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"abstract": "Porphyria cutanea tarda (PCT) is a blistering skin disorder that occurs most commonly in middle-aged individuals. It is caused by decreased uroporphyrinogen decarboxylase (UROD) activity, which results in elevated levels of uroporphyrinogen. Occurrence remains very rare in children with some sources quoting as few as 50 reports of childhood cases.1 The literature reports occasional cases of PCT onset with various drugs, including barbiturates, estrogens, griseofulvin, rifampicin, sulfonamides, imatinib, methotrexate, tamoxifen, and cyclophosphamide, however its incidence in childhood is uncommon.2-6 We present a case of new-onset PCT in an eight year-old following treatment of pre-B cell acute lymphoblastic leukemia with multi-agent chemotherapy.",
"affiliations": null,
"authors": "LaPresto|Lindsay|L|;Nyanda|Hoka|H|;Knapp|Charles F|CF|;Sopkovich|Jennifer|J|;Nelson|Christopher G|CG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "13(4)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D005260:Female; D006801:Humans; D006983:Hypertrichosis; D018962:Phlebotomy; D017119:Porphyria Cutanea Tarda; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "489-91",
"pmc": null,
"pmid": "24719070",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Porphyria cutanea tarda in a child following multi-agent chemotherapy.",
"title_normalized": "porphyria cutanea tarda in a child following multi agent chemotherapy"
} | [
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"companynumb": "US-MYLANLABS-2015M1003123",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "DOXORUBICIN"
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"abstract": "Neurological and psychiatric conditions frequently overlap in neuro-oncology. This overlapping negatively affects patients' quality of life and decreases the ability of providers to manage specific symptoms by therapy modulation, especially when psychopharmacotherapy needs to be prescribed. We describe here a patient with recurrent brain tumor, symptomatic epilepsy and depression who developed Pisa syndrome and parkinsonism after several months of valproic acid use. An accurate recognition of symptoms and treatment side effect allowed an appropriate clinical approach so as to rapidly improve both movement disorder and depression without increasing the risk of developing seizure. This has improved the autonomy and quality of life in a patient with poor prognosis.",
"affiliations": "Department of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Psychiatry, Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.;Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Applied Research Unit for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy.;Department of Psychiatry, Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Philosophy, Università degli Studi di Milano, Milan, Italy.",
"authors": "Botturi|Andrea|A|;Silvani|Antonio|A|;Pravettoni|Gabriella|G|;Paoli|Riccardo Augusto|RA|;Lucchiari|Claudio|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000446643",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000446643crn-0008-0115Case ReportReversible Valproate Induced Pisa Syndrome and Parkinsonism in a Neuro-Oncology Patient with Depression and Epilepsy Botturi Andrea ab*Silvani Antonio aPravettoni Gabriella dePaoli Riccardo Augusto bLucchiari Claudio caDepartment of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalybDepartment of Psychiatry, Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, ItalycDepartment of Philosophy, Università degli Studi di Milano, Milan, ItalydDepartment of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, ItalyeApplied Research Unit for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy*Andrea Botturi, Via Celoria 11, IT–20133 Milan (Italy), andrea.botturi@istituto-besta.itMay-Aug 2016 6 6 2016 6 6 2016 8 2 115 119 27 1 2016 9 5 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Neurological and psychiatric conditions frequently overlap in neuro-oncology. This overlapping negatively affects patients’ quality of life and decreases the ability of providers to manage specific symptoms by therapy modulation, especially when psychopharmacotherapy needs to be prescribed. We describe here a patient with recurrent brain tumor, symptomatic epilepsy and depression who developed Pisa syndrome and parkinsonism after several months of valproic acid use. An accurate recognition of symptoms and treatment side effect allowed an appropriate clinical approach so as to rapidly improve both movement disorder and depression without increasing the risk of developing seizure. This has improved the autonomy and quality of life in a patient with poor prognosis.\n\nKeywords\nParkinsonismValproic acidDepressionEpilepsyNeuro-oncology\n==== Body\nCase Report\nA 59-year-old inpatient was admitted to the neurological cancer center Istituto Neurologico ‘Carlo Besta’ for worsened condition. He had been diagnosed 3 years before with recurrent high-grade glioma and underwent two surgeries, radiotherapy plus chemotherapy. He suffered from epilepsy in therapy with levetiracetam. Since this treatment was poorly tolerated for dysphoric status, it was changed to valproic acid (VPA) (900 mg/day). However, 6 months before hospitalization – 3 after the new antiepileptic drug –, during periodical outpatient clinical evaluation, a depressed mood emerged, with work retirement, somatization, loss of weight, and sleep disorder. Furthermore, cognitive impairment seemed to be present, with short-term memory deficit and dyscalculia. The psychopathological history of the patient was characterized by the presence of hyperthymic temperament and subsyndromal hypomania. A previous depressive episode had been reported during young adulthood.\n\nSix months before hospitalization, he started taking paroxetine (20 mg/day), with slight improvement of mood at clinical global impression. The patient needed to be hospitalized, due to gait and upright posture disturbances. Brain magnetic resonance imaging (fig. 1) showed removal of bulky lesion located in the right parietal peritrigonal region. There was marked dilatation of the temporal horn, the third ventricle and the left lateral ventricle. Widespread signal alteration was prevalent in the white matter and in the splenium. After administration of gadolinium, it was not possible to observe clear signs of dissemination in the supratentorial and infratentorial region.\n\nThe electroencephalogram described rather unstable background activity, better on the left hemisphere, slower and more unstable on the right. Multifocal epileptiform abnormalities were observed in the right hemisphere. On the clinical examination, the patient showed abnormal posture with sustained lateral bending of the trunk along the sagittal plane on the right side. At the same time, bradykinesia and rigidity of the four limbs were present. Postural instability and falling were present as well. Tendon reflexes were brisk without pyramidal signs. The patient also showed tremor of the voice and hypophonia, hypomimia, short shuffling steps, trouble starting to walk, and difficulty in turning. The signs were symmetrical.\n\nThe blood level of VPA was 63 µg/ml (normal value = 40–100), and ammonemia was 57 µg/dl (normal value = 27–102). During the hospitalization, a pharmacological change was decided that involved tapering off VPA and getting on therapy with lamotrigine (LMT) up to a dose of 200 mg/day, with blood level 7.2 mg/l (normal value = 3–14). The patient was discharged with a partial regression of symptoms. In the following weeks, neurological and psychiatric condition improved. (table 1)\n\nDiscussion\nDepression accounts for 15–20% of patients with glioma within 8 months after diagnosis [1], even if various longitudinal studies have shown significant improvements in the following months. The precise cause of the depression remains unclear. Previous medical history of depression may predict an increased risk of depression in glioma. Untreated depression is an established risk factor for mortality in cancer and neurological disease [2].\n\nSelective serotonin reuptake inhibitors (SSRIs) are associated with improvements in disability and neurological impairment after cerebrovascular disease. Conflicting data are available with regard to glioma patients. Extrapyramidal symptoms (EPS) have been reported with different classes of antidepressants; they seem not to be dose-related and to be due to short-term or long-term use. The literature concerning SSRIs is controversial, because not the class in itself is responsible for EPS but the patient's own sensitivity. In any case, an increase of 5HT, due to the SSRIs reuptake inhibition, can reduce the dopaminergic tone at basal ganglia level (inducing EPS), as well as at the anterior cingulate and frontal cortex, potentially inducing emotional blunting [3]. However, SSRIs are currently used in Parkinson disease and may improve depression [4].\n\nEpilepsy occurs in about 40–60% of patients with high-grade glioma, and is itself an unfavorable prognostic factor [5]. Alper et al. [6] performed a large meta-analysis on seizure risk and found an increased risk linked to the use of the antidepressants bupropion and clomipramine. Most antidepressants included in this study showed no association with an increased seizure risk in therapeutic doses, and some were associated with a reduced risk [2]. Furthermore, a systematic revision of the Cochrane database did not appear to show any significant worsening of seizures [7].\n\nVPA is a well-known antiepileptic drug indicated for the prevention of affective episodes [8]. VPA was identified as one of the drugs capable of inducing parkinsonism in elderly patients in the French Pharmacovigilance Database. A similar association was found in a recent literature review [9]. Most cases were shown to be reversible upon VPA discontinuation, although no predictors of reversibility were identified. VPA acts as mild inhibitor of cytochrome enzyme system (CYP450) and can induce pharmacokinetic interactions with drugs metabolized by CYP2D6 and CYP2C9 (e.g. SSRIs) with increase of plasma levels [10].\n\nEPS refers to a condition of sustained lateral bending of the trunk, associated or not with rotation of the spine along the sagittal plane. It was originally described by Ekbom et al. [11] in 1972 in patients on psychiatric drugs.\n\nLMT is often used with severe epilepsy (focal and general onset seizures) [12], and is recommended in bipolar maintenance when depression is prominent. It also plays a role in treating acute bipolar and unipolar depression, for intrinsic antidepressant activity [13]. Some papers have described the use of LMT in hard to treat depression [14, 15] due to the weak CYP450-mediated metabolic interaction with SSRIs.\n\nConsistently with the literature, tapering and changing of antiepileptic drugs with LMT has improved neurological and psychiatric symptoms. The choice to remove VPA was due to a less significant EPS (percentage and severity) compared to what is reported in association with antidepressants. The scores of the psychometric scales showed a decrease of depression and disability, with recovery of daily living activity.\n\nConclusion\nNeurological and psychiatric conditions frequently overlap in neuro-oncology. This overlapping negatively affects patients’ quality of life and decreases the ability of providers to manage specific symptoms by therapy modulation, especially when psychopharmacotherapy needs to be prescribed.\n\nIn the present case, an oncology patient suffered from depression and epilepsy. However, an accurate recognition of symptoms and treatment side effects allowed an appropriate clinical approach so as to rapidly improve both movement disorder and depression without increasing the risk of developing seizure. This improved the autonomy and quality of life in a patient with poor prognosis.\n\nStatement of Ethics\nThe patient had the opportunity to discuss with his physician in charge the opportunity to publish his clinical case without revealing any personal data in order to share and improve clinical knowledge and practice. The patient signed an inform consent and gave us the authorization to publish his case. Authors guaranteed the anonymity of the patient.\n\nDisclosure Statement\nThe authors declare that the study presented received no financial support. The authors declare no conflict of interest.\n\nFig. 1 Magnetic resonance image of the brain.\n\nTable 1 Clinical characteristics over time\n\n\tT0\tT1\tT2\t\nUPDRS III\t52/108\t7/108\t0/108\t\nMMSE\t25/30\t27/30\t29/30\t\nClock Drawing Test\t1\t1\t1\t\nHAM-D\t25\t4\t3\t\nMADRS\t32\t10\t6\t\nADL\t5/6\t6/6\t6/6\t\nIADL\t1/8\t6/8\t8/8\t\nBarthel Index\t70/100\t100/100\t100/100\t\nT0 = On admission to hospital; T1 = 1 month later; T2 = 3 months later; UPDRS = Unified Parkinson Disease Rating Scale (part III motor examination); MMSE = Mini Mental State Evaluation; HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery Asberg Depression Rating Scale; ADL = Activities of Daily Living; IADL = Instrumental Activities of Daily Living.\n==== Refs\nReferences\n1 Rooney AG McNamara S Mackinnon M Fraser M Rampling R Carson A Grant R Frequency, clinical associations, and longitudinal course of major depressive disorder in adults with cerebral glioma J Clin Oncol 2011 29 4307 4312 21990406 \n2 Rooney AG Brown PD Reijneveld JC Grant R Depression in glioma: a primer for clinicians and researchers J Neurol Neurosurg Psychiatry 2014 85 230 235 24029545 \n3 Opbroek A Delgado PL Laukes C McGahuey C Katsanis J Moreno FA Manber R Emotional blunting associated with SSRI-induced sexual dysfunction Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol 2002 5 147 151 12135539 \n4 Dell'Agnello G Ceravolo R Nuti A Bellini G Piccinni A D'Avino C Dell'Osso L Bonuccelli U SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study Clin Neuropharmacol 2001 24 221 227 11479393 \n5 Vecht CJ Kerkhof M Duran-Pena A Seizure prognosis in brain tumors: new insights and evidence-based management Oncologist 2014 19 751 759 24899645 \n6 Alper K Schwartz KA Kolts RL Khan A Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports Biol Psychiatry 2007 62 345 354 17223086 \n7 Maguire MJ Weston J Singh J Marson AG Antidepressants for people with epilepsy and depression Cochrane Database Syst Rev 2014 12 CD010682 25464360 \n8 Lambert PA Carraz G Borselli S Carbel S Neuropsychotropic action of a new anti-epileptic agent: depamide Ann Med Psychol (Paris) 1966 124 707 710 5941463 \n9 Nanau RM Neuman MG Adverse drug reactions induced by valproic acid Clin Biochem 2013 46 1323 1338 23792104 \n10 Madhusoodanan S Velama U Parmar J Goia D Brenner R A current review of cytochrome P450 interactions of psychotropic drugs Ann Clin Psychiatry 2014 26 120 138 24812650 \n11 Ekbom K Lindholm H Ljungberg L New dystonic syndrome associated with butyrophenone therapy Z Neurol 1972 202 94 103 4115928 \n12 Matsuo F Bergen D Faught E Messenheimer JA Dren AT Rudd GD Lineberry CG Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group Neurology 1993 43 2284 2291 8232944 \n13 Reid JG Gitlin MJ Altshuler LL Lamotrigine in psychiatric disorders J Clin Psychiatry 2013 74 675 684 23945444 \n14 Bruno A Micò U Pandolfo G Mallamace D Abenavoli E Di Nardo F D'Arrigo C Spina E Zoccali RA Muscatello MR Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study J Psychopharmacol 2012 26 1456 1462 22351381 \n15 Chang CM Sato S Han C Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression CNS Drugs 2013 27 suppl 1 S21 S27 23712796\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "8(2)",
"journal": "Case reports in neurology",
"keywords": "Depression; Epilepsy; Neuro-oncology; Parkinsonism; Valproic acid",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "115-9",
"pmc": null,
"pmid": "27462241",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "8232944;25464360;11479393;12135539;24899645;24029545;23945444;4115928;21990406;5941463;23712796;23792104;22351381;24812650;17223086",
"title": "Reversible Valproate Induced Pisa Syndrome and Parkinsonism in a Neuro-Oncology Patient with Depression and Epilepsy.",
"title_normalized": "reversible valproate induced pisa syndrome and parkinsonism in a neuro oncology patient with depression and epilepsy"
} | [
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"companynumb": "PHHY2016IT148706",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAROXETINE"
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"abstract": "Aripiprazole is a second-generation antipsychotic drug with partial dopamine agonistic activity. Although the adverse cardiovascular effects of both typical and atypical antipsychotics are well known, similar data on aripiprazole, which was recently introduced, are scarce. Herein we report a 35-year-old female that presented to our emergency department with non-cardiogenic pulmonary edema. Chest X-ray and thoracic CT showed pulmonary edema and bilateral pleural effusion. Anamnesis showed that she had been taking sertraline 200 mg d-1 for obsessive-compulsive disorder for a long time and that aripiprazole10 mg d-1 was added for augmentation 2 months prior to presentation. We think that the CYP 2D6 inhibitor sertraline might have played a role in increasing the plasma concentration and toxicity of aripiprazole in the presented patient.",
"affiliations": null,
"authors": "Cetin|Mustafa|M|;Celik|Mustafa|M|;Cakıcı|Musa|M|;Polat|Mustafa|M|;Suner|Arif|A|",
"chemical_list": "D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1300-2163",
"issue": "25(4)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D009771:Obsessive-Compulsive Disorder; D010879:Piperazines; D011569:Psychiatric Status Rating Scales; D011654:Pulmonary Edema; D015363:Quinolones; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "287-9",
"pmc": null,
"pmid": "25487626",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aripiprazole induced non-cardiogenic pulmonary edema: a case report.",
"title_normalized": "aripiprazole induced non cardiogenic pulmonary edema a case report"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2015-03962",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
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"abstract": "OBJECTIVE\nPrimary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma involving the brain with possible leptomeningeal and ocular involvement. This study aimed to evaluate the safety and efficacy of modified intravitreal injection regimen of methotrexate (MTX) for therapeutic management of vitreoretinal lymphoma.\n\n\nMETHODS\nForty human immunodeficiency virus (HIV)-negative Chinese patients with primary vitreoretinal lymphoma were included in this retrospective noncomparative interventional case series study. Patients were treated with a modified protocol of intravitreal injection of MTX (400 µg/0.1 ml) according to the Intensive-Consolidation-Maintenance regimen. The Intensive phase of once-weekly intravitreal injections for 1 month, followed by the Consolidation phase of one injection every 2 weeks for 1 month, and then the Maintenance phase of once monthly for 1 month, for a total of 7 injections. The primary main outcome measures were clinical response to intravitreal chemotherapy, number of injections for clinical remission, progression-free survival (PFS), overall survival (OS), visual acuity (VA), complications during the study period, and cause of death were investigated.\n\n\nRESULTS\nThe duration of follow-up from the commencement of injection of MTX was 12-73 months (median 28, 30.55 ± 14.73 months). A total of 61 eyes of 40 patients were cleared clinically from malignant cells after a median 6.57 ± 3.12 (median 6, range 1-14) times of injection of MTX. A second remission was induced in 3 patients, who were treated with a further course of intravitreal chemotherapy after tumour recurred in their eyes. The median PFS and OS were 20.82 months (95% CI 14.64-27.01) and 29.29 months (95% CI 16.16-42.41), respectively. Complications that occurred during the period of treatment and follow-up included corneal epitheliopathy (3 of 61 eyes) and cataract (6 of 61 eyes). There were no cases of maculopathy, vitreous haemorrhage, optic atrophy, and sterile endophthalmitis. No patient had an irreversible loss of vision that could be attributed to the intravitreal injection of MTX.\n\n\nCONCLUSIONS\nIt can be concluded that the modified intravitreal injection regimen of MTX is an effective therapeutic approach in inducing clinical remission of intraocular involvement in PCNSL patients, associated with few complications. However, further study needs to be conducted to indicate whether the proposed approach extends life expectancy.\n\n\nCONCLUSIONS\nPrimary central nervous system lymphoma (PCNSL) can involve the vitreous and retina and is associated with a poor clinical outcome, with a survival rate of less than 3 months in absence of undergoing an effective therapeutic strategy. Methotrexate (MTX) is the most efficient cytotoxic drug for patients with vitreoretinal involvement in primary vitreoretinal lymphoma (PVRL), through intravitreal injection of MTX. In our experience, the modified protocol of intravitreal MTX according to the Intensive-Consolidation-Maintenance regimen, was effective in inducing clinical remission of PVRL with few complications. The accumulating clinical results brought us to propose the consideration of this protocol as a good first-line treatment option for PVRL.",
"affiliations": "Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.;Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.;Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.;Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.;Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. weiwenbintr@163.com.",
"authors": "Zhou|Nan|N|;Xu|Xiaolin|X|http://orcid.org/0000-0001-5449-1798;Liu|Yueming|Y|;Wang|Yaxing|Y|http://orcid.org/0000-0003-2749-7793;Wei|Wenbin|W|http://orcid.org/0000-0003-2386-0989",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41433-021-01657-0",
"fulltext": null,
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"issn_linking": "0950-222X",
"issue": null,
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
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"nlm_unique_id": "8703986",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34211136",
"pubdate": "2021-07-01",
"publication_types": "D016428:Journal Article",
"references": "1098380;11334269;1441494;12576439;18303160;30516868;8604740;15955902;14605902;9754175;7485372;10476821;3096140;15221999;17464308;10434868;17013703",
"title": "A proposed protocol of intravitreal injection of methotrexate for treatment of primary vitreoretinal lymphoma.",
"title_normalized": "a proposed protocol of intravitreal injection of methotrexate for treatment of primary vitreoretinal lymphoma"
} | [
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"companynumb": "CN-PFIZER INC-202100922235",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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... |
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"abstract": "We reported the successful administration of infliximab for late-onset OKT3-resistant rejection in two patients, who presented persistent ulcerative inflammation of the ileal graft after intestinal transplantation (ITX). Based on this experience, the present study demonstrated our long-term experience with infliximab for different types of rejection-related and inflammatory allograft alterations. Infliximab administration (5 mg/kg body weight (BW)) was initiated at a mean of 18.2 ± 14.1 months after transplantation. The number of administrations per patient averaged 8.4 ± 6.7. Repeat dosing was timed according to clinical signs and graft histology in addition to serum-levels of tumor necrosis factor alpha (TNFα), lipopolysaccharide binding protein (LBP) and C-reactive protein (CRP). Infliximab was successful in the following patients: patients with late-onset OKT3- and steroid-refractory rejection who presented persistent ulcerative alterations of the ileal graft (n = 5), patients with ulcerative ileitis/anastomositis, who did not show typical histological rejection signs (n = 2), and one patient with early-onset OKT3-resistant rejection. Infliximab was not successful in one patient with early-onset OKT3-resistant rejection that was accompanied by treatment-refractory humoral rejection. In conclusion, infliximab can expand therapeutic options for late-onset OKT3- and steroid-refractory rejection and chronic inflammatory graft alterations in intestinal allograft recipients.",
"affiliations": "Department of General, Visceral and Transplantation Surgery, Charité-Universitaetsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.",
"authors": "Gerlach|U A|UA|;Koch|M|M|;Müller|H-P|HP|;Veltzke-Schlieker|W|W|;Neuhaus|P|P|;Pascher|A|A|",
"chemical_list": "D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; C061257:lipopolysaccharide-binding protein; D002097:C-Reactive Protein; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1600-6143.2011.03497.x",
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"issn_linking": "1600-6135",
"issue": "11(5)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000209:Acute-Phase Proteins; D000328:Adult; D000911:Antibodies, Monoclonal; D001835:Body Weight; D002097:C-Reactive Protein; D002352:Carrier Proteins; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007107:Immune System; D007166:Immunosuppressive Agents; D007249:Inflammation; D000069285:Infliximab; D007422:Intestines; D008297:Male; D008562:Membrane Glycoproteins; D013256:Steroids; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1041-50",
"pmc": null,
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"publication_types": "D016428:Journal Article",
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"title": "Tumor necrosis factor alpha inhibitors as immunomodulatory antirejection agents after intestinal transplantation.",
"title_normalized": "tumor necrosis factor alpha inhibitors as immunomodulatory antirejection agents after intestinal transplantation"
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"abstract": "Anaplastic large cell lymphoma (ALCL), ALK negative (ALK-) is an aggressive lymphoproliferative disorder of mature T lymphocytes characterised by hallmark cells, CD30 positivity and lacking ALK protein expression. ALCL, ALK- has to be differentiated from peripheral T-cell lymphoma-not otherwise specified and classical Hodgkin's lymphoma. ALK- anaplastic large cell leukaemia should be considered in a patient with a history of ALCL, ALK- presenting with new leukaemia. We report a rare presentation of relapsed ALCL, ALK- with leukaemia after autologous stem cell transplantation in a 57-year-old male. Leukaemia, either as primary presentation or secondary transformation confers worse prognosis in ALCL, ALK- with very few cases reported so far. Emergency resuscitation with leukapheresis and treatment of tumour lysis syndrome along with supportive care should be followed by combination chemotherapy. Brentuximab vedotin and stem cell transplantation are the backbone of treatment for relapsed/refractory disease.",
"affiliations": "Hematology Oncology, Augusta University, Augusta, Georgia, USA nbnrj@hotmail.com.;Jersey City Medical Center, Jersey City, New Jersey, USA.;Pathology, Augusta University, Augusta, Georgia, USA.;Hematology Oncology, Augusta University, Augusta, Georgia, USA.",
"authors": "Karki|Nabin Raj|NR|http://orcid.org/0000-0001-6449-8109;Badin|Kristine|K|;Savage|Natasha|N|;Bryan|Locke|L|",
"chemical_list": "D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); oncology; screening (oncology)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000077548:Anaplastic Lymphoma Kinase; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases; D012008:Recurrence; D014182:Transplantation, Autologous",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33619137",
"pubdate": "2021-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukaemic relapse of anaplastic large cell lymphoma, ALK negative.",
"title_normalized": "leukaemic relapse of anaplastic large cell lymphoma alk negative"
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"companynumb": "US-SEATTLE GENETICS-2021SGN01376",
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{
"abstract": "Phosphine poisoning is responsible for hundreds of thousands of deaths per year in countries where access to this pesticide is unrestricted. Metal phosphides release phosphine gas on contact with moisture, and ingestion of these tablets most often results in death despite intensive support. A 36-year-old woman presented to a regional hospital after ingesting multiple aluminium phosphide pesticide tablets and rapidly developed severe cardiogenic shock. In this case, serendipitous access to an untested Extracorporeal Membrane Oxygenation (ECMO) service of a regional hospital effected a successful rescue and prevented the predicted death. We discuss the toxicology, management and the evidence for and against using ECMO in this acute poisoning.",
"affiliations": "Intensive Care Unit, 523457Sunshine Coast University Hospital, Sunshine Coast University Hospital, Queensland, Australia.;Intensive Care Unit, 523457Sunshine Coast University Hospital, Sunshine Coast University Hospital, Queensland, Australia.;Intensive Care Unit, 523457Sunshine Coast University Hospital, Sunshine Coast University Hospital, Queensland, Australia.;Intensive Care Unit, 523457Sunshine Coast University Hospital, Sunshine Coast University Hospital, Queensland, Australia.",
"authors": "A Farrar|Ross|R|;B Justus|Angelo|A|;A Masurkar|Vikram|V|;M Garrett|Peter|P|https://orcid.org/0000-0002-8852-2991",
"chemical_list": null,
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"issue": null,
"journal": "Anaesthesia and intensive care",
"keywords": "Aluminium phosphide; cardiogenic; drug overdose; extracorporeal membrane oxygenation; phosphine; poisons; shock",
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "310057X211047603",
"pmc": null,
"pmid": "34871510",
"pubdate": "2021-12-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Unexpected survival after deliberate phosphine gas poisoning: An Australian experience of extracorporeal membrane oxygenation rescue in this setting.",
"title_normalized": "unexpected survival after deliberate phosphine gas poisoning an australian experience of extracorporeal membrane oxygenation rescue in this setting"
} | [
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"companynumb": "AU-MYLANLABS-2022M1049383",
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"activesubstancename": "EPINEPHRINE"
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"abstract": "The role of immunotherapy in combination with traditional treatment regime in improving the survival of cancer patients has attracted more and more attention. Especially the abscopal effect that describes the phenomenon of localized radiotherapy leading to regression of distant unirradiated tumors and the role of enhanced radiotherapy-induced immunogenic cell death and activation of immune system have become a focus of the studies. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known a powerful stimulator of the generation, migration and activation of antigen presenting cells such as dendritic cells (DC) and macrophages. Here we report a case of a 67-year-old refractory metastatic pancreatic cancer patient who obtained evident abscopal effect and survival benefit from concurrent localized radiotherapy and GM-CSF.",
"affiliations": "a Department of Radiation Oncology , Shandong Cancer Hospital and Institute , Jinan , Shandong Province , China.;a Department of Radiation Oncology , Shandong Cancer Hospital and Institute , Jinan , Shandong Province , China.;a Department of Radiation Oncology , Shandong Cancer Hospital and Institute , Jinan , Shandong Province , China.;a Department of Radiation Oncology , Shandong Cancer Hospital and Institute , Jinan , Shandong Province , China.;a Department of Radiation Oncology , Shandong Cancer Hospital and Institute , Jinan , Shandong Province , China.",
"authors": "Shi|Fang|F|;Wang|Xin|X|;Teng|Feifei|F|;Kong|Li|L|;Yu|Jinming|J|",
"chemical_list": "D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2016.1276133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "18(3)",
"journal": "Cancer biology & therapy",
"keywords": "Abscopal effect; CD8+ T cell; GM-CSF; dentritic cell; hypofractionated radiation",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000368:Aged; D059248:Chemoradiotherapy; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "137-141",
"pmc": null,
"pmid": "28267380",
"pubdate": "2017-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26833128;22414083;20729419;20303878;23151605;26105538;19823740;17431418;24852394;21742939;16899624;19706802;26095785;22323450;22162711;18281550;17898760;23291374;20403709;16730268",
"title": "Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy.",
"title_normalized": "abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte macrophage colony stimulating factor therapy"
} | [
{
"companynumb": "CN-CELGENEUS-CHN-20170502867",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR"
}... |
{
"abstract": "BACKGROUND\nEosinophilic cystitis is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall. Due to lack of consensus and potential for side effect from various therapeutic options, treatment of the disease is often challenging.\n\n\nMETHODS\nA 64-year old woman with hypertensive nephropathy resulting in stage III chronic kidney disease, obstructive sleep apnea, and obstructive lung disease presented with a 4 month history of dysuria, urgency, frequency, and persistent hematuria. Based on eosinophilic infiltration on bladder wall biopsy in the absence of any evidence of infection, malignancy, or immune disorder, she was diagnosed with eosinophilic cystitis. Despite multiple medication regimens, her symptoms persisted, requiring high-dose prednisone with steroid-related side effects. After four months, she was started on cyclosporine, which led to symptomatic improvement and reduction in prednisone dosage. At that time, repeat urine cytology and cystoscopy did not reveal friable tissues or eosinophiluria.\n\n\nCONCLUSIONS\nThis case illustrates the utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions.",
"affiliations": "Division of Immunology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA ; Division of Immunology, Department of Internal Medicine - C42 GH, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242 USA.;Division of Immunology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA.;Division of Immunology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA.;Department of Urology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA.;Division of Immunology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA ; Present address: Division of Allergy and Clinical Immunology, John Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA.",
"authors": "Aleem|Sohaib|S|;Kumar|Bharat|B|;Fasano|Mary Beth|MB|;Takacs|Elizabeth|E|;Azar|Antoine Emile|AE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1186/s40413-016-0113-4",
"fulltext": "\n==== Front\nWorld Allergy Organ JWorld Allergy Organ JThe World Allergy Organization Journal1939-4551BioMed Central London 11310.1186/s40413-016-0113-4Case ReportSuccessful use of cyclosporine as treatment for eosinophilic cystitis: a case report Aleem Sohaib +1 319-384-6173sohaib-aleem@uiowa.eduSohaib.aleem@hotmail.com Kumar Bharat bharat-kumar@uiowa.edu Fasano Mary Beth mary-fasano@uiowa.edu Takacs Elizabeth elizabeth-takacs@uiowa.edu Azar Antoine Emile Antoine.Azar@jhmi.edu Division of Immunology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA Department of Urology, University at Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA Present address: Division of Allergy and Clinical Immunology, John Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA Division of Immunology, Department of Internal Medicine - C42 GH, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242 USA 8 7 2016 8 7 2016 2016 9 227 1 2016 24 6 2016 © Aleem et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEosinophilic cystitis is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall. Due to lack of consensus and potential for side effect from various therapeutic options, treatment of the disease is often challenging.\n\nCase presentation\nA 64-year old woman with hypertensive nephropathy resulting in stage III chronic kidney disease, obstructive sleep apnea, and obstructive lung disease presented with a 4 month history of dysuria, urgency, frequency, and persistent hematuria. Based on eosinophilic infiltration on bladder wall biopsy in the absence of any evidence of infection, malignancy, or immune disorder, she was diagnosed with eosinophilic cystitis. Despite multiple medication regimens, her symptoms persisted, requiring high-dose prednisone with steroid-related side effects. After four months, she was started on cyclosporine, which led to symptomatic improvement and reduction in prednisone dosage. At that time, repeat urine cytology and cystoscopy did not reveal friable tissues or eosinophiluria.\n\nConclusion\nThis case illustrates the utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions.\n\nKeywords\nEosinophilic cystitisCyclosporineSteroidsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nEosinophilic cystitis (EC) is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall, muscle necrosis, and fibrosis of the mucosa and muscularis propria [1]. Due to its rarity, not much is known about EC, and most of the data is derived from individual case reports and case series. Typically, patients with EC present with increased urinary frequency, nocturia, dysuria, hematuria, suprapubic pain and urinary retention [1–3]. Though there is a higher prevalence among adults, EC has been known to affect all age groups [1]. It has been associated with a number of other disorders, including chronic vesical injury, bladder neoplasms, interstitial cystitis, recurrent urinary tract infections, parasitic infections, atopic diseases and chronic granulomatous disease [2, 4–6]. Biopsy is essential for the diagnosis of EC, since other forms of cystitis may also be accompanied by eosinophiluria and cystoscopic changes that resemble EC [2, 3]. Despite multiple proposed systemic, surgical and intravesical approaches, treatment for the condition is often frustrating due to the lack of consensus and high rate of recurrence [1, 2, 7]. Among promising therapeutic agents, cyclosporine, a cyclophilin inhibitor whose downstream effects include reducing the serum levels of Interleukin-4 (IL-4), IL-5, and IL-13, has been used successfully as long-term treatment, as documented in two pediatric cases reports [5, 8]. We advance the medical literature by describing our experience of using cyclosporine in an adult female with biopsy-proven EC.\n\nCase presentation\nA 64-year old female with chronic kidney disease stage III secondary to longstanding hypertension, chronic obstructive pulmonary disease, and obstructive sleep apnea presented for evaluation of dysuria, urgency, frequency, and persistent hematuria for 4 months at the University at Iowa Hospitals and Clinics in July 2014. The rest of the review of systems was unremarkable. She had no history of atopic disease, including allergic rhinitis, asthma, and atopic dermatitis, eosinophilia, parasitic infections, toxin or radiation exposures, or recent travel. Her medication list at initial appointment with immunology included albuterol, ciclesonide and salmeterol inhalers as well as theophylline XR 300 mg, solifnenacin 10 mg, phenazopyridine 100 mg, hydrocodone-acetamenophen 5–325 mg, nebivolol 2.5 mg, omeprazole 20 mg, sucralfate 1000 mg and multivitamin oral tablets/capsule. Methenamine mandelate was recently stopped by an outside urologist as it was thought to contribute to the symptoms. She was treated with several courses of antibiotics for urinary tract infections (UTIs) since the onset of symptoms. Vital signs were stable and physical examination revealed only mild suprapubic tenderness. Cystoscopy performed prior to the visit in July 2014 showed multiple friable mucosal lesions without tumor, stone, or clot, which was consistent with diffuse hemorrhagic cystitis. Her work up during the visit showed pyuria with hematuria, elevated inflammatory markers including erythrocyte sedimentation rate, C-reactive protein and leukocytosis with neutrophilia but no peripheral eosinophilia. She had elevated Interleukin-2R (CD25) and Th2 cytokines (Interleukin-4, Interleukin-5 and Interleukin-13) with elevated Immunoglobulin E (see Table 1).Table 1 Cytokine panel and IgE level for 65 year old patient with eosinophilic cystitis\n\nTests\tReference range\tPatient’s level\t\nIgE\t0–100 IU/mL\t551\t\nSoluble Interleukin-2 Receptor (CD25)\t≤1033 pg/mL\t1351\t\nInterleukin-12\t≤6 pg/mL\t<5\t\nInterferon-γ\t≤5 pg/mL\t12\t\nInterleukin-4\t≤5 pg/mL\t8\t\nInterleukin-5\t≤5 pg/mL\t7\t\nInterleukin-10\t≤18 pg/mL\t10\t\nInterleukin-13\t≤5 pg/mL\t232\t\nInterleukin-1β\t≤36 pg/mL\t22\t\nInterleukin-6\t≤5 pg/mL\t<5\t\nInterleukin-8\t≤5 pg/mL\t<5\t\nTumor necrosis factor-α\t≤22 pg/mL\t36\t\nInterleukin-2\t≤12 pg/mL\t12\t\n\n\nShe had no serologic evidence of prevalent parasitic infections in the area (Strongyloides and Toxocara) or autoimmune disease. Cytology and culture from bladder washings in July 2014 did not identify any tumor cells or infection; biopsy of the bladder wall, which contained sections of the muscularis propria, showed eosinophil-rich inflammatory infiltrate (Figs. 1 and 2).Fig. 1 Low resolution hematoxylin and eosin (H&E) staining of bladder wall biopsy of the patient, showing abundant eosinophils in mucosa and submucosa\n\nFig. 2 High resolution hematoxylin and eosin (H&E) staining of bladder wall biopsy of the patient, showing abundant eosinophils in submucosa\n\n\n\nGram- and acid-fast bacilli stains of the biopsy were also negative. Given the lack of tumor or infection, she was diagnosed with eosinophilic cystitis.\n\nAt first, she was given combination of oral hydroxyzine 30 mg three times daily, oral prednisone taper (40 mg, 30 mg 20 and 10 mg) with dose reduced every 5 days and solifenactin without significant improvement in symptoms and hematuria. Later, she was given a trial of 6 weekly courses of intravesical methylprednisolone followed by oral prednisone, addition of loratadine 10 mg daily and monteleukast 10 mg daily with partial improvement in her symptoms without resolution of hematuria. Symptoms and hematuria would worsen if the dose of prednisone was reduced below 25 mg daily. Additionally, she developed several side effects of chronic prednisone use, including tremors, weight gain, depressed mood, visual changes, and a fragility fracture of the hip, which mandated significant dose reduction and resulted in worsening of her symptoms.\n\nRepeat cystoscopy in November 2014 showed areas of friable tissue similar to July 2014; urodynamic study in December 2014 showed small capacity bladder suggesting fibrosis of bladder wall as a complication of EC resulting in Grade 2 bilateral vesicoureteral reflux and higher risk of recurrent UTIs. She was offered surgical treatment options including suprapubic catheter, cystectomy or urinary diversion for relief of symptoms which she declined. After weighing the risks and benefits of different therapy options, oral cyclosporine (50 mg twice a day) was added to her regimen for a steroid-sparing effect and decrease Th2 cytokine profile. Over the course of three months, her prednisone dose was decreased to 7.5 mg daily, which helped to reduce her depression, tremors, and weight gain. Her renal function, as well as blood pressure, remained stable. Despite being on a potent immunosuppressant, her renal function as well as blood pressure remained stable and frequency of recurrent UTIs did not increase compared to July 2014. Due to side effects of nausea and recurrence of tremors with two weeks trial of increased dose of cyclosporine 75 mg twice daily, further dose escalation of cyclosporine were avoided. Repeat urine cytology in April 2015 did not show any eosinophils or tumor cells. She had a repeat cystoscopy after 6 months of cyclosporine use that did not show any friable mucosa, therefore no biopsy was done. Moreover, she relayed decreased urgency and frequency, and resolution of her overt hematuria.\n\nDiscussion\nTo our knowledge, this is the first case to document cyclosporine as treatment for EC in an adult patient with multiple comorbidities. Although cyclosporine did not reverse the fibrosis of the bladder wall secondary to EC, it allowed reduction in dose of oral steroids and lead to sustained significant improvement in the patient’s symptoms without major adverse effects. Serum cytokine profile was consistent with Th2 polarization; however eosinophilia was absent in the patient. This observation is in line with our current knowledge of how cyclosporine works: as a cyclophilin inhibitor, it inhibits interleukin-2 gene transcription and thus prevents T-cell proliferation and Th2 polarization. Even though long term safety data about use of cyclosporine in EC is not available, it has been well tolerated when used for interstitial cystitis [9]. Further studies are needed to evaluate the efficacy and safety of cyclosporine use for EC in adult patients with multiple comorbid conditions.\n\nConclusion\nThis case report illustrates the clinical utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions.\n\nAbbreviations\nEC, Eosinophilic cystitis; Th2, T helper cell 2; UTIs, Urinary tract infections\n\nAcknowledgment\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nWe do not have a new software or database or tools as part of the case report.\n\nAuthors’ contributions\nSA provided clinical care to the patient, drafted and edited the manuscript. BK participated in the clinical care, drafted and edited the manuscript. MBF, ET and AEA participated in the clinical care of the patient and editing 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\nThe case report does not contain individual’s protected health information, images or videos. We had received informed consent from the patient about submission of the case report.\n\nEthics approval and consent to participate\nInstitutional review board of University of Iowa waived the need for approval for the case report submitted.\n==== Refs\nReferences\n1. van den Ouden D Diagnosis and management of eosinophilic cystitis: a pooled analysis of 135 cases Eur Urol 2000 37 4 386 94 10.1159/000020183 10765067 \n2. Itano NM Malek RS Eosinophilic cystitis in adults J Urol 2001 165 3 805 7 10.1016/S0022-5347(05)66531-7 11176473 \n3. Abilov A Ozcan R Polat E Dervisoglu S Emir H Rare cause of dysuria: eosinophilic cystitis J Pediatr Urol 2013 9 1 e6 8 10.1016/j.jpurol.2012.04.005 22652390 \n4. Teegavarapu PS Sahai A Chandra A Dasgupta P Khan MS Eosinophilic cystitis and its management Int J Clin Pract 2005 59 3 356 60 10.1111/j.1742-1241.2004.00421.x 15857336 \n5. Claps A Della Corte M Gerocarni Nappo S Francalanci P Palma P Finocchi A How should eosinophilic cystitis be treated in patients with chronic granulomatous disease? Pediatr Nephrol 2014 29 11 2229 33 10.1007/s00467-014-2883-7 25037864 \n6. Littleton RH Farah RN Cerny JC Eosinophilic cystitis: an uncommon form of cystitis J Urol 1982 127 1 132 3 7057485 \n7. Zaman SR, Vermeulen TL, Parry J. Eosinophilic cystitis: treatment with intravesical steroids and oral antihistamines. BMJ Case Rep. 2013;2013. http://doi.org/10.1136/bcr-2013-009327.\n8. Pomeranz A Eliakim A Uziel Y Gottesman G Rathaus V Zehavi T Eosinophilic cystitis in a 4-year-old boy: successful long-term treatment with cyclosporin A Pediatrics 2001 108 6 E113 10.1542/peds.108.6.e113 11731640 \n9. Sairanen J Forsell T Ruutu M Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A J Urol 2004 171 6 Pt 1 2138 41 10.1097/01.ju.0000125139.91203.7a 15126772\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1939-4551",
"issue": "9()",
"journal": "The World Allergy Organization journal",
"keywords": "Cyclosporine; Eosinophilic cystitis; Steroids",
"medline_ta": "World Allergy Organ J",
"mesh_terms": null,
"nlm_unique_id": "101481283",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "27458500",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "11176473;10765067;11731640;24014555;15857336;7057485;15126772;22652390;25037864",
"title": "Successful use of cyclosporine as treatment for eosinophilic cystitis: a case report.",
"title_normalized": "successful use of cyclosporine as treatment for eosinophilic cystitis a case report"
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"activesubstancename": "MONTELUKAST SODIUM"
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... |
{
"abstract": "To characterize diphtheroid corneal infections in eyes in the chronic phase of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).\n\n\n\nObservational case series.\n\n\n\nFour eyes of 3 patients were included in this review. Each eye presented with persistent corneal epithelial defect with corneal thinning in the chronic phase of SJS/TEN. None of the epithelial defects were associated with stromal infiltration. The corneas were cultured at the time of workup of persistent epithelial defect (3 eyes) or at time of tectonic penetrating keratoplasty after perforation (1 eye). Cultures yielded abundant growth of Corynebacterium spp., including Corynebacterium jeikeium (n = 2), Corynebacterium glucuronolyticum (n = 1), and a multidrug-resistant Corynebacterium striatum isolate (n = 1). The ocular surface was stabilized with surgical intervention (1 eye) or with introduction of fortified topical antibiotic based on laboratory identification and susceptibility testing of the isolated organisms (3 eyes). Numerous risk factors for microbial keratitis were present in all 4 eyes.\n\n\n\nIn eyes with a persistent corneal epithelial defect in the chronic phase of SJS/TEN, even in the absence of an infiltrate, corneal culture should be undertaken. Recognition and treatment of Corynebacterium spp. as opportunistic pathogens may lead to favorable outcomes in cases of clinically sterile ulceration during the chronic phase of SJS/TEN.",
"affiliations": "Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.",
"authors": "Shanbhag|Swapna S|SS|;Shih|Grace|G|;Bispo|Paulo J M|PJM|;Chodosh|James|J|;Jacobs|Deborah S|DS|;Saeed|Hajirah N|HN|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D011113:Polymyxins; D014640:Vancomycin; D014295:Trimethoprim",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "40(6)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D003320:Corneal Ulcer; D003352:Corynebacterium; D003354:Corynebacterium Infections; D004338:Drug Combinations; D015818:Eye Infections, Bacterial; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011113:Polymyxins; D013262:Stevens-Johnson Syndrome; D014295:Trimethoprim; D014640:Vancomycin",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "774-779",
"pmc": null,
"pmid": "33758140",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Diphtheroids as Corneal Pathogens in Chronic Ocular Surface Disease in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.",
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"abstract": "BACKGROUND\nNeratinib and neratinib-based combinations have demonstrated efficacy for treatment of human epidermal growth factor receptor 2-positive (HER2+) early-stage and metastatic breast cancers. However, diarrhea has been reported as a common adverse event leading to neratinib discontinuation. Results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or dose escalation of neratinib from a lower starting dose to the full FDA-approved dose of 240 mg/day can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer. Dose escalation has been included in the FDA-approved label for both early-stage and metastatic HER2+ breast cancer since June 2021.\n\n\nMETHODS\nThis series of five cases details real-world clinical implementation of strategies for management of neratinib-induced diarrhea in patients with early-stage and metastatic HER2+ breast cancer, including a patient with a pre-existing gastrointestinal disorder.\nIn four of five cases, diarrhea was managed with neratinib dose escalation, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy.\n\n\nCONCLUSIONS\nThis case series shows that neratinib-associated diarrhea can be managed effectively with neratinib dose escalation from a lower initial starting dose and/or prophylactic antidiarrheal medications in a real-world clinical setting. The findings highlight the importance of patient-provider communication in proactive management of adverse events. Widespread implementation of the strategies described here may improve adherence and thereby clinical outcomes for patients with HER2+ breast cancer treated with neratinib.",
"affiliations": "Division of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA. krusem@ccf.org.;Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.;Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.;Pharmacy, Hematology and Oncology Associates of Alabama, Birmingham, AL, USA.;Division of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA.;Texas Oncology, Plano East Cancer Center, Plano, TX, USA.;Texas Oncology, Plano East Cancer Center, Plano, TX, USA.",
"authors": "Kruse|Megan L|ML|;Kang|Irene M|IM|;Bagegni|Nusayba A|NA|;Howell|W Todd|WT|;Moore|Halle C F|HCF|;Bedell|Cynthia H|CH|;Stokoe|Christopher T|CT|",
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"doi": "10.1007/s40487-021-00178-w",
"fulltext": "\n==== Front\nOncol Ther\nOncol Ther\nOncology and Therapy\n2366-1070\n2366-1089\nSpringer Healthcare Cheshire\n\n34800263\n178\n10.1007/s40487-021-00178-w\nCase Series\nManagement of Diarrhea in Patients with HER2-Positive Breast Cancer Treated with Neratinib: A Case Series and Summary of the Literature\nKruse Megan L. krusem@ccf.org\n\n1\nKang Irene M. 2\nBagegni Nusayba A. 3\nHowell W. Todd 4\nMoore Halle C. F. 1\nBedell Cynthia H. 5\nStokoe Christopher T. 5\n1 grid.239578.2 0000 0001 0675 4725 Division of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, CA-60, Cleveland, OH 44195 USA\n2 grid.42505.36 0000 0001 2156 6853 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA USA\n3 grid.4367.6 0000 0001 2355 7002 Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO USA\n4 Pharmacy, Hematology and Oncology Associates of Alabama, Birmingham, AL USA\n5 grid.477898.d 0000 0004 0428 2340 Texas Oncology, Plano East Cancer Center, Plano, TX USA\n20 11 2021\n20 11 2021\n6 2022\n10 1 279289\n13 9 2021\n29 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.\nIntroduction\n\nNeratinib and neratinib-based combinations have demonstrated efficacy for treatment of human epidermal growth factor receptor 2–positive (HER2+) early-stage and metastatic breast cancers. However, diarrhea has been reported as a common adverse event leading to neratinib discontinuation. Results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or dose escalation of neratinib from a lower starting dose to the full FDA-approved dose of 240 mg/day can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer. Dose escalation has been included in the FDA-approved label for both early-stage and metastatic HER2+ breast cancer since June 2021.\n\nCase series\n\nThis series of five cases details real-world clinical implementation of strategies for management of neratinib-induced diarrhea in patients with early-stage and metastatic HER2+ breast cancer, including a patient with a pre-existing gastrointestinal disorder.\n\nManagement and outcome\n\nIn four of five cases, diarrhea was managed with neratinib dose escalation, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy.\n\nDiscussion\n\nThis case series shows that neratinib-associated diarrhea can be managed effectively with neratinib dose escalation from a lower initial starting dose and/or prophylactic antidiarrheal medications in a real-world clinical setting. The findings highlight the importance of patient-provider communication in proactive management of adverse events. Widespread implementation of the strategies described here may improve adherence and thereby clinical outcomes for patients with HER2+ breast cancer treated with neratinib.\n\nKeywords\n\nDiarrhea\nEarly-stage breast cancer\nHER2\nMetastatic breast cancer\nNeratinib\nissue-copyright-statement© The Author(s) 2022\n==== Body\npmcKey Summary Points\n\nNeratinib and neratinib-based combinations have demonstrated efficacy for treatment of human epidermal growth factor receptor 2-positive (HER2+) early-stage and metastatic breast cancers.\t\nProactive management may reduce the incidence, duration, and severity of diarrhea, a common adverse event reported with neratinib, allowing patients to remain on treatment.\t\nThis series of five cases details real-world clinical implementation of strategies for management of neratinib-induced diarrhea in patients with early-stage and metastatic HER2+ breast cancer, including a patient with a pre-existing gastrointestinal disorder.\t\nThese cases show that neratinib-associated diarrhea can be managed effectively with neratinib dose escalation and/or prophylactic antidiarrheal medications and highlight the importance of patient-provider communication in proactive management.\t\nWidespread implementation of the strategies described in this case series may improve adherence to therapy and thereby clinical outcomes for patients with HER2+ breast cancer treated with neratinib.\t\n\nIntroduction\n\nBreast cancers characterized by human epidermal growth factor receptor 2 (HER2) overexpression represent a common, aggressive subtype, comprising approximately 20% of breast cancers [1]. Although trastuzumab has improved outcomes for patients with HER2-positive (HER2+) breast cancer, long-term follow-up of phase 3 trials has demonstrated that cancer recurs within 10 years in 25–31% of patients treated with adjuvant trastuzumab [1–4]. Metastatic and recurrent HER2+ breast cancers are often associated with an increased propensity for developing central nervous system (CNS) metastases, which occur in up to 50% of patients with HER2+ metastatic breast cancer (MBC) [1, 5, 6].\n\nIn recent years, novel neoadjuvant, adjuvant, and extended adjuvant regimens have reduced the risk of recurrence for patients with HER2+ early-stage breast cancer (ESBC) [1]. The phase 3 NOAH study demonstrated that addition of trastuzumab to neoadjuvant chemotherapy was associated with a greater proportion of patients achieving a pathologic complete response (pCR) and a significant improvement in event-free survival [7]. pCR rate was further improved with the use of neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab based on the results of the phase 2 NeoSphere and TRYPHAENA trials [8, 9]. The combination of trastuzumab and pertuzumab showed efficacy in the phase 3 APHINITY trial, and results of the phase 3 KATHERINE trial have supported adjuvant ado-trastuzumab emtansine (T-DM1) as an option for patients with residual disease [10, 11]. In patients with HER2+ ESBC treated with adjuvant trastuzumab-based therapy, extended adjuvant therapy with the oral, irreversible pan-HER tyrosine kinase inhibitor (TKI) neratinib significantly improved invasive disease-free survival in the phase 3 ExteNET study [12, 13].\n\nHER2-targeted agents, including neratinib, have also improved outcomes for patients with HER2+ MBC. Regimens demonstrating efficacy in this setting include pertuzumab in combination with trastuzumab and docetaxel, T-DM1, trastuzumab deruxtecan, and other trastuzumab plus chemotherapy combinations [1, 14–17]. Neratinib and other TKIs have shown efficacy in MBC in combination with trastuzumab, capecitabine, and/or other cytotoxic therapies [18–26]. In addition, TKI-containing combinations, such as neratinib in combination with capecitabine or paclitaxel, lapatinib plus capecitabine, and tucatinib plus trastuzumab and capecitabine, have shown benefit in patients with CNS metastases [18, 27–30].\n\nNeratinib is approved for use as extended adjuvant therapy for HER2+ ESBC or in combination with capecitabine in the treatment of HER2+ MBC [31]. In the current National Comprehensive Cancer Network Guidelines, neratinib is included as a category 2A recommendation for both HR+, HER2+ ESBC following adjuvant trastuzumab-containing therapy and HER2+ MBC third line and beyond and is also included as a treatment option for recurrent HER2+ breast cancer CNS metastases [32, 33]. Gastrointestinal (GI)-related adverse events, especially diarrhea, are common with neratinib and can lead to early discontinuation. This is likely a class effect for TKIs with broader target profiles. The mechanism is not completely understood, but may involve dysregulated ion transport, inflammation, and mucosal injury [12, 13, 18, 23, 24, 26, 34]. In the ExteNET trial, in which the use of anti-diarrheal prophylaxis was not mandated, 95% of patients on extended adjuvant neratinib experienced diarrhea, including grade 3 diarrhea in 40% of patients. Twenty-eight percent of patients discontinued because of any treatment-emergent adverse event (TEAE) and 17% discontinued because of diarrhea. [12, 35]. Early discontinuation is thought to negatively affect treatment outcomes, as subgroup analyses of ExteNET have shown that remaining on treatment for ≥ 11 of the recommended 12 months is important for neratinib efficacy [36, 37]. In the phase 3 NALA study of capecitabine plus either neratinib or lapatinib in patients with MBC previously treated with ≥ 2 HER2-directed regimens, diarrhea was managed with mandatory loperamide prophylaxis in the neratinib plus capecitabine arm, in which 24.4% of patients experienced grade 3 diarrhea, resulting in discontinuation of neratinib in only 2.6% of patients [26].\n\nThe phase 2 CONTROL study was designed to prospectively evaluate strategies for managing neratinib-induced diarrhea in HER2+ ESBC [38]. CONTROL evaluated prophylactic use of various antidiarrheal medications as well as dose escalation (DE) of neratinib from a lower starting dose to the full US Food and Drug Administration (FDA)-approved dose of 240 mg/day [38]. All preventive strategies reduced the incidence, duration, and severity of neratinib-induced diarrhea, lowering neratinib discontinuation rates compared to ExteNET, except in the loperamide-alone arm. Neratinib DE (2-week DE schedule: week 1 = 120 mg/day, week 2 = 160 mg/day, week 3 and onwards: 240 mg/day) was identified as a particularly beneficial strategy for maintaining patients on therapy based on a 13% rate of grade ≥ 3 diarrhea, a 3.3% rate of diarrhea-related discontinuation, and a 13.3% rate of discontinuation due to any TEAE [31, 38, 39]. A 2-week DE schedule also lowered the rate of constipation (all grades) compared with antidiarrheal strategies that mandated loperamide prophylaxis (33% vs. 57–75%) [38].