms and has overlapping features of multiple subtypes of PCH.\n\nCase Report\nA 4-month-old girl presented with complaints of seizure-like activity. She was born to a 20-year-old primigravida mother via spontaneous vaginal delivery at 34 weeks gestation with a birth weight of 5 pounds 14 ounces. Maternal history was significant for preeclampsia and cholestasis in the last trimester of pregnancy. The patient had an extended course in the neonatal intensive care unit (ICU) for feeding difficulties with eventual gastrostomy tube placement. She had an electroencephalography (EEG) performed at 2 weeks of age due to episodes of desaturation which revealed no electrographic seizures, but background was excessively discontinuous for the gestational age. MRI brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem as well as prominent extra-axial fluid spaces [Figure 1]. At presentation, she was noted to have microcephaly, lack of visual tracking, and bilateral esotropia. Her tone was increased in both upper and lower extremities with brisk tendon reflexes and bilateral ankle clonus. Babinski sign was positive bilaterally. Video EEG captured several episodes of epileptic spasms which remained intractable to levetiracetam, topiramate, and vigabatrin. Ketogenic diet provided short-term improvement, but seizure frequency returned to the previous frequency in spite of consistent urine ketone level of 40–80 mg/dl. Interictally, her background activity was diffusely slow with multifocal spike and wave discharges [Figure 2]. Parents declined adrenocorticotropic hormone (ACTH) and steroid therapy. Extensive metabolic testing such as renal panel with electrolytes, glucose, liver panel, serum electrolytes, urinalysis, serum lactate and pyruvate, plasma ammonia, urine organic acids, serum and urine organic acids was normal. Cerebro-spinal fluid (CSF) study of cell count, chemistry, lactate, pyruvate, amino acids and neurotransmitters was also normal. Chromosomal microarray did not reveal a diagnosis. Commercial testing for PCH via TSEN54 gene sequencing revealed sequence variant designated c.919G > T, which is predicted to result in amino acid substitution p. Ala307Ser. A novel sequence variant, designated c.17_40 del, predictive of in-frame deletion of eight amino acids, was also found. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis. She didn’t attain head control, social smile or ability to visually track. She had frequent admissions in the ICU due to breathing difficulties. The three-generation pedigree didn’t reveal any family members with similar illness, but genetic counselling was provided to the parents as TSEN54-related PCH is inherited in an autosomal recessive manner.\n\nFigure 1 (a) Mid-sagittal section (T1) shows hypoplasia with superimposed atrophy of the vermis and brainstem. (b) Axial section shows increased pericerebral cerebrospinal fluid accumulation between the cortical surface and the skull, mild cerebral atrophy, and delayed neocortical maturation. (c) Coronal image shows cerebellar hemispheres more affected than cerebellar vermis to give a dragon-fly like cerebellar pattern\n\nFigure 2 Background shows diffuse high amplitude slowing with multifocal and generalized spike wave discharges\n\nDiscussion\nPCHs are a group of clinically and genetically heterogeneous disorders characterized by Cerebellar hypoplasia, varying degrees of cerebellar atrophy, and Ventral pontine atrophy.[2] Seven subtypes have been described.[3] Among these, PCH types 2, 4 and 5 are caused by mutations in the TSEN54 gene. All these subtypes have absence of transverse pontine fibers and atrophy of the cerebellar folia, but PCH 4 and 5 have a more severe clinical course, with significant hypertonia and early neonatal death.\n\nPCH2 is characterized by seizure, developmental delay, hyperkinetic movements, visual defects, hypotonia and weakness. Seizures occur in more than 80% of these patients with mean age of onset at 2 year 5 months. Many different seizure types have been described such as febrile seizures, tonic-clonic, atypical absence, myoclonic, tonic, focal, and atonic seizures.[34] Seizures are usually intractable to anti-epileptic drugs, and a significant proportion of these patients can develop status epilepticus. Unremarkable EEG during neonatal age group changes to abnormal with growing age with evident diffuse slowing and multifocal epileptiform discharges. Typical brain MRI findings include a dragonfly-like cerebellar pattern on coronal sections as the cerebellar hemispheres are severely reduced in size though the vermis remains relatively spared.\n\nTSEN gene encodes tRNA splicing endonuclease complex which catalyzes the removal of introns from precursor tRNAs to form mature tRNAs; it is essential for translation of messenger RNA (mRNA) into proteins.[5] This enzyme complex may be also necessary for polyadenylation of mRNA. Mutations in the TSEN54 gene (located on the long arm of chromosome 17) disrupts the processing of RNA molecules and present for over 90% of patients with PCH2. Homozygous missense mutation of A307S replaces the amino acid alanine with the amino acid serine at position 307 in the TSEN54 and is responsible for the vast majority of TSEN54 mutations in PCH2. However, compound heterozygosity for nonsense or a splice site mutation along with the missense mutation in TSEN54 is seen in both PCH4 and PCH5. These subtypes are associated with increased severity of hypoplasia of the pons and cerebellum and immaturity of the cerebral cortex with more perinatal symptoms and earlier lethality than seen in PCH2. PCH type 4 is characterized by severe perinatal symptoms such as excessive clonus, congenital contractures, polyhydramnios and primary hypoventilation necessitating prolonged mechanical ventilation. Survival through the neonatal period and weaning from ventilation are extremely rare event. Pericerebral CSF accumulation, wide midline cava and delayed neocortical maturation are distinctive feature of this subtype. Only arbitrary difference exists between PCH4 and PCH5.[6] In PCH5 the vermis is more affected than the hemispheres whereas in PCH4 the vermis and the hemispheres are both severely affected. Though, PCH4 and PCH5 are phenotypically more severe than PCH2, cases with overlapping features can exist and genotypic data may help with prognostication. Complementary genetic information with consistent clinical and neuroimaging finding may not only help with prognostication related to survival, but also provide guidance regarding treatment such as preventive strategies for sleep apnea, fever induced seizures, and anesthetic induced malignant hyperthermia. Some other single gene disorders such as RELN, CHMP1A and CASK can have similar clinical and neuroimaging finding with PCH TSEN 54 and availability of genetic data can modify the counselling as inheritance pattern may be different, for example, X-linked inheritance seen with mutation of CASK gene.\n\nIn our patient, missense mutation with amino acid substitution p. Ala307Ser was seen along with a novel sequence variant designated c.17_40 del, predictive of in-frame deletion of eight amino acids. This additional mutation made the phenotype much more severe with neonatal onset severe feeding difficulty and early onset intractable epileptic spasms. Epileptic spasm has not been published in the literature with this genotype to the best of our knowledge. MRI imaging also showed some features of PCH 4 or 5 with pericerebral CSF accumulation and presence of midline cava. However, her feature is much less severe compared to a classic case of PCH 4 or PCH 5. She is still alive at 2.5 years with no ventilator- dependence.\n\nSeveral genetic based conditions are associated with early onset epileptic encephalopathy and epileptic spasms. Disruption of translation of protein, due to TSEN mutation, makes developing neuronal tissue sensitive to significant desynchronization — prominent feature of epileptic spasm. Several other genetic conditions can present with pontocerebellar hypoplasia and West syndrome such as congenital disorders of glycosylation, progressive cerebello-cerebral atrophy (missense mutations in SEPSECS), and infantile cerebral and cerebellar atrophy (missense mutations in MED17). This report adds another new entity in that list. This description also highlights the overlapping features of different PCHs. Further investigation of the genotype-phenotype correlation of mutations may contribute to our understanding of pathophysiologic mechanism in these rare conditions.\n\nSource of Support: Nil\n\nConflicts of Interest: None declared.\n==== Refs\n1 Poretti A Boltshauser E Doherty D Cerebellar hypoplasia: Differential diagnosis and diagnostic approach Am J Med Genet Part C Semin Med Genet 2014 166 211 26 24839100 \n2 Namavar Y Barth PG Baas F Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia Orphanet J Rare Dis 2011 6 50 21749694 \n3 Sánchez-Albisua I Frölich S Barth PG Steinlin M Krägeloh-Mann I Natural course of pontocerebellar hypoplasia type 2A Orphanet J Rare Dis 2014 9 70 24886362 \n4 Steinlin M Klein A Haas-Lude K Zafeiriou D Strozzi S Müller T Pontocerebellar hypoplasia type 2: Variability in clinical and imaging findings Eur J Paediatr Neurol 2007 11 146 52 17320436 \n5 Budde BS Namavar Y Barth PG Poll-The BT Nürnberg G Becker C tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia Nat Genet 2008 40 1113 8 18711368 \n6 Rudaks LI Moore L Shand KL Wilkinson C Barnett CP Novel TSEN54 mutation causing pontocerebellar hypoplasia type 4 Pediatr Neurol 2011 45 185 8 21824568\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-2327",
"issue": "19(3)",
"journal": "Annals of Indian Academy of Neurology",
"keywords": "Epileptic spasm; TSEN; West syndrome; infantile spasm; pontocerebellar hypoplasia",
"medline_ta": "Ann Indian Acad Neurol",
"mesh_terms": null,
"nlm_unique_id": "101273955",
"other_id": null,
"pages": "385-7",
"pmc": null,
"pmid": "27570394",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "17320436;24839100;24886362;21749694;21824568;18711368",
"title": "Intractable epileptic spasms in a patient with Pontocerebellar hypoplasia: Severe phenotype of type 2 or another subtype?",
"title_normalized": "intractable epileptic spasms in a patient with pontocerebellar hypoplasia severe phenotype of type 2 or another subtype"
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"abstract": "Atrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD). Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime. Despite improved therapy options, gravidity remains a substantial risk for both maternal and neonatal mortality in PAH-CHD patients. In our patient, gravidity remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and markedly increase of systolic pulmonary arterial pressure (PAP) was observed in echocardiography. Urgent Caesarian delivery was performed without any complications and a healthy baby was born. However, immediately afterwards, the patient desaturated (SpO2 65%, PaO2 37 mmHg) due to a shunt inversion with now right-to-left shunt through the residual ASD. She was admitted to our intensive care unit and specific PH therapy was escalated to a triple combination of tadalafil, ambrisentan, and iloprost. Hereafter, in a slow process of approximately three weeks, the patient's condition improved to baseline. This rare case of a young woman with high-risk pregnancy in PAH-CHD highlights the hemodynamic changes and treatment options during pregnancy in these patients and emphasizes the urgency of a close monitoring at specialized GUCH/PAH centers with experience in managing PAH under these circumstances.",
"affiliations": "1 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.;1 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.;1 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.;1 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.;1 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.;2 Center for Grown-ups with Congenital Heart Disease (GUCH), Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany.",
"authors": "Hohmann|Christopher|C|https://orcid.org/0000-0003-2821-4134;Dumitrescu|Daniel|D|;Gerhardt|Felix|F|;Kramer|Tilmann|T|;Rosenkranz|Stephan|S|;Huntgeburth|Michael|M|",
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"doi": "10.1177/2045894019835649",
"fulltext": "\n==== Front\nPulm CircPulm CircPULsppulPulmonary Circulation2045-89322045-8940SAGE Publications Sage UK: London, England 3076760110.1177/204589401983564910.1177_2045894019835649Case ReportHigh-risk pregnancy in a patient with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) with temporary shunt inversion and deoxygenation https://orcid.org/0000-0003-2821-4134Hohmann Christopher 1Dumitrescu Daniel 1Gerhardt Felix 1Kramer Tilmann 1Rosenkranz Stephan 1Huntgeburth Michael 21 Pulmonary Hypertension Center, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, Germany2 Center for Grown-ups with Congenital Heart Disease (GUCH), Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Cologne, GermanyChristopher Hohmann, Department III of Internal Medicine, Heart Center, University Hospital of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Email: christopher.hohmann@uk-koeln.de19 3 2019 Apr-Jun 2019 9 2 204589401983564923 8 2018 6 2 2019 © The Author(s) 20192019SAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Atrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD). Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime. Despite improved therapy options, gravidity remains a substantial risk for both maternal and neonatal mortality in PAH-CHD patients.\n\nIn our patient, gravidity remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and markedly increase of systolic pulmonary arterial pressure (PAP) was observed in echocardiography. Urgent Caesarian delivery was performed without any complications and a healthy baby was born. However, immediately afterwards, the patient desaturated (SpO2 65%, PaO2 37 mmHg) due to a shunt inversion with now right-to-left shunt through the residual ASD. She was admitted to our intensive care unit and specific PH therapy was escalated to a triple combination of tadalafil, ambrisentan, and iloprost. Hereafter, in a slow process of approximately three weeks, the patient's condition improved to baseline.\n\nThis rare case of a young woman with high-risk pregnancy in PAH-CHD highlights the hemodynamic changes and treatment options during pregnancy in these patients and emphasizes the urgency of a close monitoring at specialized GUCH/PAH centers with experience in managing PAH under these circumstances.\n\natrial septal defectcongenital heart diseasepulmonary arterial hypertensionpregnancyshunt inversioncover-dateApril-Jun 2019\n==== Body\nIntroduction\nAtrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD) and accounts for 8–10% of all congenital heart defects.1 It can easily remain undiagnosed in childhood, as it rarely results in manifest clinical symptoms. Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime, which is currently defined as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, a pulmonary arterial wedge pressure (PAWP) < 15 mmHg as well as a pulmonary vascular resistance (PVR) > 3 Wood units (WU) measured by right heart catheterization (RHC) at rest.2\n\nPregnancy remains associated with a substantially increased risk of mortality in PAH, especially during the peri-/postpartum period, due to hemodynamic stress and bleeding complications. The most common risks for maternal death include acute right ventricular (RV) failure as well as stroke from paradoxical embolism due to intracardiac shunting.3 Additionally, premature birth and growth retardation is frequently reported in successfully delivered newborns.4 Therefore, current guidelines advise against pregnancy in women with PAH.5 Nonetheless, despite this recommendation, an increasing number of female patients with PAH(-CHD) have the desire to found a family and become pregnant, posing a demanding challenge in patient care.\n\nHere, we describe a challenging case of a young woman with high-risk pregnancy due to PAH-CHD with temporary right-to-left shunting on atrial level and deoxygenation in the postpartum period.\n\nCase report\nA 29-year-old woman was first diagnosed with PAH in May 2015. She initially presented with progressive dyspnea, World Health Organization (WHO)/New York Heart Association (NYHA) functional class (FC) III, and peripheral edema. Transthoracic echocardiography revealed a significant dilatation of the right-sided cavities with a paradoxical septal movement and a D-shaped left ventricle. RV function was preserved. Laboratory assessments showed a substantial rise of NTproBNP (1188 ng/L, normal range < 97.5 ng/L). Morphological imaging with transesophageal echocardiography in an outside clinic had not provided any evidence of a shunt. After exclusion of several differential diagnoses, RHC was performed also in an external clinic. Hemodynamics exhibited a remarkable precapillary PH with a mPAP of 69 mmHg and PVR of 11.6 WU, so that specific dual combination treatment with tadalafil and ambrisentan was initiated. Under therapy, her clinical status improved significantly to WHO/NYHA FC II. Chemically, NTproBNP reached improved values of 444 ng/L (normal range < 97.5 ng/L).\n\nFollow-up RHC five months later in our center demonstrated a marked improvement of pulmonary hemodynamics with a mPAP of 51 mmHg and PVR of 5.7 WU. However, mixed venous oxygen saturation (SvO2) was elevated with 82%. Further oxymetry led to the suspicion of a left-to-right shunt at the atrial level (Qp:Qs 1.53). Repeated transesophageal echocardiography confirmed a left-to-right shunt due to a defect in the atrial septum (ASD secundum type, ASD II). After carefully consideration, the patient underwent surgical partial closure of the underlying ASD with a subsequent defect of 5 mm in April 2016, allowing a bidirectional shunt under specific PAH-treatment if required, following the treat-and-repair concept.\n\nSubsequently, after surgery and before pregnancy in March 2017, the patient was in a good clinical condition, with a markedly reduced systolic PAP (sPAP) in echocardiography, normal peripheral saturation (SpO2 94%), and a slight left-to-right shunt through the residual ASD under continued dual-specific PAH treatment with tadalafil and ambrisentan (Fig. 1a). During pregnancy, she was closely monitored in our outpatient grown-up congenital heart disease (GUCH/PAH) clinic and discussed in an interdisciplinary, collaborative team for high-risk pregnancies. As ambrisentan is contraindicated in pregnancy, this medication was immediately stopped after pregnancy was confirmed, leaving the patient on a monotherapy with tadalafil. As the patient did well on combination therapy and hemodynamic changes during pregnancy are expected to worsen PAH, addition of inhaled or parenteral prostanoid therapy was considered but not performed due to resilience of the patient to frequent daily inhalations or a parenteral pump therapy. Instead, the decision was made for close monitoring in our outpatient GUCH/PAH clinic. Pregnancy remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and marked increase of sPAP was observed in echocardiography. In accordance with current recommendations, urgent Caesarian delivery was performed under general anesthesia without any complications and a healthy baby was born. After an uneventful period of 72 h, the patient desaturated (SpO2 65%, PaO2 37 mmHg), presumably due to a shunt inversion with now right-to-left shunt through the residual ASD, which was accompanied by resting dyspnea (Fig. 1b). NTproBNP increased substantially from 489 ng/L to 5421 ng/L. She was admitted to our intensive care unit and targeted PH therapy was escalated to a triple combination of tadalafil (40 mg once daily), ambrisentan (10 mg once daily), and inhaled iloprost (10 µg via Breelib-Inhaler 6–8 times daily). Hereafter, in a slow process of approximately three weeks monitored under intensive care conditions, the patient's condition improved to WHO FC II, normalized peripheral saturation, and again left-to-right shunt, allowing discharge (Fig. 1c). NTproBNP values subsequently decreased to 710 ng/L one month and 485 ng/L two months after delivery, respectively. Currently, she is in good clinical condition with improved sPAP values in TTE (comparable to pre-pregnancy) and is closely monitored in our outpatient GUCH/PAH clinic.\nFig. 1. (a) Transthoracic echocardiography (TTE) before pregnancy. TTE exhibits only moderate dilatation of right heart cavities with improved sPAP and a mild left-to-right shunt through the residual ASD (yellow arrow). (b) Postpartum TTE . TTE demonstrates a substantial increase of sPAP (now supra-systemic) with a right-to-left shunt (shunt inversion, yellow arrow) in comparison to pre-pregnancy. (c) TTE after escalation of specific PAH treatment with tadalafil, ambrisentan, and iloprost. TTE shows a significant decrease of sPAP (sub-systemic) and again left-to-right-shunt through residual ASD.\n\n\n\nDiscussion\nASD is the most common CHD first diagnosed at adulthood, as patients are often free of clinical symptoms until adolescence or adulthood.6 In hemodynamically relevant ASD, a closure of the defect is pursued in the absence of relevant PAH (with a marked elevation in PVR above recommended threshold), preferably by catheter intervention if anatomically suited or otherwise surgically.1 However, guidelines for the evaluation of operability in PAH-CHD do not offer clear cut-off values regarding pulmonary hemodynamics in the preoperative state. Therefore, patients with a PVR in the range of 3–5 WU require individual treatment decisions.7 Referred to current data, closure of an ASD in an adult patient with persistent or recurrent PAH can be perilous due to the repealed outflow mechanism to systemic circulation and lead to RV failure. Therefore, this may have a worse outcome than adults with an ASD who develop a shunt inversion.8 In our case, in an interdisciplinary collaborative team with expertise in the area of grown-ups with CHD, the decision was made for a partial surgical closure of the underlying ASD on the basis of confirmed improvement of pulmonary hemodynamics under dual-targeted PH therapy.\n\nDespite advanced therapies, gravidity still poses a substantial risk for women with PAH(-CHD). Generally, between 1997 and 2007, maternal mortality rates in the range of 17–33% and neonatal mortality rates in the range of 11–13% were reported.9 Distinct physiological changes lead to an increase of blood volume, cardiac output, red cell mass, and left ventricular mass during pregnancy, whereas blood pressure and systemic vascular resistance decrease – with a nadir in the last trimester of pregnancy.10,11 Additionally, hormonal changes with increased levels of estrogen and progesterone lead to further vasodilatation.12 These hemodynamic changes may lead to increased RV stress and to right-to-left shunting. In the absence of a possibility to shunt blood from RA to LA and decrease RV preload, RV failure may finally occur. Here, particularly related to PAH-CHD, recent data report maternal mortality rates of 36% in Eisenmenger's syndrome.13\n\nOn the other hand, with improved management and extended therapeutic options, outcome of pregnancies has improved for women with long-term stabilization and nearly normal pulmonary hemodynamics under targeted PAH treatment. Therefore, current data suggest that gravidities may be successfully managed in this highly selected category of patients. In all these cases, likewise in our report, treatment with phosphodiesterase-5-inhibitors, prostanoids, and/or calcium channel blockers was continued during pregnancy. Due to potential embryotoxicity, endothelin receptor antagonists should generally be withdrawn.14 Women with continued pregnancy and PAH-CHD need to be treated and closely monitored at specialized GUCH/PAH centers with experience in managing PAH under these circumstances. As the risk of right heart failure is particularly high during labor, delivery, the extended postpartum period, and general anesthesia, planned Caesarean sections under regional anesthesia are usually arranged for gestational weeks 32–36 in order to minimize the risk of maternal complications.3 In our patient, the residual shunt through the partial ASD closure allowed shunt reversal leading to deoxygenation but prevented acute right heart failure with high mortality. As in the present case, postpartum monitoring of women with PAH is essential, as the risk of mortality is a particularly serious threat during the first four weeks after release.9–11 Especially in this phase, autotransfusion of blood and increase of PVR can lead to right heart failure. As problems and complications are anticipated, one could argue that an even more aggressive approach using upfront parenteral prostanoids (e.g. epoprostenol) with augmented vasodilator potency due to higher effective blood levels should have been warranted. However, this approach is particularly recommended in Eisenmenger's syndrome patients;5,15,16 and addition of inhaled iloprost led to a substantial improvement of the clinical status in our patient, therefore not necessarily requiring escalation by intravenous application under close surveillance. In addition, the residual shunt may have helped to prevent overt right heart failure. As illustrated in our case, patient compliance and management often complicate best medical treatment, requiring an even closer monitoring and patient education of possible risks. We want to point out that repeated critical evaluation of the therapeutic options is crucial, and any sign of deterioration of clinical status, right heart function, or vital signs should warrant a more aggressive approach.\n\nIn our case report, a close interdisciplinary collaboration between GUCH/PAH specialists, gynecologists, and intensive care specialists (“pregnancy heart team,” as requested by the current ESC Guidelines on cardiovascular disease in pregnancy [10]) as well as close monitoring of the patient were essential for the successful management of this high-risk pregnancy in a patient with PAH-CHD, despite the occurrence of severe complications in the peri-/postpartum phase.\n\nConflict of interest\nDr. Hohmann reports personal fees from Pfizer, non-financial support from Actelion, non-financial support from MSD, non-financial support from Orion Pharma, outside the submitted work; Dr. Dumitrescu reports personal fees from Actelion, personal fees from Bayer, personal fees from MSD, personal fees from Novartis, grants from Actelion, personal fees from GSK, personal fees from Servier, outside the submitted work; Dr. Gerhardt reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants from Novartis, grants and personal fees from United Therapeutics, personal fees from GSK, outside the submitted work; Dr. Kramer has nothing to disclose; Dr. Rosenkranz reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from United Therapeutics, personal fees from GSK, personal fees from Gilead, personal fees from MSD, outside the submitted work; Dr. Huntgeburth has nothing to disclose.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Geva T Martins JD Wald RM \nAtrial septal defects . Lancet \n2014 ; 383 (9932 ): 1921 –1932 .24725467 \n2 Hoeper MM Bogaard HJ Condliffe R et al \nDefinitions and diagnosis of pulmonary hypertension . J Am Coll Cardiol \n2013 ; 62 (25 Suppl ): D42 –50 .24355641 \n3 Hsu CH Gomberg-Maitland M Glassner C et al \nThe management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients . Int J Clin Pract Suppl \n2011 ; 175 : 6 –14 .\n4 Gleichner N Midwall J Hochberger D et al \nEisenmenger's syndrome and pregnancy . Obstet Gynecol Surv \n1979 ; 34 : 721 –741 .503376 \n5 Galie N Humbert M Vachiery JL et al \n2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension . Eur Heart J \n2016 ; 37 : 67 –119 .26320113 \n6 Lindsey JB Hillis LD \nClinical update: atrial septal defect in adults . Lancet \n2007 ; 369 (9569 ): 1244 –1246 .17434386 \n7 Lopes AA Barst RJ Haworth SG et al \nRepair of congenital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the congenital heart disease and pediatric task forces, pulmonary vascular research institute (PVRI) . Pulm Circ \n2014 ; 4 (2 ): 330 –341 .25006452 \n8 Manes A Palazzini M Leci E et al \nCurrent era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups . Eur Heart J \n2014 ; 35 (11 ): 716 –724 .23455361 \n9 Bedard E Dimopoulos K Gatzoulis MA \nHas there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? . Eur Heart J \n2009 ; 30 : 256 –265 .19147605 \n10 Regitz-Zagrosek V Roos-Hesselink JW Bauersachs J et al \n2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy . Eur Heart J \n2018 ; 39 (34 ): 3165 –3241 .30165544 \n11 Olsson KM Jais X \nBirth control and pregnancy management in pulmonary hypertension . Semin Respir Crit Care Med \n2013 ; 34 : 681 –688 .24037634 \n12 Hemnes AR Kiely DG Cockrill BA et al \nStatement on pregnancy in pulmonary hypertension from the Pulmonary Vascular Research Institute . Pulm Circ \n2015 ; 5 : 435 –465 .26401246 \n13 Weiss BM Zemp L Seifert B et al \nOutcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996 . J Am Coll Cardiol \n1998 ; 31 : 1650 –1657 .9626847 \n14 Kiely DG Condliffe R Webster V et al \nImproved survival in pregnancy and pulmonary hypertension using a multiprofessional approach . Brit J Obstet Gynaec \n2010 ; 117 : 565 –574 .\n15 Grünig E Benjamin N Krüger U et al \nGeneral measures and supportive therapy for pulmonary arterial hypertension: Updated Recommendations from the Cologne Consensus Conference 2018 . Int J Cardiol \n2018 ; 272S : 30 –36 .30190156 \n16 Kaemmerer H Apitz C Brockmeier K et al \nPulmonary hypertension in grown-ups with congenital heart disease: Updated Recommendations from the Cologne Consensus Conference 2018 . Int J Cardiol \n2018 ; 272S : 79 –88 .30195841\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2045-8932",
"issue": "9(2)",
"journal": "Pulmonary circulation",
"keywords": "atrial septal defect; congenital heart disease; pregnancy; pulmonary arterial hypertension; shunt inversion",
"medline_ta": "Pulm Circ",
"mesh_terms": null,
"nlm_unique_id": "101557243",
"other_id": null,
"pages": "2045894019835649",
"pmc": null,
"pmid": "30767601",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "17434386;19147605;20374595;21736676;23455361;24037634;24355641;24725467;25006452;26320113;26401246;30165544;30190156;30195841;503376;9626847",
"title": "High-risk pregnancy in a patient with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) with temporary shunt inversion and deoxygenation.",
"title_normalized": "high risk pregnancy in a patient with pulmonary arterial hypertension due to congenital heart disease pah chd with temporary shunt inversion and deoxygenation"
} | [
{
"companynumb": "DE-GILEAD-2019-0397714",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMBRISENTAN"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nAdjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC.\n\n\nMETHODS\nIn this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis.\n\n\nRESULTS\nBetween March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration.\n\n\nCONCLUSIONS\nDFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.",
"affiliations": "National Cancer Center Hospital, Tokyo, Japan.;Aichi Cancer Center Hospital, Nagoya, Japan.;National Cancer Center Hospital, Tokyo, Japan.;Aichi Cancer Center Hospital, Nagoya, Japan.;Saitama Medical University International Medical Center, Hidaka, Japan.;National Cancer Center Hospital, Tokyo, Japan.;Osaka International Cancer Institute, Osaka, Japan.;Aichi Cancer Center Hospital, Nagoya, Japan.;Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Kanagawa Cancer Center, Kanagawa, Japan.;Yokohama City University Medical Center, Yokohama, Japan.;Yamagata Prefectural Central Hospital, Yamagata, Japan.;Tokyo Medical and Dental University, Tokyo, Japan.;Niigata Cancer Center Hospital, Niigata, Japan.;Ishikawa Prefectural Central Hospital, Kanazawa, Japan.;National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Oita University Faculty of Medicine, Yufu, Japan.;Kochi Health Sciences Center, Kochi, Japan.;National Cancer Center Hospital, Tokyo, Japan.;National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Kanemitsu|Yukihide|Y|0000-0002-3366-3826;Shimizu|Yasuhiro|Y|;Mizusawa|Junki|J|;Inaba|Yoshitaka|Y|0000-0002-0850-6327;Hamaguchi|Tetsuya|T|;Shida|Dai|D|0000-0003-3294-1924;Ohue|Masayuki|M|;Komori|Koji|K|0000-0002-6834-995X;Shiomi|Akio|A|0000-0001-5657-8686;Shiozawa|Manabu|M|;Watanabe|Jun|J|0000-0002-7187-3664;Suto|Takeshi|T|;Kinugasa|Yusuke|Y|0000-0002-7885-2276;Takii|Yasumasa|Y|0000-0001-9712-8542;Bando|Hiroyuki|H|;Kobatake|Takaya|T|0000-0003-1694-7971;Inomata|Masafumi|M|0000-0002-8475-3688;Shimada|Yasuhiro|Y|;Katayama|Hiroshi|H|0000-0002-9735-6630;Fukuda|Haruhiko|H|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.21.01032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "39(34)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3789-3799",
"pmc": null,
"pmid": "34520230",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial.",
"title_normalized": "hepatectomy followed by mfolfox6 versus hepatectomy alone for liver only metastatic colorectal cancer jcog0603 a phase ii or iii randomized controlled trial"
} | [
{
"companynumb": "JP-PFIZER INC-202101380221",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of Stevens- Johnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again.",
"affiliations": "Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey. bdeveci@windowslive.com.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.;Ege University Faculty of Medicine, Department of Pediatrics, Division of Hematology, İzmir, Turkey.",
"authors": "Akıncı|Burcu|B|;Siviş|Zuhal Ö|ZÖ|;Şahin|Akkız|A|;Karapınar|Deniz Y|DY|;Balkan|Can|C|;Kavaklı|Kaan|K|;Aydınok|Yeşim|Y|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D016756:Immunoglobulins, Intravenous; D008775:Methylprednisolone; D008727:Methotrexate",
"country": "Argentina",
"delete": false,
"doi": "10.5546/aap.2018.eng.e459",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0325-0075",
"issue": "116(3)",
"journal": "Archivos argentinos de pediatria",
"keywords": "Stevens-Johnson syndrome; child; leukemia; methotrexate; toxic epidermal necrolysis",
"medline_ta": "Arch Argent Pediatr",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002648:Child; D006471:Gastrointestinal Hemorrhage; D006333:Heart Failure; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008727:Methotrexate; D008775:Methylprednisolone; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0372460",
"other_id": null,
"pages": "e459-e462",
"pmc": null,
"pmid": "29756724",
"pubdate": "2018-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia: a case report.",
"title_normalized": "stevens johnson syndrome associated with methotrexate treatment for acute lymphoblastic leukemia a case report"
} | [
{
"companynumb": "TR-ACCORD-067687",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Aspirin is the first recommended antiplatelet agent to prevention secondary stroke, but its safety and efficacy in stroke patients with glucose-6-phosphate dehydrogenase deficiency remain unclear. We sought to evaluate its safety and efficacy in ischemic stroke patients with and without glucose-6-phosphate dehydrogenase deficiency.\n\n\n\nPatients with ischemic stroke receiving aspirin (100 mg/day) for three months were recruited for a multicenter, prospective, cohort study. Blood glucose-6-phosphate dehydrogenase activity was examined after stroke. Safety outcomes including acute hemolysis, moderate-to-severe bleeding, and death (vascular, all-cause), and efficacy outcome indicated as stroke recurrence were evaluated at three months. Risk factors associated with moderate-to-severe bleeding and all-cause death were determined using multivariate or Cox regression analysis.\n\n\n\nAmong the included 1121 patients, 81 of 130 glucose-6-phosphate dehydrogenase deficient and 576 of 991 glucose-6-phosphate dehydrogenase normal patients received aspirin for three months. Acute hemolysis was observed in one of the glucose-6-phosphate dehydrogenase deficient and in none of the glucose-6-phosphate dehydrogenase normal patients (p = 0.876). The rates of moderate-to-severe bleeding were 2.5% and 0.3% (p = 0.045), and the percentages of all-cause death were 6.2% and 1.4% (p = 0.008) in the glucose-6-phosphate dehydrogenase deficient and glucose-6-phosphate dehydrogenase normal patients. Stroke recurrence rate was similar in the two groups (2.5% vs. 1.7%; p = 0.608). Glucose-6-phosphate dehydrogenase deficiency was significantly associated with increased risk of moderate-to-severe bleeding (adjust p = 0.048) and all-cause death during aspirin use (adjust p = 0.008).\n\n\n\nLong-term low-dose aspirin therapy might relate to worse safety outcomes in patients with glucose-6-phosphate dehydrogenase deficiency and large clinical trials are needed to further confirm these findings.",