\n\nTo better understand clinical management of neratinib-associated diarrhea, this series describes four patients with ESBC and one patient with MBC treated with neratinib. The aim is to discuss strategies for managing neratinib-associated diarrhea in a real-world setting, with the goal of improving the patient experience and maintaining patients on therapy. These cases were identified through the authors’ clinical practice. All identifying details, including the specific institutional settings, have been deidentified to protect the anonymity of the patients.\n\nThis article is based on previously conducted studies and anonymized case descriptions and does not contain any new studies with human participants or animals performed by any of the authors.\n\nCase Series\n\nCase 1\n\nThe patient is a 40-year-old female teacher with no medical comorbidities who was diagnosed with stage III (cT3N1M0) infiltrating ductal carcinoma (IDC) of the right breast. The patient initially self-palpated a breast mass, delaying medical attention by 2.5 months because of lack of health insurance. Imaging revealed a 7-cm breast mass and two abnormal lymph nodes. Biopsy confirmed estrogen receptor (ER)–positive (+), progesterone receptor (PR)–negative (−), HER2+ IDC. She had a strong family history of multiple relatives with breast cancer, sarcoma, and CNS tumors, and genetic testing revealed a pathogenic heterozygous TP53 916C > T germline mutation consistent with Li-Fraumeni syndrome [40].\n\nAfter a favorable clinical response to neoadjuvant therapy with TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) for six cycles, the patient underwent mastectomy with immediate reconstruction. Surgical pathology revealed a pCR (ypT0N0). As a result of toxicity associated with TCHP, she required antidiarrheal agents for grade 1 diarrhea. She completed 11 cycles of adjuvant trastuzumab plus pertuzumab and continues anastrozole, goserelin, and zoledronic acid.\n\nApproximately 6.5 months after completion of adjuvant anti-HER2 therapy, she began extended adjuvant therapy with neratinib, which is ongoing. Neratinib was initiated with DE with a starting dose of 160 mg/day, increasing by 40 mg every two weeks (q2w) until reaching the recommended dose of 240 mg/day. To manage diarrhea, the patient takes a maximum of 2 to 4 mg loperamide daily (qd) as needed (PRN). The patient was seen weekly at neratinib initiation, then q2w, and now monthly. She is tolerating therapy well, with one or two soft-formed bowel movements per day, no nausea or vomiting, and no clinical signs of recurrence.\n\nCase 2\n\nThe patient is a 62-year-old man, retired after a career in the military, who developed stage I (cT1N1M0) IDC of the right breast. He is receiving active therapy for multiple comorbidities, including diabetes, chronic obstructive pulmonary disease, atrial fibrillation, seizure disorder, and hypertension. The patient presented with a breast mass in the upper outer right quadrant; biopsy revealed ER+/PR+/HER2+ IDC. His family history includes one second-degree relative with breast cancer.\n\nFollowing neoadjuvant therapy with four cycles of doxorubicin and cyclophosphamide (AC), followed by 12 weekly cycles of docetaxel plus trastuzumab, the patient underwent mastectomy and axillary nodal excision of a 3.9-cm mass. The patient continued adjuvant trastuzumab to complete 1 year in total. Daily letrozole was added 7 months after trastuzumab initiation and is ongoing.\n\nOne week after completion of trastuzumab, the patient initiated extended adjuvant therapy with neratinib, ongoing for almost 1 year. Neratinib was initiated using DE combined with colestipol 2 g qd and loperamide PRN (maximum dose: 12 mg qd). The patient started on 120 mg/day neratinib, and the dose was increased by 40 mg q2w. The patient reached the recommended dose of 240 mg/day with no toxicities. Due to loose stools in the absence of prophylaxis, he continues to take colestipol 2 g qd and loperamide PRN for diarrhea and is doing well. Because the patient is enrolled in a patient management program through a specialty pharmacy, he was assessed and counseled by the pharmacist at neratinib initiation, with follow-up twice in the first month of therapy and monthly thereafter.\n\nCase 3\n\nThe patient is a 60-year-old female flight attendant diagnosed with stage IIIC (cT1N3M0) ER+/PR+/HER2+ IDC of the right breast. She has no family history of breast cancer. Comorbidities include hyperlipidemia and hypertension, which are unmedicated but stable. The patient underwent lumpectomy to remove a 1.2-cm tumor. Axillary lymph node dissection revealed 16 of 17 sampled lymph nodes involved with metastatic carcinoma.\n\nThe patient received adjuvant AC for 4 cycles, followed by 12 cycles of weekly paclitaxel with concurrent trastuzumab plus pertuzumab, with continuation of trastuzumab and pertuzumab to complete 1 year. After chemotherapy completion, the patient underwent radiation, followed by anastrozole, which is ongoing.\n\nExtended adjuvant therapy with neratinib was initiated < 1 month after completion of trastuzumab-based therapy. The patient initiated neratinib on a DE protocol, with a starting dose of 120 mg/day, combined with colestipol 1 g twice daily (bid), loperamide 4 mg every 4 h PRN, and diphenoxylate hydrochloride 5 mg/atropine sulfate 0.05 mg every 6 h PRN. The neratinib dose was increased by 40 mg q2w as tolerated by the patient. The patient experienced intermittent grade 2 diarrhea, which was controlled with this antidiarrheal regimen. Neratinib was paused for bilateral mastectomy, after which DE was reinitiated as before. The patient was unable to escalate to 240 mg/day because of development of grade 2 to 3 diarrhea and instead maintained a 3-day repeating dose pattern of 200, 240, and 240 mg/day. Approximately 10 months into therapy, diarrhea had improved to the point that the patient stopped taking colestipol and managed any residual diarrhea with loperamide and diphenoxylate/atropine PRN. The patient chose to remain on extended neratinib therapy for longer than 1 calendar year because of the interruption due to surgery.\n\nCase 4\n\nThe patient is a 38-year-old woman employed in sales who developed stage II (cT2N0M0) ER+/PR-/HER2+ IDC of the right breast. She is a nonsmoker and exercises regularly. She was diagnosed with Crohn’s disease in the remote past, and her symptoms are managed with hyoscyamine and FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet. She has no other comorbidities. Her family history includes a first-degree relative with breast cancer; genetic testing was negative for heritable mutations.\n\nThe patient underwent lumpectomy and sentinel lymph node biopsy, with no involvement of four sampled axillary lymph nodes. She received adjuvant TCH (docetaxel, carboplatin plus trastuzumab) for six cycles followed by trastuzumab to complete 1 year in total. Approximately 1 year after trastuzumab completion, the patient initiated neratinib for 12 months, along with ongoing tamoxifen.\n\nDespite a history of Crohn’s disease, the patient initiated neratinib at the full 240 mg/day dose with prophylactic loperamide 4 mg three times daily (tid) and colestipol 2 g bid. The patient experienced diarrhea for the first 1 to two weeks of treatment, including 1 day at grade 3, but was then able to taper off antidiarrheal medications. In months 7 to 9, she developed grade 2 palmar/plantar erythrodysesthesia (PPE), requiring neratinib dose reduction to 200 mg/day at month 8 and management with emollient and triamcinolone cream. She was able to complete 12 months of therapy at the reduced dose.\n\nCase 5\n\nThe patient is a 60-year-old female cafeteria worker who was originally diagnosed with stage II (cT1N1M0) ER-/PR+/HER2+ IDC of the right breast in 2004 and developed metastatic HER2+ recurrence involving bone and lymph nodes 4 years later. She has no comorbidities and no known family history of breast cancer. Initial treatment for stage II disease was right modified radical mastectomy followed by six cycles of adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide).\n\nThe patient has received multiple lines of therapy for MBC, including vinorelbine plus trastuzumab at initial recurrence. After development of lung metastases, she was treated with T-DM1 on a clinical trial and experienced 6 years of disease control. She again experienced excellent disease control for 3 years with capecitabine plus lapatinib followed by slow progression of pulmonary metastases.\n\nThe patient was reluctant to change to an intravenous regimen and remained asymptomatic from her disease. Upon FDA approval of neratinib in combination with capecitabine for HER2+ MBC, lapatinib was replaced with neratinib 240 mg qd with continuation of the same dose of capecitabine (1000 mg bid) based on prior tolerability. The patient received prophylactic loperamide 4 mg tid but paused the regimen after 4 days because of grade 2 nausea and grade 1 to 2 constipation. She then reinitiated neratinib with a DE schedule, starting at 120 mg/day with prophylactic loperamide 4 mg bid, with improved tolerability. She was able to titrate the neratinib dose to 160 mg/day after 1 week, to 200 mg/day after 2 additional weeks, and to 240 mg/day by week 5. The patient was able to continue on therapy with loperamide bid with regular bowel movements and no further nausea. Three months into treatment with neratinib plus capecitabine, the patient had a near-complete radiographic response, with residual scarring in the areas of prior pulmonary nodules. She remains free of recurrent diarrhea.\n\nDiscussion\n\nThe patient cases presented in this series provide examples of proactive management of diarrhea in patients with HER2+ ESBC and MBC treated with neratinib. In four of five cases, diarrhea was managed with neratinib DE, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy, although two patients were unable to reach or maintain the full approved dose, in one case because of diarrhea and the other because of PPE.\n\nManagement of diarrhea with neratinib DE and antidiarrheal prophylaxis in this series is consistent with results from the CONTROL trial [38]. Neratinib DE was effective for managing and possibly reducing neratinib-associated early-onset diarrhea in cases 1, 2, 3, and 5, allowing therapy continuation. Three patients reached the full dose, and one patient was able to titrate to her maximum tolerable dose. DE was more effective for diarrhea management than loperamide prophylaxis in case 5, consistent with results from CONTROL [38], in which antidiarrheal prophylaxis with loperamide alone was not as successful as neratinib DE. Results from CONTROL showed that 2-week neratinib DE with loperamide PRN was associated with the lowest rate of both diarrhea-associated discontinuation (3.3% vs. 4–20%) and all-grade constipation (33% vs. 57–75% in prophylaxis cohorts with mandatory loperamide and 38% with mandatory colestipol/loperamide PRN) [38] as well as a higher mean cumulative dose of neratinib compared to ExteNET (67,364.0 mg vs. 54,193.9 mg) [31, 38, 39]. Notably, neratinib DE was effective for managing neratinib-induced diarrhea in the patient with MBC described in case 5, consistent with the FDA-approved dosing strategy for MBC in addition to ESBC [31]. Because early-onset diarrhea may lead to neratinib discontinuation, proactive management of diarrhea with neratinib DE may allow for continuation of therapy across neratinib treatment settings.\n\nAntidiarrheal prophylaxis with loperamide and colestipol was effective for managing diarrhea during the early course of treatment in case 4, although neratinib dose reduction was eventually required because of subsequent PPE. Prophylactic loperamide and colestipol reduced the incidence and severity of diarrhea in CONTROL, resulting in a diarrhea-related discontinuation rate of 4%; however, as described above, prophylactic strategies were associated with a higher rate of GI adverse events compared to DE [38]. In addition, these regimens may be more inconvenient for patients because of the number of pills/tablets required per day.\n\nAlthough neratinib DE was used in most of the cases described here, some escalation schedules differed from the DE schedules evaluated in CONTROL (Fig. 1) [38]. Several patients in this series initiated neratinib on longer or slower DE intervals as a precaution due to comorbidities or other considerations that could increase the likelihood of discontinuation, suggesting that extended DE strategies may be an option. As described in case 3, for patients with slower DE or other interruptions, oncologists may consider prolonging the course of therapy to make up for missed doses.Fig. 1 Neratinib initiation strategies described in this case series. DE strategies evaluated in CONTROL are shown for comparison [38]. aPatient was unable to escalate to 240 mg/day because of grade 2 to 3 diarrhea and instead maintained a 3-day repeating dose pattern. bIn combination with capecitabine (1000 mg bid). Patient reinitiated neratinib with DE after poor tolerability with a starting dose of 240 mg/day and prophylactic loperamide. bid, twice daily; DE, dose escalation; PRN, as needed; qd, daily; qw, every week; q2w, every two weeks; tid, three times daily\n\nThe patient cases described in this series suggest that neratinib-associated diarrhea is generally manageable, even in patients with potentially complicating comorbidities. In the extended adjuvant setting, neratinib has been shown to offer greater benefit in patients with hormone receptor–positive, lymph node–positive disease who were ≤ 1 year from completion of trastuzumab, but patients with clinically significant GI comorbidities were excluded from ExteNET [12]. However, results reported in case 4 of this series demonstrate that a patient with well-managed Crohn’s disease was able to complete the entire course of neratinib with implementation of prophylactic antidiarrheal treatment. Similarly, patients with HER2+ MBC who had previously been treated with an anti-HER2 TKI were excluded from NALA [26]. The patient described in case 5 achieved disease response to neratinib plus capecitabine immediately following treatment with lapatinib plus capecitabine by managing neratinib-induced diarrhea and maintaining adherence to therapy using DE. These results suggest that some patients excluded from previous trials may be able to tolerate neratinib and thereby experience potential clinical benefit, meriting additional evaluation in an expanded patient population.\n\nThis case series highlights the importance of provider-patient communication in establishing patient expectations and managing adverse effects of neratinib. Early conversations may help identify patient concerns and manage expectations about long-term therapy [41, 42]. As described in case 5, some patients may prefer the convenience of oral therapy, which is also a consideration during the COVID-19 pandemic to minimize in-person visits [43]. Likewise, reducing the incidence of severe diarrhea may decrease inpatient admissions or reduce the need for administering additional supportive care measures in a clinical setting, thereby decreasing contact with the health care system. Providing patients with a written plan during early consultations may alleviate anxiety and establish expectations for treatment [41], although the plan may change based on clinical factors. The patient described in case 2 was enrolled in a patient management program through a specialty pharmacy, which augmented educational counseling at neratinib initiation and provided additional support for managing adverse effects. As described in this case and in case 1, frequent contact at initiation of neratinib may be beneficial, and pharmacists and advanced practice providers can play an important role in treatment optimization [44].\n\nAs described above, results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or DE of neratinib from a lower starting dose can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer [38]. The 2-week DE schedule (week 1 = 120 mg/day, week 2 = 160 mg/day, week 3 and onwards: 240 mg/day) has been included in the FDA label for both HER2+ ESBC and MBC since June 2021 [31]. An alternative DE schedule with a panel recommendation to start neratinib at a dose of 120 mg/day with PRN loperamide and escalate the dose by 40 mg/day each week until patients reach the recommended dose of 240 mg/day of neratinib has also been published [45].\n\nConclusions\n\nIn summary, this case series shows that neratinib-associated diarrhea can be effectively managed with neratinib DE from a lower initial starting dose or prophylactic antidiarrheal medications in a real-world clinical setting. Widespread adoption of the strategies described here may allow more patients to adhere to neratinib therapy and thereby improve clinical outcomes for patients with HER2+ breast cancer treated with neratinib.\n\nAcknowledgements\n\nFunding\n\nThis study and the journal’s Rapid Service Fee were funded by Puma Biotechnology, Inc., Los Angeles, CA, USA.\n\nMedical Writing, Editorial, and Other Assistance\n\nWriting and editorial support for this manuscript was funded by Puma Biotechnology, Inc., Los Angeles, CA, USA, and provided by Melanie Styers, PhD, Kristen Evaul, PhD, and Michelle Kean, PhD, of Brightly Network, LLC.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthor Contributions\n\nAll authors contributed to the conception and design of this case series, collection and assembly of data, data analysis and interpretation, and manuscript writing and revision. All authors read and approved of the final manuscript.\n\nDisclosures\n\nMegan L. Kruse: Consulting or advisory role: Lilly Oncology, Eisai, Novartis Oncology, Immunomedics, Puma Biotechnology, Inc.; Research funding: Tempus. Irene M. Kang: Consulting or advisory role: Bristol Myers Squibb, Puma Biotechnology, Inc.; Speakers’ Bureau: Puma Biotechnology, Inc.; Open Payments link: https://openpaymentsdata.cms.gov/physician/1328730. Nusayba A. Bagegni: Research funding: Sermonix Pharmaceuticals, Inc., Pfizer, AstraZeneca, Xcovery Holding Company, LLC, Novartis Pharmaceuticals Company; Daiichi Sankyo. W. Todd Howell: Employment: Hematology and Oncology Associates of Alabama. Halle C.F. Moore: Research funding: Puma Biotechnology, Inc., Daiichi Sankyo, Roche, AstraZeneca, Sermonix Pharmaceuticals, Inc. Cynthia M. Bedell: Employment: Texas Oncology PA; Consulting or advisory role: AstraZeneca, Daiichi Sankyo; Speakers’ bureau: Genentech, SeaGen, AstraZeneca, Puma Biotechnology, Inc., Daiichi Sankyo. Christopher T. Stokoe: Employment: Texas Oncology PA; Leadership: Texas Oncology PA; Honoraria: Puma Biotechnology, Inc.; Consulting or advisory role: Puma Biotechnology, Inc.; Research funding: US Oncology.\n\nCompliance with Ethics Guidelines\n\nThis article is based on previously conducted studies and anonymized case descriptions and does not contain any new studies with human participants or animals performed by any of the authors.\n\nData Availability\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n1. Loibl S Gianni L HER2-positive breast cancer Lancet 2017 389 2415 2429 10.1016/S0140-6736(16)32417-5 27939064\n2. Cameron D Piccart-Gebhart MJ Gelber RD 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial Lancet 2017 389 1195 1205 10.1016/S0140-6736(16)32616-2 28215665\n3. Slamon D Eiermann W Robert N Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early Cancer Res 2016 76 S5 04\n4. Perez EA Romond EH Suman VJ Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831 J Clin Oncol 2014 32 3744 52 10.1200/JCO.2014.55.5730 25332249\n5. Brufsky AM Mayer M Rugo HS Central nervous system metastases in patients with HER2-positive metastatic breast cancer: Incidence, treatment, and survival in patients from registHER Clin Cancer Res 2011 17 4834 43 10.1158/1078-0432.CCR-10-2962 21768129\n6. Olson EM Najita JS Sohl J Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the posttrastuzumab era Breast 2013 22 525 31 10.1016/j.breast.2012.12.006 23352568\n7. Gianni L Eiermann W Semiglazov V Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort Lancet Oncol 2014 15 640 7 10.1016/S1470-2045(14)70080-4 24657003\n8. Gianni L Pienkowski T Im YH 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial Lancet Oncol 2016 17 791 800 10.1016/S1470-2045(16)00163-7 27179402\n9. Schneeweiss A Chia S Hickish T Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive ea Eur J Cancer 2018 89 27 35 10.1016/j.ejca.2017.10.021 29223479\n10. Von Minckwitz G Procter M de Azambuja E Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer N Engl J Med 2017 377 122 31 10.1056/NEJMoa1703643 28581356\n11. Von Minckwitz G Huang CS Mano MS Trastuzumab emtansine for residual invasive HER2-positive breast cancer N Engl J Med 2019 380 617 28 10.1056/NEJMoa1814017 30516102\n12. Martin M Holmes FA Ejlertsen B Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2017 18 1688 700 10.1016/S1470-2045(17)30717-9 29146401\n13. Chan A Delaloge S Holmes FA Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2016 17 367 77 10.1016/S1470-2045(15)00551-3 26874901\n14. Verma S Miles D Gianni L Trastuzumab emtansine for HER2-positive advanced breast cancer N Engl J Med 2012 367 1783 91 10.1056/NEJMoa1209124 23020162\n15. Modi S Saura C Yamashita T Trastuzumab deruxtecan in previously treated HER2-positive breast cancer N Engl J Med 2020 382 610 21 10.1056/NEJMoa1914510 31825192\n16. Baselga J Gelmon KA Verma S Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy J Clin Oncol 2010 28 1138 44 10.1200/JCO.2009.24.2024 20124182\n17. Corteś J Fumoleau P Bianchi GV Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer J Clin Oncol 2012 30 1594 600 10.1200/JCO.2011.37.4207 22393084\n18. Awada A Colomer R Inoue K Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer the NEfERT-T randomized clinical trial JAMA Oncol 2016 2 1557 64 10.1001/jamaoncol.2016.0237 27078022\n19. Blackwell KL Burstein HJ Storniolo AM Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study J Clin Oncol 2012 30 2585 92 10.1200/JCO.2011.35.6725 22689807\n20. Blackwell KL Burstein HJ Storniolo AM Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer J Clin Oncol 2010 28 1124 30 10.1200/JCO.2008.21.4437 20124187\n21. Geyer CE Forster J Lindquist D Lapatinib plus capecitabine for HER2-positive advanced breast cancer N Engl J Med 2006 355 2733 43 10.1056/NEJMoa064320 17192538\n22. Cameron D Casey M Press M A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses Breast Cancer Res Treat 2008 112 533 43 10.1007/s10549-007-9885-0 18188694\n23. Jacobs SA Robidoux A Abraham J NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer Breast Cancer Res 2019 21 133 10.1186/s13058-019-1196-y 31796073\n24. Park JW Liu MC Yee D Adaptive randomization of neratinib in early breast cancer N Engl J Med 2016 375 11 22 10.1056/NEJMoa1513750 27406346\n25. Murthy RK Loi S Okines A Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer N Engl J Med 2020 382 597 609 10.1056/NEJMoa1914609 31825569\n26. Saura C Oliveira M Feng Y-H Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial J Clin Oncol 2020 38 3138 49 10.1200/JCO.20.00147 32678716\n27. Freedman RA Gelman RS Anders CK TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases J Clin Oncol 2019 37 1081 9 10.1200/JCO.18.01511 30860945\n28. Freedman RA Gelman RS Wefel JS Translational breast cancer research consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases J Clin Oncol 2016 34 945 52 10.1200/JCO.2015.63.0343 26834058\n29. Petrelli F Ghidini M Lonati V The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: a systematic review and pooled analysis Eur J Cancer 2017 84 141 8 10.1016/j.ejca.2017.07.024 28810186\n30. Lin NU Borges V Anders C Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial J Clin Oncol 2020 38 2610 9 10.1200/JCO.20.00775 32468955\n31. NERLYNX® (neratinib) [package insert]. Puma Biotechnology, Inc, Los Angeles, CA, 2021\n32. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: breast cancer version 8.2021. Published 13 September 2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf\n33. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: central nervous system cancers version 2.2021. Published 8 September 2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf\n34. Rugo HS Di Palma JA Tripathy D The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea Breast Cancer Res Treat 2019 175 5 15 10.1007/s10549-018-05102-x 30671765\n35. Mortimer J Di Palma J Schmid K Ye Y Jahanzeb M Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial Breast Cancer Res 2019 21 32 10.1186/s13058-019-1112-5 30813966\n36. Gnant M Iwata H Bashford A Duration of extended adjuvant therapy with neratinib in early-stage HER2+ breast cancer after trastuzumab-based therapy: exploratory analyses from the phase III ExteNET trial J Clin Oncol 2018 36 524 10.1200/JCO.2018.36.15_suppl.524\n37. Moy B Takahashi M Ohtani S Chmielowska E Association between treatment duration and overall survival in early-stage HER2+ breast cancer patients receiving extended adjuvant therapy with neratinib in the ExteNET trial J Clin Oncol 2021 39 540 10.1200/JCO.2021.39.15_suppl.540\n38. Barcenas CH Hurvitz SA Di Palma JA Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial Ann Oncol 2020 31 1223 30 10.1016/j.annonc.2020.05.012 32464281\n39. Marx G Chien AJ Garcia-Saenz J Chan A Dose escalation for mitigating diarrhea: ranked tolerability assessment of antidiarrheal regimens in patients receiving neratinib for early-stage breast cancer J Clin Oncol 2021 39 536 10.1200/JCO.2021.39.15_suppl.536\n40. Llovet P Illana FJ Martín-Morales L A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families Fam Cancer 2017 16 567 75 10.1007/s10689-017-9990-0 28573494\n41. Balogh EP Ganz PA Murphy SB Nass SJ Ferrell BR Stovall E Patient-centered cancer treatment planning: improving the quality of oncology care. Summary of an Institute of Medicine workshop Oncologist 2011 16 1800 1805 10.1634/theoncologist.2011-0252 22128118\n42. Untch M, Martin M, De Laurentiis M, Gligorov J. How to optimise extended adjuvant treatment with neratinib for patients with early HER2+ breast cancer. Oncol Ther. 2021. Online ahead of print. 10.1007/s40487-021-00153-5.\n43. Sheng JY Santa-Maria CA Mangini N Management of breast cancer during the COVID-19 pandemic: a stage- and subtype-specific approach JCO Oncol Pract 2020 16 665 74 10.1200/OP.20.00364 32603252\n44. Hicks KM Cope D Novak J Scherer S The role of the advanced practitioner in maintaining adherence in patients on oral oncolytics J Adv Pract Oncol 2017 8 7 21\n45. Jackisch C Barcenas CH Bartsch R Optimal strategies for successful initiation of neratinib in patients with HER2-positive breast cancer Clin Breast Cancer 2021 21 e575 83 10.1016/j.clbc.2021.02.001 33678567\n\n",
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"issue": null,
"journal": "Oncology and therapy",
"keywords": "Diarrhea; Early-stage breast cancer; HER2; Metastatic breast cancer; Neratinib",
"medline_ta": "Oncol Ther",
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"title": "Management of Diarrhea in Patients with HER2-Positive Breast Cancer Treated with Neratinib: A Case Series and Summary of the Literature.",
"title_normalized": "management of diarrhea in patients with her2 positive breast cancer treated with neratinib a case series and summary of the literature"
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"abstract": "Althoughtricyclic antidepressants(TCAs) are frequently prescribed to patients with depression, these drugs can also be misused. A 21-year-old comatose patient was referred to our hospital presenting with ventricular tachycardia. Despite initial treatment including intravascular lipid emulsion, ventricular fibrillation occurred soon after arrival. Venoarterial extracorporeal membrane oxygenation and therapeutic hypothermia were administered. Refractory arrhythmia disappeared on the next day. A high concentration of amitriptyline was identified in his blood samples on arrival. Mechanical bowel obstruction followed after abdominal compartment syndrome caused by anticholinergic effects, and refractory seizure occurred due to TCA intoxication. Although seizure was brought under control with anticonvulsant agents, his Glasgow Coma Scale did not recover to the full score. MRI presented irreversible damage to the bilateral frontal lobe and insula. Amitriptyline has the potential to cause unusual serious complications, such as abdominal compartment syndrome, irreversible central nervous system disability and lethal arrhythmia.",
"affiliations": "Department of Emergency and Critical Care Medicine, Hyogo Emergency Medical Center, Kobe, Japan.;Department of Plastic Surgery, Kobe University Hospital, Kobe, Japan.;Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.;Department of Emergency and Critical Care Medicine, Hyogo Emergency Medical Center, Kobe, Japan.",
"authors": "Nishimura|Takeshi|T|;Maruguchi|Hayato|H|;Nakao|Atsunori|A|;Nakayama|Shinichi|S|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline",
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"keywords": "cardiovascular system; drugs: gastrointestinal system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D001925:Brain Damage, Chronic; D003128:Coma; D006801:Humans; D007415:Intestinal Obstruction; D059325:Intra-Abdominal Hypertension; D008297:Male; D012640:Seizures; D017180:Tachycardia, Ventricular; D014693:Ventricular Fibrillation; D055815:Young Adult",
"nlm_unique_id": "101526291",
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"title": "Unusual complications from amitriptyline intoxication.",
"title_normalized": "unusual complications from amitriptyline intoxication"
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"abstract": "BACKGROUND\nDiclofenac has frequently been implicated as the cause of immune hemolytic anemias and less frequently of immune thrombocytopenia. The presence of the causative antibodies has only been demonstrated in patients with immune hemolytic anemia, but not yet in patients with thrombocytopenia. The cases of two patients in whom diclofenac simultaneously induced antibodies against platelets and RBCs are reported.\n\n\nMETHODS\nThe investigation was carried out with standard serologic tests for detection of antibodies against platelets and RBCs. The patients' sera were tested in the presence and absence of diclofenac and its metabolites.\n\n\nRESULTS\nOne of the two patients developed severe hemolysis and significant thrombocytopenic purpura. The other patient developed significant thrombocytopenia but no hemolysis. Both patients had a positive DAT and drug- and/or metabolite-dependent antibodies against RBCs and platelets.\n\n\nCONCLUSIONS\nBased on our findings and those of other investigators, we believe that diclofenac leads to the production of antibodies against RBCs and/or platelets.",
"affiliations": "University Clinic Charité, Institute for Transfusion Medicine, Humboldt University of Berlin, Germany. oliver.meyer@charite.de",
"authors": "Meyer|Oliver|O|;Hoffmann|Till|T|;Aslan|Tunay|T|;Ahrens|Norber|N|;Kiesewetter|Holger|H|;Salama|Abdulgabar|A|",
"chemical_list": "D001323:Autoantibodies; D001381:Azepines; D015395:Histocompatibility Antigens Class I; D007191:Indazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C032193:glycoprotein receptor GPIb-IX; C073385:DAT 582; D004008:Diclofenac",
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"issue": "43(3)",
"journal": "Transfusion",
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"mesh_terms": "D000328:Adult; D000368:Aged; D001323:Autoantibodies; D001381:Azepines; D001792:Blood Platelets; D003298:Coombs Test; D004008:Diclofenac; D004912:Erythrocytes; D005260:Female; D006461:Hemolysis; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007191:Indazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "0417360",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Diclofenac-induced antibodies against RBCs and platelets: two case reports and a concise review.",
"title_normalized": "diclofenac induced antibodies against rbcs and platelets two case reports and a concise review"
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"abstract": "BACKGROUND\nHemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design.\n\n\nMETHODS\nHere, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases.\n\n\nCONCLUSIONS\nOur case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.",
"affiliations": "Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA.;Department of Molecular and Human Genetics, Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.;Department of Pathology and Immunology, Baylor St. Luke's Medical Center, Baylor College of Medicine, Houston, TX, USA.;Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA.;Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA. garivero@bcm.edu.",
"authors": "Sun|Y|Y|;Blieden|C|C|;Merritt|B Y|BY|;Sosa|R|R|;Rivero|Gustavo|G|http://orcid.org/0000-0002-2866-9203",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02623-2",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2623\n10.1186/s13256-020-02623-2\nCase Report\nHemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature\nSun Y. 1 Blieden C. 2 Merritt B. Y. 3 Sosa R. 14 http://orcid.org/0000-0002-2866-9203Rivero Gustavo garivero@bcm.edu 14 1 Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX 77030 USA \n2 grid.39382.330000 0001 2160 926XDepartment of Molecular and Human Genetics, Baylor Genetics, Baylor College of Medicine, Houston, TX USA \n3 grid.39382.330000 0001 2160 926XDepartment of Pathology and Immunology, Baylor St. Luke’s Medical Center, Baylor College of Medicine, Houston, TX USA \n4 grid.39382.330000 0001 2160 926XThe Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030 USA \n1 3 2021 \n1 3 2021 \n2021 \n15 9830 10 2020 8 12 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nHemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design.\n\nCase description\nHere, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases.\n\nConclusion\nOur case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.\n\nKeywords\nHemophagocytic lymphohistiocytosisMyelodysplastic syndromeHyperinflammationissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nHemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated immunity and end organ damage. Primary HLH is linked with autosomal recessive and X-linked mutations. Secondary HLH results from predisposing conditions. Both primary and secondary HLH may be activated by an infections and malignancies. [1] The association of HLH with hematologic malignancies is accepted. However, HLH initiated by myelodysplastic syndrome (MDS) is exceedingly unusual. Although dysplasia is observed in patients with hemophagocytosis, a hyperinflammatory entity characterized by dysplastic cytopenias, MDS like karyotypic abnormality and hemophagocytosis suggests a different spectrum of disease, in which HLH originates from a clonal disorder. In this report, we present an elderly female who fulfilled HLH 2004 criteria exhibiting erythroid and megakaryocytic dysplasia associated with trisomy 8 [+ 8]. Additionally, we examine published cases in English literature to identify clinical, laboratory and cytogenetic features observed in MDS patients fulfilling HLH 2004 criteria.\n\nCase presentation\nAn 83-year-old African American female presented with lethargy, temperature of 102.9° F and tachycardia. After 9 days of broad-spectrum antibiotics, she developed hemodynamic instability requiring vasopressors, worsening liver function (peak bilirubin of 12.5 mg/dL, Aspartate aminotransferase (AST) of 689 IU/L, Alanine aminotransferase (ALT) of 239 IU/L) and leukocytosis of 16,000/uL. Her hemoglobin was 8.9/uL and platelets had fallen to 26,000/uL. Disseminated intravascular coagulation (DIC) was considered given progressive severe thrombocytopenia of 13,000 U/L, fibrinogen < 70 mg/dL and d-dimer of 12.4 mg/L. Her ferritin was 9479 ng/mL and fasting triglycerides (TAG) were 321 mg/dL. Soluble interleukin-2Rα (CD25) was < 38 pg/dL. Her human immunodeficiency virus (HIV), rapid influenza A/B, hepatitis B/C serologies were all negative. Epstein-barr virus (EBV) viral load was negative. Given concern autoimmune hepatitis, a liver biopsy showed Kupffer cell hypertrophy with hemophagocytosis. Bone marrow biopsy demonstrated hemophagocytosis (Fig 1a, b). In addition, significant erythroid nuclear fragmentation and karyorrhexis were observed (Fig 1c). Marrow cytogenetics showed 47, XX +8 [6], 46, XX [5]. Next generation sequencing (NGS) including CSFR1, SF3B1, SRSF2, U2AF1, NRAS, KRAS, FLT3, JAK2, KIT, PHF6, PDGFRA, CDKN2A, IDH1, IDH2, TET2, EZH2, CEBPA, EP300, PTPN11, P53, CREBBP, IKZF1, IKZF3, NOTCH1, RUNX1, WT1 and NPM1 showed DNMT3A p.Arg736His (c.2207G>A) and DNMT3A p.Leu859Ter (c.2576T>A) at allele frequencies of 2.7 and 2.4 %, respectively. In view of her hemophagocytosis, cytopenias, high temperature, abnormal liver function test, low fibrinogen and elevated fasting triglycerides and ferritin, she fulfilled 5/8 HLH 2004 criteria. HLH-94 regimen was initiated with dexamethasone and etoposide. She developed neutropenic sepsis and etoposide was stopped. Blood cultures were positive for Escherichia coli. Patient expired after developing hemodynamic instability.Figure 1. Bone marrow hemophagocytosis and dysplastic changes in a trisomy 8 myelodysplastic syndrome patient. a Bone marrow aspirate smear revealing active hemophagocytosis. Erythroid cells are phagocytized by histiocytic cells. b Bone marrow aspirate showing neutrophil phagocytized by histiocytic cell. Peripherally to hemophagocytosis, erythroid precursor shows megaloblastic changes. Additionally, hyposegmented neutrophils are observed. c Nucleated red cell showing nuclear fragmentation with dysmorphic features suggesting dysplasia\n\n\n\nMethods\nIn addition to our case, three additional previously published reports were included in our reviewed cases. Clinical, laboratory and karyotypic data was analyzed to investigate potential features commonly observed in patients presenting with hyperinflammation and MDS. Data aggregation from four cases presenting with HLH and MDS allowed identification of clinical outcome in patients receiving HLH directed therapy or alternative regimens.\n\nCohort analysis\nHLH is a deadly syndrome. If untreated, survival is less than 2 months [2]. Here, we describe an elderly female exhibiting hyperinflammation, refractory cytopenias, erythroid dysplasia, expansion of + 8 metaphases and bone marrow/hepatic hemophagocytosis suggesting HLH associated with MDS (HLH-MDS). In addition to our patient, three previously published HLH cases associated with MDS were included in study cohort (Table 1). 7/8 HLH criteria were observed in two (50%), and one (25%) case with 6/8 and 5/8 criteria, each. Our report and published cases are novel since 3 of 4 (75%) patients harbored a karyotypic abnormality highlighting the clonal nature of the disease. A detectable chromosomic abnormality suggests that HLH was systemically initiated by MDS rather than representing a reactive phenomenon [3-5]. In reviewed cases, patients were older than 60 years with exception of one pediatric patient. International prognostic score system (IPSS) was intermediate-1 and high-risk (2 cases, each). + 8 was detected as sole abnormality or within a complex metaphase in 75% of cases. Most of the patients succumbed to the disease, except one case treated with high dose methylprednisolone, cyclosporine (CSA) decitabine. Tamamyan et al. described 33 cases of HLH, of which 3(9%) exhibited concurrent MDS, although only one was identified by HLH 2004 [6]. Karyotypic abnormalities were not reported. As in our case, the author reported that HLH linked with MDS represented a fatal condition.Table 1 Myelodysplastic syndrome cases associated with hemophagocytic Lymphohistiocytosis (HLH)\n\n\tAge (years)\tFever\tANC (/mL)\tHb (g/dL)\tPlatelet (K/UL)\tFerritin (ng/dL)\tFibrinogen (mg/dL)\tTAG (mg/dL)\tIL-2 (pg/dL)\tHemophagocytosis\tMarrow blast (%)\tKaryotype\tR-IPSS\tHepatomegaly/splenomegaly\tHLH-2004 (points)\tOutcome\t\n1\t8\tYes\t400\t10.6\t49\t1070\t256\t306\t4250\tYes\t2.2\t46, XX, + 8 [20]\tInter-mediate\tYes/yes\t5\tAlive\t\n2\t60\tYes\t6800\t6.5\t14\t649\tNA\tNA\t4054\tYes\t2\tComplex [including + 8]a\tVery high\tYes/yes\t5\tAlive\t\n3\t68\tNA\tNA\t10.5\t45\t24,316\t129\tNA\t1025\tYes\t0\t46, XY\tLow\tNo/yes\t5\tDied\t\nCase\t83\tYes\t8900\t8.9\t13\t9479\t70\t321\t34\tYes\t0\t47, XX, + 8 [6], 46, XX [5]\tLow\tNo/no\t6\tDied\t\nANC absolute neutrophil count, Hb hemoglobin, TAG triglycerides, IL2 Interleukin 2 soluble receptor, IPSS International Prognostic Score System, NA not available\n\naPatient karyotype = 54-57,XY + 1 [2], + 3 [2], + [4], + 8 [4].add (9) (p22) [2], + 11[3].add (15) (p.11.2) [4], add (16) (q24) [4], add (19) (p13.1) [4], add (20) (p13) [4],?21 [2],2–5mar[cp4]/46,XY [8]\n\n\n\nConclusions\nEfforts to elucidate pathogenesis of HLH demonstrate that expansion of CD8+ cytotoxic T cells, low Treg frequencies and cytokine storm are frequently observed [7]. In MDS, similar clonal T cell expansion and decreased Treg frequencies results in stem cell/progenitor apoptosis in low-risk disease. Rather than hyperinflammation normally found in HLH patients, chronic low-grade inflammation develops associated with tumor-necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β) and IL-6 upregulation. Cytokine abnormalities in MDS leads to increased apoptosis and marrow hypercellularity. However, decreased marrow cellularity can develop in fraction of MDS patients harboring trisomy 8 karyotypic abnormality. Interestingly, our patient and two previously published cases harbored + 8 in their metaphase analysis at MDS diagnosis while HLH had developed [3, 5]. + 8 cells induce autologous T-cell oligoclonal expansion capable to target MDS precursor/progenitors resulting in characteristic marrow hypoplasia [8, 9]. In most of MDS cases, disease propagation depends on somatic mutations acquisition allowing dysplastic transformation. Mutations in perforin-dependent cytotoxicity are classically described in primary HLH. In our case, it is conceivable that myeloid mutations induced apoptotic and differentiation defects, and “facilitated” acquisition of HLH-like phenotype.\n\nThe preferred HLH treatment is HLH-94 protocol, but its administration is limited by MDS-induced cytopenias, as was the case with our patient. This is largely due to hemopoietic progenitor depletion initiated MDS and likely aggravated by HLH. Daitoku et al. reports superior outcome in a HLH-MDS patient treated with Methylprednisolone, CSA and decitabine[4]. Indeed, in vivo administration of hypomethylating agents (HMA) induce Foxp3+ Tregs expansion leading to immune suppression, and attenuates graft-versus-host disease [10]. The combination of HMA and immunosuppressive therapy may be promising treatment in HLH-MDS cases as suggested by the interesting outcomes in the case described by Daitoku et al.\n\nWe acknowledge limitations to our interpretation. It is possible that hyperinflammation initiated by HLH led to marrow dysplasia. However, the evidence of +8 strongly suggests a clonal etiology supporting MDS induced HLH. Secondly, sequencing did not include HLH like mutations such as PRF1, STX11, UNC13D, STXBP2, RAB27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS, among others. This may affect our ability to assign HLH as culprit for hyperinflammation in our case. However, Rui et al. recently demonstrated that epigenetic perturbations induced by DNMT3A mutations results in aberrant stem cell gene-expression associated with immune deregulation, which may have contributed to inflammatory manifestations in our case [11]. Additionally, recent data demonstrated that myeloid specific mutations including TET2, ASXL1, and DNMT3A can induce inflammasome activation in myelodysplasia and exacerbate inflammation [12-15]. In summary, HLH associated with MDS is an aggressive entity and should prompt careful evaluation hyperinflammatory signs. It is possible that targeting MDS hematopoiesis with hypomethylating agents in combination with immunosuppressive therapy to minimize hyperinflammation could improve life-threatening HLH in MDS patients.\n\nAbbreviations\nHLHHemophagocytic lymphohistiocytosis\n\nMDSMyelodysplastic syndrome\n\nHMAHypomethylating agent\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nFinancial support for this study was provided by the Texas Golfers against Cancer grant funding.\n\nAuthors’ contribution\nYS and GR contributed equally to manuscript writing. BYM sequenced marrow cells and provided analysis for next generation sequencing. CB provided morphologic details of marrow. GR, YS and RS designed plan for investigation and report of the case and studied cohort. RG conceived the study; RG and SY designed the research; RG, SY, MBY, RS, BC performed the research; RG and SY analysed and interpreted the results; RG, SY, MBY, RS and BC wrote, reviewed and approved the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and supporting materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthic approval and consent to participate\nInstitutional Review Board (IRB) approval was obtained for publication.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interest\nDr. Sun, Dr. Blieden, Dr. Merritt, Dr. Sosa and Dr. Rivero reported no conflict of interest.\n==== Refs\nReferences\n1. Filipovich AH Chandrakasan S Pathogenesis of hemophagocytic lymphohistiocytosis Hematol Oncol Clin North Am 2015 29 5 895 902 10.1016/j.hoc.2015.06.007 26461149 \n2. Otrock ZK Eby CS Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis Am J Hematol 2015 90 3 220 224 10.1002/ajh.23911 25469675 \n3. Kim SH Yi DY Lee NM Yun SW Chae SA Lim IS A rare case of hemophagocytic lymphohistiocytosis associated with myelodysplastic syndrome and trisomy 8 in a pediatric patient J Pediatr Hematol Oncol 2019 41 1 57 59 10.1097/MPH.0000000000001174 \n4. Daitoku S Aoyagi T Takao S Tada S Kuroiwa M Successful treatment of hemophagocytic lymphohistiocytosis associated with low-risk myelodysplastic syndrome by azacitidine Intern Med. 2018 57 2995 2999 10.2169/internalmedicine.0497-17 29780114 \n5. Tsuji T Yamasaki H Arima N Tsuda H Hemophagocytic lymphohistiocytosis associated with myelodysplastic syndromes Int J Hematol 2010 92 3 547 549 10.1007/s12185-010-0661-2 20820970 \n6. Tamamyan GN Kantarjian HM Ning J Jain P Sasaki K McClain KL Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes Cancer 2016 122 18 2857 2866 10.1002/cncr.30084 27244347 \n7. Humblet-Baron S Franckaert D Dooley J Bornschein S Cauwe B Schonefeldt S IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis J Allergy Clin Immunol 2016 138 1 200 209.e8 10.1016/j.jaci.2015.12.1314 26947179 \n8. Sloand EM Pfannes L Chen G Shah S Solomou EE Barrett J CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins Blood 2007 109 6 2399 2405 10.1182/blood-2006-01-030643 17090657 \n9. Olnes MJ Sloand EM Targeting immune dysregulation in myelodysplastic syndromes JAMA 2011 305 8 814 819 10.1001/jama.2011.194 21343581 \n10. Choi J Ritchey J Prior JL Holt M Shannon WD Deych E In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia Blood 2010 116 1 129 139 10.1182/blood-2009-12-257253 20424188 \n11. Lu R Wang P Parton T Zhou Y Chrysovergis K Rockowitz S Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development Cancer Cell 2016 30 1 92 107 10.1016/j.ccell.2016.05.008 27344947 \n12. Fuster JJ MacLauchlan S Zuriaga MA Polackal MN Ostriker AC Chakraborty R Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice Science 2017 355 6327 842 847 10.1126/science.aag1381 28104796 \n13. Zhang X Su J Jeong M Ko M Huang Y Park HJ DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells Nat Genet 2016 48 9 1014 1023 10.1038/ng.3610 27428748 \n14. Pan F Weeks O Yang FC Xu M The TET2 interactors and their links to hematological malignancies IUBMB Life 2015 67 6 438 445 10.1002/iub.1389 26099018 \n15. Basiorka AA McGraw KL Eksioglu EA Chen X Johnson J Zhang L The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype Blood 2016 128 25 2960 2975 10.1182/blood-2016-07-730556 27737891\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Hemophagocytic lymphohistiocytosis; Hyperinflammation; Myelodysplastic syndrome",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001853:Bone Marrow; D002898:Chromosomes, Human, Pair 8; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D059785:Karyotype; D051359:Lymphohistiocytosis, Hemophagocytic; D009190:Myelodysplastic Syndromes; D014314:Trisomy",
"nlm_unique_id": "101293382",
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"pubdate": "2021-03-01",
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"references": "27344947;26099018;25469675;17090657;27244347;21343581;20424188;27737891;28104796;29683949;20820970;26947179;29780114;27428748;26461149",
"title": "Hemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature.",
"title_normalized": "hemophagocytic lymphohistiocytosis and myelodysplastic syndrome a case report and review of the literature"
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"abstract": "OBJECTIVE\nWe describe a case of transient visual loss following cataract surgery with unpreserved intracameral lidocaine.\n\n\nMETHODS\nA 50-year-old man with posterior polar cataract underwent phacoemulsification. Following capsulorhexis and hydrodelineation with 0.5 cc of unpreserved lidocaine 1%, a portion of fluid reached behind the crystalline lens and caused the posterior capsule rupture. Cataract extraction and anterior vitrectomy were performed. Anesthetic administration was repeated to relieve the discomfort felt by the patient. A three-piece hydrophobic acrylic intraocular lens was implanted in the ciliary sulcus.\n\n\nRESULTS\nOn the first postoperative morning, the patient's vision was recorded as having no light perception. The relative afferent pupillary defect (RAPD) was found to be 4+. The retina and optic nerve head appeared normal. In the afternoon, the visual acuity (VA) was improved to 3-m count-finger. On the second postoperative morning, the patient's VA was improved to 4/10. On the third postoperative day, his VA returned to normal at 20/20 without RAPD.\n\n\nCONCLUSIONS\nIn the event of posterior capsular rupture, to reduce retinal toxicity risks, intracameral lidocaine should not be repeated.",
"affiliations": "Farabi Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Farabi Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Farabi Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Eshraghi|Bahram|B|;Katoozpour|Ramon|R|;Anvari|Pasha|P|",
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"doi": "10.1016/j.joco.2015.12.005",
"fulltext": "\n==== Front\nJ Curr OphthalmolJ Curr OphthalmolJournal of Current Ophthalmology2452-2325Elsevier S2452-2325(15)30028-710.1016/j.joco.2015.12.005ArticleTransient complete visual loss after intracameral anesthetic injection in cataract surgery Eshraghi Bahram Katoozpour Ramon Anvari Pasha panvari@razi.tums.ac.ir∗Farabi Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran∗ Corresponding author. Farabi Eye Research Center, Tehran University of Medical Sciences, Qazvin Square, Tehran, Iran. panvari@razi.tums.ac.ir05 2 2016 Sep-Dec 2015 05 2 2016 27 3-4 129 131 18 10 2015 28 12 2015 28 12 2015 Copyright © 2016, Iranian Society of Ophthalmology. Production and hosting by Elsevier B.V.2016Iranian Society of OphthalmologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nWe describe a case of transient visual loss following cataract surgery with unpreserved intracameral lidocaine.\n\nMethod\nA 50-year-old man with posterior polar cataract underwent phacoemulsification. Following capsulorhexis and hydrodelineation with 0.5 cc of unpreserved lidocaine 1%, a portion of fluid reached behind the crystalline lens and caused the posterior capsule rupture. Cataract extraction and anterior vitrectomy were performed. Anesthetic administration was repeated to relieve the discomfort felt by the patient. A three-piece hydrophobic acrylic intraocular lens was implanted in the ciliary sulcus.\n\nResults\nOn the first postoperative morning, the patient's vision was recorded as having no light perception. The relative afferent pupillary defect (RAPD) was found to be 4+. The retina and optic nerve head appeared normal. In the afternoon, the visual acuity (VA) was improved to 3-m count-finger. On the second postoperative morning, the patient's VA was improved to 4/10. On the third postoperative day, his VA returned to normal at 20/20 without RAPD.\n\nConclusion\nIn the event of posterior capsular rupture, to reduce retinal toxicity risks, intracameral lidocaine should not be repeated.\n\nKeywords\nIntracameral lidocaineRetinal toxicityAmaurosisVision loss\n==== Body\nIntroduction\nUsing unpreserved intracameral lidocaine as an adjunct anesthetic to topical anesthesia has become a widespread technique in cataract surgery. While safety and efficacy of intracameral lidocaine is well-documented, retinal toxic effects and transient visual loss caused by lidocaine have been suggested.\n\nWe report a case of transient, complete visual loss, following posterior polar cataract surgery with posterior capsular rupture.\n\nCase report\nA 50-year-old man presented to our clinic complaining of blurred vision for one year in his right eye. Preoperative best-corrected visual acuity was 10/20. Slit-lamp examination revealed a posterior polar cataract. His intraocular pressure and other ocular examinations including relative afferent pupillary defect (RAPD) were unremarkable. He was accordingly scheduled for phacoemulsification cataract surgery.\n\nA small-incision cataract surgery was performed under topical anesthesia and intracameral lidocaine. Following capsulorhexis and hydrodelineation with 0.5 cc-unpreserved lidocaine 1%, a portion of fluid reached behind the crystalline lens and caused the posterior capsule rupture.\n\nCataract extraction and anterior vitrectomy were performed. During the anterior vitrectomy procedure, the patient experienced an intense pain. This prompted us to repeat the anesthetic.\n\nAn additional 0.5 cc of lidocaine 1% was administered to relieve his discomfort. A three-piece hydrophobic acrylic (HOYA) – intraocular lens (IOL) was placed in the ciliary sulcus. At the conclusion of surgery, the eye was patched, and the patient was discharged.\n\nOn the first post-operative morning, the patient complained of not being able to see anything. His vision was recorded as having no light perception. The RAPD was found to be 4+. The fundus was examined under full pupillary dilation. The retina appeared normal, and the optic disc was not edematous. In the afternoon, the patient's visual acuity (VA) was improved to 3-m count-finger. On the second postoperative morning, the patient's VA was improved to 4/10. Vision assessment on the early morning of the third postoperative day was surprising. The patient's VA had improved to 20/20 without RAPD, and all other ocular examinations were normal.\n\nDiscussion\nThe preferred technique for cataract surgeons in the United States is topical anesthesia (37%; range 22–63%). In a survey conducted by David Learning,1 76% of respondents preferred using topical anesthesia with intracameral lidocaine injection. Intracameral unpreserved lidocaine augments analgesia and significantly decreases intraoperative pain perception. Lidocaine is a useful adjunct, particularly in cases involving pupillary manipulation and peripheral iridectomy.\n\nWhile lidocaine has been reported to be safe and effective,2, 3 temporary visual loss4, 5, 6 and retinal toxicity4, 6 following the use of intracameral lidocaine have been highlighted in recent reports. An increased possibility of adverse effects of lidocaine on the retina and optic nerve is introduced in the event of compromise to the posterior lens capsule.4\n\nOur patient had experienced transient visual loss while receiving intracameral lidocaine and had an associated posterior capsule rupture, which has an incidence of between 26% and 36% in posterior polar cataract surgeries.7, 8 Normally, during cataract surgery, the lens capsule, zonules, and vitreous humor have a barrier effect against instilled intracameral lidocaine, and hence, the retina will not be affected. Pars plana lensectomy and vitrectomy facilitate the diffusion of the lidocaine into the posterior chamber.4\n\nGills et al.9 reported amaurosis in four patients following the use of intracameral lidocaine, and in each case, the posterior capsule was not intact. All four patients recovered completely within hours. Hoffman and Fine4 reported on a patient with complete visual loss after intracameral lidocaine to repair a traumatic corneal graft dehiscence with a capsular tear, which was fully recovered several hours postoperatively. Falzon et al.10 reported a case of transient, complete loss of vision following phacoemulsification with an intracameral ophthalmic viscosurgical device (OVD) and lidocaine solution complicated by posterior capsule rupture, which improved to 20/80 after one day and 20/25 in one week.\n\nFull recovery of visual acuity in our patient required three days, in contrast to the majority of reports (Table 1) with capsular tear4, 9 that had complete VA improvements within hours. The longer time span in recovery of VA in our patient might be explained by a higher volume of lidocaine that was diffused in the vitreous.\n\nLincoff et al. reported three cases of inadvertent intravitreal lidocaine injections,6 all of which resulted in immediate decreased vision, with recovery occurring within four hours. Schechter5 reported a case of inadvertent intraocular lidocaine injection with an immediate visual acuity of NLP (no light perception) that improved to 20/40 after one day and to 20/20 in one week.\n\nToxicity of lidocaine to rodent retinal ganglion cells has been documented.11 Lidocaine affects the pigment transport in retinal cells of crayfish and frogs. This inhibition is probably due to an anesthetic-induced disruption of intercellular ionic balance and increased plasma membrane permeability. Furthermore, intravitreal injection of lidocaine has also been investigated in cats, rabbits, and rats.6, 12, 13 In these animal studies, the electroretinogram analyses revealed a reversible reduction in the amplitude and extinguished b-waves which fully recovered within 10–24 h. In cats, intravitreal injection of lidocaine has been followed with vacuolization of nerve layers and presence of microscopic lesions in synapses between horizontal, bipolar cells, and photoreceptors. In addition, histopathological retinal structure changes near the injection sites have been detected.\n\nOne limitation of our study is that the patient did not consent to perform the ERG and mfERG tests. However, in the presence of positive RAPD, normal retinal examination, and full recovery of vision, the most plausible cause of vision loss would be attributed to lidocaine retinal toxicity. In view of the above, when posterior capsular rupture occurs, it is wise not to repeat intracameral lidocaine to minimize potential retinal toxicity risks.\n\nFunding\nThe authors did not receive any financial support from any public or private sources. The authors have no financial or proprietary interest in a product, method, or material described herein.\n\nPeer review under responsibility of the Iranian Society of Ophthalmology.\n\nTable 1 Intraocular lidocaine injection recovery rates in different cases.\n\nAuthor\tProcedure\tConcentration\tRecovery\t\nSchechter (1985)\tInadvertent intraocular lidocaine injection\t–\tNLP\n1st day: 20/40\n1st week: 20/20 in 1\t\nLincoff et al. (1985)\tInadvertent intravitreal lidocaine injection in removal of a skin tumor\t0.5 cc of 2% lidocaine-epinephrine 1: 100,000\tCF in the inferior field and to NLP in the superior field recovery occurring in 4 h, 1st day: 20/20\t\nLincoff et al. (1985)\tInadvertent intravitreal lidocaine injection in retrobulbar injection prior to a scleral buckle procedure for a retinal detachment.\t0.3 cc lidocaine 2%-epinephrine 1: 100,000\tRecovered to 20/40.\t\nLincoff et al. (1985)\tInadvertent intraocular injection in obtaining akinesia prior to a cataract operation\tLidocaine 1.5%-epinephrine 1:200,000\tPermanent field defect\t\nHoffman and Fine (1997)\tIntracameral lidocaine in repairing corneal graft dehiscence\tLidocaine 4% topical drops and a 0.5 cc of intracameral nonpreserved lidocaine 1% l\tPostoperative NLP within hours CF\n1st day UCVA: 20/200\n1st week: 20/50\n1-month BCVA: 20/25\t\nFalzon et al (2009)\tIntracameral lidocaine in Phacoemulsification complicated by a posterior capsule rupture\tSodium hyaluronate 1.5%–lidocaine 1%, Visthesia\tNLP 6 h: CF\n1st day BCVA: 20/80\n1st week BCVA 20/25\t\nCurrent case\tIntracameral Anesthetic Injection in Cataract Surgery\t1 cc of unpreserved lidocaine 1%,\tNLP 1st day: 3 m CF\n2nd day 4/10\n3rd day: 20/20\t\nAbbreviations: NLP: no light perception, CF: counting finger, UCVA: uncorrected visual acuity, BCVA: best-corrected visual acuity.\n==== Refs\nReferences\n1 Learning D.V. Practice styles and preferences of ASCRS members—1998 survey J Cataract Refract Surg 25 1999 851 859 10374168 \n2 Gills J.P. Williams D.L. Advantage of marcaine for topical anesthesia [letter] J Cataract Refract Surg 19 1993 819 8271192 \n3 Martin R.G. Miller J.D. Cox C.C. III Safety and efficacy of intracameral injections of unpreserved lidocaine to reduce intraocular sensation J Cataract Refract Surg 24 1998 961 963 9682118 \n4 Hoffman R.S. Fine I.H. Transient no light perception visual acuity after intracameral lidocaine injection J Cataract Refract Surg 23 1997 957 958 9292686 \n5 Schechter R.J. Management of inadvertent intraocular injections Ann Ophthalmol 17 1985 771 775 4091378 \n6 Lincoff H. Zweifach P. Brodie S. Intraocular injection of lidocaine Ophthalmology 92 1985 1587 1591 4080331 \n7 Osher R.H. Yu B.C.-Y. Koch D.D. Posterior polar cataracts: a predisposition to intraoperative posterior capsule rupture J Cataract Refract Surg 16 1990 157 162 2329471 \n8 Vasavada A.R. Singh R. Phacoemulsification in posterior polar developmental cataracts Lu L.W. Fine I.H. Phacoemulsification in Difficult and Challenging Cases. New York, NY, Thieme 1999 121 128 \n9 Gills J.P. Johnson D.E. Cherchio M. Raanan M.G. Intraocular anesthesia Davis D.B. Mandel M.R. Ophthalmology Clinics of North America vol. 11 1998 65 71 \n10 Falzon K. Guerin Marc B. Tim F. Transient, complete loss of vision secondary to posterior diffusion of an ophthalmic viscosurgical device–lidocaine solution during complicated phacoemulsification J Cataract Refract Surg 35 2009 1472 1473 19631139 \n11 Grosskreutz C.L. Katowitz W.R. Freeman E.E. Dreyer E.B. Lidocaine toxicity to rat retinal ganglion cells Curr Eye Res 18 5 1999 363 367 10372998 \n12 Stangos N. Rey P. Leuenberger P. Korol S. The effect of xylocaine injections on the rebbit's retina: averaged ERG and electronmicroscopy Vis Res 11 1971 1208 1209 5156810 \n13 Liang Chanping Peyman Gholam A. Sun Guang Toxicity of intraocular lidocaine and bupivacaine Am J Ophthalmol 125.2 1998 191 196 9467446\n\n",
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"issue": "27(3-4)",
"journal": "Journal of current ophthalmology",
"keywords": "Amaurosis; Intracameral lidocaine; Retinal toxicity; Vision loss",
"medline_ta": "J Curr Ophthalmol",
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"references": "8271192;19631139;5156810;4091378;4080331;10372998;10374168;9682118;9467446;9292686;2329471",
"title": "Transient complete visual loss after intracameral anesthetic injection in cataract surgery.",
"title_normalized": "transient complete visual loss after intracameral anesthetic injection in cataract surgery"
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"abstract": "BACKGROUND\nChemotherapeutic agents of direct cell damage play a role in initiating thrombotic microangiopathy (TMA), however still being underdiagnosed. Decitabine (DAC) is a pyrimidine analogue of the nucleoside cytidine, which can lead to injury to endothelium. Biopsy-proven DAC-induced kidney injury is rare.\nA 47-year-old Chinese man with membranous nephropathy presented recurrent edema and acute kidney injury after a 3-day course of low dose DAC infusion because of cyclophosphamide-relating thrombocytopenia.\n\n\nMETHODS\nLaboratory data revealed nephrotic syndrome, hematuria, renal glycosuria and hypokalemia with hyperchloridemia. Renal pathological findings revealed TMA with secondary glomerular crescents formation (28%), partial foot process effacement and acute tubular necrosis. A diagnosis of DAC-induced renal TMA was considered.\n\n\nMETHODS\nAs DAC had been timely discontinued before admission, the patient only received supportive treatment.\n\n\nRESULTS\nThe patient achieved rapid remission of acute kidney injury after DAC withdrawal, and his serum creatinine further decreased to normal level after 6 months.\n\n\nCONCLUSIONS\nCareful monitoring of renal function especially serum creatinine should be emphasized during DAC treatment.",
"affiliations": "Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.",
"authors": "Qin|Ai-Bo|AB|0000-0002-3502-9829;Tan|Ying|Y|;Su|Tao|T|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D000077209:Decitabine; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000022901",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-03697\n10.1097/MD.0000000000022901\n22901\n5200\nResearch Article\nClinical Case Report\nDecitabine-induced kidney thrombotic microangiopathy with glomerular crescents formation and tubular necrosis\nA case reporthttp://orcid.org/0000-0002-3502-9829Qin Ai-bo MD Tan Ying MD, PhD Su Tao MD∗ Saranathan. Maya Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.\n∗ Correspondence: Tao Su, Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing 100034, China (e-mail: tao.su@bjmu.edu.cn).\n23 10 2020 \n23 10 2020 \n99 43 e2290122 4 2020 24 8 2020 25 9 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nChemotherapeutic agents of direct cell damage play a role in initiating thrombotic microangiopathy (TMA), however still being underdiagnosed. Decitabine (DAC) is a pyrimidine analogue of the nucleoside cytidine, which can lead to injury to endothelium. Biopsy-proven DAC-induced kidney injury is rare.\n\nPatient concerns:\nA 47-year-old Chinese man with membranous nephropathy presented recurrent edema and acute kidney injury after a 3-day course of low dose DAC infusion because of cyclophosphamide-relating thrombocytopenia.\n\nDiagnosis:\nLaboratory data revealed nephrotic syndrome, hematuria, renal glycosuria and hypokalemia with hyperchloridemia. Renal pathological findings revealed TMA with secondary glomerular crescents formation (28%), partial foot process effacement and acute tubular necrosis. A diagnosis of DAC-induced renal TMA was considered.\n\nInterventions:\nAs DAC had been timely discontinued before admission, the patient only received supportive treatment.\n\nOutcomes:\nThe patient achieved rapid remission of acute kidney injury after DAC withdrawal, and his serum creatinine further decreased to normal level after 6 months.\n\nConclusion:\nCareful monitoring of renal function especially serum creatinine should be emphasized during DAC treatment.\n\nKeywords\ndecitabinethrombotic microangiopathycrescent formationtubular necrosisNational Science and Technology Major Projects for major new drugs innovation and development2017ZX09304028Tao SuOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThrombotic microangiopathy (TMA) is a group of critical syndromes with specific pathologic features showing arteriolar or capillary damage, characterized by microvascular thrombosis occlusion, microangiopathic hemolytic anemia, thrombocytopenia and target-organ dysfunction (ie, acute kidney injury, [AKI]). Among various secondary causes, drug-induced etiology is an important one, which is considered to play a pathogenetic role in initiating TMA. There are many drugs that are associated with TMA, such as chemotherapy drugs, quinine, cyclosporine, tacrolimus, and antibiotics.[1] These identified chemotherapy drugs include mitomycin C, gemcitabine, platinum salts and pegylated liposomal doxorubicin.[2] However, there is sometimes neither thrombocytopenia nor hemolytic anemia in kidney TMA. This may not be proved until kidney biopsies are performed. Glomerular crescents formation happens to be observed in TMA cases.[3]\n\nDecitabine (5-aza 2′-deoxycytidine, DAC) is a pyrimidine analogue of the nucleoside cytidine.[4] As a potent DNA demethylating agent, DAC produces cytotoxicity by inhibiting DNA methylation in rapidly dividing cells and has effect to control myelodysplastic syndromes, acute or chronic myelogenous leukemia.[5–9] At low doses, DAC could promote megakaryocyte maturation and platelet (PLT) production in immune thrombocytopenia.[10] Clinical trials have reported good tolerance. Herein, we report a rare case of kidney TMA with crescents and tubular necrosis induced by DAC in a preceding membranous nephropathy (MN) patient.\n\n2 Case presentation\nA 47-year-old man complained of aggravated edema for 10 days’ duration. He had a history of nephrotic syndrome for almost 2 years by supportive therapy until 4 months ago when he was diagnosed with typical MN at a local hospital. The patient was administered oral prednisone 60 mg/d initially combined with intravenous cyclophosphamide (CTX) 0.8 g every 2 weeks until 6 weeks ago when he happened to notice petechiae on his body. The treatment of CTX was discontinued (the accumulated dose of CTX was nearly 5.0 g). Although no alternative agent was utilized after the discontinuation of CTX, his urine protein decreased from a baseline 12.7 g/d to 2.7 g/d and he achieved partial remission. On examination, his blood pressure was 140/85 mmHg. Laboratory data showed normal white blood cell and hemoglobin, the PLT count was 60 × 103/μL and it dropped to 10 × 103/μL 2 weeks later, but the hemoglobin level remained at 12.2 g/dl. Impaired megakaryocyte maturation and PLT production were observed in bone marrow smear. The patient was suspected of immune thrombocytopenic purpura. He undertook once PLT transfusion and was injected a low-dose DAC at 10 mg per day for 3 days. No diarrhea occurred. However, the patient complained recurrent edema with an almost 15 kg weight gain the following 10 days, meanwhile, his serum creatinine (SCr) level was elevated from a baseline 89 μmol/L to 392 μmol/L, but the PLT count returned to 69 × 103/μL (Fig. 2).\n\nThe patient was admitted for investigation and treatment to Peking University First Hospital. On admission, the physical examination revealed a blood pressure of 168/105 mmHg. He had a “moon face” and severe anasarca. Laboratory data collected at the time of admission showed SCr level was spontaneously declined to 256 μmol/L, with an increase of PLT count to 194 × 103/μL. Serum LDH was 460 IU/mL, Coombs’ test was negative and no schistocytes were detected. Urine protein was 11.9 g/d, sediments red blood cells were 8-10/HP. Anti-phospholipase A2 receptor (PLA2R) antibody was 107 RU/mL (<20 RU/mL). Complement 3 (C3), C4, and factor H concentrations were in normal range. Anti-factor H, anti-glomerular basement membrane (GBM) and anti-neutrophil cytoplasmic antibodies were negative. No monoclonal immunoglobulin was detected from serum and urine by immune fixation electrophoresis. As shown in Table 1, hypokalemia with hyperchloremia, hypouricemia and renal glycosuria (serum glucose was 4.75 mmol/L) suggested tubular injury. No sign of renal venous thrombosis was found by ultrasound examination. Taken together, a diagnosis of new-onset AKI with hematuria after DAC exposure, superimposed on a pre-existing but non-remission MN could be made. The occurrence of severe thrombocytopenia is considered CTX-relating adverse reaction, because thrombocytopenia happened 4 weeks prior to the increase of SCr, and started recovery around 4 weeks after CTX withdrawal (Fig. 2).\n\nTable 1 Laboratory data on admission.\n\nThe patient underwent a repeat renal biopsy. Biopsy sample included 50 glomeruli and 7 of them showed ischaemic sclerosis. All the glomeruli demonstrated an MN pattern as diffuse GBM thickening with subepithelial immune complex deposits, and foot process effacement (Fig. 1A and D). Twelve glomeruli (28% of total) showed involvement by crescents, including 6 cellular and 6 fibro-cellular crescents (Fig. 1A). No fibrinoid necrosis was found. Immunofluorescence staining revealed granular-like deposit along the GBM as IgG (3+), C3 (3+), PLA2R (2+), IgA (-), IgM (-). One arteriole showed obvious segmental expansion of subendothelial zone and myxoid edema with narrowed vascular lumen, but glomerular capillaries remained intact (Fig. 1B). Tubular epithelial cells presented severe vacuolization and granular degeneration, several naked renal tubules with detached epithelial cell fragments, and mildly infiltrated lymphoplasmacytes in the interstitium (Fig. 1C). No dense deposit was observed in mesangial region under electronic microscope.\n\nFigure 1 Findings on Kidney biopsy. (A) A glomerulus showing extracapillary cellular crescent on the basis of diffusely thickened glomerular basement membrane (PASM + Masson staining, ×200). (B) One involved arteriole showing obvious expansion of subendothelial zone and myxoid edema with narrowed vascular lumen (PASM + Masson staining, ×400). (C) Vacuolization and granular degeneration of tubular epithelial cells, naked renal tubules, and mildly infiltrated lymphoplasmacytes in the interstitium (Hematoxylin-Eosin staining, ×200). (D) A large amount of electron density deposits and foot process effacement (Electron microscopy, ×8000).\n\nAs DAC had already been discontinued before admission, the patient's renal function got a further recovery (Fig. 2). Three weeks later when he was dismissed, the SCr was 157 μmol/L. And the SCr was finally maintained at 115 to 134 μmol/L the following 6 months. The patient was given another course of prednisone and oral CTX at 25 mg/d for the treatment of MN. No thrombocytopenia relapsed. The final diagnosis was DAC-induced TMA with glomerular crescents and tubular necrosis superimposed on pre-existing anti-PLA2R related MN.\n\nFigure 2 The change of serum creatinine and platelet count during the course of the disease. PLT = platelet; Scr = serum creatinine.\n\n3 Discussion\nTMA is a disease with special histopathological characteristics involving glomeruli and/or arterial endocapillary cell proliferation and swelling. It could be triggered by drugs, infections and systemic diseases. Typical presentation is the presence of microangiopathic hemolysis anemia, thrombocytopenic purpura, renal and neurological abnormalities. However, diagnosis of TMA may sometimes be delayed or misdiagnosed, because drug-induced bone marrow depression is usually firstly suspected. Sometimes in case of kidney TMA, thrombocytopenia and hemolytic anemia can be transient or even absent. The progressive kidney failure, new or exacerbated hypertension are valuable clues.[2] Vascular damage manifested by arteriolar or glomerular capillary thrombosis with endothelium and vessel wall injuries are definite pathological findings of TMA. Here we reported a case of renal TMA with crescents formation and tubular necrosis induced by DAC. Despite of no obvious presentation of systemic TMA, pathological findings provided more helpful information. In the absence of common causes leading to TMA such as diarrhea and infection, the DAC was identified the culprit. Toxic effect of DAC on renal tubular epithelial cells also contributed to the occurrence of AKI.\n\nChemotherapeutic agents serve as one major cause of TMA but still being underdiagnosed. Vascular injury showing TMA as a result is reported with increasing frequency, because all the chemo-therapeutic drugs have direct cell damage to endothelial cells. DAC is a deoxycytidine analogue as an antineoplastic agent. Its antineoplastic efficacy comes from 2 distinct mechanisms: cytotoxicity and induction of hypomethylation. DAC was approved in 2006 for high-risk myelodysplastic syndromes of all French-American-British subtypes.[5] In recent years, the treatment of immune thrombocytopenia with low-dose of DAC has been studied in some centers.[10] Nephrotoxicity of DAC is mild, rare and dose-dependent overall. In phase II clinical trials, DAC can lead to direct injury to endothelium. There have been 3 clinical trials describing an increase of serum creatinine in several patients (3/21, 5/50 and 1/66, respectively).[7–9] Only 1 trial detailed the information of DAC associated kidney injury in 3 elder patients.[7] The SCr was 97-115 μmol/L before DAC infusion, and increased by 41.7%, 63.6%, 46.2% respectively within 3 weeks after therapy at the dose of 30, 75, 100 mg/m2. Among them, the renal function of 1 patient improved rapidly 1 week after drug withdrawal, while for another patient who was treated with a second course of DAC resulting in a further increase of SCr, and a delayed recovery to 4 months after drug withdrawal. This patient was finally reported a biopsy-proven acute tubulointerstitial nephritis. Here in the current study, we reported a special case of DAC associated AKI as renal TMA, crescents formation and tubular necrosis, however the remission of renal function after withdrawal was relatively satisfactory. At present, most of the DAC-based chemotherapy regimens are given every 3-6 weeks. And as described above, mild kidney injury recovered quickly, so it is reasonable to measure SCr within 1 week after DAC infusion and prior to the start of next chemotherapy. In patients with underlying kidney disease, Scr and urine test should both be monitored.\n\nThe prevalence of crescents formation in MN is rare. In a cohort published recently, 12 of these 15 patients diagnosed with MN and necrotizing crescentic glomerulonephritis, were associated with anti-neutrophil cytoplasmic antibody and anti-GBM antibodies.[11] Rodriguez EF et al reported that in all antibodies-negative MN patients, average 25% (range, 2%-73%) were involvement with crescents.[12] Crescents could also be induced by TMA. The reported prevalence is around 5.6%, average 26% of glomeruli. The frequency is similar as that we reported in the current patient. Crescent formation was speculated to be induced by endocapillary hypercellularity in response to severe injury to the glomerular capillary or arteriole wall, indicating worse long-term prognosis.\n\nIt is well-known that there is almost 50% of TMA patients with genes mutations coding different components of complement cascade. Patients carrying specific human leukocyte antigen (HLA) alleles such as HLA-DRB1∗11 were associated with TMA and affecting clinical outcome.[13] MN is also recognized as a disease having genetic predisposition. HLA alleles DRB1 ∗1501 DRB1 ∗0301 are independent risk alleles, and DRB1 ∗1502 indicates worse renal outcome of MN.[14] Thus, it is supposed that toxic drugs act as the initiating event of TMA in patients predisposed by genetic defects in the complement cascade with high-risk HLA alleles.\n\nTo conclude, we reported a case of DAC-induced TMA with crescents formation and tubular necrosis. The patient achieved rapid remission of TMA after immediate discontinuation of the offending drug. It is worthy of careful monitoring of renal function during DAC treatment.\n\nAuthor Contributions\nApproval of final manuscript: all authors.\n\nConceptualization: Tao Su and Ying Tan.\n\nData curation: Ai-bo Qin.\n\nValidation: Tao Su\n\nWriting – original draft preparation: Ai-bo Qin.\n\nWriting – review & editing: Tao Su and Ying Tan.\n\nAbbreviations: AKI = acute kidney injury, CTX = cyclophosphamide, DAC = Decitabine, GBM = glomerular basement membrane, MN = membranous nephropathy, PLT = platelet, Scr = serum creatinine, TMA = thrombotic microangiopathy.\n\nHow to cite this article: Qin Ab, Tan Y, Su T. Decitabine-induced kidney thrombotic microangiopathy with glomerular crescents formation and tubular necrosis: a case report. Medicine. 2020;99:43(e22901).\n\nThis work was supported by the National Science and Technology Major Projects for major new drugs innovation and development under Grant 2017ZX09304028.\n\nThe study was performed in compliance with the Declaration of Helsinki and approved by the Ethics Committee of Peking University First Hospital. Written informed consent was obtained from the patient for publication of the case report and any accompanying images.\n\nThe authors have no conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files\n==== Refs\nReferences\n[1] Al-Nouri ZL Reese JA Terrell DR \nDrug-induced thrombotic microangiopathy: a systematic review of published reports\n. Blood \n2015 ;125 :616 –8\n.25414441 \n[2] Izzedine H Perazella MA \nThrombotic microangiopathy, cancer, and cancer drugs\n. American journal of kidney diseases: the official journal of the National Kidney Foundation \n2015 ;66 :857 –68\n.25943718 \n[3] Singh N McNeely J Parikh S \nKidney complications of hematopoietic stem cell transplantation\n. Am J Kidney Dis \n2013 ;61 :809 –21\n.23291149 \n[4] Sorm F Piskala A Cihak A \n5-Azacytidine, a new, highly effective cancerostatic\n. Experientia \n1964 ;20 :202 –3\n.\n[5] Kantarjian H Issa JP Rosenfeld CS \nDecitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study\n. Cancer \n2006 ;106 :1794 –803\n.16532500 \n[6] Santini V Allione B Zini G \nA phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia\n. Leukemia \n2018 ;32 :413 –8\n.28607470 \n[7] van Groeningen CJ Leyva A O’Brien AM \nPhase I and pharmacokinetic study of 5-aza-2’-deoxycytidine (NSC 127716) in cancer patients\n. Cancer Res \n1986 ;46 :4831 –6\n.2425959 \n[8] Issa JP Garcia-Manero G Giles FJ \nPhase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic malignancies\n. Blood \n2004 ;103 :1635 –40\n.14604977 \n[9] Wijermans P Lubbert M Verhoef G \nLow-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients\n. J Clin Oncol \n2000 ;18 :956 –62\n.10694544 \n[10] Zhou H Hou Y Liu X \nLow-dose decitabine promotes megakaryocyte maturation and platelet production in healthy controls and immune thrombocytopenia\n. Thromb Haemost \n2015 ;113 :1021 –34\n.25566808 \n[11] Nikolopoulou A Huang-Doran I McAdoo SP \nMembranous glomerulonephritis with crescents\n. Kidney Int Rep \n2019 ;4 :1577 –84\n.31890999 \n[12] Rodriguez EF Nasr SH Larsen CP \nMembranous nephropathy with crescents: a series of 19 cases\n. Am J Kidney Dis \n2014 ;64 :66 –73\n.24709471 \n[13] Balassa K Andrikovics H Remenyi P \nThe potential role of HLA-DRB1∗11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy\n. Blood Marrow Transplant \n2015 ;50 :1321 –5\n.\n[14] Wang HY Cui Z Xie LJ \nHLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy\n. Kidney Int \n2018 ;94 :974 –82\n.30173899\n\n",
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"journal": "Medicine",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D058186:Acute Kidney Injury; D000964:Antimetabolites, Antineoplastic; D000072700:Conservative Treatment; D003520:Cyclophosphamide; D000077209:Decitabine; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007678:Kidney Glomerulus; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome; D013921:Thrombocytopenia; D057049:Thrombotic Microangiopathies; D028761:Withholding Treatment",
"nlm_unique_id": "2985248R",
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"pages": "e22901",
"pmc": null,
"pmid": "33120841",
"pubdate": "2020-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Decitabine-induced kidney thrombotic microangiopathy with glomerular crescents formation and tubular necrosis: A case report.",
"title_normalized": "decitabine induced kidney thrombotic microangiopathy with glomerular crescents formation and tubular necrosis a case report"
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"abstract": "BACKGROUND\nIn the last decade immune checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017 the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability (MSI), regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden (TMB), likewise benefit from immune checkpoint therapy.\n\n\nMETHODS\nHere we present two cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab.\n\n\nCONCLUSIONS\nColorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype especially in patients that are refractory to standard chemotherapy.",
"affiliations": null,
"authors": "Schenck|Kristina|K|;Masetti|Michael|M|;Pfarr|Nicole|N|;Lorenzen|Sylvie|S|",
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"title": "PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation.",
"title_normalized": "pd 1 blockade elicits ongoing remission in two cases of refractory microsatellite stable cancer harboring a pole mutation"
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"abstract": "OBJECTIVE\nAlthough acellular porcine corneal stroma (APCS) is a promising alternative to the human donor cornea for lamellar keratoplasty, here, we report 2 patients who exhibited persistent epithelial defects and sterile keratolysis after APCS transplantation to treat peripheral corneal diseases.\n\n\nMETHODS\nTwo patients with different peripheral corneal diseases underwent lamellar keratoplasty by using D-shaped lamellar APCS as graft materials. Standard keratoplasty postoperative treatments, including topical antibiotic-corticosteroid, tacrolimus, and artificial tears, were applied.\n\n\nRESULTS\nPatient 1 was a 7-year-old boy with limbal dermoid, and patient 2 was a 50-year-old man suffered from simultaneous Mooren ulcer with pterygium. Both patients developed persistent graft epithelial defects postoperatively, which were refractory to conventional nonsurgical therapies. The APCS grafts were noted to start sterile keratolysis at approximately 1 month after implantation and were completely dissolved within 3 months, leaving vascularized scars in the previously grafted area.\n\n\nCONCLUSIONS\nThese 2 cases demonstrated that given the high risk of postoperative persistent epithelial defect and sterile keratolysis, the application of APCS in peripheral keratoplasty may need further evaluation.",
"affiliations": "State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.",
"authors": "Li|Saiqun|S|;Xiao|Peng|P|;Deng|Yuqing|Y|;Li|Meng|M|;Wang|Qian|Q|;Yuan|Jin|J|",
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"mesh_terms": "D002648:Child; D002828:Choristoma; D003316:Corneal Diseases; D003319:Corneal Stroma; D016039:Corneal Transplantation; D003320:Corneal Ulcer; D019573:Epithelium, Corneal; D006130:Growth Disorders; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D014183:Transplantation, Heterologous",
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"title": "Acellular Porcine Corneal Stroma May Not Be Optimal for Peripheral Keratoplasty: Reports of 2 Cases.",
"title_normalized": "acellular porcine corneal stroma may not be optimal for peripheral keratoplasty reports of 2 cases"
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"abstract": "Owing to the drug's favorable hydrophilic and pharmacokinetic characteristics, a number of case reports have demonstrated effective treatment of atenolol overdose with hemodialysis. However, the efficiency of atenolol clearance throughout hemodialysis treatments has not previously been examined. In this report, a patient with impaired renal function was successfully treated with two 5-hour intermittent high-flux high-efficiency hemodialysis therapies after atenolol overdose. Serial atenolol levels were measured during his hemodialysis treatments. We observed an over 50% plasma atenolol concentration reduction after each 5-hour hemodialysis therapy. Hemodialysis therapy is an effective treatment for atenolol overdose, especially in patients with impaired renal function.",
"affiliations": "Department of Medicine, London Health Sciences Centre, Nephrology Division, Western University, London, Canada.",
"authors": "Huang|Shih-Han S|SH|;Tirona|Rommel G|RG|;Ross|Cameron|C|;Suri|Rita S|RS|",
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"keywords": "Hemodialysis; atenolol; drug intoxication; overdose",
"medline_ta": "Hemodial Int",
"mesh_terms": "D001262:Atenolol; D062787:Drug Overdose; D006801:Humans; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D051437:Renal Insufficiency",
"nlm_unique_id": "101093910",
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"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: atenolol overdose successfully treated with hemodialysis.",
"title_normalized": "case report atenolol overdose successfully treated with hemodialysis"
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"activesubstancename": "LAMOTRIGINE"
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... |
{
"abstract": "Purpose To develop and validate a predictive model for postembolization syndrome (PES) following transarterial hepatic chemoembolization (TACE) for hepatocellular carcinoma. Materials and Methods In this single-center, retrospective study, 370 patients underwent 513 TACE procedures between October 2014 and September 2016. Seventy percent of the patients were randomly assigned to a training data set and the remaining 30% were assigned to a testing data set. Variables included demographic, laboratory, clinical, and procedural details. PES was defined as pain and/or nausea beyond 6 hours after TACE that required intravenous medication for symptom control. The predictive model was developed by using conditional inference trees and Lasso regression. Results Demographics, laboratory data, performance, tumor characteristics, and procedural details were statistically similar for the training and testing data sets. Overall, 83 of 370 patients (22.4%) after 107 of 513 TACE procedures (20.8%) met the predefined criteria. Factors identified at univariable analysis included large tumor burden (P = .004), drug-eluting embolic TACE (P = .03), doxorubicin dose (P = .003), history of PES (P < .001) and chronic pain (P < .001), of which history of PES, tumor burden, and drug-eluting embolic TACE were identified as the strongest predictors by the multivariable analysis and were used to develop the predictive model. When applied to the testing data set, the model demonstrated an area under the curve of 0.62, sensitivity of 79% (22 of 28), specificity of 44.2% (53 of 120), and a negative predictive value of 90% (53 of 59). Conclusion The model identified history of postembolization syndrome, tumor burden, and drug-eluting embolic chemoembolization as predictors of protracted recovery because of postembolization syndrome. © RSNA, 2018.",
"affiliations": "From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).;From the Division of Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Room H3630, Stanford, CA 94305-5642 (M.H.K., M.A.A.M., R.S., A.K., K.J., N.K.); and Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, Calif (V.S., M.D.).",
"authors": "Khalaf|Mohamed H|MH|0000-0002-3323-2698;Sundaram|Vandana|V|;AbdelRazek Mohammed|Mohammed Ahmed|MA|;Shah|Rajesh|R|;Khosla|Ankaj|A|;Jackson|Katherine|K|;Desai|Manisha|M|;Kothary|Nishita|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1148/radiol.2018180257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8419",
"issue": "290(1)",
"journal": "Radiology",
"keywords": null,
"medline_ta": "Radiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012189:Retrospective Studies; D013577:Syndrome",
"nlm_unique_id": "0401260",
"other_id": null,
"pages": "254-261",
"pmc": null,
"pmid": "30299233",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "A Predictive Model for Postembolization Syndrome after Transarterial Hepatic Chemoembolization of Hepatocellular Carcinoma.",
"title_normalized": "a predictive model for postembolization syndrome after transarterial hepatic chemoembolization of hepatocellular carcinoma"
} | [
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"abstract": "BACKGROUND\nA 59-year-old man with a 7-year history of Parkinson disease (PD) presented with episodes of sudden, severe headaches with neck pain, tachycardia, sweating and pallor. During these episodes, the patient showed marked elevations in blood pressure, regardless of posture. This was unusual, given that he had no prior history of hypertension. The array of symptoms raised suspicions of pheochromocytoma, but diagnosis was challenging, as the standard diagnostic biochemical tests were confounded by dopaminergic medications. Further work-up revealed left adrenal medullary hyperplasia. Several reports exist of pseudopheochromocytoma in patients on dopaminergic therapy, but this is the first documented case of pheochromocytoma syndrome due to adrenal medullary hyperplasia in a patient with PD. This case highlights the challenges of performing a diagnostic work-up in a PD patient with symptoms suggestive of pheochromocytoma, and illustrates the utility of (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission CT in making a diagnosis.Investigations. Physical examination, laboratory tests, abdominal MRI scan, abdominal (123)I-MIBG scan, abdominal (18)F-fluorodeoxyglucose PET scan.\n\n\nMETHODS\nPheochromocytoma syndrome due to adrenal medullary hyperplasia.Management. Surgical excision of the left adrenal gland.",
"affiliations": "Movement Disorders Program, Department of Neurology, Medical College of Georgia, 1429 Harper Street, Augusta, GA 30912, USA. shmehta@mcg.edu",
"authors": "Mehta|Shyamal H|SH|;Prakash|Rajan|R|;Prisant|L Michael|LM|;Isales|Carlos M|CM|;Morgan|John C|JC|;Williams|Hadyn|H|;Sethi|Kapil D|KD|",
"chemical_list": "D002395:Catecholamines; D019797:3-Iodobenzylguanidine",
"country": "England",
"delete": false,
"doi": "10.1038/nrneurol.2009.55",
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"issn_linking": "1759-4758",
"issue": "5(6)",
"journal": "Nature reviews. Neurology",
"keywords": null,
"medline_ta": "Nat Rev Neurol",
"mesh_terms": "D019797:3-Iodobenzylguanidine; D000310:Adrenal Gland Neoplasms; D002395:Catecholamines; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D010673:Pheochromocytoma; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "101500072",
"other_id": null,
"pages": "343-7",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11903030;18249320;7740240;18815650;7109836;15912041;12889078;15378121;11794715;16918946;8740342;3404174;17594783;14764749;11499649;1495678;9425401;7889639;16112304",
"title": "Diagnosis of pheochromocytoma in the setting of Parkinson disease.",
"title_normalized": "diagnosis of pheochromocytoma in the setting of parkinson disease"
} | [
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"companynumb": "US-IMPAX LABORATORIES, INC-2018-IPXL-02086",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SELEGILINE"
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"abstract": "A possible case of sprue-like enteropathy (SLE) induced by the use of telmisartan is reported. Telmisartan is an angiotensin-receptor II blocker (type 1) used for the treatment of hypertension. Several cases of SLE associated with olmesartan and other drugs of the same group have been reported. In all cases, SLE resolved following therapy withdrawal. We describe the case of an 80-year-old woman who presented with diarrhoea and abdominal pain. In the past 5 years she had been treated with telmisartan 40 mg once a day for hypertension, so we hypothesised that symptoms might be caused by telmisartan. After treatment discontinuation, diarrhoea disappeared. Three causality algorithms were applied and revealed a possible or likely causal relationship. At present, the patient remains asymptomatic. There is a causal relationship between the use of telmisartan and SLE. This association should be taken into account by physicians when prescribing and reviewing drug therapies.",
"affiliations": "Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.;Servicio Navarro de Salud - Osasunbidea, Pamplona, Spain.",
"authors": "Alzueta|Natalia|N|;Echeverría|Amaya|A|;Sanz|Lorea|L|;Fontela|Carmen|C|;Acín|Teresa|T|;Montenegro|Lidia|L|;Garjón|Javier|J|",
"chemical_list": "D000959:Antihypertensive Agents; D000077333:Telmisartan",
"country": "England",
"delete": false,
"doi": "10.1136/ejhpharm-2018-001669",
"fulltext": null,
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"issn_linking": "2047-9956",
"issue": "27(1)",
"journal": "European journal of hospital pharmacy : science and practice",
"keywords": "adverse event; angiotensin-receptor Ii blocker; diarrhea; sprue-like enteropathy; telmisartan",
"medline_ta": "Eur J Hosp Pharm",
"mesh_terms": "D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D002446:Celiac Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension; D000077333:Telmisartan",
"nlm_unique_id": "101578294",
"other_id": null,
"pages": "49-51",
"pmc": null,
"pmid": "32064089",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24187471;22728033;24805127;837643;25103353;25199794;7249508;28670240;25103354;29163738;28291561",
"title": "Telmisartan-induced sprue-like enteropathy: a case report.",
"title_normalized": "telmisartan induced sprue like enteropathy a case report"
} | [
{
"companynumb": "ES-PRINSTON PHARMACEUTICAL INC.-2018PRN01485",
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"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
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{
"abstract": "A 64-year-old man undergoing abdominal aortic aneurysm repair with no history of diabetes mellitus had an episode of marked hyperglycemia during surgery. The peak concentration of glucose in plasma was 43.2 mmol/L. This hyperglycemia responded immediately to administration of 30 units of regular insulin. Factors involved in the hyperglycemia included surgical stress, multiple medications, and the anesthetic used (isoflurane), but do not fully account for the magnitude of the increase in glucose. The data suggest that the patient may have had an underlying insulin deficiency, which was unmasked by the stress of surgery.",
"affiliations": "Department of Pathology, University of North Carolina, Chapel Hill 27599.",
"authors": "Ellison|D A|DA|;Forman|D T|DT|",
"chemical_list": "D001786:Blood Glucose",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "0009-9147",
"issue": "36(5)",
"journal": "Clinical chemistry",
"keywords": null,
"medline_ta": "Clin Chem",
"mesh_terms": "D000368:Aged; D001012:Aorta, Abdominal; D001786:Blood Glucose; D006801:Humans; D006943:Hyperglycemia; D007431:Intraoperative Complications; D008297:Male",
"nlm_unique_id": "9421549",
"other_id": null,
"pages": "815-7",
"pmc": null,
"pmid": "2337999",
"pubdate": "1990-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient hyperglycemia during abdominal aortic surgery.",
"title_normalized": "transient hyperglycemia during abdominal aortic surgery"
} | [
{
"companynumb": "US-BAXTER-2021BAX017642",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOFLURANE"
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... |
{
"abstract": "Lamin A/C cardiac disease is a genetic cardiomyopathy and arrhythmia syndrome caused by alterations in the function of the nuclear lamin A and C proteins. It is inherited in an autosomal dominant manner and usually presents in mid- to late adulthood with atrioventricular conduction abnormalities, atrial and ventricular arrhythmias, biventricular dysfunction, and advanced heart failure. While rare, women of childbearing age can exhibit an aggressive disease course, and appropriate risk stratification and management are critical. Here, we present a case of newly diagnosed lamin A/C cardiac disease in a pregnant woman.",
"affiliations": "Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Maternal and Child Health Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Cardiac Electrophysiology Section, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Reza|Nosheen|N|https://orcid.org/0000-0002-2942-3731;Chowns|Jessica L|JL|;Marzolf|Amy|A|;Kim|Jessica|J|;Levine|Lisa D|LD|https://orcid.org/0000-0002-6811-7980;Supple|Gregory|G|;Owens|Anjali Tiku|AT|https://orcid.org/0000-0002-9669-8495",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/3512706",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2019/3512706Case ReportAntepartum Diagnosis and Management of Lamin A/C Disease https://orcid.org/0000-0002-2942-3731Reza Nosheen nosheen.reza@pennmedicine.upenn.edu\n1\nChowns Jessica L. \n1\nMarzolf Amy \n1\nKim Jessica \n1\nhttps://orcid.org/0000-0002-6811-7980Levine Lisa D. \n2\nSupple Gregory \n3\nhttps://orcid.org/0000-0002-9669-8495Owens Anjali Tiku \n1\n\n1Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA\n2Maternal and Child Health Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA\n3Cardiac Electrophysiology Section, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAAcademic Editor: Hajime Kataoka\n\n2019 11 11 2019 2019 351270614 5 2019 24 9 2019 11 10 2019 Copyright © 2019 Nosheen Reza et al.2019This 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.Lamin A/C cardiac disease is a genetic cardiomyopathy and arrhythmia syndrome caused by alterations in the function of the nuclear lamin A and C proteins. It is inherited in an autosomal dominant manner and usually presents in mid- to late adulthood with atrioventricular conduction abnormalities, atrial and ventricular arrhythmias, biventricular dysfunction, and advanced heart failure. While rare, women of childbearing age can exhibit an aggressive disease course, and appropriate risk stratification and management are critical. Here, we present a case of newly diagnosed lamin A/C cardiac disease in a pregnant woman.\n\nWinkelman Family Fund in Cardiovascular InnovationNational Institutes of HealthHG009495\n==== Body\n1. Introduction\nThe majority of arrhythmias in pregnancy are benign, but the recognition of arrhythmias with high-risk features is critical to the avoidance of adverse maternal and fetal outcomes. We report this rare case of the antepartum diagnosis and management of lamin A/C disease.\n\n2. Case Report\nA 33-year-old woman presented to our electrophysiology clinic for evaluation of 1st degree atrioventricular (AV) delay. She had been diagnosed with this finding 2 years prior while undergoing biannual fitness testing in the Navy. At that time, she had undergone Holter monitoring and treadmill stress echocardiography that did not show malignant conduction disease, arrhythmias, or structural heart disease.\n\nAt this electrophysiology clinic visit, she reported mild exercise intolerance and a sense that her “heart was not keeping up,” which she attributed to physical deconditioning. Her electrocardiogram (ECG) was notable for sinus rhythm at 71 beats per minute with a PR interval of 214 milliseconds and was otherwise unremarkable (Figure 1(a)). She underwent repeat treadmill stress testing to assess her heart rate response and AV conduction; she achieved 78% of the maximum predicted heart rate and had superiorly directed premature ventricular contractions (PVCs) and slow accelerated idioventricular rhythm during recovery. Cardiac magnetic resonance imaging, performed to evaluate for infiltrative disease, showed normal biventricular function, normal chamber structure and dimensions, and no late gadolinium enhancement. She was diagnosed with high vagal tone.\n\nAt her next follow-up two years later at age 35, she was 22 weeks pregnant with her first child. She reported becoming easily dyspneic with exercise in the context of a 10-15-pound weight gain and intermittent palpitations. Her ECG showed sinus bradycardia, a competing junctional rhythm, occasional PVCs, and poor R wave progression—all of which were new (Figure 1(c)). Review of her family history revealed that her father died at age 47 while awaiting heart transplantation for presumed end-stage ischemic cardiomyopathy. Given these findings, a 30-day ambulatory arrhythmia monitor was ordered, and within the first two weeks, sinus node dysfunction and frequent multifocal ventricular arrhythmias were captured (Figure 2). In the setting of both her tachy- and bradyarrhythmias and concerning family history, a genetic disorder was suspected. She underwent urgent and successful dual-chamber implantable cardioverter defibrillator (ICD) implantation at 25 weeks gestation, was started on metoprolol, and established care with our Maternal-Fetal Medicine program.\n\nShe was referred to our inherited cardiovascular disease center for genetic counseling and testing. Her three-generation family history was notable for cardiomyopathy in her father and heart issues in her paternal grandfather (Figure 3). She underwent genetic sequencing of 121 genes associated with cardiomyopathy and arrhythmia through GeneDx (Gaithersburg, Maryland) and was found to be heterozygous for two different pathogenic variants—a frameshift variant in LMNA (c.1174_1178delAGCCC; p.Ser392TyrfsX32) and a missense variant in MYBPC3 (c.1504C>T; p.Arg502Trp). This specific LMNA variant had not previously been reported but was predicted to result in either protein truncation or loss of protein product through nonsense-mediated mRNA decay and was therefore felt to be the likely cause of her arrhythmias. The MYBPC3 (c.1504C>T) variant had previously been reported in multiple individuals in association with hypertrophic cardiomyopathy. Cascade screening of first-degree relatives was recommended.\n\nAt 32 weeks gestation, device interrogation and manual review of reported events showed several prolonged episodes of atrial fibrillation. After extensive discussion regarding the risks and benefits of therapeutic anticoagulation, she was started on prophylactic enoxaparin with the plan to undergo induction of labor at term (37 weeks gestation). She underwent an uncomplicated low transverse cesarean section due to nonreassuring fetal heart tones during her induction. She was discharged on therapeutic enoxaparin for thromboprophylaxis given limited data on the use of direct oral anticoagulants during breastfeeding.\n\n3. Discussion\nThe lamin A/C gene (LMNA) is located on chromosome 1q21-22 and encodes two main nuclear laminar proteins, lamin A and lamin C, by alternative splicing [1]. These type V intermediate filament proteins are expressed in terminally differentiated somatic cells and are required for normal formation of the cell's nuclear envelope. When these proteins are disrupted, the stability of the nuclear membrane along with DNA replication, transcription, and nuclear organization are threatened [2]. Lamin A/C cardiac disease is inherited in an autosomal dominant pattern; therefore, heterozygotes often manifest disease, although with variable expressivity.\n\nDiseases caused by variants in lamin A/C are collectively termed laminopathies and affect skeletal muscle (e.g., autosomal dominant and recessive Emery-Dreifuss muscular dystrophy, autosomal dominant limb-girdle muscular dystrophy), adipose tissue (e.g., familial partial lipodystrophy), peripheral nervous tissue (e.g., sensory and motor axonal neuropathy), and cardiac muscle [1]. There is wide variability among these phenotypes, with some patients first and only displaying cardiac manifestations characterized by AV conduction abnormalities, arrhythmias, biventricular dysfunction, and advanced heart failure. In addition, the majority of pathogenic LMNA variant carriers with muscular dystrophy-predominant symptoms also develop cardiac complications. Natural history studies have shown that conduction disease without other structural heart disease develops in a majority of these patients by the age of 30 with heart failure mostly manifesting around 20 years later [3]. Variants in LMNA have been found in 5-8% of familial dilated cardiomyopathy (DCM) cases, making these variants among the most frequently implicated in the development of DCM [1, 2, 4]. Our patient did not exhibit any other laminopathic signs or symptoms, including neuromuscular symptoms, and had stable left ventricular structure and function on her serial third trimester and postpartum transthoracic echocardiograms. She will remain under periodic echocardiographic surveillance.\n\nConduction disturbances associated with LMNA include atrial and ventricular arrhythmias and AV conduction delays and blocks. Typically, sinoatrial disease becomes apparent first and manifests as sinus bradycardia, sick sinus syndrome with sinus arrest and junctional escape rhythms, and first-degree AV delay. Supraventricular arrhythmias include atrial fibrillation, atrial flutter, and atrial tachycardia. In a multicenter international study of LMNA pathogenic or likely pathogenic variant carriers, 45% of patients who had atrial fibrillation on presentation progressed to persistent or permanent forms within the median follow-up period of 7 years [5]. In comparison to genotype-negative idiopathic DCM patients, LMNA variant carriers experienced a significantly higher risk of arterial and venous thromboembolic complications (HR 4.8, 95% CI: 2.2-10.6), raising the possibility of an additional prothrombotic phenotype [6]. Pregnancy is, in itself, a hypercoagulable state, and this combined with our patient's episodes of atrial fibrillation necessitated the consideration of systemic anticoagulation and delivery.\n\n\nLMNA carriers have significantly worse cardiovascular outcomes compared to other DCM patients with increased mortality due to sudden cardiac death and severe heart failure [1]. In a multicenter European study of 269 LMNA variant carriers, independent risk factors for malignant ventricular arrhythmias included nonsustained ventricular tachycardia (VT), left ventricular ejection fraction < 45% at first clinical contact, male sex, and nonmissense (i.e., insertion, deletion, truncations, and splice site) variants [7]. In this same study, there was a high rate of appropriate ICD therapies in patients who had received a primary prevention device (8 per 100 person-years with a median follow-up period of 29 months). Similarly, in another study, 42% of patients with genetically confirmed lamin A/C disease and primary prevention ICDs sustained appropriate shocks [8]. These data are the foundation for the 2015 European Society of Cardiology guideline class IIa recommendation to consider ICD implantation in patients with DCM, a confirmed disease-causing LMNA variant, and clinical risk factors [9].\n\nOur patient's known pathogenic variant, positive family history, and documented progressive conduction disease with new and frequent multifocal ventricular arrhythmias were thought to confer a high enough risk of sudden cardiac death to warrant primary prevention ICD implantation, regardless of her pregnant state. The risks of bradycardia and asystole were also important considerations in implanting a pacing system given that these rhythms could be acutely life threatening to the patient and fetus. As the patient was already at 25 weeks gestation at the time of device implantation, the risks of radiation exposure to the fetus were somewhat attenuated. A dual-chamber device can be implanted with very low dose fluoroscopy, as was the case here, with only 2 minutes of low frame rate fluoroscopy used. A significantly higher fluoroscopy dose would have been used to implant a cardiac resynchronization therapy lead; therefore, her device was implanted with appropriate programming to minimize right ventricular pacing.\n\nData on catheter ablation for management of ventricular arrhythmias in lamin A/C disease are limited. In a recent international multicenter study of 25 LMNA patients with drug-refractory VT, catheter ablation was associated with poor procedural success and a very high rate of ventricular arrhythmia recurrence. Notably, at a follow-up, 44% of patients were on or awaiting advanced therapies for end-stage heart failure, and 26% died [10]. Catheter ablation is mostly palliative, and further prospective studies are needed to assess whether guideline-directed medical therapy can delay the onset and progression of advanced heart failure. At this time, heart transplantation is the only curative therapy for lamin A/C cardiac disease. A phase 3, randomized, placebo-controlled clinical trial evaluating the safety and efficacy of a selective oral inhibitor of p32 mitogen-activated protein kinase in treating patients with symptomatic LMNA DCM (NCT03439514) is currently enrolling and expected to reach study completion in July 2020 [11].\n\nArrhythmias are one of the most common cardiac conditions in pregnancy. Contributors to this proarrhythmic state include myocardial stretch due to a 50% increase in blood volume, hormonal changes, and an increase in circulating catecholamines [12]. Supraventricular tachycardias are thought to be the most frequent sustained arrhythmias that women experience during this time [13]. Sustained VT and ventricular fibrillation are quite rare in pregnancy with registry data showing a 1.4% incidence in women with underlying structural heart disease [14].\n\nData on obstetrical and fetal outcomes in lamin A/C cardiac disease are exceedingly scarce. The only published case series describes 11 pregnancies in 5 LMNA variant carriers. Of the 5 women, 4 had palpitations or AV conduction abnormalities prior to or during their pregnancies. No major cardiac events were observed during their pregnancies. Unfortunately, no systematic electrocardiographic data were reported, precluding direct comparison with our patient [15].\n\nThe proband and her sister (Figure 3, individual III-3) were both heterozygous for disease-associated variants in LMNA and MYBPC3. Although the clinical lab interpreted the MYBPC3 c.1504C>T variant as pathogenic, the variant has conflicting interpretations of pathogenicity in ClinVar [16]. At this time, the proband is only exhibiting a phenotype consistent with the pathogenic LMNA variant; her left ventricular wall thickness is normal. Individuals with LMNA-related cardiac disease generally exhibit a highly penetrant phenotype, consistent with the proband's presentation and course, while penetrance is reduced for MYBPC3 variants. The proband and her sister will remain under clinical surveillance for manifestations of LMNA-related cardiac disease and of hypertrophic cardiomyopathy. At this time, the proband's sister's clinical phenotyping, consisting of a physical exam, electrocardiogram, and echocardiogram performed at another institution, shows no evidence of disease. She is scheduled to undergo additional phenotyping with cardiac magnetic resonance imaging and ambulatory electrocardiographic monitoring.\n\nTo our knowledge, this is the first report of the diagnosis and management of lamin A/C cardiac disease progression during pregnancy. Our patient experienced a typical disease course as described above with progressive sinoatrial and AV abnormalities and ultimately atrial and ventricular tachyarrhythmias necessitating dedicated management, but whether this course was hastened by her pregnancy remains unclear.\n\n4. Conclusions\nProgressive conduction system disease in a young individual is a hallmark of lamin A/C disease. With the mean age of mothers at first birth in the United States rising, it is likely that we will see genetic cardiomyopathies like lamin A/C disease, thought usually to present in mid- to late adulthood, become manifest in antepartum and postpartum women [17]. Cardiologists should be aware of LMNA-related cardiac disease and the importance of electrocardiographic monitoring in the diagnosis of inherited arrhythmia and cardiomyopathy syndromes.\n\nAcknowledgments\nDr. Reza is supported by the National Institutes of Health National Human Genome Research Institute Ruth L. Kirschstein Institutional National Research Service T32 Award in Genomic Medicine (T32 HG009495). Dr. Owens is supported by the Winkelman Family Fund in Cardiovascular Innovation.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest regarding the publication of this article.\n\nFigure 1 Serial ECGs: initial ECG performed at age 33 (a) with sinus rhythm and prolonged PR interval. Surveillance ECG performed one year later at age 34 (b) with slowing of the sinus rate and prolonged PR interval. First ECG during pregnancy performed at age 35 (c) showed new sinus bradycardia with competing junctional rhythm, occasional PVCs (RBS axis), and lower voltage QRS and poor R wave progression. Paper speed and amplification: 25 mm/s and 1 mV/10 mm.\n\nFigure 2 Mobile cardiac outpatient telemetry: frequent multifocal ventricular arrhythmias.\n\nFigure 3 Pedigree: numbers below symbols denote current age or age at death. + denotes normal allele.\n==== Refs\n1 Taylor M. R. Fain P. R. Sinagra G. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations Journal of the American College of Cardiology 2003 41 5 771 780 10.1016/s0735-1097(02)02954-6 2-s2.0-0037420074 12628721 \n2 Sylvius N. Tesson F. Lamin A/C and cardiac diseases Current Opinion in Cardiology 2006 21 3 159 165 10.1097/01.hco.0000221575.33501.58 2-s2.0-33748175926 16601451 \n3 van Berlo J. H. de Voogt W. G. van der Kooi A. J. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? Journal of Molecular Medicine 2005 83 1 79 83 10.1007/s00109-004-0589-1 2-s2.0-19944431159 15551023 \n4 Fu Y. Eisen H. J. Genetics of dilated cardiomyopathy Current Cardiology Reports 2018 20 11 10.1007/s11886-018-1061-0 2-s2.0-85053894614 \n5 Kumar S. Baldinger S. H. Gandjbakhch E. Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers Journal of the American College of Cardiology 2016 68 21 2299 2307 10.1016/j.jacc.2016.08.058 2-s2.0-84997610257 27884249 \n6 van Rijsingen I. A. Bakker A. Azim D. Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications International Journal of Cardiology 2013 168 1 472 477 10.1016/j.ijcard.2012.09.118 2-s2.0-84883775486 23073275 \n7 van Rijsingen I. A. W. Arbustini E. Elliott P. M. Risk factors for malignant ventricular arrhythmias in lamin A/C mutation carriers: a European cohort study Journal of the American College of Cardiology 2012 59 5 493 500 10.1016/j.jacc.2011.08.078 2-s2.0-84856194138 22281253 \n8 Meune C. Van Berlo J. H. Anselme F. Bonne G. Pinto Y. M. Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations New England Journal of Medicine 2006 354 2 209 210 10.1056/NEJMc052632 2-s2.0-30444446953 16407522 \n9 Priori S. G. Blomström-Lundqvist C. Mazzanti A. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC) European Heart Journal 2015 36 41 2793 2867 10.1093/eurheartj/ehv316 2-s2.0-84983158344 26320108 \n10 Kumar S. Androulakis A. F. A. Sellal J. M. Multicenter experience with catheter ablation for ventricular tachycardia in lamin A/C cardiomyopathy Circulation Arrhythmia and Electrophysiology 2016 9 8 10.1161/circep.116.004357 2-s2.0-84983359043 27506821 \n11 A study of ARRY-371797 in patients with symptomatic dilated cardiomyopathy due to a lamin A/C gene mutation https://ClinicalTrials.gov/show/NCT03439514 \n12 MacIntyre C. Iwuala C. Parkash R. Cardiac arrhythmias and pregnancy Current Treatment Options in Cardiovascular Medicine 2018 20 8 p. 63 10.1007/s11936-018-0660-9 2-s2.0-85049891858 29995282 \n13 Vaidya V. R. Arora S. Patel N. Burden of arrhythmia in pregnancy Circulation 2017 135 6 619 621 10.1161/circulationaha.116.026681 2-s2.0-85012076889 28154000 \n14 Ertekin E. van Hagen I. M. Salam A. M. Ventricular tachyarrhythmia during pregnancy in women with heart disease: data from the ROPAC, a registry from the European Society of Cardiology International Journal of Cardiology 2016 220 131 136 10.1016/j.ijcard.2016.06.061 2-s2.0-84976871168 27376569 \n15 Palojoki E. Kaartinen M. Kaaja R. Pregnancy and childbirth in carriers of the lamin A/C‐gene mutation European Journal of Heart Failure 2010 12 6 630 633 10.1093/eurjhf/hfq059 2-s2.0-77953011596 20413395 \n16 National Center for Biotechnology Information ClinVar; [VCV000042540.4] 2019 Bethesda, MD, USA United States National Library of Medicine September 2019, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000042540.4 \n17 Mathews T. J. Hamilton B. E. Mean age of mothers is on the rise: United States 2000–2014 NCHS data brief, no 232 2016 Hyattsville, MD National Center for Health Statistics\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2019()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "3512706",
"pmc": null,
"pmid": "31815019",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "27506821;30259183;26828319;16407522;16601451;12628721;29995282;23073275;22281253;28154000;26320108;20413395;15551023;27884249;27376569",
"title": "Antepartum Diagnosis and Management of Lamin A/C Disease.",
"title_normalized": "antepartum diagnosis and management of lamin a c disease"
} | [
{
"companynumb": "NVSC2019US079365",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "We investigated the safety and efficacy of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) associated with severe inherited thrombophilia. In this single-center cohort study, we enrolled 56 consecutive VTE patients with severe inherited thrombophilia, defined as the presence of antithrombin (n = 18), protein C (n = 12) and protein S (n = 12) deficiencies, homozygous Factor V Leiden (n = 3) and prothrombin G20210AA (n = 4) mutations, or combined defects (n = 7). During a median follow-up of 44.5 (IQR 30-52.5) months, rivaroxaban was used in 30 (53.6%), apixabanin 14 (25%), and dabigatran in 12 (21.4%) subjects. Recurrent nonfatal VTE was observed in 5 (8.9%) patients (2.4 per 100 patient-years), treated with rivaroxaban (n = 4) and apixaban (n = 1). Major bleeding and clinically relevant non-major bleeding (CRNMB) occurred in 2 (3.5%) and 4 (7%) subjects, respectively (0.96 per 100 patient-years and 1.92 per 100 patient-years, respectively), including 4 patients on rivaroxaban. The event-free survival analysis showed that the use of rivaroxaban was associated with increased risk of recurrent VTE or bleeding, compared with apixaban or dabigatran (HR 2.76, 95% CI 1.26-3.92, p = 0.039). In conclusion, the results of our cohort study indicate that full-dose dabigatran or apixaban are effective and safe in patients with severe inherited thrombophilia.",
"affiliations": "Institute of Cardiology, John Paul II Hospital, Jagiellonian University Medical College, Krakow, Poland.;Institute of Cardiology, John Paul II Hospital, Jagiellonian University Medical College, Krakow, Poland.;Faculty of Mathematics and Natural Sciences, University of Rzeszow, Rzeszow, Poland.;Institute of Cardiology, John Paul II Hospital, Jagiellonian University Medical College, Krakow, Poland. mmundas@cyf-kr.edu.pl.",
"authors": "Zuk|Joanna|J|;Papuga-Szela|Elzbieta|E|;Zareba|Lech|L|;Undas|Anetta|A|http://orcid.org/0000-0002-0667-8109",
"chemical_list": "D000925:Anticoagulants; D011516:Prothrombin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-03012-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "113(2)",
"journal": "International journal of hematology",
"keywords": "Bleeding; Direct oral anticoagulants; Rivaroxaban; Severe inherited thrombophilia; Venous thromboembolism",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011516:Prothrombin; D012720:Severity of Illness Index; D019851:Thrombophilia; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "190-198",
"pmc": null,
"pmid": "33040276",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "32125293;24963045;28607330;30516757",
"title": "Direct oral anticoagulants in patients with severe inherited thrombophilia: a single-center cohort study.",
"title_normalized": "direct oral anticoagulants in patients with severe inherited thrombophilia a single center cohort study"
} | [
{
"companynumb": "PL-JNJFOC-20201111153",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nWe examined whether fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed before chemotherapy could predict the onset of acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer and ILD treated with chemotherapy.\n\n\nMETHODS\nThirty-three patients with lung cancer and ILD who underwent 18F-FDG PET/CT and were treated with chemotherapy at Kumamoto University Hospital between April 2006 and March 2018 were retrospectively analyzed. The maximum standardized uptake value (SUVmax) of interstitial lesions was measured to quantify the background ILD activity. A prediction model of AE-ILD was developed using logistic regression analyses for the SUVmax, and receiver operating characteristic (ROC) curve analyses were conducted.\n\n\nRESULTS\nAmong the 33 patients, 7 experienced AE-ILD. The SUVmax of contralateral interstitial lesions was significantly higher in patients with vs. without AE-ILD (median SUVmax: 2.220 vs. 1.795, P = 0.025). Univariable logistic regression analyses showed that the SUVmax of contralateral interstitial lesions trended towards being significantly associated with the onset of AE-ILD [odds ratio: 8.683, 95% confidence interval (CI) 0.88-85.83, P = 0.064]. The area under the ROC curve of the SUVmax for predicting AE-ILD was 0.780 (95% CI 0.579-0.982, P = 0.025). The optimal cut-off value for SUVmax was 2.005, with sensitivity and specificity values of 0.857 and 0.769, respectively.\n\n\nCONCLUSIONS\nThe SUVmax of contralateral interstitial lesions in 18F-FDG PET/CT images might be useful for predicting the onset of AE-ILD in patients with lung cancer and ILD treated with chemotherapy.",
"affiliations": "Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan. ksaruwat@kuh.kumamoto-u.ac.jp.;Department of Diagnostic Radiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.;Department of Diagnostic Radiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.",
"authors": "Akaike|Kimitaka|K|;Saruwatari|Koichi|K|;Oda|Seitaro|S|;Shiraishi|Shinya|S|;Takahashi|Hiroshi|H|;Hamada|Shohei|S|;Iyama|Shinji|S|;Horio|Yuko|Y|;Tomita|Yusuke|Y|;Saeki|Sho|S|;Okamoto|Shinichiro|S|;Ichiyasu|Hidenori|H|;Fujii|Kazuhiko|K|;Sakagami|Takuro|T|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-019-01584-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "25(4)",
"journal": "International journal of clinical oncology",
"keywords": "Acute exacerbation; Chemotherapy; Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography; Interstitial lung disease; Lung cancer",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000368:Aged; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D012372:ROC Curve; D012189:Retrospective Studies; D012680:Sensitivity and Specificity",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "681-690",
"pmc": null,
"pmid": "31781994",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": "21623239;22577296;27133752;23699745;21471066;30168753;12882453;28449678;28232605;21036764;19289428;17512190;19659650;28274530;19420811;10210213;25166895;27480571",
"title": "Predictive value of 18F-FDG PET/CT for acute exacerbation of interstitial lung disease in patients with lung cancer and interstitial lung disease treated with chemotherapy.",
"title_normalized": "predictive value of 18f fdg pet ct for acute exacerbation of interstitial lung disease in patients with lung cancer and interstitial lung disease treated with chemotherapy"