"affiliations": "Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.;Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.;Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.;Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, China.;Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, China.;Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.;Department of Neurology, Meizhou People's Hospital, Meizhou, China.;Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.;Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, China.;Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.;Department of Neurology, Meizhou People's Hospital, Meizhou, China.;Section II, Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.;Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.",
"authors": "Chen|Yicong|Y|;Li|Jianle|J|;Ou|Zilin|Z|;Zhang|Yusheng|Y|;Liang|Zhijian|Z|;Deng|Weisheng|W|;Huang|Weixian|W|;Wu|Zhengdong|Z|;Jiang|Haihong|H|;Liu|Qinghua|Q|;Ouyang|Fubing|F|;Xing|Shihui|S|;Zeng|Jinsheng|J|0000-0003-4280-0439",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D005954:Glucosephosphate Dehydrogenase; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1177/1747493020950903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4930",
"issue": "16(4)",
"journal": "International journal of stroke : official journal of the International Stroke Society",
"keywords": "Aspirin; G6PD deficiency; efficacy; ischemic stroke; safety",
"medline_ta": "Int J Stroke",
"mesh_terms": "D001241:Aspirin; D002545:Brain Ischemia; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005954:Glucosephosphate Dehydrogenase; D005955:Glucosephosphate Dehydrogenase Deficiency; D006801:Humans; D002546:Ischemic Attack, Transient; D000083242:Ischemic Stroke; D010975:Platelet Aggregation Inhibitors; D011446:Prospective Studies; D020521:Stroke",
"nlm_unique_id": "101274068",
"other_id": null,
"pages": "411-419",
"pmc": null,
"pmid": "32878589",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and efficacy of low-dose aspirin in ischemic stroke patients with different G6PD conditions.",
"title_normalized": "safety and efficacy of low dose aspirin in ischemic stroke patients with different g6pd conditions"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-305829",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nThis phase III trial aimed to confirm the superiority of weekly docetaxel and cisplatin over docetaxel monotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC).\n\n\nMETHODS\nChemotherapy-naïve patients with stage III, stage IV, or recurrent NSCLC age ≥ 70 years with a performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were randomly assigned to receive docetaxel 60 mg/m(2) on day 1, every 3 weeks, or docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on days 1, 8, and 15, every 4 weeks. The primary end point was overall survival (OS).\n\n\nRESULTS\nIn the first interim analysis, OS of the doublet arm was inferior to that of the monotherapy arm (hazard ratio [HR], 1.56; 95% CI, 0.98 to 2.49), and the predictive probability that the doublet arm would be statistically superior to the monotherapy arm on final analysis was 0.996%, which led to early study termination. In total, 276 patients with a median age of 76 years (range, 70 to 87 years) were enrolled. At the updated analysis, the median survival time was 14.8 months for the monotherapy arm and 13.3 months for the doublet arm (HR, 1.18; 95% CI, 0.83 to 1.69). The rates of grade ≥ 3 neutropenia and febrile neutropenia were higher in the monotherapy arm, and those of anorexia and hyponatremia were higher in the doublet arm.\n\n\nCONCLUSIONS\nThis study failed to demonstrate any survival advantage of weekly docetaxel plus cisplatin over docetaxel monotherapy as first-line chemotherapy for advanced NSCLC in elderly patients.",
"affiliations": "Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan. t-abe@niigata-cc.jp.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.;Tetsuya Abe and Akira Yokoyama, Niigata Cancer Center Hospital, Niigata; Koji Takeda, Osaka City General Hospital; Shinzoh Kudoh, Osaka City University; Shinichiro Nakamura, West Japan Oncology Group Data Center; Kazuhiko Nakagawa, Kinki University, Osaka; Yuichiro Ohe, National Cancer Center Hospital East, Chiba; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroaki Okamoto, Yokohama Municipal Citizens Hospital, Kanagawa; Nobuyuki Yamamoto, Wakayama Medical University School of Medicine, Wakayama; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Koichi Minato, Gunma Cancer Center, Gunma; Toshiyuki Sawa, Gifu Municipal Hospital, Gifu; Yasuo Iwamoto, Hiroshima City Hospital, Hiroshima; Hideo Saka, Nagoya Medical Center; Masahiko Ando, Nagoya University Hospital, Aichi; Junki Mizusawa and Taro Shibata, Japan Clincal Oncology Group Data Center, National Cancer Center; Nagahiro Saijo, Japanese Society of Medical Oncology; and Tomohide Tamura, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Abe|Tetsuya|T|;Takeda|Koji|K|;Ohe|Yuichiro|Y|;Kudoh|Shinzoh|S|;Ichinose|Yukito|Y|;Okamoto|Hiroaki|H|;Yamamoto|Nobuyuki|N|;Yoshioka|Hiroshige|H|;Minato|Koichi|K|;Sawa|Toshiyuki|T|;Iwamoto|Yasuo|Y|;Saka|Hideo|H|;Mizusawa|Junki|J|;Shibata|Taro|T|;Nakamura|Shinichiro|S|;Ando|Masahiko|M|;Yokoyama|Akira|A|;Nakagawa|Kazuhiko|K|;Saijo|Nagahiro|N|;Tamura|Tomohide|T|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2014.55.8627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "33(6)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D011788:Quality of Life; D043823:Taxoids",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "575-81",
"pmc": null,
"pmid": "25584004",
"pubdate": "2015-02-20",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L.",
"title_normalized": "randomized phase iii trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non small cell lung cancer the intergroup trial jcog0803 wjog4307l"
} | [
{
"companynumb": "JP-SANOFI-AVENTIS-2011SA049733",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCurrently, there are few studies that describe pregnancy in dermatomyositis/polymyositis patients, and they are largely limited to case reports or studies with few samples.\n\n\nOBJECTIVE\nTherefore, we describe the pregnancy in a large sample of patients with dermatomyositis/polymyositis and to analyze the outcomes in those who became pregnant during or after disease onset.\n\n\nMETHODS\nThe present single-center study analyzed 98 female patients with idiopathic inflammatory myopathies (60 dermatomyositis and 38 polymyositis patients). They were interviewed to obtain obstetric antecedent and demographic data from June 2011 to June 2012.\n\n\nRESULTS\nSeventy-eight (79.6%) of the 98 patients had obstetric histories. Six polymyositis and 9 dermatomyositis patients became pregnant after disease onset. The pregnancy outcomes in these cases were good, except in the following cases: 1 disease reactivation, 1 intrauterine growth retardation, 1 diabetes mellitus, 1 hypertension, 1 hypothyroidism, and 2 fetal losses (same patient). Moreover, 2 patients developed dermatomyositis during pregnancy and 4 (2 polymyositis and 2 dermatomyositis) during the postpartum period with good control after glucocorticoid and immunosuppressant therapy.\n\n\nCONCLUSIONS\nThe adverse obstetric events were related to clinical intercurrences and the pregnancy does not seem to carry a worse prognosis specifically in disease (for example: disease relapsing). Moreover, dermatomyositis or polymyositis onset during pregnancy or the postpartum period had good outcome after drug therapy.",
"affiliations": "Departamento de Reumatologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.;Departamento de Reumatologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.;Departamento de Reumatologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.;Departamento de Reumatologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil. Electronic address: samuel.shinjo@gmail.com.",
"authors": "Missumi|Larissa Sayuri|LS|;Souza|Fernando Henrique Carlos de|FH|;Andrade|Joelma Queiroz|JQ|;Shinjo|Samuel Katsuyuki|SK|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0482-5004",
"issue": "55(2)",
"journal": "Revista brasileira de reumatologia",
"keywords": "Dermatomiosite; Dermatomyositis; Gestação; Inflammatory myopathies; Intercorrências obstétricas; Miopatias inflamatórias; Obstetric intercurrences; Polimiosite; Polymyositis; Pregnancy",
"medline_ta": "Rev Bras Reumatol",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D017285:Polymyositis; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0404256",
"other_id": null,
"pages": "95-102",
"pmc": null,
"pmid": "25577487",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pregnancy outcomes in dermatomyositis and polymyositis patients.",
"title_normalized": "pregnancy outcomes in dermatomyositis and polymyositis patients"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-136078",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
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"abstract": "Cerebral venous sinus thrombosis is a challenging diagnosis due in part to its variable clinical presentation and rarity. The annual incidence ranges from 0.22 to 1.57 per 100,000. The etiology of such disease is related to hypercoagulability states. Although illicit androgen use is a well-known cause of prothrombotic states, its risk of causing cerebral venous sinus thrombosis has been infrequently reported. We present the case of a 33-year-old male with no known past medical history who presented to the emergency department (ED) with persistent seizure activity, neurological deficits, and history of worsening headaches who was found to have an extensive superior sagittal sinus thrombosis on imaging. Radiologic findings demonstrated pathognomonic findings of cord sign and delta sign, the previous being highly specific but of low incidence. An inconclusive hypercoagulability workup prompted further questioning which revealed illicit androgenic anabolic steroid use. Prompt treatment with anticoagulation and anti-seizure medication was pursued with full resolution of his neurologic symptomatology.",
"affiliations": "Medical Education, Nova Southeastern University, Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.;Medical Education, Nova Southeastern University, Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.;Medical Education, Nova Southeastern University, Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.;Family Medicine, Advent Health Orlando, Orlando, USA.;Family Medicine, Advent Health Orlando, Orlando, USA.",
"authors": "Hashmi|Ariba|A|;Kim|Paul|P|;Ahmad|Syed W|SW|;Faucheux|Jason|J|;Gandikal|Naz|N|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5491Endocrinology/Diabetes/MetabolismNeurologyRadiologySuperior Sagittal Venous Sinus Thrombosis in a Patient with Illicit Testosterone Use Muacevic Alexander Adler John R Hashmi Ariba 1Kim Paul 1Ahmad Syed W 1Faucheux Jason 2Gandikal Naz 2\n1 \nMedical Education, Nova Southeastern University, Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA \n2 \nFamily Medicine, Advent Health Orlando, Orlando, USA \nSyed W. Ahmad sa1615@mynsu.nova.edu26 8 2019 8 2019 11 8 e549115 8 2019 26 8 2019 Copyright © 2019, Hashmi et al.2019Hashmi 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/22586-superior-sagittal-venous-sinus-thrombosis-in-a-patient-with-illicit-testosterone-useCerebral venous sinus thrombosis is a challenging diagnosis due in part to its variable clinical presentation and rarity. The annual incidence ranges from 0.22 to 1.57 per 100,000. The etiology of such disease is related to hypercoagulability states. Although illicit androgen use is a well-known cause of prothrombotic states, its risk of causing cerebral venous sinus thrombosis has been infrequently reported. We present the case of a 33-year-old male with no known past medical history who presented to the emergency department (ED) with persistent seizure activity, neurological deficits, and history of worsening headaches who was found to have an extensive superior sagittal sinus thrombosis on imaging. Radiologic findings demonstrated pathognomonic findings of cord sign and delta sign, the previous being highly specific but of low incidence. An inconclusive hypercoagulability workup prompted further questioning which revealed illicit androgenic anabolic steroid use. Prompt treatment with anticoagulation and anti-seizure medication was pursued with full resolution of his neurologic symptomatology.\n\nsuperior sagittal sinuscerebral venous sinus thrombosiscord signdelta signtestosterone replacement therapyandrogenic anabolic steroidsanabolic steroidscoagulationgeneral tonic-clonic seizureshypercoagulabilityThe 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\nCerebral venous sinus thrombosis (CVST) is an uncommon cause of cerebrovascular pathology relative to arterial strokes. The annual incidence ranges from 0.22 to 1.57 per 100,000 [1]. Patients may present with varying degrees of nonspecific neurologic symptomatology making the diagnosis difficult and requiring a high index of suspicion. Symptoms can manifest as a result of ischemia, infarction, or hemorrhage with focal cerebral injury. In addition, venous thrombosis reduces drainage of the cerebral microvasculature, leading to an increase in upstream intracranial pressure and further decline of normal cerebral hemodynamics [2]. Certain hypercoagulable states and risk factors, such as pregnancy, have been associated with CVST but androgenic anabolic steroid (AAS) use is relatively rare.\n\nCase presentation\nWe report the case of a 33-year-old Hispanic male who was brought to the emergency department (ED) by emergency medical service (EMS) after his wife witnessed an episode of sustained tonic-clonic seizure activity while at home. Several weeks prior, the patient was seen in the ED by a mid-level provider for non-specific headaches for which a non-contrast computed tomography (CT) scan of the head was ordered with no dictated significant findings. With a negative workup, the patient was discharged home with muscle relaxers for a presumed tension headache. On readmission to the ED, a stat repeat non-contrast CT head was ordered due to new-onset sustained seizure activity. Sagittal imaging revealed a positive cord sign with hyperdensity of the superior sagittal sinus (Figure 1). \n\nFigure 1 Sagittal non-contrast computed tomography (CT) of the thrombus demonstrating a cord sign\nThis suggested an extensive superior sagittal sinus thrombosis extending the entire length of the sinus. Axial CT venography of the brain revealed an empty delta sign consisting of a triangular area of contrast enhancement with a center of low-attenuation revealing the thrombus (Figure 2).\n\nFigure 2 Axial computed tomography venography (CTV) of the thrombus demonstrating delta sign\nThe large burden of the thrombosis extending from the frontal end of the superior sagittal sinus and ending at the confluence of the sinuses can be visualized in the serial sagittal images (Figure 3).\n\nFigure 3 Serial sagittal non-contrast computed tomography (CT) demonstrating a left-to-right progression of sinuses with thrombus\nDue to persistent episodes of seizure activity, the patient was intubated and given a loading dose of Dilantin® (phenytoin) and Keppra® (levetiracetam). Weight-based Lovenox® (enoxaparin) was started for anticoagulation, and the patient was transferred to the intensive care unit (ICU). Further investigation to reveal the etiology of the thrombosis was pursued. Hypercoagulability studies showed non-specific findings but failed to clarify a true etiology (Table 1). Further questioning with the patient's spouse and family revealed that the patient had recently started receiving 300 mg/ml of AAS injections from his personal fitness trainer for approximately the last 45 days. Within the month, the patient started complaining of dizziness, weakness, and near syncopal episodes. Worsening headaches prompted his initial visit to the ED. Per the patient's spouse, she noted his gait to be unsteady and that the patient was utilizing his right-sided extremities while neglecting his left side. Of note, the patient had been diagnosed with low testosterone levels by his primary care provider prior to receiving AAS injections. He had been receiving prescribed testosterone replacement therapy until his insurance refused coverage, prompting the patient to seek AAS from his personal trainer. Androgenic studies were pursued, and the results highlighted abnormally high testosterone levels, offering a source of etiology for the patient’s venous sinus thrombosis formation (Table 2). As the patient stabilized and was extubated, the neurological examination found him to have left-sided hemineglect. The patient was otherwise neurologically intact with no other gross deficits. He did incidentally have concerns for aspiration pneumonia but was appropriately treated with antibiotics. With continued observation and treatment, a complete resolution of his neurologic deficits was achieved, and intravenous (IV) anticoagulation was bridged to oral warfarin. The patient was discharged home with oral anticoagulation, prophylactic anti-seizure medications, and the remaining doses of antibiotics for aspiration pneumonia. He was strongly advised to discontinue all testosterone supplementation until further outpatient follow-up.\n\nTable 1 Hypercoagulability Testing Results\nSignificant Coagulability Testing\tLevels\t\nD-Dimer\t0.9 (0.0 - 0.5)\t\nProtein S Activity\t> 150\t\nProtein C Activity\t> 150 \t\nAntithrombin III\t150 \t\nFactor 8\t> 500\t\nFactor 2 Gene Mutation\tNegative\t\nFactor V Leiden Mutation\tNegative\t\nTable 2 Androgen Testing Results\nAndrogen Testing\tLevels\t\nTestosterone Level\t968 ng/dl (300 - 950 ng/dl)\t\nTestosterone-free Adult Male\t334 pg/mL (47 - 244 pg/mL)\t\n% Free Testosterone\t3.5% (1.6 - 2.9%)\t\nBioavailable Testosterone\t891 ng/dL (72.0 - 235.0 ng/dL)\t\nSex Hormone Binding Globulin\t5 nmol/L (11 - 80 nmol/L)\t\nDiscussion\nDural venous sinuses are found in the superficial meningeal layer where they receive blood from the cerebral veins and cerebrospinal fluid (CSF) from the arachnoid granulations. The sinuses collectively empty into the internal jugular vein. Therefore, thrombosis of the dural sinus may attribute symptoms to a lack of venous outflow, as well as increased intracranial pressure. The thrombosis can eventually lead to hemorrhage due to the lack of drainage and cerebral parenchymal injury. CVST accounts for less than 1% of all strokes, with a median age of 37 years, affecting women more commonly than men at a 3:1 ratio [3]. The case presented highlights a male individual less than the expected age. The patient’s symptoms of headache, dizziness, seizure activity, and hemineglect have previously been noted to occur in patients with isolated sinus thrombosis compared to other dural sinus regions [4]. In a previous cohort study, 40% of individuals studied with CVST were found to have seizure activity when presenting (a far greater incidence when compared to arterial cerebrovascular strokes). Focal deficits in the absence of focal injury have also been reported in as many as 37% of cases, as seen in this case [5]. The extent of the patient’s thrombosis was also of significance as it spanned the length of the entire superior sagittal sinus attributing to the positive radiologic cord sign, a relatively rare image finding compared to the delta sign which was also visualized [6]. The patient’s symptoms and radiologic findings support the importance of considering seizures, focal neurological deficit, and the radiologic cord sign when making an accurate diagnosis of cerebral vein thrombosis.\n\nThe etiology of sinus thrombosis is most often associated with prothrombotic states. AAS use is associated with thrombus formation through several proposed mechanisms. The effect of AAS use on lipid metabolism has been well-documented. A literature review which quantified the effects of AAS use on serum lipid levels was published in the Archives of Internal Medicine in 1991 and showed that AAS use reduced high-density lipoprotein (HDL) levels by 52% and increased low-density lipoprotein (LDL) levels by 36% [7]. AAS use has also been shown to induce myocardial hypertrophy and directly inhibit myocardial contractility and relaxation, leading to pro-arrhythmic states [8]. Furthermore, AAS use has been shown to directly affect hemostasis. A study by Ferenchick et al. examined the relationship between AAS use and coagulation. The study compared 49 weightlifters separated into AAS users and non-users. Plasma assays showed a 10% increase in thrombin/antithrombin complexes, a 20% increase in prothrombin fragment 1+2, and a 9% increase in D-dimer levels in the AAS users. The activities of antithrombin III and protein S were also higher in AAS users by 18% and 19%, respectively. The study concluded that AAS use increased activation of both the coagulation and fibrinolytic pathways, leading to an abnormal hemostatic response which could potentiate thrombus formation [9]. These findings offer some perspective into the non-specific coagulation study results seen in the case presented (Table 1). In addition, AAS use has demonstrated inhibition of vasodilation from endothelial-dependent and independent mechanisms, causing further homeostatic insult in animal models [10].\n\nComparatively, the metabolic effects of testosterone replacement therapy do not induce the same prothrombotic changes as does AAS use. A study by Stefen et al. examined the effects of long-term testosterone replacement in hypogonadal and elderly men on lipid and lipoprotein levels. Twenty-two subjects were enrolled in the study, split between 11 male subjects with hypopituitarism and 11 otherwise healthy elderly males. Results specific for the hypogonadal males showed a decrease in total cholesterol from 255 ± 12.1 mg/dl to 214 ± 10.6 mg/dl after six months and a further decrease to 206 ± 9 mg/dl after one year of treatment with a P-value < 0.0001. Similarly, the LDL concentrations decreased from 178 ± 10.3 mg/dl to 149 ± 10.2 mg/dl after six months and 140 ± 7.3 mg/dl after one year of treatment with a P-value < 0.001 [11].\n\nFurthermore, a literature review which quantified the cardiovascular effects related to hypogonadism and testosterone therapy was published in the American Journal of Cardiology in 2005. Observational studies, interventional studies, and short-term data were included in the review. Short-term testosterone therapy was determined to be beneficial and lower cardiovascular risk factors. Among the effects, the most prominent were improved insulin sensitivity, central obesity, decreased total cholesterol, and LDL. Some studies showed testosterone therapy had an HDL-lowering effect but was found to be insignificant in other studies. The long-term cardiovascular effects were determined to be neutral to beneficial. In addition, testosterone therapy was not contraindicated in men with cerebrovascular disease and hypogonadism [12].\n\nAnother contributing factor to consider is the recurrent transient decreases in cerebral blood flow. In a study by Neerav et al., deep inspiratory breath-holding, as in the Valsalva maneuver, was shown to reduce venous blood flow in the superior sagittal sinus by up to 30.8%. Specific to our patient, frequent resistance training and use of the Valsalva maneuver might have had an impact in thrombogenesis [13].\n\nThe patient presented in this case could have developed a CVST through a combination of abnormal hemostasis, increased platelet aggregation, elevated factor VIII levels, and transient decreases in cerebral blood flow.\n\nConclusions\nCVST is a clinically challenging diagnosis due to its variable clinical presentation. This case highlights the importance of several key factors that culminated in the patient’s acute presentation. The primary care physician of this patient prescribed testosterone replacement based off of current recommendation guidelines, and it is assumed that the patient was informed of the potential side effects. However, this case emphasizes the importance of active patient education on pursued treatment modality, as well as the ramifications of departure from medical advice. Unknowingly, the patient presumed both prescription hormone replacement and AAS were analogous, which further exemplifies the need for patient education regarding hormone replacement therapy. In addition, a more thorough history would have revealed the patient’s use of AAS during the first ED admission. This information, as part of the social and medical history, along with the nonspecific neurologic symptoms, would have raised the index of suspicion of CVST for both the provider and radiologist, emphasizing the importance of a thorough history. Although the incidence of cerebrovascular accidents attributable to CVST is low, it is nevertheless an important component of the evaluation of a patient with nonspecific neurologic symptomatology.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 The incidence of cerebral venous thrombosis: a cross-sectional study Stroke Coutinho JM Zuurbier SM Aramideh M Stam J 3375 3377 43 2012 22996960 \n2 Letter by Kovacs regarding article, \"Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association\" Stroke Kovacs MJ 0 42 2011 \n3 Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) Stroke Ferro JM Canhão P Stam J Bousser MG Barinagarrementeria F; ISCVT Investigators 664 670 35 2004 14976332 \n4 Migraine-like visual phenomena associated with cerebral venous thrombosis Headache Newman DS Levine SR Curtis VL Welch KM 82 85 29 1989 2708040 \n5 Early seizures in cerebral vein and dural sinus thrombosis: risk factors and role of antiepileptics Stroke Ferro JM Canhão P Bousser MG Stam J Barinagarrementeria F; ISCVT Investigators 1152 1158 39 2008 18309177 \n6 Small juxtacortical hemorrhages in cerebral venous thrombosis Ann Neurol Coutinho JM van den Berg R Zuurbier SM VanBavel E Troost D Majoie CB Stam J 908 916 75 2014 24816819 \n7 Atherogenic effects of anabolic steroids on serum lipid levels. A literature review Arch Intern Med Glazer G 1925 1933 151 1991 1929679 \n8 Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: a Doppler myocardial and strain imaging analysis Br J Sports Med D’Andrea A Caso P Salerno G 149 155 41 2007 17178777 \n9 Anabolic-androgenic steroid abuse in weight lifters: evidence for activation of the hemostatic system Am J Hematol Ferenchick GS Hirokawa S Mammen EF Schwartz KA 282 288 49 1995 7639272 \n10 Enhanced vasoconstriction and reduced vasorelaxation induced by testosterone and nandrolone in hypercholesterolemic rabbits Pharmacol Res Ammar EM Said SA Hassan MS 253 259 50 2004 15225667 \n11 Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men Atherosclerosis Zgliczynski S Ossowski M Slowinska-Srzednicka J 35 43 121 1996 8678922 \n12 Cardiovascular issues in hypogonadism and testosterone therapy Am J Cardiol Shabsigh R Katz M Yan G Makhsida N 67 72 96 2005 15979436 \n13 Physiologic variations in dural venous sinus flow on phase-contrast MR imaging AJR Am J Roentgenol Mehta NR Jones L Kraut MA Melhem ER 221 225 175 2000 10882276\n\n",
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"keywords": "anabolic steroids; androgenic anabolic steroids; cerebral venous sinus thrombosis; coagulation; cord sign; delta sign; general tonic-clonic seizures; hypercoagulability; superior sagittal sinus; testosterone replacement therapy",
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"title": "Superior Sagittal Venous Sinus Thrombosis in a Patient with Illicit Testosterone Use.",
"title_normalized": "superior sagittal venous sinus thrombosis in a patient with illicit testosterone use"
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"abstract": "Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Re-analyses showed that there may be degradation of trazodone in postmortem blood stored at 4°C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0mg/L with liver concentrations to at least 2.2mg/kg. Overall, trazodone concentrations ranged from 0.08-6.1mg/L in peripheral blood, 0.07-7.1mg/L in central blood, and 0.39-26mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N=19). The liver to peripheral blood ratios showed a median value of 2.8L/kg (N=18). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution.",
"affiliations": "Forensic Toxicology Laboratory, County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101 San Diego, CA 92123 USA. Electronic address: Iain.McIntyre@sdcounty.ca.gov.;Forensic Toxicology Laboratory, County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101 San Diego, CA 92123 USA.;County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101 San Diego, CA 92123 USA.",
"authors": "McIntyre|Iain M|IM|;Mallett|Phyllis|P|;Stabley|Robert|R|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D014196:Trazodone",
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"keywords": "Central blood; Liver; Peripheral blood; Postmortem redistribution; Trazodone",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D002853:Chromatography, Liquid; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D017367:Serotonin Uptake Inhibitors; D013048:Specimen Handling; D014018:Tissue Distribution; D014196:Trazodone; D055815:Young Adult",
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"title": "Postmortem distribution of trazodone concentrations.",
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"abstract": "Mesalazine-induced eosinophilic pneumonia has been rarely reported. We reported a case of mesalazine-induced eosinophilic pneumonia in a 56-year-old female who took mesalazine without a prescription for suspected ulcerative colitis. She had an elevated eosinophil count in peripheral blood and bronchoalveolar lavage fluid. Eosinophil infiltration was also noted in bone marrow aspirates. Chest radiograph and computed tomography demonstrated bilateral upper lung predominant infiltrates and spirometry showed a restrictive ventilatory defect with a reduced diffusion capacity. The patient recovered after cessation of mesalazine therapy. Mesalazine-induced lung damage should be considered in patients who develop unexplained respiratory symptoms while taking this agent.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People's Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People's Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People's Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People's Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People's Republic of China.;Department of Pathology, Jishuitan Hospital, Fourth Medical College of Peking University, Beijing, People's Republic of China.",
"authors": "Zhang|Yunjian|Y|;Luo|Ling|L|;Wang|Xiaofang|X|;Liu|Xiaoyang|X|;Wang|Xiaoyan|X|;Ding|Yi|Y|",