} | [
{
"companynumb": "JP-PFIZER INC-2020164890",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "The authors present a case of a male with Multiple Sclerosis (MS) who developed unilateral Fingolimod-Associated Macular Edema (FAME) 10 years after initiating fingolimod therapy. By reporting this case study, the authors present a comprehensive review on FAME, its current incidence, and therapy options in MS patients.\nA 58-year-old Caucasian male patient was referred to the hospital with a history of MS. He was on fingolimod treatment for 10 years. The patient presented with a referring second episode of blurred vision in his left eye (OS). His best corrected visual acuity (BCVA) was 20/20 (right eye - OD) and 20/30 (OS). Dilated fundus examination of the OS revealed dull foveal reflex with retinal thickening. Spectral domain optical coherence tomography (SD-OCT) scan demonstrated increased central macular thickness of 459 μm, foveal cysts and subretinal fluid. Neurologists decided to discontinue fingolimod treatment based on the ophthalmological findings. Three months post fingolimod discontinuation, macular edema resolved and BCVA was 20/20 (OD) and 20/25 (OS).\nThe authors report a case of late onset FAME. FAME may occur several years after starting fingolimod treatment and it should be part of differential diagnosis of blurred vision in patients receiving fingolimod. Both Microcystic Macular Edema secondary to MS and Macular Edema Associated with MS-induced Uveitis should always be excluded. Those two conditions, secondary to MS, might show the lack of drug effectiveness and the possible need for changing the existing therapy in order to prevent further disease progress.",
"affiliations": "Department of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.;General Hospital of Athens Korgialenio Benakio, Athens, Attica, Greece.",
"authors": "Karakosta|Christina|C|https://orcid.org/0000-0001-9349-4043;Kourentis|Christina|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1120672121999632",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": null,
"journal": "European journal of ophthalmology",
"keywords": "CME; Retinal pathology/research; pharmacology; retina – medical therapies; systemic drug retinal toxicity",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "1120672121999632",
"pmc": null,
"pmid": "33645300",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fingolimod-associated macular edema: A case report of late onset.",
"title_normalized": "fingolimod associated macular edema a case report of late onset"
} | [
{
"companynumb": "GR-ALKEM LABORATORIES LIMITED-GR-ALKEM-2021-01382",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"druga... |
{
"abstract": "BACKGROUND\nThe Brazilian HIV/AIDS management and treatment guideline (PCDT), published in 2013, recommends and standardizes the use of highly active antiretroviral therapy (HAART) in all adult patients, in spite of LTCD4 count. This study aimed to analyze the first year of HAART use in patients from a reference center on HIV/AIDS management in Fortaleza, Ceará.\n\n\nMETHODS\nThis descriptive study reviewed all prescription forms of antiretroviral regimens initiation and changes from January to July 2014. All antiretroviral regimen changes that occurred during the first year of therapy were evaluated. Data were analyzed with SPSS version 20. Mean, standard deviation and frequency, Student's t and Mann-Whitney tests calculations were used, with significance at p<0.05.\n\n\nRESULTS\nFrom 527 patients initiating HAART, 16.5% (n=87) had a regimen change in the first year. These patients were mostly male (59.8%; n=52), aged 20 to 39 years, with only one HAART change (72.4%; n=63). Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir. Mean time of HAART changes was 120 days, with adverse reactions as the most prevalent cause. HAART was effective in decreasing viral load since second month of treatment (p=0.003) and increasing LTCD4 lymphocytes since fifth month (p<0.001).\n\n\nCONCLUSIONS\nThe main cause of initial HAART changes was adverse reaction and most patients had only one change in the HAART regimen. HAART prescription was in accordance to the PCDT from 2013.",
"affiliations": "Pharmacist, Resident in Infectology, Escola de Saúde Pública do Ceará (ESP-CE), Hospital São José de Doenças Infecciosas (HSJ), Fortaleza, CE, Brazil.;PhD in Drug Development and Technological Innovation, Universidade Federal do Ceará (UFC). Managing Pharmacist, HSJ Laboratory, Fortaleza, CE, Brazil.;MSc in Medical Sciences, UFC. Pharmacist, Centro de Farmácia (CENFAR), HSJ, Fortaleza, CE, Brazil.;Specialist in Hospital Pharmacy, ESP-CE. Pharmacist, CENFAR, HSJ, Fortaleza, CE, Brazil.;PhD in Infectious and Parasitic Diseases, Universidade de São Paulo (USP). MD, HSJ, Fortaleza, CE, Brazil.",
"authors": "Bandeira|Antonio Carlos Policarpo Carmo Sá|ACPCS|;Elias|Darcielle Bruna Dias|DBD|;Cavalcante|Malena Gadelha|MG|;Lima|Denise Girão Limaverde|DGL|;Távora|Lara Gurgel Fernandes|LGF|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.63.07.606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0104-4230",
"issue": "63(7)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000328:Adult; D000704:Analysis of Variance; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D001938:Brazil; D018791:CD4 Lymphocyte Count; D057915:Drug Substitution; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D015995:Prevalence; D012737:Sex Factors; D055815:Young Adult",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "606-612",
"pmc": null,
"pmid": "28977086",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antiretroviral changes during the first year of therapy.",
"title_normalized": "antiretroviral changes during the first year of therapy"
} | [
{
"companynumb": "BR-ABBVIE-17P-020-2126694-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
"drugadditional":... |
{
"abstract": "Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure.",
"affiliations": "University Department of Medicine, Dubrava University Hospital, Avenija Gojka Suska 6, Zagreb, Croatia. ivica.grgurevic@zg.htnet.hr",
"authors": "Grgurević|Ivica|I|;Pejsa|Vlatko|V|;Morović-Vergles|Jadranka|J|;Dobrić|Ivan|I|;Gasparović|Vladimir|V|;Tudorić|Neven|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime; C040738:cefuroxime axetil",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "16(3)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D000368:Aged; D000380:Agranulocytosis; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D013262:Stevens-Johnson Syndrome; D014552:Urinary Tract Infections",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "133-7",
"pmc": null,
"pmid": "18812062",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime.",
"title_normalized": "fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime"
} | [
{
"companynumb": "HR-PFIZER INC-2011239986",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDrugs are related to the etiology of acute pancreatitis in approximately 1.4-2.0% of cases. Although antibiotics constitute a small number of the drugs suspected, tetracycline is the most encountered antibiotic among those drugs.\n\n\nMETHODS\nA 33-year-old woman was admitted to the emergency room complaining of nausea and abdominal pain after the use of doxycycline 500 mg and ornidazole 500 mg twice daily for three days for a vaginal infection. She experienced epigastric pain, which worsened over time and radiated to her back. After a detailed evaluation, she was diagnosed as having mild acute pancreatitis which improved with medical treatment. All other possible causes of pancreatitis were eliminated.\n\n\nCONCLUSIONS\nAntibiotic-associated pancreatitis usually has a silent and mild course. To the best of our knowledge the literature reports only two cases of doxycycline-induced acute pancreatitis reported and there are no reports of pancreatitis associated with ornidazole. Our case is the first case reported in which doxycycline and ornidazole coadministration induced acute pancreatitis.",
"affiliations": "Department of Gastroenterology, Baskent University, Ankara, Turkey.",
"authors": "Ocal|Serkan|S|;Selçuk|Haldun|H|;Korkmaz|Murat|M|;Unal|Hakan|H|;Yilmaz|Uğur|U|",
"chemical_list": "D000900:Anti-Bacterial Agents; D009950:Ornidazole; D004318:Doxycycline",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8577",
"issue": "11(6)",
"journal": "JOP : Journal of the pancreas",
"keywords": null,
"medline_ta": "JOP",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000900:Anti-Bacterial Agents; D004318:Doxycycline; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D009950:Ornidazole; D010195:Pancreatitis; D014623:Vaginal Diseases",
"nlm_unique_id": "101091810",
"other_id": null,
"pages": "614-6",
"pmc": null,
"pmid": "21068497",
"pubdate": "2010-11-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute pancreatitis following doxycycline and ornidazole coadministration.",
"title_normalized": "acute pancreatitis following doxycycline and ornidazole coadministration"
} | [
{
"companynumb": "TR-ENDO PHARMACEUTICALS INC-2016-003362",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ORNIDAZOLE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nQVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD.\n\n\nMETHODS\nThis multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety.\n\n\nRESULTS\nOf the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%).\n\n\nCONCLUSIONS\nQVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD.\n\n\nBACKGROUND\nNCT01120717.",
"affiliations": "III.Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz K.d.ö.R., Mainz, Germany.;Universitätsklinikum Leipzig, Leipzig, Germany POIS Leipzig GbR, Leipzig, Germany.;Pneumologische Praxis, Marburg, Germany.;Kardio-Pneumologische Praxis, Berlin, Germany.;Novartis Pharma GmbH, Nürnberg, Germany.;Novartis Pharma GmbH, Nürnberg, Germany.;Universitätsmedizin der Johannes Gutenberg-Universität, Mainz, Germany.",
"authors": "Buhl|Roland|R|;Gessner|Christian|C|;Schuermann|Wolfgang|W|;Foerster|Karin|K|;Sieder|Christian|C|;Hiltl|Simone|S|;Korn|Stephanie|S|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004338:Drug Combinations; D004983:Ethanolamines; D007189:Indans; D015363:Quinolones; D012602:Scopolamine Derivatives; C554862:indacaterol-glycopyrronium combination; D006024:Glycopyrrolate; D000068759:Formoterol Fumarate; D000069447:Tiotropium Bromide",
"country": "England",
"delete": false,
"doi": "10.1136/thoraxjnl-2014-206345",
"fulltext": "\n==== Front\nThoraxThoraxthoraxjnlthoraxThorax0040-63761468-3296BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 25677679thoraxjnl-2014-20634510.1136/thoraxjnl-2014-2063451506Chronic Obstructive Pulmonary DiseaseOriginal articleEfficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study Buhl Roland 1Gessner Christian 23Schuermann Wolfgang 4Foerster Karin 5Sieder Christian 6Hiltl Simone 6Korn Stephanie 7\n1 III.Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz K.d.ö.R., Mainz, Germany\n2 Universitätsklinikum Leipzig, Leipzig, Germany\n3 POIS Leipzig GbR, Leipzig, Germany\n4 Pneumologische Praxis, Marburg, Germany\n5 Kardio-Pneumologische Praxis, Berlin, Germany\n6 Novartis Pharma GmbH, Nürnberg, Germany\n7 Universitätsmedizin der Johannes Gutenberg-Universität, Mainz, GermanyCorrespondence to Dr Roland Buhl, III.Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz K.d.ö.R., Langenbeckstrasse 1, Mainz 55131, Germany; roland.buhl@unimedizin-mainz.de4 2015 12 2 2015 70 4 311 319 24 9 2014 13 1 2015 16 1 2015 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2015This 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/Background\nQVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD.\n\nMethods\nThis multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety.\n\nResults\nOf the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: –0.69 units; 95% CI −2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%).\n\nConclusions\nQVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD.\n\nTrial registration number\nNCT01120717.\n\nCOPD Pharmacologyspecial-featureunlocked\n==== Body\nKey messages\nWhat is the key question?\nIs QVA149 non-inferior to tiotropium plus formoterol (TIO+FOR) combination in improving health-related quality of life (HRQoL) of patients with COPD?\n\nWhat is the bottom line?\nQVA149 is non-inferior to TIO+FOR combination with respect to HRQoL, but shows significant improvements in breathlessness and lung function.\n\nWhy read on?\nThis is the first non-inferiority trial comparing active pharmacological treatments using HRQoL as a primary endpoint.\n\nIntroduction\nGlobal Initiative for Chronic Obstructive Lung Disease (GOLD) 2014 strategy, and the 2010 National Institute for Health and Care Excellence (NICE) guidelines recommend the use of combined bronchodilators of different pharmacological classes in patients with COPD.1\n2 Combining bronchodilators has proved to be more efficacious and reduces the risk of side effects compared with increasing doses of monotherapy.3–6 The complementary mechanisms of action of long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) significantly improve bronchodilation in patients with COPD in comparison with respective monotherapies,6–8 and hence are recommended first-line treatment in patients with moderate-to-severe COPD.1\n\nQVA149 is an inhaled once-daily (o.d.) dual bronchodilator containing a fixed-dose combination of the LABA indacaterol9 and the LAMA glycopyrronium10, being approved for the maintenance treatment of patients with symptomatic COPD in the European Union. Clinical studies have demonstrated the efficacy and safety profile of once-daily QVA149 in patients with COPD.3\n8\n11\n12 Tiotropium (TIO), a LAMA, and formoterol (FOR), a LABA, are well-accepted bronchodilators for the treatment of COPD.6\n13\n14 The free-dose combination of TIO plus FOR, delivered via two separate inhalers, has an established efficacy in a number of clinical trials, is recommended by COPD guidelines and has been widely used for many years. The combination has been shown to significantly improve lung function, symptoms, reduce the number of COPD exacerbations and improve health-related quality of life (HRQoL).6\n14–17\n\nThe BEACON study had shown non-inferiority of QVA149 compared with the free-dose combination of its monocomponents.18 However, in view of the wide usage and standard-of-care treatment with TIO and FOR free-dose combination, it remains conjectural whether QVA149 is non-inferior to this LABA/LAMA combination. The question examined by this study pertains to a highly relevant comparison based on the expectation that single inhalation QVA149 would have comparable patient-reported outcomes, and safety profile as the TIO+FOR free combination treatment, taken twice-daily via two separate inhalers.\n\nIn the QUANTIFY study, QVA149 o.d. was compared with TIO o.d. plus FOR twice-daily (b.i.d.) over a period of 26 weeks in patients with moderate-to-severe COPD. This study, though conducted for German health authorities, has wider scientific implications considering the wide usage of the TIO+FOR combination. Assessment of non-inferiority of QVA149 to TIO+FOR combination was based on a prespecified non-inferiority margin of 4 units on the St George's Respiratory Questionnaire-COPD (SGRQ-C), which is a sensible definition for the limit of a clinically relevant effect for the improvement in SGRQ-C.19\n\nPatients and methods\nStudy design and treatments\nThis was a 26-week multicentre, randomised, blinded, triple-dummy, parallel-group, non-inferiority design. After screening and a run-in period (up to 2 weeks), patients were randomised (1:1) to receive QVA149 (indacaterol 110 μg and glycopyrronium 50 μg) o.d. (delivered via the Breezhaler device (Novartis Pharma AG, Stein, Switzerland)) or TIO 18 μg o.d. (delivered via the HandiHaler device (Boehringer Ingelheim, Ingelheim, Germany)) plus FOR 12 μg b.i.d. (delivered via the Aerolizer device (Novartis Pharma AG)) and corresponding placebos (figure 1).14\n15\n20 Data were obtained from three examinations in each subject at baseline (visit 3), week 12 (visit 5), and week 26 (visit 7). The study did not include a placebo arm, as both treatments tested had shown efficacy in placebo-controlled trials.11\n21\n22 Salbutamol was used as a rescue drug. Patients receiving inhaled corticosteroids (ICS) at baseline continued treatment (or the ICS component alone if taken as a fixed combination with a bronchodilator) at the same or equivalent dose and regimen. The study was approved by institutional review boards and ethics committees, and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent before study participation. Additional details are included in the online supplementary data.\n\nFigure 1 Study design. b.i.d., twice daily; o.d., once daily; Pbo, placebo.\n\nPatients\nThe study population included men and women aged ≥40 years with moderate-to-severe COPD (GOLD II or III as defined in the GOLD 2010 strategy), current or ex-smokers with a smoking history of at least 10 pack-years, post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and <80% of predicted value, and post-bronchodilator FEV1 to forced vital capacity (FVC) ratio <0.70 at screening. The patient population was similar to those included in other efficacy trials using the TIO and FOR combination.14\n15 Key exclusion criteria included COPD exacerbation that needed treatment with antibiotics, systemic corticosteroids (oral or intravenous) or hospitalisation in the 6 weeks before pre-screening or between pre-screening and randomisation (visits 1 and 3). Detailed inclusion and exclusion criteria are provided in the online supplementary appendix.\n\nAssessments\nHRQoL for eligible patients was measured using SGRQ-C.23 Dyspnoea was assessed using the Transition Dyspnoea Index (TDI), and spirometry (FEV1 and FVC) was done according to American Thoracic Society/ European Respiratory Society standards.24 The primary objective was to demonstrate non-inferiority of QVA149 compared with TIO+FOR combination for HRQoL with respect to the improvement in SGRQ-C. Secondary endpoints included TDI scores, symptoms of SGRQ-C, spirometry (FEV1 and FVC), rate of moderate and severe COPD exacerbations requiring hospitalisation and time to first moderate/severe exacerbation during the treatment period. Moderate exacerbations were those managed with antibiotics and/or systemic corticosteroids; severe exacerbations were those that resulted in hospitalisation. Trough FEV1 measurements were done 45 and 15 min pre-dose (23 h 15 min and 23 h 45 min after the morning dose, respectively). FEV1 30 min measurements were performed 30 min after the morning dose. Study drug compliance was assessed by the study nurse by recording capsule counts.\n\nAdverse events (AEs) and serious AEs (SAEs), including COPD exacerbations and vital signs, were recorded at each visit. ECG and laboratory analyses (haematology, clinical chemistry and urine analysis) were also carried out.\n\nStatistical analysis\nThe non-inferiority margin was predefined as 4 units, which has been reported in the literature as a sensible definition for the limit for a clinically relevant effect for the SGRQ-C.19 However, this trial was powered to achieve a confidence interval (CI) that allowed excluding even a smaller difference of 3 units. The full analysis set (FAS) was used for the primary efficacy and safety analysis and the per-protocol set (PPS) analysis was conducted as a sensitivity measure. No interim analyses were performed.\n\nThe primary analysis was performed using an analysis of covariance model. The model contained treatment, SGRQ-C at baseline and centre as fixed effects. The estimated adjusted treatment difference for QVA149 minus TIO+FOR was displayed together with the associated 95% CI and p value (two-sided). In addition, a one-sided p value for the shifted null hypothesis of inferiority was given. The non-inferiority of QVA149 over TIO+FOR was claimed if the shifted, one-sided p value was <2.5% or, equivalently, if the 95% CI lay entirely to the left (smaller than) of the non-inferiority margin of four points. A true difference of 0 SGRQ-C units and a common standard deviation of 13 were assumed, leading to 396 patients/group to achieve 90% power to reject the null hypothesis of inferiority >3 points for QVA149 versus TIO+FOR. To compensate for drop-out, a minimum of 440 patients per group were to be enrolled into this trial.\n\nResults\nPatients\nOf the 1246 patients screened, 934 were randomised to QVA149 (N=476) or TIO+FOR (N=458), and 821 (87.9%) patients completed the study (figure 2). Completion and withdrawal rates were similar between the two treatment groups (figure 2). Baseline patient demographics, and other clinical characteristics were numerically comparable across the two treatment groups (table 1).\n\nTable 1 Baseline demographics and clinical characteristics\n\n\tQVA149 (110/50 µg)\n(N=476)\tTIO (18 µg)+FOR (12 µg)\n(N=458)\tTotal\n(N=934)\t\nAge, years\t62.6 (8.4)\t63.1 (8.2)\t62.9 (8.3)\t\nGender, n (%)\t\n Male\t317 (66.6)\t298 (65.1)\t615 (65.8)\t\nRace, n (%)\t\n Caucasian\t472 (99.2)\t454 (99.1)\t926 (99.1)\t\nDuration of COPD (years)\t6.5 (5.3)\t6.8 (5.2)\t6.6 (5.2)\t\nSeverity of COPD*, n (%)\t\n Moderate\t267 (57.7)\t253 (55.7)\t520 (56.7)\t\n Severe\t193 (41.7)\t195 (43.0)\t388 (42.3)\t\nCOPD exacerbation history, n (%)\t\n 0\t411 (86.3)\t396 (86.5)\t807 (86.4)\t\n 1\t60 (12.6)\t57 (12.4)\t117 (12.5)\t\n ≥2\t3 (0.6)\t4 (0.9)\t7 (0.7)\t\nICS use at baseline, n (%)\t201 (42.2)\t184 (40.2)\t385 (41.2)\t\nSmoking history, n (%)\t\n Current smokers\t234 (49.2)\t224 (48.9)\t458 (49.0)\t\nNumber of pack-years\t41.1 (19.1)\t41.8 (19.6)\t41.4 (19.3)\t\nPre-bronchodilator FEV1 (L)\t1.34 (0.5)\t1.31 (0.5)\t1.33 (0.5)\t\nPost-bronchodilator FEV1 (L)\t1.6 (0.5)\t1.5 (0.5)\t1.6 (0.5)\t\nPost-bronchodilator FEV1, % predicted\t53.3 (13.4)\t53.0 (13.2)\t53.2 (13.3)\t\nPost-bronchodilator FEV1 reversibility, %†\t19.3 (18.4)\t19.6 (18.2)\t19.4 (18·3)\t\nPost-bronchodilator FEV1/FVC (%)\t53.3 (10.5)\t52.1 (10.0)\t52.7 (10.3)\t\nBDI\t6.5 (2.0)\t6.4 (2.1)\t–\t\nSGRQ-C total score\t44.7 (17.7)\t45.7 (17.7)\t–\t\nData are mean (SD) unless otherwise stated.\n\n*COPD severity is based on the GOLD 2010 criteria.\n\n†Assessed after administration of 84 µg ipratropium bromide and 400 µg salbutamol.\n\nBDI, Baseline Dyspnoea Index; FEV1, forced expiratory volume in 1 s; FOR, formoterol; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; Pack-years, total years of smoking multiplied by cigarette packs smoked per day; SGRQ-C, St George's Respiratory Questionnaire-COPD; TIO, tiotropium.\n\nFigure 2 Patient disposition. FOR, formoterol; TIO, tiotropium.\n\nDetails on concomitant drugs are provided as online supplementary data.\n\nEfficacy\nAll the 934 randomised patients were included in the FAS. In the PPS analysis, 747 (80%) patients were included (QVA149: n=373 and TIO+FOR: n=374). Non-inferiority was met (p<0.001; one-sided, shifted test) for QVA149 compared with TIO+FOR as the upper margin of the CI was lower than the predefined non-inferiority margin of 4 units (figure 3). The change from baseline in the SGRQ-C total score (FAS and PPS) was comparable in both groups (figure 4A and see online supplementary figure S1A).\n\nFigure 3 SGRQ-C score at week 26, change from baseline in each treatment group (by FAS and PPS). The non-inferiority margin was –4 to 4 units (shown by dotted line). FAS, full analysis set; FOR, formoterol; PPS, per-protocol set; SGRQ-C, St George's Respiratory Questionnaire for patients with COPD; TIO, tiotropium.\n\nFigure 4 SGRQ-C total score after 26 weeks. (A) LSM change from baseline in SGRQ-C total scores during treatment and (B) percentages of patients achieving the minimum clinically important difference (≥4 units) in SGRQ-C score after 26 weeks (FAS). FOR, formoterol; FAS, full analysis set; LSM, least squares mean; RR, risk ratio; SGRQ-C, St George's Respiratory Questionnaire in patients with COPD; TIO, tiotropium; ns, not significant.\n\nIn the FAS, the percentage of patients achieving the minimum clinically important difference (MCID) of 4 units in the SGRQ-C total score25 was similar in the QVA149 and TIO+FOR groups (figure 4B). However, in the PPS, the difference was significantly in favour of QVA149 (p=0.038; see online supplementary figure S1B). Similar improvements in symptom, activity and impact scores of SGRQ-C (see online supplementary table S1) were seen with QVA149 versus TIO+FOR. A subgroup analysis on SGRQ-C based on gender, age group, use of ICS and disease stage (according to GOLD 2010) at week 26 showed no statistically significant influence of the variables (online supplementary table S2).\n\nThe TDI total score showed similar reduction in dyspnoea with QVA149 and TIO+FOR in the FAS (figure 5A) and PPS (online supplementary figure S2A). Significantly more patients receiving QVA149 achieved the MCID ≥1 unit in dyspnoea26 versus TIO+FOR in the FAS (p=0.033; figure 5B) and PPS (p=0.009; online supplementary figure S2B).\n\nFigure 5 TDI total score. (A) TDI total score (LSM) after 26 weeks and (B) percentages of patients achieving the minimum clinically important difference (≥1 units) (FAS). FOR, formoterol; FAS, full analysis set; LSM, least squares mean; RR, risk ratio; TDI, Transition Dyspnoea Index; TIO, tiotropium. ns, not significant. @p<0.05.\n\nCompared with TIO+FOR, patients receiving QVA149 showed a higher pre-dose FEV1 in the FAS (p<0.001) (figure 6A) and the PPS (p<0.001) (online supplementary table S3). Similarly, improvements in pre-dose FVC values were significantly greater in the QVA149 group than in the TIO+FOR group in the FAS (figure 6B) and PPS (see online supplementary table S3). Post-dose FEV1 and post-dose FVC showed no significant differences between the treatment groups (figure 6A, B and online supplementary table S3).\n\nFigure 6 Lung function at week 12 and week 26 (FAS). (A) Pre-dose and post-dose FEV1 and (B) pre-dose and post-dose FVC. FAS, full analysis set; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity. *p<0.001; #p<0.01; ns, not significant.\n\nThe percentage of patients who had at least one moderate or severe exacerbation, and time to first moderate or severe exacerbation, analysed using the Kaplan–Meier method were comparable between the two treatment groups (see online supplementary figure S3 and table S4).\n\nSafety\nOverall, the study drug exposure was similar between both groups. The mean±SD duration of exposure was 167.2±44.6 days in the QVA149 group and 169.0±41.0 days in the TIO+FOR group. The average drug compliance was nearly 100% in both treatment groups (mean±SD: QVA149 99.5±8.6, TIO 98.9±11.0 and FOR 97.9±10.8). Table 2 summarises the individual AEs, which were similar in both treatment groups.\n\nTable 2 Most frequent AEs (excluding COPD exacerbations) in safety set population\n\n\tQVA149 (110/50 µg)\n(N=476)\tTIO (18 µg)+ FOR (12 µg)\n(N=458)\tRR (95% CI)*\t\nPatients with any AE(s) (total)\t 208 (43.7)\t 195 (42.6)\t1.03 (0.89 to 1.19)\t\nPreferred term\t\n Nasopharyngitis\t42 (8.8)\t53 (11.6)\t0.76 (0.52 to 1.12)\t\n Cough\t26 (5.5)\t20 (4.4)\t1.25 (0.71 to 2.18)\t\n Dyspnoea\t9 (1.9)\t17 (3.7)\t0.51 (0.24 to 1.14)\t\n Headache\t7 (1.5)\t9 (2.0)\t0.75 (0.29 to 1.96)\t\n Hypertension\t7 (1.5)\t5 (1.1)\t1.35 (0.44 to 3.91)\t\n Back pain\t6 (1.3)\t7 (1.5)\t0.83 (0.29 to 2.37)\t\n Dry mouth\t6 (1.3)\t6 (1.3)\t0.96 (0.33 to 2.83)\t\n Rhinitis\t6 (1.3)\t5 (1.1)\t1.16 (0.37 to 3.51)\t\n Bronchitis\t5 (1.1)\t3 (0.7)\t1.60 (0.40 to 5.74)\t\n Hypercholesterolaemia\t5 (1.1)\t1 (0.2)\t4.81 (0.58 to 21.36)\t\n Influenza\t4 (0.8)\t5 (1.1)\t0.77 (0.23 to 2.72)\t\n Diarrhoea\t4 (0.8)\t2 (0.4)\t1.92 (0.37 to 8.09)\t\n Myocardial infarction\t4 (0.8)\t1 (0.2)\t3.85 (0.46 to 18.24)\t\n Dysphonia\t3 (0.6)\t4 (0.9)\t0.72 (0.19 to 3.01)\t\n Cystitis\t2 (0.4)\t6 (1.3)\t0.32 (0.09 to 1.58)\t\n Chest discomfort\t2 (0.4)\t4 (0.9)\t0.48 (0.12 to 2.50)\t\n Vertigo\t2 (0.4)\t4 (0.9)\t0.48 (0.12 to 2.50)\t\n Muscle spasms\t1 (0.2)\t7 (1.5)\t0.14 (0.03 to 1.11)\t\n Pneumonia†\t1 (0.2)\t8 (1.7)\t0.12 (0.03 to 0.96)\t\n Upper abdominal pain\t1 (0.2)\t4 (0.9)\t0.24 (0.05 to 2.03)\t\n Upper respiratory tract infection\t0 (0)\t4 (0.9)\tNE (0.01 to 1.98)\t\nData are presented as n (%) unless otherwise stated. Listed adverse events (using Medical Dictionary for Regulatory Activities high-level group terms) occurred in at least four patients in any treatment group. Safety set population included all patients, receiving at least one dose of study drug.\n\n*Risk ratio is calculated as % of QVA149/ % of TIO+FOR.\n\n†Confirmed by chest X-ray examination.\n\nAE, adverse event; FOR, formoterol; NE, not estimable; RR, risk ratio; TIO, tiotropium.\n\nPneumonia occurred at a higher frequency in the TIO+FOR group than in the QVA149 group. The number of AEs leading to study discontinuation was comparable in both groups (table 3).\n\nTable 3 SAEs, deaths and discontinuation of the study drug\n\n\tQVA149 (110/50 µg)\n(N=476)\tTIO (18 µg)+ FOR (12 µg)\n(N=458)\tRR (95% CI)*\t\nPatients with any AE(s)\t208 (43.7)\t195 (42.6)\t1.03 (0.89 to 1.19)\t\n AE(s) with suspected drug relationship\t32 (6.7)\t24 (5.2)\t1.28 (0.77 to 2.12)\t\n AE(s) requiring concomitant medication/non-drug treatment\t96 (20.2)\t99 (21.6)\t0.93 (0.73 to 1.20)\t\n AE(s) leading to dose adjustment or study drug interruption\t12 (2.5)\t9 (2.0)\t1.28 (0.55 to 2.92)\t\nPatients with SAE(s)\t30 (6.3)\t24 (5.2)\t1.20 (0.72 to 2.01)\t\n SAE(s) with suspected drug relation\t3 (0.6)\t1 (0.2)\t2.89 (0.33 to 15.14)\t\nDiscontinuations\t\n Due to AEs\t20 (4.2)\t14 (3.1)\t1.38 (0.70 to 2.63)\t\n Due to SAEs\t8 (1.7)\t6 (1.3)\t1.28 (0.46 to 3.47)\t\nDeaths\t3 (0.6)\t3 (0.7)\t0.96 (0.22 to 4.21)\t\nData are presented as n (%) unless otherwise stated. Safety set included all patients who received at least one dose of the study drug.\n\n*Risk ratio is calculated as: % of QVA149/% of TIO+FOR.\n\nAE, adverse event; FOR, formoterol; RR, risk ratio; SAE, serious adverse event; TIO, tiotropium.\n\nPneumonia led to premature discontinuation in four patients in the TIO+FOR group, with two patients showing a causal relationship to the study drug. Other AEs leading to study drug discontinuation were cough (n=2 in each group), dyspnoea (QVA149, n=2 and TIO+FOR, n=1), and myocardial infarction (QVA149, n=2). Overall, AEs with a suspected relationship to the study drug were comparable in both treatment groups (table 3).\n\nOverall SAEs and SAEs leading to study discontinuations were comparable in both treatment groups (table 3). Three cases of SAEs in the QVA149 group (one patient each of cerebral ischaemia, tachycardia and an unknown reason leading to death), and one case of SAE (stress cardiomyopathy) in the TIO+FOR group were suspected to be study drug-related.\n\nOverall, three deaths were reported in each group (table 3). In the QVA149 group, the causes of death were myocardial infarction (n=1), pulmonary embolism (n=1) and an unknown reason (n=1). In the TIO+FOR group, the causes of death were acute cardiac failure (n=1), coronary artery disease (n=1) and acute dyspnoea and brain injury (n=1).\n\nDiscussion\nThe QUANTIFY study, for the first time, compared the efficacy of a fixed-dose LABA/LAMA combination (QVA149) with a free-dose combination (TIO+FOR). The combination of TIO and FOR, the standard-of-care LABA and LAMA, respectively, is suggested to be the most widely used free-dose LABA/LAMA combination, hence used as an active comparator in this study. To our knowledge, use of HRQoL as a primary endpoint for comparing active pharmacological interventions for COPD has not been previously evaluated. Moreover, it is well recognised that the effectiveness of COPD treatments should not be assessed by lung function alone.27 This is of particular relevance as the study focused on patient-reported outcomes, which are of key importance, for patients and their physicians and also for health technology assessments.28 The study met its primary endpoint by demonstrating non-inferiority of QVA149 versus TIO+FOR in terms of HRQoL, as assessed by the SGRQ-C. The non-inferiority margin of –4 points is an accepted threshold.19 The study was powered to exclude a difference of –3 units and would have reached non-inferiority even for –1 units. The treatment difference between QVA149 and TIO+FOR indicated a numerical improvement in favour of QVA149. This seemingly small difference, albeit not significant, indicates that more patients receiving QVA149 may achieve clinically relevant improvements in quality of life than those receiving TIO+FOR.19 This was corroborated with a numerically higher percentage of QVA149-treated patients achieving clinically relevant improvement in SGRQ-C25 compared with patients receiving TIO+FOR, which reached statistical significance in the PPS population.\n\nConcomitant drugs did not influence efficacy parameters as the patient baseline characteristics were comparable between treatment groups. Also, the study was undertaken within a close geographical area, so ethnicity and regional factors become negligible. Dyspnoea is the cardinal symptom of COPD and is the major symptom causing patients with COPD to seek medical attention, and also the most relevant burden on patients.1\n26 Responder rates, which are based on validated response criteria such as MCID, are accepted for comparing active treatments, as the response definition already includes a threshold for relevance.25\n29 QVA149 demonstrated a statistically significant improvement in TDI responder rates (MCID of ≥1 point improvement) compared with TIO+FOR, which was consistent with the BLAZE and the SHINE studies, with the difference being that these studies used only TIO as an active comparator.3\n29\n\nStatistically significant improvements in pre-dose FEV1 and FVC were seen in a comparison of QVA149 with TIO+FOR. It is plausible that this bronchodilatory effect might have enabled patients to attain greater levels of activity, and hence improved quality of life.30\n31 As expected, the treatment difference was not as pronounced for post-dose FEV1 and FVC, as both LABAs (indacaterol and formoterol) are potent bronchodilators with a fast onset of action.32 The simultaneous inhalation of LABA and LAMA from a single device is not the underlying cause, as the effects of QVA149 on lung function are similar to those with the concurrent administration of its monocomponents.18 There was an observed lung function decline in both treatment groups during the study (QVA149 vs TIO+FOR: 49 vs 47 mL in pre-dose FEV1) from week 12 to week 26 which may be potentially due to seasonal aspects as the patients entered this study during summer and the study was concluded in winter.33\n\nAlthough this study was neither designed nor powered to examine exacerbation rates, fewer patients receiving QVA149 had at least one moderate or severe exacerbation compared with those receiving TIO+FOR. The prevention and reduction of exacerbations might be consequent to improved 24 h bronchodilation34 and potentially contributed to the improvements in SGRQ total score and TDI responders in the QVA149 group as exacerbations are generally associated with worse health outcomes.12\n35\n\nThe beneficial clinical effects of QVA149 versus TIO+FOR treatments are probably a consequence of more potent bronchodilation translating into greater improvements in health status. This view is supported by similar results when single once-daily bronchodilators were compared with drugs with a twice-daily regimen.36\n37 It is tempting to speculate about other ‘real-life’ benefits of one versus several inhalation(s) a day, which cannot be substantiated in a triple-dummy design, owing to difficulties with different inhalers, complex medication regimens involving multiple drugs and dosing intervals, and the potential to make mistakes.\n\nThe incidence and severity of AEs and SAEs were as expected for the patient population in the stage of disease studied, with no clinically relevant differences between the groups. At first instance, the low incidence of typical side effects (eg, dry mouth in the TIO+FOR arm, cough upon inhalation in the QVA149 arm) is surprising. However, this is in line with other QVA149 trials that included tiotropium as comparator. Additionally, the QUANTIFY study recruited many patients with previous exposure to both drugs, who had experienced these side effects and no longer considered them noteworthy.3\n12\n29 There were no additional safety concerns for either QVA149 or TIO+FOR. The results were consistent with previous clinical studies.8\n11\n12\n15\n\nThere was nearly 100% compliance with treatment in both groups, which is generally expected in a trial. Clinical evidence suggests that adherence to COPD treatment in routine life is strongly correlated with dosing frequency, with once-daily dosing having the highest adherence relative to twice- or thrice-daily dosing.5 Hence, even more pronounced treatment differences can be expected in favour of QVA149 in a real-life setting as patients tend to forget their medication. In addition, QVA149 offers the benefits of dual bronchodilation via a single inhaler device, making it a more convenient option and improving adherence compared with once-daily tiotropium plus twice-daily formoterol inhaled via two different devices.\n\nThe study has certain limitations. First, the study only considered the incidence of at least one exacerbation, rather than the number of exacerbations experienced during the study. This was due to the protocol modification during the course of the study, allowing patients with a COPD exacerbation to remain in the study, instead of being withdrawn. Second, because the study was conducted between May and April the following year, seasonal factors might have influenced results. This potential risk was minimised both by randomisation and the large patient population. There was no difference in seasonal exposure to treatment between the two study arms. Third, as most patients in this trial had non-frequent exacerbations, reflecting the real-life situation, effectiveness assessment in patients with frequent exacerbations would be of interest in future trials. Finally, without a placebo arm the possibility cannot be excluded that some of the improvements seen were mainly due to better patient management in a clinical trial. However, in the QUANTIFY study all differences between the two active treatments were in favour of QVA149, strongly supporting a real treatment effect rather than a random placebo effect.\n\nConclusions\nThe QUANTIFY study showed that QVA149 is non-inferior to the standard-of-care, free-dose LABA/LAMA combination of tiotropium plus formoterol, for health-related quality of life, with consistent improvement in lung function and dyspnoea. The study supports the premise that QVA149 treatment can be a simpler alternative, suggesting improved patient adherence and compliance. QVA149 has the potential to be more effective than the free combination of TIO+FOR.\n\nSupplementary Material\nWeb supplement\n The authors thank the patients who participated, and the staff at the participating clinical centres. The authors were assisted in the preparation of the manuscript by Vivek Khanna (Novartis). All authors participated in the development and writing of the manuscript and take full responsibility for its content. All authors approved the final draft that was submitted.\n\nContributors: RB and SK contributed to the design of the study. RB, the principal investigator of the study, read and commented on the full study report, and had final responsibility for the decision to submit for publication. CG, WS, KF and SK, investigators of the study, contributed to the writing of each draft of the manuscript. SH and CS, as employees of the sponsor, contributed to the design and preparation, conduct, analysis and interpretation of the study for the manuscript, and also contributed to the writing of each draft of the manuscript.\n\nFunding: The study was supported and funded by Novartis Pharma GmbH, Germany. Writing support was funded by Novartis Pharma AG, Basel, Switzerland. No restrictions were placed on authors regarding the statements made in the manuscript.\n\nCompeting interests: RB has received reimbursement for attending scientific conferences, and/or fees for speaking and/or consulting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, Takeda and Roche. SK has served as an advisor to GlaxoSmithKline and received lecture fees from Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Takeda and Grifols. CG has served as an advisor to Boehringer Ingelheim, Chiesi, Novartis and Teva and received lectures fees from Almirall, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis. KF has received speakers fees from Almirall, Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Janssen Cilag, MSD, Mundipharma and Novartis. CS and SH are employees of Novartis Pharma GmbH.\n\nPatient consent: Obtained.\n\nEthics approval: Institutional review boards and ethics committees at participating centres.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 National Clinical Guideline Centre . Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care . London , 2010 \nhttps://www.nice.org.uk/guidance/qs10 \n2 GOLD . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease \n2014 \nhttp://www.goldcopd.com/ \n3 Bateman ED , Ferguson GT , Barnes N , et al \nDual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study . Eur Respir J \n2013 ;42 :1484 –94 . 10.1183/09031936.00200212 23722616 \n4 Donohue JF , Maleki-Yazdi MR , Kilbride S , et al \nEfficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD . Respir Med \n2013 ;107 :1538 –46 . 10.1016/j.rmed.2013.06.001 23830094 \n5 Toy EL , Beaulieu NU , McHale JM , et al \nTreatment of COPD: Relationships between daily dosing frequency, adherence, resource use, and costs . Respir Med \n2011 ;105 :435 –41 . 10.1016/j.rmed.2010.09.006 20880687 \n6 van Noord JA , Aumann JL , Janssens E , et al \nComparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD . Eur Respir J \n2005 ;26 :214 –22 . 10.1183/09031936.05.00140404 16055868 \n7 van Noord JA , Aumann JL , Janssens E , et al \nCombining tiotropium and salmeterol in COPD: effects on airflow obstruction and symptoms . Respir Med \n2010 ;104 :995 –1004 . 10.1016/j.rmed.2010.02.017 20303247 \n8 Vogelmeier CF , Bateman ED , Pallante J , et al \nEfficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study . Lancet Respir Med \n2013 ;1 :51 –60 . 10.1016/S2213-2600(12)70052-8 24321804 \n9 McKeage K \nIndacaterol: a review of its use as maintenance therapy in patients with chronic obstructive pulmonary disease . Drugs \n2012 ;72 :543 –63 . 10.2165/11208490-000000000-00000 22356291 \n10 Buhl R , Banerji D \nProfile of glycopyrronium for once-daily treatment of moderate-to-severe COPD . Int J Chron Obstruct Pulmon Dis \n2012 ;7 :729 –41 . 10.2147/COPD.S36001 23118536 \n11 Dahl R , Chapman KR , Rudolf M , et al \nSafety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study . Respir Med \n2013 ;107 :1558 –67 . 10.1016/j.rmed.2013.05.016 23867808 \n12 Wedzicha JA , Decramer M , Ficker JH , et al \nAnalysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study . Lancet Respir Med \n2013 ;1 :199 –209 . 10.1016/S2213-2600(13)70052-3 24429126 \n13 Cazzola M , Molimard M \nThe scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD . Pulm Pharmacol Ther \n2010 ;23 :257 –67 . 10.1016/j.pupt.2010.03.003 20381630 \n14 Vogelmeier C , Kardos P , Harari S , et al \nFormoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study . Respir Med \n2008 ;102 :1511 –20 . 10.1016/j.rmed.2008.07.020 18804362 \n15 Tashkin DP , Pearle J , Iezzoni D , et al \nFormoterol and tiotropium compared with tiotropium alone for treatment of COPD . COPD \n2009 ;6 :17 –25 . 10.1080/15412550902724073 19229704 \n16 van der Molen T , Cazzola M \nBeyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes . Prim Care Respir J \n2012 ;21 :101 –8 . 10.4104/pcrj.2011.00102 22222945 \n17 Wang J , Jin D , Zuo P , et al \nComparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis . Respirology \n2011 ;16 :350 –8 . 10.1111/j.1440-1843.2010.01912.x 21138499 \n18 Dahl R , Jadayel D , Alagappan VK , et al \nEfficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study . Int J Chron Obstruct Pulmon Dis \n2013 ;8 :501 –8 . 10.2147/COPD.S49615 24159259 \n19 Jones PW \nSt. George's Respiratory Questionnaire: MCID . COPD \n2005 ;2 :75 –9 . 10.1081/COPD-200050513 17136966 \n20 Karner C , Cates CJ \nLong-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease . Cochrane Database Syst Rev \n2012 ;4 :CD008989 .\n21 Karner C , Chong J , Poole P \nTiotropium versus placebo for chronic obstructive pulmonary disease . Cochrane Database Syst Rev \n2012 ;7 :CD009285 .\n22 Kew KM , Mavergames C , Walters JA \nLong-acting beta2-agonists for chronic obstructive pulmonary disease . Cochrane Database Syst Rev \n2013 ;10 :CD010177 .\n23 Jones PW , Quirk FH , Baveystock CM , et al \nA self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire . Am Rev Respir Dis \n1992 ;145 :1321 –7 . 10.1164/ajrccm/145.6.1321 1595997 \n24 Miller MR , Hankinson J , Brusasco V , et al \nStandardisation of spirometry . Eur Respir J \n2005 ;26 :319 –38 . 10.1183/09031936.05.00034805 16055882 \n25 Jones PW , Beeh KM , Chapman KR , et al \nMinimal clinically important differences in pharmacological trials . Am J Respir Crit Care Med \n2014 ;189 :250 –5 . 10.1164/rccm.201310-1863PP 24383418 \n26 Witek TJ Jr, Mahler DA \nMinimal important difference of the transition dyspnoea index in a multinational clinical trial . Eur Respir J \n2003 ;21 :267 –72 . 10.1183/09031936.03.00068503a 12608440 \n27 Glaab T , Vogelmeier C , Buhl R \nOutcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations . Respir Res \n2010 ;11 :79 \n10.1186/1465-9921-11-79 20565728 \n28 Sullivan SD , Watkins J , Sweet B , et al \nHealth technology assessment in health-care decisions in the United States . Value Health \n2009 ;12 (Suppl 2) :S39 –44 . 10.1111/j.1524-4733.2009.00557.x 19523183 \n29 Mahler DA , Decramer M , D'Urzo A , et al \nDual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study . Eur Respir J \n2014 ;43 :1599 –609 . 10.1183/09031936.00124013 24176997 \n30 Watz H , Krippner F , Kirsten A , et al \nEffects of indacaterol on lung volumes and physical activity in moderate chronic obstructive pulmonary disease . Am J Respir Crit Care Med \n2012 ;185 :A2257 .\n31 Westwood M , Bourbeau J , Jones PW , et al \nRelationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review . Respir Res \n2011 ;12 :40 \n10.1186/1465-9921-12-40 21477298 \n32 Dahl R , Chung KF , Buhl R , et al \nEfficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD . Thorax \n2010 ;65 :473 –9 . 10.1136/thx.2009.125435 20522841 \n33 Donaldson GC , Seemungal T , Jeffries DJ , et al \nEffect of temperature on lung function and symptoms in chronic obstructive pulmonary disease . Eur Respir J \n1999 ;13 :844 –9 . 10.1034/j.1399-3003.1999.13d25.x 10362051 \n34 Beeh KM , Glaab T , Stowasser S , et al \nCharacterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial . Respir Res \n2013 ;14 :116 \n10.1186/1465-9921-14-116 24168767 \n35 Spencer S , Calverley PM , Burge PS , et al \nImpact of preventing exacerbations on deterioration of health status in COPD . Eur Respir J \n2004 ;23 :\n698 –702 . 10.1183/09031936.04.00121404 15176682 \n36 Kornmann O , Dahl R , Centanni S , et al \nOnce-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison . Eur Respir J \n2011 ;37 :273 –9 . 10.1183/09031936.00045810 20693243 \n37 Vincken W , van Noord JA , Greefhorst AP , et al \nImproved health outcomes in patients with COPD during 1 yr's treatment with tiotropium . Eur Respir J \n2002 ;19 :209 –16 . 10.1183/09031936.02.00238702 11871363\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0040-6376",
"issue": "70(4)",
"journal": "Thorax",
"keywords": "COPD Pharmacology",
"medline_ta": "Thorax",
"mesh_terms": "D058666:Adrenergic beta-2 Receptor Agonists; D000368:Aged; D001993:Bronchodilator Agents; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004983:Ethanolamines; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006024:Glycopyrrolate; D006801:Humans; D007189:Indans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D011788:Quality of Life; D015363:Quinolones; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide; D016896:Treatment Outcome; D014797:Vital Capacity",
"nlm_unique_id": "0417353",
"other_id": null,
"pages": "311-9",
"pmc": null,
"pmid": "25677679",
"pubdate": "2015-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "11871363;24176997;15176682;1595997;10362051;16055868;16055882;17136966;18804362;19229704;19523183;20522841;20381630;20565728;20303247;20880687;21138499;20693243;21477298;22356291;22222945;22513969;22786525;23118536;23830094;23867808;24159259;24127118;23722616;24321804;24429126;24168767;24383418;12608440",
"title": "Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study.",
"title_normalized": "efficacy and safety of once daily qva149 compared with the free combination of once daily tiotropium plus twice daily formoterol in patients with moderate to severe copd quantify a randomised non inferiority study"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-08839GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FORMOTEROL"
},
... |
{
"abstract": "OBJECTIVE\nCardiac late effects are responsible for a significant burden of mortality and morbidity among pediatric Hodgkin's lymphoma (HL) survivors (HLS). The aim of our study was to assess clinical and subclinical cardiac sequelae in a cohort of childhood HLS treated in the 1980s with doxorubicin, bleomycin, vinblastine, and dacarbazine (the ABVD regimen) and limited-field radiotherapy (RT).\n\n\nMETHODS\nWe retrospectively examined a series of HLS treated from 1979 to 1989. We searched for subtle cardiac abnormalities in a subgroup of asymptomatic individuals, who underwent rest and exercise echocardiography at least 20 years after completing their therapies. Their cardiac assessment included physical examination, electrocardiogram (ECG), and resting and postexercise echocardiograms.\n\n\nRESULTS\nOn thorough cardiac assessment a mean of 21 years after their diagnosis, none of the 53 unselected asymptomatic HLS showed physical signs or significant ECG abnormalities during or after the stress echo test. Twenty-two (41%) of the 53 patients revealed valvular abnormalities, with mitral regurgitation in 28%, aortic regurgitation in 9%, and both in 4%. No significant myocardial dysfunction as a result of previous combined doxorubicin treatment and chest RT was identified. Only 2 individuals had mild pericardial alterations.\n\n\nCONCLUSIONS\nThe present study shows that long-term cardiac effects are common in HLS treated with the ABVD regimen and RT. The most frequent complications observed in this sample were essentially coronary artery disease and valvular abnormalities. None of the survivors in this sample showed overt congestive heart failure, a finding in contrast with larger studies.",
"affiliations": "Cardiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatrics Departments, Ospedali Santi Paolo e Carlo, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.;Mario Negri Institute for Pharmacological Research IRCCS, Milan - Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.",
"authors": "Materazzo|Carlo|C|;Massimino|Maura|M|;Schiavello|Elisabetta|E|;Podda|Marta|M|;Gandola|Lorenza|L|;Cefalo|Graziella|G|;Catania|Serena|S|;Meazza|Cristina|C|;Moschetti|Ivan|I|;Terenziani|Monica|M|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.5301/tj.5000670",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "103(6)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine; D004317:Doxorubicin; D005260:Female; D006321:Heart; D006331:Heart Diseases; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D017741:Survivors; D014747:Vinblastine",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "566-571",
"pmc": null,
"pmid": "28708228",
"pubdate": "2017-11-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical and subclinical cardiac late effects in pediatric Hodgkin's lymphoma survivors.",
"title_normalized": "clinical and subclinical cardiac late effects in pediatric hodgkin s lymphoma survivors"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1082024",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Chronic neutrophilic leukaemia is a very rare disease with diagnosis based on persistent leucocytosis >25×103/μl and monocytes <1×103/μl. The revised WHO criteria 2016 included CSF3R gene mutations as a diagnostic finding. We report the case of a 77-year-old man who was found to have asymptomatic persistent mature neutrophilic leucocytosis with monocytosis. Molecular study confirmed the presence of a CSF3R gene mutation in the absence of morphological or genetic features of myelodysplasia or other forms of myelodysplastic syndrome. The patient's medical history was significant for coronary artery disease, hypertension, chronic obstructive pulmonary disease, bilateral cystic bronchiectasis, moderate pulmonary hypertension, tuberculosis treated 27 years previously, hypothyroidism, and a thyroid nodule. He had hepatosplenomegaly but no lymphadenopathy, and no other malignancy was seen on computed tomography (CT) scanning. At the time of evaluation, he was free of symptoms and had no evidence of infection or drug-induced leucocytosis. The patient was referred to an oncology centre and treated with hydroxyurea and subsequently azacitidine. However, he developed pancytopenia with bone marrow aplasia. He died with neutropenia sepsis. The presence of persistent monocytosis in this case created a diagnostic dilemma as to whether the disease was a variant of chronic neutrophilic leukaemia or was reactive monocytosis.\nThe presence of a CSF3R gene mutation is diagnostic for chronic neutrophilic leukaemia (CNL).The monocytosis in this patient might have been a new variant of CNL.",
"affiliations": "Internal Medicine Department, KFMMC, Dhahran, Kingdom of Saudi Arabia.;Internal Medicine Department, KFMMC, Dhahran, Kingdom of Saudi Arabia.;Internal Medicine Department, KFMMC, Dhahran, Kingdom of Saudi Arabia.;Internal Medicine Department, KFMMC, Dhahran, Kingdom of Saudi Arabia.;Internal Medicine Department, KFMMC, Dhahran, Kingdom of Saudi Arabia.;Radiology Department, Nuclear medicine division, KFMMC Dhahran, Kingdom of Saudi Arabia.;Clinical Hematology and Internal Medicine, Ain Shams University, Cairo, Egypt.",
"authors": "Alromaih|Laila|L|;Abdalla|Leena|L|;Jamal|Arifa|A|;Osman|Assim|A|;Bakkar|Mohanad|M|;Samad|Lina Abdul|LA|;Ahmed|Tamer M|TM|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2021_002595",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "8(5)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Chronic neutrophilic leukaemia; atypical chronic myeloid leukaemia; chronic myelomonocytic leukaemia; colony-stimulating factor 3 receptor mutation; myeloproliferative neoplasm",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002595",
"pmc": null,
"pmid": "34123950",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "29512199;29878489;29085786;27069254;31769070",
"title": "Chronic Neutrophilic Leukemia with Monocytosis.",
"title_normalized": "chronic neutrophilic leukemia with monocytosis"
} | [
{
"companynumb": "SA-CELGENE-SAU-20210607895",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": "4",
... |
{
"abstract": "Catheter related infections are reported as one of the most common source of nosocomial infections. Rhizobium radibacter infections are generally manifested by fever and leukocytosis. Here, a 14 months-old girl diagnosed as T (-) B (-) NK (+) severe combined immunodeficiency (SCID) is presented. She had received repeated (x3) unconditioned haploidentical hematopoetic stem cell transplantations. During the follow-up, she has been arised an asymptomatic infection with R. Radiobacter, which was isolated from central venous catheter and peripheral blood while she was clinically stable, free of symptoms, fever or leukocytosis. She was treated successfully with cefepime and amikacin and did not require catheter removal. So, it is once more clear that the blood cultures should be obtained on regular basis from all patients with an intravascular device, even they were asymptomatic.",
"affiliations": "Ankara University School of Medicine, Department of Pediatric Immunology-Allergy, Ankara, Turkey. drferol@yahoo.com.tr",
"authors": "Erol Cipe|Funda|F|;Doğu|Figen|F|;Sucuoğlu|Deniz|D|;Aysev|Derya|D|;Ikincioğulları|Aydan|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime; D000583:Amikacin",
"country": "Italy",
"delete": false,
"doi": "10.3855/jidc.1009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1972-2680",
"issue": "4(8)",
"journal": "Journal of infection in developing countries",
"keywords": null,
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D016960:Agrobacterium tumefaciens; D000583:Amikacin; D000900:Anti-Bacterial Agents; D001769:Blood; D055499:Catheter-Related Infections; D002405:Catheterization, Central Venous; D057785:Catheters; D000077723:Cefepime; D002511:Cephalosporins; D003428:Cross Infection; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D016511:Severe Combined Immunodeficiency; D033581:Stem Cell Transplantation",
"nlm_unique_id": "101305410",
"other_id": null,
"pages": "530-2",
"pmc": null,
"pmid": "20818107",
"pubdate": "2010-09-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asymptomatic catheter related Rhizobium radiobacter infection in a haploidentical hemapoetic stem cell recipient.",
"title_normalized": "asymptomatic catheter related rhizobium radiobacter infection in a haploidentical hemapoetic stem cell recipient"
} | [
{
"companynumb": "TR-B.BRAUN MEDICAL INC.-2115446",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nWe present spontaneous retrobulbar hemorrhage in a 52-year-old woman with history of breast cancer and tamoxifen intake which was first thought to be an orbital metastasis.\n\n\nMETHODS\nA 52-year-old woman with history of breast cancer and tamoxifen intake was referred due to severe proptosis and visual loss. Orbital imaging showed an intra-conal mass. After exploration, multiple fragments of dark brown mass in the retrobulbar area were excised. Microscopic diagnosis was blood clot. All of clinical signs and symptoms were improved 1 week after operation.\n\n\nCONCLUSIONS\nSpontaneous retrobulbar hemorrhage is a rare condition that may have unknown etiologies, and its symptoms may mimic orbital metastasis. Since both breast cancer and tamoxifen intake can cause coagulation disorders, they might be possible causes for retrobulbar hemorrhage in this case.",
"affiliations": "Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran.;Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran.;Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran.;Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran.",
"authors": "Rajabi|Mohammad Taher|MT|;Hassanpoor|Narges|N|;Parsa|Razieh|R|;Niyousha|Mohamad Reza|MR|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.joco.2015.12.004",