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"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S107012tcrm-12-975Case ReportMesalazine-induced eosinophilic pneumonia with bone marrow infiltration: a case report and literature review Zhang Yunjian 1Luo Ling 1Wang Xiaofang 1Liu Xiaoyang 1Wang Xiaoyan 1Ding Yi 21 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Fourth Medical College of Peking University, Beijing, People’s Republic of China2 Department of Pathology, Jishuitan Hospital, Fourth Medical College of Peking University, Beijing, People’s Republic of ChinaCorrespondence: Yunjian Zhang, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Jishuitan Hospital, Fourth Medical College of Peking University, No 31, East Xinjiekou Street, Xicheng District, Beijing 100035, People’s Republic of China, Tel +86 136 9320 5037, Email zhangyjian@126.com2016 14 6 2016 12 975 981 © 2016 Zhang et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Mesalazine-induced eosinophilic pneumonia has been rarely reported. We reported a case of mesalazine-induced eosinophilic pneumonia in a 56-year-old female who took mesalazine without a prescription for suspected ulcerative colitis. She had an elevated eosinophil count in peripheral blood and bronchoalveolar lavage fluid. Eosinophil infiltration was also noted in bone marrow aspirates. Chest radiograph and computed tomography demonstrated bilateral upper lung predominant infiltrates and spirometry showed a restrictive ventilatory defect with a reduced diffusion capacity. The patient recovered after cessation of mesalazine therapy. Mesalazine-induced lung damage should be considered in patients who develop unexplained respiratory symptoms while taking this agent.\n\nKeywords\nmesalazinepneumoniaeosinophilcolitis\n==== Body\nIntroduction\nMesalazine and other 5-aminosalicylate agents remain the current standard of care for inducing remission in mild-to-moderate active ulcerative colitis. Pulmonary toxicity secondary to mesalazine is very rare due to its lack of sulfapyridine moiety. Eosinophilic pneumonia is characterized by an abnormal accumulation of eosinophils in the lung, but apart from secondary causes, such as infection and medication, its etiology remains unknown. Though scattered case reports of mesalazine-associated interstitial lung diseases, such as organizing pneumonia, broncholitis obliterans, and interstitial lymphocytic pneumonia, are available,1–6 mesalazine-associated eosinophilic pneumonia has been sparsely reported.7–10 We report a case of eosinophilic pneumonia in a woman who took mesalazine for suspected ulcerative colitis and also carry out a literature review of reported cases of mesalazine-eosinophilic pneumonia.\n\nCase report\nThis study was approved by the review boards of Jishuitan Hospital and Fourth Medical College of Peking University. Patient consent to this study was not required because the retrospective nature of the study. A 56-year-old woman was admitted to our hospital on July 1, 2015 because of intermittent fever and nonproductive cough for 2 weeks and exertional dyspnea and chest pain for 1 week. She described no chills, rigors, and night sweats. The patient developed abdominal pain and had mucus stools on April 20, 2015. Laboratory tests at a local clinic on May 20, 2015 showed leukocytes at 6.9×109/L with 67.9% neutrophils and 0.12% eosinophils. Her hemoglobin level was 129 g/L and platelet count was 276×109/L. The occult stool test was weakly positive. She started mesalazine 0.5 g three times a day for 6 weeks without a prescription. The patient began coughing on June 17, 2015 and also had fatigue and fever (as high as 39.4°C). Laboratory examinations revealed leukocytes at 12.75×109/L with 76.2% neutrophils and 6.9% eosinophils. Her hemoglobin level stood at 124 g/L and platelet count was 485×109/L. A chest radiograph and computed tomography (CT) scan showed minor peripheral patchy opacity in bilateral upper and mid lungs with a narrowed right costophrenic angle (Figure 1A and B). A 10-day course of intravenous levofloxacin and ceftazidine was administered, and the patient continued mesalazine. Nevertheless, the patient was still febrile. On June 24, 2015, the patient developed right chest pain and aggravating exertional dyspnea. She denied symptoms of palpitations and paroxysmal nocturnal dyspnea. She denied the use of tobacco products and had no occupational exposure to chemical fumes, including biomass fuel. The patient was allergic to penicillin and metronidazole. She had hypertension for 5 years, which was controlled by taking sustained release nifedipine. There was no family history of asthma.\n\nPhysical examination at admission showed a blood pressure of 117/70 mmHg, a pulse rate of 101 beats/min, a respiratory rate of 20 breaths/min, and a temperature of 37.4°C. No crackles were noted in both lungs. Clubbing, cyanosis, or peripheral edema was absent. Cardiovascular and abdominal examinations were unremarkable. Review of the systems was unremarkable for skin rashes, joint pain, and weight loss.\n\nLaboratory investigations revealed leukocytes at 25.54×109/L with 67.4% neutrophils and 21.8% eosinophils. Her hemoglobin was 111 g/L and platelet count 593×109/L. Renal and liver function were normal, and no splenomegaly was noted. Chest radiograph showed progressing opacity predominantly in bilateral upper lungs (Figure 1C). Chest CT scan revealed bilateral patchy consolidations with interlobular septal thickening (Figure 1D and 1E). The single-breath diffusing capacity of the lung for carbon monoxide (DLco) was 46% of the predicted values. Transbronchial biopsy revealed chronic inflammation and exudation of fibrin (Figure 2A), and bronchoalveolar lavage fluid (BALF) showed 1×106 cells/mL with 18% macrophages, 22% neutrophils, 33% eosinophils, and 27% lymphocytes (Figure 2B). Bone marrow aspirate showed infiltration by mature eosinophils (Figure 2C), but the ratio of promyelocytes to their precursors was normal, and the percentage of eosinophils was 18, with normal morphology. Arterial blood gas analysis revealed a pH of 7.523, a partial pressure of carbon dioxide (pCO2) of 29.7 mmHg, a partial pressure of oxygen (pO2) of 59.5 mmHg, and a bicarbonate level of 23.2 mmol/L on room air. Tests for adenovirus, respiratory syncytial virus, seasonal influenza A and B, parainfluenza virus, Mycoplasma pneumoniae, Chlamydia, and Legionella pneumophila were negative. Tuberculin skin test and sputum and BALF tests for acid-fast bacilli excluded tuberculosis. Rheumatoid factor, antinuclear antibodies, anti-double-strand DNA antibody, antiextractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibody were negative. C-reactive protein was at 191 mg/dL, erythrocyte sedimentation rate was at 65 mm/h, and immunoglobulin E was at >100 IU/mL. Colonoscopy at 2 weeks after admission demonstrated focal erythema, erosions, and edematous swollen mucosa in the rectum.\n\nMesalazine-induced eosinophilic pneumonia was diagnosed, and mesalazine was discontinued. Currently, there is no consensus for the use of corticosteroid therapy for mesalazine-induced eosinophilic pneumonia, and our patient was not given corticosteroids. Besides, four out of nine reported cases also recovered without corticosteroid therapy. The patient improved in symptoms, and 4 weeks after cessation of mesalazine, she was discharged. CT scan showed bilateral ground glass opacity (Figure 1E). At 5 weeks of follow-up after discharge, the patient was asymptomatic with a normalized eosinophil count (Figure 3). Spirometry continued to show a restrictive defect and a reduced DLco (44%) (Table 1), but the patient felt no apparent exertional dyspnea after discharge.\n\nDiscussion\nEosinophilic pneumonia is characterized by eosinophilic infiltration in the lungs, radiographic abnormalities, impaired lung function, and peripheral blood eosinophilia. The causes of eosinophilic pneumonia remain largely unknown, and the disease may occur secondary to medications, such as mesalazine. We describe a case of eosinophilic pneumonia in a woman who took mesalazine for proctitis. The case was confirmed by clinical manifestations, medication history, BALF cytology, and radiological findings. The case is noted for eosinophilia in peripheral blood and for infiltration of mature eosinophils in the lungs and the bone marrow. Though it has not been reported in mesalazine-associated eosinophilic pneumonia, eosinophil infiltration in the bone marrow due to other drugs, such as minocycline, has been described.11\n\nThe first case of mesalazine-induced lung hypersensitivity was reported in 1991.12 Over the past two decades, several cases of mesalazine-induced pulmonary toxicity have been reported, particularly eosinophilic pneumonia.7,9,13–19 The incidence of lung disease from mesalazine is unknown; however, reports from mesalazine-induced lung disease have increased, and the pathogenesis is still unknown.8 Immune-mediated injury and direct cytotoxic effect are considered as causes of drug-induced lung injury.\n\nSymptoms related to mesalazine-induced eosinophilic pneumonia can range from being asymptomatic to fever, cough, and shortness of breath. Women were reported to be affected more often than men.6 Among nine previously published case reports of mesalazine-induced eosinophilic pneumonia, there were three males13,16,17 and six females7,9,14,15,18,19 with a mean age of 34 years (ranging from 23 years to 50 years). Most cases occurred between 1 month and 7 months after the initiation of the drug, with rare cases occurring 2 years later.7,9,13–19 The clinicopathologic and radiologic features of these patients and our patient are summarized in Table 2.\n\nThe diagnosis of mesalazine-induced eosinophilic pneumonia can be challenging. Laboratory tests may reveal peripheral eosinophilia. Eosinophilia in peripheral blood was found in all nine patients previously reported with eosinophils ranging from 16% to 63%.7,9,13–19 Arterial blood gas can show hypoxia. Pulmonary function tests usually demonstrate a restrictive picture with a reduced diffusing capacity as seen in our case. Nonspecific interstitial infiltrate or consolidation is usually seen in the chest radiograph or CT scan. In some cases, characteristic finding described as wandering shadow is observed.7,16 If the diagnosis remains unclear, bronchoscopy and BAL should be performed. The BAL frequently shows an elevated count of eosinophils, while transbronchial lung biopsy may reveal interstitial infiltrates or alveolar exudates. Preferably, the presence of eosinophilia in peripheral blood, BAL, or lung tissue should be used as indicators for diagnosing mesalazine-induced eosinophilic pneumonia in patients with a medication history of mesalazine.\n\nThe most essential aspect of diagnosing mesalazine-induced eosinophilic pneumonia is a high index of suspicion. A detailed history and laboratory and diagnostic studies can help to distinguish inflammatory bowel disease-associated lung involvement from mesalazine-related toxicity. In the present patient, it is reasonable to establish a diagnosis of mesalazine-induced pneumonia for several reasons: 1) the appearance of respiratory symptoms during drug therapy; 2) clinical, radiological, and BALF findings consistent with mesalazine-induced eosinophilic lung disease; 3) the absence of established criteria required for diagnosing inflammatory bowel disease; 4) other lung diseases, such as those due to infections, were excluded; 5) clinical and radiological improvements after mesalazine discontinuation.\n\nThe most important aspect of treatment involves discontinuation of therapy with mesalazine. Mesalazine cessation usually leads to improvement in both clinical and radiographic pictures. The role of steroids for mesalazine-induced eosinophilic pneumonia is unclear. Corticosteroid therapy can lead to rapid recovery. However, several reports also describe full recovery after discontinuation of mesalazine without steroid therapy.7,15,16,19 Our patient also markedly improved by simple cessation of mesalazine intake. The prognosis of mesalazine-induced lung injury is good.\n\nOne limitation of this report is that transbronchial biopsy failed to detect infiltration by eosinophils in the lung tissues of the patient. This is probably due to the small area of lung tissues that can be biopsied via the transbronchial approach. The biopsy site may not be representative of lesions characteristic of eosinophilic pneumonia. It remains to be seen whether increasing the number of biopsies at multiple sites would lead to a higher rate of positive finding.\n\nConclusion\nMesalazine-induced eosinophilic pneumonia is an extremely rare entity. Clinical and imaging manifestations are not specific. The diagnosis is relied on the history of mesalazine therapy, eosinophilia in blood, pulmonary histiocytic infiltration with eosinophils, and marked improvement of symptoms and radiologic abnormalities after the discontinuation of mesalazine. The possibility of drug-induced eosinophilic pneumonia should be fully considered in patients developing unexplained respiratory symptoms while on mesalazine therapy.\n\nAcknowledgments\nThis work was supported by the Project of Beijing Municipal Science and Technology Commission (Z141107002514153).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Radiologic features of eosinophilic pneumonia in a 56-year-old woman who took mesalazine for suspected ulcerative colitis.\n\nNotes: (A) Chest radiograph before admission (June 17, 2015) shows bilateral minor opacity in the upper lung fields, and (B) chest CT scan (June 27, 2015) reveals peripheral opacity in both lungs; (C) chest radiograph after admission (July 4, 2015) shows deterioration of bilateral opacity and (D) bilateral patchy consolidations with interlobular septal thickening in both lungs on CT scan (July 15, 2015). (E) CT scan upon discharge (August 6, 2015) shows bilateral minor ground glass opacity.\n\nAbbreviation: CT, computed tomography.\n\nFigure 2 Pathological findings.\n\nNotes: (A) Transbronchial biopsy reveals chronic inflammation and exudation of fibrin. (B) Photomicrograph of BALF shows infiltration by eosinophils (arrow), hematoxylin and eosin stain ×400. (C) Photomicrograph of bone marrow aspirate shows infiltration by mature eosinophils (arrow), Wright–Giemsa stain ×1,000.\n\nAbbreviation: BALF, bronchoalveolar lavage fluid.\n\nFigure 3 Changes in eosinophil counts.\n\nNote: Arrow indicates date of mesalazine cessation.\n\nAbbreviation: EOS, eosinophils.\n\nTable 1 Changes in respiratory function in the patient\n\n\tFVC\n(L, %pred)\tFEV1\n(L, %pred)\tFEV1/\nFVC (%)\tTLC\n(L, %pred)\tRV\n(L, %pred)\tRV/\nTLC (%)\tDLco\n(%pred)\t\nJuly 28, 2015\t1.83 (72%)\t1.54 (73%)\t84\t1.84 (47%)\t0.71 (50%)\t39\t46\t\nAugust 6, 2015\t2.18 (86%)\t1.69 (80%)\t77\t3.73 (95%)\t1.54 (110%)\t41\t56\t\nSeptember 9, 2015\t2.55 (93%)\t2.04 (91%)\t80\t3.33 (77%)\t0.78 (50%)\t23\t44\t\nAbbreviations: FVC, forced vital capacity; FEV1, forced expiratory volume in one second; TLC, total lung capacity; RV, residual volume; DLco, diffusing capacity of the lung for carbon monoxide.\n\nTable 2 Clinicopathologic, radiologic, and treatment outcomes of reported cases of mesalazine-associated eosinophilic pneumonia\n\nAuthors (country)\tAge/sex\tPrimary disease\tOnset time\tClinical manifestations\tImaging features\tPathology\tEOS% in BALF\tEOS% in peripheral blood\tIntervention\tPrognosis\t\nFerrusquía et al13 (Spain)\t32/M\tUC\t12 months\tFever, fatigue, night sweats, dyspnea, dry cough, and chest pain\tLeft lower lobe and lingual lobe nodules, mediastinal lymphadenopathy, bilateral lower lung ground glass opacity 4 weeks later, and pericardial effusion\tTBLB, bulla, and vascular and interstitial eosinophil infiltration\t72\t63\tCessation + steroid hormone\tPeripheral eosinophil count is normal several days after mesalazine cessation, and imaging abnormalities disappear. DLco is still low at 6 months\t\nKim et al9(South Korea)\t30/F\tUC\t19 days\tFatigue, muscle ache, and coughing\tBilateral peripheral consolidations and thickened septa\tBiopsy reveals bulla, giant macrophages, and eosinophils\t1.6\t24.5\tCessation + steroid hormone\tFull recovery\t\nFayaz et al14 (UK)\t24/F\tUC\t2 years\tDyspnea and chest pain\tBilateral infiltrates and left pleural effusion\tThoracoscope reveals eosinophilic granuloma\tNA\tElevated\tCessation\tFull recovery\t\nShimizu et al15 (Japan)\t50/F\tUC\t1 month\tFever and dry cough\tBilateral infiltrates\tNA\t20\tNA\tCessation\tFull recovery\t\nPark et al16 (South Korea)\t35/M\tCD\tUnknown\tFever and dry cough\tBilateral migratory infiltrates\tNA\tElevated\tElevated\tCessation\tFull recovery\t\nHakoda et al17 (Japan)\t30/M\tUC\t1 month\tFever and coughing\tBilateral infiltrates\tTBLB and unknown\tElevated\tElevated\tCessation + steroid hormone\tRecovery\t\nZamir et al18 (Israel)\t23/F\tUC\t2 months\tFever and coughing\tBilateral peripheral infiltrates\tNA\tNA\tElevated\tCessation + steroid hormone\tSymptoms and imaging abnormalities disappear at one week\t\nTanigawa et al7 (Japan)\t35/F\tUC\t6 months\tLow fever and dry cough\tBilateral migratory infiltrates\tTBLB and organizing eosinophilic pneumonia\tNA\tNA\tCessation\tRecovery\t\nHoneybourne19 (UK)\t30/F\tUC\t7 months\tIntermittent fever, body weight loss, dry cough, progressive dyspnea, and chest pain\tBilateral apex predominant infiltrates and mild bilateral pleural effusion\tThoracoscopic biopsy reveals chronic eosinophilic pneumonia\tNA\t16\tCessation\tNormal imaging and eosinophil count several weeks later\t\nThe current case\t56/F\tProctitis\t1 month\tFever, fatigue, dry cough, and dyspnea\tBilateral upper lung predominant infiltrates\tTBLB and bulla and massive eosinophils\t33\t21.8\tCessation\tImprovement at 1 week, normal imaging at 4 weeks, and normal eosinophil count at 2 months\t\nAbbreviations: EOS, eosinophils; BALF, bronchoalveolar lavage fluid; UC, ulcerative colitis; TBLB, transbronchial lung biopsy; DLco, diffusing capacity of the lung for carbon monoxide; NA, not available or not done; CD, Crohn’s disease; F, female; M, male.\n==== Refs\nReferences\n1 Michy B Raymond S Graffin B Pneumopathie organisée apparue sous mésalazine [Organizing pneumonia during treatment with mesalazine] Rev Mal Respir 2014 31 1 70 77 24461446 \n2 Shindoh Y Horaguchi R Hayashi K Suda Y Iijima H Shindoh C A case of lung injury induced by long-term administration of mesalazine Nihon Kokyuki Gakkai Zasshi/J Jpn Respir Soc 2011 49 11 861 866 Japanese \n3 Đurić M Považan Đ Sečen S Jović J Differential diagnosis problem of pulmonary changes in ulcerative colitis Vojnosanit Pregl 2010 67 6 511 514 20629432 \n4 Taguchi S Furuta J Ohara G Kagohashi K Satoh H Severe airflow obstruction in a patient with ulcerative colitis and toxic epidermal necrolysis: a case report Exp Ther Med 2015 9 5 1944 1946 26136919 \n5 Haralambou G Teirstein AS Gil J Present DH Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine Mt Sinai J Med 2001 68 6 384 388 11687866 \n6 Sossai P Cappellato MG Stefani S Can a drug-induced pulmonary hypersensitivity reaction be dose-dependent? A case with mesalamine Mt Sinai J Med 2001 68 6 389 395 11687867 \n7 Tanigawa K Sugiyama K Matsuyama H Mesalazine-induced eosinophilic pneumonia Respiration 1999 66 1 69 72 9973695 \n8 Inoue M Horita N Kimura N Kojima R Miyazawa N Three cases of mesalazine-induced pneumonitis with eosinophilia Respir Investig 2014 52 3 209 212 \n9 Kim JH Lee JH Koh ES Acute eosinophilic pneumonia related to a mesalazine suppository Asia Pac Allergy 2013 3 2 136 139 23667838 \n10 Franco AI Escobar L Garcia XA Mesalazine-induced eosinophilic pneumonia in a patient with ulcerative colitis disease: a case report and literature review Int J Colorectal Dis 2016 31 4 927 929 26189026 \n11 Bentur L Bar-Kana Y Livni E Severe minocycline-induced eosinophilic pneumonia: extrapulmonary manifestations and the use of in vitro immunoassays Ann Pharmacother 1997 31 6 733 735 9184714 \n12 Le Gros V Saveuse H Lesur G Brion N Lung and skin hypersensitivity to 5-aminosalicylic acid Br Med J 1991 302 6782 970 1827746 \n13 Ferrusquía J Pérez-Martínez I Gómez de la Torre R Gastroenterology case report of mesalazine-induced cardiopulmonary hypersensitivity World J Gastroenterol 2015 21 13 4069 4077 25852295 \n14 Fayaz M Sultan A Nawaz M Sultan N Mesalazine-induced eosinophilic variant of Wegener’s granulomatosis in an ulcerative colitis patient J Ayub Med Coll Abbottabad 2009 21 4 171 173 21067054 \n15 Shimizu T Hayashi M Shimizu N Kinebuchi S Toyama J A case of mesalazine-induced lung injury improved by only discontinuation of mesalazine Nihon Kokyuki Gakkai Zasshi/J Jpn Respi Soc 2009 47 6 543 547 Japanese \n16 Park JE Hwangbo Y Chang R Mesalazine-induced eosinophilic pneumonia in a patient with Crohn’s disease Korean J Gastroenterol/Taehan Sohwagi Hakhoe chi 2009 53 2 116 120 Korean 19237838 \n17 Hakoda Y Aoshima M Kinoshita M Sakurai M Ohyashiki K A case of eosinophilic pneumonia possibly associated with 5-aminosalicylic acid (5-ASA) Nihon Kokyuki Gakkai Zasshi/J Jpn Respir Soc 2004 42 5 404 409 Japanese \n18 Zamir D Weizman J Zamir C Fireman Z Weiner P Mesalamine-induced hypersensitivity pneumonitis Harefuah 1999 137 1–2 28 30 87 86 Hebrew 10959271 \n19 Honeybourne D Mesalazine toxicity Br Med J 1994 308 6927 533 8166873\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "12()",
"journal": "Therapeutics and clinical risk management",
"keywords": "colitis; eosinophil; mesalazine; pneumonia",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "975-81",
"pmc": null,
"pmid": "27366075",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "1827746;23667838;15168457;20629432;19237838;24853024;11687866;9973695;11687867;26136919;10959271;24461446;26189026;8166873;9184714;22171492;19601534;25852295;21067054",
"title": "Mesalazine-induced eosinophilic pneumonia with bone marrow infiltration: a case report and literature review.",
"title_normalized": "mesalazine induced eosinophilic pneumonia with bone marrow infiltration a case report and literature review"
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"abstract": "This is a case of a 72 year old male with a chronic methicillin-resistant Staphylococcus aureus prosthetic joint infection. After the third intravenous dose of bacteriophage therapy, an unusual, reversible transaminitis prompted stoppage of bacteriophage therapy. Nevertheless, treatment was successful and the patient's severe chronic infection was eradicated.",
"affiliations": "Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Department of Orthopedic surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Department of Orthopedic surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.;Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.;Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, MD 21702, USA.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, MD 21702, USA.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, MD 21702, USA.",
"authors": "Doub|James B|JB|;Ng|Vincent Y|VY|;Johnson|Aaron J|AJ|0000-0002-0764-1455;Slomka|Magdalena|M|;Fackler|Joseph|J|;Horne|Bri'Anna|B|0000-0002-7546-864X;Brownstein|Michael J|MJ|;Henry|Matthew|M|;Malagon|Francisco|F|;Biswas|Biswajit|B|",
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"country": "Switzerland",
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"doi": "10.3390/antibiotics9050241",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382 MDPI \n\n10.3390/antibiotics9050241\nantibiotics-09-00241\nCase Report\nSalvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection\nDoub James B. 1* Ng Vincent Y. 2 https://orcid.org/0000-0002-0764-1455Johnson Aaron J. 2 Slomka Magdalena 1 Fackler Joseph 3 https://orcid.org/0000-0002-7546-864XHorne Bri’Anna 3 Brownstein Michael J. 3 Henry Matthew 4 Malagon Francisco 4 Biswas Biswajit 4 1 Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Mslomka@som.umaryland.edu\n2 Department of Orthopedic surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Vng@som.umaryland.edu (V.Y.N.); Ajohnson1@som.umaryland.edu (A.J.J.)\n3 Adaptive Phage Therapeutics, Gaithersburg, MD 20878, USA; jfackler@aphage.com (J.F.); bhorne@aphage.com (B.H.); Mjbrownstein@gmail.com (M.J.B.)\n4 Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, MD 21702, USA; Matthew.Henry@mail.mil (M.H.); Francisco.Malagon.civ@mail.mil (F.M.); biswajit.biswas.civ@mail.mil (B.B.)\n* Correspondence: Jdoub@ihv.umaryland.edu; Tel.: +1-410-706-3454; Fax: +1-410-328-9106\n09 5 2020 \n5 2020 \n9 5 24111 4 2020 07 5 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).This is a case of a 72 year old male with a chronic methicillin-resistant Staphylococcus aureus prosthetic joint infection. After the third intravenous dose of bacteriophage therapy, an unusual, reversible transaminitis prompted stoppage of bacteriophage therapy. Nevertheless, treatment was successful and the patient’s severe chronic infection was eradicated. \n\nbacteriophage therapyprosthetic joint infectionmethicillin resistance Staphylococcus aureusmedication induced hepatitisbiofilm\n==== Body\n1. Introduction\nProsthetic joint infections (PJI) are one of the most serious complications of joint replacement surgery. Conservative estimates are that approximately 1–2% of all prostheses will become infected over the life of the implant [1]. The financial burden of treating these infections is staggering. It is estimated that they will cost the US healthcare system $1.62 billion in 2020 [1]. In addition, patients have significant morbidity and mortality as a direct result of our current medical and surgical management to treat these infections [2]. In one study, the five year mortality for prosthetic joint infections is over 20% [2]. PJIs are hard to treat because of bacterial biofilms on the prostheses. Unfortunately, conventional antibiotics have limited ability to cure biofilm infections [3]. This is in part due to the almost dormant metabolic activity of bacteria in biofilms and the architecture of biofilms [3]. The concentrations of conventional antibiotics needed to have activity to bacteria in biofilms can be up to 1000 times higher than the same bacteria in a planktonic state [3]. Therefore, new antimicrobial therapies are needed to treat PJI’s that focus on disrupting biofilms.\n\nIn nature, bacteria are prey to viruses called bacteriophages. These viruses have a very narrow spectrum of activity and can be either be lytic or lysogenic. Lytic phages hold the most promise in clinical medicine to treat infections given their ability to cause bacterial lysis. Bacteriophages live in dynamic relationships with bacteria and have coevolved over time. Given this coevolution, bacteriophages have developed innate ability penetrate biofilms and lyse bacteria inside biofilms [4,5,6]. Bacteriophages also have the ability to disrupt the biofilm’s extracellular matrix with the use of depolymerase enzymes [4,5,6]. It is therefore postulated that bacteriophages may be promising agents to help cure clinical biofilm infections. This case report shows the potential benefit of bacteriophage therapy in treating chronic methicillin-resistant Staphylococcus aureus (MRSA) PJIs. It also reinforces the need for phase 1 and 2 clinical trials to further assess the safety and efficacy of bacteriophage therapy in PJIs in combination with standard-of-care antibiotic therapies. \n\n2. Case\nA 72-year-old male with morbid obesity (BMI 41) and hyperlipidemia presented to the University of Maryland Medical Center with a chronic MRSA PJI. Twenty years prior he had a methicillin sensitive Staphylococcus aureus (MSSA) septic arthritis and intraosseous abscess of his right knee that was treated with intravenous (IV) cefazolin. One year later, he fractured his distal right femur, requiring open reduction and internal fixation with a lateral plate. He developed severe osteoarthritis over the subsequent decade, and in 2012 he underwent right knee arthroplasty. In 2014, he developed a Staphlylococcus epidermidis right knee PJI and underwent debridement, antibiotics, and implant retention (DAIR), but infection recurred, requiring a two-stage revision. In 2016, a fall led to an abrasion over the right knee, and three weeks later, he developed erythema and an effusion. Arthrocentesis revealed MRSA infection. Since the distal femur fracture never fully healed, DAIR was performed. Three weeks later, DAIR was repeated because of worsening symptoms. Hickman catheters were placed and Intraarticular (IA) and IV vancomycin therapy was started. After 5 weeks, vancomycin was changed to IV daptomycin. He completed 3 more weeks of IV daptomycin and a total of 8 weeks of IA vancomycin. His liver function remained normal while on daptomycin. He was then transitioned to chronic oral doxycycline therapy. For two years, oral doxycycline suppressed his infection, but it was stopped and three weeks later the infection recurred. Repeat arthrocentesis culture grew MRSA. Despite resumption of doxycycline, symptoms worsened. Since his distal femur fracture had healed poorly (Figure 1), a standard 2 stage revision was deemed not feasible and the patient refused amputation. He therefore presented to the University of Maryland Medical Center for a second opinion. \n\nPatient elected to undergo DAIR with IA and IV bacteriophage therapy to salvage the prosthesis. Repeat arthrocentesis grew MRSA. This isolate was sent to Adaptive Phage Therapeutics (APT) and a virulent, lytic bacteriophage was identified that had lytic activity to the isolate. 2.7 × 109 PFU vials of SaGR51φ1 were created by APT. Each vial had less than 1 Endotoxin unit/ml. Please see methods section for more information on isolation and preparation of bacteriophage therapy. Expanded access was granted by the FDA (IND #19274) and by the University of Maryland Baltimore Institutional Review Board (IRB # HP-0087888EU). Consent for emergency use authorization was obtained, and treatment protocol was reviewed by University of Maryland Baltimore Institutional Review Board who deemed this emergency use was acceptable in accordance with 21 CFR 56.102(d) and 21 CFR 56.104(c) [7]. \n\nDAIR was attempted at the University of Maryland Medical Center by an experienced tumor surgeon, Dr. Vincent Y. Ng. Intraoperatively, numerous sinus tracts, gross purulence, and extensive soft tissue infection were present. Extensive erosion of the distal femoral bone stock was present, and gross loosening of the prosthesis was evident. Therefore, prosthesis could not be salvaged. Explant of prosthesis components with placement of static vancomycin and tobramycin spacer was conducted. To allow for femoral reconstruction, clearance of the extensive MRSA infection was required. At the end of surgery, the patient received two doses of IA bacteriophage (5.4 × 109 PFU) in 10 mL of normal saline (NS) and was started on IV daptomycin 1000 mg daily. Daily IV bacteriophage (2.7 × 109 PFU in 50 mL of NS) was started the next day. After the third IV dose of bacteriophage, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased to 136 and 86. The next day, AST and ALT were 692 and 462 and bacteriophage therapy was discontinued. Bilirubin, PT/INR, alkaline phosphate, and creatine kinase remained normal. Albumin decreased to 2.7 from baseline of 3.6, as had occurred with his numerous previous surgeries. Daily cumulative doses of Tylenol were less than 1.5 grams. Hepatitis A, B, and C serologies were negative. Tests for influenza, adenovirus, parainfluenza, enterovirus, RSV, EBV, CMV, mycoplasma, chlamydia, and coronavirus were negative. Ultrasound showed hepatomegaly, but no ductal or other abnormalities were seen. Daptomycin was continued at same dose. AST and ALT decreased to normal 10 days later. Figure 2 shows liver function tests over the course of therapy. CRP trended to normal 14 days after surgery. \n\nIV daptomycin was continued for 6 weeks, and then antibiotics were stopped. Three weeks off antibiotics, the patient underwent a second debridement surgery to confirm clearance of infection and resection of the grossly malunited distal femur fracture and heterotopic bone. Another static vancomycin spacer was inserted. No infection was seen operatively, but another IA bacteriophage dose of 2.7 × 109 PFU in 10 mL of NS was given. Eight cultures from soft tissues, femoral canal, and devitalized bone were all negative. Daily monitoring for 5 days showed no elevations in AST or ALT. Two months later, after optimization of BMI, implantation of a cemented distal femoral megaprosthesis was performed off antibiotics. Given the severity of the previous infection, an additional IA bacteriophage dose of 2.7 × 109 PFU in 10 mL of NS was given. Intraoperative cultures were again negative. No elevations in AST or ALT were observed. One week later, the patient was discharged to receive rehabilitation to strengthen his right lower extremity.\n\n3. Methods\n3.1. Bacterial Isolation\nThe Staphylococcus aureus (SaWF54) bacterial isolate collected from the patient’s synovial fluid was provided to APT to identify a bacteriophage appropriate for therapeutic use. The isolated colony was purified three times on tryptic soy agar media. The colony purified isolate was then screened against S. aureus bacteriophage previously collected and stored in APT’s PhageBank™. All media used in the growth of the clinical isolate was certified to be of nonanimal origin.\n\n3.2. Bacteriophage Screening Using the Host Range Quick Test (HRQT)\nThe Host Range Quick Test (HRQT) was used to observe sensitivities against the S. aureus PhageBank™ [8]. A liquid culture of the SaWF54 isolate was grown to ~0.1 OD600 and serially diluted to ~1 × 107 CFU/mL in a microtiter plate containing Tryptic soy broth (TSB) and tetrazolium dye. Individual bacteriophage strains were introduced to the patient strain within the wells of the microtiter dish. The interaction of bacteriophage and the patient’s isolate was observed for 48 h. Bacteriophage sensitivity was measured by the inhibition of cellular respiration. Bacteriophage that successfully inhibited or slowed the rate of respiration were also tested for plaquing in a double agar overlay method. The S. aureus bacteriophage, SaGR51Φ1, showed inhibition for >30 h relative to the bacterial host control well in the HRQT and was selected for therapy.\n\n3.3. Phage Amplification and Purification\nThe Navy’s medical research center (NMRC) plaque purified the selected bacteriophage three times in preparation for the two-step amplification process [9]. The plaque purified bacteriophage was used to first infect a 100 mL culture of a producer S. aureus strain SaGR51 grown to ~0.1 OD600 and infected at a MOI of ~0.1. Bacterial lysis was observed using a spectrophotometer at an O.D600, and the 100 mL lysate was then filtered through 0.22 µm filtration unit.\n\nThe small-scale preparation was then used to infect 3.6 L batch of the producer strain SaGR51 under the same growth conditions and MOI as the 100 mL lysate. After the lysis event, the 3.6 L lysate was centrifuged and sequentially filtered.\n\nThe bacteriophage was concentrated via PEG8000 10% precipitation overnight at 4 °C and centrifugation at 12,000× g for one hour. The pellet was recovered and treated with one volume of chloroform to remove excess cellular debris prior to purification by cesium chloride (CsCl) Continuous Gradient ultracentrifugation. Bacteriophage particles extracted from the CsCl bands were dialyzed four times and 0.22 µm filtered. Approximately, seven (7) mL of this lysate was transferred to APT for further processing [9].\n\n3.4. Repurification, Final Therapy Formulation, and Quality Control Testing\nAfter receiving the purified bacteriophage material from NMRC, APT further purified the phage of contaminants such as endotoxins via its proprietary purification methods. After purification, the purified phage was formulated, sterile filtered, and filled in pre-sterilized single-use vials using a fully enclosed, robotically operated ISO 5 classified isolator (VanRx Microcell) in APT’s cleanroom. The lot of final therapeutic vials were quality control tested for sterility (USP <71>), endotoxin levels, and host cell protein levels. The results from initial quality control testing can be found in Table 1.\n\n4. Discussion\nTo this research team’s knowledge, this is the first case of bacteriophage therapy being used successfully as an adjuvant therapy to cure a chronic MRSA PJI. Two other successful bacteriophage treatments of MSSA and Pseudomonas PJIs have been reported [10,11]. Unique to our case is that no chronic suppression antibiotics were used. Little is known about optimal treatment durations or routes of administration to use in PJIs. The plan was to treat longer, but therapy was stopped when significant transaminitis occurred. In spite of this, successful sterilization of the patient’s joint and devitalized bone was achieved with IA and 3 days of IV bacteriophage therapy in combinations with standard of care IV antibiotics for 6 weeks. Given the ability of bacteriophages to self-replicate, perhaps only a few days of bacteriophage therapy are required as an adjunct to surgical debridement. Clinical trials are needed to determine adequate duration of bacteriophage therapy in this setting [10,11]. \n\nTo date, all PJI patients who were successfully treated with bacteriophages required surgical debridement [10,11]. This surgery allows for manual scrubbing of biofilm, ensures that the prosthesis is salvable, and allows instilment of bacteriophages directly to the biofilm. Local dosing of bacteriophages may be vital to clear biofilm infections, but limited data beyond case reports is available [10,11,12]. No adverse events occurred with repeated IA doses, which may be due to limited systemic absorption. Future studies need to be conducted to determine appropriate routes of administration in PJIs. \n\nThe most unique aspect of our case was the transaminitis that occurred following the third IV bacteriophage dose. This seemed to be caused by the bacteriophage therapy. No other liver function derangement was seen, and the transaminitis was reversible and non-life-threatening. Figure 2 shows liver function over the course of bacteriophage therapy. \n\nThe patient had hepatomegaly, but nonalcoholic fatty liver disease could not be proven radiographically, and biopsy was deferred. Over 99% of IV bacteriophage therapy is rapidly cleared by the liver and spleen [13,14,15]. This research team’s theory is that underlying steatosis caused liver macrophages to induce a dysregulated local cytokine response when challenged with large numbers of bacteriophages that needed to be hepatically cleared. This local response could have led to inflammatory changes in the hepatocytes, causing a rise in AST and ALT. This is supported by studies evaluating the role of liver macrophages in steatosis and in older studies evaluating hepatic clearance of bacteriophages [13,14,15]. It is unknown whether mild to moderate elevations in liver enzymes commonly occur following bacteriophage administration. Additionally, it is unknown if continuing IV bacteriophage would have worsened the transaminitis or resulted in adaptation and resolution. For now, intravenous bacteriophage should be used with caution in patients with underlying liver pathology and liver enzymes should be monitored closely. This case is limited because we did not evaluate our patient’s cytokine response to bacteriophage therapy. Future studies should evaluate this response to learn more about the normal human cytokine response to bacteriophage therapy. \n\nIn conclusion, salvage of the patient’s prosthesis was not possible because of severe bone erosion. However, we were able to sterilize the patient’s severe chronic MRSA PJI with a single virulent bacteriophage given IA and IV for 3 days in combination with IV antibiotics. Further PJI studies are needed to establish the optimal duration and route of administration of phages. Bacteriophage therapy has tremendous potential to help cure PJIs, but phase 1 and 2 clinical trials need to be conducted.\n\nAcknowledgments\nWe are grateful to Adaptive Phage Therapeutics for providing the bacteriophage used in this case, and to the University of Maryland research pharmacy staff for preparing the bacteriophages for administration in this case. We are also grateful to Naval Medical Research Center for initial isolation and identification of the phages used for this case. From APT lab, we thank Jarrar Haider, Brittany Sisson, Martin Lee, Joseph Tewell, Viet Dang, Gustavo Aguilar, and Bryce Walker. \n\nAuthor Contributions\nJ.B.D. and V.Y.N. carried out the clinical experimental treatment. J.B.D. wrote the manuscript with contributions from V.Y.N., A.J.J., M.S., B.H., J.F., M.J.B. and B.B. Isolation of bacteriophage was conducted by F.M., B.B., and M.H. J.F. and B.H. purified bacteriophage therapy. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nJoseph Fackler, Bri’Anna Horne and Michael J. Brownstein are affiliated with APT.\n\nFigure 1 Xray anterior-posterior and lateral views of the right femur showing prior incompletely united distal femoral shaft fracture.\n\nFigure 2 Graph of liver function tests over time of phage therapy.\n\nantibiotics-09-00241-t001_Table 1Table 1 Final therapeutic preparation details provided to this patient for the treatment of S. aureus prosthetic joint infections (PJI) infection.\n\nPhage ID\tLot Number\tTiter\n(PFU/mL)\tEndotoxin (EU/dose)\tHost Cell Protein (ng/mL)\tUSP <71>\nSterility\t\nSaGR51Φ1\teIND19092601\t2.7 × 109\t<1\t<10\tPASSED\n==== Refs\nReferences\n1. Kurtz S.M. Lau E. Watson H. Schmier J. Parvizi J. Economic Burden of Periprosthetic Joint Infection in the United States J. Arthroplast. 2012 27 61 65.e1 10.1016/j.arth.2012.02.022 22554729 \n2. Natsuhara K. Shelton T.J. Meehan J.P. Lum Z.C. Mortality During Total Hip Periprosthetic Joint Infection J. Arthroplast. 2019 34 S337 S342 10.1016/j.arth.2018.12.024 30642705 \n3. Mah T.-F.C. O’Toole G.A. Mechanisms of biofilm resistance to antimicrobial agents Trends Microbiol. 2001 9 34 39 10.1016/S0966-842X(00)01913-2 11166241 \n4. Leron K. Targeting Enterococcus faecalis Biofilms with Phage Therapy Appl. Environ. Microbiol. 2015 81 2696 2705 25662974 \n5. Fong S.A. Drilling A. Morales S. Cornet M.E. Woodworth B.A. Fokkens W.J. Psaltis A.J. Vreugde S. Wormald P.J. Activity of Bacteriophages in Removing Biofilms of Pseudomonas aeruginosa Isolates from Chronic Rhinosinusitis Patients Front. Microbiol. 2017 7 10.3389/fcimb.2017.00418 29018773 \n6. Yilmaz C. Colak M. Yilmaz B.C. Ersoz G. Kutateladze M. Gozlugol M. Bacteriophage Therapy in Implant-Related Infections J. Bone Jt. Surg. Am. Vol. 2013 95 117 125 10.2106/JBJS.K.01135 \n7. Payne K. Code of Federal Regulations Government Publishing Office Washington, DC, USA 4 2019 381 384 \n8. Henry M. Biswas B. Vincent L. Mokashi V. Schuch R. A Bishop-Lilly K. Sozhamannan S. Development of a high throughput assay for indirectly measuring phage growth using the OmniLogTM system Bacteriophage 2012 2 159 167 10.4161/bact.21440 23275867 \n9. Estrella L.A. Quinones J. Henry M. Hannah R.M. Pope R.K. Hamilton T. Teneza-Mora N. Hall E. Biswajit B. Characterization of novel Staphylococcus aureus lytic phage and defining their combinatorial virulence using the OmniLog® system Bacteriophage 2016 6 e1219440 10.1080/21597081.2016.1219440 27738555 \n10. Ferry T. Leboucher G. Fevre C. Herry Y. Conrad A. Josse J. Batailler C. Chidiac C. Medina M. Lustig S. Salvage Debridement, Antibiotics and Implant Retention (“DAIR”) With Local Injection of a Selected Cocktail of Bacteriophages: Is It an Option for an Elderly Patient With Relapsing Staphylococcus aureus Prosthetic-Joint Infection? Open Forum Infect. Dis. 2018 5 ofy269 10.1093/ofid/ofy269 30474047 \n11. Tkhilaishvili T. Winkler T. Müller M. Perka C. Trampuz A. Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa Antimicrob. Agents Chemother. 2019 64 00924 01019 10.1128/AAC.00924-19 \n12. Onesa J. Bacteriophage application for difficult-to-treat musculoskeletal infections: Development of a standard multidisciplinary treatment protocol Viruses 2019 11 891 10.3390/v11100891 31548497 \n13. Uhr J.W. Weissman G. Intracellular distribution and degradation of bacteriophage in mammalian tissues J. Immunol. 1965 94 544 550 14299028 \n14. Inchley C. The actvity of mouse Kupffer cells following intravenous injection of T4 bacteriophage Clin. Exp. Immunol. 1969 5 173 187 5370053 \n15. Kazankov K. Jørgensen S.M.D. Thomsen K.L. Møller H.J. Vilstrup H. George J. Schuppan D. Grønbæk H. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Nat. Rev. Gastroenterol. Hepatol. 2018 16 145 159 10.1038/s41575-018-0082-x\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "9(5)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "bacteriophage therapy; biofilm; medication induced hepatitis; methicillin resistance Staphylococcus aureus; prosthetic joint infection",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32397354",
"pubdate": "2020-05-09",
"publication_types": "D002363:Case Reports",
"references": "11166241;5370053;31527029;30474047;14299028;30642705;25662974;31548497;23275867;29018773;23324958;27738555;30482910;22554729",
"title": "Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection.",
"title_normalized": "salvage bacteriophage therapy for a chronic mrsa prosthetic joint infection"
} | [
{
"companynumb": "US-009507513-2007USA005683",
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"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "We report a treatment failure to azithromycin 2.0 g caused by a urethral Neisseria gonorrhoeae isolate with high-level azithromycin resistance in California. This report describes the epidemiological case investigation and phenotypic and genetic characterization of the treatment failure isolate.",
"affiliations": "From the *San Francisco Public Health Laboratory, San Francisco Department of Public Health, San Francisco, CA; †Neisseria Reference Laboratory, Department of Global Health and Center for AIDS and STD, University of Washington, Seattle, WA; ‡Public Health Laboratory, San Luis Obispo Department of Public Health, San Luis Obispo, CA; and §Sexually Transmitted Disease (STD) Control Branch, Division of Communicable Disease Control (DCDC), Center for Infectious Diseases (CID), California Department of Public Health (CDPH), Richmond, CA.",
"authors": "Gose|Severin O|SO|;Soge|Olusegun O|OO|;Beebe|James L|JL|;Nguyen|Duylinh|D|;Stoltey|Juliet E|JE|;Bauer|Heidi M|HM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D017963:Azithromycin",
"country": "United States",
"delete": false,
"doi": "10.1097/OLQ.0000000000000265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-5717",
"issue": "42(5)",
"journal": "Sexually transmitted diseases",
"keywords": null,
"medline_ta": "Sex Transm Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002140:California; D002443:Ceftriaxone; D016358:Contact Tracing; D024881:Drug Resistance, Bacterial; D005260:Female; D006069:Gonorrhea; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae; D011159:Population Surveillance; D017211:Treatment Failure; D014481:United States; D014526:Urethritis",
"nlm_unique_id": "7705941",
"other_id": null,
"pages": "279-80",
"pmc": null,
"pmid": "25868141",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10952602;18552343;24305088;25451056;19734823;20123998;10508026;24243880;25031289;24514092;23064537;19468025;22184617;15073688;12183262;20585125",
"title": "Failure of azithromycin 2.0 g in the treatment of gonococcal urethritis caused by high-level resistance in California.",
"title_normalized": "failure of azithromycin 2 0 g in the treatment of gonococcal urethritis caused by high level resistance in california"
} | [
{
"companynumb": "US-APOTEX-2018AP007988",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": nul... |
{
"abstract": "The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer's disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer's disease or another dementing disorder if not for the systematic investigation to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient's cognition improved greatly.",
"affiliations": "Department of Neurology, University of Louisville, Louisville, KY, USA.;University of Louisville, School of Medicine, Louisville, KY, USA.;Department of Neurology, University of Louisville, Louisville, KY, USA.;Department of Neurology, University of Louisville, Louisville, KY, USA.",
"authors": "Kurlawala|Zimple|Z|;Roberts|Jeffrey A|JA|;McMillan|Joseph D|JD|;Friedland|Robert P|RP|",
"chemical_list": "D001569:Benzodiazepines; D003975:Diazepam",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/JAD-180745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1387-2877",
"issue": "66(3)",
"journal": "Journal of Alzheimer's disease : JAD",
"keywords": "Alzheimer’s disease; benzodiazepine; dementia; diazepam",
"medline_ta": "J Alzheimers Dis",
"mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D001569:Benzodiazepines; D003937:Diagnosis, Differential; D003975:Diazepam; D006801:Humans; D008297:Male; D008569:Memory Disorders",
"nlm_unique_id": "9814863",
"other_id": null,
"pages": "935-938",
"pmc": null,
"pmid": "30400100",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diazepam Toxicity Presenting as a Dementia Disorder.",
"title_normalized": "diazepam toxicity presenting as a dementia disorder"
} | [
{
"companynumb": "US-PFIZER INC-2018467549",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NITROGLYCERIN"
},
"drugadditional": null,
... |
{
"abstract": "The management of choroid plexus carcinoma (CPC) is challenging and multifaceted. Here, we discuss a 3-year-old girl with CPC and Li-Fraumeni syndrome who achieved full remission after surgery and chemotherapy, with radiation therapy spared. At recurrence, we used a novel, standard-dose cytotoxic chemotherapy regimen, focal proton radiation therapy, and targeted agents based on morphoproteomic analysis to achieve long-term survival. We highlight the rationale for our therapy at recurrence, as well as the risk-benefit analyses necessary in decision making for these patients. Our strategy may be effective in managing other patients with recurrent CPC and Li-Fraumeni syndrome.",
"affiliations": "*Department of Pediatrics, University of Colorado School of Medicine †Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO ‡Pediatric Neuro-Oncology, Children's Hospital Los Angeles, Los Angeles, CA §Department of Pediatric Oncology, Dana-Farber Cancer Institute ∥Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA ¶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI #Department of Pathology, UTHealth McGovern Medical School, Houston, TX **AbbVie, Chicago, IL.",
"authors": "McEvoy|Matthew|M|;Robison|Nathan|N|;Manley|Peter|P|;Yock|Torunn|T|;Konopka|Kristine|K|;Brown|Robert E|RE|;Wolff|Johannes|J|;Green|Adam L|AL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000965",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "39(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002277:Carcinoma; D002675:Child, Preschool; D016545:Choroid Plexus Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome; D008279:Magnetic Resonance Imaging; D060787:Neoplasm Grading; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e473-e475",
"pmc": null,
"pmid": "28859040",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21601526;22529099;23301664;25662896;10382700;25106865;22271210;18381756;25017376;25336695;20308654;23794020;24166581;20586629;21990040;12402146;24573247;22162424;16000081;21593785",
"title": "Successful Treatment of Recurrent Li-Fraumeni Syndrome-related Choroid Plexus Carcinoma.",
"title_normalized": "successful treatment of recurrent li fraumeni syndrome related choroid plexus carcinoma"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201800379",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare autoimmune disorder characterized by vesiculobullous mucocutaneous eruptions. LABD also has been reported as a drug-induced reaction. Idiopathic LABD and drug-induced LABD are clinically indistinguishable and can resemble bullous pemphigoid, dermatitis herpetiformis, or bullous erythema multiforme. LABD is diagnosed with direct immunofluorescence (DIF), and idiopathic LABD can be distinguished from drug-induced LABD with a careful medication history. We present the case of a 54-year-old man with drug-induced LABD after ingestion of rimantadine, zanamivir, and azithromycin for presumed influenza. The patient's bullous eruption resolved with discontinuation of the offending medications and treatment with prednisone and pentoxifylline.",
"affiliations": "University of Texas Medical Branch, Galveston TX 77550, USA. jecummin@utmb.edu",
"authors": "Cummings|Julie E|JE|;Snyder|Renee R|RR|;Kelly|Erica B|EB|;Raimer|Sharon S|SS|",
"chemical_list": "D000890:Anti-Infective Agents; D007070:Immunoglobulin A; D012299:Rimantadine; D017963:Azithromycin; D053243:Zanamivir",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "79(3)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000890:Anti-Infective Agents; D001327:Autoimmune Diseases; D017963:Azithromycin; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D007070:Immunoglobulin A; D008297:Male; D008875:Middle Aged; D012299:Rimantadine; D012867:Skin; D012872:Skin Diseases, Vesiculobullous; D013262:Stevens-Johnson Syndrome; D053243:Zanamivir",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "203-7",
"pmc": null,
"pmid": "17674585",
"pubdate": "2007-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced linear immunoglobulin A bullous dermatosis mimicking Stevens-Johnson syndrome: a case report.",
"title_normalized": "drug induced linear immunoglobulin a bullous dermatosis mimicking stevens johnson syndrome a case report"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-B0477588A",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZANAMIVIR"
},
"drugadditional": "1",
... |
{
"abstract": "Off-label use of rituximab is commonly requested for patients with resistant nephropathies. The outcomes and tolerability of rituximab in adult patients with nephropathy treated at our hospital (from 2013 to 2018) were described. Data were retrieved from electronic medical records. Response was classified as complete remission (CR), partial remission (PR), or no response (NR) according to the KDIGO criteria. A total of 89 requests were received for 61 patients. Median age was 58 years (45.9% female). Idiopathic membranous nephropathy (MN) (n = 30) was the most frequent indication, followed by minimal change disease (MCD) (n = 15) and secondary membranoproliferative glomerulonephritis (MPGN) (n = 12). Three patients with focal segmental glomerulosclerosis (FSGS) were included. After most treatment cycles in MN, a CR or PR was observed; median proteinuria levels significantly decreased for these patients (6000 mg/24h (IQR 3584-10,300) vs. 1468.8 (IQR 500-4604.25), p < 0.01). In MPGN, no response was documented after 46.7% of rituximab cycles. A CR or PR was described with the majority of rituximab cycles in MCD, with a significant decrease in proteinuria (6000 mg/24 h (IQR 4007-11,426) vs. 196.8 (IQR 100-1300), p = 0.013). No cycles produced a response in FSGS. Mean CD19+ B-cell decreased in all types of nephropathy (10.44% vs. 0.29%, p < 0.0001). Eleven patients presented infusion-related reactions, and 17 presented infectious complications. The majority of patients with MN and MCD had complete or partial responses; however, neither MPGN nor FSGS had encouraging results.",
"affiliations": "Department of Clinical Pharmacology, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.;Department of Clinical Pharmacology, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.;Department of Internal Medicine, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.;Department of Nephrology, Referrer in Complex Glomerular Diseases in Adults, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.;Pharmacy Service, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.;Department of Clinical Pharmacology, Vall d'Hebron Hospital Universitari, 08035 Barcelona, Spain.",
"authors": "Sans-Pola|Carla|C|0000-0002-5834-3183;Agustí|Antònia|A|;Bosch|Josep Àngel|JÀ|;Agraz|Irene|I|0000-0002-4223-6834;Alerany|Carmen|C|;Danés|Immaculada|I|0000-0002-8711-9666",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10214941",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n10.3390/jcm10214941\njcm-10-04941\nArticle\nOff-Label Use of Rituximab in Patients with Different Types of Nephropathies in a Tertiary Hospital: A Retrospective Study\nhttps://orcid.org/0000-0002-5834-3183\nSans-Pola Carla 123\nAgustí Antònia 123*\nBosch Josep Àngel 45\nhttps://orcid.org/0000-0002-4223-6834\nAgraz Irene 6\nAlerany Carmen 7\nhttps://orcid.org/0000-0002-8711-9666\nDanés Immaculada 123\nCarcas-Sansuán Antonio J. Academic Editor\nBorobia Pérez Alberto M. Academic Editor\n1 Department of Clinical Pharmacology, Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain; csp.mir@icf.uab.cat (C.S.-P.); id@icf.uab.cat (I.D.)\n2 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain\n3 Immunomediated Diseases and Innovative Therapies Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain\n4 Department of Internal Medicine, Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain; jaboschg@gmail.com\n5 Department of Internal Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain\n6 Department of Nephrology, Referrer in Complex Glomerular Diseases in Adults, Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain; iagraz@vhebron.net\n7 Pharmacy Service, Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain; calerany@vhebron.net\n* Correspondence: antonia.ficf@gmail.com or ag@icf.uab.cat\n26 10 2021\n11 2021\n10 21 494117 9 2021\n24 10 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nOff-label use of rituximab is commonly requested for patients with resistant nephropathies. The outcomes and tolerability of rituximab in adult patients with nephropathy treated at our hospital (from 2013 to 2018) were described. Data were retrieved from electronic medical records. Response was classified as complete remission (CR), partial remission (PR), or no response (NR) according to the KDIGO criteria. A total of 89 requests were received for 61 patients. Median age was 58 years (45.9% female). Idiopathic membranous nephropathy (MN) (n = 30) was the most frequent indication, followed by minimal change disease (MCD) (n = 15) and secondary membranoproliferative glomerulonephritis (MPGN) (n = 12). Three patients with focal segmental glomerulosclerosis (FSGS) were included. After most treatment cycles in MN, a CR or PR was observed; median proteinuria levels significantly decreased for these patients (6000 mg/24h (IQR 3584–10,300) vs. 1468.8 (IQR 500–4604.25), p < 0.01). In MPGN, no response was documented after 46.7% of rituximab cycles. A CR or PR was described with the majority of rituximab cycles in MCD, with a significant decrease in proteinuria (6000 mg/24 h (IQR 4007–11,426) vs. 196.8 (IQR 100–1300), p = 0.013). No cycles produced a response in FSGS. Mean CD19+ B-cell decreased in all types of nephropathy (10.44% vs. 0.29%, p < 0.0001). Eleven patients presented infusion-related reactions, and 17 presented infectious complications. The majority of patients with MN and MCD had complete or partial responses; however, neither MPGN nor FSGS had encouraging results.\n\nrituximab\noff-label\nglomerulonephritis\nnephropathy\nclinical pharmacology\n==== Body\npmc1. Introduction\n\nRituximab is a chimeric mouse/human monoclonal antibody that binds specifically to the transmembrane antigen CD20 located on B lymphocytes. It was initially approved by the European Medicines Agency in 1998 for the treatment of patients with chemoresistant stage III–IV lymphoma. Since then, its indications have broadened, and it is currently authorized for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, and pemphigus vulgaris. However, it is also often prescribed off-label for the treatment of other indications, such as patients with resistant glomerulonephritis [1].\n\nOff-label medicine use refers to the prescription of a drug for unapproved indications, routes of administration, or patient groups [2]. Despite it being commonly used in clinical practice, the evidence on the efficacy, safety, and tolerability of the off-label use of medicines is often scarce.\n\nSince 2009, Spanish legislation regulates and classifies drug use in special situations, including the use of medicines in unapproved conditions, the use of unmarketed drugs, and compassionate use [3]. Taking into account that off-label use may increase the hospital spending on drugs and overall risks, the Catalan Health Service released an Instruction in 2010 to regulate its use in Catalonia [4]. A retrospective study published in 2013 described all the off-label rituximab requests received in the Vall d’Hebron University Hospital and described a high number of requests for hematologic diseases (46%), systemic connective tissue disorders (27%), and nephropathies (20%) [5]. A subsequent prospective study of patients treated with off-label drugs in five Catalan public hospitals included a total of 232 requests for 226 patients with 102 different diseases [6]. The most frequent pharmacological group was monoclonal antibodies, rituximab being the most frequent, which was used in 22 different indications in a one-year period.\n\nSo far, some case-series and small cohorts of patients with different refractory nephropathies treated with rituximab have been published [7,8,9,10,11,12].\n\nMembranous nephropathy (MN) is the most common cause of nephrotic syndrome in non-diabetic Caucasian adults [13]. Most cases are idiopathic (primary MN), but approximately 25% of MN are secondary. Most patients with primary MN have antibodies against podocyte proteins: 70–80% have circulating anti-phospholipase A2 receptor 1 (anti-PLA2R) autoantibodies, and a small percentage of patients with secondary MN can have them too [14]. There is a tight correlation between autoantibody levels and disease activity; thus, decreasing PLA2R-antibodies titer has become an important goal [14,15,16]. The ideal treatment of patients with primary membranous nephropathy is still unknown. They have been classically treated with alkylating agents, corticosteroids, and calcineurin inhibitors; however, the treatment benefits of these medicines remain uncertain and have been associated with serious adverse events [17]. The existing evidence that B lymphocytes play a crucial role in the pathogenesis of membranous nephropathy led to the testing of rituximab as a therapeutic approach. Some observational studies have described the safety and efficacy profile of rituximab in these patients [8,9,10], and a randomized non-inferiority clinical trial concluded that rituximab was non-inferior to cyclosporine in inducing complete or partial response of proteinuria after one year [18]. Although this has since then shed some light on the use of rituximab for the treatment of MN, it is noteworthy that only 30% of patients included in the clinical trial had a history of immunosuppressive therapy use and may not have been representative of the rituximab utilization in those patients with more history of failure with other immunosuppressants. Furthermore, another clinical trial showed that treatment with corticosteroid–cyclophosphamide (Ponticelli regimen) induced remission in a significantly greater number of patients with primary MN than tacrolimus–rituximab [16].\n\nMembranoproliferative glomerulonephritis (MPGN) is produced by deposits of antibodies that accumulate and proliferate in the basal membrane [19]. Current guidelines recommend treatment with corticosteroids and cytotoxic agents, with or without plasmapheresis, depending on the severity [17]. Rituximab has also been suggested as a treatment option for patients with primary MPGN; however, data on its use on these patients are limited to case reports and retrospective studies [11].\n\nMinimal Change Disease (MCD) is not characterized by immune deposits and has no glomerular lesions under light microscopy [19]. Its pathogenic mechanisms primarily affect the podocyte, and, together with focal segmental glomerulosclerosis (FSGS), it is known as podocytopathy. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend high-dose oral corticosteroids for initial treatment of MCD and FSGS [15]. In patients with contraindications for corticosteroids, they recommend initial treatment with cyclophosphamide, calcineurin inhibitors, or mycophenolate mofetil for MCD, and calcineurin inhibitors for FSGS. MCD is thought to be T cell-mediated; thus, the role of rituximab in this disease is still unclear. Some published clinical studies have described the efficacy of rituximab in MCD in pediatric patients; however, its clinical role in adult patients remains undetermined [20,21].\n\nCurrently, predictive biomarkers for rituximab treatment efficacy are unknown. However, measurement of CD19+ B cells in blood can be used as marker of successful B cell depletion and treatment efficacy [22].\n\nThe aim of this study was to assess the rate of response and tolerability of off-label use of rituximab in patients with resistant nephropathies, as well as the clinical evolution of treated patients\n\n2. Materials and Methods\n\nA retrospective observational study of adult patients with different types of primary or secondary nephropathy treated with off-label rituximab at the Vall d’Hebron University Hospital from January 2013 to December 2017 was performed. Patients were identified from a register of the off-label rituximab requests received at the Pharmacy Service. Patients were followed-up until December 2018. The study was conducted at the Clinical Pharmacology department, in collaboration with the Nephrology and Pharmacy departments.\n\nA review of electronic medical records was carried out to obtain demographic data, clinical data, information on the indication for rituximab use (clinical, biological, pathological, and image data according to each type of nephropathy), dosage and treatment regimen of rituximab, previous and concomitant treatments, short-term and long-term rituximab treatment outcomes, and adverse events. This information was verified by consulting the clinicians responsible for the patient’s care. Data were collected using data collection sheets and were registered into a database specifically designed for this study.\n\nAll patients treated with rituximab in the Vall d’Hebron University Hospital receive premedication intravenously before rituximab infusions, consisting of paracetamol 1 g, methylprednisolone 100 mg, and dexchlorpheniramine 5 mg, and after, they all receive prophylactic treatment with trimethoprim/sulfamethoxazole 160/800 mg to prevent infections.\n\nTreatment response was classified as complete remission (CR), partial remission (PR), or no response (NR) according to the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines for Glomerulonephritis criteria [17]. CR is defined as urinary protein excretion < 0.3 g/24 h (uPCR < 300 mg/g or < 30 mg/mmol), confirmed by two values at least 1 week apart, accompanied by a normal serum albumin concentration and a normal serum creatinine. PR refers to a urinary protein excretion < 3.5 g/24 h (uPCR < 3500 mg/g or < 350 mg/mmol) and a 50% or greater reduction from peak values, confirmed by two values at least 1 week apart, accompanied by an improvement or normalization of the serum albumin concentration and stable serum creatinine. Normal levels of protein excretion in urine are considered to be <150 mg/24 h [19]. The treatment response was assessed after each rituximab treatment cycle and for each type of nephropathy separately. Additionally, the proportion of patients who always had a CR or a PR and the proportion of those who never responded were also described. Before and after rituximab treatment CD19+ B-cell levels were only assessed for patients from 2015 to 2017 due to missing values for patients from previous years. For MN, before and after anti-PLA2R antibodies were also assessed (negative: < 14 RU/mL, borderline: 14–20 RU/mL, and positive: >20 RU/mL) [14]. Only patients from 2016 and 2017 were included in this analysis due to missing values for patients in previous years.\n\nAdverse events were classified and assessed according to the Medical Dictionary for Regulatory Activities (MedDRA®) [23] and the algorithm of the Spanish Pharmacovigilance System [24,25]. The International Classification of Diseases, 11th revision (ICD-11) was used to classify medical indications for rituximab use [26].\n\nThe study was conducted according to international ethical recommendations and was approved by the local Research Ethics Committee following the national directives related to post-authorization studies.\n\nStatistical analysis of categorical and continuous variables was performed by means of the distribution of frequencies and proportions, median, and interquartile range (IQR). Statistical differences were assessed using the Wilcoxon signed-rank test. Significance was set at a level of 0.05 and was two-tailed. The analysis was performed using RStudio 4.0.3 software (RStudio Team. RStudio: Integrated Development for R. RStudio, Inc., Boston, MA, USA).\n\n3. Results\n\nA total of 89 requests for off-label use of rituximab were received for 61 patients during the study period. All requests were approved. The median age was 58 (IQR 47.0–71.0) years, and 28 (45.9%) were female. Their baseline characteristics can be seen in Table 1. All prescribers were nephrologists. In most cases, each rituximab request or treatment cycle consisted of the administration of two doses of 1000 mg given intravenously on day 1 and day 14. Only 6.5% of cycles were adjusted to body surface (four cycles corresponding to four patients).\n\nThe most frequent indication was idiopathic membranous nephropathy (MN), with a total of 30 patients (49.2%), followed by minimal change disease (MCD) with 15 patients (24.6%) and secondary membranoproliferative glomerulonephritis (MPGN) with 12 patients (19.7%). Additionally, three patients (4.9%) with focal segmental glomerulosclerosis (FSGS) and one case of pauci-immune crescentic glomerulonephritis (PIGN), a rapidly progressive glomerulonephritis, were included. The most frequent comorbidities were hypertension and hyperlipidemia. In total, 15 patients had been previously diagnosed with a neoplasm (11 malignant; none were active at the moment of treatment with rituximab). Table 1 shows other comorbidities, previous treatments, and the median time from diagnosis to the first rituximab request for each type of nephropathy.\n\n3.1. Membranous Nephropathy\n\nIdiopathic MN was the most frequent type of nephropathy among included patients. There were two patients with secondary MN. One of them had a type 2 renal papillary carcinoma and persistent negative anti-PLA2R antibodies. The other one had a concomitant active VHC infection and positive anti-PLA2R. One of the patients with idiopathic MN was lost to follow-up after the first rituximab cycle.\n\nThere were a total of 47 rituximab requests for 30 MN patients. The median time from diagnosis to the first treatment cycle was 31.5 months (IQR 7.75–96.25), with a median time of follow-up of 33 months (IQR 19.25–51). Most patients had received some previous immunosuppressive treatment, with tacrolimus being the most frequent (19; 63.3%). Nineteen patients (63.3%) were receiving treatment with ACEIs and/or ARBs. Median baseline proteinuria levels for patients with MN were high, and their baseline renal function was slightly compromised (Table 1).\n\nThe median number of rituximab cycles was one (IQR 1–2), with a maximum of four. After rituximab treatment, the median proteinuria and serum albumin levels significantly decreased (Figure S1 and Table 2). However, for most patients this value was still over the considered normal level. Table 2 shows proteinuria, serum creatinine, and serum albumin levels before and after treatment for each type of nephropathy.\n\nAll but one patient had positive baseline levels of anti-PLA2R antibodies, with a median value of 57.65 RU/mL (IQR 14.15–105.1). After rituximab treatment, the median levels of anti-PLA2R antibodies were 2.6 RU/mL (IQR 2–5.7).\n\nTable 3 shows the results after each rituximab treatment cycle for each type of nephropathy. After most cycles in patients with MN, a CR or PR was observed (36.2% and 40.4%, respectively). The median time from the treatment cycle to response was 2 months (IQR 1–5).\n\nA total of 23.3% and 26.7% of patients always had a CR or PR after rituximab cycles, respectively. However, eight patients (26.7%) never responded (Table S1). Among the patients that relapsed after having responded partially or completely to rituximab, the median time from treatment to relapse was 24 months (IQR 16–31). Additional information can be found in Table S1.\n\nA total of 22 patients (73.3%) received concomitant treatment with one or more immunosuppressive medication during the treatment with rituximab, and the same number of patients needed further therapy after rituximab, either to maintain disease remission or to treat new flares. Table 4 shows concomitant and post-rituximab treatments.\n\n3.2. Membranoproliferative Glomerulonephritis\n\nMost of the included MPGN cases were related to HCV infection and type II cryoglobulinemia. There was only one patient with idiopathic MPGN. There was a total of 15 off-label rituximab requests for 12 patients. Median time from diagnosis to the first cycle was 4 months (IQR 1–10), and median follow-up time was 26 months (IQR 9.25–63). See Table 1 for baseline characteristics.\n\nFor these patients, the median number of previous immunosuppressants was 1.5 (IQR 1–3), and the most frequently used were corticosteroids (7; 58.3%), followed by cyclophosphamide (4; 33.3%), in accordance with current clinical practice guidelines. In addition, to treat HCV infection prior to the rituximab treatment, four patients with HCV-related secondary MPGN had already received antiviral therapy, such as entecavir, ritonavir, lamivudine, ribavirin, and sofosbuvir. Median baseline proteinuria levels for patients with MPGN were high, although they appeared to be milder than for patients with MN; however, their baseline renal function appeared to be highly compromised.\n\nThe median number of rituximab cycles was one (IQR 1–2), and the patient who received the higher number of treatment cycles received a total of two. A total of 46.7% of cycles did not induce disease remission (Table 3), and there was no significant difference between before and after proteinuria levels (Table 2). Among those cycles that induced remission, the median time from treatment to response was 0.5 months (IQR 0–1).\n\nHalf of the MPGN patients never responded to rituximab (Table S1). A total of 10 patients (83.3%) received concomitant therapy, with a median number of concomitant immunosuppressants of 1.5 (IQR 1–3) (Table 4). Other therapies were also used concomitantly in some patients, such as plasmapheresis (1; 8.3%), hemodialysis (1; 8.3%), and antiviral medicines to treat the HCV infection (3; 25%). Most patients required other therapies after rituximab treatment to achieve disease remission (Table 4).\n\n3.3. Minimal Change Disease\n\nAll cases of MCD were idiopathic. There was a total of 23 requests for 15 patients. One patient who received only one cycle was lost to follow-up. The median time from diagnosis to the first treatment cycle was 15.5 months (IQR 9–38.75). Median follow-up time was 24 months (IQR 17–30.5). Most patients had received prior immunosuppressant treatments. The median baseline proteinuria was high, and serum albumin levels were accordingly low. Their renal function (glomerular filtration rate and serum creatinine) was not as compromised. Other baseline characteristics can be seen in Table 1. A total of 86.7% of patients had a steroid-dependent nephrotic syndrome.\n\nThe median number of rituximab cycles was one (IQR 1–2), with a maximum of three. There was a significant decrease in before and after rituximab proteinuria and a significant increase in serum albumin levels (Table 2). As seen in Table 3 after most cycles, some response was observed (CR in 56.5% and PR in 26.1% PR). The median time from treatment cycle to response was 1 month (IQR 1–1).\n\nA total of 66.7% of patients (n = 10) always had a CR after rituximab cycles, and only 13.3% of them (n = 2) never responded (Table S1). Among the patients who relapsed after having a PR or CR, the median time from treatment to relapse was 15 months (IQR 12.75–27).\n\nA total of 12 patients (80%) received one or more concomitant immunosuppressants during their treatment with rituximab, with a median number of two different agents (IQR 1.5–2) (Table 4). The need for immunosuppressive treatment seemed lower after receiving rituximab (median 1; IQR 0–1.5), mainly due to a reduction in the use of corticosteroids. Treatments after rituximab therapy can be seen in Table 4.\n\n3.4. Focal Segmental Glomerulosclerosis\n\nTwo patients with idiopathic FSGS and one patient with genetic FSGS, related to LMX1B gene mutation, were included. There were three requests for three patients. The median time from diagnosis to the first request was 9.5 months (IQR 7.25–11.75). Baseline proteinuria levels were very high, with accordingly low serum albumin levels, and their baseline renal function was compromised. Other baseline characteristics can be seen in Table 1.\n\nAll patients had received two or more previous immunosuppressive drugs, with a median of four (IQR 3–4), and two of them had received previous treatment with ACEIs and/or ARBs (Table 1). None of the cycles produced a treatment response (Table 3), and there were no significant differences in before and after proteinuria levels (Table 2). All patients required concomitant and post-rituximab medication (Table 4). Two of them required hemodialysis.