"fulltext": "\n==== Front\nJ Curr OphthalmolJ Curr OphthalmolJournal of Current Ophthalmology2452-2325Elsevier S2452-2325(15)30043-310.1016/j.joco.2015.12.004Case ReportSpontaneous retrobulbar hemorrhage in a patient with breast cancer: A case report Rajabi Mohammad Taher Hassanpoor Narges nargeshassanpoor@gmail.com∗Parsa Razieh Niyousha Mohamad Reza Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran∗ Corresponding author. Eye Research Center, Farabi Eye Hospital, Qazvin Square, Tehran 1336616351, Iran. Tel.: +98 2155418113. nargeshassanpoor@gmail.com03 2 2016 3 2016 03 2 2016 28 1 48 51 14 11 2015 29 12 2015 29 12 2015 Copyright © 2016, Iranian Society of Ophthalmology. Production and hosting by Elsevier B.V.2016Iranian Society of OphthalmologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nWe present spontaneous retrobulbar hemorrhage in a 52-year-old woman with history of breast cancer and tamoxifen intake which was first thought to be an orbital metastasis.\n\nCase report\nA 52-year-old woman with history of breast cancer and tamoxifen intake was referred due to severe proptosis and visual loss. Orbital imaging showed an intra-conal mass. After exploration, multiple fragments of dark brown mass in the retrobulbar area were excised. Microscopic diagnosis was blood clot. All of clinical signs and symptoms were improved 1 week after operation.\n\nConclusion\nSpontaneous retrobulbar hemorrhage is a rare condition that may have unknown etiologies, and its symptoms may mimic orbital metastasis. Since both breast cancer and tamoxifen intake can cause coagulation disorders, they might be possible causes for retrobulbar hemorrhage in this case.\n\nKeywords\nSpontaneous retrobulbar hemorrhageBreast cancerTamoxifen\n==== Body\nIntroduction\nRetrobulbar hemorrhage may occur spontaneously or as a subsequent of a distinct etiology. Some etiologies known until now include orbital vascular anomalies, subsequent trauma, surgery around the orbit, and systemic disease such as coagulopathy, toxic conditions, and uncontrolled hypertension.1 It has been reported secondary to orbital tumor and pseudotumor. Spontaneous retrobulbar hemorrhage is a rare condition.1 Symptoms may occur gradually or suddenly. Herein, we present a case of spontaneous retrobulbar hemorrhage that developed symptoms mimicking orbital mass and did not have known etiology except history of breast cancer and tamoxifen intake.\n\nCase report\nA 52-year-old woman with history of breast cancer was referred to Oculoplastic Service, Farabi Eye Hospital, Tehran, Iran for evaluating proptosis. A compressive orbital mass was detected in her MRI and was taken to the neurologic department. She had complained of acute ocular pain and progressive visual loss in her left eye from 2 weeks earlier. She had been using tamoxifen since 5 years earlier after mastectomy due to her right breast cancer. She had no history of other systemic disease or trauma. On examination, left eye visual acuity was finger count at 1 m, and she had a left afferent pupillary defect. There was a severe inferolateral proptosis (28 mm in Hertel exophthalmometry), secondary ptosis, and limitation of ocular motility in almost all directions, especially in elevation and adduction (Fig. 1). There was not any evidence of concurrent periorbital hematoma or subconjunctival hemorrhage. Her left eye intraocular pressure was 23 mm Hg. At fundus examination, optic disc margin was blurred. Routine lab tests and hematologic tests including bleeding time, clotting time, and platelet count were within normal limits without evidence of bleeding tendency. Her systemic blood pressure was 138/98 mmHg. The patient was not on Aspirin or any type of anticoagulation.\n\nOrbital CT scan showed an elliptical well-defined mass within the left intraconal space. It was a high-density and homogenous consistency mass that compressed and displaced the optic nerve to the supranasal side (Fig. 2). Orbital T1 weighted MRI demonstrated an intraconal mass extending to the orbital apex that had a hypointense layer around the hyperintense mass without enhancement (Fig. 3a, c). At the T2 weighted MR scan, the intraconal mass was isointense but the superior part of the mass was hyperintense, and the other part that was near the orbital apex was hypointense (Fig. 3b). The patient underwent supralateral lid crease orbitotomy. While opening the mass, at first a yellowish liquid was depleted, and then gelatinous, semiclotted blood was removed. Finally, a solid mass that was similar to a hard blood clot remained (Fig. 4). Pathologic report confirmed the diagnosis of blood clot. Visual acuity dramatically improved to 20/30 one week after operation, and other clinical symptoms and signs improved completely.\n\nDiscussion\nSpontaneous retrobulbar hemorrhage without known etiology is rare.1 In many case reports differentiation between retrobulbar hematoma and tumor metastasis according to clinical symptoms has been impossible. Metastatic breast cancer is the leading cause of orbital metastasis and is responsible for 48–53% of orbital metastatic tumors.2\n\nImaging such as CT scan and MRI plays an important role to differentiate between metastatic breast cancer and retrobulbar hematoma. There are multiple characteristic features to diagnose metastatic breast cancer in MRI and CT scan, including diffuse intraconal lesions, intra-muscle masses, and diffuse enhancement of retro-bulbar fat with abnormal heterogenous hypointensity and fibrotic infiltration and bone destruction contagious to the mass.3 But in our case, axial T1 weighted MRI obtained 15 days after beginning of symptoms demonstrated a halo of low signal mass surrounding a high signal mass. T2 weighted image revealed layering pattern of signal. These findings express a hematoma that has started to undergo physical changes and biochemical hemoglobin lysis. On the other hand, a deeper part of the hematoma had a solid part that was hypointense both at T1 and T2 and presented like a foreign body at MRI (Hypointense at T1 and T2). Even though it was predictable that the mass could be a hematoma considering the acute onset and multilayer nature of the mass in MRI, we did not offer a needle aspiration before surgery for two reasons: Firstly, the deeper part of the mass seemed to be dense and solid according to MRI, so we could not aspirate it easily. Secondly, the most important differential diagnosis in this patient was orbital metastasis, and needle aspiration did not seem to be a good plan for its management.\n\nSeveral cases of retrobulbar hemorrhage without definite etiology similar to our case has been reported.1, 2, 4 Matsuura et al.3 reported a patient with orbital discomfort and exophthalmos without concomitant trauma, which firstly has been mistaken to be an orbital tumor. Orbital CT scan revealed a round mass without enhancement, after surgical removal and diagnosis was blood cyst.3 Tsatsami et al.5 reported a 75-year-old man who presented with sudden onset visual loss, orbital pain, and exophthalmos. Histologic finding demonstrated pseudotumor with hemorrhagic changes.\n\nPatients with history of breast cancer are at higher risk for coagulation disorders compared with the healthy population. Tumor cell properties change balance between coagulation and fibrinolysis mechanism.6 Furthermore, hypercoagulability state could be induced by different medical interventions such as hormonal agents in this group of patients. Breast cancer is a known cause for chronic disseminated intravascular coagulopathy.7\n\nNumerous clinical studies revealed that Tamoxifen could increase the risk of venous and arterial thrombosis rather than increasing bleeding tendency.6, 8 The presented case did not have any known disease that can cause retrobulbar hemorrhage except for history of breast cancer and Tamoxifen intake. As there was not any evidence for orbital metastasis or disease recurrence in this patient, we cannot easily attribute this orbital hemorrhage to them. The second most important suspicious cause for hemorrhage in this patient could be Tamoxifen, if we could consider it as a cause for chronic mild disseminated intravascular coagulopathy.9 As we know, this is the first case report of spontaneous orbital hemorrhage in a patient with history of breast cancer and tamoxifen intake, so it could be considered as a basis for further research.\n\nPeer review under responsibility of the Iranian Society of Ophthalmology.\n\nFig. 1 Photograph showing proptosis and lateral displacement of globe.\n\nFig. 2 Orbital CT scan, axial view showing a well-defined intraconal mass in the left orbit that pushed the optic nerve medially.\n\nFig. 3 a. T1 weighted axial MRI. b. T2 weighted. c. T1 weighted MRI with contrast but unfortunately without fat suppression. Orbital MRI shows an intraconal mass extending to the orbital apex that was multilayer without enhancement. Small arrow shows a part of the mass that is hypointense in T1 and hyperintense in T2, which was the yellowish liquid plasma during surgery. Thick arrow showing the gelatinous part of the mass that was semiclotted blood. Thin arrow shows the clot part of the mass that was solid and present as foreign body at MRI and was hypointense both at T1 and T2.\n\nFig. 4 a. Gelatinous part of the mass that was semiclotted blood. b. solid part of the mass that was hypointense both at T1 and T2.\n==== Refs\nReferences\n1 Kwon J.H. Song Y.J. Choi S.S. Kim K.U. Spontaneous intraorbital hemorrhage: a case report J Korean Neurosurg Soc 44 2008 156 158 19096667 \n2 Meltzer D.E. Chang A.H. Shatzkes D.R. Case 152: orbital metastatic disease from breast carcinoma Radiology 253 2009 893 896 19952028 \n3 Matsuura H. Baba M. Kudo M. Nakaoka T. Spontaneous intraorbital hematoma mimicking orbital neoplasm–case report Neurol Med Chir (Tokyo) 35 1995 45 47 7700483 \n4 Yamashita T. Hosoda H. Shinonaga M. Fujitsu K. Kuwabara T. Unilateral exophthalmos caused by organized hematoma of the orbit–report of a case No Shinkei Geka 6 1978 185 189 634446 \n5 Tsutsumi S. Higo T. Kondo A. Abe Y. Yasumoto Y. Ito M. Orbital pseudotumor associated with retrobulbar hematoma: case report Neurol Med Chir (Tokyo) 47 2007 265 268 17587779 \n6 Kyriazi V. Breast cancer as an acquired thrombophilic state J Breast Cancer 15 2012 148 156 22807931 \n7 Sallah S. Wan J. Nguyen N. Hanrahan L. Sigounas G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study Thromb Haemost 86 2001 828 833 11583315 \n8 Jokuszies A. Radtke C. Betzler C. Branski L. Krämer R. Vogt P.M. Is tamoxifen associated with an increased risk for thromboembolic complications in patients undergoing microvascular breast reconstruction? Ger Med Sci 11 2013 Doc05 \n9 Kim Yoon Joon Kim Ok Kim Jinkwon Cerebral venous thrombosis in a breast cancer patient taking tamoxifen: report of a case Int J Surg Case Rep 6 2015 77 80 25528030\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-2325",
"issue": "28(1)",
"journal": "Journal of current ophthalmology",
"keywords": "Breast cancer; Spontaneous retrobulbar hemorrhage; Tamoxifen",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "48-51",
"pmc": null,
"pmid": "27239604",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "23423877;11583315;7700483;19952028;634446;22807931;17587779;19096667;25528030",
"title": "Spontaneous retrobulbar hemorrhage in a patient with breast cancer: A case report.",
"title_normalized": "spontaneous retrobulbar hemorrhage in a patient with breast cancer a case report"
} | [
{
"companynumb": "IR-MYLANLABS-2016M1019168",
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"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
... |
{
"abstract": "Carbidopa is being explored as a novel therapy for hyperadrenergic symptoms of autonomic disorders, due to its potential to decrease peripheral catecholamine levels. This study retrospectively characterized patients in our autonomic clinic who were prescribed carbidopa for open label treatment of autonomic symptoms. 23 patients were included; approximately half had postural orthostatic tachycardia syndrome. Those with documented plasma catecholamines had elevated standing norepinephrine. Patients typically had multiple comorbidities and multiple failed therapies. 19 took carbidopa (typically 25 mg three times daily); 12 continued it for longer than 3 months. 11 patients reported better symptom control with carbidopa, most commonly tremor and gastrointestinal dysfunction. 4 patients reported side effects. In this small retrospective study, carbidopa was well tolerated in patients with dysautonomia, and half reported symptomatic benefit. Larger, placebo-controlled trials are warranted for further investigation of this therapy.",
"affiliations": "Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America. Electronic address: Elisabeth.golden@utsouthwestern.edu.;Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America.;Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America.",
"authors": "Golden|Elisabeth P|EP|;Park|Christine J|CJ|;Vernino|Steven|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.autneu.2021.102888",
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"fulltext_license": null,
"issn_linking": "1566-0702",
"issue": "236()",
"journal": "Autonomic neuroscience : basic & clinical",
"keywords": "Baroreflex failure; Carbidopa; Dysautonomia; Postural orthostatic tachycardia syndrome",
"medline_ta": "Auton Neurosci",
"mesh_terms": null,
"nlm_unique_id": "100909359",
"other_id": null,
"pages": "102888",
"pmc": null,
"pmid": "34610497",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Symptomatic use of carbidopa in autonomic disorders.",
"title_normalized": "symptomatic use of carbidopa in autonomic disorders"
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{
"actiondrug": "5",
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"activesubstancename": "CARBIDOPA"
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"drugadditional": "3",
... |
{
"abstract": "Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a rare non-Hodgkin's lymphoma that arises as a single, or multiple dome-shaped tumours on the skin. The histology is characterised by the presence of atypical lymphocytes with large irregularly shaped nuclei that express the surface marker CD30. There can be significant heterogeneity in clinical manifestation and histological pattern and in rare cases accurate diagnosis can be a challenge. Here, we present an unusual case presentation of cutaneous CD30+ anaplastic large cell lymphoma with significant granulomatous histology pattern that mimicked sarcoid. After a lack of durable response to treatments that included glucocorticoid and methotrexate, targeted treatment with anti-CD30 monoclonal antibody drug conjugate (brentuximab vedotin) yielded long-term clinical remission.",
"affiliations": "Medicine, Division of Hematology Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Pathology, Geisinger Medical Laboratories, Danville, Pennsylvania, USA.;Dermatology, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, USA hkwong@uams.edu.",
"authors": "Sasapu|Appalanaidu|A|;Dunn|Andrew L J|ALJ|;Gardner|Jerad|J|;Wong|Henry K|HK|http://orcid.org/0000-0001-9181-7195",
"chemical_list": "D018796:Immunoconjugates; D000079963:Brentuximab Vedotin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "dermatology; oncology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000079963:Brentuximab Vedotin; D006801:Humans; D018796:Immunoconjugates; D017728:Lymphoma, Large-Cell, Anaplastic; D054446:Lymphoma, Primary Cutaneous Anaplastic Large Cell; D012878:Skin Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34290015",
"pubdate": "2021-07-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Remission of refractory granulomatous primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin.",
"title_normalized": "remission of refractory granulomatous primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin"
} | [
{
"companynumb": "US-PFIZER INC-202200338389",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nStage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT).\n\n\nMETHODS\nTreatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed.\n\n\nRESULTS\nBetween February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis.\n\n\nCONCLUSIONS\nConcurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.",
"affiliations": "University of Groningen and Department of Pulmonary Diseases, University Medical Center Groningen, Hanzeplein 1, P,O, Box 30,001, Groningen 9700 RB, The Netherlands. g.s.m.a.kerner@umcg.nl.",
"authors": "Kerner|Gerald S M A|GS|;van Dullemen|Leon F A|LF|;Wiegman|Erwin M|EM|;Widder|Joachim|J|;Blokzijl|Edwin|E|;Driever|Ellen M|EM|;van Putten|John W G|JW|;Liesker|Jeroen J W|JJ|;Renkema|Tineke E J|TE|;Pieterman|Remge M|RM|;Mertens|Marc J F|MJ|;Hiltermann|Thijo J N|TJ|;Groen|Harry J M|HJ|",
"chemical_list": "D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D014747:Vinblastine; C056507:gemcitabine; D016190:Carboplatin; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/1748-717X-9-190",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 25174943117010.1186/1748-717X-9-190ResearchConcurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer Kerner Gerald SMA g.s.m.a.kerner@umcg.nl van Dullemen Leon FA l.f.a.van.dulemen@umcg.nl Wiegman Erwin M e.wiegman@isala.nl Widder Joachim j.widder@umcg.nl Blokzijl Edwin e.blokzijl@umcg.nl Driever Ellen M e.m.driever@umcg.nl van Putten John WG jwg.van.putten@mzg.nl Liesker Jeroen JW j.liesker@sze.nl Renkema Tineke EJ tejrenkema@gmail.com Pieterman Remge M r.pieterman@ozg.eu Mertens Marc JF m.j.f.mertens@wza.nl Hiltermann Thijo JN t.j.n.hiltermann@umcg.nl Groen Harry JM h.j.m.groen@umcg.nl University of Groningen and Department of Pulmonary Diseases, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, Groningen, 9700 RB The Netherlands University of Groningen and Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands Martini Hospital, Groningen, The Netherlands Scheper Hospital, Emmen, The Netherlands Refaja Hospital, Stadskanaal, The Netherlands Ommelander Hospital Group, Delfzijl, The Netherlands Wilhelmina Hospital, Assen, The Netherlands 29 8 2014 29 8 2014 2014 9 19022 3 2014 16 8 2014 © Kerner et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nStage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT).\n\nPatients & methods\nTreatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed.\n\nResults\nBetween February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36–86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis.\n\nConclusion\nConcurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.\n\nKeywords\nGemcitabineStage III NSCLCRadiotherapyConcurrent chemoradiotherapyissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nAt presentation approximately 30% of patients with non-small-cell lung cancer (NSCLC) have locally advanced (stage III) disease [1]. Median overall survival for clinically staged NSCLC stage IIIA is 14 months and for stage IIIB 10 months with five-year survival of 19% and 7%, respectively [2]. For good performance patients with unresectable stage III disease, the treatment of choice is concurrent chemoradiotherapy [3, 4]. Different treatment modalities are used in practice, but none is clearly superior to others [5–11].\n\nGemcitabine is among the strongest radiosensitizing drugs available, but its use in lung cancer has been limited due to substantial toxicity when combining full-dose gemcitabine with radiotherapy in treatment of stage III NSCLC [12, 13]. Excess rates of radiation pneumonitis have been reported using gemcitabine in chemoradiation for lung cancer in earlier studies that had used 2D radiotherapy [14, 15]. Previously, a phase I trial was conducted at our institution establishing a safe schedule of concurrent weekly 300 mg/m2 gemcitabine and 3D-CRT [16]. These results were confirmed in a phase II trial at our institution [17].\n\nHere we report survival time and treatment related toxicity of this treatment regimen in a consecutive cohort of patients receiving gemcitabine-based concurrent chemoradiotherapy for stage III unresectable NSCLC over a period of 7 years. A subgroup analysis of patients aged >70 years was planned a priori.\n\nMaterials and methods\nPatient selection\nFrom February 2002 until December 2009, consecutive patients with stage III unresectable NSCLC who were treated with concurrent chemoradiotherapy with gemcitabine as radiosensitizer referred to one radiotherapy department from 6 hospitals in the northern part of the Netherlands were studied. Staging was performed by whole body 18 F-FDG-PET, contrast enhanced chest CT, bronchoscopy, endoscopic ultrasound with fine-needle biopsy and mediastinoscopy. Treatment-related decisions were made during the weekly multidisciplinary meetings. The decision for treating these patients with this scheme, which was regarded as the standard treatment protocol for NSCLC stage III, was based on physical condition (performance status according to WHO), co-morbidity, and expected radiotherapy dose–volume constraints.\n\nInduction chemotherapy\nChemotherapy consisted of two cycles of cisplatin 75 mg/m2 on day 1 and gemcitabine 1125 mg/m2 administered intravenously on day 1 and 8 of each 21-day cycle. This dose of gemcitabine provides the same dose intensity as the older 3 out of 4 week schedule. Anti-emetics were ondansetron 8 mg twice daily on days 1 and 2, and dexamethasone 8 mg twice a day on days 1 and 2 of each cycle and aprepitant 125 mg on day 1 and 80 mg on days 2 and 3. The interval between the first dose of induction chemotherapy and the start of radiotherapy was 6 weeks.\n\nRadiotherapy with gemcitabine as sensitizer\nPatients received 3D-CRT to a total dose of 60 Gy, administered over 5 weeks in once daily fractions of 2.4 Gy five days per week, together with once weekly gemcitabine 300 mg/m2. Gemcitabine was omitted when leucocytes were below 3.109/L or platelets below 100.109/L. The gross target volume (GTV) was delineated on the planning-CT and included the primary tumor and enlarged FDG-avid, or pathologically proven lymph nodes. Until 2005, tumor motion was determined with fluoroscopy and respective margins were added to the GTV, thereafter, an internal target volume (ITV) was individually delineated using a 4D-planning CT. A 5 mm margin was added to arrive at the clinical target volume, another 6 mm were added for the planning target volume (PTV). Radiotherapy was delivered using 6 MV photons, the dose was specified at the isocenter and was corrected for pulmonary heterogeneity. The total radiation dose administered corresponded to an equivalent dose of 62 Gy if it were given in 2 Gy daily fractions.\n\nDose constraints\nThe spinal cord dose was constrained to 50 Gy. The mean lung dose (MLD) should not exceed 20 Gy (uncorrected for the slightly higher dose per fraction; this would equal 21.6 Gy converted to 2Gy/fraction equivalent dose using an alpha/beta of 3Gy in the linear quadratic formula). The V20 (the volume of the total lung volume receiving ≥ 20 Gy) was constrained to 30% (this value is challenging to recalculate using the linear-quadratic formula, but will correspond to a value about 8% higher if given in 2Gy daily fractions).\n\nFor patients with high-volume disease, a proof-planning was made and evaluated for feasibility by the radiation oncologist. If necessary, the radiation dose was adapted. If the pulmonary dose constraints were still considerably exceeded after radiation dose reduction, patients were excluded from this protocol.\n\nTreatment evaluation\nComplete blood cell counts were performed on days 1, 8, and 22 of each induction chemotherapy cycle. On day 1 of each cycle, patient evaluation also included liver and renal functions, performance status, and toxicity scoring. During radiotherapy, complete blood cell counts and toxicity evaluation were performed. Two months after completion of treatment a response CT scan was obtained and patients were followed every 3 months with physical examination, laboratory tests and chest x-ray. Disease progression was defined according to RECIST 1.0 criteria [18]. Toxicity (esophagitis, and radiation pneumonitis) related to treatment was retrospectively scored using the Common Toxicity Criteria (CTCAE 3.0) of the National Cancer Institute.\n\nStatistical analysis\nDescriptive statistics were used to characterize clinical features and toxicity. Using the Kaplan-Meier method, overall survival (OS) and progression-free survival (PFS) were calculated from the date of diagnosis until death, loss to follow-up, or first documentation of progressive disease, respectively. A subgroup analysis in patients aged over 70 years was performed to evaluate the outcome in elderly patients. Cox regression analysis was performed with the variables age, smoking, gender, histology, radiation dose, WHO performance score and PTV. A p-value of < 0.05 was considered statistically significant. All calculations were performed using SPSS 20.0 (International Business Machines Corp, Armonk, NY, USA).\n\nResults\nThree hundred and eighteen subsequent patients receiving concurrent chemoradiotherapy with gemcitabine as a radiosensitizer were studied. Median age was 64 years (range 36–86); male/female was 72/28%; WHO PS 0/1/2 was 44, 53 and 3%. A total of 93 patients were aged ≥ 70.\n\nChemotherapy\nTwo hundred and forty-two patients (76%) received cisplatin and gemcitabine as induction, 42 (13%) received carboplatin and gemcitabine, and 9 patients (3%) received other schedules. Twenty five (8%) patients did not receive induction chemotherapy. A total of 259 patients (81%) received all 5 weekly doses of gemcitabine during radiotherapy, 244 (76%) received both full dose gemcitabine and full dose radiotherapy. Fifty-one patients (16%) received between 1 and 4 gemcitabine administrations weekly, mainly due to neutropenia and thrombocytopenia. For the remaining 8, no information was available. Patient characteristics are detailed in Table 1. Interestingly, advanced age did not lead to decreasing the concomitant gemcitabine dose (Table 2).Table 1 \nPatient characteristics\n\n\n\tNumber of patients\t\t\n\t (N = 318)\t %\t\nAge\t64 (36–86)\t\t\nMale/Female ratio\t229/89\t72/28\t\nWHO 0\t129\t44\t\n1\t151\t53\t\n2\t10\t3\t\nUnknown\t28\t\t\nHistology\t\t\t\nAdenocarcinoma\t68\t21.4\t\nSquamous cell\t157\t49.4\t\nNSCLC-NOS\t93\t29.2\t\nSmokers\t\t\t\nNone\t9\t3\t\nCurrent\t163\t51\t\nFormer\t109\t34\t\nUnknown\t37\t12\t\nInduction treatment\t\t\t\nCisplatin/gemcitabine\t242\t76\t\nCarboplatin/gemcitabine\t42\t13\t\nPlatinum/pemetrexed\t4\t1\t\nOther\t5\t2\t\nNo induction\t25\t8\t\nRadiotherapy dose received\t\t\t\n30-59 Gy\t34\t11\t\n60 Gy\t284\t89\t\n>60 Gy\t0\t0\t\nDuring chemoradiotherapy:\t\t\t\nReceived 5 gemcitabine cycles\t\t\t\nand 60 Gy\t244\t76\t\nReceived 1–4 gemcitabine cycles\t\t\t\nand/or received less\t\t\t\nthen 60 Gy\t74\t24\t\nTable 2 \nNumber of cycles of weekly gemcitabine with respect to age in stage III NSCLC\n\n\n\tAge < 70\t\tAge ≥ 70\t\tTotal\t\t\n1\t1\t(<1%)\t0\t\t1\t(<1%)\t\n2\t7\t(3%)\t3\t(3%)\t10\t(3%)\t\n3\t9\t(4%)\t7\t(8%)\t16\t(5%)\t\n4\t13\t(6%)\t11\t(12%)\t24\t(8%)\t\n5\t188\t(84%)\t71\t(76%)\t259\t(84%)\t\nFrom 8 patients the weekly gemcitabine dosage was not specified.\n\n\n\nSeven patients (2%) had a tumor resection after chemoradiotherapy.\n\nRadiotherapy\nThe radiotherapy dose was 60 Gy in 284 patients (89%) while less than 60 Gy (range, 29 to 58 Gy) was administered in 34 patients (11%). These 34 patients included 17 patients with increased risk of radiation pneumonitis due to increased V20 and 8 patients who stopped treatment due to radiation related toxicity including 3 patients with CTC grade 3 esophagitis. Nine patients received less than 60 Gy for undocumented reasons.\n\nThe median PTV was 431 cc with the 90th percentile at 734 cc. Median V20 was 22.7% and the 90th percentile was 31.0%. In patients aged ≥ 70, median PTV was not different at 411 cc with the 90th percentile at 702 cc. Median V20 was 23%, with the 90th percentile at 30.6%.\n\nSurvival\nMedian PFS was 15.5 months (95% CI., 12.9-18.1) (Figure 1a) and median OS was 24.6 months (95% CI., 21.0-28.1) with a 5-year survival of 26% (Figure 1b). In the 244 patients who completed full concurrent treatment, median survival was 26.3 months (95% CI., 21.9-30.6 months) with a 5-year survival of 27%. In patients aged ≥ 70, median PFS was 18.7 (95% CI., 10.0-27.4) and OS was 26.2 months (95% CI., 19.0-33.4) with a 19% 5 year survival rate.Figure 1 \nSurvival of 318 patients treated with gemcitabine and 3D concurrent radiotherapy. a. Median Progression Free Survival was 15.5 months (95% CI., 12.9-18.1). b. Median Overall Survival was 24.6 months (95% CI., 21.0-28.1) with a 5-year survival of 26%.\n\n\n\nUsing univariate Cox analysis, current smoking at diagnosis, squamous cell histology, higher WHO performance score, male gender and larger PTV, were all identified as negative factors influencing survival. In multivariate Cox analysis, current smoking, male gender and larger PTV remained as negative factors influencing survival.\n\nToxicity\nMost common toxicities were CTC grade 2 esophagitis (13.6%), and CTC grade 2 radiation pneumonitis (17.7%) (Table 3). CTC grade ≥3 esophagitis was seen in 9.7% with 2 CTC grade 5 events. One patient had an esophageal ulcerative stenosis which resulted in death due to a massive hemorrhage. The second patient received a stent for an esophageal stenosis. Later this patient developed an esophageal-bronchial fistula and died 22 months later. Three percent (N = 10) of the patients had CTC grade ≥3 radiation pneumonitis. Three patients had a grade 5 event (all aged above 70 years). For these three patients, the PTV was 508, 600 and 578 cc (the 75% percentile of the whole cohort was 576 cc), with a V20 of 16, 34, and 30%, respectively. The first patient had no induction chemotherapy, the two others were treated with induction carboplatin and gemcitabine. In patients who completed the full chemoradiotherapy (N = 244), 7% had CTC grade ≥3 esophagitis (including 1 CTC grade 5 event), and 4% CTC grade ≥3 radiation pneumonitis (including 2 CTC grade 5 events). In patients aged 70 and older (N = 93), 9 patients (9.7%) had CTC grade 3 esophagitis, 4 patients (4.3%) had CTC grade 3 radiation pneumonitis, and three patients (3.2%) died due to pneumonitis. The other patients died due to progressive disease.Table 3 \nRadiation toxicity CTC ≥ 2 in patients with stage III NSCLC treated with concurrent gemcitabine and 3D radiotherapy\n\n\nToxicity\tTotal\t\tAge < 70\t\tAge ≥ 70\t\t\n\tN = 318\t%\tN = 225\t%\tN = 93\t%\t\nEsophagitis\t\t\t\t\t\t\t\nCTC 2\t43\t13.6\t32\t14.3\t11\t11.8\t\nCTC 3\t29\t9.1\t20\t8.9\t9\t9.7\t\nCTC 4\t1\t0.3\t1\t0.4\t0\t\t\nCTC 5\t2\t0.6\t2\t0.9\t0\t\t\nRadiation pneumonitis\t\t\t\t\t\t\t\nCTC 2\t52\t17.7\t38\t17.0\t14\t15.1\t\nCTC 3\t6\t2.0\t2\t0.9\t4\t4.3\t\nCTC 4\t1\t0.3\t1\t0.4\t0\t\t\nCTC 5\t3\t0.9\t0\t\t3\t3.2\t\n\n\nDiscussion\nIn this paper, we described outcome and toxicity of weekly gemcitabine and 5 weeks of 3D-CRT for stage III NSCLC. The overall median survival was 24,6 months. Although comparisons between uncontrolled single institution series should be interpreted with great caution due to possible variation in patient selection criteria, in other concurrent chemoradiotherapy regimens median survival was between 15.3 and 26 months [5–10, 19–21]. In addition, esophageal toxicity and radiation pneumonitis was also in the same range as other recent studies with concurrent chemoradiation [5–10, 19–21].\n\nIn 2003 it had been shown that concurrent low-dose gemcitabine and 3D-CRT had acceptable toxicity [16]. Subsequently, a phase 2 study showed a median PFS of 12.4 months and OS of 21.6 months with acceptable toxicity [17]. This was the reason to adopt the here reported regimen as our protocol in the region, because we were unable to recognize excessive toxicity as reported by others, in our patients. For instance, in a study from Blanco et al., drug dosage was adapted due to toxicity while other studies have been closed due to unacceptable toxicity profiles (especially pulmonary toxicity) [15, 22, 23]. Price et al. investigated gemcitabine at a lower dosage (100 mg/m2) combined with a lower radiation dosage (55 Gy) given in a shorter time span (4 weeks) in a study that was prematurely closed due to slow accrual. There were 2 deaths in the gemcitabine arm due to acceleration of pre-existing interstitial lung disease [24]. Of note, in that study a daily fraction-dose of 2.75 Gy was given and the lung-dose-constraints had not been adapted for this higher dose per fraction. To our knowledge, there are no further reports using hypofractionated accelerated radiotherapy combined with gemcitabine.\n\nThe main factors that are important concerning pulmonary toxicity (i.e. radiation pneumonitis) during chemoradiation with concurrent low-dose gemcitabine are not completely understood. Lung dose, the use of conformal radiotherapy and the timing of the gemcitabine dosage are primary candidates. The CALGB 30105 trial showed that a V20 of 40% was associated with significant grade 3–5 pulmonary toxicity [25], which would be expected with any other combination treatment, even with radiotherapy alone. We observed no unexpected pulmonary toxicity rates, because at our institute, the constraint for V20 was set at a rather conservative 30% (uncorrected for the slightly higher daily fraction dose of 2.4 Gy) and indeed the vast majority (90%) of treated patients had a V20 lower than 30%. Elective nodal irradiation was completely foregone in the first year of this study, with no ensuing statistically significant toxicity differences. However, all three patients in our study who died due to radiation pneumonitis were aged above 70 – and had V20 of 16, 34 and 30%, respectively. The CALGB study also identified older age to be associated with increased pulmonary toxicity [25].\n\nAlso for esophageal toxicity, radiation technique had been shown to be critical. In a phase 1 study, which initially started using 2D conformal techniques, but halfway switched to 3D techniques, the percentage of the esophagus irradiated to 60 Gy dropped from 68 to 18%, and grade 2 esophagitis dropped from 5/10 patients to 2/14 patients [14].\n\nAdministration of gemcitabine more frequently than once weekly was also associated with increased toxicity. One study administered gemcitabine twice weekly (50 mg/m2) with 3D radiotherapy with elective nodal irradiation of the mediastinum [22]. Of note, the PTV’s in that study were three times as large as ours due to elective nodal irradiation. Due to unacceptable toxicity, the gemcitabine dose was reduced to 35 mg/m2, but even after this reduction, still more severe CTC grade ≥ 3 esophageal and pulmonary toxicity was observed compared to our study. Our once weekly schedule featured 3 (for 50 mg/ m2) to 4.3 times (for 35 mg/ m2) the cumulative weekly gemcitabine dose [22]. This suggests that timing of drug administration may trigger toxicity, as was also demonstrated in our previous phase 1 and 2 clinical trials.\n\nThere were a total of 5 (1.6%) non-hematological grade 5 events in our study, which is comparable to other mainstream treatment regimens [6, 7, 10, 20].\n\nConclusions\nTreatment of patients with unresectable stage III NSCLC with cisplatin and gemcitabine followed by concurrent gemcitabine and 3D conformal radiotherapy was safe and yielded effectiveness and toxicity rates comparable with other drugs in our hands. These results are very likely due to conservative radiation dose-constraints and 3D-conformal radiotherapy avoiding irradiation of excessive volumes of uninvolved mediastinal areas. Although age was not a factor influencing survival and the absolute incidence at 3% grade 5 pneumonitis in patients older than 70 years was what could be expected, patients above 70 years of age should be selected with great caution for this regimen.\n\nCompeting interest\n\nThrough H.J.M.G, the hospital receives research grants from Eli Lilly, Pfizer and Roche. All remaining authors have declared no conflicts of interest.\n\nAuthors’ contribution\n\nStudy concept and design was done by LFAD, EMW, TJNH and HJMG. Data acquisition was done by GSMAK, LFAD, EMW, JW, EB, EMD, JWGP, JJWL, TEJR, RMP, MJFM. Quality control and assurance was done by EMW, JW and EB. Data analysis, interpretation and statistical analysis was done by GSMAK, JW and HG. Manuscript preparation was done by GSMAK and HJMG. Editing and review was done by LFAD, EMW, JW, EB, EMD, JWGP, JJWL, TEJR, RMP, MJFM and TJNH. All authors attest to its validity and legitimacy of the presented facts and agree to its submission. All authors read and approved the final manuscript.\n\nFunding\nThis work was partly supported by CTMM, the Center for Translational Molecular Medicine, project AIRFORCE (grant 030–103). CTMM is a non-commercial entity that pays G.S.M.A.K his salary. CTMM did not play a role in the study design, in data collection, analysis and writing of the manuscript.\n==== Refs\nReferences\n1. Mountain CF Revisions in the international system for staging lung cancer Chest 1997 111 1710 1717 10.1378/chest.111.6.1710 9187198 \n2. 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Scalliet P Goor G Galdermans D van Meerbeek J Groen HJM Van der Leest AHW Westerink H Jungnelius U Turrisi A Gemcitabine with thoracic radiotherapy in chemonaive patients with advanced non-small-cell lung cancer Proc Am Soc Clin Oncol 1998 17 499 \n14. Zinner RG Komaki R Cox JD Glisson BS Pisters KM Herbst RS Kies M Liao Z Hong WK Fossella FV Dose escalation of gemcitabine is possible with concurrent chest three-dimensional rather than two-dimensional radiotherapy: a phase I trial in patients with stage III non-small-cell lung cancer Int J Radiat Oncol Biol Phys 2009 73 119 127 10.1016/j.ijrobp.2008.03.069 18556142 \n15. Arrieta O Gallardo-Rincon D Villarreal-Garza C Michel RM Astorga-Ramos AM Martinez-Barrera L de la Garza J High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin J Thorac Oncol 2009 4 845 852 10.1097/JTO.0b013e3181a97e17 19487963 \n16. van Putten JW Price A van der Leest AH Gregor A Little FA Groen HJ A Phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small cell lung cancer Clin Cancer Res 2003 9 2472 2477 12855620 \n17. Wachters FM van der Leest AHD Klinkenberg TJ Groen HJM Treatment of unresectable locally advanced non-small-cell lung cancer with cisplatin and gemcitabine followed by concurrent radiation and gemcitabine Therapeutic strategies in advanced non-small-cell lung cancer 2006 1 Haren Drukkerij Van Ark 25 39 \n18. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 \n19. Belderbos J Uitterhoeve L van Zandwijk N Belderbos H Rodrigus P van de Vaart P Price A van Walree N Legrand C Dussenne S Bartelink H Giaccone G Koning C Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972–22973) Eur J Cancer 2007 43 114 121 10.1016/j.ejca.2006.09.005 17084621 \n20. Curran WJ Jr Paulus R Langer CJ Komaki R Lee JS Hauser S Movsas B Wasserman T Rosenthal SA Gore E Machtay M Sause W Cox JD Sequential vs Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410 J Natl Cancer Inst 2011 103 1452 1460 10.1093/jnci/djr325 21903745 \n21. Hoang T Dahlberg SE Schiller JH Mehta MP Fitzgerald TJ Belinsky SA Johnson DH Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study J Clin Oncol 2012 30 616 622 10.1200/JCO.2011.36.9116 22271472 \n22. Blanco R Sole J Montesinos J Mesia C Algara M Terrassa J Gay M Domenech M Bastus R Bover I Nogue M Vadell C Induction chemotherapy with cisplatin and gemcitabine followed by concurrent chemoradiation with twice-weekly gemcitabine in unresectable stage III non-small cell lung cancer: final results of a phase II study Lung Cancer 2008 62 62 71 10.1016/j.lungcan.2008.02.024 18440089 \n23. Choy H Jain AK Moughan J Curran W Whipple G Demas WF Ettinger DS RTOG 0017: a phase I trial of concurrent gemcitabine/carboplatin or gemcitabine/paclitaxel and radiation therapy (“ping-pong trial”) followed by adjuvant chemotherapy for patients with favorable prognosis inoperable stage IIIA/B non-small cell lung cancer J Thorac Oncol 2009 4 80 86 10.1097/JTO.0b013e318191503f 19096311 \n24. Price A Yellowlees A Keerie C Russell S Faivre-Finn C Gilligan D Snee M Skailes G Hatton M Erridge S Mohammed N Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer Lung Cancer 2012 77 532 536 10.1016/j.lungcan.2012.05.089 22672970 \n25. Salama JK Stinchcombe TE Gu L Wang X Morano K Bogart JA Crawford JC Socinski MA Blackstock AW Vokes EE Pulmonary toxicity in Stage III non-small cell lung cancer patients treated with high-dose (74 Gy) 3-dimensional conformal thoracic radiotherapy and concurrent chemotherapy following induction chemotherapy: a secondary analysis of Cancer and Leukemia Group B (CALGB) trial 30105 Int J Radiat Oncol Biol Phys 2011 81 e269 274 10.1016/j.ijrobp.2011.01.056 21477940\n\n",
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"issn_linking": "1748-717X",
"issue": "9()",
"journal": "Radiation oncology (London, England)",
"keywords": null,
"medline_ta": "Radiat Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents; D020266:Radiotherapy, Conformal; D016896:Treatment Outcome; D014747:Vinblastine",
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"pmid": "25174943",
"pubdate": "2014-08-29",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21477940;23860613;19096311;18556142;21903745;19001323;22672970;20556756;16983107;20351327;22271472;12743155;19487963;20625120;17762336;9187198;12855620;22138037;17084621;17026812;10655437;10394591;18440089",
"title": "Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.",
"title_normalized": "concurrent gemcitabine and 3d radiotherapy in patients with stage iii unresectable non small cell lung cancer"
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"abstract": "OBJECTIVE\nOur aim was to evaluate the clinical profile, treatment, and outcome of ceftriaxone-associated postrenal acute renal failure (PARF) in children.\n\n\nMETHODS\nWe retrospectively studied 31 consecutive cases from 2003 to 2012 for PARF after ceftriaxone treatment. There was no past history of urolithiasis or nephropathy in these children.\n\n\nRESULTS\nThe average time of ceftriaxone administration before PARF was 5.2 days. The major symptoms apart from anuria included flank pain (>3 years old, 25/25), excessive crying (<3 years, 6/6), and vomiting (19/33). Ultrasound showed mild hydronephrosis (25/31) and ureteric calculi (11/31). Nine children recovered after 1 to 4 days of pharmacotherapy. Twenty-one children who were resistant to pharmacotherapy underwent retrograde ureteral catheterization. After catheterization of their ureters, normal urine flow was observed, and the symptoms subsided immediately. Catheter insertion failed in 1 child who subsequently underwent 3 sessions of hemodialysis before normal urination was restored. Ceftriaxone was verified to be the main component of the calculi in 4 children by tandem mass spectrometric analysis. The recovery was complete in all cases.\n\n\nCONCLUSIONS\nCeftriaxone therapy in children may cause PARF. Early diagnosis and prompt pharmacological therapy are important in relieving the condition. Retrograde ureteral catheterization is an effective treatment of those who fail to respond to pharmacotherapy.",
"affiliations": "Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, and.",
"authors": "Li|Ning|N|;Zhou|Xuefeng|X|;Yuan|Jiyan|J|;Chen|Guiying|G|;Jiang|Hongliang|H|;Zhang|Wen|W|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2013-2103",
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"issue": "133(4)",
"journal": "Pediatrics",
"keywords": "acute renal failure; ceftriaxone; child",
"medline_ta": "Pediatrics",
"mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "0376422",
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"pmc": null,
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"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ceftriaxone and acute renal failure in children.",
"title_normalized": "ceftriaxone and acute renal failure in children"
} | [
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"abstract": "OBJECTIVE\nTo describe two cases of catastrophic, bilateral retinal vascular occlusion following intravitreal (IVT) bevacizumab injection.\n\n\nMETHODS\nCase series. Main outcome measures included clinical and fluorescein angiography (FA) findings.\n\n\nRESULTS\nCase 1 - A 65-year-old woman with calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis (CREST) syndrome developed acute, severe, bilateral visual loss two weeks following bilateral IVT bevacizumab injection for proliferative diabetic retinopathy. Examination and FA revealed moderate anterior chamber inflammation, bilateral perivascular retinal hemorrhages and near total retinal vascular occlusion. Extensive testing revealed moderately elevated anti-B2 glycoprotein (antiphospholipid) antibodies. Case 2 - An 85-year-old man with polymyalgia rheumatica and left eye exudative age-related macular degeneration experienced severe, bilateral, sequential visual loss in the left then right eye approximately three weeks following IVT bevacizumab left eye injection. Examination revealed bilateral panuveitis, diffuse perivascular exudates, and intraretinal hemorrhages. FA showed diffuse venous leakage. Extensive testing revealed an elevated anti-nuclear antibody and mildly elevated anti-cardiolipin antibody.\n\n\nCONCLUSIONS\nPatients with underlying retinal vascular vulnerabilities may be at increased risk of catastrophic, bilateral retinal vascular occlusion following treatment with IVT bevacizumab. The moderate to severe intraocular inflammation in both cases, and the contralateral involvement following unilateral IVT injection in Case 2, suggest a possible delayed immune-mediated mechanism.",
"affiliations": "West Coast Retina Medical Group, San Francisco, California. The Department of Ophthalmology, California Pacific Medical Center, San Francisco, California. Massachusetts Eye and Ear Infirmary, Harvard Medical School, Ocular Immunology and Uveitis Service, Boston, Massachusetts. The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California. The Francis I. Proctor Foundation, UCSF School of Medicine, San Francisco, California. Massachusetts Eye and Ear Infirmary, Harvard Medical School, Vitreoretinal Service, Boston, Massachusetts. Ophthalmic Consultants of Boston, Vitreoretinal Service, Boston, Massachusetts. Ophthalmic Consultants of Boston, Uveitis Service, Boston, Massachusetts.",
"authors": "Ng|Caleb C|CC|;Brill|Daniel|D|;Cunningham|Emmett T|ET|;Burckhard|Braden A|BA|;Jumper|J Michael|JM|;Heier|Jeffrey|J|;Rifkin|Lana M|LM|;Eliott|Dean|D|;McDonald|H Richard|HR|;Sobrin|Lucia|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000001158",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
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"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33988542",
"pubdate": "2021-05-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Catastrophic, Bilateral Retinal Vascular Occlusion after Intravitreal Bevacizumab Injection.",
"title_normalized": "catastrophic bilateral retinal vascular occlusion after intravitreal bevacizumab injection"
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{
"abstract": "Omalizumab is a recombinant humanized anti-IgE monoclonal antibody, approved for patients affected by chronic spontaneous urticaria resistant to antihistamines. Although the clinical benefit of omalizumab has been established in several clinical trials, there are very little data about long-term treatment with this drug and real-life reports regarding its use in patients affected by comorbidities other than urticaria are lacking.\nTo assess omalizumab efficacy and safety in a heterogeneous population of patients affected by chronic spontaneous urticaria and several comorbidities in a real-world setting.\nPatients affected by chronic spontaneous urticaria with weekly urticaria activity score >16 resistant to antihistamines were treated with omalizumab 300 mg injection as add-on to H1-antihistamines administered every 4 weeks for 6 months. Clinical assessment of weekly urticaria activity score, dermatology life quality index and blood tests were performed at baseline, 12, 24 and 52 weeks of treatment. Response was assessed based on reduction weekly urticaria activity score.\nThirty-two patients (22F; 10M) with a mean age of 52.4 years (range 27-72) affected by chronic spontaneous urticaria were enrolled. Comorbidities affecting our study population were divided into 6 categories: cardio-metabolic (77%), oncologic (19%), infectious (16%), allergic (45%) immunologic (41%) and others (18%). Omalizumab determined a satisfactory reduction of symptoms of chronic spontaneous urticaria and an amelioration of quality of life within our population. No relevant alterations regarding patients' underlying conditions were encountered. This is the first study regarding the use of omalizumab for chronic spontaneous urticaria in a population of adult patients affected by several comorbidities, eg, cardio-metabolic, oncologic, infectious, allergic, immunologic and psychiatric diseases. Real-life data represent a valuable source of information about a drug's safety and efficacy profile, especially in patients affected by different comorbidities that are widely diffused in Western countries.",
"affiliations": "Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of L'Aquila, L'Aquila, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.;Dermatology Department, University of Rome, Tor Vergata, Italy.",
"authors": "Vollono|Laura|L|;Piccolo|Arianna|A|;Lanna|Caterina|C|;Esposito|Maria|M|;Bavetta|Mauro|M|;Campione|Elena|E|;Bianchi|Luca|L|;Diluvio|Laura|L|",
"chemical_list": "D018926:Anti-Allergic Agents; D000069444:Omalizumab",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S214307",
"fulltext": "\n==== Front\nDrug Des Devel TherDrug Des Devel TherDDDTdddtDrug Design, Development and Therapy1177-8881Dove 21430710.2147/DDDT.S214307Original ResearchOmalizumab for chronic spontaneous urticaria in “complex” patients: data from real-life clinical practice Vollono et alVollono et alVollono Laura 1Piccolo Arianna 1Lanna Caterina 1Esposito Maria 2Bavetta Mauro 1Campione Elena 1Bianchi Luca 1Diluvio Laura 11 Dermatology Department, University of Rome, Tor Vergata, Italy2 Dermatology Department, University of L’Aquila, L’Aquila, ItalyCorrespondence: Laura Vollono Dermatology Department, University of Rome Tor Vergata, Viale Oxford 81, Rome00133, ItalyTel +39 06 2090 0252Email laura.vollono@gmail.com06 9 2019 2019 13 3181 3186 07 5 2019 02 8 2019 © 2019 Vollono et al.2019Vollono et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Introduction\nOmalizumab is a recombinant humanized anti-IgE monoclonal antibody, approved for patients affected by chronic spontaneous urticaria resistant to antihistamines. Although the clinical benefit of omalizumab has been established in several clinical trials, there are very little data about long-term treatment with this drug and real-life reports regarding its use in patients affected by comorbidities other than urticaria are lacking.\n\nObjectives\nTo assess omalizumab efficacy and safety in a heterogeneous population of patients affected by chronic spontaneous urticaria and several comorbidities in a real-world setting.\n\nMaterials and methods\nPatients affected by chronic spontaneous urticaria with weekly urticaria activity score >16 resistant to antihistamines were treated with omalizumab 300 mg injection as add-on to H1-antihistamines administered every 4 weeks for 6 months. Clinical assessment of weekly urticaria activity score, dermatology life quality index and blood tests were performed at baseline, 12, 24 and 52 weeks of treatment. Response was assessed based on reduction weekly urticaria activity score.\n\nResults\nThirty-two patients (22F; 10M) with a mean age of 52.4 years (range 27–72) affected by chronic spontaneous urticaria were enrolled. Comorbidities affecting our study population were divided into 6 categories: cardio-metabolic (77%), oncologic (19%), infectious (16%), allergic (45%) immunologic (41%) and others (18%). Omalizumab determined a satisfactory reduction of symptoms of chronic spontaneous urticaria and an amelioration of quality of life within our population. No relevant alterations regarding patients’ underlying conditions were encountered. This is the first study regarding the use of omalizumab for chronic spontaneous urticaria in a population of adult patients affected by several comorbidities, eg, cardio-metabolic, oncologic, infectious, allergic, immunologic and psychiatric diseases. Real-life data represent a valuable source of information about a drug’s safety and efficacy profile, especially in patients affected by different comorbidities that are widely diffused in Western countries.\n\nKeywords\nchronic spontaneous urticariaomalizumaboncologiccardiovascularallergic and immunologic conditionscomorbidities\n==== Body\nIntroduction\nChronic spontaneous urticaria (CSU) is a condition characterized by the presence of wheals lasting for more than 6 weeks, variably associated with the presence of angioedema.1,2 CSU is the most common type of urticaria and affects about 1% of the population, causing a notable deterioration in the patient’s quality of life and bearing a substantial social and health care burden.3–6 The presence of angioedema in patients affected by CSU has been associated with a prolonged disease duration compared with those experiencing wheals only.7 CSU is twice as common in women as in men, and most commonly affects patients aged 20–40 years.4,8 Unlike inducible urticaria, which is provoked by a variety of physical stimuli (cold, heat, pressure, etc.), its exact nosology is still not fully elucidated. The release of histamine from mast cells in the skin is considered a key factor in its pathogenesis.2,8–10 A role of functional autoantibodies against the high-affinity immunoglobulin E (IgE) receptor and other autoantibodies such as anti-thyroperoxidase has been postulated.8,11 Although modern second-generation H1-antihistamines are the standard of care for patients with CSU, adjunctive treatments may be required for effective control of symptoms in many patients.4 Omalizumab is a humanized IgG1k monoclonal antibody that specifically binds to free human IgE, firstly indicated for the treatment of allergy-induced asthma.12,13 In 2014, FDA approved omalizumab also for patients affected by CSU aged 12 years or older who continue to have symptoms despite antihistamines treatment. Omalizumab represents the first biologic medicine and the first new class of pharmacological agent approved for CSU since the introduction of non-sedating H1-antihistamines and it is available in Italy since 2015. Randomized controlled trials showed a good safety and tolerability profile in patients affected by CSU.14–16 However, safety data of long-term treatment with this biologic drug are scarce and real-life reports regarding its use in patients affected by comorbidities other than CSU are lacking. We hereby present our experience with the use of omalizumab in a heterogeneous Italian population of patients affected by CSU and other different comorbidities in a real-life setting.\n\nMaterials and methods\nThis study is a retrospective analysis of data collected at the Urticaria Clinic of the Dermatology Department of Policlinico Tor Vergata, Rome, Italy. Written informed consent was obtained from all patients included in the study. In view of the retrospective nature of the study, only a notification to the Ethical Committee of the investigator Center (Policlinico Tor Vergata, Rome, Italy) was required and submitted. Patients aged >18 years affected by moderate-to-severe CSU [defined as weekly Urticaria Activity Score (UAS7) >28], who remained symptomatic despite H1-antihistamines at up to 4 times the licensed dose, were included in the study. Medical history, presence of angioedema, clinical assignment of UAS-7, Dermatology Life Quality Index (DLQI) and laboratory assessments (complete blood count, liver and renal function test, electrophoresis, parasitology stool test, thyroid function test, antithyroid antibody test, antinuclear antibody [ANA] test, extractable nuclear antigen [ENA] test, IgE level assessment [PRIST]) were performed at BaseLine (BL), 12 weeks (W12), 24 weeks (W24) and 52 weeks (W52) of therapy. Patients received 300 mg subcutaneous injection as add-on to H1-antihistamines administered every 4 weeks for 6 months, followed by an 8-week treatment interruption. In case of recurrence, a second cycle of 5 additional doses of omalizumab 300 mg every 4 weeks (5 months) had been administered. Clinical response was assessed based on reduction of UAS-7 [outcomes were classified as complete (=0), partial (=0–28) or no response (>28)] and DLQI [outcomes were classified as complete (<6), partial (6–10) or no response (>10)]. Safety has been monitored performing blood and instrumental tests.\n\nResults\nA total of 32 patients (22 F;10 M) with mean age of 52.4 years (range 27–72) affected by CSU were enrolled. Mean duration of urticaria symptoms before treatment with omalizumab was 7 years (range 1–40). Three out of the enrolled patients were diagnosed with concomitant inducible urticaria (CIndU) triggered by physical activity, cold and UV light, respectively. Ten patients reported angioedema concurrently with itch and wheals. Comorbidities affecting our study population were divided into 6 categories, as reported in Table 1. Thirteen patients completed 2 cycles of treatment (13 months), while 10 patients had completed 1 cycle of treatment (6 months) and 8 patients had undergone 12 weeks (1/2 cycle) of treatment to date. One patient stopped the treatment because of increased arterial blood pressure after 24 weeks of treatment, whilst one other patient experienced acute ischemic heart disease (NSTEMI myocardial infarction) not leading to discontinuation. One patient reported generalized arthralgia and myalgia immediately after the first injection but not following subsequential injections. One patient referred regular episodes of fatigue and sleepiness the day after omalizumab injections, not leading to treatment discontinuation. Mild, transient local skin immediate reactions were observed in one patient. No cases of anaphylaxis or serious adverse events were reported in our patients. Twenty patients added second-generation H1-antihistamines to omalizumab because of persistence of pruritus and wheals after 2–4 weeks of treatment with omalizumab in monotherapy. Two patients affected by atopic dermatitis received methotrexate 15mg/week during treatment with omalizumab. Patients taking medications for their underlying conditions continued therapy under surveillance of their referral physicians. The trends of UAS-7 and DLQI median scores in our population are shown in Figures 1 and 2.Table 1 Percentages of patients affected by different comorbidities in our study population\n\nCardiometabolic\n77%\tOncologic\n22%\tInfectious\n16%\tAllergic\n45%\tImmunologic\n41%\tOthers\n18%\t\nArterial hypertension (29%), dyslipidemia (22%), severe osteoporosis (6%), lower limb ischemia (3%), diabetes (6%), hepatic steatosis (3%), tachycardia (3%), ischemic cardiomyopathy (3%)\tBreast carcinoma (9%), in-situ melanoma (3%), thyroid carcinoma (3%), laryngealcarcinoma (3%), pituitary adenoma (3%)\tWidespread poxvirus infection (3%), resistant helicobacter pylorii infection to (6%), previous hepatitis C virus infection (6%)\tAllergic rhinitis (12%), asthma (16%), contact allergy (6%), severe atopic dermatitis (6%)\tHashimoto thyroiditis (22%), vitiligo (6%) alopecia areata (3%) ulcerative colitis (3%), urticarial vasculitis (3%).\tGeneralized anxiety disorder (9%), thalassaemia minor (3%), hypogonadism (3%), chronic renal failure (3%)\t\n\nFigure 1 Trend of median UAS-7 score. UAS-7 median score decreased from 29.5 at baseline (BL) over 32 patients to 20.0 at W12 over 32 patients and kept decreasing to a value of 10.0 over 25 patients at W24. A further reduction of UAS-7 was observed at W46, with a mean value of 4.0 over 13 patients.\n\nFigure 2 Trend of median DLQI score. DLQI median score decreased from a value of 20,0 at BL over 32 patients to 14.6 over 32 patients at W12, to a value of 7.3 over 25 patients at W24 and reduced to a value of 5.0 over 13 patients at W46.\n\n\n\nDiscussion\nThis observational study investigated the effect of omalizumab administered to a population of patients simultaneously affected by CSU and cardiometabolic, oncologic, infectious, immunologic and psychiatric comorbidities. To our knowledge, this is the first real-life report regarding the use of this anti-IgE antibody in such “complex” patients.\n\nAlongside with data reported in literature, we observed a very low discontinuation rate due to AEs (0.32%).17–19 No serious adverse events or case of anaphylaxis were reported in our cohort. In fact, data from RCTs and post-marketing surveillance showed that hypersensitivity reactions to the drug are infrequent and anaphylaxis is rare.20\n\nIn our cohort, two patients with a history of previous Hepatitis C Virus (HCV)-related hepatitis are successfully treated and their viral load did not change during therapy, suggesting that there is no risk of HCV exacerbation. The HCV infection did not seem to diminish the efficacy of omalizumab in this subset of patients. Only few cases of patients undergoing treatment with omalizumab with concurrent infection by hepatotropic virus, in particular, Hepatitis B Virus (HBV) and C virus, have been reported to date.21–23 In all patients, no side effects or infection worsening were documented, with concurrent substantial improvement of symptoms of asthma or urticaria. A decrease in the viral load was detected in a patient with active infection by HBV. A case of a patient with cytomegalic hepatitis treated with valganciclovir and omalizumab for CSU described remission of the infective symptoms and good control of CSU.24 These reports suggest that omalizumab is safe in terms of liver function.\n\nIn our cohort, we did not observe a higher incidence of viral infections during treatment with omalizumab. While a higher incidence of nasopharyngitis, influenza, upper respiratory tract infection in children treated with omalizumab has been reported in the literature, other authors observed a decrease in the duration of rhinovirus infections, viral shedding and risk of rhinovirus illnesses, hypothesizing a role of the anti-IgE agent in improving virus-induced IFN-alpha response.25–27\n\nAlthough IgE blockade may theoretically impair the immune control of parasites, we did not report any case of parasitic infections. Our findings align with the overall low risk of parasitic infections reported in RCTs and in observational studies.28,29\n\nOne case of acute ischemic heart disease not leading to discontinuation was reported in our cohort. No patient reported bleeding or thrombosis. Only one patient, a post-menopausal female aged 54, interrupted the therapy because of an increase in arterial blood pressure 6 months after treatment. Bisoprolol was administered with good control of symptoms. On the other hand, our series includes other 9 patients with preexisting arterial hypertension, who underwent treatment with omalizumab without any complication or significant alteration of blood pressure value.\n\nNo data regarding cardiovascular and cerebrovascular adverse events (AEs) in patients treated with omalizumab for CSU are available to date. In a post-marketing observational study on asthma patients, a higher rate of cardiovascular and cerebrovascular serious AEs (arterial and venous thrombosis) was noticed compared to no-treated patients.30 A real-life retrospective analysis asthma patients treated with omalizumab for uncontrolled severe asthma reported one case of venous thrombosis not leading to discontinuation of therapy.29 Surveillance is advisable owing to the apparently very low frequency of these AEs. The higher incidence of arterial hypertension in asthma patients is well documented, as well as its association with obesity and the overall increased cardiovascular risk of patients affected by asthma.31–33 On the contrary, cardiovascular risk does not seem to be increased in patients affected by CSU.34\n\nOur data-set included one patient with chronic renal failure (CRF). Regular laboratory, clinical and instrumental assessments did not show any significant modification. The patient obtained a satisfactory control of symptoms of CSU without any worsening of his general conditions.\n\nOur series includes 7 patients with a history of previous cancer (see Table 1). All of them were regularly monitored with physical examination, blood and instrumental tests as recommended by their referral physicians. These patients had been monitored from BL for a medium range of 12 months, without any known neoplastic recurrence or progression. These results are consistent with literature data, showing that treatment with omalizumab was not associated with an increased risk of malignancies.35 Our findings may further support the idea that omalizumab treatment is safe also in patients with previous cancers, as it does not seem to increase the risk of relapse. Long-term real-life data on a larger population are needed in order to further confirm this hypothesis.\n\nTwo patients of our series were affected by both CSU and severe atopic dermatitis (AD). They were treated with methotrexate (15 mg/week) and concurrently started omalizumab treatment, with satisfying results. Observational studies of omalizumab for AD, in general, report more positive results compared to the RCTs.36 The interpretation of improvement as an effect of treatment should accommodate the fact that most patients with AD (75%) have a spontaneous remission of disease before adolescence.37 Thus, recommendation for use in clinical practice awaits evidence from larger randomized controlled trials.\n\nOur patients affected by immunoallergic comorbidities reported improvement of symptoms related to their underlying condition, requiring lower doses of their medications.\n\nRegarding psychiatric comorbidities, no specific assessment has been performed during treatment. However, we did not observe any worsening of clinical symptoms. From the other hand, DLQI of both patients who were affected or not by psychiatric comorbidities was significantly reduced during treatment with omalizumab, suggesting that mental health of CSU patients may benefit from the improvement of clinical symptoms.\n\nRelevant limitations of our study are the small sample, the lack of controls and the relatively short period of follow-up (average 12 months). Observation of this cohort of patients over time may represent an interesting source of information about omalizumab safety profile. The main strength of our work is the heterogeneity of comorbidities affecting our population. These diseases are widely diffused in Western countries; however, safety data on affected patients are commonly not available from RCTs, owing to their exclusion criteria. Data from real-life observational studies therefore represent a valuable source of information for clinicians who have to deal with “complex” patients still needing treatment for CSU. In our study, we focused on the safety profile of omalizumab in such patients. Given the heterogeneity of comorbidities and related classes of medications, interactions between such drugs and omalizumab were not analyzed in our population. Investigating the possible drug interactions between omalizumab and other concomitant medications and the possible influence of the latter on the response to omalizumab represents a very fertile field for future research.\n\nConclusion\nOur results suggest that omalizumab may be considered as a safe and well-tolerated therapeutic option even in patients affected by several comorbidities. Further analysis based on a larger cohort of patients and a longer period of treatment is required to confirm our preliminary observations.\n\nAcknowledgment\nThe authors wish to thank Novartis Farma Italia for support in the publication of this manuscript and Dr Valeria Manuelli for proofreading.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Marzano \nAV , Pigatto \nP , Cristaudo \nA . Management of chronic spontaneous urticaria: practical parameters . G Ital Dermatol Venereol . 2015 ;150 :237 –246 .25714626 \n2. Zuberbier \nT , Aberer \nW , Asero \nR. \nThe EAACI/GA 2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update . Allergy . 2014 ;69 :868 –887 . doi:10.1111/all.12462 24785199 \n3. Balp \n-M-M , Vietri \nJ , Tian \nH , Isherwood \nG . The impact of chronic urticaria from the patient’s perspective: a survey in five European countries . Patient - Patient-Centered Outcomes Res . 2015 ;8 :551 –558 . doi:10.1007/s40271-015-0145-9 \n4. Maurer \nM , Ma \nD , Wei \nJF , et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report1 . Allergy . 2011 ;66 :317 –330 . doi:10.1111/j.1398-9995.2011.02683.x 21083565 \n5. Maurer \nM , Church \nMK , Marsland \nAM , et al. Questions and answers in chronic urticaria: where do we stand and where do we go? \nJ Eur Acad Dermatol Venereol . 2016 ;30 :7 –15 . doi:10.1111/jdv.13695 \n6. Staubach \nP , Eckhardt-Henn \nA , Dechene \nM , et al. Quality of life in patients with chronic urticaria is differentially impaired and determined by psychiatric comorbidity . Br J Dermatol . 2006 ;154 :294 –298 . doi:10.1111/bjd.2006.154.issue-2 16433799 \n7. Maurer \nM , Sofen \nH , Ortiz \nB , Kianifard \nF , Gabriel \nS , Bernstein \nJA . Positive impact of omalizumab on angioedema and quality of life in patients with refractory chronic idiopathic/spontaneous urticaria: analyses according to the presence or absence of angioedema . J Eur Acad Dermatol Venereol . 2017 ;31 :1056 –1063 . doi:10.1111/jdv.2017.31.issue-6 27911016 \n8. Greaves \nMW . Chronic Urticaria . N Engl J Med . 1995 ;332 :1767 –1772 . doi:10.1056/NEJM199506293322608 7760895 \n9. Altman \nK , Chang \nC . Pathogenic intracellular and autoimmune mechanisms in urticaria and angioedema . Clin Rev Allergy Immunol . 2013 ;45 :47 –62 . doi:10.1007/s12016-012-8326-y 22674016 \n10. Beck \nL , Bernstein \nJ , Maurer \nM . A review of international recommendations for the diagnosis and management of chronic urticaria . Acta Derm Venereol . 2017 ;97 ::149–158. doi:10.2340/00015555-2496 \n11. Chang \nTW , Chen \nC , Lin \nCJ . The potential pharmacologic mechanisms of Omalizumab in patients with chronic spontaneous urticaria . J Allergy Clin Immunol . 2015 ;135 :337 –342 . doi:10.1016/j.jaci.2014.04.036 24948369 \n12. Zhao \nZ-T , Ji \nCM , Yu \nWJ \nOmalizumab for the treatment of chronic spontaneous urticaria: a meta-analysis of randomized clinical trials . J Allergy Clin Immunol . 2016 ;137 :1742 –1750.e4 . doi:10.1016/j.jaci.2015.12.1342 27040372 \n13. Global initiative for asthma . Global strategy for asthma management and prevention ; 2017 Available from: \nwww.ginasthma.com. Accessed 8 09 , 2019.\n14. Kaplan \nA , Ledford \nD , Ashby \nM . Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy . J Allergy Clin Immunol . 2013 ;132 ::101–109. doi:10.1016/j.jaci.2013.05.013 \n15. Maurer \nM , Rosén \nK , Hsieh \nHJ. \nOmalizumab for the treatment of chronic idiopathic or spontaneous urticaria . N Engl J Med . 2013 ;368 :924 –935 . doi:10.1056/NEJMoa1215372 23432142 \n16. Saini \nSS , Bindslev-Jensen \nC , Maurer \nM . Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H 1 antihistamines: a randomized, placebo-controlled study . J Invest Dermatol . 2015 ;135 :67 –75 . doi:10.1038/jid.2014.306 25046337 \n17. Cazzola \nM , Camiciottoli \nG , Bonavia \nM. \nItalian real-life experience of omalizumab . Respir Med . 2010 ;104 :1410 –1416 . doi:10.1016/j.rmed.2010.04.013 20483574 \n18. Cherrez-Ojeda \nI , Maurer \nM , Bernstein \nJA . Learnings from real-life experience of using omalizumab for chronic urticaria in Latin America . World Allergy Organ J . 2019 ;12 :100011 . doi:10.1016/j.waojou.2019.100011 30937137 \n19. Košnik \nM , Kopač \nP , Eržen \nR. \nOmalizumab in chronic urticaria: our experience and literature review . Acta Dermatovenerol Alp Pannonica Adriat . 2014 ;23 :57 –61 . doi:10.15570/actaapa.2014.14 25242162 \n20. Cox L, Platts-Mills TA, Finegold Iet al. American academy of allergy, asthma & immunology.; american college of allergy, asthma and immunology. American academy of allergy, asthma &immunology/american college of allergy, asthma and immunology joint taskforce report on omalizumab-associated anaphylaxis . J Allergy Clin Immunol . 2007 ;120 (6 ):1373e –1377e .17996286 \n21. Antonicelli \nL , Stagnozzi \nG , Giuliodoro \nS . The safety of Omalizumab therapy in a patient with severe persistent allergic asthma and hepatitis C . Ann Allergy Asthma Immunol . 2009 ;103 :269 –270 . doi:10.1016/S1081-1206(10)60194-9 19788028 \n22. Chicharro \nP , Rodríguez-Jiménez \nP , de Argila \nD . Efficacy and safety of omalizumab in a patient with chronic spontaneous urticaria and active hepatitis B virus infection . Actas Dermosifiliogr . 2017 ;108 :383 –384 . doi:10.1016/j.ad.2016.10.005 27914623 \n23. Leiva-Salinas \nM , Francés \nL , Marin‐Cabanas \nI . Effectiveness and safety of omalizumab in a patient with chronic urticaria and hepatitis C . J Eur Acad Dermatol Venereol . 2015 ;29 :1027 –1028 . doi:10.1111/jdv.12669 24629127 \n24. Gonçalves \nR , Valente \nC , Ferreira \nE , Serra \nJE , Da Cunha \nJS . Cytomegalic hepatitis in a patient receiving omalizumab . IDCases . 2016 ;5 :83 –84 . doi:10.1016/j.idcr.2016.08.001 27583207 \n25. Odajima \nH , Ebisawa \nM , Nagakura \nT , et al. Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of Omalizumab in children with severe uncontrolled asthma . Allergology Int . 2017 ;66 :106 –115 . doi:10.1016/j.alit.2016.06.004 \n26. Esquivel \nA , Busse \nWW , Calatroni \nA . Effects of omalizumab on rhinovirus infections, illnesses, and exacerbations of asthma . Am J Respir Crit Care Med . 2017 ;196 :985 –992 . doi:10.1164/rccm.201701-0120OC 28608756 \n27. Teach \nSJ , Kull \nS , Rennert \nS , et al. Preseasonal treatment with either Omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations . J Allergy Clin Immunol . 2015 ;136 :1476 –1485 . doi:10.1016/j.jaci.2015.04.010 26518090 \n28. Cruz \nAA , Lima \nF , Sarinho \nE , et al. Safety of anti-immunoglobulin E therapy with Omalizumab in allergic patients at risk of geohelminth infection . Clin Exp Allergy . 2007 ;37 :197 –207 . doi:10.1111/cea.2007.37.issue-2 17250692 \n29. Di Bona \nD , Fiorino \nI , Taurino \nM , et al. Long-term “real-life” safety of Omalizumab in patients with severe uncontrolled asthma: a nine-year study . Respir Med . 2017 ;130 :55 –60 . doi:10.1016/j.rmed.2017.07.013 29206634 \n30. Iribarren \nC , Rahmaoui \nA , Long \nAA , et al. Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study in moderate to severe asthma . J Allergy Clin Immunol . 2017 ;139 :1489 –1495.e5 . doi:10.1016/j.jaci.2016.07.038 27639934 \n31. Chipps \nBE , Zeiger \nRS , Luskin \nAT . Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO . Ann Allergy Asthma Immunol . 2017 ;119 :524 –532.e2 . doi:10.1016/j.anai.2017.09.056 29054589 \n32. Ali \nZ , Ulrik \nCS . Obesity and asthma: a coincidence or a causal relationship? A systematic review . Respir Med . 2013 ;107 :1287 –1300 . doi:10.1016/j.rmed.2013.03.019 23642708 \n33. Xu \nM , Xu \nJ , Asthma \nYX . Risk of cardiovascular disease or all-cause mortality: a meta-analysis . Ann Saudi Med . 2017 ;37 :99 –105 . doi:10.5144/0256-4947.2017.99 28377538 \n34. Egeberg \nA , Kofoed \nK , Gislason \nG , Vestergaard \nC , Thyssen \nJ . Cardiovascular risk is not increased in patients with chronic urticaria: a retrospective population-based cohort study . Acta Derm Venereol . 2017 ;97 :261 –262 . doi:10.2340/00015555-2516 27535552 \n35. Long \nA , Rahmaoui \nA , Rothman \nKJ , et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without Omalizumab . J Allergy Clin Immunol . 2014 ;134 :560 –567.e4 . doi:10.1016/j.jaci.2014.02.007 24679845 \n36. Holm \nJG , Agner \nT , Sand \nC , Thomsen \nSF . Omalizumab for atopic dermatitis: case series and a systematic review of the literature . Int J Dermatol . 2017 ;56 :18 –26 . doi:10.1111/ijd.2017.56.issue-1 27337170 \n37. Thomsen \nSF . Atopic dermatitis: natural history, diagnosis, and treatment . ISRN Allergy . 2014 ;2014 :1 –7 . doi:10.1155/2014/354250\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-8881",