\n\n3.5. Pauci-Immune Crescentic Glomerulonephritis\n\nThe single case of rapidly progressive glomerulonephritis was a 72-year-old patient who did not respond to previous treatment with corticosteroids (Table 1). Anti-glomerular basement membrane antibodies (Anti-GBM) and antineutrophil cytoplasmic antibodies (ANCA) were both negative, and the patient was diagnosed with pauci-immune crescentic glomerulonephritis (PICGN). The patient received one rituximab cycle, but no response was achieved (Table 2, Table 3 and Table S1) and eventually required treatment with plasmapheresis and cyclophosphamide with bad results (Table 4).\n\n3.6. CD19+ B-Cell Levels\n\nFrom the year 2015 to 2017, 31 patients received one or more rituximab treatment cycles: 13 MN patients (41.9%), 12 MCD patients (38.7%), 4 MPGN patients (12.9%), and 2 other patients with a FSGS and a RPGN. Considering all the patients included in this period (n = 31), the CD19+ B cell values (in percentage) were higher before rituximab treatment than after, with mean values of 10.44% (95% confidence interval (95% CI) 7.6–14.2) and 0.29% (95% CI 0.008–1), respectively. This difference was statistically significant (p < 0.0001). The median time from treatment to CD19+ B cell assessment was of 1 month (IQR 1–2).\n\nAll patients had a depletion of CD19+ B cells after rituximab treatment, and most (80.6%) responded to rituximab; however, six patients (19.4%) did not have a significant decrease in proteinuria levels and did not respond to the treatment. It is worth mentioning that four patients had no detectable CD19+ B cells at baseline but were treated with rituximab regardless because of the severity of their disease. They all had a complete or partial response. Figure 1 shows mean CD19+ B cell values before and after rituximab for each of the three main types of nephropathies (MN, MCD, and MPGN) in this period.\n\n3.7. Adverse Events\n\nTwenty-eight patients (45.9%) presented adverse events during the study period (Table 5). Eleven patients (18.0%) presented infusion-related adverse reactions, such as skin rash, uvular edema, rhinorrhea, sneezing, and dysphonia during the infusion. One of these patients presented a similar reaction after the first administration of ofatumumab. One patient had a serum sickness-like reaction after the rituximab administration. Other adverse events included a non-ST elevation myocardial infarction during the infusion that required coronary catheterization and stent implantation. Seventeen patients (27.9%) presented one or more infectious complications during the study period. Five patients (8.2%) did not receive any further rituximab cycles due to adverse events (three infusion reactions, one serum sickness-like, and one myocardial infarction).\n\n4. Discussion\n\nThe results of this study show that the off-label use of rituximab among our patient cohort was mainly for the treatment of idiopathic membranous nephropathy (MN), minimal change disease (MCD), and membranoproliferative glomerulonephritis (MPGN). Some complete and partial responses after rituximab treatment were achieved in patients with MN and MCD; however, treatment response in patients with MPGN or focal segmental glomerulosclerosis (FSGS) was scarce. Most patients had received immunosuppressive treatments before the first rituximab request.\n\nAvailable evidence for using rituximab to treat these diseases is variable and still scarce, mainly based on observational studies and case-series. In patients with MN, some observational studies have described the safety and effectiveness profile of rituximab [8,9,10,27]. A randomized non-inferiority clinical trial (MENTOR) published in 2018, which included 130 patients with membranous nephropathy and compared rituximab and cyclosporine for the treatment of these patients, concluded that rituximab was non-inferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months [18]. Sixty percent of patients of the rituximab group had a complete or partial remission at 24 months, after two cycles of rituximab administered at the beginning of the study and after 6 months in the case of partial response. Patients included in our study had a greater previous exposure to other immunosuppressants before rituximab use than those included in the MENTOR study, suggesting that could probably have a more severe or prolonged disease. Another randomized open-label controlled clinical trial (STARMEN) concluded that treatment with a traditional Ponticelli regimen induced remission in a significantly greater number of patients than a sequential treatment of tacrolimus and rituximab [16]. It is worth noting that patients who had received previous treatment with corticosteroids, other immunosuppressive agents, or any other biologic agent some time before screening, and those who were nonresponsive to previous immunosuppressants, were excluded from this trial. This is far from the reality of patients with MN treated with rituximab in clinical practice. Thus, once again, patients included in our study had a greater previous exposure to other immunosuppressants before rituximab use. This suggests that the results from currently available clinical trials may not be applicable in patients with a more severe disease. Additionally, while it is true that a cyclophosphamide-based regime mostly results in rapid control of the disease, it is worth noting that they are sometimes avoided or discontinued in clinical practice due to its long-term toxicity. It is speculated by some authors that this toxicity could be decreased by reducing glucocorticoid administration or by using less cyclophosphamide but in combination with rituximab [28].\n\nDespite this, our results show that most of the patients with MN had either a complete or a partial response after rituximab treatment, and in half of them, some response was always maintained during follow-up. Among those patients who relapsed after a response, the median time from treatment to relapse was 24 months. There were significant differences in before and after proteinuria levels and a decrease in anti-PLA2R antibody levels. In the STARMEN trial, anti-PLA2R levels showed a significant decrease in both groups, and early immunologic response was followed by clinical remission in most patients, which confirms the usefulness of anti-PLA2R monitoring in this disease [16]. Another trial shows that anti-PLA2R levels are early markers of rituximab efficacy, whereas the effect on proteinuria remission appears after 6 months, suggesting that they should be included in criteria for remission [15]. There are currently other ongoing clinical trials evaluating the use of rituximab in MN (clinicaltrials.gov, NCT04154787, NCT03949855, NCT04743739, NCT03018535, NCT03880643, NCT03804359, and NCT00977977).\n\nSome studies showed partial and complete responses in idiopathic MPGN, but rituximab was not effective in patients with complement-mediated C3 glomerulonephritis and dense deposit disease [11]. The results of these studies have been variable, and it is still difficult to draw any conclusions. There are no results from randomized clinical trials evaluating rituximab in MPGN. Our results show that half of the patients with MPGN never responded to rituximab, and there were no differences between the before and after proteinuria levels. However, more than half of patients with some response after rituximab treatment did not relapse during the follow-up period. Most of these patients had MPGN related to HCV infection and received specific antiviral treatment after rituximab, which could have contributed to the maintenance of the therapeutic response during the follow-up period. Due to the limited number of patients in our study, these results should be confirmed with larger studies.\n\nAs for MCD and FSGS, Hansrivijit et al. conducted a systematic review and meta-analysis that included a total of 221 adult patients with MCD or FSGS, and the results indicated that rituximab may be considered as an additional treatment to the standard therapy for these patients [29]. In this study, 53.6% of patients with FSGS and 80.3% with MCD achieved remission, with disease recurring in 47.3% and 35.9%, respectively. These results must be interpreted taking into account a possible publication bias. Recently, a retrospective study assessing the use of rituximab for refractory or relapsed FSGS or MCD in 25 patients has been completed, but no results have been published yet (clinicaltrials.gov, NCT04369183), and there is currently an ongoing phase 3 clinical trial that aims to enroll 40 patients (clinicaltrials.gov, NCT03298698). In our study, most patients with MCD always had a complete or partial response after rituximab treatment, and most patients achieved a complete or partial response after rituximab cycles. More than half of them maintained the good response during study follow-up period. The fact that the number of immunosuppressive agents seemed to decrease after having received treatment with rituximab suggests a better outcome in these patients during the study period. In a similar way to MN, MCD patients had a significant decrease in proteinuria levels after treatment compared with baseline. The limited available evidence in patients with FSGS suggests that rituximab does not achieve great results, and similarly, the results in our patients with FSGS were not good. However, a recently published retrospective study that included 21 patients with FSGS suggests that rituximab significantly reduces the number of relapses [30]. The small number of patients treated in our center does not allow us to draw any conclusions.\n\nThe interpretation of these results should be carried out bearing in mind that the patients were refractory to or dependent on other treatments. Additionally, the fact that some patients were receiving concomitant immunosuppressant treatments and that the majority needed further treatment after rituximab treatment to maintain disease remission or to treat new flares, including plasmapheresis and hemodialysis, needs to be considered.\n\nOur CD19+ B cell count analysis showed that there were statistically significant differences between the values before and after rituximab treatment and that most of the patients included in this analysis had a decrease in CD19 levels and a decreased proteinuria. However, we do not have enough evidence to conclude that those patients with no changes in CD19 levels did not respond to treatment with rituximab. Some of our patients with no CD19+ B cells at baseline responded to rituximab. Similar cases of treatment success despite the absence of circulating B cells have been described, and some authors suggest a possible role of CD20+ T cells in the pathogenesis of MCD [29]. The study by Fervenza et al. shows that, after rituximab, the CD19+ counts remained low at 12 months. Thus, a residual therapeutic effect of rituximab beyond this time period cannot be ruled out [18]. Nonetheless, in three previous studies, CD19+ counts at 12 months showed no relation to proteinuria response [15,31,32], and there is a lack of information on CD19 counts from other clinical trials [16,18].\n\nThe existence of anti-rituximab antibodies that could neutralize rituximab B cell cytotoxicity and consequently impact the clinical outcome of patients has been suggested as a possible explanation for the course of those patients that respond to the first cycles of rituximab but stop achieving responses for subsequent cycles. Some authors suggest that fully human anti-CD20, such as ofatumumab, could be a therapeutic alternative for these patients [33].\n\nAdverse events identified in our study were similar to previously published observational case series [8,10,11,12,34]. Infections were the most frequently described adverse events in our study, with a higher rate than in clinical trials and meta-analysis [18,31,33,34,35]. However, it is worth noting that most of our patients received other immunosuppressant drugs concomitantly or after treatment with rituximab, which can have an impact on the incidence of infections. A total of 71% of patients in the rituximab group included in the MENTOR trial presented an adverse event during the trial study period, and 25% presented an infusion-related reaction (18% in our study) [18].\n\nThis study has some limitations. Firstly, it is an observational study with a retrospective design and without a control group; thus, results might be subject to bias. For the same reason, some results were missing in clinical records, and missing values had to be handled in some analyses. In addition, the group of diseases included, although they are all nephropathies, had different pathogenetic mechanisms involved, and the characteristics of the patients were also different. Consequently, this implies a smaller number of patients in each group. In addition, only one center was included in our study; therefore, our results can be affected by a selection bias and cannot be extrapolated to other hospitals in other geographical areas. Treatment strategies may have changed during the study period, and rituximab is probably used more frequently in some patients with MN in the later years. The main strengths of our study are, on the one hand, that the participating center is a third-level hospital with all medical and surgical specialties and a high level of complexity; and, on the other hand, all patients were followed by the same two nephrologists, both of whom are experts in glomerular disease and assessed patients following the same criteria. Additionally, each patient was normally assessed by the same nephrology specialist in each visit. This reduces the variability in the assessment of the treatment response. Furthermore, all rituximab requests were assessed and approved by the drug and therapeutics committee, which guarantees an additional thorough evaluation of each case.\n\n5. Conclusions\n\nAmong our patients, membranous nephropathy, minimal change disease, and membranoproliferative glomerulonephritis were the main indications for off-label use of rituximab in nephropathies. Some short-term partial and complete response was achieved for patients with membranous nephropathy and minimal change disease, but neither membranoproliferative glomerulonephritis nor focal segmental glomerulosclerosis had encouraging results in our study. Data from future prospective studies and clinical trials may provide useful information on the results of rituximab treatment in patients with these diseases to further improve clinical practice and off-label prescribing decisions.\n\nAcknowledgments\n\nWe thank Xavier Barroso (Catalan Institute of Pharmacology Foundation) for his technical support with the database and Xavier Vidal (Department of Clinical Pharmacology, Vall d’Hebron Hospital Universitari) for his support with statistics and data analysis.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/jcm10214941/s1, Table S1: Observed patient outcomes for each type of nephropathy, Figure S1: Proteinuria levels before and after rituximab (RTX) treatment for each type of nephropathy.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, I.D., A.A., J.À.B., I.A., and C.A.; methodology, C.S.-P., I.D., and A.A.; software (statistics), C.S.-P.; validation, I.D., A.A., J.À.B., and I.A.; formal analysis, C.S.-P.; investigation, C.S.-P., I.D., A.A., and J.À.B.; data curation, C.S.-P.; writing—original draft preparation, C.S.-P.; writing—review and editing, I.D., A.A., J.À.B., and I.A.; visualization, C.S.-P.; supervision, I.D., A.A., and J.À.B.; project administration, I.D. and A.A. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and the study was approved by the Ethics Committee of Vall d’Hebron Hospital Universitari (protocol code FIC-RITUX-2018-01 and date of approval 10 July 2018).\n\nInformed Consent Statement\n\nPatient consent was waived because the study was retrospective, containing deidentified data.\n\nData Availability Statement\n\nThe data presented in this study are available on request from the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 CD19+ B cell values before and after rituximab (RTX) for each of the three main types of nephropathy (MN, MCD, and MPGN). MN: membranous nephropathy. MPGN: membranoproliferative glomerulonephritis. MCD: minimal change disease. Rtx: rituximab.\n\njcm-10-04941-t001_Table 1 Table 1 Baseline clinical characteristics of patients.\n\nType of GN\nn (%)\tMN\n30 (49.2)\tMPGN\n12 (19.7)\tMCD\n15 (24.6)\tFSGS\n3 (4.9)\tPICGN\n1 (1.6)\t\nAge (median (IQR)) years\t61 (45–71)\t58 (53–66)\t53 (43–7)\t52 (48–60)\t72\t\nSex\nWomen, n (%)\nMen, n (%)\t\n12 (40)\n18 (60)\t\n7 (58.3)\n5 (41.7)\t\n7 (46.6)\n8 (53.3)\t\n2 (66.7)\n1 (33.3)\t\n0\n1 (100)\t\nTobacco smoking, n (%)\t11 (36.7)\t8 (66.6)\t6 (40.0)\t1 (33.3)\t1 (100)\t\nAlcohol consumption, n (%)\t4 (13.3)\t3 (25.0)\t0\t0\t1 (100)\t\nComorbidities, n (%)\nHypertension\nHyperlipidemia\nObesity\nType 2 diabetes\nHyperuricemia\nNeoplasms\nAutoimmune diseases\nHepatitis C infection\nHepatitis B infection\nType II cryoglobulinemia\t\n16 (53.3)\n17 (56.7)\n4 (13.3)\n5 (16.7)\n9 (30.0)\n6 (20.0)\n2 (6.7)\n1 (3.3)\n1 (3.3)\n0\t\n8 (66.7)\n4 (33.3)\n1 (8.3)\n3 (25.0)\n0\n6 (50.0)\n5 (41.7)\n9 (75.0)\n3 (25.0)\n9 (75.0)\t\n6 (40.0)\n3 (20.0)\n4 (26.7)\n1 (6.7)\n1 (6.7)\n2 (13.3)\n4 (26.7)\n1 (6.7)\n0\n0\t\n1 (33.3)\n2 (66.7)\n1 (33.3)\n1 (33.3)\n0\n0\n2 (66.7)\n0\n0\n0\t\n1 (100)\n0\n0\n0\n0\n1 (100)\n1 (100)\n0\n0\n0\t\nProteinuria (median (IQR))\nmg/24 h\t6700\n(3584–12,800)\t1856\n(771.5–3423.8)\t6000\n(4300–11,800)\t8078\n(4418.8–10,313.2)\tN/D\t\nSerum creatinine (median (IQR))\nmg/dL\t1.11\n(0.89–1.83)\t2.06\n(1.21–2.93)\t0.98\n(0.78–1.52)\t1.9\n(1.37–2.03)\t7.26\t\nSerum albumin (median (IQR))\ng/dL\t3.08\n(2.4–3.6)\t3.13\n(3.03–3.56)\t2.9\n(2.26–3.1)\t2.97\n(2.89–3.39)\tN/D\t\nGlomerular filtration rate\n(median (IQR))\nmL/min/1.73 m2\t75 (59–89)\t29 (20.5–48.5)\t77.5 (52–90)\t40 (33–63.9)\t7\t\nMonths from diagnosis to first RTX cycle (median (IQR))\t31.5\n(7.75–96.25)\t4\n(1–10)\t15.5\n(9–38.75)\t9.50\n(7.25–11.75)\t0\t\nNo. of previous immunosuppressive treatments (median (IQR))\t1 (1–2)\t1.5 (1–3)\t2 (1.5–2)\t4 (3–4)\t1\t\nPrevious immunosuppressants\nn (%)\nCorticosteroids\nTacrolimus\nMycophenolate mofetil\nOther\t\n\n10 (33.3)\n19 (63.3)\n4 (13.3)\n5 (16.7)\t\n\n7 (58.3)\n3 (25.0)\n1 (8.3)\n5 (41.7)\t\n\n13 (86.7)\n10 (66.7)\n2 (13.3)\n3 (20.0)\t\n\n3 (100)\n2 (66.7)\n2 (66.7)\n2 (66.7)\t\n\n1 (100)\n0\n0\n0\t\nOther\t\t\t\t\t\t\nACEIs or ARBs n (%)\t19 (63.3)\t3 (2.5)\t10 (66.7)\t2 (66.7)\t0\t\nMN: membranous nephropathy. MPGN: membranoproliferative glomerulonephritis. MCD: minimal change disease. FSGS: focal segmental glomerulosclerosis. RTX: rituximab. N/D: No data available. IQR: interquartile range.\n\njcm-10-04941-t002_Table 2 Table 2 Proteinuria, serum creatinine, and serum albumin values before and after rituximab treatment for the three main types of nephropathies.\n\n\tMN\tMPGN\tMCD\t\nBefore\tAfter\tp\tBefore\tAfter\tp\tBefore\tAfter\tp\t\nProteinuria\n(median (IQR))\nmg/24 h\t6000\n(3584–10,300)\t1468.8\n(500–4604.25)\t<0.01\t1856\n(771.5–3423.8)\t1000\n(846–6036)\t0.59\t6000\n(4007–11,426)\t196.8\n(100–1300)\t0.013\t\nSerum creatinine (median (IQR))\nmg/dL\t1.01\n(0.89–1.26)\t1.05\n(0.91–1.33)\t0.58\t1.7\n(1.21–2.78)\t1.55\n(1.18–3.08)\t0.64\t1.05\n(0.79–1.53)\t0.88\n(0.74–1.16)\t0.56\t\nSerum albumin (median (IQR))\ng/dL\t3.34\n(2.528–3.653)\t3.85\n(3–4.095)\t0.002\t3.13\n(3.1–3.56)\t3.305\n(3.028–4.033)\t0.33\t2.9\n(2.26–3.25)\t4\n(3.6–4.22)\t0.003\t\nN: membranous nephropathy. MPGN: membranoproliferative glomerulonephritis. MCD: minimal change disease. IQR: interquartile range.\n\njcm-10-04941-t003_Table 3 Table 3 Observed outcome after each rituximab treatment cycle.\n\nType of GN\tMN\tMPGN\tMCD\tFSGS\tPICGN\t\nNo. of RTX treatment cycles, n\t\n47\t\n15\t\n23\t\n3\t\n1\t\nOutcome after RTX treatment cycles:\nCR, n (%)\nPR, n (%)\nNR, n (%)\nUnknown, n (%)\t\n\n17 (36.2)\n19 (40.4)\n10 (21.3)\n1 (2.1) a\t\n\n4 (26.7)\n4 (26.7)\n7 (46.7)\n0\t\n\n13 (56.5)\n6 (26.1)\n3 (13.0)\n1 (4.3) a\t\n\n0\n0\n3 (100)\n0\t\n\n0\n0\n1 (100)\n0\t\nMN: membranous nephropathy. MPGN: membranoproliferative glomerulonephritis. MCD: minimal change disease. FSGS: focal segmental glomerulosclerosis. CR: complete response. PR: partial response. NR: no response. RTX: rituximab. a Patients lost to follow-up.\n\njcm-10-04941-t004_Table 4 Table 4 Concomitant and post-RTX treatment.\n\nType of GN\nn (%)\tMN\n30 (49.2)\tMPGN\n12 (19.7)\tMCD\n15 (24.6)\tFSGS\n3 (4.9)\tPICGN\n1 (1.6)\t\nNo. of concomitant immunosuppressive treatments (median (IQR))\t1 (1–2)\t1.5 (1–3)\t2 (1.5–2)\t4 (3–4)\t1\t\nConcomitant immunosuppressants, n (%)\nCorticosteroids\nTacrolimus\nMycophenolate mofetil\nCyclosporine A\t\n4 (13.3)\n16 (53.3)\n2 (6.7)\n2 (6.7)\t\n3 (25.0)\n2 (16.7)\n3 (25.0)\n1 (8.3)\t\n7 (46.7)\n4 (26.7)\n3 (20.0)\n1 (6.7)\t\n2 (66.7%)\n1 (33.3)\n0\n1 (33.3)\t\n1 (100)\n0\n0\n0\t\nNo. of post-RTX immunosuppressive treatments (median (IQR))\t1 (0.25–2)\t2.5 (2–3)\t1 (0–1.5)\t1 (1–2.5)\t2\t\nPost-RTX immunosuppressants, n (%)\nCorticosteroids\nTacrolimus\nMycophenolate mofetil\nOther\t\n5 (16.7)\n18 (60.0)\n3 (10.0)\n5 (16.7)\t\n2 (16.7)\n5 (41.7)\n2 (16.7)\n1 (8.3)\t\n4 (26.7)\n4 (26.7)\n4 (26.7)\n0\t\n1 (33.3)\n1 (33.3)\n0\n1 (33.3)\t\n0\n0\n0\n1 (100)\t\nPost-RTX plasmapheresis, n (%)\t0\t4 (33.3)\t0\t0\t1 (100)\t\nPost-RTX hemodialysis, n (%)\t2 (6.7)\t2 (16.7)\t2 (13.3)\t2 (66.7)\t0\t\nMN: membranous nephropathy. MPGN: membranoproliferative glomerulonephritis. MCD: minimal change disease. FSGS: focal segmental glomerulosclerosis. IQR: interquartile range.\n\njcm-10-04941-t005_Table 5 Table 5 Summary of adverse events.\n\nAdverse Event\tn (%)\t\nAny adverse event\t28 (45.9)\t\nAdverse eventsa:\t\t\nInfections\t24 (39.3)\t\nSepsis without septic shock\t5 (8.2)\t\nUrinary tract infection\t4 (6.6)\t\nSepsis with septic shock\t3 (4.9)\t\nLower respiratory infection\t3 (4.9)\t\nBacterial cellulitis\t2 (3.3)\t\nCytomegaloviral disease\t2 (3.3)\t\nDental abscess\t1 (1.6)\t\nPostoperative wound infection\t1 (1.6)\t\nPyothorax\t1 (1.6)\t\nGastroenteritis due to Campylobacter\t1 (1.6)\t\nIntestinal infections due to Clostridioides difficile\t1 (1.6)\t\nInfusion-related reaction\t11 (18.0)\t\nSerum sickness-like reaction\t1 (1.6)\t\nST-elevation myocardial infarction\t1 (1.6)\t\na 28 patients presented 37 adverse events during the study period.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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"issn_linking": "2077-0383",
"issue": "10(21)",
"journal": "Journal of clinical medicine",
"keywords": "clinical pharmacology; glomerulonephritis; nephropathy; off-label; rituximab",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34768461",
"pubdate": "2021-10-26",
"publication_types": "D016428:Journal Article",
"references": "28573137;23700188;33166580;20705965;28487395;32944889;25196202;32942039;30683678;34007154;25579715;28875476;27450163;19571279;28540057;32293308;33912740;17943078;31269364;33745547;22322817;25427622;33628202;31998325;28577748;27352623",
"title": "Off-Label Use of Rituximab in Patients with Different Types of Nephropathies in a Tertiary Hospital: A Retrospective Study.",
"title_normalized": "off label use of rituximab in patients with different types of nephropathies in a tertiary hospital a retrospective study"
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"fulfillexpeditecriteria": "1",
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{
"abstract": "The use of levetiracetam for the treatment of epilepsy in women of childbearing age has increased as more evidence of teratogenicity of other broad-spectrum antiepileptic medications becomes available. Levetiracetam appears to be associated with a low incidence of major congenital malformations based on data from pregnancy registries. Major pregnancy-related changes in the pharmacokinetics of levetiracetam have been described in several case series, demonstrating a role for careful therapeutic drug monitoring of levetiracetam in pregnant patients. Extended-release levetiracetam provides a way to improve medication adherence in adults with epilepsy by allowing once/day dosing and may be considered for use in pregnancy to minimize the fluctuation of levetiracetam levels throughout the day, thus potentially minimizing dose-related adverse effects. In this case report, we describe a 16-year-old, compliant, pregnant patient who experienced subtherapeutic levetiracetam blood concentrations that occurred with use of extended-release levetiracetam. She experienced a breakthrough seizure with once/day dosing during her third trimester with low subsequent trough levels despite multiple dose increases. After changing to twice/day dosing of extended-release levetiracetam at delivery, the patient experienced no seizures and delivered a healthy infant without complications. This is the first case report, to our knowledge, to describe seizure breakthrough during pregnancy with an extended-release formulation of an antiepileptic medication. Pharmacokinetic changes associated with pregnancy may increase apparent clearance of extended-release formulations of levetiracetam, leading to periods of subtherapeutic blood or central nervous system concentrations. These changes support the important role of therapeutic monitoring of levetiracetam plasma concentrations to help maintain seizure control in women with epilepsy during pregnancy.",
"affiliations": "Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.",
"authors": "Garrity|Lisa C|LC|;Turner|Michele|M|;Standridge|Shannon M|SM|",
"chemical_list": "D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(7)",
"journal": "Pharmacotherapy",
"keywords": "antiepileptic medication; extended-release; levetiracetam; pharmacokinetics; pregnancy; therapeutic drug monitoring",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D011247:Pregnancy; D011248:Pregnancy Complications; D012640:Seizures",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e128-32",
"pmc": null,
"pmid": "24807683",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam.",
"title_normalized": "increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once day extended release levetiracetam"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-01732",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "Elderly patients with secondary acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS) are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. In the present paper, we reported a case of secondary leukemia following MDS in an 80-year-old male patient who was deemed unfit for chemotherapy owing to his old age and poor physical condition. Despite a high tumor burden, treatment with AZA exerted a remarkable response, leading to an immediate cytoreduction in our case. Our results suggest that AZA can be an attractive therapeutic option for elderly MDS or AML patients, offering adequate efficacy and high tolerability.",
"affiliations": "National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan.;National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan.;National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan.;National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan.;National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan.",
"authors": "Kumode|Takahiro|T|;Fukui|Ayano|A|;Eguchi|Go|G|;Yamaguchi|Terufumi|T|;Maeda|Yasuhiro|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/793928",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/793928Case ReportA Case of Secondary Leukemia Subsequent to Myelodysplastic Syndromes Successfully Treated with Azacitidine Kumode Takahiro Fukui Ayano Eguchi Go Yamaguchi Terufumi Maeda Yasuhiro *National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan*Yasuhiro Maeda: ymaeda@ommc-hp.jpAcademic Editor: Thomas R. Chauncey\n\n2014 31 3 2014 2014 7939287 2 2014 16 3 2014 Copyright © 2014 Takahiro Kumode et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Elderly patients with secondary acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS) are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. In the present paper, we reported a case of secondary leukemia following MDS in an 80-year-old male patient who was deemed unfit for chemotherapy owing to his old age and poor physical condition. Despite a high tumor burden, treatment with AZA exerted a remarkable response, leading to an immediate cytoreduction in our case. Our results suggest that AZA can be an attractive therapeutic option for elderly MDS or AML patients, offering adequate efficacy and high tolerability.\n==== Body\n1. Case and Introduction\nAn 80-year-old Japanese man who was originally diagnosed with myelodysplastic syndromes (MDS) and refractory anemia with excess of blasts-2 in November 2011 was admitted to our hospital in December 2011 owing to the development of acute myeloid leukemia (AML). Prior to admission, the patient had refused therapy for MDS. His medical history included hypertension, chronic heart failure, chronic atrial fibrillation, and dementia. Laboratory findings at admission revealed a white blood cell (WBC) count of 3.3 × 109/L with 85% blast cells, a hemoglobin (Hb) level of 7.5 g/dL, and a platelet count of 65 × 109/L. Wilms' tumor gene (wt1) mRNA level in the peripheral blood was 12,0000 copies/μg of RNA. Bone marrow aspiration showed 56.4% myoblasts, and G-band karyotype analysis revealed 46,XY,del(20)(q11.2q13.1) [13/20]. Surface marker analysis demonstrated that the blast cells were cluster of differentiations (CD)2−, CD7+, CD19−, CD13+, CD14−, CD15−, CD33−, CD41−, CD61−, CD64−, CD65−, CD11b−, CD34+, CD56−, CD117+, and human leukocyte antigen-death receptor+. The patient was deemed medically unfit for chemotherapy because of his old age and poor physical condition. Therefore, he was started on azacitidine (AZA) at 100 mg/day intravenously for 5 consecutive days every 4 weeks. As shown in Figure 1, after 2 cycles of AZA therapy, he achieved complete remission (CR) according to the Cheson criteria [1] despite of residual del(20)(q11.213.1) clone.\n\nThe patient was able to maintain CR and a normal peripheral blood wt1 mRNA level without any AML therapy for almost a year. However, his disease relapsed with a high tumor burden, and he was readmitted to our hospital in November 2012 (Figure 2). Laboratory analysis of peripheral blood revealed a WBC count of 104.5 × 109/L with 95% blast cells, an Hb level of 7.9 g/dL, and a platelet count of 71 × 109/L. AZA therapy was once again initiated, resulting in a rapid reduction of peripheral blood blast cell percentage to <5% immediately after therapy started. After 2 cycles of AZA therapy, the bone marrow demonstrated persisting multilineage dysplasia with a reduction of blasts to <5%, indicating CR despite of residual del(20)(q11.213.1) clone. Although the patient continued to receive AZA therapy, he succumbed to disease progression in July 2013, which was 20 months after his original diagnosis of AML (Figure 2).\n\n2. Discussion and Conclusion\nElderly patients with secondary AML following MDS are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. The Cancer and Leukemia Group B and AZA-001 studies have confirmed the efficacy of AZA in high-risk MDS patients whose bone marrow blasts were ≥20% but <30%, which currently meets the criteria for a diagnosis of AML according to the World Health Organization Guidelines [2, 3]. Subsequently, several other studies have suggested that AML patients could benefit from AZA therapy. In a study involving 82 AML patients, including 25 with secondary AML subsequent to MDS, Maurillo et al. reported that AZA was a potentially effective therapy for elderly patients who had previously untreated AML with a WBC count of <10 × 109/L [4]. Al-Ali et al. studied 40 AML patients, including 20 newly diagnosed and 20 relapsed or refractory cases, who were deemed medically unfit for or resistant to chemotherapy. Among these patients, 16 had AML secondary to MDS. All enrolled patients were treated with AZA. Those with newly diagnosed AML experienced a median survival time of 7.7 months and an estimated 1-year survival of 39%, with a median follow-up period of 13 months. These reported results were superior to the published outcomes of standard nonintensive treatments. In addition, the median survival time of newly diagnosed AML patients who achieved stable disease was statistically similar to that of patients in CR, partial remission, or hematological improvement [5]. More recently, in a single-institutional study enrolling 227 consecutive older AML patients, including 74 with secondary AML, van der Helm et al. retrospectively compared the efficacy and tolerability of AZA, intensive chemotherapy, and best supportive care. They reported that in comparison to intensive chemotherapy, AZA resulted in a comparable overall survival but higher tolerability [6]. These observations suggest that, unlike intensive chemotherapy, achieving CR with AZA might not be necessary for an improved survival in elderly AML patients. Currently, no biological prognostic factors have been established to predict AZA's efficacy in MDS or AML patients. Itzykson et al. investigated the effect of the ten-eleven translocation 2(TET2) gene mutations on AZA's efficacy in 86 MDS or low blast count AML patients and reported that the presence of a TET2 mutation predicted a higher response rate to AZA than the presence of wild-type TET2 did. However, response duration and survival were comparable between mutated and wild-type groups [7]. On the other hand, Voso et al. showed that TET2 mutations did not have impact on the response to AZA and there were no differences of duration of response and survival between mutated and wild-type groups [8]. More recently, several researches about predictive markers in MDS after treatment of hypomethylating agents were reported [9–12]. According to some reports, TP53 mutations did not predict response to AZA and their prognosis was identically dismal [9–11]. Although the patients group was small, patients with del20q might have higher response to AZA [9]. Actually, our present case had del20q as well and was seen as remarkable response to AZA. Ahn et al. reported that SRSF2, spliceosomal gene, mutation might be regarded as a risk factor of leukemic transformation compared with other spliceosomal gene mutations [12]. It has been suggested that the efficacy of AZA in AML patients with high tumor burden is limited and that cytoreductive chemotherapy is necessary for these patients. However, in the present case with a high tumor burden, AZA exerted a remarkable response, leading to an immediate cytoreduction similar to what is observed with other intense chemotherapy regimens. Therefore, our results suggest that there are good responders to AZA among both MDS and AML patients. If these good responders could be identified via useful biological prognostic factors prior to the beginning of therapy, treatment with AZA could be encouraged. In conclusion, AZA can be an attractive therapeutic option for elderly MDS or AML patients who are deemed medically unfit for or resistant to chemotherapy.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Clinical course after disease onset. RCC: red cell concentrates, PC: platelet concentrates, Aza: azacitidine, BMA: bone marrow aspiration, CR: complete remission, WBC: white blood cells, Net: neutrophils, Hb: hemoglobin, and Plt: platelets.\n\nFigure 2 Clinical course after disease relapse.\n==== Refs\n1 Cheson BD Bennett JM Kopecky KJ Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia Journal of Clinical Oncology 2003 21 24 4642 4649 2-s2.0-1542753559 14673054 \n2 Fenaux P Mufti GJ Hellström-Lindberg E Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia Journal of Clinical Oncology 2010 28 4 562 569 2-s2.0-77449149373 20026804 \n3 Silverman LR McKenzie DR Peterson BL Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B Journal of Clinical Oncology 2006 24 24 3895 3903 2-s2.0-33748474416 16921040 \n4 Maurillo L Venditti A Spagnoli A Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian compassionate program Cancer 2012 118 4 1014 1022 2-s2.0-84856802139 21761399 \n5 Al-Ali HK Jaekel N Junghanss C Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study Leukemia and Lymphoma 2012 53 1 110 117 2-s2.0-84855416811 21767242 \n6 van der Helm LH Scheepers ER Veeger NJ Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients Journal of Hematology and Oncology 2013 6, article 29 \n7 Itzykson R Kosmider O Cluzeau T Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias Leukemia 2011 25 7 1147 1152 2-s2.0-79960229916 21494260 \n8 Voso MT Fabiani E Piciocchi A Role of BCL2L10 methylation and TET2 mutations in higher risk myelodysplastic syndromes treated with 5-Azacytidine Leukemia 2011 25 12 1910 1913 2-s2.0-83555165094 21760590 \n9 Kuendgen A Muller-Thomas C Urbaniak P Possible biomarkers to predict response in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) treated with 5-azacitidine Blood 2013 122 21, abstract 2757 \n10 Kulasekararaj A Mohamedali A Smith A Comprehensive mutational screening of 5-azacitidine treated myelodysplastic syndrome (MDS) patients fails to identify a specific mutational profile predicting response to therapy Blood 2013 122 21, abstract 2792 \n11 Muller-Thomas C Rudelius M Rondak I Response to azacitidine is independent of TP53 mutations in higher-risk myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML) Blood 2013 122 21, abstract 2797 \n12 Ahn JS Kim HR Kim HJ Clinical significance of SF3B1, U2AF1 and SRSF2 spliceosomal gene mutations for the treatment of hypomethylating agents in myelodysplastic syndrome Blood 2013 122 21, abstract 2802\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2014()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "793928",
"pmc": null,
"pmid": "24799912",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "21494260;21760590;21767242;23587459;14673054;21761399;20026804;16921040",
"title": "A case of secondary leukemia subsequent to myelodysplastic syndromes successfully treated with azacitidine.",
"title_normalized": "a case of secondary leukemia subsequent to myelodysplastic syndromes successfully treated with azacitidine"
} | [
{
"companynumb": "JP-CELGENEUS-087-50794-14081699",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
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{
"abstract": "CACNA1C (NM_000719.6) encodes an L-type calcium voltage-gated calcium channel (Cav 1.2), and pathogenic variants have been associated with two distinct clinical entities: Timothy syndrome and Brugada syndrome. Thus far, CACNA1C has not been reported as a gene associated with epileptic encephalopathy and is less commonly associated with epilepsy. We report three individuals from two families with variants in CACNA1C. Patient 1 presented with neonatal onset epileptic encephalopathy (NOEE) and was found to have a de novo missense variant in CACNA1C (c.4087G>A (p.V1363M)) on exome sequencing. In Family 2, Patient 2 presented with congenital cardiac anomalies and cardiomyopathy and was found to have a paternally inherited splice site variant, c.3717+1_3717+2insA, on a cardiomyopathy panel. Her father, Patient 3, presented with learning difficulties, late-onset epilepsy, and congenital cardiac anomalies. Family 2 highlights variable expressivity seen within a family. This case series expands the clinical and molecular phenotype of CACNA1C-related disorders and highlights the need to include CACNA1C on epilepsy gene panels.",
"affiliations": "Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington.;Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.;Department of Biochemistry and Institution for Protein Design, University of Washington, Seattle, Washington.;Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.;Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.;Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.;Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.;Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.;Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington.",
"authors": "Bozarth|Xiuhua|X|0000-0003-3136-7393;Dines|Jennifer N|JN|;Cong|Qian|Q|;Mirzaa|Ghayda M|GM|;Foss|Kimberly|K|;Lawrence Merritt|J|J|;Thies|Jenny|J|;Mefford|Heather C|HC|;Novotny|Edward|E|",
"chemical_list": "C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.40657",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "176(12)",
"journal": "American journal of medical genetics. Part A",
"keywords": "CACNA1C; electroencephalogram; epileptic encephalopathy; exome sequencing; neonatal onset epileptic encephalopathy",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000483:Alleles; D020746:Calcium Channels, L-Type; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D004827:Epilepsy; D019066:Facies; D056726:Genetic Association Studies; D005838:Genotype; D006330:Heart Defects, Congenital; D006801:Humans; D007231:Infant, Newborn; D007859:Learning Disabilities; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D013329:Structure-Activity Relationship",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "2733-2739",
"pmc": null,
"pmid": "30513141",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "22106044;25882468;21988835;19342611;20223028;24463508;28733343;7572644;28493952;24996399;17582678;19606473;24162465;24035711;19561590;29959160;24039744;26582918;23575362;16207890;27601186;28211989;9405178;17224476;21372292;8235588;15965027;19151095;23044011;24321233;15090038;25338716;1318983;26432245;7798527;15454078;24681721;25260352;15863612;21910241;25633834;16360093",
"title": "Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.",
"title_normalized": "expanding clinical phenotype in cacna1c related disorders from neonatal onset severe epileptic encephalopathy to late onset epilepsy"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US01474",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PYRIDOXAL PHOSPHATE ANHYDROUS"
},
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{
"abstract": "OBJECTIVE\nDystonic tremor (DT) is defined as a postural/kinetic tremor occurring in the body region affected by dystonia. DT is typically characterized by focal tremors with irregular amplitudes and variable frequencies typically below 7Hz. Pharmacological treatment is generally unsuccessful and guidelines for deep brain stimulation (DBS) targeting and indications are scarce. In this article, we present the outcome and neurophysiologic data of two patients with refractory, focal limb DT treated with Globus Pallidus interna (Gpi) DBS and critically review the current literature regarding surgical treatment of DT discussing stereotactic targets and treatment considerations.\n\n\nMETHODS\nA search of literature concerning treatment of DT was conducted. Additionally, Gpi DBS was performed in two patients with DT and microelectrode recordings for multi unit analysis (MUAs) and local field potentials (LFPs) were obtained.\n\n\nRESULTS\nThe mean percentage improvement in tremor severity was 80.5% at 3 years follow up. MUAs and LFPs did not show significant differences in DT patients compared with other forms of dystonia or PD except for higher interspikes bursting indices. LFP recordings in DT demonstrated high power at low frequencies with action (<3.5Hz).\n\n\nCONCLUSIONS\nGpi DBS is an effective treatment in patients with focal limb DT without associated generalized dystonia. Intraoperative neurophysiologic findings suggest that DT is part of phenotypic motor manifestations in dystonia.",
"affiliations": "Department of Neurology, Albany Medical College, Albany, NY, United States. Electronic address: RamireA@mail.amc.edu.;Center for Neuroscience and Neuropharmacology, Albany, NY, United States.;Center for Neuroscience and Neuropharmacology, Albany, NY, United States.;Department of Neurosurgery, Albany Medical Center, Albany, NY, United States.;Department of Neurology, Albany Medical College, Albany, NY, United States.;Department of Neurosurgery, Albany Medical Center, Albany, NY, United States.;Center for Neuroscience and Neuropharmacology, Albany, NY, United States.;Center for Neuroscience and Neuropharmacology, Albany, NY, United States; Department of Neurosurgery, Albany Medical Center, Albany, NY, United States. Electronic address: RamireA@mail.amc.edu.",
"authors": "Ramirez-Zamora|Adolfo|A|;Kaszuba|Brian|B|;Gee|Lucy|L|;Prusik|Julia|J|;Molho|Eric|E|;Wilock|Meghan|M|;Shin|Damian|D|;Pilitsis|Julie G|JG|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2016.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "150()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Deep brain stimulation; Dystonia neurophysiology; Dystonic tremor; Globus pallidus interna; Local field potentials; Tremor",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D046690:Deep Brain Stimulation; D004421:Dystonia; D005260:Female; D005917:Globus Pallidus; D006801:Humans; D064795:Intraoperative Neurophysiological Monitoring; D008875:Middle Aged; D016896:Treatment Outcome; D014202:Tremor",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "169-176",
"pmc": null,
"pmid": "27685658",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical outcome and intraoperative neurophysiology for focal limb dystonic tremor without generalized dystonia treated with deep brain stimulation.",
"title_normalized": "clinical outcome and intraoperative neurophysiology for focal limb dystonic tremor without generalized dystonia treated with deep brain stimulation"
} | [
{
"companynumb": "US-ROCHE-1842806",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACLOFEN"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nNo standard treatment has been established for poorly-differentiated neuroendocrine carcinomas (PDNEC). The aim of this study is to evaluate the response to the combination of three drugs.\n\n\nMETHODS\nWe reviewed 21 PDNEC patients treated from 2008 to 2013 in two Institutions. Five patients were initially treated with epirubicin, fluorouracil and temozolomide. Because of toxicity, the regimen was modified into cisplatin, capecitabine and dacarbazine (scheme B-CLOVER regimen).\n\n\nRESULTS\nPrimary tumor site was: pancreas 7 (33%), lung 5 (24%), colon-rectum 5 (24%), unknown 3 (14%) and stomach 1 (5%). The response rate was 24% (0 complete response, 24% partial responses, 38% stable disease, 9% progression and 19% unassessable). The global overall survival (OS) is 13 months (range=1-29) and progression-free survival (PFS) was 6 months (range=1-11).\n\n\nCONCLUSIONS\nThe combination chemotherapy of cisplatinum, capecitabine and dacarbazine is feasible and should be considered as an option for PDNEC.",
"affiliations": "Istituto di Oncologia, Policlinico di Monza, Monza, Italy emilio.bajetta@policlinicodimonza.it.;Istituto di Oncologia, Policlinico di Monza, Monza, Italy.;Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Ospedale della Misericordia, Grosseto, Italy.;Istituto di Oncologia, Policlinico di Monza, Monza, Italy.;Biostatistics Unit, Clinica San Gaudenzio, Novara, Italy.",
"authors": "Bajetta|Emilio|E|;Catena|Laura|L|;Biondani|Pamela|P|;Pusceddu|Sara|S|;Valente|Monica|M|;Bianco|Nadia|N|;Novelli|Eugenio|E|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "34(10)",
"journal": "Anticancer research",
"keywords": "PDNEC; Poorly-differentiated neuroendocrine carcinoma; chemotherapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D018278:Carcinoma, Neuroendocrine; D002945:Cisplatin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5657-60",
"pmc": null,
"pmid": "25275070",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Activity of a three-drug combination including cisplatin (CLOVER regimen) for poorly differentiated neuroendocrine carcinoma.",
"title_normalized": "activity of a three drug combination including cisplatin clover regimen for poorly differentiated neuroendocrine carcinoma"
} | [
{
"companynumb": "IT-BAUSCH-BL-2015-000412",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report 5 cases of corneal deposits after administration of topical ciprofloxacin as postoperative medication after uneventful cataract surgery.\n\n\nMETHODS\nObservational Case Series.\n\n\nMETHODS\nFive patients ranging from 60 to 72 years of age.\n\n\nMETHODS\nAll cases were operated by small-incision cataract surgery technique and prescribed postoperatively ciprofloxacin and prednisolone acetate eye drops. All cases had corneal deposits on second follow-up visit (15 days after cataract surgery) with decreased visual acuity. Ciprofloxacin eye drops were immediately discontinued and replaced by topical artificial tear substitute and tobramycin eye drop along with prednisolone acetate. In 1 case, surgical debridement was done.\n\n\nRESULTS\nComplete resolution of corneal deposit occurred in 2 months with good recovery of visual acuity in cases managed conservatively. The case with surgical debridement required more time for healing and visual recovery.\n\n\nCONCLUSIONS\nMore frequent and prolonged application of ciprofloxacin drops can lead to drug precipitation, which can interfere with surgical outcome.",
"affiliations": "Department of Ophthalmology, Tulsi Eye Hospital, Nashik, Maharashtra, India. Electronic address: swati_anuja@yahoo.com.;Department of Ophthalmology, Tulsi Eye Hospital, Nashik, Maharashtra, India.",
"authors": "Vijay Zawar|Swati|S|;Mahadik|Sanjay|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D009883:Ophthalmic Solutions; D002939:Ciprofloxacin; C009935:prednisolone acetate; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4182",
"issue": "49(4)",
"journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie",
"keywords": null,
"medline_ta": "Can J Ophthalmol",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000900:Anti-Bacterial Agents; D002387:Cataract Extraction; D011232:Chemical Precipitation; D002939:Ciprofloxacin; D003316:Corneal Diseases; D009877:Endophthalmitis; D005938:Glucocorticoids; D006801:Humans; D008875:Middle Aged; D009883:Ophthalmic Solutions; D011182:Postoperative Care; D011239:Prednisolone; D014792:Visual Acuity",
"nlm_unique_id": "0045312",
"other_id": null,
"pages": "392-4",
"pmc": null,
"pmid": "25103659",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Corneal deposit after topical ciprofloxacin as postoperative medication after cataract surgery.",
"title_normalized": "corneal deposit after topical ciprofloxacin as postoperative medication after cataract surgery"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2014-01610",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditio... |
{
"abstract": "This case describes a 34year old female who underwent an HLA identical living donor kidney transplant with a positive flow cytometric crossmatch (FCXM), but without any donor specific antibody (DSA). Tests to detect non-HLA antibody and autoantibody were negative. Allograft functioned well without rejection. She later received a pancreas allograft, again with a weakly positive FCXM, without DSA. After good initial graft function, she developed hyperglycemia six weeks posttransplant. Cross-sectional imaging demonstrated non-enhancing pancreas allograft with new vein thrombosis. She underwent transplant pancreatectomy, the explant pathology demonstrated changes consistent with severe acute antibody mediated rejection (AMR) causing thrombosis of the pancreas allograft. She had also developed several de-novo class-I DSAs at this time. Despite extensive testing, we could not identify a causative antibody for the initial positive FCXMs or its role in the eventual rejection of the pancreas allograft.",
"affiliations": "Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, VA, United States. Electronic address: kunal.yadav@vcuhealth.org.;Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, VA, United States.;Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, VA, United States.;Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States.;Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States.;Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States.;Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States.;Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States.;Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, VA, United States.",
"authors": "Yadav|Kunal|K|;Cotterell|Adrian|A|;Kimball|Pamela|P|;Warmke|Laura|L|;Contos|Melissa|M|;Gupta|Gaurav|G|;King|Anne|A|;Kumar|Dhiren|D|;Levy|Marlon|M|",
"chemical_list": "D006680:HLA Antigens; D007518:Isoantibodies",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.trim.2018.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-3274",
"issue": "47()",
"journal": "Transplant immunology",
"keywords": null,
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D019412:Anatomy, Cross-Sectional; D001788:Blood Grouping and Crossmatching; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D006680:HLA Antigens; D006648:Histocompatibility; D006801:Humans; D006943:Hyperglycemia; D007518:Isoantibodies; D016030:Kidney Transplantation; D019520:Living Donors; D009336:Necrosis; D010179:Pancreas; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D013927:Thrombosis; D014184:Transplantation, Homologous",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "22-25",
"pmc": null,
"pmid": "29317301",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antibody mediated rejection due to de-novo DSA causing venous thrombosis of pancreas allograft - A case report.",
"title_normalized": "antibody mediated rejection due to de novo dsa causing venous thrombosis of pancreas allograft a case report"
} | [
{
"companynumb": "US-ASTELLAS-2018US019516",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "A 39-year-old woman being treated for osteomyelitis with vancomycin developed severe neutropenia and drug fever. After she discontinued therapy, both disorders quickly resolved. These adverse reactions have rarely been reported with vancomycin, and share many similarities with regard to clinical features and postulated mechanisms of induction. To our knowledge this is the first case documenting drug fever as a principal component of vancomycin-induced neutropenia, and provides further evidence in support of an immune-mediated mechanism.",
"affiliations": "State University of New York at Buffalo School of Pharmacy, and the Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, USA. psmith@mfhs.edu",
"authors": "Smith|P F|PF|;Taylor|C T|CT|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.19.3.240.30912",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "19(2)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D005334:Fever; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010019:Osteomyelitis; D014640:Vancomycin",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "240-4",
"pmc": null,
"pmid": "10030777",
"pubdate": "1999-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Vancomycin-induced neutropenia associated with fever: similarities between two immune-mediated drug reactions.",
"title_normalized": "vancomycin induced neutropenia associated with fever similarities between two immune mediated drug reactions"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP011882",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Suburothelial hemorrhages (Antopol-Goldman lesions) are a rare but important condition. When unsuspected in a patient with a bleeding diathesis on anticoagulation therapy, computed tomography may lead to incorrect diagnoses of renal or transitional cell carcinoma resulting in inappropriate nephrectomy. We present a patient with supratherapeutic international normalized ratio and thigh hematoma who was found to have nonenhancing solid lesions of the bilateral renal pelves consistent with suburothelial hemorrhage. The patient's INR was controlled, and he was discharged with hematology follow-up 4 weeks later.",
"affiliations": "University of Virginia School of Medicine, Charlottesville, VA. Electronic address: jtm5mm@virginia.edu.;Department of Urology, University of Virginia, Charlottesville, VA.;Department of Urology, University of Virginia, Charlottesville, VA; Department of Radiology, University of Virginia, Charlottesville, VA.;Department of Urology, University of Virginia, Charlottesville, VA.",
"authors": "Morgan|John T|JT|;Farhi|Jacques|J|;Chahin|Jonathan|J|;Zillioux|Jacqueline|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2020.04.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "141()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": null,
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "e22-e23",
"pmc": null,
"pmid": "32315692",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Suburothelial Hematomas Masquerading as Neoplasms in a Patient with Supra-Therapeutic INR.",
"title_normalized": "suburothelial hematomas masquerading as neoplasms in a patient with supra therapeutic inr"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-038943",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least 1 year post HSCT. Patients underwent either a TBI- (N=18) or busulfan- (N=4) based cytoreduction followed by T-cell-depleted transplants from alternative donors. Twenty patients were alive at time of the study with a 5- and 10-year overall survival of 100 and 84% and no evidence of chronic GvHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, 4 (22%) developed hypothyroidism, 7 (39%) had insulin resistance and 5 (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism and gonadal dysfunction after busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes.",
"affiliations": "Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Psychiatry, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"authors": "Anur|P|P|;Friedman|D N|DN|;Sklar|C|C|;Oeffinger|K|K|;Castiel|M|M|;Kearney|J|J|;Singh|B|B|;Prockop|S E|SE|;Kernan|N A|NA|;Scaradavou|A|A|;Kobos|R|R|;Curran|K|K|;Ruggiero|J|J|;Zakak|N|N|;O'Reilly|R J|RJ|;Boulad|F|F|",
"chemical_list": "D002066:Busulfan",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2016.32",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "51(7)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D005199:Fanconi Anemia; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D013997:Time Factors; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D055815:Young Adult",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "938-44",
"pmc": null,
"pmid": "26999465",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "7627092;23264422;18623197;19308039;9572999;17717135;20494929;16543466;12946993;22053284;16125637;21278355;11041401;12525204;22441708;26017459;15687239;23777771;18302713;21653322;21801135;17038525;17621377;22294495;17983932;20072151;17234738;12393516;16131570;8547667;18677717;24144640;20548092;11167755;20685399;17426088;23821350;12393424",
"title": "Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors.",
"title_normalized": "late effects in patients with fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors"
} | [
{
"companynumb": "US-TEVA-689811USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "A man in his late 60s developed shock after ingesting 7500 mg of metoprolol tartrate that was refractory to all medical treatment including hyperinsulinaemic euglycaemia, intravenous lipid emulsion and dialysis, eventually needing rescue extracorporeal membrane oxygenation. A brief review of the recommended treatments in beta-blocker overdose is therefore warranted.",
"affiliations": "Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE shameen.salam.ccf@gmail.com.;Department of Clinical Pharmacology, St Vincent's Hospital and Research Center, Erie, Pennsylvania, USA.;Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE.",
"authors": "Salam|Shameen|S|http://orcid.org/0000-0003-4748-3700;Nornhold|Brandon|B|;Mallat|Jihad|J|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D008790:Metoprolol",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; cardiovascular system; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D005217:Fat Emulsions, Intravenous; D006801:Humans; D008297:Male; D008790:Metoprolol; D006435:Renal Dialysis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33952561",
"pubdate": "2021-05-05",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Massive metoprolol overdose requiring ECMO: brief review of the evidence behind recommended treatments.",
"title_normalized": "massive metoprolol overdose requiring ecmo brief review of the evidence behind recommended treatments"
} | [
{
"companynumb": "AE-YoungTech Pharmaceuticals, Inc.-2121999",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METOPROLOL TARTRATE"
},
"dru... |
{
"abstract": "A 32-year-old woman presented at 12 weeks' gestation with a severe nodulopustular reaction involving the central region of the forehead and the right cheek (Figures 1 and 2). This had progressively worsened over a several-week period despite use of topical metronidazole. A Demodex preparation revealed numerous Demodex mites from each pustule that was sampled. Based on the clinical findings and the positive Demodex preparations, the woman was diagnosed with nodular demodicosis.",
"affiliations": "From the Division of Dermatology, The Ohio State University Wexner Medical Center, Gahanna, OH; andrew.krispinsky@osumc.edu.;Dermatology of the Central States, Bexley, OH.",
"authors": "Krispinsky|Andrew|A|;Zirwas|Matthew|M|",
"chemical_list": "D000890:Anti-Infective Agents; D000977:Antiparasitic Agents; D008795:Metronidazole; D007559:Ivermectin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-9740",
"issue": "17(5)",
"journal": "Skinmed",
"keywords": null,
"medline_ta": "Skinmed",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents; D000977:Antiparasitic Agents; D004359:Drug Therapy, Combination; D005148:Facial Dermatoses; D005260:Female; D006801:Humans; D007559:Ivermectin; D008795:Metronidazole; D008924:Mite Infestations; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic",
"nlm_unique_id": "101168327",
"other_id": null,
"pages": "334-336",
"pmc": null,
"pmid": "31782709",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nodular Demodicosis in a Pregnant Woman Treated with Oral Ivermectin and Metronidazole.",
"title_normalized": "nodular demodicosis in a pregnant woman treated with oral ivermectin and metronidazole"
} | [
{
"companynumb": "US-009507513-1912USA005848",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Streptococcus pneumonia is a cause of serious mortality and morbidity, especially among small children. However, currently, it causes lower rates of invasive infections due to successful vaccination programs Case. We report an exceptional case of a 6-month-old child with meningoencephalitis caused by Streptococcus pneumonia despite the administration of two doses of pneumococcal conjugate vaccine (PCV). Meningitis progressed rapidly and led to widespread damage in parenchymal brain tissue with the emergence of fulminant meningoencephalitis. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed widespread brain lesions, suggesting extensive parenchymal injury.\n\n\n\nSuch diffuse white matter lesions among pediatric patients with Streptococcus pneumonia meningoencephalitis despite two doses of PCV have not been reported previously.",
"affiliations": "Departments of Pediatric Intensive Care, Ankara University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Intensive Care, Ankara University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Neurology, Ankara University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Intensive Care, Ankara University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Infection, Ankara University Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Radiology, Ankara Unive Faculty of Medicine, Ankara, Turkey.;Departments of Pediatric Infection, Ankara University Faculty of Medicine, Ankara, Turkey.",
"authors": "Azapağası|Ebru|E|;Kendirli|Tanıl|T|;Tuncer|Gökçen Öz|GÖ|;Özcan|Serhan|S|;Özdemir|Halil|H|;Fitöz|Suat|S|;İnce|Erdal|E|",
"chemical_list": "D022242:Pneumococcal Vaccines; D018074:Vaccines, Conjugate",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "62(6)",
"journal": "The Turkish journal of pediatrics",
"keywords": "meningitis; meningoencephalitis; pneumococcal conjugate vaccine; serotype 19F; streptococcus pneumoniae",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D002648:Child; D006801:Humans; D007223:Infant; D008590:Meningoencephalitis; D011008:Pneumococcal Infections; D022242:Pneumococcal Vaccines; D013296:Streptococcus pneumoniae; D018074:Vaccines, Conjugate; D066127:White Matter",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "1058-1063",
"pmc": null,
"pmid": "33372445",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of fulminant pneumococcus meningoencephalitis progressing with white matter involvement despite two doses of conjugated pneumococcus vaccine.",
"title_normalized": "a case of fulminant pneumococcus meningoencephalitis progressing with white matter involvement despite two doses of conjugated pneumococcus vaccine"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-309838",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nEmicizumab (Hemlibra™) is approved for prophylaxis of Haemophilia A (HA) patients with and without inhibitors. However, real-world data on emicizumab use in the elderly HA patients with concomitant cardiovascular risk factors are lacking.\n\n\nOBJECTIVE\nTo evaluate the safety and efficacy of emicizumab in a real-world cohort of elderly HA patients.\n\n\nMETHODS\nA prospective longitudinal observational study on HA patients over 50 years old treated, followed and monitored during emicizumab prophylaxis was conducted. We documented any bleeding or adverse events and collected plasma samples for emicizumab levels, aPTT and thrombin generation (TG).\n\n\nRESULTS\nSeventeen HA patients (2 with inhibitor), whose median age was 62.4 years (range: 51.5-77.1) composed the cohort, including 9/17 with multiple cardiovascular risk factors (high risk group). Seven patients had chronic HIV infection. The median follow-up of our cohort was 400 days (range 89-805, IQR 211-479 days). The median annualized bleeding rate (ABR) significantly decreased for all patients. Among patients who displayed significant bleeding tendencies, emicizumab steady state levels as well as TG were lower as compared with the group. The ABR of four patients concomitantly treated by antiplatelet agents was significantly higher compared with the rest of the cohort. Neither thrombosis nor thrombotic microangiopathy (TMA) was encountered.\n\n\nCONCLUSIONS\nEmicizumab prophylaxis for HA patients older than 50 years including those with cardiovascular risk factors was well tolerated. As lower emicizumab and TG levels were observed among bleeding patients, we suggest that monitoring laboratory assays could be of value within this age group.",
"affiliations": "National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;Department of Pathophysiology, First Moscow State Medical University (Sechenov University).;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.;National Hemophilia Center, Sheba Medical center, Tel Hashomer, Israel.",
"authors": "Misgav|Mudi|M|;Brutman-Barazani|Tami|T|;Budnik|Ivan|I|;Avishai|Einat|E|;Schapiro|Jonathan|J|;Bashari|Dalia|D|;Barg|Assaf A|AA|https://orcid.org/0000-0003-0961-2567;Lubetsky|Aaron|A|;Livnat|Tami|T|https://orcid.org/0000-0002-1279-2557;Kenet|Gili|G|https://orcid.org/0000-0003-3494-9823",
"chemical_list": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; C000608208:emicizumab",
"country": "England",
"delete": false,
"doi": "10.1111/hae.14261",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-8216",
"issue": "27(2)",
"journal": "Haemophilia : the official journal of the World Federation of Hemophilia",
"keywords": "HIV; cardiovascular risk factors; elderly patients; emicizumab; thrombin generation",
"medline_ta": "Haemophilia",
"mesh_terms": "D000368:Aged; D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D015658:HIV Infections; D006467:Hemophilia A; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "9442916",
"other_id": null,
"pages": "253-260",
"pmc": null,
"pmid": "33595174",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data.",
"title_normalized": "emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors real world data"
} | [
{
"companynumb": "IL-DSJP-DSE-2021-116031",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRASUGREL HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Clofazimine is an antimicrobial agent that has activity in vitro against mycobacteria. Increasingly, it has been used for the treatment of nontuberculous mycobacteria (NTM), despite limited data supporting its use in this setting. The objective of this study was to evaluate the safety, tolerability, and clinical outcomes associated with clofazimine in patients with NTM infection.\n\n\n\nThis observational-cohort study assessed clofazimine as used for pediatric and adult cystic fibrosis (CF) and non-CF patients with pulmonary and extrapulmonary NTM infection as part of a multidrug regimen from 2006 to 2014. Treatment regimens and adverse drug reactions (ADRs) were captured.\n\n\n\nA total of 112 patients were included (median age, 62 years); 24 patients (21%) had CF. Eighty-seven (78%) had refractory disease with failure of previous therapy. Fifty-four patients (48%) had Mycobacterium abscessus complex, 41 (37%) had Mycobacterium avium complex, and 16 (14%) had two NTM species. The median duration of clofazimine use was 383 days (range, 3-2,419 days). Sixteen patients (14%) stopped clofazimine due to an ADR after a median of 101 days (95% CI, 63-119). Forty-one of 82 patients (50%) with pulmonary disease converted to negative NTM cultures within 12 months.\n\n\n\nClofazimine was a safe, reasonably tolerated, and active oral drug for NTM infection in our heterogeneous population of pediatric and adult CF and non-CF patients. It should be considered as an alternative drug for treatment of NTM disease.",
"affiliations": "Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO; Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO. Electronic address: stacey.martiniano@childrenscolorado.org.;Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO.;Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO.;Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO.;Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.;Department of Medicine, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO; Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO.",
"authors": "Martiniano|Stacey L|SL|;Wagner|Brandie D|BD|;Levin|Adrah|A|;Nick|Jerry A|JA|;Sagel|Scott D|SD|;Daley|Charles L|CL|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D002991:Clofazimine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2017.04.175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "152(4)",
"journal": "Chest",
"keywords": "Mycobacterium abscessus; Mycobacterium avium; clofazimine; cystic fibrosis; nontuberculous mycobacteria",
"medline_ta": "Chest",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D002648:Child; D002991:Clofazimine; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D011014:Pneumonia; D013902:Radiography, Thoracic; D012189:Retrospective Studies; D013183:Sputum; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "800-809",
"pmc": null,
"pmid": "28483608",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection.",
"title_normalized": "safety and effectiveness of clofazimine for primary and refractory nontuberculous mycobacterial infection"
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"abstract": "Cushing's syndrome due to ectopic adrenocorticotrophic hormone (ACTH) secretion is uncommon, accounting for 9 to 18% of cases; approximately 10% of ACTH producing tumours are caused by thymic carcinomas.1 We describe a young lady who presented with Cushing's syndrome secondary to a primary neuroendocrine tumour (NET) arising from the thymus. She had surgical resection of her primary tumour with remission of her Cushing's syndrome however subsequently went on to have locoregional recurrence followed by distant metastases to her bilateral ovaries. She underwent 6 surgeries including bilateral adrenalectomy and had 3 cycles of chemotherapy over the course of the 8 years since her diagnosis. Due to the rarity and highly aggressive nature of this disease, we highlight the need for a multidisciplinary team approach and use of multiple modalities in the management of our patient. Timely use of bilateral adrenalectomy particularly in young patients is important to prevent further complications and facilitate other treatment modalities.",
"affiliations": "Division of Endocrinology, Department of Medicine, Hospital Putrajaya, Federal Territory of Putrajaya, Malaysia.;Division of Endocrinology, Department of Medicine, Hospital Putrajaya, Federal Territory of Putrajaya, Malaysia.",