"issue": "13()",
"journal": "Drug design, development and therapy",
"keywords": "allergic and immunologic conditions; cardiovascular; chronic spontaneous urticaria; comorbidities; omalizumab; oncologic",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D018926:Anti-Allergic Agents; D000080223:Chronic Urticaria; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007558:Italy; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab; D011788:Quality of Life; D012189:Retrospective Studies",
"nlm_unique_id": "101475745",
"other_id": null,
"pages": "3181-3186",
"pmc": null,
"pmid": "31564834",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27040372;16433799;27583207;19788028;7760895;20483574;27507228;27535552;25714626;26476961;30937137;26518090;27911016;24948369;22674016;28377538;25242162;23642708;27639934;24679845;24629127;25006501;23810097;17996286;28608756;17250692;27337170;27286498;23432142;27914623;27349620;24785199;25046337;29206634;21083565;29054589",
"title": "Omalizumab for chronic spontaneous urticaria in \"complex\" patients: data from real-life clinical practice.",
"title_normalized": "omalizumab for chronic spontaneous urticaria in complex patients data from real life clinical practice"
} | [
{
"companynumb": "IT-ROCHE-2480638",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "OMALIZUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Immunosuppression following organ transplantation is a known risk factor for the development of lymphoproliferative disorders. Mycosis fungoides, a rare entity in pediatric patients, has seldom been reported as a post-transplant lymphoproliferative disorder. We report a case of folliculotropic mycosis fungoides in a pediatric patient following liver transplantation that was initially diagnosed as tinea capitis.",
"affiliations": "Ohio State University College of Medicine, Columbus, Ohio.;Section of Dermatopathology, Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Section of Pediatric Dermatology, Departments of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.",
"authors": "Wang|Rebecca F|RF|http://orcid.org/0000-0002-0776-6565;Sokumbi|Olayemi|O|;Chiu|Yvonne E|YE|http://orcid.org/0000-0003-2869-2718",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13768",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "36(3)",
"journal": "Pediatric dermatology",
"keywords": "alopecia; cutaneous T-cell lymphoma; folliculotropic mycosis fungoides; infection-fungal; neoplasms-malignant",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D003937:Diagnosis, Differential; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D009182:Mycosis Fungoides; D012878:Skin Neoplasms; D014006:Tinea Capitis",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "386-387",
"pmc": null,
"pmid": "30791127",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Folliculotropic mycosis fungoides in a pediatric patient mimicking black dot tinea capitis.",
"title_normalized": "folliculotropic mycosis fungoides in a pediatric patient mimicking black dot tinea capitis"
} | [
{
"companynumb": "US-TEVA-2019-US-1067935",
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"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1"... |
{
"abstract": "Primary myelofibrosis is characterized by bone marrow fibrosis, splenomegaly and presence of JAK-2 V617F mutation in more than 90% of patients. Ruxolitinib is a Janus kinase inhibitor used for the treatment of primary myelofibrosis. We describe herein a persistent foot ulcer development attributed to ruxolitinib therapy. We are unaware of any previous reports of this phenomenon in the scientific literature. A thorough examination of the lower extremities is perhaps necessary before initiating this oral agent. If ruxolitinib therapy cannot be safely discontinued, diligent wound care and a course of antibiotics are warranted.",
"affiliations": "1 Department of Medicine, Eisenhower Medical Center, USA.;2 Lucy Curci Cancer Center, Eisenhower Medical Center, USA.;2 Lucy Curci Cancer Center, Eisenhower Medical Center, USA.",
"authors": "Del Rosario|Michael|M|;Tsai|Henry|H|;Dasanu|Constantin A|CA|",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053614:Janus Kinase 2",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217697488",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "24(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Naranjo nomogram; Primary myelofibrosis; adverse drug reaction; ruxolitinib; ulcer",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D016523:Foot Ulcer; D006801:Humans; D053614:Janus Kinase 2; D000075242:Janus Kinase Inhibitors; D008297:Male; D009154:Mutation; D009570:Nitriles; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "226-228",
"pmc": null,
"pmid": "28436280",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent foot ulcer due to ruxolitinib therapy for primary myelofibrosis.",
"title_normalized": "persistent foot ulcer due to ruxolitinib therapy for primary myelofibrosis"
} | [
{
"companynumb": "US-MYLANLABS-2017M1057244",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Nowadays fentanyl and its analogs represent the most numerous group among synthetic opioid and, due to their higher potency in comparison to traditionl opioids, the main cause of the critical increase of fatal intoxications opioids-intake related in the USA. We developed an LC-MS/MS method for the detection and quantification of fentanyl and its analogs in hair, then applied to 117 real samples, 97 collected from drugs users and 20 from postmortem cases of drugs addicts. The ionization and MRM parameters have been optimized for 27 molecules: 20 reached the acceptance criteria for identification and quantification. LODs and LOQs of 0.2 and 0.5 pg/mg, respectively, were reached for most of the substances, except for five compounds for which were set at 0.5 and 1.0 pg/mg. 2 out of the 97 samples collected from drug users tested positive; one for carfentanil, butyryl fentanyl, THFF and ocfentanil; the other one for 3-methyl norfentanyl. 2 out of the 20 postmortem samples show positive results: one only for fentanyl, the other for furanyl fentanyl, acetyl fentanyl, methoxyacetyl fentanyl, methoxyacetyl norfentanyl, ocfentanil and 4-ANPP. Despite the relatively small number of samples, the results suggest that the method should be included in routine hair analyses for monitoring the new synthetic opioids potential intake by drug users.",
"affiliations": "Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy. Electronic address: frafre93@gmail.com.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy.;Department of Medicine, Surgery and Health, University of Trieste, Trieste, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy; U.O. Medicina Legale, IRCCS Fondazione Mondino, Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy; U.O. Medicina Legale, IRCCS Fondazione Mondino, Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini 12, 27100, Pavia, Italy.",
"authors": "Freni|Francesca|F|;Moretti|Matteo|M|;Radaelli|Davide|D|;Carelli|Claudia|C|;Osculati|Antonio Marco Maria|AMM|;Tronconi|Livio|L|;Vignali|Claudia|C|;Morini|Luca|L|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1016/j.jpba.2020.113476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0731-7085",
"issue": "189()",
"journal": "Journal of pharmaceutical and biomedical analysis",
"keywords": "Fentanyl; Fentanyl analogs; Hair; LC–MS/MS",
"medline_ta": "J Pharm Biomed Anal",
"mesh_terms": "D000701:Analgesics, Opioid; D002853:Chromatography, Liquid; D005283:Fentanyl; D007558:Italy; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "8309336",
"other_id": null,
"pages": "113476",
"pmc": null,
"pmid": "32693203",
"pubdate": "2020-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Determination of fentanyl and 19 derivatives in hair: Application to an Italian population.",
"title_normalized": "determination of fentanyl and 19 derivatives in hair application to an italian population"
} | [
{
"companynumb": "IT-PFIZER INC-2020308362",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDonepezil is a drug which is being used more and more widely in mild-moderate Alzheimer's disease. In general, it is well tolerated and the side-effects are basically cholinergic-dependent. Symptomatic disorders of cardiac rhythm associated with the use of donepezil are extremely unusual.\n\n\nMETHODS\nWe describe the case of an 81 year old patient with hypertensive cardiopathy, who developed sinus bradycardia, fainting and left cardiac failure three weeks after starting treatment with donepezil. When donepezil was stopped the sinus bradycardia disappeared, a 24 hour electrocardiographic holter showed no signs of sinus node disease and no episodes of this type occurred during the following six months.\n\n\nCONCLUSIONS\nSymptomatic sinus bradycardia is a possible adverse effect of treatment with donepezil in Alzheimer's disease.",
"affiliations": "Servicio de Medicina Interna, Hospital Regional Universitario Infanta Cristina, Badajoz, España.",
"authors": "Calvo-Romero|J M|JM|;Ramos-Salado|J L|JL|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "28(11)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D001146:Arrhythmia, Sinus; D001919:Bradycardia; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007189:Indans; D010880:Piperidines",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "1070-2",
"pmc": null,
"pmid": "10390778",
"pubdate": "1999",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Symptomatic sinus bradycardia associated with donepezil.",
"title_normalized": "symptomatic sinus bradycardia associated with donepezil"
} | [
{
"companynumb": "ES-AUROBINDO-AUR-APL-2021-033120",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": null,... |
{
"abstract": "We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.",
"affiliations": "Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, AP-HP CUP, Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.;Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, AP-HP CUP, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Equipe Mobile d'Infectiologie, Hôpital Cochin, Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Equipe Mobile d'Infectiologie, Hôpital Cochin, Paris, France.;Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, AP-HP CUP, Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.;Gustave Roussy Institute, Hematology Department, Paris-Saclay University, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Service de Virologie, Hôpital Cochin, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Service de Virologie, Hôpital Cochin, Paris, France.;Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, AP-HP CUP, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hematology Department, Hôpital Cochin, Paris, France.;Personalized Medicine Pharmacogenomics, therapeutic optimization, eDIAG plateform, laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Université de Paris, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Paris, France.;Personalized Medicine Pharmacogenomics, therapeutic optimization, eDIAG plateform, laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Université de Paris, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.;Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Equipe Mobile d'Infectiologie, Hôpital Cochin, Paris, France.;Inserm IPLESP , Sorbonne University , Paris, France.;Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.",
"authors": "Szwebel|Tali-Anne|TA|;Veyer|David|D|;Robillard|Nicolas|N|;Eshagh|Deborah|D|;Canoui|Etienne|E|;Bruneau|Thomas|T|;Contejean|Adrien|A|;Azoulay|Celia|C|;Serrano|Thomas|T|;Hueso|Thomas|T|;Izquierdo|Laure|L|;Rozenberg|Flore|F|;Terrier|Benjamin|B|;Vignon|Marguerite|M|;Laurent-Puig|Pierre|P|;Taly|Valérie|V|;Bélec|Laurent|L|;Kernéis|Solen|S|;Lacombe|Karine|K|;Péré|Hélène|H|0000-0002-3225-4238",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D012367:RNA, Viral; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s12015-020-10107-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2629-3277",
"issue": "17(1)",
"journal": "Stem cell reviews and reports",
"keywords": null,
"medline_ta": "Stem Cell Rev Rep",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000086382:COVID-19; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008214:Lymphocytes; D016393:Lymphoma, B-Cell; D012367:RNA, Viral; D000086402:SARS-CoV-2; D019562:Viral Load",
"nlm_unique_id": "101752767",
"other_id": null,
"pages": "296-299",
"pmc": null,
"pmid": "33403488",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016422:Letter; D013485:Research Support, Non-U.S. Gov't",
"references": "32503849;32959052;32803231;33205351",
"title": "Usefulness of Plasma SARS-CoV-2 RNA Quantification by Droplet-based Digital PCR to Monitor Treatment Against COVID-19 in a B-cell Lymphoma Patient.",
"title_normalized": "usefulness of plasma sars cov 2 rna quantification by droplet based digital pcr to monitor treatment against covid 19 in a b cell lymphoma patient"
} | [
{
"companynumb": "FR-ABBVIE-21K-056-3760323-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS), also known as hypersensitivity syndrome, is an idiosyncratic drug reaction presenting with fever, diffuse lymphadenopathy, exfoliative dermatitis, and visceral involvement, which may include hepatitis, pneumonitis, pericarditis, myocarditis, nephritis, and colitis. This report describes a 19-year-old, previously healthy man with manifestations of hypersensitivity (DRESS) syndrome after acquiring a titanium bioprosthesis for a spinal fracture. To our knowledge, there have been no prior reports of DRESS syndrome in association with titanium bioprosthetic implants.",
"affiliations": "Veterans Affairs Medical Center and Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.",
"authors": "Nawaz|Fareha|F|;Wall|Barry M|BM|",
"chemical_list": "D014025:Titanium",
"country": "United States",
"delete": false,
"doi": "10.1097/MAJ.0b013e318141f723",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "334(3)",
"journal": "The American journal of the medical sciences",
"keywords": null,
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000328:Adult; D001705:Bioprosthesis; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D006801:Humans; D006968:Hypersensitivity, Delayed; D007668:Kidney; D008297:Male; D016103:Spinal Fractures; D013577:Syndrome; D014025:Titanium; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "215-8",
"pmc": null,
"pmid": "17873538",
"pubdate": "2007-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome: suspected association with titanium bioprosthesis.",
"title_normalized": "drug rash with eosinophilia and systemic symptoms dress syndrome suspected association with titanium bioprosthesis"
} | [
{
"companynumb": "US-BAUSCH-BL-2019-059149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "In patients with age-related macular degeneration (AMD), the intravitreal injection of antivascular endothelial growth factor (anti-VEGF) agents reduces disease progression and choroidal neovascularization. We report on a first case of ischaemic colitis associated with intravitreal injection of the anti-VEGF agent aflibercept in an 80-year-old female patient. Conservative treatment resulted in a favourable clinical outcome. The anti-VEGF agent was discontinued, and the symptoms did not recur. Although the intravitreal injection of anti-VEGF agents has not previously been linked to the occurrence of ischaemic colitis, consideration of aflibercept's pharmacological properties and the chronological relationship between the administration of this anti-VEGF agent and the occurrence of this systemic adverse event are strongly suggestive of a causal relationship in the present case. Although systemic complications have been rarely associated with intravitreal injections of anti-VEGF agents, physicians should be aware that novel adverse events can still occur in AMD patients treated with anti-VEGF agents.",
"affiliations": "Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.;Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.;Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.;Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.;Laboratoire de Pharmacologie, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.;Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique, CHU Amiens-Picardie, Amiens, France.",
"authors": "Batteux|Benjamin|B|0000-0001-9466-7110;Gras|Valérie|V|;Mahboud|Yanis|Y|;Liabeuf|Sophie|S|0000-0001-5384-9006;Bennis|Youssef|Y|;Masmoudi|Kamel|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "85(4)",
"journal": "British journal of clinical pharmacology",
"keywords": "adverse effect; intravitreal aflibercept; ischaemic colitis; pharmacovigilance",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D017091:Colitis, Ischemic; D003106:Colon; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa; D058449:Intravitreal Injections; D008268:Macular Degeneration; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "845-848",
"pmc": null,
"pmid": "30610744",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19712924;25001321;20538658;16799557;29149325;19443462;30610744;19417570;21855670;17686822;25960733;21526923;12609947;23722722;11350732;7249508;28585152;18054636;22866908",
"title": "Ischaemic colitis associated with intravitreal administration of aflibercept: A first case report.",
"title_normalized": "ischaemic colitis associated with intravitreal administration of aflibercept a first case report"
} | [
{
"companynumb": "FR-REGENERON PHARMACEUTICALS, INC.-2019-18079",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFLIBERCEPT"
},
"drugaddi... |
{
"abstract": "Complications while on dabigatran therapy, particularly bleeding and thrombosis, are occurring, and require laboratory assessment. The utility of routine coagulation assays has been previously evaluated in stable patients, but not those with acute complications. The purpose of this study was to determine how to employ routine coagulation assays to assess dabigatran in patients with acute complications. Seventeen patients on dabigatran presenting with various complications were evaluated. In addition, plasma samples with various fibrinogen levels were spiked in vitro with dabigatran ranging from low trough levels to the highest supratherapeutic concentrations reported (5000 ng/ml). INR, partial thromboplastin time (PTT), thrombin time (TT, Diagnostica Stago reagent), and fibrinogen were assayed and results compared to that of the Hemoclot Thrombin Inhibitors assay. Interference in the Clauss fibrinogen assay was assessed using a variety of commercial reagents. The majority of patients on dabigatran with acute complications demonstrated a significant negative bias in PTT results compared to normal plasma. TT remained highly sensitive to the presence of dabigatran (at least 10 ng/ml) under all circumstances investigated. There was wide variation in the sensitivity of commercial fibrinogen assays to dabigatran, with some even showing interference in the therapeutic range but this could be mitigated. The PTT is unreliable as a method for assessment of dabigatran in patients with acute complications. The TT assay is a simple and reliable alternative, particularly when combined with a fibrinogen level.",
"affiliations": "aDivision of Hematopathology, Department of Laboratory Medicine and Pathology, bDivision of Neurology, Department of Medicine, University of Alberta and Alberta Health Services, Alberta, Canada.",
"authors": "Stang|Linda|L|;Nahirniak|Susan|S|;Butcher|Ken|K|;Szkotak|Artur J|AJ|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "25(5)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D000069604:Dabigatran; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015091:beta-Alanine",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "426-34",
"pmc": null,
"pmid": "24637695",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dabigatran assessment in patients with acute complications using routine coagulation assays.",
"title_normalized": "dabigatran assessment in patients with acute complications using routine coagulation assays"
} | [
{
"companynumb": "CA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2013-BI-17887GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Reports on accidental intravenous epinephrine overdose in children are extremely rare, although medication errors in the management of pediatric anaphylaxis seem to be frequent. We report a case of a 12-year-old boy presenting with a long-lasting skin rash and dyspnea who was incorrectly diagnosed with early anaphylactic shock and was treated with 10-fold the recommended dose administered by the wrong route (intravenous instead of intramuscular). He reacted with acute loss of consciousness and acute cardiorespiratory failure due to arterial hypotension, ischemic heart failure, and severe pulmonary edema. He responded rapidly to mechanical ventilation, treatment with diuretics, and low-dose inotropes and recovered without sequelae. Despite this ultimately favorable outcome, we report this case to remind the scientific community that inadvertent and accidental epinephrine overdosing is probably an underrecognized event, which can result in potentially lethal complications. Heightening the awareness of the personnel, implementing safety precautions for the dosage and the route of administration, stocking of prefilled intramuscular dose syringes for emergency use in anaphylaxis and, ideally, introducing a standardized drug order form should reduce potential risks and facilitate proper and optimal treatment for all acutely ill children.",
"affiliations": "From the University Children's Hospital, Division of Respiratory and Critical Care Medicine, University of Basel, Basel, Switzerland.",
"authors": "André|Maya Caroline|MC|;Hammer|Jürg|J|",
"chemical_list": "D002316:Cardiotonic Agents; D004232:Diuretics; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001407",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "35(6)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D061605:Administration, Intravenous; D000707:Anaphylaxis; D002316:Cardiotonic Agents; D002648:Child; D003951:Diagnostic Errors; D004232:Diuretics; D062787:Drug Overdose; D004837:Epinephrine; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008508:Medication Errors; D012121:Respiration, Artificial; D016896:Treatment Outcome",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e110-e112",
"pmc": null,
"pmid": "29406471",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-Threatening Accidental Intravenous Epinephrine Overdose in a 12-Year-Old Boy.",
"title_normalized": "life threatening accidental intravenous epinephrine overdose in a 12 year old boy"
} | [
{
"companynumb": "CH-MYLANLABS-2019M1063353",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Valacyclovir, a prodrug of acyclovir, is the first-line treatment for herpes zoster, but the renal function must be monitored, because acyclovir is metabolized by the kidneys. We herein report a case of valacyclovir-induced neurotoxicity with no preceding renal impairment. An 88-year-old man was admitted because of an impaired consciousness after the administration of valacyclovir at 3,000 mg daily for herpes zoster on the chest. His consciousness level gradually improved with hydration and valacyclovir withdrawal. It was later confirmed that the level of acyclovir on admission had been 35.45 μg/mL in the blood and 36.45 μg/mL in the cerebrospinal fluid.",
"affiliations": "Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.;Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.;Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.;Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.;Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.;Department of General Internal Medicine, Matsushita Memorial Hospital, Japan.",
"authors": "Yoshimura|Takashi|T|;Kawasaki|Tatsuya|T|;Shirota|Ayumi|A|;Saeki|Masashi|M|;Okada|Yuki|Y|;Okada|Hiroshi|H|",
"chemical_list": "D000998:Antiviral Agents; D011355:Prodrugs; D000077483:Valacyclovir",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0403-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2987726310.2169/internalmedicine.0403-17Case ReportValacyclovir-induced Neurotoxicity in a Patient with a Preserved Renal Function Yoshimura Takashi 1Kawasaki Tatsuya 1Shirota Ayumi 1Saeki Masashi 1Okada Yuki 1Okada Hiroshi 1\n1 Department of General Internal Medicine, Matsushita Memorial Hospital, JapanCorrespondence to Dr. Takashi Yoshimura, takashi.yoshimura@jp.panasonic.com\n\n6 6 2018 1 11 2018 57 21 3213 3216 24 10 2017 13 3 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Valacyclovir, a prodrug of acyclovir, is the first-line treatment for herpes zoster, but the renal function must be monitored, because acyclovir is metabolized by the kidneys. We herein report a case of valacyclovir-induced neurotoxicity with no preceding renal impairment. An 88-year-old man was admitted because of an impaired consciousness after the administration of valacyclovir at 3,000 mg daily for herpes zoster on the chest. His consciousness level gradually improved with hydration and valacyclovir withdrawal. It was later confirmed that the level of acyclovir on admission had been 35.45 μg/mL in the blood and 36.45 μg/mL in the cerebrospinal fluid. \n\nherpes zosterneurotoxicityrenal impairmentvalacyclovir\n==== Body\nIntroduction\nHerpes zoster, reactivation of the latent varicella-zoster virus in ganglia, can spread to the neural tissue and the corresponding cutaneous dermatome (1). Antiviral drugs inhibiting the replication of herpes zoster by triphosphates, such as acyclovir and its prodrug valacyclovir, have been established as the first-line treatment for this condition (1) with an excellent safety profile (2,3). However, attention should be paid to drug-induced neurotoxicity in patients with renal impairment, as these agents are metabolized by the kidneys (4).\n\nWe herein report a case of herpes zoster in which valacyclovir-induced neurotoxicity developed in the setting of no preceding renal impairment.\n\nCase Report\nAn 88-year-old man was admitted to our hospital because of an impaired consciousness. The patient had been in his normal state of health until six days before admission, when painful skin blisters developed on the right side of the chest. A diagnosis of herpes zoster was made, and valacyclovir at 3,000 mg daily with levofloxacin at 500 mg daily was prescribed by his physician. Laboratory tests performed 2 weeks before admission indicated a normal renal function with a creatinine level of 0.43 mg/dL and urea nitrogen level of 17.1 mg/dL (Table). One day before admission, his consciousness level was slightly decreased, and intravenous hydration was initiated with little improvement. The next day, the patient was referred to another hospital because the level of consciousness had deteriorated. Computed tomography of the brain and abdomen obtained without the administration of contrast material reportedly was unremarkable. He was then transferred to the emergency department of our hospital for further examination.\n\nTable. Laboratory Data.\n\nVariable\t\tReference range\t\tTwo weeks \nbefore \nadmission\t\tOn admission\t\tSix days after \nadmission\t\nWhite blood cell count (/μL)\t\t4,000-9,000\t\t14,000\t\t8,500\t\t12,000\t\nHemoglobin (g/dL)\t\t11.5-16.5\t\t13.4\t\t11.3\t\t12.3\t\nPlatelet count (/μL)\t\t150,000-420,000\t\t292,000\t\t177,000\t\t117,000\t\nTotal bilirubin (mg/dL)\t\t≤1.2\t\t\t\t0.2\t\t0.4\t\nAspartate aminotransferase (U/L)\t\t≤30\t\t17\t\t48\t\t24\t\nAlanine aminotransferase (U/L)\t\t≤30\t\t13\t\t36\t\t31\t\nLactate dehydrogenase (U/L)\t\t110-120\t\t281\t\t353\t\t287\t\nTotal protein (g/dL)\t\t6.7-8.8\t\t\t\t4.5\t\t4.3\t\t\nAlbumin (g/dL)\t\t≥4.0\t\t3.5\t\t2.3\t\t2.3\t\t\nSodium (mEq/L)\t\t135-147\t\t148\t\t151\t\t159\t\nPotassium (mEq/L)\t\t3.6-5.0\t\t4.3\t\t3.0\t\t2.9\t\nChloride (mEq/L)\t\t100-110\t\t107\t\t110\t\t120\t\nUrea nitrogen (mg/dL)\t\t8-20\t\t17.1\t\t68\t\t47\t\nCreatinine (mg/dL)\t\t0.45-0.81\t\t0.43\t\t1.60\t\t0.91\t\nAmylase (U/L)\t\t37-125\t\t\t\t299\t\t36\t\t\nCreatine kinase (U/L)\t\t≤175\t\t\t\t414\t\t31\t\t\nC-reactive protein (mg/dL)\t\t≤0.25\t\t\t\t5.00\t\t2.36\t\nBlood sugar (mg/dL)\t\t70-108\t\t288\t\t222\t\t165\t\nLow-density lipoprotein cholesterol (mg/dL)\t\t70-139\t\t78\t\t\t\t\t\nTriglyceride (mg/dL)\t\t35-148\t\t94\t\t\t\t\t\nGlycated hemoglobin (%)\t\t4.6-6.2\t\t\t\t8.1\t\t\t\t\neGFR (mL/min/1.73 m2)\t\t≥60\t\t135.1\t\t32.1\t\t59.5\t\neGFR: estimated glomerular filtration rate\n\nThe patient had a history of asthma, dyslipidemia, heart failure, overactive bladder, hypertension, diabetes mellitus, reflux esophagitis, benign prostate hypertrophy, and pancreatitis. His medications included ipragliflozin at 50 mg, omeprazole at 10 mg, metformin at 500 mg, amlodipine at 5 mg, imidapril at 5 mg, glimepiride at 0.5 mg, tamsulosin at 0.2 mg, and imidafenacin at 0.1 mg. The last administration of valacyclovir was 32 hours before admission, and that of levofloxacin was 48 hours before admission. He did not smoke or drink and had no known allergies. His family history was unclear because he had lived alone for decades with little contact with his relatives.\n\nOn an examination, he was not lethargic but was drowsy and disoriented (Japan Coma Scale 3). The blood pressure was 91/63 mmHg, the pulse was 50 beats per minute, the respiratory rate was 14 breaths per minute, and the oxygen saturation was 96% while breathing ambient air. The body surface temperature was below the lower limit of the measurable range; the rectal temperature was not measured at the emergency department. His capillary blood glucose level was 224 mg/dL. Manual muscle testing was not performed, but he continued to move his upper extremities. There was no muscle fasciculation, increased or decreased muscle tonus, sensory impairment, or tendon reflex abnormalities.\n\nThe findings of arterial blood gases, assessed with a supplemental oxygen flow at 1 liter per minute via nasal cannula, were a partial oxygen pressure of 130.0 mmHg, partial carbon dioxide of 56.3 mmHg, lactate of 9 mg/dL, bicarbonate of 30.2 mmol/L, and pH of 7.349. The C-reactive protein level was 5.00 mg/dL, the urea nitrogen level was 68 mg/dL, and the creatinine level was 1.60 mg/dL. The other results are shown in the Table. His cerebrospinal fluid was clear with a first pressure of 105 mm of water, last pressure of 50 mm of water, protein level of 85 mg/dL, glucose level of 151 mg/dL, and cell count of 1 per cubic millimeter. Electrocardiography demonstrated sinus bradycardia with a heart rate of 40 beats per minute and prominent J waves (Figure). The chest radiograph findings were normal.\n\nFigure. Electrocardiogram findings on admission. Faint P waves in lead V4 (arrows) indicate sinus bradycardia. Neither prolonged QT intervals nor ST-segment changes are obvious, but prominent J waves are noted (arrowheads).\n\nA tentative diagnosis of valacyclovir-induced neurotoxicity was made, and hydration was intravenously initiated, along with valacyclovir withdrawal and passive warming with blankets. Echocardiography revealed a left ventricular ejection fraction of 44%, normal chamber sizes, and mild mitral and tricuspid valve regurgitation. Blood cultures were obtained and later found to be sterile. His body surface temperature returned to 36.4°C at 12 hours after admission, accompanied by the disappearance of the prominent J waves when the blood pressure and heart rate were 94/44 mmHg and 74 beats per minute, respectively. The fractional excretion of urea, assessed 3 days after admission, was 28.8% (reference 50-65%, with the value ≤35% indicating prerenal acute kidney injury) (5). The cerebrospinal fluid was confirmed to be negative for herpes simplex virus, cytomegalovirus, and varicella zoster virus. His consciousness level and laboratory tests, as shown in Table, gradually improved within a week after admission, although the subsequent clinical course was complicated with liver enzyme elevation and pressure ulcers, which were treated conservatively. It was later confirmed that the levels of acyclovir were 35.45 μg/mL in the blood (therapeutic reference ranges, 0.4 to 2.0) (6,7) and 36.45 μg/mL in the cerebrospinal fluid on admission, and 0.63 μg/mL in the blood 6 days after admission.\n\nThe patient was scheduled to be transferred to a rehabilitation hospital, but approximately one month after admission, hemodynamic collapse suddenly occurred. Resuscitation was performed without success, and no autopsy was performed.\n\nDiscussion\nOur patient likely developed neurotoxicity due to valacyclovir; however, the possibility of acute encephalitis due to herpes zoster or other organisms cannot be completely ruled out. Acute encephalitis is a rare but serious complication of herpes zoster infection, and this unusual condition is generally accompanied by disseminated skin lesions and pleocytosis in the cerebrospinal fluid (1,8), none of which were observed in the present case. Acute encephalitis associated with herpes zoster usually occurs around a week after the onset of skin eruption, whereas drug-induced neurotoxicity develops within three days after the administration of antiviral drugs (9,10). The direct effects of valacyclovir on the brain remain unclear, but high concentrations of valacyclovir may inhibit deoxyribonucleic acid polymerase, resulting in alteration of the mitochondrial function (6,11).\n\nDrugs other than valacyclovir were also considered as causes of the impaired consciousness in the present case. In particular, concerns persist regarding the neurotoxic effects of levofloxacin, a third-generation fluorinated quinolone antibiotic, because of its predominantly renal excretion (12) and simultaneous administration with valacyclovir. Neurotoxic manifestations related to quinolones include headache, dizziness, seizures, delirium, and confusion (13). The diversity of symptoms may be explained by variability in the binding potency of quinolones to gamma-aminobutyric acid receptors (14), which is considered to be one mechanism underlying quinolone-induced neurotoxicity (15). Although the concentration of levofloxacin was not measured in the present case, we consider levofloxacin-induced neurotoxicity to be less likely due to the half-life of levofloxacin (i.e., 4 to 7 hours in healthy volunteers (16) and 34.5 hours in patients who needed extended daily dialysis (17). The present case was transferred to our hospital 48 hours after the cessation of levofloxacin. His renal function was not severely impaired on admission and improved afterwards, but consciousness recovery was delayed.\n\nIt has become increasingly recognized that renal impairment is a risk factor of acyclovir neurotoxicity because acyclovir, which is the active drug of valacyclovir, is excreted by the kidneys via tubular secretion and glomerular filtration, although valacyclovir itself is eliminated in the feces (4,6,18). Dose adjustment of valacyclovir should be considered in patients with renal impairment, e.g. creatinine clearance <50 mL/min (1). The half-life of acyclovir is approximately 3 hours in healthy volunteers, whereas it can be extended up to 14 hours in patients with end-stage renal disease (6,19). The mechanism underlying the new onset of renal impairment in the present case remains unclear, but a gradual loss of appetite due to the herpes zoster infection may have led to dehydration and renal impairment. This speculation was consistent with the decreased fractional excretion of urea (5). Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, may have exacerbated the dehydration in the present case.\n\nAnother explanation for the transient renal impairment is the direct toxic effects of valacyclovir on the renal function, although the risk of valacyclovir-induced renal impairment is likely low (20). Drug interaction with valacyclovir has been reported, such as for antacids like cimetidine, probenecid, digoxin, and thiazide diuretics (21), but none of these had been prescribed in the present case. As the bioavailability of valacyclovir is three to four times higher than that of acyclovir (19,22), individual vulnerability and frailty should be carefully considered in order to avoid valacyclovir-induced neurotoxicity. This condition is likely to occur among elderly patients not only because they are prone to dehydration but also because the severity and incidence of herpes zoster increases with age (1,23). Drug-induced neurotoxicity is generally resolved within two to seven days after the cessation of antiviral drugs, along with supportive care, and hemodialysis may be considered in severe cases because acyclovir has a low volume distribution and low protein binding (6). In such high-risk patients, a potent helicase-primase inhibitor, amenamevir, which was recently approved for the treatment of herpes zoster, may be considered as an alternative to acyclovir and valacyclovir, as this novel class of antiviral agents seems to require no dose adjustment for renal impairment (24,25). It is important to note that we cannot completely rule out the possibility of other drugs, such as levofloxacin, as the cause of the transient renal impairment.\n\nThis case highlights the importance of closely monitoring herpes zoster patients treated with antiviral agents, particularly vulnerable and frail elderly patients, even in the absence of preceding renal impairment.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Dworkin RH , Johnson RW , Breuer J , et al \nRecommendations for the management of herpes zoster . Clin Infect Dis \n44 : S1 -26 , 2007 .17143845 \n2. Wassilew SW , Wutzler P ; Brivddin Herpes Zoster Study Group . \nOral brivudin in comparison with acyclovir for improved therapy of herpes zoster in immunocompetent patients: results of a randomized, double-blind, multicentered study . Antiviral Res \n59 : 49 -56 , 2003 .12834860 \n3. Beutner KR , Friedman DJ , Forszpaniak C , Andersen PL , Wood MJ \nValaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults . Antimicrob Agents Chemother \n39 : 1546 -1553 , 1995 .7492102 \n4. Blum MR , Liao SH , de Miranda P \nOverview of acyclovir pharmacokinetic disposition in adults and children . Am J Med \n73 : 186 -192 , 1982 .7048911 \n5. Carvounis CP , Nisar S , Guro-Razuman S \nSignificance of the fractional excretion of urea in the differential diagnosis of acute renal failure . Kidney Int \n62 : 2223 -2229 , 2002 .12427149 \n6. Huguenel C , Felton D , Bruccoleri R , Salhanick S \nCase files of the Harvard medical toxicology fellowship: valacyclovir neurotoxicity and unintentional overdose . J Med Toxicol \n11 : 132 -136 , 2015 .25539699 \n7. Lycke J , Andersen O , Svennerholm B , Appelgren L , Dahlöf C \nAcyclovir concentrations in serum and cerebrospinal fluid at steady state . J Antimicrob Chemother \n24 : 947 -954 , 1989 .2621178 \n8. Jemsek J , Greenberg SB , Taber L , Harvey D , Gershon A \nCouch RB. Herpes zoster-associated encephalitis: clinicopathologic report of 12 cases and review of the literature . Medicine (Baltimore) \n62 : 81 -97 , 1983 .6298562 \n9. Adair JC , Gold M , Bond RE \nAcyclovir neurotoxicity: clinical experience and review of the literature . South Med J \n87 : 1227 -1231 , 1994 .7973922 \n10. Hughes BA , Kimmel DW , Aksamit AJ \nHerpes zoster-associated meningoencephalitis in patients with systemic cancer . Mayo Clin Proc \n68 : 652 -655 , 1993 .8350638 \n11. Lewis W , Dalakas MC \nMitochondrial toxicity of antiviral drugs . Nat Med \n1 : 417 -422 , 1995 .7585087 \n12. Stahlmann R , Lode H \nFluoroquinolones in the elderly: safety considerations . Drugs Aging \n20 : 289 -302 , 2003 .12641485 \n13. Grill MF , Maganti RK \nNeurotoxic effects associated with antibiotic use: management considerations . Br J Clin Pharmacol \n72 : 381 -393 , 2011 .21501212 \n14. Akahane K , Tsutomi Y , Kimura Y , Kitano Y \nLevofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding . Chemotherapy \n40 : 412 -417 , 1994 .7842825 \n15. Akahane K , Sekiguchi M , Une T , Osada Y \nStructure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites . Antimicrob Agents Chemother \n33 : 1704 -1708 , 1989 .2556076 \n16. Davis R , Bryson HM \nLevofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy . Drugs \n47 : 677 -700 , 1994 .7516863 \n17. Czock D , Hüsig-Linde C , Langhoff A , et al \nPharmacokinetics of moxifloxacin and levofloxacin in intensive care unit patients who have acute renal failure and undergo extended daily dialysis . Clin J Am Soc Nephrol \n1 : 1263 -1268 , 2006 .17699357 \n18. Asahi T , Tsutsui M , Wakasugi M , et al \nValacyclovir neurotoxicity: clinical experience and review of the literature . Eur J Neurol \n16 : 457 -460 , 2009 .19187258 \n19. Beutner KR \nValacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy . Antiviral Res \n28 : 281 -290 , 1995 .8669888 \n20. Lam NN , Weir MA , Yao Z , et al \nRisk of acute kidney injury from oral acyclovir: a population-based study . Am J Kidney Dis \n61 : 723 -729 , 2013 .23312723 \n21. Valtrex (Valacyclovir Hydrochloride) Caplets - FDA [Internet]. [cited 2018 Jan. 15]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020487s014lbl.pdf\n22. Soul-Lawton J , Seaber E , On N , Wootton R , Rolan P , Posner J \nAbsolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans . Antimicrob Agents Chemother \n39 : 2759 -2764 , 1995 .8593015 \n23. Oxman MN , Levin MJ , Johnson GR , et al \n; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults . N Engl J Med \n352 : 2271 -2284 , 2005 .15930418 \n24. James SH , Larson KB , Acosta EP , Prichard MN \nHelicase-primase as a target of new therapies for herpes simplex virus infections . Clin Pharmacol Ther \n97 : 66 -78 , 2015 .25670384 \n25. Kawashima M , Nemoto O , Honda M , et al \n; study investigators. Amenamevir, a novel helicase-primase inhibitor, for treatment of herpes zoster: a randomized, double-blind, valaciclovir-controlled phase 3 study . J Dermatol \n44 : 1219 -1227 , 2017 .28681394\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "herpes zoster; neurotoxicity; renal impairment; valacyclovir",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000998:Antiviral Agents; D006562:Herpes Zoster; D006801:Humans; D007668:Kidney; D008297:Male; D020258:Neurotoxicity Syndromes; D011355:Prodrugs; D000077483:Valacyclovir",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3213-3216",
"pmc": null,
"pmid": "29877263",
"pubdate": "2018-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7048911;23312723;7842825;25670384;8593015;2556076;8350638;28681394;6298562;17143845;12834860;7973922;12641485;2621178;15930418;25539699;19187258;21501212;7492102;17699357;7585087;12427149;8669888;7516863",
"title": "Valacyclovir-induced Neurotoxicity in a Patient with a Preserved Renal Function.",
"title_normalized": "valacyclovir induced neurotoxicity in a patient with a preserved renal function"
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"activesubstancename": "LEVOFLOXACIN"
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"abstract": "We report a case of fenpyroximate poisoning with cholinergic signs that could be due to mixing it with anticholinesterase. Clinicians should consider co-ingestion of pesticides to proper diagnosis and management of the pesticide poisoning.",
"affiliations": "Department of Internal Medicine Minab Abolfazl Hospital Hormozgan University of Medical Science Hormozgan Iran.;Department of Pharmacology and Toxicology School of Pharmacy Shahid Beheshti University of Medical Science Tehran Iran.",
"authors": "Kheirkhah|Soodabeh|S|;Bahmani|Kiumars|K|https://orcid.org/0000-0002-1053-778X",
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"doi": "10.1002/ccr3.3159",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3159\nCCR33159\nCase Report\nCase Reports\nA rare case of fenpyroximate poisoning with presenting anticholinesterase poisoning signs\nKHEIRKHAH and BAHMANIKheirkhah Soodabeh \n1\n Bahmani Kiumars https://orcid.org/0000-0002-1053-778X\n2\nkiumarsbahmani@yahoo.com \n1 \nDepartment of Internal Medicine\nMinab Abolfazl Hospital\nHormozgan University of Medical Science\nHormozgan\nIran\n\n\n2 \nDepartment of Pharmacology and Toxicology\nSchool of Pharmacy\nShahid Beheshti University of Medical Science\nTehran\nIran\n\n* Correspondence\n\nKiumars Bahmani, Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Science, Tehran, Iran.\n\nEmail: kiumarsbahmani@yahoo.com\n\n20 7 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122406 2408\n28 2 2020 14 5 2020 15 6 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis 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\nWe report a case of fenpyroximate poisoning with cholinergic signs that could be due to mixing it with anticholinesterase. Clinicians should consider co‐ingestion of pesticides to proper diagnosis and management of the pesticide poisoning.\n\nWe report a case of fenpyroximate poisoning with cholinergic signs that could be due to mixing it with anticholinesterase. Clinicians should consider co‐ingestion of pesticides to proper diagnosis and management of the pesticide poisoning.\n\n\nanticholinesterasefenpyroximatepoisoning source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nKheirkhah \nS \n, \nBahmani \nK \n. A rare case of fenpyroximate poisoning with presenting anticholinesterase poisoning signs\n. Clin Case Rep . 2020 ;8 :2406 –2408\n. 10.1002/ccr3.3159\n==== Body\n1 INTRODUCTION\nFenpyroximate is a mitochondrial proton‐translocating NADH ubiquinone oxidoreductase (complex I) inhibitor.\n1\n It is used in the agricultural sector as an acaricide. Acute and chronic toxicity studies of fenpyroximate in laboratory animals have been conducted by oral lavage.\n2\n There are few case reports of poisoning with fenpyroxymate, and there is no report of fenpyroxymate poisoning with co‐ingestion of other drugs and poisons. In this study, we report a rare case of fenpyroximate poisoning with unusual symptoms suspected with anticholinesterase co‐ingestion.\n\n2 CASE PRESENTATION\nA 29‐year‐old man admitted to the hospital following ingestion of 15 tablets of alprazolam 0.5 mg and 15 tablets of valproate sodium 500 mg and 120 mL of fenpyroximate 5%. The patient was under medical care with alprazolam and valproate. At the presentation, the patient was unconscious, with sialorrhea, lacrimation, and diarrhea; emesis, sweating, and pulmonary; and upper airway secretions, but he had not miosis and pupils were normal in size. His systolic blood pressure and heart rate were 60 mm Hg and 120, respectively. Venous blood gas analysis showed metabolic acidosis (pH 7.35; PCO2 42 mm Hg; PO2 62.1 mm Hg; base excess −3 mmol/L,). Cardiac function was normal, EKG and echocardiography were performed, and ejection fraction was %50. We performed gastric lavage and admit the patient in the intensive care unit. Atropine challenge test was positive; therefore, co‐ingestion of an anticholinesterase agent (organophosphate or carbamate) suspected, but butyrylcholinesterase activity measuring was not available at the time for confirmation so atropine was administrated considering cholinergic signs of the patient. After 14 hours, cholinergic signs diminished and atropine administration was discontinued. According to anesthetist consultation, the patient was not intubated, one day after admission, patient's body temperature raised, leukocytosis has been documented with domination of neutrophils, and ceftriaxone and clindamycin were administrated for him until discharging from ICU. The patient was discharged after 9 days hospitalization with clinically stable conditions and referred to psychiatrist for the further treatment. Although the patient was discharged in good general condition, but due to pyrosis, endoscopic gastric evaluation was performed at the follow‐up, which was reported to be erosive gastropathy.\n\n3 DISCUSSION\nFenpyroximate is an acaricide that inhibit complex I of the mitochondrial respiratory chain.\n3\n They decrease ATP production and therefore ATP content of the cell.\n4\n The symptoms and signs of toxicity include the following: nausea, vomiting, incoordination, convulsions, central nervous system depression and respiratory distress, bradycardia, and arrhythmia.\n5\n However, in this patient remarkably has shown with signs and symptoms of anticholinesterase poisoning that could be on the consequence of co‐ingestion with most likely organophosphate or carbamate pesticide. This patient had not miosis, one of the most frequent findings in anticholinesterase poisoning; however, it could be due to co‐ingestion of alprazolam and valproate.\n6\n, \n7\n Jallow MF et al research showed that the farmers were not aware of safety measures of pesticide using\n8\n consequently most of them mixes the pesticides.\n9\n Lee HY et.al reported severe metabolic acidosis following ingestion of 70ml of fenpyroximate \n10\n; however, in the present patient metabolic acidosis was mild that might be because of immediate referring to hospital and decontamination. Kuruppu Arachchi et al. reported acute neurotoxicity as consequence of fenpyroximate poisoning,\n1\n but our patient had not sign of acute neurotoxicity. The inhibition of mitochondrial complex I leading to dysfunction of mitochondria and generation of reactive oxygen species is hypothesized as a mechanism of fenpyroximate induced neurotoxicity,\n11\n and there is a case report of a 58‐year‐old man who developed parkinsonism two years after intentional fenpyroximate intoxication.\n12\n Lack of acute neurotoxicity in our patient could be result of alprazolam co‐ingestion because benzodiazepines have neuroprotective effects. They enhance GABA transmission and thus counteract excitotoxic degenerative mechanisms and also reduce and cerebral metabolic rate.\n13\n\n\n\n4 CONCLUSION\nPesticide poisoning can be caused by mixing pesticides with each other or other drugs and poisons sometimes. They can cause misdiagnosis and increase the severity of complications, or they might have protective effects like alprazolam in mentioned case. Our case had mix signs and symptoms of fenpyroximate and anticholinesterase poisoning, and clinicians should be aware of this for proper diagnosis and treatment of pesticide poisoning cases.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nDr. Soodabeh Kheirkhah: was responsible for visiting the patient, physical examination, management, follow‐up of the patient, and reviewing the manuscript. Dr. Kiumars Bahmani: was responsible for toxicology consultation, drafting the manuscript, and revision of the manuscript.\n\nAcknowledgments\nThe authors wish to sincerely thank the patient and his family for granting permission to use the clinical records for the purpose of scientific publication. Published with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nKuruppu Arachchi \nA \n, \nSundaresan \nK \n, \nUmakanth \nM \n, \nThivakaran \nT \n. Acute neurotoxicity following Fenpyroximate poisoning\n. Ceylon Med J . 2019 ;63 (4 ):186 .\n2 \n\nLewis \nK \n, \nGreen \nA \n, \nTzilivakis \nJ \n, \nWarner \nD \n. The Pesticide Properties DataBase (PPDB) Developed by the Agriculture & Environment Research Unit (AERU)\n. University of Hertfordshire. 2006, 2015.\n3 \n\nLee \nBK \n, \nJeung \nKW \n, \nRyu \nHH \n, \nHeo \nT \n, \nMin \nYI \n, \nLee \nHY \n. A case of fatal fenazaquin intoxication showing severe lactic acidosis\n. J Korean Soc Emerg Med . 2010 ;21 (4 ):520 –523\n.\n4 \n\nObata \nT \n, \nFujii \nK \n, \nYoshiya \nH \n, \nTsutsumiuchi \nK \n, \nYoshioka \nH \n. Synthesis and insecticidal and acaricidal activity of new N‐(α‐substituted phenoxybenzyl)‐4‐pyrimidinamines\n. Pesticide Sci . 1992 ;34 (2 ):133 –138\n.\n5 \n\nPatel \nF \n. Pesticidal suicide: adult fatal rotenone poisoning\n. J Forensic Leg Med . 2011 ;18 (7 ):340 –342\n.21907942 \n6 \n\nMalone \nJD \n, \nCamara \nEG \n, \nKrug \nJJ \n. Ophthalmologic effects of psychotropic medications\n. Psychosomatics . 1992 ;33 (3 ):271 –277\n.1410200 \n7 \n\nManoguerra \nAS \n, \nErdman \nAR \n, \nWoolf \nAD \n et al Valproic acid poisoning: an evidence‐based consensus guideline for out‐of‐hospital management\n. Clin Toxicol . 2008 ;46 (7 ):661 –676\n.\n8 \n\nJallow \nMF \n, \nAwadh \nDG \n, \nAlbaho \nMS \n, \nDevi \nVY \n, \nThomas \nBM \n. Pesticide knowledge and safety practices among farm workers in Kuwait: Results of a survey\n. Int J Environ Res Public Health . 2017 ;14 (4 ):340 .\n9 \n\nMengistie \nBT \n, \nMol \nAP \n, \nOosterveer \nP \n. Pesticide use practices among smallholder vegetable farmers in Ethiopian Central Rift Valley\n. Environ Dev Sustain . 2017 ;19 (1 ):301 –324\n.\n10 \n\nLee \nHY \n, \nLee \nBK \n, \nJeung \nKW \n, \nLee \nGS \n, \nJung \nYH \n, \nJeong \nIS \n. A case of near‐fatal fenpyroximate intoxication: The role of percutaneous cardiopulmonary support and therapeutic hypothermia\n. Clin Toxicol . 2012 ;50 (9 ):858 –861\n.\n11 \n\nRamachandiran \nS \n, \nHansen \nJM \n, \nJones \nDP \n, \nRichardson \nJR \n, \nMiller \nGW \n. Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase‐3 activation\n. Toxicol Sci . 2007 ;95 (1 ):163 –71\n.17018646 \n12 \n\nKim \nKJ \n, \nKim \nJM \n, \nBae \nYJ \n, \nSong \nYS \n, \nKim \nSE \n. 123I‐FP‐CIT SPECT and MRI Findings in a Patient With Parkinsonism After Fenpyroximate Intoxication\n. Clin Nuclear Med . 2018 ;43 (6 ):e178 –e179\n.\n13 \n\nHunt \nK \n, \nBose \nG \n. Clinical neuroprotection and secondary neuronal injury mechanisms\n. Anaesth Intensive Care Med . 2020 ;21 (6 ):293 –297\n.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "anticholinesterase; fenpyroximate; poisoning",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2406-2408",
"pmc": null,
"pmid": "33363750",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "18608263;22963274;28338612;17018646;1410200;29629914;21907942",
"title": "A rare case of fenpyroximate poisoning with presenting anticholinesterase poisoning signs.",
"title_normalized": "a rare case of fenpyroximate poisoning with presenting anticholinesterase poisoning signs"
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"companynumb": "IR-PFIZER INC-202100942439",