"authors": "Lau|Eunice Yi Chwen|EYC|;Hussein|Zanariah|Z|",
"chemical_list": null,
"country": "Thailand",
"delete": false,
"doi": "10.15605/jafes.036.01.13",
"fulltext": "\n==== Front\nJ ASEAN Fed Endocr Soc\nJ ASEAN Fed Endocr Soc\nJAFES\nJournal of the ASEAN Federation of Endocrine Societies\n0857-1074\n2308-118X\nJournal of the ASEAN Federation of Endocrine Societies\n\nJAFES-36-1-098\n10.15605/jafes.036.01.13\nCase Report\nEctopic Cushing’s Syndrome secondary to Recurrent Thymic Neuroendocrine Carcinoma with Bilateral Ovarian Metastases: A Case Report\nLau Eunice Yi Chwen\nHussein Zanariah\nDivision of Endocrinology, Department of Medicine, Hospital Putrajaya, Federal Territory of Putrajaya, Malaysia\nCorresponding author: Eunice Yi Chwen Lau, MD, Endocrinology Fellow-in-Training / Physician Putrajaya Hospital, Presint 7, 62250 Federal Territory of Putrajaya, Malaysia. Tel. No.: (60)3-83124200, Fax No.:(60)3-88880137. E-mail: eunique_lyc@yahoo.com, ORCiD: https://orcid.org/0000-0003-2425-2096\n04 5 2021\n2021\n36 1 98102\n21 1 2021\n25 3 2021\n© 2021 Journal of the ASEAN Federation of Endocrine Societies\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International.\nCushing’s syndrome due to ectopic adrenocorticotrophic hormone (ACTH) secretion is uncommon, accounting for 9 to 18% of cases; approximately 10% of ACTH producing tumours are caused by thymic carcinomas.1 We describe a young lady who presented with Cushing’s syndrome secondary to a primary neuroendocrine tumour (NET) arising from the thymus. She had surgical resection of her primary tumour with remission of her Cushing’s syndrome however subsequently went on to have locoregional recurrence followed by distant metastases to her bilateral ovaries. She underwent 6 surgeries including bilateral adrenalectomy and had 3 cycles of chemotherapy over the course of the 8 years since her diagnosis. Due to the rarity and highly aggressive nature of this disease, we highlight the need for a multidisciplinary team approach and use of multiple modalities in the management of our patient. Timely use of bilateral adrenalectomy particularly in young patients is important to prevent further complications and facilitate other treatment modalities.\n\nadrenalectomy\nectopic ACTH syndrome\nKrukenberg tumour\nneuroendocrine tumour\nthymic tumour\n==== Body\nINTRODUCTION\n\nThymic neuroendocrine tumours (TNETs) are rare tumours with an incidence of 0.02 per 100,000 population per year among Caucasians and 0.04 per 100,000 population per year among Asian or Pacific Islanders based on data from the SEER database.2 In the latest 2015 World Health Organisation classification, TNETs have been classified into 4 categories: Typical carcinoids (TC) (low grade or grade 1) and atypical carcinoids (AC) (intermediate grade or grade 2) which are well differentiated; large and small cell neuroendocrine carcinomas (high grade or grade 3) which are poorly differentiated.3 Data have suggested that Asian patients may have a predominance of AC with one study in Beijing showing AC in 60%, TC in 10% and 27% were poorly differentiated. By comparison, the SEER database which comprised of 83% Caucasians, only 10% of patients were AC.4 Diagnosis may be challenging as one-third of patients are asymptomatic and are only identified on routine imaging. Others may present with mass effect due to compression of surrounding nerves or vessels. Carcinoid syndrome is rare, occurring in less than 1% of TNETS while approximately 40 to 50% can present with ectopic ACTH syndrome.4 Twenty five percent of patients are associated with multiple endocrine neoplasia 1 (MEN-1) syndrome.4 As this is a rare condition, there is a lack of prospective trials or large series and cases are managed in a similar manner as broncho-pulmonary carcinoids. Ovarian metastases can occur in neuroendocrine tumours (NETs) but they are uncommon and there is no current recommendation on their management in this situation. In this case report, we present a complex case of a young female with recurrent metastatic thymic neuroendocrine tumour with bilateral ovarian metastases and the multiple treatment modalities that were used over the years for her disease control.\n\nCASE\n\nA 23-year-old female of Indian ethnicity presented with hyperpigmentation, acne, progressive weight gain and irregular menses over 3 years. Clinically, she appeared cushingoid with truncal obesity and moon facies. She achieved menarche at age 13 and previous menses were regular. She had no history of past medical illness and no family history suggestive of MEN-1 syndrome. Her initial investigations performed at a private medical centre showed a markedly elevated adrenocorticotrophic hormone (ACTH) level of 221 mIU/L and positive high dose dexamethasone suppression test. Computed tomography of the thorax, abdomen and pelvis (CTTAP) showed an anterior mediastinal mass measuring 2.1x2.8x3.0 cm, located behind the sternum and hyperplasia of the adrenal glands. She underwent surgical removal of her anterior mediastinal mass by a cardiothoracic surgeon at a private centre. Histopathology showed a moderately differentiated neuroendocrine tumour grade 2 with a mitotic index 5/10 hpf and Ki-67 proliferative index of 10%. The tumour stained positive for synaptophysin, chromogranin and ACTH and was negative for thyroid transcription factor-1 (TTF-1). Post-operatively, she displayed clinical resolution of her Cushing’s syndrome with resumption of her regular menses and a Gallium-68 (Ga-68) DOTATOC positron emission tomography (PET)/CT scan 4 months post-operatively showed no evidence of somatostatin receptor (SSTR) avid disease.\n\nA year post-surgery, she developed progressive weight gain and increasing ACTH levels. CTTAP showed recurrence with multiple solid nodules at the site of her previous surgery in the upper left mediastinum. Ga-68 DOTATOC PET/CT scan showed new focus of SSTR avid disease in the superior mediastinal node anterior to the innominate artery and multiple pre-vascular nodes near the previous surgical site. F18-Fluorodeoxyglucose (F18-FDG) PET/CT scan showed concordant uptake with the Ga-68 DOTATOC PET/CT scan. She had her second surgery approximately 3 years after her first surgery, with complete removal of her mediastinal tumour. Histopathology was consistent with an intermediate grade metastatic neuroendocrine tumour.\n\nHer symptoms recurred a year after her second surgery. She developed diabetes and hypertension requiring medical therapy and was commenced on ketoconazole. CTTAP imaging showed an enlarged left supraclavicular node measuring 1.2 cm in the short axis diameter and reduction in size of her mediastinal lesion measuring 1.3x2cm. Ga-68 DOTANOC PET/CT showed new focus of uptake at the left supraclavicular node with resolution of previous uptake at the superior mediastinum and pre-vascular nodes. Subsequently, 4½ years after her first surgery, an attempt was made to remove the left supraclavicular lymph node. However, adhesions to the surrounding structures resulted in inability to completely remove the node.\n\nPost-operatively, she had persistent Cushing’s syndrome. Metyrapone was added to her therapy, nevertheless she continued to have difficult to control diabetes, hypokalaemia and progressive cushingoid features. CTTAP imaging approximately 1½ years after her 3rd surgery showed multiple rounded lobulated lesions along the right postero-lateral uterine body largest measuring 4.6x4.4x5.2 cm. There was no significant change in the left supraclavicular lesion. F18-FDG PET/CT scan showed uptake in both the supraclavicular and pelvic lesion, while Ga-68 DOTANOC PET/CT scan showed uptake in the supraclavicular lesion and right level II cervical nodes and anterior mediastinal node.\n\nAt this point decision was made for bilateral adrenalectomy (5½ years after first surgery) for management of her hypercortisolism. Prior to adrenalectomy, she required 3000 mg of metyrapone, 400 mg ketoconazole, 200 mg spironolactone, 160 mg valsartan, 10 mg amlodipine, 2000 mg metformin, 120 mg of modified release gliclazide, 10 U of intermediate acting insulin, 20 mg atorvastatin, 1200 mg potassium chloride and 1000 IU cholecalciferol per day.\n\nPost-operatively, she had resolution of her Cushing’s features, was able to stop all her potassium supplements, antihypertensive and antidiabetic medications and was put on glucocorticoid and mineralocorticoid replacement.\n\nHowever, she continued to have increasing hyperpigmentation (Figure 1) and CTTAP imaging surveillance 6 months after her surgery showed increase in size of her uterine lesion likely right adnexal in origin measuring 5.8x5.2x5.2 cm in size (Figure 2A). Ga-68 DOTANOC PET/CT and F18-FDG PET/CT imaging were performed showing predominantly FDG avid disease (Figure 2B and 2C), hence she was deemed unsuitable for peptide receptor radionuclide therapy (PRRT). Following multidisciplinary team discussion, she was recommended for surgery to remove the adnexal lesion. She was offered bilateral salphingoopherectomy and hysterectomy and the implications were discussed in terms of long-term gonadal function and bone health. She opted for a more conservative approach and underwent laparotomy, right salphingoopherectomy, left cystectomy, omentectomy and appendectomy.\n\nFigure 1 ACTH induced hyperpigmentation.\n\nFigure 2 (A) CT image showing heterogenous multilobulated pelvic lesion; (B) Ga-68 DOTANOC PET-CT showing pelvic lesion with no SSTR avid disease. (C) FDG PET-CT showing FDG hypermetabolism of the pelvic lesion.\n\nIntra-operative findings showed a right large ovarian tumour measuring 10x10 cm adherent to the right pelvic wall and 2 cysts in the left ovary measuring 1x1 cm and 2x2 cm (Figure 3A). Histopathology showed high grade metastatic neuroendocrine carcinoma with a Ki-67 proliferative index of 10%, mitotic figures of >10/2 mm2 and presence of capsular breach, lymphovascular invasion in both right and left ovaries. Marked improvement in ACTH levels were noted after surgery (Figure 4). Prior to surgery she continued to have her normal periods but was amenorrhoeic after. She was also given 3 cycles of chemotherapy with etopside (100 mg/m2 Day 1 to 3) and cisplatin (25 mg/m2 Day 1 to 3). However, CTTAP at 6 months showed progression of her left adnexal mass and ACTH levels continued to increase (Figure 4). She went on to have extrafascial hysterectomy and left salphingoopherectomy 8 months after the 5th surgery. Intra-operative findings showed a 6-week size uterus, a 3x3 cm left ovarian tumour with intact capsule and a ruptured right sided pelvic wall tumour measuring 5x4 cm (Figure 3B). Left ovarian histopathology was consistent with a high-grade neuroendocrine tumour (mitosis >10/2 mm2).\n\nFigure 3 (A) Large right ovarian tumour, 2 left ovarian cysts and omentum; (B) Ruptured right pelvic tumour, uterus with left ovarian tumour.\n\nFigure 4 ACTH trend since diagnosis and corresponding normal range. Difference in ACTH cut-offs before and after 22 months was due to a change in assay used.\n\nAfter surgery, her ACTH levels reduced to 49.5pmol/L and the trend is demonstrated in Figure 4. She developed symptoms of flushing and fatigue despite adequate glucocorticoid and mineralocorticoid replacement and was started on conjugated oestrogen 0.625 mg and medroxyprogesterone 5 mg daily. She is currently still followed-up at our centre and remains positive with good family support.\n\nDISCUSSION\n\nTNETs consist of 2% of all mediastinal tumours and 5% of all thymic tumours, making ectopic ACTH secreting TNETs exceedingly rare. TNETs usually present around the 5th decade and have a male predominance.2,5 Comparatively, TNETs associated with ectopic ACTH syndrome appear to present younger, around 21 to 35 years of age with hyperpigmentation being a prominent feature.6,7 They also appear to have poorer outcomes, although it is uncertain whether this is due primarily to the metabolic complications associated with Cushing’s syndrome or more aggressive tumour behaviour.6\n\nA recent study of ectopic ACTH secreting TNETs in China showed median overall survival of 41 months and progression free survival of 28 months with significant improvement after complete resection.7 There appears to be wide heterogeneity in the tumours, while some may be rapidly progressive, others are more indolent and may recur up to 8 years after surgery.5,6\n\nOur patient achieved clinical and biochemical remission after initial tumour resection. However, her disease subsequently progressed over the period of several years requiring repeat surgery followed by adrenalectomy when the tumour became unresectable. Ovarian metastases while uncommon, can occur in TNETs as shown in this case. Most of the treatment decisions for this patient were made after multidisciplinary discussion with oncologists, surgeons, endocrinologists, radiologists, and gynaecologists. As there are no clear guidelines on the management of this disease, a multidisciplinary approach is important, and we highlight the multiple treatment modalities and review the evidence for their use.\n\nIn the past TNETS have been managed in a similar manner to bronchopulmonary carcinoids and were classified and graded as a single class of tumours. However, in recent years they have been acknowledged as having their own distinct behaviour and genetic background. Unlike their lung counterparts, TNETs have a more aggressive clinical course and frequently metastasize to lymph nodes, bone and lung.8,9 Less commonly, metastases have been reported in widespread locations including the oesophagus, chest wall, liver, brain, pancreas, kidney and adrenal gland.8,9\n\nIn our patient, the tumour metastasized to both ovaries. This case is unique as our patient had bilateral ovarian metastases from a TNET which showed evidence of ACTH production. There has been report of ACTH secreting pancreatic NET presenting with bilateral ovarian metastasis but to our knowledge there is no published report of a functioning thymic NET with ovarian metastases.10 Generally thymic malignancies metastasize to intrathoracic sites first, with abdominal sites being involved later during the disease.11 Liver metastasis were the most common site of extra-thoracic metastasis with ovarian metastasis being rare.11 In neuroendocrine tumours, ovarian metastases were estimated to occur in approximately 2% patients and usually originated from midgut tumours predominantly the small bowel.12,13 They were usually bilateral, unlike primary ovarian lesions which were unilateral and could range from microscopic foci up to large tumours of 9.5 cm like our case.13 Previous reports have suggested that patients usually had well-differentiated NETs and 76% had synchronous liver and peritoneal metastases (including mesentery and omentum).13\n\nRadical surgery has been widely agreed as the only option for cure. However, this may not be feasible in all patients as more than 50% have locally advanced disease or metastases at presentation. Even after radical surgery, recurrence is common as demonstrated by our case. Studies have shown that the most important independent prognostic factor is the completeness of resection whereby those who achieved R0 resection had improved overall survival compared to those who did not.5,7 Early stage tumours have also been reported to survive longer and have less recurrence.5 On the other hand, tumour histology did not appear to have significant prognostic implication. For recurrent or metastatic disease surgery may be considered if feasible. For primary ovarian NETs prophylactic omentectomy and hysterectomy have been performed as adapted from the management of ovarian cancer although it is uncertain whether this provides any additional benefit.14 Our patient was initially offered bilateral salphingoopherectomy and hysterectomy however she opted for a more conservative approach. Despite adjuvant chemotherapy, her disease continued to progress, and she subsequently required repeat surgery. This led to improvement in her ACTH levels. During this surgery, it was noted that the pelvic tumour had ruptured, likely leading to intraperitoneal seeding. This has been shown to greatly increase the risk of relapse in epithelial ovarian cancers.15 Hence, she will require careful monitoring for relapse with ACTH levels and imaging as well as long-term female gonadal hormone replacement on top of her adrenal hormone replacement.\n\nFor tumours that are metastatic or unresectable chemotherapy and radiotherapy may play a role although clear evidence is lacking. One study showed possible benefit of adjuvant therapy on progression free survival but not for overall survival7 while another study failed to show any benefit at all5 as was the case in our patient. Patients that require adjuvant therapy probably had poorer prognosis and more extensive disease hence more research is needed to clearly evaluate this area.\n\nIn our patient, there was also difficulty in managing the metabolic complications of her Cushing’s syndrome. Similar to previous reports, tumour recurrence was associated with re-development of Cushing’s syndrome.6 Management of hypercortisolism is important and can be managed medically with drugs such as ketoconazole, metyrapone and less commonly mitotane in view of its serious side effects. In ectopic ACTH secreting neuroendocrine tumours, bilateral adrenalectomy is usually reserved for situations as in our patient whereby the primary tumour cannot be completely removed, have local recurrence or metastatic disease. The other instance would be when the primary tumour is occult and remains unidentified during follow-up. One study showed improvement in metabolic and adverse events (infection, fracture, thrombosis) scores in patients with refractory ACTH dependant Cushing’s who underwent bilateral adrenalectomy compared to those who used steroidogenesis inhibitors alone.16 Hence, early bilateral adrenalectomy should be considered in those with reasonable life expectancy from their primary tumour as this may facilitate surgical resection or other treatment modalities in initially unresectable tumours and prevent further adverse complications.\n\nCONCLUSION\n\nACTH producing TNET is an aggressive disease, and a multidisciplinary team approach is needed. First-line treatment is surgery, especially in young patients. There is also the challenge of uncontrolled Cushing’s and early adrenalectomy may be considered to optimize management. Young patients may have a prolonged disease course like our patient, requiring multiple treatment modalities as the disease progresses.\n\nEthical Consideration\n\nPatient consent was obtained before submission of the manuscript.\n\nStatement of Authorship\n\nBoth authors certified fulfilment of ICMJE authorship criteria.\n\nAuthor Disclosure\n\nBoth authors declared no conflict of interest.\n\nFunding Source\n\nNone.\n==== Refs\nReferences\n\n1 Wajchenberg BL, Mendonca BB, Liberman B, et al . Ectopic adrenocorticotropic hormone syndrome. Endo Rev. 1994;15 (6 ):752-87. PMID: . 10.1210/edrv-15-6-752.7705280\n2 Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: A SEER database analysis of 160 patients. Ann Surg. 2010;251 (6 ):1117-21. PMID: . 10.1097/SLA.0b013e3181dd4ec4.20485130\n3 Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th ed. Lyon, IARC Press; 2015. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Lung-Pleura-Thymus-And-Heart-2015.\n4 Jia R, Sulentic P, Xu JM, Grossman AB. Thymic neuroendocrine neoplasms: Biological behaviour and therapy. Neuroendocrinol. 2017;105 (2 ):105-14. PMID: . 10.1159/000472255.28355610\n5 Filosso PL, Yao X, Ahmad U, et al . Outcome of primary neuroendocrine tumors of the thymus: A joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. J Thorac Cardiovasc Surg. 2015;149 (1 ):103-9.e2. PMID: . 10.1016/j.jtcvs.2014.08.061.25308116\n6 Neary NM, Lopez-Chavez A, Abel BS, et al . Neuroendocrine ACTH-Producing tumor of the thymus—Experience with 12 patients over 25 years. J Clin Endocrinol Metab. 2012;97 (7 ): 2223-30. PMID: . PMCID: . 10.1210/jc.2011-3355.22508705\n7 Chen YY, Li SQ, Liu HS, et al . Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus: 30-year experience with 16 patients at a single institute in the People’s Republic of China. Onco Targets Ther. 2016;9 :2193-201. PMID: . PMCID: . 10.2147/OTT.S100585.27217765\n8 Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol. 2000; 114 (1 ):100–10. PMID: . 10.1309/3PDN-PMT5-EQTM-H0CD.10884805\n9 Araki T, Sholl LM, Hatabu H, Nishino M. Radiological features and metastatic patterns of thymic neuroendocrine tumours. Clin Radiol. 2018;73 (5 ):479-44. PMID: . 10.1016/j.crad.2017.11.025.29310810\n10 Oberg KC, Wells K, Seraj IM, et al . ACTH-secreting islet cell tumor of the pancreas presenting as bilateral ovarian tumors and Cushing’s Syndrome. Int J Gynecol Pathol. 2002;21 (3 ):276-80. PMID: . 10.1097/00004347-200207000-00012.12068175\n11 Khandelwal A, Sholl LM, Araki T, et al . Patterns of metastasis and recurrence in thymic epithelial tumours: Longitudinal imaging review in correlation with histological subtypes. Clin Radiol. 2016;71 (10 ): 1010-7. PMID: . PMCID: . 10.1016/j.crad.2016.05.007.27267746\n12 Pavel M, Grossman A, Arnold R, et al . ENETS consensus guidelines for the management of brain, cardiac and ovarian metastases from neuroendocrine tumors. Neuroendocrinol. 2010;91 :326-32. PMID: . 10.1159/000287277.20453466\n13 Strosberg J, Nasir A, Cragun Jet al . Metastatic carcinoid tumor to the ovary: A clinicopathologic analysis of seventeen cases. Gynecol Oncol. 2007;106 (1 ):65-8. PMID: . 10.1016/j.ygyno.2007.02.034.17475313\n14 Sehouli J, Woopen H, Pavel Met al . Neuroendocrine neoplasm of the ovary: A retrospective study of the North Eastern German Society of Gynecologic Oncology (NOGGO). Anticancer Res. 2016;36 (3 ):1003-9. PMID: .26976990\n15 Tan DSP, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006;7 (11 ):925–34. PMID: . 10.1016/S1470-2045(06)70939-1.17081918\n16 Morris LF, Harris RS, Milton DR, et al . Impact and timing of bilateral adrenalectomy for refractory ACTH-dependent Cushing’s syndrome. Surgery. 2013;154 (6 ):1174-83. PMID: . PMCID: . 10.1016/j.surg.2013.06.017.24383115\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0857-1074",
"issue": "36(1)",
"journal": "Journal of the ASEAN Federation of Endocrine Societies",
"keywords": "Krukenberg tumour; adrenalectomy; ectopic ACTH syndrome; neuroendocrine tumour; thymic tumour",
"medline_ta": "J ASEAN Fed Endocr Soc",
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"references": "12068175;26976990;17475313;27217765;29310810;10884805;20485130;7705280;24383115;27267746;22508705;28355610;17081918;20453466;25308116",
"title": "Ectopic Cushing's Syndrome secondary to Recurrent Thymic Neuroendocrine Carcinoma with Bilateral Ovarian Metastases: A Case Report.",
"title_normalized": "ectopic cushing s syndrome secondary to recurrent thymic neuroendocrine carcinoma with bilateral ovarian metastases a case report"
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{
"abstract": "Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study's aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa.\n\n\n\nAt two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity.\n\n\n\nParticipants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group.\n\n\n\nReduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.",
"affiliations": "Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).;Department of Psychiatry, University of California, San Diego, San Diego (Kaye, Wierenga, Bischoff-Grethe, Berner, Ely, Bailer, Paulus); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Berner); Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna (Bailer); Laureate Institute for Brain Research, Tulsa, Okla. (Paulus); Departments of Neuroscience and Psychiatry, University of Rochester Medical Center, Rochester, New York (Fudge).",
"authors": "Kaye|Walter H|WH|;Wierenga|Christina E|CE|;Bischoff-Grethe|Amanda|A|;Berner|Laura A|LA|;Ely|Alice V|AV|;Bailer|Ursula F|UF|;Paulus|Martin P|MP|;Fudge|Julie L|JL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2019.19030261",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "177(7)",
"journal": "The American journal of psychiatry",
"keywords": "Anorexia Nervosa; Feeding and Eating Disorders; Neuroimaging; Reward Processing; fMRI",
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000328:Adult; D000856:Anorexia Nervosa; D016022:Case-Control Studies; D002421:Caudate Nucleus; D002540:Cerebral Cortex; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D006815:Hunger; D008279:Magnetic Resonance Imaging; D009434:Neural Pathways; D011699:Putamen; D012074:Remission Induction; D013649:Taste; D055815:Young Adult",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "601-610",
"pmc": null,
"pmid": "32160766",
"pubdate": "2020-07-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16052493;16733340;12621304;20570701;27911750;28231717;26107161;15992780;12154366;30654643;30027294;9879800;23727314;29849148;29722047;28259721;2341869;26806872;23201365;28070928;28334444;27146018;21354260;15569892;23732817;22484411;29286444;30027213;18614684;27013897;21714958;22832566;30410758;14573322;22498079;22131407;27357684;22314879;26084229;30115929;17487228;25377622;26457555;26836623;12773496;19423807;20186719;18591467;19007893;27753106;25481622;19811532;28249187;25922939;10481833",
"title": "Neural Insensitivity to the Effects of Hunger in Women Remitted From Anorexia Nervosa.",
"title_normalized": "neural insensitivity to the effects of hunger in women remitted from anorexia nervosa"
} | [
{
"companynumb": "US-OTSUKA-2020_021749",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a patient with advanced breast cancer treated with three cycles of docetaxel who developed repeated episodes of hypersensitivity pneumonitis, progressed to respiratory failure and death despite treatment with corticosteroids and supportive care. Docetaxel-induced hypersensitivity pneumonitis was diagnosed by excluding infection and tumor spread with bronchoalveolar lavage and lung biopsy. Physicians should consider such a condition in all patients who present with interstitial pneumonitis and respiratory failure when they are receiving docetaxel and treat them aggressively with steroids and supportive care, as it can be fatal.",
"affiliations": null,
"authors": "Gurram|Murali Krishna|MK|;Pulivarthi|Swaroopa|S|;McGary|Carl T|CT|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D064704:Levofloxacin; D011241:Prednisone; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1700/1334.14814",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "99(3)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000542:Alveolitis, Extrinsic Allergic; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D000077143:Docetaxel; D004342:Drug Hypersensitivity; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D064704:Levofloxacin; D015411:Mastectomy, Modified Radical; D008775:Methylprednisolone; D008875:Middle Aged; D011241:Prednisone; D012131:Respiratory Insufficiency; D043823:Taxoids; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "e100-3",
"pmc": null,
"pmid": "24158075",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal hypersensitivity pneumonitis associated with docetaxel.",
"title_normalized": "fatal hypersensitivity pneumonitis associated with docetaxel"
} | [
{
"companynumb": "US-PFIZER INC-2013310204",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe the novel use of femtosecond laser technology for therapeutic resection of infectious foci in a case of multidrug-resistant Nocardia asteroides keratitis.\n\n\nMETHODS\nA 30-year-old man presented with a corneal infiltrate. Cultures were taken, and fortified vancomycin and tobramycin were initiated. After 3 negative cultures and minimal improvement on various broad-spectrum antibiotics, all topical medications were stopped and a final fourth corneal culture grew N. asteroides. Treatment with topical amikacin was initiated, but the infection continued to worsen. With drug sensitivities still pending, the patient's clinical status continued to deteriorate rapidly, despite treatment with amikacin, gatifloxacin, and polymyxin B/trimethoprim. The femtosecond laser was then used to perform targeted lamellar keratectomy.\n\n\nRESULTS\nFemtosecond laser-assisted lamellar keratectomy successfully removed the infected tissue and allowed for increased penetration of topical antibiotics. Drug sensitivities finally returned, revealing multidrug resistance and sensitivity only to trimethoprim/sulfamethoxazole and tobramycin, some of which the patient had previously tried and failed. The infection fully resolved after readministering polymyxin B/trimethoprim and tobramycin, leaving minimal residual scarring.\n\n\nCONCLUSIONS\nMultidrug-resistant N. asteroides keratitis can be difficult to manage even with appropriate antibiotic therapy based on drug sensitivity testing. Femtosecond laser-assisted resections may facilitate treatment in these cases by safely and precisely debulking infected tissue and enhancing penetration of topical medications.",
"affiliations": "Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL.",
"authors": "Shah|Parth|P|;Zhu|Dagny|D|;Culbertson|William W|WW|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000583:Amikacin; D014031:Tobramycin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001318",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "36(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D000583:Amikacin; D000900:Anti-Bacterial Agents; D048988:Corneal Surgery, Laser; D003320:Corneal Ulcer; D024901:Drug Resistance, Multiple, Bacterial; D015818:Eye Infections, Bacterial; D006801:Humans; D008297:Male; D009617:Nocardia Infections; D009616:Nocardia asteroides; D014031:Tobramycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1429-1431",
"pmc": null,
"pmid": "28834821",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic Femtosecond Laser-Assisted Lamellar Keratectomy for Multidrug-Resistant Nocardia Keratitis.",
"title_normalized": "therapeutic femtosecond laser assisted lamellar keratectomy for multidrug resistant nocardia keratitis"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2017GSK171997",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nThe study purpose was to analyze midterm outcomes in a prospective trial of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous pancreas-kidney transplantation (SPKT).\n\n\nMETHODS\nFrom February 2005 to October 2008, 46 SPKTs (45 portal-enteric drainage) were prospectively randomized as part of a larger kidney transplant study to receive either single-dose Alem (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum three doses administered) with tacrolimus/mycophenolate ± steroids.\n\n\nRESULTS\nOf 222 kidney transplant patients enrolled in the study, 46 received SPKTs; 28 (61%) received Alem and 18 (39%) rATG induction. Follow-up ranged from 67 to 111 months (mean 80 months). There were no significant differences between the two groups in 5 years actual patient (86% Alem vs 89% rATG), kidney (82% Alem vs 61% rATG, p = 0.17) or pancreas (68% Alem vs 56% rATG) graft survival rates. Five years death-censored kidney (92% Alem vs 69% rATG, p = 0.09) and pancreas (76% Alem vs 56% rATG, p = 0.198) graft survival rates were slightly higher in patients receiving Alem. Acute rejection (21% Alem vs 44% rATG, p = 0.12) and major infection (39% Alem vs 67% rATG, p = 0.13) rates were slightly lower in the Alem group; cytomegalovirus infections were significantly lower (0 Alem vs 17% rATG, p = 0.05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thrombosis (3.6% Alem vs 11% rATG), postoperative bleeding (11% Alem vs 0 rATG), other surgical complications, readmissions or freedom from steroids between groups. In patients with functioning grafts, 5 years mean serum creatinine (1.4 Alem vs 1.6 mg/dl rATG), calculated abbreviated modification of diet in renal disease glomerular filtration rate (55 Alem vs 52 ml/min/1.73 m(2) rATG), hemoglobin A1c (both 5.4%) and C-peptide (2.6 Alem vs 2.3 ng/ml rATG) levels were similar.\n\n\nCONCLUSIONS\nSingle-dose Alem and multiple-dose rATG induction provide similar midterm patient survival and graft functional outcomes with no major differences in morbidity or resource utilization.",
"affiliations": "Wake Forest School of Medicine, Department of General Surgery , Medical Center Blvd, Winston-Salem, NC 27157 , USA +1 336 716 0548 ; +1 336 713 5055 ; rstratta@wakehealth.edu.",
"authors": "Stratta|Robert J|RJ|;Rogers|Jeffrey|J|;Orlando|Giuseppe|G|;Farooq|Umar|U|;Al-Shraideh|Yousef|Y|;Doares|William|W|;Kaczmorski|Scott|S|;Farney|Alan C|AC|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1517/14712598.2014.953049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1471-2598",
"issue": "14(12)",
"journal": "Expert opinion on biological therapy",
"keywords": "ATG; alemtuzumab; immunosuppression; induction",
"medline_ta": "Expert Opin Biol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D003586:Cytomegalovirus Infections; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D011817:Rabbits; D019172:Transplantation Conditioning; D055815:Young Adult",
"nlm_unique_id": "101125414",
"other_id": null,
"pages": "1723-30",
"pmc": null,
"pmid": "25156622",
"pubdate": "2014-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Depleting antibody induction in simultaneous pancreas-kidney transplantation: a prospective single-center comparison of alemtuzumab versus rabbit anti-thymocyte globulin.",
"title_normalized": "depleting antibody induction in simultaneous pancreas kidney transplantation a prospective single center comparison of alemtuzumab versus rabbit anti thymocyte globulin"
} | [
{
"companynumb": "US-SA-2014SA166732",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat patients with non-small cell lung cancer (NSCLC) and EGFR driver mutations. Although some patients discontinued these treatments because of adverse events, it is unclear whether switching EGFR-TKI because of adverse events provides a benefit.\n\n\nMETHODS\nThis retrospective study evaluated data from 22 patients with EGFR mutation-positive NSCLC who received at least two EGFR-TKIs that were switched because of adverse events (March 2011 to September 2017). Progression-free survival 2 (PFS2) was defined as the time from starting of the first EGFR-TKI treatment to disease progression during the second EGFR-TKI treatment.\n\n\nRESULTS\nSeventeen patients received gefitinib as the first EGFR-TKI treatment, while four patients received afatinib and one patient received erlotinib. The median time to failure of the first EGFR-TKI treatment was 1.6 months. The EGFR-TKIs were switched because of hepatotoxicity (n = 16), interstitial lung disease (n = 3), and other reasons (n = 3). The median washout period was 1.1 months. Seventeen patients received erlotinib as the second EGFR-TKI treatment, while three patients received gefitinib and two patients received afatinib. The median PFS for the second EGFR-TKI treatment was 15.2 months. The median PFS2 was 17.7 months and the median overall survival was 32.8 months.\n\n\nCONCLUSIONS\nSwitching EGFR-TKIs because of adverse events provided a clinical benefit for patients with EGFR mutation-positive NSCLC. Appropriate judgment regarding switching from one EGFR-TKI to another may improve the performance status and prognosis of patients with EGFR mutation-positive NSCLC.",
"affiliations": "Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.",
"authors": "Sakata|Yoshihiko|Y|http://orcid.org/0000-0002-3300-9138;Kawamura|Kodai|K|;Shingu|Naoki|N|;Hiroshige|Shigeo|S|;Yasuda|Yuko|Y|;Eguchi|Yoshitomo|Y|;Anan|Keisuke|K|;Hisanaga|Junpei|J|;Nitawaki|Tatsuya|T|;Nakano|Aiko|A|;Ichikado|Kazuya|K|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13103",
"fulltext": "\n==== Front\nAsia Pac J Clin Oncol\nAsia Pac J Clin Oncol\n10.1111/(ISSN)1743-7563\nAJCO\nAsia-Pacific Journal of Clinical Oncology\n1743-7555 1743-7563 John Wiley and Sons Inc. Hoboken \n\n10.1111/ajco.13103\nAJCO13103\nOriginal Article\nOriginal Articles\nThe effects of switching EGFR‐TKI treatments for non‐small cell lung cancer because of adverse events\nSAKATA et al.Sakata Yoshihiko http://orcid.org/0000-0002-3300-9138\n1\nyoshihiko-sakata@saiseikaikumamoto.jp Kawamura Kodai \n1\n Shingu Naoki \n1\n Hiroshige Shigeo \n1\n Yasuda Yuko \n1\n Eguchi Yoshitomo \n1\n Anan Keisuke \n1\n Hisanaga Junpei \n1\n Nitawaki Tatsuya \n1\n Nakano Aiko \n1\n Ichikado Kazuya \n1\n \n1 \nDivision of Respiratory Medicine\nSaiseikai Kumamoto Hospital\nKumamoto\nJapan\n\n* Correspondence\nYoshihiko Sakata, Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, 5‐3‐1 Chikami, Kumamoto 861–4193, Japan.\nEmail: yoshihiko-sakata@saiseikaikumamoto.jp\n\n02 12 2018 \n4 2020 \n16 2 10.1111/ajco.v16.2e113 e117\n28 12 2017 05 10 2018 © 2018 The Authors. Asia‐Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nBackground\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are used to treat patients with non‐small cell lung cancer (NSCLC) and EGFR driver mutations. Although some patients discontinued these treatments because of adverse events, it is unclear whether switching EGFR‐TKI because of adverse events provides a benefit.\n\nMethods\nThis retrospective study evaluated data from 22 patients with EGFR mutation‐positive NSCLC who received at least two EGFR‐TKIs that were switched because of adverse events (March 2011 to September 2017). Progression‐free survival 2 (PFS2) was defined as the time from starting of the first EGFR‐TKI treatment to disease progression during the second EGFR‐TKI treatment.\n\nResults\nSeventeen patients received gefitinib as the first EGFR‐TKI treatment, while four patients received afatinib and one patient received erlotinib. The median time to failure of the first EGFR‐TKI treatment was 1.6 months. The EGFR‐TKIs were switched because of hepatotoxicity (n = 16), interstitial lung disease (n = 3), and other reasons (n = 3). The median washout period was 1.1 months. Seventeen patients received erlotinib as the second EGFR‐TKI treatment, while three patients received gefitinib and two patients received afatinib. The median PFS for the second EGFR‐TKI treatment was 15.2 months. The median PFS2 was 17.7 months and the median overall survival was 32.8 months.\n\nConclusions\nSwitching EGFR‐TKIs because of adverse events provided a clinical benefit for patients with EGFR mutation‐positive NSCLC. Appropriate judgment regarding switching from one EGFR‐TKI to another may improve the performance status and prognosis of patients with EGFR mutation‐positive NSCLC.\n\nepidermal growth factor receptornon‐small cell lung cancertyrosine kinase inhibitor source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:24.07.2020\n\n\nSakata \nY \n, \nKawamura \nK \n, \nShingu \nN \n, et al. The effects of switching EGFR‐TKI treatments for non‐small cell lung cancer because of adverse events\n. Asia‐Pac J Clin Oncol . 2020 ;16 :e113 –e117\n. 10.1111/ajco.13103 \n30506897\n==== Body\n1 INTRODUCTION\nPatients with advanced non‐small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations can receive first‐line treatment using EGFR tyrosine kinase inhibitors (EGFR‐TKIs).1, 2 These drugs include gefitinib, erlotinib, and afatinib, which provide response rates of approximately 60‐70% and a median progression‐free survival (PFS) of approximately 12 months.3, 4, 5 However, a small proportion of patients with NSCLC and EGFR mutations discontinue EGFR‐TKI therapy because of adverse events (AEs).6, 7 In clinical practice, one approach to this development is switching from one EGFR‐TKI to another. However, to the best of our knowledge, only a few case series have evaluated treatment response after switching EGFR‐TKIs because of AEs, rather than disease progression (PD).8, 9 Therefore, this retrospective study evaluated the efficacy and outcomes of switching EGFR‐TKIs because of AEs.\n\n2 PATIENTS AND METHODS\nThis retrospective study was approved by the institutional review board of Saiseikai Kumamoto Hospital (approved number: 597). We identified patients with advanced NSCLC who received at least two EGFR‐TKIs between March 2011 and March 2017 by searching our hospital's prescription drug database. All patients were followed‐up until September 2017. We identified 45 patients who underwent EGFR‐TKI switching, although 21 patients switched because of PD and were excluded. In addition, we excluded two patients who were lost to follow‐up. Thus, 22 patients who switched EGFR‐TKIs because of AEs were included. Treatment response was determined based on version 1.1 of the Response Evaluation Criteria in Solid Tumors. We defined patients without clear PD within 6 weeks as stable disease. Time to treatment failure (TTF) was assessed from the first EGFR‐TKI treatment start date to the date of the first instance of PD or treatment withdrawal because of AEs. PFS was calculated from the start date of EGFR‐TKI treatment to the date of the first instance of PD or death or lost to follow‐up. PFS2 was defined as the time from the start of the first EGFR‐TKI treatment to PD that was detected during the second EGFR‐TKI treatment. Overall survival (OS) was defined as the time from the start of the first EGFR‐TKI treatment to the date of death or data cut‐off and was estimated using the Kaplan‐Meier method. AEs were graded according to version 4.0 of the National Cancer Institute's Common Toxicity Criteria for Adverse Events. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R software (The R Foundation for Statistical Computing, Vienna, Austria).10\n\n\n3 RESULTS\nThe characteristics and clinical outcomes of the 22 patients are summarized in Table 1. Two patients received platinum‐based chemotherapy as first‐line treatment. Seventeen patients received gefitinib as the first EGFR‐TKI treatment, while four patients received afatinib and one patient received erlotinib. The median TTF was 1.6 months (95% confidence interval [CI]: 1.1‐3.0 months). The reasons for switching EGFR‐TKIs were hepatotoxicity (n = 16), interstitial lung disease (ILD; n = 3), rash (n = 1), and combined factors (n = 2). Four out of 16 patients who had developed the first EGFR‐TKI (gefitinib)‐related hepatotoxicity had mild hepatotoxicity (less than Grade 2) while receiving the second EGFR‐TKI. Two patients who had stopped receiving gefitinib because of hepatotoxicity were continued on active surveillance for relatively long periods (11 and 7 months, respectively).\n\nTable 1 Characteristics of patients with EGFR mutation‐positive NSCLC who received both first‐ and second‐line EGFR‐TKI\n\nNo.\tSex\tAge\tPS\tEGFR mutation\tTKI sequence\tReasons for discontinuation (according to CTCAE v4.0)\tResponse to first TKI\tTTF\tInterval between TKIs\tResponse to second TKI\tPFS for second TKI\tPFS2\tOS\t\n1\tF\t49\t1\t19del\tG (1) → E (2)\tHepatotoxicity (Gr3)\tPR\t5.8\t1.2\tSD\t2.1\t9.1\t30.3\t\n2\tM\t81\t1\t19del\tG (1) → E (2)\tILD (Gr3)\tPR\t3.6\t3.0\tPR\t1.8\t8.4\t8.4\t\n3\tM\t79\t0\t19del\tG (2) → E (3)\tHepatotoxicity (Gr3)\tSD\t1.7\t3.7\tPR\t9.8\t15.2\t25.9\t\n4\tF\t71\t0\t19del\tG (1) → E (2)\tHepatotoxicity (Gr4)\tPR\t1.1\t7.7\tSD\t19.1\t27.9\t58.3a\n\t\n5\tF\t83\t0\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr2)\tCR\t3.0\t1.7\tCR\t9.3\t14.0\t19.8\t\n6\tF\t75\t1\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr2)\tPR\t–\t0.6\tSD\t2.4\t17.3\t31.2\t\n7\tM\t63\t0\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr3)\tPR\t2.4\t0.8\tSD\t30.1\t33.4\t53.3a\n\t\n8\tF\t59\t0\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr3)\tPR\t1.1\t1.1\tPR\t12.5\t14.7\t32.8\t\n9\tM\t56\t0\t19del\tG (1) → E (2)\tHepatotoxicity (Gr3)\tPR\t1.6\t0.5\tPR\t45.8a\n\t47.9a\n\t47.9a\n\t\n10\tF\t62\t0\tL858R\tG (1) → E (3)\tHepatotoxicity (Gr4)\tPR\t0.9\t11.2\tPR\t8.9\t20.9\t40.1\t\n11\tF\t84\t0\t19del\tG (1) → E (2)\tHepatotoxicity (Gr2)\tPR\t1.4\t0.9\tSD\t32.8\t35.2\t46.8a\n\t\n12\tF\t69\t1\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr4)\tPR\t4.6\t0.9\tSD\t1.6\t7.1\t20.6\t\n13\tF\t67\t0\t19del\tA (2) → G (3)\tParonychia, anorexia, diarrhea (Gr2)\tPR\t2.3\t1.0\tSD\t30.5\t33.8\t36.8a\n\t\n14\tF\t58\t0\t19del\tA (1) → E (2)\tILD (Gr2)\tPR\t4.1\t2.3\tPR\t30.3a\n\t36.7a\n\t36.7a\n\t\n15\tF\t61\t1\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr4)\tSD\t1.6\t1.4\tSD\t17.3\t20.3\t22.4\t\n16\tF\t57\t0\t19del\tA (1) → E (2)\tILD (Gr2)\tSD\t1.5\t1.1\tSD\t1.7\t4.4\t7.4\t\n17\tF\t70\t0\t19del\tG (1) → E (2)\tHepatotoxicity (Gr3)\tPR\t0.8\t2.0\tSD\t3.7\t6.5\t27.3a\n\t\n18\tF\t67\t0\t19del\tE (1) → G (2)\tRash (Gr3)\tPR\t6.8\t0.4\tSD\t18.4\t25.6\t27.1a\n\t\n19\tM\t69\t0\tL858R\tG (1) → E (2)\tHepatotoxicity (Gr4)\tSD\t1.1\t1.5\tPR\t15.2\t17.7\t24.2a\n\t\n20\tM\t74\t0\tL858R\tG (1) → A (2)\tHepatotoxicity (Gr3)\tSD\t1.4\t1.5\tSD\t10.3a\n\t13.2a\n\t13.2a\n\t\n21\tM\t74\t0\t19del\tG (1) → A (2)\tHepatotoxicity (Gr2)\tPR\t1.6\t0.6\tSD\t11.0a\n\t13.2a\n\t13.2a\n\t\n22\tF\t50\t0\tL858R\tA (1) → G (2)\tRash, anorexia, diarrhea (Gr2)\tSD\t0.3\t0.5\tPR\t6.2a\n\t7.0a\n\t7.0a\n\t\nA, afatinib; CR, complete response; CTCAE, common terminology criteria for adverse events; E, erlotinib; EGFR, epidermal growth factor receptor; F, female; Gr, grade; G, gefitinib; ILD, interstitial lung disease; L858R, exon‐21 mutation L858R; M, male; OS, overall survival; PD, progressive disease; PFS, progression‐free survival; PR, partial response; PS, performance status; SD, stable disease; TK1, tyrosine kinase inhibitor; TTF, time to treatment failure; 19del, exon‐19 deletion.\n\nUnit of time is months.\n\na Patients have continued the second EGFR‐TKI treatment, or back‐line therapy, and the latest follow‐up data were collected on 30 September 2017.\n\nJohn Wiley & Sons, Ltd.Three patients developed the first EGFR‐TKI‐related ILD. One of the three patients relapsed due to ILD while receiving the second EGFR‐TKI, which resulted in the death of the patient.\n\nPatient 2 was treated with gefitinib as first‐line chemotherapy. After 17 weeks of gefitinib treatment, the patient had a gefitinib‐induced Grade 3 ILD. The discontinuation of gefitinib and initiation of methylprednisolone (40 mg/day) treatment brought about improvement in the findings. Three months after the discontinuation of gefitinib and the tapering off of prednisolone (10 mg/day), the patient received and continued with erlotinib treatment for 8 weeks. However, the patient had recurrence and died of ILD.\n\nPatient 14 was treated with afatinib as a first‐line chemotherapy. After 18 weeks of afatinib treatment, the patient had an afatinib‐induced asymptomatic ILD. The discontinuation of afatinib and initiation of prednisolone (20 mg/day) treatment also resulted in an improvement of the findings. Ten weeks after the discontinuation of afatinib and the tapering off of prednisolone (5 mg/day), the patient was commenced on erlotinib, which was continued while the steroid therapy was completed after 2 weeks. No recurrent ILD was observed during the observation period.\n\nPatient 16 was treated with afatinib as first‐line chemotherapy. After 7 weeks of afatinib treatment, the patient developed difficulty in breathing, and chest computed tomography demonstrated localized ground‐glass opacity around the primary lung tumor. It was discovered that the patient had been treated in combination with hyperthermia treatment without the permission of the attending physician. Five weeks after the discontinuation of afatinib, the patient received erlotinib and continued on the treatment for 7 weeks. However, the patient hoped to receive alternative medicine and was lost to follow‐up.\n\nThe median interval between the first and second EGFR‐TKI treatments was 1.1 months (95% CI: 0.8‐1.7 months). Seventeen patients received erlotinib as the second EGFR‐TKI treatment, while three patients received gefitinib and two patients received afatinib. At the data cut‐off date (30 September 2017), five patients were continuing the second EGFR‐TKI treatment (Figure 1) and 12 patients had been treated using back‐line therapy. The median PFS for the second EGFR‐TKI treatment was 15.2 months (95% CI: 3.7‐30.1 months). The median PFS2 was 17.7 months (95% CI: 14.0‐27.9 months) (Figure 2), and the median OS was 32.8 months (95% CI: 22.4 months to not reached) (Figure 3).\n\nFigure 1 The swimmer plots for durations of the first and second EGFR‐TKI treatments. Black arrows indicate that the patient is still receiving treatment.\n\nTTF, time to treatment failure; TKI, tyrosine kinase inhibitor; PFS, progression‐free survival [Color figure can be viewed at wileyonlinelibrary.com]\n\nFigure 2 Progression‐free survival from the start of the first EGFR‐TKI treatment to progression during the second EGFR‐TKI treatment (PFS2).\n\nCI, confidence interval\n\nFigure 3 Overall survival among all patients.\n\nCI, confidence interval\n\n4 DISCUSSION\nPatients with EGFR mutation‐positive NSCLC can receive EGFR‐TKIs as a standard treatment,1, 2 and most patients are treated with relatively controlled toxicity. However, some patients experience AEs and do not wish to continue treatment using the same drug. For example, two studies of patients with EGFR mutation‐positive NSCLC indicated that 6.1‐7.7% of patients refused to continue EGFR‐TKI treatment because of various AEs such as ILD and hepatitis.6, 7 Although there are some case reports describing successful EGFR‐TKI rechallenge after recovery from EGFR‐TKI‐induced AEs, few studies have examined switching EGFR‐TKIs because of AEs, rather than PD. For example, Takeda et al. reported five patients who discontinued treatment with first EGFR‐TKI, because of severe drug‐related toxicity (ILD in three cases, hepatotoxicity in one case, and rash in one case), and subsequently received a second EGFR‐TKI treatment.8 Kashiwabara et al. reported five patients who refused to continue treatment using first EGFR‐TKI, but were subsequently rechallenged using a second EGFR‐TKI.9 Neither report examined the safety of the second EGFR‐TKI treatment and whether it provided a beneficial effect or not. Thus, the present study builds on the experience of those researchers.\n\nThe present study evaluated PFS2, which is a surrogate endpoint for OS and is generally defined as the time from randomization to objective tumor progression or death during next‐line treatment.11 However, we defined PFS2 as the time from the start of the first EGFR‐TKI treatment to PD during the second EGFR‐TKI treatment. We believe that this approach provides a reasonable endpoint for evaluating the effect of switching EGFR‐TKI treatments, and we observed that the PFS and PFS2 outcomes were favorable, compared to the results from previous trials of EGFR‐TKI treatments. These results suggest that switching EGFR‐TKI treatments is a valid approach. In addition, hepatotoxicity was the main reason for switching EGFR‐TKIs in the present study, and the AEs were not always serious. Similarly, several case reports have suggested that switching EGFR‐TKIs may be possible in cases with severe hepatic dysfunction.12, 13, 14 Thus, our findings and those previous results indicate that EGFR‐TKI switching is likely effective for patients who develop hepatitis and have an EGFR driver mutation. Furthermore, switching EGFR‐TKIs before the patient develops severe hepatitis may protect their performance status for back‐line therapy.\n\nApproximately 60% of patients with EGFR mutations have the T790M mutation when they experience PD during the first EGFR‐TKI treatment, and sequential treatment using a third‐generation EGFR‐TKI is critical for these patients.15 In addition, a previous study revealed that long periods of EGFR‐TKI treatment before rebiopsy may provide useful information regarding expression of the T790M mutation.16 Therefore, our results also provide useful data for treating patients who experience AEs during EGFR‐TKI treatment.\n\nThe present study has several limitations. First, we retrospectively searched for clinical records from a single institution, and the sample size was small. Furthermore, PFS may not be an adequate endpoint in retrospective study, because evaluation interval was not performed periodically. Second, there is a possibility of selection bias, as we only included patients who received a first and second EGFR‐TKI, although approximately 8% of patients do not respond to gefitinib.17 Thus, although these cases are rare, it is possible that we excluded patients who could not receive a second EGFR‐TKI treatment because of early PD or serious AEs. Third, the follow‐up period was short and 12 of the 22 patients were continuing treatment using a second EGFR‐TKI or back‐line chemotherapy at the data cut‐off point. In this context, retrospective analysis of real‐world Japanese clinical data revealed that the median OS after first‐line treatment was approximately 30.8 months in patients with an EGFR mutation.18 In contrast, the present study revealed a median OS of 32.8 months. Although it appears that our findings do not indicate inferior OS after EGFR‐TKI switching, further studies with longer follow‐ups are needed to evaluate this possibility.\n\nIn conclusion, switching EGFR‐TKI treatments because of AEs is an effective option for patients with EGFR mutation‐positive NSCLC.\n\nETHICAL CONSIDERATIONS\nThe study protocol was approved by the Research Ethics Committee of our institution, and the research complied with the 1964 Declaration of Helsinki and its later amendments.\n\nCONFLICTS OF INTEREST\nThe authors declare that they have no conflicts of interest.\n\nSupporting information\nAppendix Table. Additional characteristics of patients with EGFR mutation‐positive NSCLC who received both first‐ and second‐line EGFR‐TKI\n\nClick here for additional data file.\n==== Refs\nREFERENCES\n1 \n\nHanna \nN \n, \nJohnson \nD \n, \nTemin \nS , Jr\n, et al. Systemic therapy for stage IV Non–Small‐Cell lung cancer: American society of clinical oncology clinical practice guideline update\n. J Clin Oncol . 2017 ;35 :3484 –3515\n.28806116 \n2 \n\nNovello \nS \n, \nBarlesi \nF \n, \nCalifano \nR \n, et al. Metastatic non‐small‐cell lung cancer: eSMO clinical practice guidelines for diagnosis, treatment and follow‐up\n. Ann Oncol . 2016 ;27 (Suppl 5 ):v1 –v27\n.27664245 \n3 \n\nMaemondo \nM \n, \nInoue \nA \n, \nKobayashi \nK \n, et al. Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR\n. N Engl J Med . 2010 ;362 :2380 –2388\n.20573926 \n4 \n\nRosell \nR \n, \nCarcereny \nE \n, \nGervais \nR \n, et al. Erlotinib versus standard chemotherapy as first‐line treatment for European patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer (EURTAC): a multicentre, open‐label, randomized phase 3 trial\n. Lancet Oncol . 2012 ;13 :239 –246\n.22285168 \n5 \n\nSequist \nLV \n, \nYang \nJC \n, \nYamamoto \nN \n, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations\n. J Clin Oncol . 2013 ;31 :3327 –3334\n.23816960 \n6 \n\nTakeda \nM \n, \nOkamoto \nI \n, \nNakagawa \nK \n. Pooled safety analysis of EGFR‐TKI treatment for EGFR mutation‐positive non‐small cell lung cancer\n. Lung Cancer . 2015 ;88 :74 –79\n.25704957 \n7 \n\nDing \nPN \n, \nLord \nSJ \n, \nGebski \nV \n, et al. Risk of treatment‐related toxicities from EGFR tyrosine kinase inhibitors: a meta‐analysis of clinical trials of gefitinib, erlotinib, and afatinib in advanced EGFR‐mutated non‐small cell lung cancer\n. J Thorac Oncol . 2017 ;12 :633 –643\n.28007626 \n8 \n\nTakeda \nM \n, \nOkamoto \nI \n, \nTsurutani \nJ \n, \nOiso \nN \n, \nKawada \nA \n, \nNakagawa \nK \n. Clinical impact of switching to a second EGFR‐TKI after a severe AE related to a first EGFR‐TKI in EGFR‐mutated NSCLC\n. Jpn J Clin Oncol . 2012 ;42 :528 –533\n.22457323 \n9 \n\nKashiwabara \nK \n, \nSemba \nH \n, \nFujii \nS \n, \nTsumura \nS \n. Outcome in advanced non‐small cell lung cancer patients with successful rechallenge after recovery from epidermal growth factor receptor tyrosine kinase inhibitor‐induced interstitial lung disease\n. Cancer Chemother Pharmacol . 2017 ;79 :705 –710\n.28258422 \n10 \n\nKanda \nY \n. Investigation of the freely available easy‐to‐use software ‘EZR’ for medical statistics\n. Bone Marrow Transplant . 2013 ;48 :452 –458\n.23208313 \n11 \nEuropeanMedicine Agency \n. Guideline on the Evaluation of Anticancer Medicinal Products in Man . London, England : European Medicines Agency ; 2012 \nhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137128.pdf\n\n12 \n\nKijima \nT \n, \nShimizu \nT \n, \nNonen \nS \n, et al. Safe and successful treatment with erlotinib after gefitinib‐induced hepatotoxicity: difference in metabolism as a possible mechanism\n. J Clin Oncol . 2011 ;29 :e588 –590\n.21502555 \n13 \n\nKu \nGY \n, \nChopra \nA , Jr\n, \nLopesGde \nL \n. Successful treatment of two lung cancer patients with erlotinib following gefitinib‐induced hepatotoxicity\n. Lung Cancer . 2010 ;70 :223 –225\n.20817304 \n14 \n\nKunimasa \nK \n, \nYoshioka \nH \n, \nIwasaku \nM \n, et al. Successful treatment of non‐small cell lung cancer with gefitinib after severe erlotinib‐related hepatotoxicity\n. Intern Med . 2012 ;51 :431 –434\n.22333382 \n15 \n\nMok \nTS \n, \nWu \nY‐L \n, \nAhn \nM‐J \n, et al. Osimertinib or Platinum‐Pemetrexed in EGFR T790M‐Positive lung cancer\n. N Engl J Med . 2017 ;376 :629 –640\n.27959700 \n16 \n\nKawamura \nT \n, \nKenmotsu \nH \n, \nOmori \nS \n, et al. Clinical factors predicting detection of t790m mutation in rebiopsy for EGFR‐mutant non‐small‐cell lung cancer\n. Clin Lung Cancer . 2018 ;19 :e247 –252\n.28866043 \n17 \n\nFukuhara \nT \n, \nMaemondo \nM \n, \nInoue \nA \n, et al. Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation\n. Lung Cancer . 2015 ;88 :181 –186\n.25726043 \n18 \n\nInoue \nA \n, \nYoshida \nK \n, \nMorita \nS \n, et al. Characteristics and overall survival of EGFR mutation‐positive non‐small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients\n. Jpn J Clin Oncol . 2016 ;465 :462 –467\n.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1743-7555",
"issue": "16(2)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "epidermal growth factor receptor; non-small cell lung cancer; tyrosine kinase inhibitor",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D064420:Drug-Related Side Effects and Adverse Reactions; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "e113-e117",
"pmc": null,
"pmid": "30506897",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": "26977054;20817304;23816960;23208313;22457323;22285168;28007626;30506897;21502555;25726043;20573926;28258422;27664245;28806116;28866043;27959700;22333382;25704957",
"title": "The effects of switching EGFR-TKI treatments for non-small cell lung cancer because of adverse events.",
"title_normalized": "the effects of switching egfr tki treatments for non small cell lung cancer because of adverse events"
} | [
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-245345",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"abstract": "To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents.\n\n\n\nIndividually linked health data in Denmark (2000-2012), Finland (2005-2014), Iceland (2004-2017), Norway (2005-2015), Sweden (2006-2015), Germany (2006-2015), Australia (New South Wales, 2004-2012), Hong Kong (2001-2015), UK (2006-2016), and the US (Medicaid, 2000-2013, and IBM MarketScan, 2012-2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics.\n\n\n\nWe included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries.\n\n\n\nAntipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population.",
"affiliations": "Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. Electronic address: johan.reutfors@ki.se.;Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.;Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's, Harvard Medical School, Boston, MA, United States of America.;Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK.;Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.;Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway; Department of Global Public Health and Primary Care, University of Bergen, Norway.;Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.;Finnish Institute for Health and Welfare, Helsinki, Finland; Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.;Centre for Big Data Research in Health, Faculty of Medicine, UNSW, Sydney, Australia.;Harvard T.H. Chan School of Public Health, Boston, MA, United States of America.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.;Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.;Finnish Institute for Health and Welfare, Helsinki, Finland.;Aarhus University, Aarhus, Denmark.;Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK; Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Erasmus University Medical Centre, Rotterdam, The Netherlands.;Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.;Centre for Big Data Research in Health, Faculty of Medicine, UNSW, Sydney, Australia.;Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.;Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK.;Aarhus University, Aarhus, Denmark.;Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Centre for Big Data Research in Health, Faculty of Medicine, UNSW, Sydney, Australia.;Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Internal Medicine, Danderyd Hospital, Stockholm, Sweden.",
"authors": "Reutfors|Johan|J|;Cesta|Carolyn E|CE|;Cohen|Jacqueline M|JM|;Bateman|Brian T|BT|;Brauer|Ruth|R|;Einarsdóttir|Kristjana|K|;Engeland|Anders|A|;Furu|Kari|K|;Gissler|Mika|M|;Havard|Alys|A|;Hernandez-Diaz|Sonia|S|;Huybrechts|Krista F|KF|;Karlstad|Øystein|Ø|;Leinonen|Maarit K|MK|;Li|Jiong|J|;Man|Kenneth K C|KKC|;Pazzagli|Laura|L|;Schaffer|Andrea|A|;Schink|Tania|T|;Wang|Zixuan|Z|;Yu|Yongfu|Y|;Zoega|Helga|H|;Bröms|Gabriella|G|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2020.03.048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "220()",
"journal": "Schizophrenia research",
"keywords": "Antipsychotics; Drug utilization study; Epidemiology; Pharmacological treatment; Pregnancy",
"medline_ta": "Schizophr Res",
"mesh_terms": "D014150:Antipsychotic Agents; D001315:Australia; D005260:Female; D005387:Finland; D005858:Germany; D006723:Hong Kong; D006801:Humans; D009664:Norway; D011247:Pregnancy; D013548:Sweden; D014481:United States",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "106-115",
"pmc": null,
"pmid": "32295750",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Antipsychotic drug use in pregnancy: A multinational study from ten countries.",
"title_normalized": "antipsychotic drug use in pregnancy a multinational study from ten countries"
} | [
{
"companynumb": "SE-ALKEM LABORATORIES LIMITED-SE-ALKEM-2022-00542",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "Renal clearance is the major elimination pathway for sofosbuvir (SOF). We assessed the safety and efficacy of SOF-containing regimens in patients with varying baseline estimated glomerular filtration rate (eGFR).\n\n\n\nHCV-TARGET database is a multicentre, longitudinal 'real-world' treatment cohort.\n\n\n\nA total of 1789 patients [genotypes 1 (72%), 2 (17%) 3 (9%), 4-6 (2%)] had baseline eGFR determination: 73 with eGFR≤45 (18 with eGFR≤30, 5 on dialysis) were compared to 1716 with eGFR>45 ml/min/1.73 m(2) . Patients with baseline eGFR≤45 vs. >45 differed in being female (55% vs. 36%), age ≥65 years (24% vs. 16%), Black race (22% vs. 12%), having cirrhosis with decompensation (73% vs. 24%) and being post-transplant (49% vs. 10%), all P < 0.05. All patients with eGFR≤45 were treated with SOF 400 mg/day (including those on haemodialysis) and had median starting ribavirin (RBV) dose of 800 mg (IQR: 400-1200). Sustained virologic response (SVR) frequencies were similar across eGFR groups, ranging from 82-83%. Patients with eGFR ≤45 more frequently experienced anaemia, worsening renal function and serious AEs (all P < 0.05), and these associations persisted when limiting analysis to RBV-free regimens. Patients with baseline eGFR≤30 and eGFR 31-45 had similar frequencies of efficacy and safety outcomes.\n\n\n\nSustained viral clearance was achieved in 83% of patients with renal impairment (eGFR ≤45 ml/min/1.73 m(2) ) treated with SOF-containing regimens. However, these patients had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV. Patient with renal impairment require close monitoring and should be treated by providers extensively experienced with SOF-containing regimens.",
"affiliations": "University of California San Francisco, San Francisco, CA, USA.;Saint Louis University School of Medicine, St Louis, MO, USA.;Massachusetts General Hospital, Boston, MA, USA.;Yale University School of Medicine, New Haven, CT, USA.;University of North Carolina, Chapel Hill, NC, USA.;Massachusetts General Hospital, Boston, MA, USA.;Yale University School of Medicine, New Haven, CT, USA.;University of Florida, Gainesville, FL, USA.;University of North Carolina, Chapel Hill, NC, USA.;University of California San Francisco, San Francisco, CA, USA.",
"authors": "Saxena|Varun|V|;Koraishy|Farrukh M|FM|;Sise|Meghan E|ME|;Lim|Joseph K|JK|;Schmidt|Monica|M|;Chung|Raymond T|RT|;Liapakis|Annmarie|A|;Nelson|David R|DR|;Fried|Michael W|MW|;Terrault|Norah A|NA|;|||",
"chemical_list": "D000998:Antiviral Agents; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "36(6)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "decompensated cirrhosis; haemodialysis; liver transplantation; sustained virologic response",
"medline_ta": "Liver Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D005919:Glomerular Filtration Rate; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009656:North America; D012044:Regression Analysis; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D055815:Young Adult",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "807-16",
"pmc": null,
"pmid": "26923436",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10075613;17592100;19003880;23669289;23696464;23813604;24001168;24935352;25218788;25614962;25641426;26095179;26365684;3992076;6740666",
"title": "Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function.",
"title_normalized": "safety and efficacy of sofosbuvir containing regimens in hepatitis c infected patients with impaired renal function"
} | [
{
"companynumb": "US-JNJFOC-20160607075",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": null,
... |
{
"abstract": "Guidelines recommend steroid plus cyclical cyclophosphamide (St-Cp) therapy for patients with idiopathic membranous nephropathy at high risk of progression to ESRD. Rituximab (Rtx) may be a safer alternative. In this retrospective, observational cohort study, we compared time to any adverse event (primary outcome); serious or nonserious events; partial and complete remission of the nephrotic syndrome; and a composite of doubling of serum creatinine, ESRD, or death between 100 Rtx-treated patients and 103 patients who received daily St-Cp We monitored patients with standardized protocols and adjusted for baseline characteristics by Cox regression. Over a median follow-up of 40 months, the Rtx group had significantly fewer adverse events than the St-Cp group (63 versus 173; P<0.001), both serious (11 versus 46; P<0.001) and nonserious (52 versus 127; P<0.001). Cumulative incidence of any first (35.5% versus 69.0%; P<0.001), serious (16.4% versus 30.2%; P=0.002), or nonserious (23.6% versus 60.8%; P<0.001) event was significantly lower with Rtx Adjusted hazard ratios (95% confidence intervals) between Rtx and St-Cp groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events. Although the cumulative incidence of partial remission was lower in the Rtx group, rates of complete remission and the composite renal end point did not differ significantly between groups. Because of its superior safety profile, we suggest that Rtx might replace St-Cp as first-line immunosuppressive therapy in patients with idiopathic membranous nephropathy and nephrotic syndrome.",
"affiliations": "Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands; jan.vandenbrand@radboudumc.nl giuseppe.remuzzi@marionegri.it.;Unit of Nephrology, Azienda Socio Sanitaria Territoriale Ospedale Papa Giovanni XXIII, Bergamo, Italy; and.;IRCCS - Instituto di Ricerche Farmacologiche \"Mario Negri\", Department of Renal Medicine, Clinical Research Center for Rare Diseases \"Ado e Cele Daccò\", Ranica, Bergamo, Italy.;Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.;IRCCS - Instituto di Ricerche Farmacologiche \"Mario Negri\", Department of Renal Medicine, Clinical Research Center for Rare Diseases \"Ado e Cele Daccò\", Ranica, Bergamo, Italy.;IRCCS - Instituto di Ricerche Farmacologiche \"Mario Negri\", Department of Renal Medicine, Clinical Research Center for Rare Diseases \"Ado e Cele Daccò\", Ranica, Bergamo, Italy.;Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.;Unit of Nephrology, Azienda Socio Sanitaria Territoriale Ospedale Papa Giovanni XXIII, Bergamo, Italy; and jan.vandenbrand@radboudumc.nl giuseppe.remuzzi@marionegri.it.",
"authors": "van den Brand|Jan A J G|JAJG|;Ruggenenti|Piero|P|;Chianca|Antonietta|A|;Hofstra|Julia M|JM|;Perna|Annalisa|A|;Ruggiero|Barbara|B|;Wetzels|Jack F M|JFM|;Remuzzi|Giuseppe|G|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D003404:Creatinine; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.2016091022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "28(9)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": "adverse events; clinical epidemiology; cyclophosphamide; drug safety; membranous nephropathy; rituximab",
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D003404:Creatinine; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D005260:Female; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009404:Nephrotic Syndrome; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "2729-2737",
"pmc": null,
"pmid": "28487395",
"pubdate": "2017-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "9322882;17494881;14585769;17702725;25364141;23813556;12354476;24029426;25318831;22822077;18336067;9501711;25804280;26276965;24855280;22157712;27756808;1640953;21616914;6366560;17660026;26413273;2642605;26087670;21784898;8544420",
"title": "Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy.",
"title_normalized": "safety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy"
} | [
{
"companynumb": "PHHY2017NL172337",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In November 2020, atezolizumab plus bevacizumab became available for the treatment of hepatocellular carcinoma (HCC), and its efficacy is expected as a new treatment option for HCC. However, the occurrence of immune-related adverse events (irAEs) associated with the administration of immune checkpoint inhibitors is a major concern in clinical practice. We reported a case of irAE-induced myocarditis after the treatment for HCC. Based on the symptoms and echocardiographic findings, we suspected irAE-induced myocarditis and acute heart failure, and the patient was admitted to the hospital for further investigation and treatment. From starting the patient on therapy with methylprednisolone succinate sodium, the laboratory data and symptoms tended to improve. The patient was discharged to home on the 25th day of treatment. Because the number of patients with irAE myocarditis is expected to increase in clinical practice in the near future, further accumulation and investigation of cases are necessary.",
"affiliations": "Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. hisashi7@kitasato-u.ac.jp.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Cardiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Cardiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.",
"authors": "Iwasaki|Shuichiro|S|;Hidaka|Hisashi|H|http://orcid.org/0000-0002-4151-5663;Uojima|Haruki|H|;Hashimura|Miho|M|;Nabeta|Takeru|T|;Sanoyama|Itaru|I|;Wada|Naohisa|N|;Kubota|Kousuke|K|;Nakazawa|Takahide|T|;Shibuya|Akitaka|A|;Koizumi|Wasaburo|W|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; D000068258:Bevacizumab; C000594389:atezolizumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01442-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Atezolizumab plus bevacizumab; Hepatocellular carcinoma (HCC); Immune-related adverse events (irAEs); Myocarditis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008113:Liver Neoplasms; D009205:Myocarditis",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1233-1239",
"pmc": null,
"pmid": "34024039",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of immune checkpoint inhibitor-associated myocarditis after initiation of atezolizumab plus bevacizumab therapy for advanced hepatocellular carcinoma.",
"title_normalized": "a case of immune checkpoint inhibitor associated myocarditis after initiation of atezolizumab plus bevacizumab therapy for advanced hepatocellular carcinoma"
} | [
{
"companynumb": "JP-PFIZER INC-2021648541",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
... |
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