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"abstract": "Gallbladder (GB) empyema is an uncommon complication in acute myeloid leukaemia (AML). Non-specific signs and symptoms and rarity of disease in AML make it difficult to diagnose early. We report a case of 13-year-old boy who had AML and developed GB empyema in the neutropaenic period. The patient was managed with antibiotics, ultrasound-guided tapping and interval cholecystectomy and recovered well. GB empyema is a life-threatening complication which should be kept as a possibility while evaluating patients with neutropaenia with pain abdomen localised to right hypochondrium as early diagnosis and treatment can lead to better outcomes.",
"affiliations": "Department of Pediatrics, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Pediatrics, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Pediatrics, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Pediatric hematoncology and BMT, Medanta The Medicity, Gurgaon, Haryana, India.",
"authors": "Pant|Gitika|G|http://orcid.org/0000-0003-3878-0770;Kumar|Archana|A|;Verma|Nishant|N|;Sharma|Anil|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents",
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"keywords": "malignant disease and immunosuppression; paediatric oncology",
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"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002763:Cholecystectomy; D002764:Cholecystitis; D003937:Diagnosis, Differential; D005334:Fever; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D014057:Tomography, X-Ray Computed",
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"pubdate": "2018-08-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Gallbladder empyema complicating acute myeloid leukaemia in an adolescent boy.",
"title_normalized": "gallbladder empyema complicating acute myeloid leukaemia in an adolescent boy"
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"abstract": "Metastatic breast cancer is one of the leading causes of cancer-related death in women. Limited studies have been done on the genomic evolution between primary and metastatic breast cancer. We reconstructed the genomic evolution through the 16-yr history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long-term exposure to hormonal therapy. Genomic and transcriptome profiling was performed on primary breast tumor (2002), initial recurrence (2012), and liver metastasis (2015) samples. Cell-free DNA analysis was performed at 11 time points (2015-2017). Mutational analysis revealed a low mutational burden in the primary tumor that doubled at the time of progression, with driver mutations in PI3K-Akt and RAS-RAF signaling pathways. Phylogenetic analysis showed an early branching off between primary tumor and metastasis. Liquid biopsies, although initially negative, started to detect an ESR1 E380Q mutation in 2016 with increasing allele frequency until the end of 2017. Transcriptome analysis revealed 721 (193 up, 528 down) genes to be differentially expressed between primary tumor and first relapse. The most significantly down-regulated genes were TFF1 and PGR, indicating resistance to aromatase inhibitor (AI) therapy. The most up-regulated genes included PTHLH, S100P, and SOX2, promoting tumor growth and metastasis. This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread, and treatment resistance.",
"affiliations": "Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA.;Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.",
"authors": "Xu|Bing|B|;Amallraja|Anu|A|;Swaminathan|Padmapriya|P|;Elsey|Rachel|R|;Davis|Christel|C|;Theel|Stephanie|S|;Viet|Sarah|S|;Petersen|Jason|J|;Krie|Amy|A|;Davies|Gareth|G|;Williams|Casey B|CB|;Ehli|Erik|E|;Meißner|Tobias|T|",
"chemical_list": "D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
"country": "United States",
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"doi": "10.1101/mcs.a005629",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case Stud\nCold Spring Harb Mol Case Stud\ncshmcs\ncshmcs\ncshmcs\nCold Spring Harbor Molecular Case Studies\n2373-2873 Cold Spring Harbor Laboratory Press \n\n33008833\n10.1101/mcs.a005629\nMCS005629Xu\nResearch Article\nCase report: 16-yr life history and genomic evolution of an ER+ HER2− breast cancer\nGenomic evolution of an ER+ HER2− breast cancerGenomic evolution of an ER+ HER2 − breast cancerXu Bing 1 Amallraja Anu 1 Swaminathan Padmapriya 1 Elsey Rachel 1 Davis Christel 2 Theel Stephanie 2 Viet Sarah 2 Petersen Jason 2 Krie Amy 1 Davies Gareth 2 Williams Casey B. 1 Ehli Erik 2 Meißner Tobias 1 1 Center for Precision Oncology, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA;\n2 Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, USA\nCorresponding author: tobias.meissner@avera.org\n12 2020 \n6 6 a0056291 6 2020 28 9 2020 © 2020 Xu et al.; Published by Cold Spring Harbor Laboratory Press2020This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Metastatic breast cancer is one of the leading causes of cancer-related death in women. Limited studies have been done on the genomic evolution between primary and metastatic breast cancer. We reconstructed the genomic evolution through the 16-yr history of an ER+ HER2− breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long-term exposure to hormonal therapy. Genomic and transcriptome profiling was performed on primary breast tumor (2002), initial recurrence (2012), and liver metastasis (2015) samples. Cell-free DNA analysis was performed at 11 time points (2015–2017). Mutational analysis revealed a low mutational burden in the primary tumor that doubled at the time of progression, with driver mutations in PI3K–Akt and RAS–RAF signaling pathways. Phylogenetic analysis showed an early branching off between primary tumor and metastasis. Liquid biopsies, although initially negative, started to detect an ESR1 E380Q mutation in 2016 with increasing allele frequency until the end of 2017. Transcriptome analysis revealed 721 (193 up, 528 down) genes to be differentially expressed between primary tumor and first relapse. The most significantly down-regulated genes were TFF1 and PGR, indicating resistance to aromatase inhibitor (AI) therapy. The most up-regulated genes included PTHLH, S100P, and SOX2, promoting tumor growth and metastasis. This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread, and treatment resistance.\n\nmultifocal breast carcinomaAvera McKennan Hospital & University Health Center and Avera McKennan Foundation\n==== Body\nINTRODUCTION\nBreast cancer is the most common malignancy affecting women in the United States, causing the most cancer-related deaths (Howlader et al. n.d.; Breast Cancer Statistics and Resource 2017). However, patients normally do not die from the primary disease, but as a consequence of metastasis (Fouad et al. 2015). Hormone receptor–positive disease accounts for >60% of all breast cancer (American Cancer Society n.d.). The 20-yr recurrence risk of distant metastasis in estrogen receptor (ER)-positive breast cancer is between 10% and 40% and depends on the size of the primary tumor and number of positive lymph nodes (Pan et al. 2017). More than one-half of the recurrence happens after 5 yr of initial diagnosis (Dowling et al. 2019). Little is known about the triggers of metastasis or how the metastatic disease is different from the primary tumor. Developing sequencing technology made it possible to identify the cancer drivers and closely track disease evolution on the genomic and transcriptomic level.\n\nHere we present a patient who was diagnosed with stage III ER-positive breast cancer and developed distant recurrences after 10 years of remission. The patient survived late-stage disease for another 6 years and passed away as a result of extensive disease burden and cancer-related complications. Tissue samples were collected from the patient's breast tumor at initial diagnosis, first recurrence in supraclavicular lymph node, and distant metastasis in the liver. Eleven liquid biopsies were collected after distant metastasis. DNA and RNA from the samples were extracted, sequenced, and analyzed. From the genomic and transcriptomic analysis, we were able to identify potential disease drivers and resistance mechanisms at each stage of the disease, reconstruct the cancer evolutionary tree, and investigate the relationship between the metastases and primary tumor.\n\nRESULTS\nClinical Presentation\nA 46-yr-old premenopausal Caucasian female presented with stage III invasive ductal carcinoma of the breast in January 2002. The patient‘s treatment history is summarized in Figure 1A. Solid and liquid samples collected from 2002 to 2017 are gathered in Table 1.\n\nFigure 1. Patient disease history with treatment and tumor molecular profiles. (A) Disease and treatment history, with red explosions indicating disease progression and an × mark on the time axis indicating treatment on hold because of adverse events. T1, M1, and M2 on the time line indicate when solid tumor samples were collected. Treatment duration is plotted according to the time axis on top. Treatment strip color is assigned per drug class: blue for chemotherapies; red for estrogen receptor antagonists; pink for aromatase inhibitors; purple for mTOR inhibitor; yellow for tyrosine kinase inhibitors; lilac for MEK inhibitor; and green for immunotherapy. (B) Driver mutations from solid tissue samples and liquid biopsies (cfDNA). The table is shaded with a stream graph representing the mutation load during disease progression. Driver mutations are shown with colored bands with the band widths representing mutation allele frequency.\n\nTable 1. Sample information\n\nTumor sample\tTest\tAverage coverage\t\nSample\tSpecimen site\tCollection year\tER\tPR\tHER2\t\nT1\tRight breast\t2002\t+\t+\t–\tWES\t190×\t\n\t\t\tRNA-seq\t46M\t\nM1\tRight scalene lymph node\t2012\t+\t–\t–\tWES\t181×\t\nRNA-seq\t75M\t\nM2\tLiver\t2015\t+\t+\t–\tTargeted Sequencing (FoundationOne 315 gene)\t462×\t\nLiquid biopsies\tBlood\t2015–2016\tNA\tNA\tNA\tTargeted Gene Sequencing (Guardant 70 gene)\tMin 15,000×\t\nLiquid biopsies\tBlood\t2017\tNA\tNA\tNA\tTargeted Gene Sequencing (FoundationAct 67 gene)\t10,000×\t\nSolid and liquid samples collected from 2002 to 2017.\n\nAt initial diagnosis, the patient's tumor was characterized as ER-positive, progesterone receptor (PR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative by immunohistochemistry (IHC). Right breast mastectomy and axillary lymph node dissection were performed. The patient was treated adjuvantly with doxorubicin and cyclophosphamide followed by paclitaxel (AC-T). She was then maintained on tamoxifen for 2 years, followed by 8 years of aromatase inhibitor therapy (anastrozole).\n\nIn May 2012, the patient returned to the clinic with recurrent disease at the right supraclavicular lymph node and possible metastatic nodules in the right upper lobe of the lung and anterior mediastinum. The lymph node metastasis was ER-positive, PR-negative, and HER2-negative. She started on single-agent exemestane. Everolimus was added in July 2012. Radiation therapy to the regional lymphatics and right chest wall was completed in December 2012. In January 2013, restaging positron emission tomography (PET) demonstrated a complete metabolic response. The disease was considered stable for 24 mo under this regimen.\n\nIn May 2014, progressive liver lesions were shown on computerized tomography (CT) scan. In response to disease progression, the patient was moved to the next line of treatment with fulvestrant and exemestane.\n\nIn September 2014, evidence of progression in the liver, pleura, and bones was found through CT scan. The treatment was switched to single-agent capecitabine. The patient was stable for 6 mo.\n\nIn March 2015, new lesions were found in the patient's liver. The previous disease in her mediastinal lymph nodes increased in size. The liver lesion tested ER-positive, PR-positive, and HER2-negative by IHC. In April 2015, treatment was changed to paclitaxel plus everolimus and sorafenib.\n\nTo guide treatment and track tumor evolution, genomic testing was performed first through targeted DNA sequencing of a liver biopsy (through FoundationOne test) and subsequently liquid biopsies (through Guardant360 and FoundationAct tests) from August 2015 to November 2017. Mutational findings are summarized in Figure 1B.\n\nIn August 2015, all treatments were held for 2 wk because of severe neutropenia. The regimen was then changed to everolimus plus vinorelbine and crizotinib.\n\nIn February 2016, because of progression in the liver, the patient started a new line of treatment with trametinib, eribulin, and everolimus. A CT scan in April 2016 suggested a 20% reduction in liver tumor volume. In July 2016, crizotinib was added to the regimen as a result of progression in the liver and the right pleura.\n\nIn early September 2016, the patient finished 11 cycles of eribulin. Her CT scan showed slight progression on the chest wall. She was switched to carboplatin plus exemestane and cabozantinib. Everolimus was added to the regimen at the end of December 2016.\n\nIn late February 2017, new lesions were detected on the patient's bone scan. The patient started a new regimen of atezolizumab, fulvestrant, everolimus, and cabozantinib. Protein-bound paclitaxel was added in early May. In June 2017, everolimus was held because of thrombocytopenia and neutropenia. Later in June, slight progression was seen on a CT scan, and trametinib was added.\n\nIn October 2017, all therapy was held because of her implant that had eroded through the chest wall, which was then surgically removed. The patient continued to have an open area at the right breast but wished to continue with aggressive treatment after surgery. Treatment was restarted at the beginning of November 2017. At the end of November, CT showed progression in the lungs and retroperitoneal lymph nodes. In mid-December 2017, the patient's therapy was changed to protein-bound paclitaxel, cabozantinib, atezolizumab, abemaciclib, and fulvestrant.\n\nAt the end of January 2018, the patient struggled with wound healing and a large pneumothorax developed on the right with communication at the wound site. There were no good options to treat the pneumothorax based on her status. Because of the significant tumor burden in the liver, the patient was not capable of tolerating further treatment. The patient was referred to hospice and passed away a week later.\n\nThe patient was enrolled into the multicenter clinical trial “Identifying Molecular Drivers of Cancer (CCD)” (NCT02470715). Therapies were selected by incorporating recommendations of a molecular tumor board consisting of oncologists, pharmacists, nurses, genetic counselors, bioinformaticians, patient advocates, and molecular biologists. The therapies ultimately given were furthermore based on the treating physician's consideration of patient preferences, drug toxicities, and availability (i.e., insurance coverage). For administration of drug combinations, we routinely followed Nikanjam et al. (2016), or other data where available. Patients generally did not receive treatment without at least safety data being available. In addition, patients were monitored closely, and adverse event management was planned on the basis of theoretical drug metabolism, with the result that no treatment-related mortality occurred.\n\nGermline Variants\nThe patient was identified as having the single-nucleotide polymorphism (SNP) FGFR4 p.G388R (rs351855-G/A). No germline alteration was detected among genes commonly included in breast cancer–related or hereditary cancer panels.\n\nTumor Mutation Burden\nThe tumor mutation burden at diagnosis in 2002 (T1) was 4 mutations/Mb, which increased to 16 mutations/Mb at first recurrence in 2012 (M1) and 17 mutations/Mb in the liver biopsy in 2015 (M2).\n\nSomatic Mutational Signatures\nSomatic mutational signatures are unique combinations of nucleotide mutations generated by certain mutational processes (Alexandrov et al. 2013). Among the 30 COSMIC mutational signatures (Alexandrov et al. 2013; Cosmic 2020), APOBEC signature was detected in all three tumor samples (signature 13 in T1, signature 2 and signature 13 in M1 and M2). Signature 1 (common in cancer) and Signature 10 (POLE) were in all three samples. Signature 7 (mutation possibly due to ultraviolet light exposure) is found in T1 and M1 (Supplemental Fig. 1).\n\nSomatic Mutations\nThe mutational profile from T1 and M1 samples were from whole-exome sequencing, whereas the M2 liver sample was tested through FoundationOne assay (324 genes) (Fig. 1B; Supplemental Files 1 and 2). We limited our analysis to driver mutations in genes from the FoundationOne assay. Multiple driver mutations affecting the PI3K–Akt signaling pathway were detected (PIK3CA, PTEN, PIK3R2, PIK3CG, MTOR). The phylogenetic tree (Fig. 2) represents the shared history of known and predicted driver mutations among T1, M1, and M2. The two known drivers, PIK3CA Q546R and TP53 E180K, are present in all three solid tumor samples, with TP53 E180K being subclonal (detected in a fraction of the tumor cells in the sample) in T1 but clonal (detected in all tumor cells of the sample) in M1 and M2. The tree shows early branching off between T1 and M1/M2, with T1 containing four private predicted drivers in ALK, APC, CDKN1B, and ERBB2. As the disease progressed, the total number of driver mutations raised from n = 8 in T1 to 10 and 14 in M1 and M2, and the number of private driver mutations were 4, 6, and 12, respectively, signifying evolution in the tumor at each location and progressive disease evolution with time.\n\nFigure 2. Phylogenetic reconstruction of the tumor history of the patient. Text in bold represents known driver variants as determined by Cancer Genome Interpreter.\n\nThe proportion of clonal mutations among the drivers increased at disease recurrence and decreased again when disease further progressed with more driver mutations. At initial diagnosis, only one out of nine driver mutations was clonal and all the others were subclonal. The tumor sample from the first recurrence (M1) shared four of the driver mutations from T1. The clonal status of the driver mutations are presented in Supplemental File 3.\n\nLiquid biopsies (circulating tumor DNA [ctDNA], n = 11) were performed from August 2015 to November 2017 (Fig. 1B; Supplemental File 1; Supplemental Fig. 2). The first two liquid biopsies were negative with initial ctDNA mutations being detected in November 2015. The number of mutations with known cancer-related activity increased to the 20s over time. An ESR1 E380Q mutation, which was not previously detected, appeared in the ctDNA by the end of 2016 after exemestane treatment was restarted and had rapidly increased in allele frequency by the end of 2017 (from 0.9% to 28.3%) (Supplemental Fig. 2).\n\nCopy-Number Variations\nNo copy-number variations were detected in the analyzed samples.\n\nDifferential Expression Analysis\nRNA-seq analysis of T1 and M1 revealed gene expression changes between initial diagnosis and disease recurrence after 10 years. Seven hundred and twenty-one genes were significantly differentially expressed between T1 and M1 (P < 0.05), among which 298 genes are differentially expressed with log2 fold change ≥3 with 184 genes up-regulated and 114 genes down-regulated in M1 (Supplemental File 4). Table 2 lists the top 15 differentially expressed genes that are reported to be breast cancer–related or intersected with the Cosmic Cancer Gene Census (https://cancer.sanger.ac.uk/census). At disease recurrence, several tumor-suppressor genes were down-regulated, including RGS7, PTPRT, and TFF1. Down-regulation of estrogen-dependent genes (CCND1, TFF1, PGR, GREB1) might be the result of prolonged use of aromatase inhibitors (Mackay et al. 2007). Among the up-regulated genes in M1, SOX2, MUC16, PTHLH, S100P, and CEACAM6 have been reported to promote tumor growth and metastasis in various cancer types (Arumugam et al. 2005; Dowen et al. 2005; Fuentes et al. 2007; Lewis-Wambi et al. 2008; Leis et al. 2012; Urosevic et al. 2014; Liu et al. 2017; Wuebben and Rizzino 2017; Kanwal et al. 2018).\n\nTable 2. Top differentially regulated genes between T1 and M1\n\nUp-regulated genes\tDown-regulated genes\t\nGene Symbol\tEntrezID\tLog2FC\tFDR\tGene Symbol\tEntrezID\tLog2FC\tFDR\t\nSOX2\t6657\t7.60\t4.34 × 10−25\tTFF1\t7031\t−6.37\t2.08 × 10−27\t\nPTHLH\t5744\t7.33\t6.96 × 10−24\tPGR\t5241\t−6.05\t6.48 × 10−25\t\nMUC16\t94,025\t4.55\t3.03 × 10−07\tGREB1\t9687\t−5.72\t1.53 × 10−22\t\nS100P\t6286\t4.08\t2.16 × 10−05\tSCGB2A2\t4250\t−5.04\t2.67 × 10−17\t\nSSX1\t6756\t3.67\t4.49 × 10−04\tCYP24A1\t1591\t−4.89\t1.52 × 10−16\t\nCEACAM6\t4680\t3.63\t5.45 × 10−04\tDACH1\t1602\t−4.51\t3.56 × 10−14\t\nDCAF12L2\t340,578\t3.37\t3.80 × 10−03\tAREG\t374\t−4.50\t3.48 × 10−14\t\nTNFSF10\t8743\t3.30\t5.39 × 10−03\tRGS7\t6000\t−4.00\t2.45 × 10−11\t\nMLLT3\t4300\t3.21\t9.23 × 10−03\tPTPRT\t11,122\t−3.94\t4.19 × 10−11\t\nCEACAM1\t634\t3.15\t1.42 × 10−02\tNTRK3\t4916\t−3.83\t1.57 × 10−10\t\nMUC4\t4585\t3.05\t2.45 × 10−02\tSCUBE2\t57,758\t−3.73\t5.18 × 10−10\t\nHES6\t55,502\t3.04\t3.04 × 10−02\tKRT5\t3852\t−3.51\t6.90 × 10−09\t\nHUNK\t30,811\t3.01\t3.29 × 10−02\tIGF1R\t3480\t−3.19\t1.42 × 10−07\t\nTMPRSS2\t7113\t2.94\t4.81 × 10−02\tCOX6C\t1345\t−3.07\t4.81 × 10−07\t\nKLF5\t688\t2.93\t4.85 × 10−02\tCCND1\t595\t−2.93\t1.73 × 10−06\t\nAll genes listed in this table are in Cancer Gene Census (CGS) by Catalog of Somatic Mutations in Cancer (COSMIC) or have been reported to be related to breast cancer.\n\n(FC) Fold change, (FDR) false discovery rate.\n\nPathway analysis between T1 and M1 showed enrichment (P < 0.05) for the hallmark gene sets “Estrogen Response early and late” and “Epithelial mesenchymal transition.” A KEGG pathway analysis suggested that the “Olfactory transduction pathway” was up-regulated in M1. Down-regulated pathways include “Protein digestion and absorption,” “Neuroactive ligand–receptor interaction,” “ECM–receptor interaction,” “PI3K–Akt signaling pathway,” and “Estrogen signaling pathway.” Intersections of the differentially regulated pathways are presented in Supplemental File 5.\n\nDISCUSSION\nBreast cancer is the leading cause of cancer death in women around the world, the vast majority of those deaths are caused by metastatic disease (Breast Cancer - Metastatic - Statistics 2017). Through phylogenetic reconstruction of the presented patient's cancer, an increased mutational rate over time, from the primary tumor at diagnosis to samples taken at relapse, is revealed. In addition, a high level of tumor heterogeneity was found with metastatic sites sharing only two driver mutations with the primary tumor but having acquired additional de novo driver mutations. We also demonstrate how transcriptome profiling aids in uncovering the mechanisms that lead to the patient's initial relapse, indicating expression profile changes that promote tumor progression and metastasis as well as reduced sensitivity and resistance to therapy.\n\nPatient Case Tumor Evolution\nIt is known that tumors are a heterogenous group of cells in regards to their genomic profile (Dagogo-Jack and Shaw 2018). Mutations present only in a subgroup of the tumor cells are defined as subclonal mutations, whereas mutations present in all of the tumor cells in the sample are defined as clonal mutations (Lawrence et al. 2013). A clonality analysis of the tumor sample at diagnosis supported this fact with PIK3CA Q546R identified as the only clonal mutation with an additional eight subclonal driver mutations.\n\nAs disease progressed, the patient's cancer evolved over time with changes to the mutational profile. According to the branching evolution theory, clones diverge from common ancestor and expand simultaneously while accumulating new driver mutations. Clones that carry treatment resistant mutations gain advantages and expand (Davis et al. 2017). As seen in this case, the TP53 E180K mutation, which was initially subclonal in 2002 (T1), presented clonal in the relapse sample in 2012 (M1) as well as later samples. TP53 encodes the tumor protein p53 (p53). Hormonal therapy in ER-positive breast cancer depends on p53-mediated cell cycle arrest (el-Deiry et al. 1993; Varma and Conrad 2000). Oncogenic mutations of TP53, such as the one observed here, can decrease the effect of hormonal therapy (Love 1989). In this case, tumor cells that harbor the TP53 mutation may have gained survival advantages and expanded while the patient was maintained on hormonal therapy in the 10 years prior to relapse. We also observed an accumulation of de novo mutations. Although the number of driver mutations increased with disease progression, the majority of driver mutations in metastatic samples were de novo. Half of the driver mutations (n = 4) in the 2002 biopsy were not detected in later samples. By 2015, PIK3CA Q546R and TP53 E180K were the only two driver mutations shared with previous samples (Fig. 1B; 2). A similar trend of emerging de novo mutations as well as competing and evolving subclonal mutations was reported previously within a larger patient cohort (Miller et al. 2016). The evolving mutational landscape can be the result of natural disease progression or selective pressure from treatment. No matter the cause, considering tumor heterogeneity and the dynamic changes in tumor genetic alterations, genomic profiling from single tumor tissue biopsies may not capture all alterations within the tumor. Repeat liquid biopsies may overcome this limitation (Esposito et al. 2016).\n\nA sample-based phylogenetic reconstruction of the patient's tumor evolution (Fig. 2) revealed an early branching off between the initial tumor and metastatic samples, suggesting a change of mutation profile between primary tumor and metastasis. Further changes are observed between M1 and M2 as well. The increase in tumor mutational burden, numbers of total driver and private driver mutations with the progression of disease, show that despite continuous therapy, the disease continued to evolve and become heterogenous, before and after recurrence. Although multiregional sequencing of each tumor biopsy could provide more insight and resolution into such heterogeneity, the tests performed here represent what is routinely available to a clinical provider. Tracking the presence and clonality of actionable variants such as PIK3CA Q546R and TP53 E180K can be very beneficial in the context of precision oncology.\n\nMutational Signatures\nApart from the driver mutations discussed above, most mutations identified were classified as passenger mutations, which are generally considered to not be involved in tumorigenesis (Pon and Marra 2015). However, the combinations of mutation types arising from specific mutagenesis processes can be characterized as somatic mutational signatures. Inference of somatic mutational signatures based on COSMIC mutational signatures on the three solid tissue samples (T1, M1, M2), revealing presence of APOBEC-related mutational signatures. Apolipoprotein B mRNA editing enzyme (APOBEC) is a family of cytidine deaminases. The APOBEC protein family protects humans from viral infections through causing lethal viral cDNA hypermutations (Harris and Liddament 2004) but can be a driving force of somatic hypermutation in cancer (Roberts and Gordenin 2014), resulting in tumor evolution, higher heterogeneity and rising treatment resistance, and poor prognosis (Swanton et al. 2015). The identification of somatic mutational signatures holds its value in supporting new therapeutic options and revealing possible resistance. In this patient case, the detection of APOBEC activity via mutational signature analysis could have presented the option of using PARP inhibitors or ATR inhibitors (Kanu et al. 2016; Buisson et al. 2017; Green et al. 2017; Nikkilä et al. 2017; Ma et al. 2018) and utilizing aggressive treatment plans (Swanton et al. 2015). In addition, tamoxifen administration is suggested to be used with close monitoring because of potential APOBEC3B-mediated tamoxifen resistance (Law et al. 2016).\n\nGermline Analysis\nGermline analysis identified the SNP FGFR4 p.G388R (rs351855-G/A), which is a common SNP with global minor allele frequency of 0.29952 (A), changing glycine (G) at FGFR4 codon 388 to arginine (R) (Ulaganathan et al. 2015). FGFR4, as a member of the fibroblast growth factor receptor family, is a tyrosine kinase receptor for fibroblast growth factors (FGFs). When activated, FGFR4 fires up the downstream signaling, including the PI3K–Akt and RAS–RAF pathways. It can also phosphorylate signal transducer and activator of transcription 3 (STAT3) directly (Tang et al. 2018). With FGFR4 Arg388 allele, as seen in this patient, the receptor exposes an additional membrane-proximal cytoplasmic STAT3 binding site. The additional STAT3 binding site recruits STAT3 to the cell membrane and increases STAT3 phosphorylation (Ulaganathan et al. 2015). When overactivated, STAT3 promotes tumorigenesis through up-regulating tumorigenesis genes, releasing inflammatory cytokines and contributing to epithelial–mesenchymal transformation (EMT) (Real et al. 2002; Leslie et al. 2006; Chen and Han 2008; Ogura et al. 2008; Thiery et al. 2009).\n\nThe overactivation of STAT3 due to the germline variation at FGFR4 may have acted as a resistance mechanism to everolimus treatment in this patient (Fig. 3). In this patient, by blocking mTORC1 with everolimus, one would expect down-regulated transcriptional activity of STAT3, which is one of the downstream effectors of mTORC1. However, with the FGFR4 G388R variant, STAT3 was phosphorylated independent of mTORC1. Blocking mTORC1 with everolimus in this patient might have not been as efficient as for patients with wild-type FGFR4. Because of sample limitation, we were unable to examine the actual phosphorylation level of STAT3. The effect of FGFR4 G388R in cancer recurrence in this patient remains a hypothesis.\n\nFigure 3. Pathways affected by mutations. DNA-based analysis from solid tumors revealed multiple somatic mutations in the PI3K–Akt signaling pathway (PIK3CA, PIK3R1, PTEN, MTOR) across all samples. Other mutations were detected in both solid and liquid samples, affecting RAS–RAF, cell cycle, and other critical pathways regulating apoptosis and cell proliferation. Germline variant FGFR4 p.G388R was detected. It creates an additional binding site for STAT3 at the cell membrane so it can be phosphorylated without upstream signals from preclinical studies. If the above conclusion holds true in this patient, the activated STAT3 might have established a resistance mechanism for treatment targeting the PI3K-mTOR pathway.\n\nTranscriptome Profiling\nIn addition to genomic alterations identified through DNA profiling, transcriptome profiling can reveal changes in gene expression levels, which may affect protein expression and signal transduction. For this case report, we were especially interested in how gene expression is regulated, as the patient did not present with DNA copy-number changes, as well as which genes were differentially expressed between the metastatic and primary tumors. Comparing the transcriptome profile from the first recurrence in 2012 (M1) with the sample from the initial diagnosis in 2002 (T1), we identified multiple oncogenes to be up-regulated as well as tumor suppressors to be down-regulated.\n\nDown-Regulation of PGR in M1 Was in Agreement with Results from IHC Staining\nTFF1 and CCND1, both estrogen-dependent genes, were down-regulated in M1, possibly because of aromatase inhibitors used for 10 years (Mackay et al. 2007). However, the anticancer effect of down-regulated CCND1 could have been diminished as a result of a RB1 Q217* nonsense mutation appearing in 2012. The RB1 gene encodes retinoblastoma protein (Rb). Rb functions as a tumor suppressor through binding to E2F, a transcription factor, to prevent cell division caused by E2F-dependent transcription (Dick and Rubin 2013). CCND1 phosphorylates Rb, which dissociates the Rb–E2F complex. The released E2F would then start the subsequent transcription and promote cell division (Ortega et al. 2002). Down-regulation of CCND1 with hormonal therapy is supposed to stop this process by reducing Rb phosphorylation and limiting the free E2F level, but RB1 Q217* causes an early termination of the peptide leading to a missing E2F binding domain (aa380–787) (Dick and Rubin 2013). Rb thus loses the function of forming the Rb–E2F complex and the cellular free E2F level is not affected by the phosphorylation status of Rb or CCND1 expression level.\n\nIn the presented case, we hypothesize that although the CCND1 transcription level was successfully decreased by hormonal therapy, the RB1 mutation, which was not present at diagnosis, was one of the causes for treatment resistance and disease recurrence in 2012.\n\nAmong the differentially regulated genes, down-regulation of GREB1 and up-regulation of SOX2 may have presented an additional resistance mechanism to the patient's hormonal therapy and treatments targeting the PI3K–AKT pathway. GREB1 is a tumor promoter. In ER+ breast cancer, ESR1, when activated by E2, binds to estrogen response elements upstream of the GREB1 promotor and up-regulates GREB1 expression (Deschênes et al. 2007; Sun et al. 2007; Yang et al. 2014). Higher E2 level is correlated with GREB1 overexpression (Sun et al. 2007). When up-regulated, GREB1 promotes cell proliferation and migration. GREB1 knockdown does not affect migration but can decrease cell proliferation rate and slow down disease progression (Hodgkinson et al. 2018). The GREB1 down-regulation observed here in 2012 was probably achieved by the prolonged hormonal therapy the patient was on. In 2002 GREB1 expression was elevated as a result of ER-positive status. From 2002 to 2012, the patient was on tamoxifen and anastrozole. Decreased E2 production and ESR1 activity lead to down-regulation of GREB1 expression. Down-regulation of GREB1 was supposed to control disease progression; however, a recent study suggested that the growth suppression caused by GREB1 knockdown can be reversed by constitutive activation of the PI3K–Akt pathway (Haines et al. n.d.), which was the case in this patient.\n\nSOX2 was the topmost up-regulated gene in 2012 with a log2 fold change of 7.6 compared to the 2002 sample. SOX2 overexpression promotes cell invasion through activating PI3K–Akt pathway (Yang et al. 2014). In this patient, the growth suppression caused by GREB1 down-regulation through hormonal therapy may have been reversed by SOX2 up-regulation, presenting a resistance mechanism for hormonal therapy. Because of sample limitation, we were not able to assess SOX2 expression status in later stages of the tumor evolution, but if SOX2 up-regulation remained after 2012, it might have also caused resistance toward everolimus, which was targeting the PI3K–Akt pathway through blocking mTOR (Strimpakos et al. 2009).\n\nIn addition, we performed pathway enrichment analysis, which revealed EMT-related genes enriched in the 2012 sample. EMT is one of the important processes in cancer development when cells acquire mesenchymal properties and lose the original shape and reduce intercellular adhesion. The loosely bonded, small, and flexible cells are more capable of invasion and spreading the disease to distance (Thiery et al. 2009). One of the critical events in EMT is the up-regulation of PI3K–Akt pathway (Larue and Bellacosa 2005), which was present in this patient as discussed above.\n\nCopy-Number Variations\nCopy-number variations (CNVs) are commonly found in advanced stage breast cancer (Zhang et al. 2018). However, no CNV was detected in this patient. It is an unusual finding, but because analysis in the advanced stage samples was limited to either targeted sequencing or liquid biopsies, CNV changes outside the targeted regions might have gone undetected.\n\nClinical Implications\nUnraveling the molecular makeup of a patient's tumor has become an important factor to deliver treatment plans that best suit the patient (Schmidt et al. 2016; Sicklick et al. 2019). One of the best clinical responses received for this patient was achieved in 2016 with 20% tumor reduction as determined by imaging. At the time, the patient was treated with a combination of trametinib, everolimus, and eribulin. According to the molecular profile of the tumor, during this period, the PI3K–mTOR and RAS–RAF pathways were two of the major pathways affected by mutations in PIK3CA, PTEN, mTOR, and NF1. We hypothesize that at that time this regimen precisely targeted the tumor cells, with the MEK inhibitor trametinib blocking the RAS–RAF pathway, everolimus acting on mTORC1 to down-regulate the PI3K–mTOR pathway, and eribulin disrupting the microtubule network and decreasing cell division, which lead to a reduction in tumor size.\n\nAs stated, the tumor genome changed with disease progression. To achieve the best clinical response, one hypothesis would be to constantly change treatment strategy in response to the changing molecular profile of tumor cells (Xu et al. 2017; Kosovec et al. 2018; Xu et al. 2019; Zhang et al. 2019). However, taking repeated tissue biopsies is often not feasible. Liquid biopsy, which tests for ctDNA in the plasma, provides a noninvasive, less expensive alternative to solid tissue biopsy since being introduced in the mid-2010s (Davis et al. 2017; Sheridan 2019). We monitored this patient with repeat liquid biopsies after distant metastasis was detected in mid-2015. Initial ctDNA profiling was negative. When the patient presented with active disease in the liver, mutations started to be picked up in the plasma samples 2 months later, with an overall trend of increasing mutation numbers, as well as increasing allele frequencies, which we considered as an indication of increased tumor burden. A positive association between plasma ctDNA and tumor burden has been reported in other studies as well (Bettegowda et al. 2014; Lee et al. 2018).\n\nTreatment resistance is the leading cause of therapeutic failure (Diaz et al. 2012; Aparicio and Caldas 2013). New driver mutations are an important source of treatment resistance. Detecting rising resistance mechanisms and adjusting treatment plans accordingly in a timely manner is crucial to control the disease (Housman et al. 2014). Through liquid biopsy, we observed an emerging ESR1 E380Q mutation that could be a possible acquired resistance mechanism to aromatase inhibitor therapy in this patient (Li et al. 2013; Jeselsohn et al. 2015). The patient was on aromatase inhibitors (anastrozole and exemestane) for 10 years before distant metastasis appeared in 2014. Her treatment was switched to chemotherapy and kinase inhibitors for 2 years (09.2014–09.2016) before exemestane was added back to the regimen in September 2016 when the patient progressed in the liver and right pleura. The ESR1 E380Q mutation, which had not been detected in previous samples, in neither solid (2002–2015) nor liquid biopsies (08.2015–07.2016), appeared in the first ctDNA test (11.2016) after exemestane was added in September 2016 (Supplemental Fig. 2). ESR1 encodes for estrogen receptor alpha (ERɑ). ERɑ, when combined with estrogen, travels to the nucleus and promotes transcription of genes involved in cell proliferation and survival through binding to the promoter sequence of the genes (Ip et al. 1979; Katzenellenbogen et al. 1987). This process is considered one of the key components of tumorigenesis in ER-positive breast cancer (Rose et al. 1980; Sunderland and Osborne 1991). Aromatase inhibitors are commonly used to stop this process by reducing estrogen production (Buzdar 2003). However, alterations in the ligand binding domain of ESR1, such as observed here, would lead to estrogen-independent constitutive transactivation (Toy et al. 2013), in which case estrogen is not needed in ERɑ activation, and lower estrogen levels through aromatase inhibitor will not decrease the activity of ERɑ to promote tumor growth. ESR1 ligand binding domain mutations have been observed as acquired resistance mutations to aromatase inhibitors (Jeselsohn et al. 2015). A study of 171 patients with advanced breast cancer found ESR1 mutations exclusively in ER-positive breast cancer patients previously exposed to aromatase inhibitors (Schiavon et al. 2015). Another study observed that even with confirmed ESR1 E380Q mutation in tumor tissue, the variant went undetected in plasma DNA (Takeshita et al. 2017). The authors believed that this was because the ESR1 E380Q mutation in the tumor was only in a subgroup of cancer cells. In our case, we observed the emergence of ESR1 E380Q mutation in the first liquid biopsy after exemestane was restarted. The allele frequency of the mutation started low at 0.9 but quickly increased in the following tests (Supplemental Fig. 2). We cannot rule out the possibility that the ESR1 mutation was present in the primary tumor cells, went undetected because of tumor heterogeneity or low concentration of ctDNA, and expanded after exemestane was restarted. Based on previous research (Miller et al. 2016), ESR1 E380Q is more likely an acquired resistant mutation after prolonged exposure to aromatase inhibitors. Eventually, exemestane was switched to fulvestrant, an ER antagonist, to control ER overactivation and overcome resistance to aromatase inhibitors.\n\nAnother potential treatment resistance mechanism we observed in this patient was the occurrence of PTEN mutations, which were firstly detected in liver metastatic tissue in 2015 and later observed in ctDNA from 2016 on. It has been suggested that PTEN loss of function could lead to resistance to the PI3K inhibitor alpelisib (BYL719) (Juric et al. 2015). Given the PIK3CA driver mutations, this patient would have been a candidate for PI3K inhibition if the drug was available during her treatment. However, she may not have gotten the best clinical outcome from PI3K inhibition because of her PTEN mutations.\n\nGenomic and transcriptome profiling makes it possible to generate patient-specific cancer molecular profiles. In addition to “traditional” pathology (IHC, FISH)-derived biomarkers, those genomics-derived molecular profiles provide additional insights on oncogenesis and disease progression. The relevance between molecular aberrations, disease progression, and potential treatment can be direct, when proven by clinical trials, or indirect, if the evidence is still being investigated in early-stage trials or preclinical studies only. As an example, the germline variant FGFR4 G388R as identified in this patient would be considered as indirect evidence (preclinical study). Molecular data that has not been demonstrated to have significant clinical utility can still be informative to a clinician, regarding which pathways are activated and potentially driving tumor growth and progression. These biomarkers would not be utilized directly to make treatment decisions, but could be used to inform the clinician on potential resistance mechanisms and possibility of a poor response.\n\nConclusion\nIn summary, we demonstrate that molecular profiling can provide valuable information to guide decision making for a patient's cancer treatment. Although genomic profiling has been utilized in clinical practice more in recent years, transcriptome analysis has rarely been considered. As of today, no transcriptome profiling test has been approved for clinical application. In this case report, with detailed analysis of information acquired from germline DNA alterations, somatic mutations, and gene expression profiling, we hope to emphasize the importance of closely monitoring cancer genomic profile and the significance of including transcriptome profiling while treating cancer patients.\n\nMETHODS\nSample Collection\nTumor tissues were collected from the primary breast tumor (T1) in 2002, initial recurrence at right supraclavicular lymph node (M1) in 2012, and further metastasis in the liver (M2) in 2015. Peripheral blood was collected for cell-free DNA analysis and matched germline sequencing. Sample names, collection time, and pathology characteristics, together with genomic tests performed and average coverage, are presented in Table 1.\n\nTissue Preparation and Sequencing\nDNA/RNA extraction and sequencing from T1, M1, and normal blood (buffy coat) was performed at Avera Institute of Human Genetics. In short, we utilized one rapid run flow cell on the Illumina HiSeq2500 platform (Illumina) in 2 × 125 fashion. Lane 1 housed whole-exome libraries (Clinical Research Exome v1; Agilent), whereas lane 2 retained the RNA libraries (TruSeq RNA Access; Illumina). Appropriate adapter trimming was performed and a spike-in of 1% PhiX control for each well was used.\n\nSample M2 was fixed in formaldehyde and embedded in paraffin wax. The formalin-fixed, paraffin-embedded (FFPE) sample was then sent to Foundation Medicine for sequencing using FoundationOne assay, which covers 3769 exons of 236 cancer-related genes and 47 introns of 19 genes with frequent rearrangements, at an average depth of 250× (Frampton et al. 2013).\n\nctDNA was isolated and sequenced by the Guardant360 assay from August 2015 to November 2016. The remaining samples from February 2017 to November 2017 were sequenced through the FoundationAct assay. Guardant360 is a 73-gene ctDNA sequencing (average coverage = 8000×) test with analytic validation (Lanman et al. 2015; Odegaard et al. 2018). FoundationAct tests for ctDNA with a coverage of 62 genes to the depth of 5000× (Clark et al. 2018).\n\nVariant/Copy-Number Calling and Annotation\nRaw exome sequencing data from the two tumor (T1, M1) and matched normal samples were processed through multiple tools: BBDuk from BBTools suite 36.32 (BBDuk Guide n.d.; SourceForge n.d.) to trim adapters, FastQC 0.11.5 (Babraham Bioinformatics n.d.) and Qualimap 2.2 (García-Alcalde et al. 2012) for quality control, BWA-MEM 0.7.15 (Li 2013) to generate mapped alignments to the human genome reference (hs37d5), sambamba 0.6.3 (Tarasov et al. 2015) to mark duplicate reads, ABRA 0.97 (Mose et al. 2014) to realign indel regions. VarDict 1.5.1 (Lai et al. 2016) was used to call somatic and germline variants, whereas CNVkit 0.9.5 (Talevich et al. 2016) was used to call copy-number variants, and ANNOVAR (Wang et al. 2010) was used to annotate all variants.\n\nA previously published method of checking for cross-sample contamination was used to verify tumor-normal matching (Stephens et al. 2018). The number of nonsynonymous variants per 1 Mb of DNA adjusted to the exome panel size was calculated as the tumor mutation burden of a sample. Tumor purity was computationally estimated by Sequenza (Favero et al. 2015). Palimpsest (Shinde et al. 2018) was used to calculate cancer cell fraction (CCF) and determine clonality status for the somatic variants per sample. A phylogenetic tree for the patient was constructed by LICHeE (Popic et al. 2015) based on CCF data for variants classified as drivers by CancerGenomeInterpreter (Tamborero et al. 2018). The R package deconstructSigs (Rosenthal et al. 2016) was used to infer Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures v2 (Cosmic 2020).\n\nDifferential Gene Expression\niDEG (individualized differentially expressed genes) (Li et al. 2019), a method to compare two conditions without replicates, was used to identify differentially expressed genes (DEGs) between T1 and M1.\n\nPathway Analysis\nFor downstream pathway analysis, we selected DEGs with a false discovery rate of ≤0.05 and absolute fold change greater than three. Gene sets from KEGG, Reactome, Biocarta, MSigDB Hallmark, Progeny, and Wikipathways were downloaded in gmt format. DEGs and their normalized gene expression values at the time points T1 and M1 were tested using MixEnrich (Li et al. 2017) to identify bidirectional and concordantly dysregulated pathways. DEGs were tested for their enrichment in KEGG pathways using gProfileR (Reimand et al. 2007) package in R.\n\nDrug–Gene Interaction\nUp-regulated DEGs were used to check for their interaction with drugs in DGIdb (Drug Gene Interaction database) (Griffith et al. 2013; Wagner et al. 2016; Cotto et al. 2018).\n\nADDITIONAL INFORMATION\nData Deposition and Access\nRaw sequencing data has been uploaded to European Genome-phenome Archive (https://www.ebi.ac.uk/ega/) and is available under accession number EGAS00001004624.\n\nEthics Statement\nThe patient provided written and informed consent. This study was approved by the WIRB (protocol #20140659).\n\nAcknowledgments\nThe authors are grateful to the patient and her family for donating medical data and samples to this research. We thank Karla Flak for her assistance. The work of the authors was supported by the Avera McKennan Hospital & University Health Center and Avera McKennan Foundation.\n\nAuthor Contributions\nStudy concept and design was done by B.X., C.B.W., and T.M. Sample acquisition, preparation, and sequencing were performed by C.D., S.T., S.V., and J.P. The data were analyzed by B.X., A.A., P.S., and T.M. Administrative, technical, or material support was provided by G.D., E.E., and C.B.W. The study was supervised by E.E., C.B.W., and T.M. The drafting and revision of the manuscript was done by all authors. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "6(6)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "multifocal breast carcinoma",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D004252:DNA Mutational Analysis; D047628:Estrogen Receptor alpha; D019143:Evolution, Molecular; D005260:Female; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases; D010802:Phylogeny; D018719:Receptor, ErbB-2; D055748:SOXB1 Transcription Factors; D015398:Signal Transduction; D059467:Transcriptome; D000071163:Trefoil Factor-1",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33008833",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28288641;27634334;17463000;25198391;16288291;29552305;26122181;23770567;25319062;24142049;29771315;11960696;28698210;30619750;3607768;25944252;16510571;27502118;31190187;29989342;30070748;31011206;29691297;17478515;22722843;29797257;22914218;12400004;17555561;28856074;29973689;15516966;29156001;26474073;24055055;28655787;23594950;28388544;27730215;26560360;26091828;30120226;31485041;24880666;24185512;24700142;20601685;24122041;27100738;27389805;29117498;25409150;21822303;30337938;18848474;2654333;6988911;29115304;24553385;25340638;32337479;11032025;28589853;26017070;29166868;18614350;28535155;19945376;17457812;32308852;31807023;760195;28110020;17666587;29592813;25568919;8242752;23445095;17587138;26615782;23945592;16061848;26675719;24907369;19013721;26531824;15632002;26899170;27060149;27197880;29936259;25697820;14667279;2045868",
"title": "Case report: 16-yr life history and genomic evolution of an ER+ HER2- breast cancer.",
"title_normalized": "case report 16 yr life history and genomic evolution of an er her2 breast cancer"
} | [
{
"companynumb": "US-BAYER-2021-055927",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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"drugadditional": null,
... |
{
"abstract": "The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.",
"affiliations": "Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Markovic.svetomir@mayo.edu.",
"authors": "Vera|Jesus|J|http://orcid.org/0000-0002-7803-2024;Paludo|Jonas|J|;Kottschade|Lisa|L|;Brandt|Jessica|J|;Yan|Yiyi|Y|;Block|Matthew|M|;McWilliams|Robert|R|;Dronca|Roxana|R|;Loprinzi|Charles|C|;Grothey|Axel|A|;Markovic|Svetomir N|SN|",
"chemical_list": "D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D020928:Mitogen-Activated Protein Kinases; C561627:dabrafenib; D003078:Colchicine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-019-4654-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "27(10)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Colchicine; Dabrafenib; MAPK pathway; Pyrexia; Trametinib",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003078:Colchicine; D004789:Enzyme Activation; D005334:Fever; D006801:Humans; D007093:Imidazoles; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "3869-3875",
"pmc": null,
"pmid": "30767130",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "28724377;23712190;25411413;28891408;26753005;24583796;28444112;20149136;20818433;19733345;23134356;25579568;26942566;21480191;26001859;22738946",
"title": "Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine.",
"title_normalized": "case series of dabrafenib trametinib induced pyrexia successfully treated with colchicine"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/19/0115490",
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"activesubstancename": "COLCHICINE"
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"abstract": "BACKGROUND\nFebrile neutropenia is generally recognised as a complication of myelosuppressive chemotherapy. Recombinant human granulocyte colony stimulating factor (G-CSF) is commonly used as a primary or secondary prophylaxis to reduce the degree and duration of neutropenia in patients at risk of developing chemotherapy-induced neutropenic fever and infectious complications. G-CSF is known to decrease mortality and increase the possibility of maintaining adequate chemotherapy dose intensity and density, which is essential in curable malignancies. Common side effects are generally mild. However, potentially fatal adverse events have also been reported.\n\n\nMETHODS\nHerein, we summarise previously reported and report two new independent cases of G-CSF-induced aortitis, both in patients treated with chemotherapy for breast cancer. The two cases, identified only a few months apart, share several common characteristics including type of cancer, gender, age, chemotherapy, G-CSF treatment regimen, and time span from G-CSF initiation to aortitis manifestation. The two cases were both diagnosed by CT scan and successfully treated with corticosteroids along with discontinuation of G-CSF.\n\n\nCONCLUSIONS\nThis case report highlights that although aortitis is a rare adverse event of G-CSF treatment, it should be considered in cases of unexplained fever and/or clinical and laboratory findings that do not respond to antibiotics.",
"affiliations": "Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Rheumatology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: ioannis.parodis@ki.se.;Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Rheumatology, Karolinska University Hospital, Stockholm, Sweden.;Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Rheumatology, Karolinska University Hospital, Stockholm, Sweden.;Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.;Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.;Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden; Oncology/Pathology Department, Karolinska Institutet, Stockholm, Sweden.;HHLH Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: oscar.wiklander@ki.se.",
"authors": "Parodis|Ioannis|I|;Dani|Lara|L|;Notarnicola|Antonella|A|;Martenhed|Git|G|;Fernström|Pontus|P|;Matikas|Alexios|A|;Wiklander|Oscar P B|OPB|",
"chemical_list": "D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.autrev.2018.12.011",
"fulltext": null,
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"issn_linking": "1568-9972",
"issue": "18(6)",
"journal": "Autoimmunity reviews",
"keywords": "Aortitis; Cancer; Febrile neutropenia; G-CSF; Myelosuppressive chemotherapy",
"medline_ta": "Autoimmun Rev",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001025:Aortitis; D001943:Breast Neoplasms; D005260:Female; D005334:Fever; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia",
"nlm_unique_id": "101128967",
"other_id": null,
"pages": "615-620",
"pmc": null,
"pmid": "30959218",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "G-CSF-induced aortitis: Two cases and review of the literature.",
"title_normalized": "g csf induced aortitis two cases and review of the literature"
} | [
{
"companynumb": "SE-TEVA-2019-SE-1064153",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "EPIRUBICIN"
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{
"abstract": "Behcet's disease is a chronic, idiopathic vasculitis with multisystem involvement commonly characterized by the classic triad of oral lesions, genital ulcerations, and uveitis. We discuss the case of a 22-year-old woman with a long-standing history of oral ulcers and vulvovaginal burning who presented with acute painless uveitis. With this presentation, there was an initial concern for infectious retinitis for which she was started on systemic antiviral therapy. Subsequent infectious disease workup was ultimately negative. Given her medical history and current presentation, she was diagnosed and treated for an acute inflammatory episode of ocular Behcet's disease. The patient's vision returned to baseline prior to discharge after treatment with systemic glucocorticoids. The diagnosis of Behcet's disease in the setting of painless vision loss can oftentimes be elusive. However, it is important for clinicians to keep this condition as a differential diagnosis in patients presenting with acute onset uveitis as the progression of Behcet's disease can lead to severe vision loss and blindness without prompt and adequate treatment.",
"affiliations": "Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA, USA.;Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA, USA.;College of Osteopathic Medicine, Kansas City University of Medicine and Biosciences, Kansas City, MO, USA.;Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA, USA.",
"authors": "Patel|Arti A|AA|https://orcid.org/0000-0002-6518-2103;Stutman|Amelia|A|;Patel|Prarak|P|;Capoccia|Madhavi|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X20981460",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20981460\n10.1177_2050313X20981460\nCase Report\nElusive diagnosis of Behcet’s disease in setting of painless vision loss\nhttps://orcid.org/0000-0002-6518-2103Patel Arti A 1 Stutman Amelia 1 Patel Prarak 2 Capoccia Madhavi 1 1 Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA, USA\n2 College of Osteopathic Medicine, Kansas City University of Medicine and Biosciences, Kansas City, MO, USA\nArti A Patel, Department of Family Medicine, Lehigh Valley Health Network, 1200 S Cedar Crest Blvd., Allentown, PA 18103, USA. Email: Arti.Patel@lvhn.org\n14 12 2020 \n2020 \n8 2050313X209814601 7 2020 26 11 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Behcet’s disease is a chronic, idiopathic vasculitis with multisystem involvement commonly characterized by the classic triad of oral lesions, genital ulcerations, and uveitis. We discuss the case of a 22-year-old woman with a long-standing history of oral ulcers and vulvovaginal burning who presented with acute painless uveitis. With this presentation, there was an initial concern for infectious retinitis for which she was started on systemic antiviral therapy. Subsequent infectious disease workup was ultimately negative. Given her medical history and current presentation, she was diagnosed and treated for an acute inflammatory episode of ocular Behcet’s disease. The patient’s vision returned to baseline prior to discharge after treatment with systemic glucocorticoids. The diagnosis of Behcet’s disease in the setting of painless vision loss can oftentimes be elusive. However, it is important for clinicians to keep this condition as a differential diagnosis in patients presenting with acute onset uveitis as the progression of Behcet’s disease can lead to severe vision loss and blindness without prompt and adequate treatment.\n\nBehcet’s diseaseuveitisvision lossulcerationssteroidscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nBehcet’s disease (BD) is a rare, chronic, multisystem, relapsing vasculitis involving both arteries and veins.1 As described by Dr. Hulusi Behcet in 1937, the classic triad of BD consists of recurrent oral lesions, genital ulcerations, and uveitis.1 Ocular involvement is typically characterized by nongranulomatous inflammation with symptoms of photophobia, floaters, and visual loss.2 In addition, patients can present with cardiac, pulmonary, musculoskeletal, and neurological manifestations.1 Herein, we present the case of a young adult female with a history of recurrent oral ulcers and vulvovaginal burning who presented with acute on chronic onset of significant painless visual impairment.\n\nCase report\nA 22-year-old female with a history of recurrent oral ulcers and vulvovaginal burning presented to the emergency department with painless bilateral uveitis of 8 months duration which acutely worsened in the past 2 weeks. Of note, the patient was seen outpatient by ophthalmology 5 days prior to presentation whereby a dilated eye exam demonstrated intraretinal hemorrhage in the right eye, dot-blot hemorrhage in the left eye, and bilateral vitritis with concern for cytomegalovirus retinitis (CMV) retinitis. Recommendations included 1% prednisolone eye drops twice a day, 1% cyclopentolate eye drops twice a day, and valganciclovir twice a day. However, the patient was only compliant with the cyclopentolate drops due to financial hardship. On presentation, she also endorsed floaters, blurry vision, and flashes of light. She denied any acute oral or genital symptoms; however, she reported a history of recurrent “canker sores” and burning in the vulvovaginal area that began approximately 5 years ago. She denied a history of genital ulcers. Physical exam was remarkable for photophobia and visual acuity of 20/50 in the right eye and 20/80 in the left eye with correction. Intraocular pressure in each eye was 16 mmHg by tonometry and pupils were equal, round, and reactive to light bilaterally. Extraocular movements were intact bilaterally. A slit lamp eye examination showed a flat macula and similar hemorrhages as seen in the ophthalmology office 5 days prior to presentation. Laboratory evaluation revealed an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Extensive infectious disease testing for CMV, Herpes simplex virus (HSV), HIV, Varicella-zoster virus (VZV), syphilis, toxoplasmosis, tuberculosis, Hepatitis B and C was undergone, all of which resulted negative. Likewise, rheumatologic workup including testing for antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), angiotensin-converting enzyme (ACE), and human leukocyte antigen B27 (HLA-B27) was negative.\n\nWith concern for infectious retinitis, the patient was started on a course of IV acyclovir 10 mg/kg every 8 h. Her hospital course was complicated by acute kidney injury (AKI) secondary to acyclovir-induced nephrotoxicity; the medication was immediately discontinued, and she was given IV hydration to resolve the AKI. After discussion with ophthalmology about the patient’s clinical course, presentation, and laboratory data, there was concern for BD as she met clinical diagnostic criteria. She was started on IV methylprednisolone 250 mg every 6 h for 3 days. The patient experienced significant improvement of photophobia and complete resolution of blurry vision and flashes of light.\n\nAt this point with the patient’s negative infectious workup, it was felt a more detailed rheumatologic workup was needed. The patient was instructed to follow-up with outpatient rheumatology for skin pathergy testing to provide additional support to the diagnosis of BD and for long-term management. In that time, she was discharged home with a 2-week oral prednisone taper (50 mg daily for 7 days and 25 mg daily for the next 7 days) and valacyclovir to provide coverage for possible underlying retinitis.\n\nUnfortunately due to financial hardship, this patient was unable to follow-up with the outpatient rheumatologist. Less than 3 months later she presented to the hospital with similar ocular symptoms and was readmitted for painless panuveitis. Of note, the patient reported she developed a painful ulcer on her labia a month prior that resolved spontaneously. She was given high-dose intravenous steroids for 3 days. Pathergy testing performed by rheumatology during this hospitalization was negative. Her vision returned to baseline and the patient was discharged with a scheduled outpatient rheumatology follow-up to determine long-term therapy.\n\nDiscussion\nBD remains largely a clinical diagnosis based on criteria from the International Criteria for Behcet’s Disease (ICBD) as there has been no census on specific laboratory values for BD. The presence of ocular lesions, oral aphthous ulcers, and genital ulcers are each assigned 2 points.3 Skin lesions, central nervous system involvement, and vascular manifestations are each assigned 1 point with an additional point for a positive skin pathergy test.3 A total score of 4 or high is indicative of BD (Table 1). The above patient had oral ulcers and ocular lesions for a score of 4. On subsequent presentation she reported genital ulcers, bringing her score to a 6.\n\nTable 1. International Criteria for Behcet’s Disease.\n\nSymptoms\tPoints\t\nGenital aphthosis\t2\t\nOcular lesions\t2\t\nOral aphthosis\t2\t\nSkin lesions\t1\t\nNeurologic manifestations\t1\t\nVascular manifestations\t1\t\nPositive pathergy test\t1\t\nTable 1: A pathergy test is optional and is not required for diagnosis. If performed and is positive, an additional point is assigned.\n\nBD usually presents in individuals between the ages of 30–40 years old with an equal predilection for both sexes, though males typically have a more severe disease course.4 Approximately 70% of people with BD will have some form of ocular involvement during their disease course, and 80% of those people will present with bilateral signs and symptoms.4 Ocular BD is characterized by recurrent inflammatory episodes of uveitis flare-ups.2 Patients who have inflammation of the anterior chamber of the eye will usually experience photophobia.4 Those with posterior chamber inflammation will present with floaters and visual loss with retinal involvement which can ultimately progress to blindness, warranting prompt identification and treatment of the condition.4 Despite aggressive management, many patients will still develop moderate or severe visual impairment.2\n\nTreatment of BD involves management of the acute flare along with initiation of long-term maintenance therapy with the goal of reducing and preventing recurrences of BD. The acute inflammatory stage of ocular BD is typically treated with topical mydriatics and topical and systemic corticosteroids.1 In a previously published case report, a 31-year-old man with chronic oral and genital lesions who was repeatedly misdiagnosed was eventually diagnosed with BD and immediately started on high-dose corticosteroids; after approximately a week of treatment, his lesions resolved.5 However, practitioners should exercise caution for long-term usage of systemic steroids as they can result in significant adverse side effects. Traditionally steroid sparing, immunosuppressive agents have been used for long-term management of BD which includes azathioprine or cyclosporine.6 Recently, biologic agents such as tumor necrosis factor (TNF)—alpha inhibitors (infliximab) or anti-CD20 agents (rituximab) have been shown to induce remission when patients are resistant to the traditional agents.6 Currently, there is no evidence that supports the use of antiviral therapy in the management of ocular BD.7\n\nThis case highlights the importance of broadening the differential in the setting of acute on chronic uveitis for proper management of the disease. In a published case series of 14 patients, researchers found the mean time to diagnosis of BD was 5.5 years.8 Early in this patient’s presentation, there was high suspicion for infectious retinitis, and the patient was started on IV acyclovir; however, this should have been discontinued earlier to prevent iatrogenic injury as the infectious disease workup was negative.9 Furthermore, early identification and adequate treatment of her acute and chronic BD greatly reduced the severity of her ocular symptoms and prevented blindness, preserving sight in an otherwise healthy young female.\n\nConclusion\nBD is a chronic, multisystem, relapsing inflammatory condition that can affect multiple body systems. The classic symptom triad of BD is oral ulcers, genital lesions, and ocular involvement. This patient, who had a history of oral ulcers and genital burning, presented with painless bilateral uveitis and was ultimately found to have acute BD. The importance of having BD on the differential when a patient presents with uveitis cannot be understated. Adequate treatment of the acute inflammatory stage of ocular BD led to close resolution of her symptoms and prevented blindness.\n\nAuthor contributions: All authors listed have contributed sufficiently to the project to be included as authors. All authors read and approved the final manuscript.\n\nConsent for publication: Patient informed consent form obtained\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nEthics approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article\n\nORCID iD: Arti A Patel \nhttps://orcid.org/0000-0002-6518-2103\n==== Refs\nReferences\n1 \nAlpsoy E. \nNew evidence-based treatment approach in Behçet’s disease\n. Patholog Res Int \n2012 ; 2012 : 871019 .22007346 \n2 \nKaçmaz RO Kempen JH Newcomb C , et al\nOcular inflammation in Behçet disease: incidence of ocular complications and of loss of visual acuity\n. Am J Ophthalmol \n2008 ; 146 (6 ): 828 –836\n.18708181 \n3 \nInternational Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD) . The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria\n. J Eur Acad Dermatol Venereol \n2014 ; 28 (3 ): 338 –347\n.23441863 \n4 \nUcar-Comlekoglu D Fox A Sen HN. \nGender differences in Behçet’s disease associated uveitis\n. J Ophthalmol \n2014 ; 2014 : 820710 .24864195 \n5 \nMeda J Seni J Mpondo B , et al\nBehcet’s disease presenting with recurrent ocular, oral, and scrotal inflammatory lesions in a young Tanzanian man: a case report\n. Clin Case Rep \n2014 ; 2 (4 ): 133 –136\n.25356270 \n6 \nAlpsoy E. \nBehçet’s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions\n. J Dermatol \n2016 ; 43 (6 ): 620 –632\n.27075942 \n7 \nZierhut M El-Asrar AMA Bodaghi B , et al\nTherapy of ocular Behçet disease\n. Ocular Immun Inflam \n2014 ; 22 (1 ): 64 –76\n.\n8 \nLiozon E Roussin C Puechal X , et al\nBehcet’s disease in east African patients may not be unusual and is an HLA-b51 negative condition: a case series from Mayotte (Comoros)\n. Joint Bone Spine \n2011 ; 78 (2 ): 166 –170\n.20599413 \n9 \nYildiz C Ozsurekci Y Gucer S , et al\nAcute kidney injury due to acyclovir\n. CEN Case Reports \n2012 ; 2 (1 ): 38 –40\n.28509218\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "8()",
"journal": "SAGE open medical case reports",
"keywords": "Behcet’s disease; steroids; ulcerations; uveitis; vision loss",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X20981460",
"pmc": null,
"pmid": "33403115",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24864195;20599413;28509218;24377434;22007346;27075942;18708181;25356270;23441863",
"title": "Elusive diagnosis of Behcet's disease in setting of painless vision loss.",
"title_normalized": "elusive diagnosis of behcet s disease in setting of painless vision loss"
} | [
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"abstract": "This is the report of a case of methotrexate nephrotoxicity for which glucarpidase was used. We use the case to review a number of teaching points related to this new treatment option.",
"affiliations": "Department of Medicine, University of Florida, Gainesville, FL, USA.",
"authors": "Iqbal|Saima|S|;Armaghani|Avan|A|;Aiyer|Ravi|R|;Kazory|Amir|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate",
"country": "England",
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"issue": "19(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Methotrexate; Voraxaze; carboxypeptidase G2; glucarpidase; nephrotoxicity",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011623:gamma-Glutamyl Hydrolase",
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"title": "Methotrexate nephrotoxicity: Novel treatment, new approach.",
"title_normalized": "methotrexate nephrotoxicity novel treatment new approach"
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{
"abstract": "Pyomyositis has recently been recognized as a primary infection of the large skeletal muscles, and it is often accompanied by single or multiple intramuscular abscess formation. Immunocompromised patients, including those with diabetes mellitus, human immunodeficiency virus infection, and cancer, as well as those undergoing chemotherapy, are at a greater risk of developing pyomyositis. A 78-year-old Japanese man with recurrent gastric cancer being treated with chemotherapy presented with sudden-onset pain in his left lower extremity while undergoing a second-line regimen with irinotecan. T2-weighted magnetic resonance imaging (MRI) showed an abnormally high-intensity signal in the left internal and external obturator muscles, a finding consistent with pyomyositis. Following intensive antibiotic treatment, the patient recovered completely and was able to resume chemotherapy with irinotecan. For a patient who developed pyomyositis during chemotherapy for gastric cancer, early diagnosis using MRI followed by administration of timely intensive antibiotic therapy resulted in complete recovery.",
"affiliations": "Department of Surgery, Izumo City General Medical Center, Izumo, Japan.;Department of Surgery, Izumo City General Medical Center, Izumo, Japan.;Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.;Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.;Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.;Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.",
"authors": "Nakayama|Yoko|Y|;Sugiyama|Akira|A|;Yamamoto|Tetsu|T|;Hyakudomi|Ryoji|R|;Hirahara|Noriyuki|N|;Tajima|Yoshitsugu|Y|",
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"doi": "10.1159/000518242",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. 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\n10.1159/000518242\ncro-0014-1220\nCase Report\nPyomyositis in a Patient Undergoing Chemotherapy for Gastric Cancer: A Case Report and Literature Review\nNakayama Yoko a *\nSugiyama Akira a\nYamamoto Tetsu b\nHyakudomi Ryoji b\nHirahara Noriyuki b\nTajima Yoshitsugu b\naDepartment of Surgery, Izumo City General Medical Center, Izumo, Japan\nbDepartment of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan\n*Yoko Nakayama, yoccon716@gmail.com\nMay-Aug 2021\n16 8 2021\n16 8 2021\n14 2 12201227\n26 5 2021\n26 6 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nPyomyositis has recently been recognized as a primary infection of the large skeletal muscles, and it is often accompanied by single or multiple intramuscular abscess formation. Immunocompromised patients, including those with diabetes mellitus, human immunodeficiency virus infection, and cancer, as well as those undergoing chemotherapy, are at a greater risk of developing pyomyositis. A 78-year-old Japanese man with recurrent gastric cancer being treated with chemotherapy presented with sudden-onset pain in his left lower extremity while undergoing a second-line regimen with irinotecan. T2-weighted magnetic resonance imaging (MRI) showed an abnormally high-intensity signal in the left internal and external obturator muscles, a finding consistent with pyomyositis. Following intensive antibiotic treatment, the patient recovered completely and was able to resume chemotherapy with irinotecan. For a patient who developed pyomyositis during chemotherapy for gastric cancer, early diagnosis using MRI followed by administration of timely intensive antibiotic therapy resulted in complete recovery.\n\nKeywords\n\nPyomyositis\nGastric cancer\nChemotherapy\nIrinotecan\nAntibiotics\n==== Body\npmcIntroduction\n\nPyomyositis is a purulent infection involving the large skeletal muscles, is usually caused by Staphylococcus aureus, and often presents with single or multiple intramuscular abscesses [1, 2]. Although pyomyositis is classically a tropical disease, it is being increasingly recognized in temperate climates and encountered particularly in immunocompromised patients, such as those with diabetes mellitus, human immunodeficiency virus infection, autoimmune disorders, chronic liver diseases, rheumatologic conditions, intravenous drug addiction, and malignancies, especially in those undergoing chemotherapy [1, 3]. A definitive diagnosis of pyomyositis can be difficult because of its rare occurrence and varied clinical manifestations; however, a delay in diagnosis can result in serious complications, including multiple abscess formation, septicemia, multi-organ system failure, and occasionally death [1, 4, 5].\n\nAlthough pyomyositis has recently been recognized as a rare but important complication in patients with hematological malignancies undergoing chemotherapy [3], to the best of our knowledge, only 10 such cases in patients with solid tumors undergoing chemotherapy have been reported [6, 7, 8, 9, 10, 11, 12, 13, 14]. A patient with advanced pyomyositis, requiring interventional treatment with percutaneous or operative drainage and debridement, may have to defer or interrupt a potentially life-saving chemotherapeutic regimen. Chemotherapy was resumed only in 2 of the 10 previously reported cases. Therefore, early diagnosis and effective treatment of pyomyositis in patients with malignant tumors during chemotherapy are crucial. Here, we report the first case of pyomyositis detected at an early stage during chemotherapy for gastric cancer; this is the only reported case of solid cancer in which chemotherapy was continued without recurrence of pyomyositis after 22 months of onset.\n\nCase Report/Case Presentation\n\nA 78-year-old Japanese man, who underwent 13 cycles of second-line chemotherapy with irinotecan for recurrent gastric cancer, was urgently admitted to our hospital with a chief complaint of sudden-onset, movement-related pain in his left lower extremity associated with a high-grade fever of 38.3°C. After completing his last 12-day cycle of chemotherapy, he experienced a transient episode of nausea and high-grade fever, and severe manifestations subsequently occurred 2 days later.\n\nThe patient had undergone a distal gastrectomy, with D2 lymphadenectomy and a Roux-en-Y reconstruction, for gastric cancer in December 2015. Histopathological examination of the resected specimens revealed a human epidermal growth factor receptor-2-positive, papillary adenocarcinoma of the stomach, further classified as T2N1M0, Stage IIA based on the Union for International Cancer Control TNM classification. Adjuvant chemotherapy with tegafur, gimeracil, and oteracil (TS-1) was planned to be administered to the patient for 1 year after the diagnosis. However, at 7 months after adjuvant chemotherapy with TS-1, left supraclavicular and multiple para-aortic lymph-node metastases were detected on the follow-up computed tomography (CT) scan. Thus, he was administered combination chemotherapy with capecitabine, cisplatin, and trastuzumab for 6 months. However, his left supraclavicular and multiple para-aortic lymph-node metastases worsened; therefore, he was administered chemotherapy with irinotecan, after which he showed stable disease. The patient was taking oral medications for diabetes mellitus and hypertension while receiving chemotherapy; thus, the disorders were well managed and controlled.\n\nPhysical examination on admission did not reveal any signs of erythema, swelling, or tenderness in the left lower extremity. However, blood tests demonstrated leukocytosis, with a white blood cell count of 12,500/µL (normal range, 4,000–9,000/µL) and a left shift of 95.5%. In addition, the C-reactive protein level had significantly increased to 20.6 mg/dL (normal range, 0–0.3 mg/dL). Liver enzymes were slightly elevated, with aspartate transaminase, alanine transaminase, and gamma-glutamyl transpeptidase levels at 57 IU/L (normal range, 8–40 IU/L), 87 IU/L (normal range, 5–39 IU/L), and 326 IU/L (normal range, 10–47 IU/L), respectively. Serum lactic acid dehydrogenase and creatine kinase levels were within normal limits.\n\nAn enhanced CT scan of the abdomen and pelvis did not show any remarkable changes, such as intramuscular abscess or hematoma development, thrombophlebitis, fracture, or metastatic tumors (shown in Fig. 1a, b). There was no evidence of bacteremia or urinary tract infection in either blood or urine cultures. A biliary tract infection complicated with pseudogout of the left hip joint was suspected, and the patient was treated empirically with intravenous broad-spectrum antibiotics consisting of a piperacillin-tazobactam combination (4.5 g/8 h) and oral acetaminophen (1,200 mg/day).\n\nAfter initiating antibiotic treatment, fever and inflammatory reactions decreased. However, the patient continued to complain of persistent pain in the left thigh. Magnetic resonance imaging (MRI) examination of the pelvis, performed on the sixth day of hospitalization, revealed marked enlargement of the left internal and external obturator, pectineus, and adductor muscles on T1-weighted images (shown in Fig. 2a). The affected muscles showed an abnormally high signal intensity on T2-weighted (shown in Fig. 2b) and short tau inversion recovery sequence images (shown in Fig. 2c). These findings were consistent with a diagnosis of pyomyositis. The patient's left lower extremity pain improved after 12 days of intravenous antibiotic treatment with piperacillin-tazobactam. The patient was discharged and received oral cefdinir (100 mg/6 h) for an additional 4 weeks.\n\nAt the 7-week follow-up, an MRI scan showed complete resolution of the previous signs of pyomyositis (shown in Fig. 2d–f). The patient's full range of left hip motion was restored without any lasting sequelae. Therefore, he resumed chemotherapy with irinotecan, which was administered for an additional 8 cycles. At the 22-month follow-up after discharge, while undergoing fifth-line chemotherapy for newly developed lesions in the liver and lung, the patient showed no signs of recurrent pyomyositis.\n\nDiscussion/Conclusion\n\nPyomyositis is a primary acute infection of skeletal muscles and is often associated with abscess formation [1, 2]. In 12–40% of cases, patients had multiple abscesses, and the most common lesions were in the quadriceps muscles, followed by bulky muscles such as the gluteal muscles [4]. Skeletal muscle tissue is naturally resistant to infection. Therefore, it has been suggested that pyomyositis is induced by local mechanical trauma, parasitic infection, malnutrition, and a compromised immune system [5]. Our patient had diabetes mellitus and relapsing gastric cancer, and he was undergoing chemotherapy for the latter diagnosis, which may have increased his susceptibility to pyomyositis. Walling et al. reported that 15% of pyomyositis patients had diabetes mellitus [15]. It has been reported that skeletal muscle damage is caused by muscle infarction, even without frank infarction, local vascular insufficiency, and hypoxia due to diabetic microvascular diseases [15]. Development of pyomyositis in patients with neoplastic disease after chemotherapy is usually ascribed to neutropenia and/or immunodeficiency, caused by cancer. However, subclinical myopathy secondary to malignancy and/or its treatment is another possible cause [4]. Several chemotherapeutic drugs have been reported to induce muscle toxicity-related pyomyositis [9], although irinotecan muscle toxicity has never been reported. Notwithstanding, the exact pathogenesis is currently poorly understood; our patient had several pyomyositis risks, such as diabetes mellitus and cancer, and was undergoing chemotherapy.\n\nPyomyositis has 3 clinical stages [1, 4, 5], including the invasive stage, which is characterized by an onset of manifestations, including low-grade fever, localized swelling, mild pain, and tenderness of the affected muscle. Typically, pus cannot be aspirated from the affected site at this stage. Next is the suppurative stage, when most patients present with high-grade fever, distinct muscle swelling, and tenderness. Aspiration of pus from the infected site can be performed at this stage. In the third stage, that is, the late stage, the systemic manifestations of sepsis, metastatic abscesses, and multi-organ dysfunction occur [4, 6].\n\nBecause of lack of awareness, nonspecific features, and atypical presentations, a wide range of differential diagnoses are often considered such as septic arthritis, cellulitis, muscle hematoma, deep venous thrombosis, osteosarcoma, and polymyositis. Thus, the correct diagnosis is often missed, especially in the early stage [1, 5]. Various noninvasive diagnostic modalities, such as ultrasonography, CT, and MRI, are useful in confirming the diagnosis of pyomyositis [1, 2, 4, 5]. Some studies suggest that MRI is the most useful modality to diagnose pyomyositis at an early stage because it can demonstrate both the site and extent of inflammatory muscle involvement [5].\n\nIn these patients, the affected muscles are usually enlarged, showing a homogeneous intermediate signal intensity on T1-weighted MRI studies [2]. T2-weighted MRI may reveal diffuse muscle enlargement with hyperintensity, which may be associated with swelling of fascial planes, an abnormal signal intensity shown by the adjacent bone, or with fluid accumulation in the involved joint [1, 2, 16]. A CT scan can be performed more easily than an MRI, but the former imaging technique has lower sensitivity and provides lesser anatomical information than the latter [16]. For our patient, an enhanced CT scan was performed when he was admitted with leg pain and high fever, but it showed no remarkable changes. MRI examination was performed on the sixth day after admission, which led to a diagnosis of pyomyositis.\n\nPyomyositis is a rare complication in patients undergoing chemotherapy for cancer. To the best of our knowledge, only 10 patients with solid tumors, who were undergoing chemotherapeutic regimens, have been diagnosed with pyomyositis (Table 1). While the majority of previously reported cases of pyomyositis were diagnosed at the suppurative or late stage with single or multiple muscle abscesses requiring surgical or CT-guided drainage, our patient was diagnosed with pyomyositis at an early stage, using an MRI study. As abscess formation had not yet occurred, the patient could be treated successfully with antibiotics without surgical intervention.\n\nThe National Comprehensive Cancer Network clinical practice guidelines for prevention and treatment of cancer-related infections recommend that a patient diagnosed with a condition causing complex bacteremia, such as pyomyositis, should receive antibiotic therapy for 7–14 days, although the regimen may need modification on a case-to-case basis [17, 18]. As S. aureus is the most common causative organism [1], the timely administration of a broad-spectrum antibiotic agent providing S. aureus coverage is usually sufficient to manage the infection at an early stage empirically, because blood cultures exhibit positivity in only 30% of cases [2]. Once the abscess has formed, however, interventional treatment with percutaneous or surgical drainage and debridement should be performed on an emergency basis to ensure complete recovery [1, 5]. In the present case, blood culture was negative; however, administration of piperacillin-tazobactam was effective, and inflammation was controlled. There was no recurrence of pyomyositis after switching to oral cefdinir.\n\nThe present case was diagnosed and treated at an early stage, without surgical treatment. Purulent myositis did not recur, although the tumor development gradually progressed, and chemotherapy is being continued to date. McRae and Sharma [12] and Kitayama et al. [14] reported that it was possible to resume chemotherapy after treatment for myositis in patients who required surgical treatment; however, McRae and Sharma [12] reported resuming chemotherapy only once, and Kitayama et al. [14] did not clearly state the time periods. In contrast, Keith and Bramwell [9] and Yamada et al. [10] reported that they were unable to resume chemotherapy, and their patients died due to primary cancer progression. Chemotherapy could be resumed in the case of upper extremity muscle inflammation, but those in the lower extremity were not resumed. Muscle trauma might cause pyomyositis [1, 4, 5]. Surgical treatment for pyomyositis in the bulky muscle, especially in the lower extremity rather than the upper extremity, may form a new onset site and prolong the inflammatory response. This may be one of the reasons why chemotherapy cannot usually be resumed. In addition, infection during chemotherapy may affect prognosis [19], and further, an inflammatory response may affect the pharmacodynamics of anticancer drugs [20]. Therefore, early diagnosis and treatment without surgical intervention for pyomyositis leads to the resumption of treatment for cancer by controlling infection and inflammatory response; this may improve the prognosis of patients.\n\nIn summary, pyomyositis is a rare complication of chemotherapy in patients with a solid malignancy. When a patient undergoing chemotherapy complains of localized muscular pain, an MRI study should be performed promptly, as early detection and treatment are key to achieving a better prognosis in case of pyomyositis. We suggest that timely diagnosis and effective treatment of pyomyositis can enable the patient to resume chemotherapy early and, thereby, control the progression of a life-threatening malignancy.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for the 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. The local Ethical Committee of the Izumo City General Medical Center in Shimane, Japan, provided approval for the publication of this case report (Receipt No: 3-1).\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNo funding was received for this report.\n\nAuthor Contributions\n\nY.N. wrote the initial draft. Y.N., T.Y., and A.S. performed the surgery. A.S., T.Y., R.H., N.H., and Y.T. provided valuable guidance and edited the discussion section. All authors read and approved the final draft of the manuscript.\n\nData Availability Statement\n\nAll data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.\n\nFig. 1 Enhanced CT scan of the pelvis. Axial (a) and coronal (b) enhanced CT imaging showing no remarkable changes such as intramuscular abscesses, hematoma development, or intravascular defects. CT, computed tomography.\n\nFig. 2 MRI observations of the pelvis. The first line shows the onset (a–c), while the second line shows the seventh week after the treatment (d–f). a Axial T1-weighted image showing diffuse enlargement of the left internal (white arrowheads) and external obturator (arrow) muscles with intermediate signal intensity. b Axial T2-weighted image showing a high signal intensity in the left internal (white arrowheads) and external obturator muscles (arrow) with no evidence of an abscess, soft tissue gas, or tumor development. c A coronal short tau inversion recovery sequence image showing a high signal intensity in the left internal (white arrowheads) and external obturator (arrow) and adductor muscles (open arrowheads). d Axial T1-weighted image showing improvement of the diffuse enlargement. e Axial T2-weighted image showing a change in the signal intensity. f A coronal short tau inversion recovery sequence image showing the disappearance of the high signal intensity. MRI, magnetic resonance imaging.\n\nTable 1 Pyomyositis related to chemotherapy for patients with solid tumors\n\nCase No.\tAge/Sex\tPrimary tumor\tChemotherapy\tSite\tPyomyositis\tRestart chemotherapy\tReference No.\t\n\t\t\tregimen\t\tstage\ttreatment\t\t\t\n1\t43/M\tRetroperitoneal teratoma\tVCR, BLM, and CDDP\tLeft psoas muscle\tSuppurative\tSurgical drainage\tNo\t[9]\t\n2\t40/M\tRetroperitoneal teratoma\tVCR, BLM, and CDDP\tLeft psoas muscle\tSuppurative\tSurgical drainage\tNo\t[9]\t\n3\t58/F\tEndometrial cancer\tPTXandCBDCA\tLeft gluteus médius muscle\tSuppurative\tCT-guided drainage\tNR\t[14]\t\n4\t58/F\tEndometrial cancer\tDTXandCBDCA\tBilateral femoral muscles\tSuppurative\tSurgical drainage\tNo\t[16]\t\n5\t46/F\tCervical cancer\tCDDP, 5-FU, and IFN-a\tRight gluteus muscle\tSuppurative\tCT-guided drainage\tNR\t[10]\t\n6\t67/M\tLung cancer\tCDDP, VDS, and MMC\tBilateral gluteus maximus, right adductor magnus, left biceps femoris, and soleus muscles\tSuppurative\tSurgical drainage\tNo\t[11]\t\n7\t62/M\tLung cancer\tAMRandVNR\tLeft upper extremity and right lower extremity\tSuppurative\tSurgical drainage debridement\tNo\t[13]\t\n8\t47/F\tBreast cancer\t5-FU, DTX, and CPA\tRight calf\tSuppurative\tSurgical drainage\tNo\t[12]\t\n9\t26/F\tBreast cancer\tDTX, CBDCA, and HER\tRight upper extremity\tSuppurative\tSurgical drainage\tYes\t[15]\t\n10\t80/F\tBreast cancer\tNabPTX\tRight shoulder joint muscles\tLate\tSurgical drainage\tYes\t[17]\t\n11\t78/M\tGastric cancer\tCPT-11\tLeft internal and external obturator, pectineus, and adductor muscles\tInvasive\tAntibiotics\tYes\tOur case\t\nAMR, amrubicin; BLM, bleomycin; CBDCA, carboplatin; CDDP, cisplatin; CPA, cyclophosphamide; CPT-11, irinotecan; DTX, docetaxel; 5-FU, 5-fluorouracil, HER, trastuzumab; IFN-a, interferon alpha; MMC, mitomycin C; NabPTX, nab-paclitaxel; NR, not recorded; MTX, methotrexate; PTX, paclitaxel; VCR, vincristine; VDS, vindesine; VNR, vinorelbine; VP-16, etoposide; CT, computed tomography.\n==== Refs\nReferences\n\n1 Agarwal V Chauhan S Gupta RK Pyomyositis Neuroimaging Clin N Am 2011 11 21 (4) 975 83 22032510\n2 Mitsionis GI Manoudis GN Lykissas MG Sionti I Motsis E Georgoulis AD Pyomyositis in children: early diagnosis and treatment J Pediatr Surg 2009 11 44 (11) 2173 8 19944229\n3 Chiu SK Lin JC Wang NC Peng MY Chang FY Impact of underlying diseases on the clinical characteristics and outcome of primary pyomyositis J Microbiol Immunol Infect 2008 8 41 (4) 286 93 18787734\n4 Chiedozi LC Pyomyositis. Review of 205 cases in 112 patients Am J Surg 1979 2 137 (2) 255 9 426186\n5 Chauhan S Jain S Varma S Chauhan SS Tropical pyomyositis (myositis tropicans): current perspective Postgrad Med J 2004 5 80 (943) 267 70 15138315\n6 Maguire J Kaye SB Psoas abscess: unusual complication of effective chemotherapy for teratoma Br Med J (Clin Res Ed) 1985 6 290 (6485) 1870\n7 Segreti EM Munkarah A Levenback C Successful percutaneous drainage of gluteal pyomyositis occurring after intra-arterial chemotherapy and pelvic irradiation Gynecol Oncol 1994 6 53 (3) 376 9 8206415\n8 Teramoto S Konishi M Mikasa K Hamada K Maeda K Sakamoto M A case of multiple muscular abscesses of the lower limbs by Staphylococcus aureus after chemotherapy for lung cancer Kansenshogaku Zasshi 1997 9 71 (9) 939 43 9339633\n9 Keith BD Bramwell VH Pyomyositis after chemotherapy for breast cancer Am J Clin Oncol 2000 2 23 (1) 42 4 10683075\n10 Yamada K Wasa J Sugiura H Horio Y A case of multiple pyomyositis after chemotherapy for lung cancer Gan to Kagaku Ryoho 2006 6 33 (6) 837 40 16770109\n11 Singh P Chan W Blomfield P McIntosh R Pyomyositis after chemotherapy for endometrial cancer Int J Gynecol Cancer 2010 10 20 (7) 1256 8 21297556\n12 McRae M Sharma S Forearm pyomyositis in a breast cancer patient on chemotherapy J Plast Reconstr Aesthet Surg 2010 10 63 (10) e737 9 20570231\n13 Nakao Y Yokoyama M Nishiyama S Hashiguchi M Aihara S Yasunaga M Pyomyositis associated with chemotherapy for endometrial cancer: a case report World J Surg Oncol 2013 2 11 45 23442230\n14 Kitayama H Sugiyama J Hirayama M Onada Y Tsuji Y Shoulder pain after fall, septic shock, and pyomyositis associated with breast cancer chemotherapy and lymphedema Case Rep Oncol 2016 11 9 (3) 726 32 27920709\n15 Walling DM Kaelin WG Pyomyositis in patients with diabetes mellitus Rev Infect Dis 1991 9 13 (5) 797 802 1962087\n16 Kwak YG Choi SH Kim T Park SY Seo SH Kim MB Clinical guidelines for the antibiotic treatment for community-acquired skin and soft tissue infection Infect Chemother 2017 12 49 (4) 301 25 29299899\n17 National Comprehensive Cancer Network NCCN guidelines: prevention and treatment of cancer-related infections 2018 Pennsylvania National Comprehensive Cancer Network [cited 2018 Oct 11]. Available from: https://www.nccn.org\n18 Elting LS Rubenstein EB Rolston KV Bodey GP Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials Clin Infect Dis 1997 8 25 (2) 247 59 9332520\n19 Dendle C Gilbertson M Spelman T Stuart RL Korman TM Thursky K Infection is an independent predictor of death in diffuse large b cell lymphoma Sci Rep 2017 6 7 (1) 4395 28667319\n20 Slaviero KA Clarke SJ Rivory LP Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy Lancet Oncol 2003 4 4 (4) 224 32 12681266\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(2)",
"journal": "Case reports in oncology",
"keywords": "Antibiotics; Chemotherapy; Gastric cancer; Irinotecan; Pyomyositis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1220-1227",
"pmc": null,
"pmid": "34703439",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Pyomyositis in a Patient Undergoing Chemotherapy for Gastric Cancer: A Case Report and Literature Review.",
"title_normalized": "pyomyositis in a patient undergoing chemotherapy for gastric cancer a case report and literature review"
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"abstract": "BACKGROUND\nCytomegalovirus (CMV) is a highly prevalent herpesvirus that can present with cutaneous disease in immunocompromised individuals. This may reflect systemic involvement, which is associated with significant morbidity and mortality.\n\n\nOBJECTIVE\nTo report a case of cutaneous CMV in an immunocompromised patient and to discuss the differential diagnosis of genital ulcers.\n\n\nMETHODS\nA medical chart review was conducted on a patient who presented with a scrotal ulcer after renal transplantation. A review of the literature on cutaneous CMV disease was also completed.\n\n\nRESULTS\nBiopsy of the scrotal ulcer revealed classic findings of CMV disease. The patient also developed CMV viremia. Treatment with valganciclovir resolved his scrotal ulcer and viremia.\n\n\nCONCLUSIONS\nThe differential diagnosis for genital ulcers is broad, especially in the immunocompromised patient. Cutaneous CMV disease should be ruled out with biopsy and immunohistochemical examination in immunocompromised patients, as it may reflect systemic involvement and significantly affect patient care.",
"affiliations": "Department of Dermatology and Skin Science, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada rpinca@alumni.ubc.ca.;Department of Pathology and Laboratory Medicine and Department of Dermatology and Skin Science, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Dermatology and Skin Science, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.",
"authors": "Pinca|Rebeca|R|;Crawford|Richard I|RI|;Au|Sheila|S|",
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"issue": "20(6)",
"journal": "Journal of cutaneous medicine and surgery",
"keywords": "cytomegalovirus (CMV); genital ulcer; herpes simplex virus (HSV); human immunodeficiency virus (HIV); immunocompromise; infectious disease; renal transplant",
"medline_ta": "J Cutan Med Surg",
"mesh_terms": "D000368:Aged; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D003937:Diagnosis, Differential; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D012611:Scrotum; D012883:Skin Ulcer",
"nlm_unique_id": "9614685",
"other_id": null,
"pages": "567-569",
"pmc": null,
"pmid": "27207356",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cytomegalovirus Scrotal Ulcer in a Renal Transplant Patient.",
"title_normalized": "cytomegalovirus scrotal ulcer in a renal transplant patient"
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"abstract": "We report the case of a patient with suspected ulcerating necrotizing herpetic stromal keratitis who showed no improvement despite intensive (amongst others antiherpetic) topical and systemic therapy. The ulcer healed following amniotic membrane transplantation and penetrating excimer laser keratoplasty was performed to improve visual acuity. The excision showed deep stromal proof of herpes simplex virus (HSV) type 1 antigens.",
"affiliations": "Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes UKS, Kirrberger Str. 100, Gebäude 22, 66424, Homburg/Saar, Deutschland, corinna.spira@uks.eu.",
"authors": "Spira|C|C|;Szentmáry|N|N|;Hasenfus|A|A|;Sauter|M|M|;Smola|S|S|;Seitz|B|B|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00347-013-2941-8",
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"issue": "111(7)",
"journal": "Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft",
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"medline_ta": "Ophthalmologe",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000650:Amnion; D000998:Antiviral Agents; D001684:Biological Dressings; D003131:Combined Modality Therapy; D006801:Humans; D016849:Keratitis, Herpetic; D015948:Keratoplasty, Penetrating; D053685:Laser Therapy; D008297:Male; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "9206148",
"other_id": null,
"pages": "654-9",
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"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "17074561;2165231;12589832;22424312;10366086;8593015;18236375;11481259;14507749;17030720;21448683;794567;2413240;10090359;15140857;20490992;9732374;15621867",
"title": "Therapy refractory stromal Herpes keratitis under aciclovir.",
"title_normalized": "therapy refractory stromal herpes keratitis under aciclovir"
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"companynumb": "DE-ACTAVIS-2015-10279",
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"abstract": "In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved.",
"affiliations": "Department of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, Gumi, Korea.;Department of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, Gumi, Korea.;Department of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, Gumi, Korea.;Department of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, Gumi, Korea.",
"authors": "Lee|Yoon-Suk|YS|;Kim|Byung-Kook|BK|;Lee|Ho-Jae|HJ|;Dan|Jinmyoung|J|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; D000225:Adenine; C106812:adefovir dipivoxil",
"country": "Korea (South)",
"delete": false,
"doi": "10.4055/cios.2016.8.2.232",
"fulltext": "\n==== Front\nClin Orthop SurgClin Orthop SurgCIOSClinics in Orthopedic Surgery2005-291X2005-4408The Korean Orthopaedic Association 10.4055/cios.2016.8.2.232Case ReportPathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B Lee Yoon-Suk MDKim Byung-Kook MDLee Ho-Jae MDDan Jinmyoung MDDepartment of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, Gumi, Korea.\nCorrespondence to: Jinmyoung Dan, MD. Department of Orthopaedic Surgery, CHA Gumi Medical Center, CHA University, 12 Sinsi-ro 10-gil, Gumi 39295, Korea. Tel: +82-54-450-9869, Fax: +82-54-450-9899, osjmdan@gmail.com6 2016 10 5 2016 8 2 232 236 09 9 2015 20 10 2015 Copyright © 2016 by The Korean Orthopaedic Association2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved.\n\nChronic hepatitis BAdefovir dipivoxilFanconi syndromeOsteomalaciaSpontaneous fractures\n==== Body\nFanconi syndrome (also known as Fanconi's syndrome) is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate, and bicarbonate are passed into the urine, instead of being reabsorbed.1) Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate levels of available phosphate and calcium.\n\nAdefovir dipivoxil (ADV) is a commonly used antiviral agent in the treatment of chronic hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection. According to the literature, high-dose ADV therapy (60–120 mg/day) is nephrotoxic, whereas low-dose ADV therapy (daily dose of 10 mg) has been reported to be safe.23)\n\nAlthough use of low-dose ADV therapy for chronic hepatitis B has been advocated in large clinical trials, several cases of hypophosphatemic osteomalacia due to Fanconi syndrome in patients receiving prolonged ADV treatment have been reported recently.4) However, a report of pathologic fracture induced by low dose ADV therapy is rare.\n\nHere, we report a case of pathologic fracture of the femoral neck that developed in a chronic hepatitis B patient who was receiving prolonged ADV therapy at a dose of 10 mg daily.\n\nCASE REPORT\nA 43-year-old male presented in June 2011 with lower back and left hip pain, especially while bearing weight. The patient initially had dull and generalized aches. The pain then progressed to the lower back and left hip, which had developed 8 months and 3 months before the hospital visit, respectively and had aggravated since that time. He also had a history of right sixth rib fracture without a traumatic event 3 years before. He had chronic hepatitis B which was diagnosed 10 years ago and was prescribed lamivudine at the time of diagnosis. Lamivudine was changed to low-dose ADV daily after 3 years due to development of lamivudine resistance. He had no antecedent trauma or other medical history and was previously not taking any medication that is known to affect skeletal health or result in nephrotoxicity.\n\nThe patient showed an antalgic gait and mild tenderness on the lower back and left hip joint, but there was no abnormal finding on the physical examination, including the Patrick test and percussion test.\n\nLaboratory investigations showed hypophosphatemia (1.0 mg/dL), mild hypokalemia (3.4 mmol/L), normocalcemia (8.5 mg/dL), and mild metabolic acidosis. He had normal levels of serum parathyroid hormone (29.36 pg/mL), 25-hydroxyvitamin D3 (27.5 nmol/L), and 1,25-dihydroxyvitamin D3 (46.7 pmol/L), but had mild renal impairment (estimated glomerular filtration rate, 61.75 mL/min) with upper limit of normal for serum creatinine (1.2 mg/dL). Thyroid function tests and serum levels of epinephrine, norepinephrine, and dopamine were within the reference range. Levels of bone turnover markers confirmed accelerated bone remodeling with a markedly elevated level of serum alkaline phosphatase of 314 IU/L (normal range, 40 to 160 IU/L), an increased serum osteocalcin level of 14.3 ng/mL (normal range, 4 to 12 ng/mL) and an increased urinary deoxypyridinoline/creatinine ratio of 12.08 nmol/mmoL (normal range, 2.4 to 5.4 nmol/mmoL). Liver function tests including hepatic enzymes, albumin, globulin, and bilirubin were within the normal range. HBV DNA level on quantitative PCR was below 20 IU/mL. Autoimmune serology for antinuclear antibodies, antineutrophilic cytoplasmic antibodies, anti-glomerular basement membrane antibodies and cryoglobulin was negative. Serum protein electrophoresis, free light chain kappa/lambda ratio, and peripheral blood smear result showed no evidence of multiple myeloma. Electrophoresis for alkaline phosphatase isoenzymes showed increased activity of bone fraction.\n\nUrinalysis revealed significant glycosuria and proteinuria in the absence of hyperglycemia. Bone densitometry showed abnormally low bone mineral density with a mean lumbar T-score of –4.86 standard deviations and a mean lumbar Z-score of –4.69 standard deviations (lowest at L4 with a T-score of –5.57).\n\nPlain radiographs of the chest, pelvis and hip joint showed no evidence of fracture or pathologic lesions (Fig. 1).\n\nWhole body bone scintigraphy displayed increased uptake in the right sixth rib and left femoral neck area. Hot uptake in the right sixth rib was due to rib fracture which was diagnosed 3 years ago (Fig. 2).\n\nMagnetic resonance imaging (MRI) revealed abnormal signals in both femoral neck areas. A significant dark line and signal changes were seen in the left femoral neck area on both T1- and T2-weighted images. A slight dark line was also observed in the upper portion of the right femoral neck. Based on these findings, pathologic fracture of the femoral neck was highly suspected, especially on the left side of the hip (Fig. 3).\n\nBased on these results, a diagnosis of insufficiency fracture of the left femoral neck owing to hypophosphataemic osteomalacia in the context of Fanconi syndrome secondary to ADV therapy was made. Based on MRI findings and patient's symptoms, fixation of the left femoral neck with multiple cannulated screws was performed (Fig. 4). The suspected pathologic fracture of the right femoral neck was treated conservatively. ADV therapy was discontinued immediately after the diagnosis of acquired Fanconi syndrome was made and entecavir was prescribed at a daily dose of 1 mg. Elemental phosphate supplementation (2,722 mg/day), was started, and calcium carbonate (1,500 mg/day) and vitamin D3 (400 IU/day) were also prescribed.\n\nThe patient reported improvement in the symptoms 2 weeks after the treatment. Phosphate supplementation was discontinued after normalization of serum phosphate, 2 weeks after the treatment was started. At postoperative 6 weeks, the patient reported significant improvement in symptoms and ADL and returned to social activity. After 4 months of follow-up, normalization of hypokalemia, glycosuria and proteinuria and improvement in hypophosphatemia were observed.\n\nAfter 14 months of follow-up, all laboratory test results, including those of blood and urine tests, were within the normal range and bone densitometry showed significant improvement in bone density (mean lumbar T-score: –1.4, lowest at L1 with a T-score of –1.8). The patient returned to previous social activity and follow-up X-ray of both femoral heads showed no signs of avascular osteonecrosis (AVN) (Fig. 5).\n\nDISCUSSION\nA number of therapeutic drugs are toxic to the renal proximal tubule and can cause the renal Fanconi syndrome. The most serious complications are bone demineralization from urinary phosphate wasting and progressive decline in kidney function.\n\nOsteomalacia is a disorder of bone, characterized by decreased mineralization of newly formed osteoid at sites of bone turnover. Osteomalacia may be asymptomatic and can present radiologically as osteopenia. It can also produce characteristic symptoms, independently of the underlying cause, including diffuse bone and joint pain, muscle weakness, and difficulty walking. These symptoms may have an insidious onset. Bone pain is usually most pronounced in the lower spine, pelvis, and lower extremities, where fractures have occurred, and it may be associated with tenderness on palpation. The pain is characterized as dull and aching, and is aggravated by activity and weight bearing. Fractures may occur with little or no trauma, typically involving the ribs, vertebrae, and long bones.5)\n\nThese problems may be caused by various nutritional, medical, and surgical situations like malabsorption, gastric bypass surgery, celiac sprue, chronic hepatic disease, chronic kidney disease or toxic effect of drugs.\n\nADV is an orally bioavailable prodrug of adefovir that possesses potent in vitro activity against the HBV and the HIV. In general, drug toxicity in the renal proximal tubule is a dose-related phenomenon. ADV is excreted unchanged in the urine through glomerular filtration and tubular secretion and is known to be nephrotoxic at doses of 60 mg daily and above. Thus, the long-term safety of ADV, particularly nephrotoxicity, is a major concern in clinical trials. However, many clinical studies have shown that at a lower dose of 10 mg/day, ADV has a favorable risk-benefit profile with little or no evidence of renal toxicity after long-term therapy.23)\n\nADV-induced hypophosphatemic osteomalacia is a rare condition, but several such case reports have been published recently.46) Although it is generally believed that ADV 10 mg daily is not nephrotoxic with an incidence of renal events similar to that observed in the placebo group, ADV can be nephrotoxic even at low doses. For patients taking ADV, some reports recommend regular monitoring of renal function, calcium and phosphate levels. More frequent monitoring is needed in patients with pre-existing renal insufficiency.7)\n\nFemoral neck insufficiency fractures are rare and are known to be associated with a variety of conditions such as vitamin D deficiency or renal dysfunction. In case of druginduced Fanconi syndrome, hypophosphatemic osteomalacia leads to a generalized defect in bone mineralization, causing excessive accumulation of undermineralized bone matrix and a lack of structural support for the periosteum. This generalized softening of the bone is associated with aches and pains in bones, muscles, and joints. These early signs of osteomalacia are often misdiagnosed as other conditions such as polymyalgia rheumatica, arthritis, or fibromyalgia. There are a number of published case reports of patients with spontaneous (atraumatic) femoral neck fractures, covering a range of etiologies. The femoral neck insufficiency fractures can become complete fractures if the symptoms and signs of hip injury are ignored. The consequences of a displaced femoral neck fracture can be devastating.\n\nMajority of patients with osteomalacia induced femoral neck fracture are treated conservatively with bed rest and medical therapy. But some patients who have progressively worsening of fracture displacement are treated surgically.89)\n\nAnatomically, femoral neck is an important passage for blood vessels that supply the femoral head and a pathologic fracture of this area can lead to disabilities resulting from severe pain and limited motion of the involved hip joint. Delayed diagnosis and inappropriate treatment can increase the possibility of avascular necrosis, and if displacement occurs, surgical treatment can be complex.10)\n\nIn our case, the patient's medical and medication history was taken thoroughly at the initial visit. Based on the patient's history and appropriate blood and urinary tests, early diagnosis of Fanconi syndrome was made and treatment was initiated early. With respect to the pathologic fracture of the femoral neck, early diagnosis established by bone scan and magnetic resonance (MR) imaging and early surgical treatment successfully prevented fracture progression and occurrence of AVN.\n\nIn conclusion, if a chronic hepatitis B patient who is receiving prolonged treatment with ADV complains of hip or back pain, early diagnostic studies related to Fanconi syndrome should be performed and additional radiologic evaluations such as plain X-ray, bone scan, dual energy X-ray absorptiometry, and MR imaging of the affected area should be performed to rule out pathologic fractures. As soon as the diagnosis of Fanconi syndrome is made, cessation of ADV and supplementation of elemental phosphorus and calcium should be carried out immediately to improve the symptoms of Fanconi syndrome. As delayed treatment of the pathologic fracture could lead to severe complications or burdensome operation, early immobilization and treatment should be performed to achieve reliable healing as soon as possible. The orthopaedic surgeons should be aware of osteomalacia and pathologic fractures caused by ADV administered as anti-HBV therapy.\n\nCONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.\n\nFig. 1 Plain radiograph of the pelvis and both femoral heads shows no evidence of fracture or pathologic lesions.\nFig. 2 The 99mTc-hydroxymethylene diphosphonate whole body bone scintigraphy displays increased uptake in the right sixth rib and left femoral neck area. Hot uptake in the right sixth rib was due to rib fracture which was diagnosed 3 years ago.\nFig. 3 Magnetic resonance imaging revealing abnormal signals in both femoral neck areas. (A) Coronal T1-weighted image of both femoral neck areas. (B) Axial T1-weighted image of both femoral neck areas. Dark line and signal changes were seen in both femoral neck areas, especially on the left side of the hip. (C) Coronal T1-weighted image of the left femoral neck area. (D) Coronal T2-weighted image of the left femoral neck area.\nFig. 4 Plain radiographs after operation show normal anatomical relation in hip without pathologic lesion. (A, B) Immediate postoperative radiographs of the left femoral neck. Three cannulated screws were inserted in a reverse triangular pattern. (C, D) Radiographs of the left femoral neck at 8 months after surgery.\nFig. 5 Follow-up X-ray of both femoral heads at 14 months after initial treatment. The radiograph shows no signs of avascular osteonecrosis in both femoral neck areas and no loosening of screws in the left femoral neck.\n==== Refs\n1 Clarke BL Wynne AG Wilson DM Fitzpatrick LA Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features Clin Endocrinol (Oxf) 1995 43 4 479 490 7586624 \n2 Izzedine H Hulot JS Launay-Vacher V Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies Kidney Int 2004 66 3 1153 1158 15327411 \n3 Hadziyannis SJ Tassopoulos NC Heathcote EJ Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years Gastroenterology 2006 131 6 1743 1751 17087951 \n4 Kim DH Sung DH Min YK Hypophosphatemic osteomalacia induced by low-dose adefovir therapy: focus on manifestations in the skeletal system and literature review J Bone Miner Metab 2013 31 2 240 246 22976054 \n5 Frame B Parfitt AM Osteomalacia: current concepts Ann Intern Med 1978 89 6 966 982 363010 \n6 Eguchi H Tsuruta M Tani J Kuwahara R Hiromatsu Y Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B Intern Med 2014 53 3 233 237 24492692 \n7 Law ST Li KK Ho YY Nephrotoxicity, including acquired Fanconi's syndrome, caused by adefovir dipivoxil: is there a safe dose? J Clin Pharm Ther 2012 37 2 128 131 21714795 \n8 Chamseddine AH Alasiry AA Zein HK Spontaneous simultaneous bilateral femoral neck fractures secondary to osteomalacia: a case report and review of the literature Eur J Orthop Surg Traumatol 2012 22 Suppl 1 139 143 26662766 \n9 Tanaka M Setoguchi T Ishidou Y Pathological femoral fractures due to osteomalacia associated with adefovir dipivoxil treatment for hepatitis B: a case report Diagn Pathol 2012 7 108 22906214 \n10 Della Rocca GJ Gaps and opportunities in the management of the young femoral neck fracture Injury 2015 46 3 515 518 25496856\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2005-291X",
"issue": "8(2)",
"journal": "Clinics in orthopedic surgery",
"keywords": "Adefovir dipivoxil; Chronic hepatitis B; Fanconi syndrome; Osteomalacia; Spontaneous fractures",
"medline_ta": "Clin Orthop Surg",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000998:Antiviral Agents; D005198:Fanconi Syndrome; D005265:Femoral Neck Fractures; D005598:Fractures, Spontaneous; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D063065:Organophosphonates; D010018:Osteomalacia",
"nlm_unique_id": "101505087",
"other_id": null,
"pages": "232-6",
"pmc": null,
"pmid": "27247753",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24492692;7586624;15327411;26662766;22976054;363010;17087951;21714795;22906214;25496856",
"title": "Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B.",
"title_normalized": "pathologic femoral neck fracture due to fanconi syndrome induced by adefovir dipivoxil therapy for hepatitis b"
} | [
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"activesubstancename": "ADEFOVIR DIPIVOXIL"
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"abstract": "Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. We demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT, and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELISA assays).",
"affiliations": "Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.;Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.;Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.;Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.;Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.;Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.",
"authors": "Qin|Shizhen|S|;Zhou|Yong|Y|;Gray|Li|L|;Kusebauch|Ulrike|U|;McEvoy|Laurence|L|;Antoine|Daniel J|DJ|;Hampson|Lucy|L|;Park|Kevin B|KB|;Campbell|David|D|;Caballero|Juan|J|;Glusman|Gustavo|G|;Yan|Xiaowei|X|;Kim|Taek-Kyun|TK|;Yuan|Yue|Y|;Wang|Kai|K|;Rowen|Lee|L|;Moritz|Robert L|RL|;Omenn|Gilbert S|GS|;Pirmohamed|Munir|M|;Hood|Leroy|L|",
"chemical_list": "D015415:Biomarkers; D000082:Acetaminophen; D002251:Carbon Tetrachloride",
"country": "United States",
"delete": false,
"doi": "10.1021/acs.jproteome.6b00547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1535-3893",
"issue": "15(10)",
"journal": "Journal of proteome research",
"keywords": "acetaminophen; biomarker panel; drug-induced liver injury; liver-enriched proteins; selected reaction monitoring",
"medline_ta": "J Proteome Res",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D001774:Blood Chemical Analysis; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D006801:Humans; D051379:Mice; D008875:Middle Aged; D040901:Proteomics",
"nlm_unique_id": "101128775",
"other_id": null,
"pages": "3724-3740",
"pmc": null,
"pmid": "27575953",
"pubdate": "2016-10-07",
"publication_types": "D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients.",
"title_normalized": "identification of organ enriched protein biomarkers of acute liver injury by targeted quantitative proteomics of blood in acetaminophen and carbon tetrachloride treated mouse models and acetaminophen overdose patients"
} | [
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"companynumb": "US-JNJFOC-20161101320",
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"occurcountry": "GB",
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"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "Given the poor prognosis of relapsed/refractory myeloid malignancies, the concept of sequential conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven to be an effective approach. We sought to evaluate a sequential scheme combining fludarabine, amsacrine, and cytarabine (FLAMSA) for cytoreduction, followed by reduced-intensity conditioning with busulfan and melphalan (FLAMSA-BuMel), which was designed to be suitable for both HLA-matched and haploidentical HSCT. This single-center retrospective study included 36 adult patients with high-risk myeloid malignancies who underwent allo-HSCT from HLA-matched (n = 19) or haploidentical (n = 17) donors. Along with the standard prophylaxis for graft-versus-host disease (GVHD), patients with a haploidentical donor received post-transplantation high-dose cyclophosphamide. A post-transplantation consolidation treatment with low-dose 5-azacytidine and prophylactic donor lymphocyte infusions was provided whenever possible. Thirty patients (83%) achieved complete remission on day +30. With a median follow-up of 30.0 months, the 2-year overall survival was 89% in the HLA-matched group versus 34% in the haploidentical group (P = .0018). The 2-year disease-free survival in these 2 groups was 68% and 34%, respectively (P = .013). At 2 years, the probability of relapse was 32% and 20%, respectively, and nonrelapse mortality was 0% and 58%, respectively (P = .0003). The leading cause of death was relapse in the HLA-matched group (3 of 19) and hemorrhagic events (5 of 17) in the haploidentical group, favored by significantly delayed platelet reconstitution and a severe GVHD context. These data confirm the feasibility of FLAMSA-BuMel as a sequential conditioning in allo-HSCT for high-risk myeloid malignancies. The use of bone marrow as the preferred graft source might reduce the incidence of acute GVHD and nonrelapse mortality in the haploidentical transplantation setting.",
"affiliations": "Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France. Electronic address: ludovic.jondreville@sorbonne-universite.fr.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France.",
"authors": "Jondreville|Ludovic|L|;Roos-Weil|Damien|D|;Uzunov|Madalina|M|;Boussen|Inès|I|;Grenier|Adrien|A|;Norol|Françoise|F|;Morel|Véronique|V|;Nguyen|Stéphanie|S|;Souchet|Laetitia|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.07.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": "27(11)",
"journal": "Transplantation and cellular therapy",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Refractory myeloid malignancy; Relapse; Salvage; Sequential conditioning",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": null,
"nlm_unique_id": "101774629",
"other_id": null,
"pages": "915.e1-915.e8",
"pmc": null,
"pmid": "34329755",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "FLAMSA-Busulfan-Melphalan as a Sequential Conditioning Regimen in HLA-Matched or Haploidentical Hematopoietic Stem Cell Transplantation for High-Risk Myeloid Diseases.",
"title_normalized": "flamsa busulfan melphalan as a sequential conditioning regimen in hla matched or haploidentical hematopoietic stem cell transplantation for high risk myeloid diseases"
} | [
{
"companynumb": "FR-PFIZER INC-202101108549",
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"activesubstancename": "CYTARABINE"
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{
"abstract": "Avelumab is an anti-PD-L1 (programmed death-ligand 1) immune checkpoint inhibitor (ICIs) and the monoclonal antibody that constitutes a major development in the immunotherapy of cancer. In 2017, The European Medicine Agency (EMA) approved it as an orphan drug for treatment of gastric cancer. Avelumab has recently been approved in the United States, Europe and Japan for treatment of metastatic Merkel cell carcinoma (MCC). Avelumab inhibits the interaction of Programmed cell death protein 1 (PD-1) on immune cells with PD-L1 on tumor cells, thus banishing immunosuppressive signals and leading to enhanced immune cell activation. Here we are revealing a case of the patient with metastatic gastric cancer receiving avelumab with the development of undesirable endocrinopathies during the course of treatment. We suggested that patients receiving avelumab immunotherapy should be monitored for signs and symptoms of thyroiditis, hypothyroidism and adrenal insufficiency, which may require immediate attention and supportive treatment by immunosuppression and respective hormone replacement.",
"affiliations": "Department of Medicine, Icahn School of Medicine Mount Sinai, Queens Hospital Center, Jamaica, New York.;Department of Medicine, Icahn School of Medicine Mount Sinai, Queens Hospital Center, Jamaica, New York.;Department of Medicine, Icahn School of Medicine Mount Sinai, Queens Hospital Center, Jamaica, New York.;Department of Medicine, Icahn School of Medicine Mount Sinai, Queens Hospital Center, Jamaica, New York.",
"authors": "Aziz|Kashif|K|;Shahbaz|Amir|A|;Umair|Muhammad|M|;Sachmechi|Isaac|I|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.17179/excli2018-1357",
"fulltext": "\n==== Front\nEXCLI JEXCLI JEXCLI JEXCLI Journal1611-2156Leibniz Research Centre for Working Environment and Human Factors 2018-135710.17179/excli2018-1357Doc526Case ReportAvelumab inducing hypothyroidism and hypoadrenalism: A case report and review of literature Aziz Kashif *1Shahbaz Amir 1Umair Muhammad 1Sachmechi Isaac 1\n1 Department of Medicine, Icahn School of Medicine Mount Sinai, Queens Hospital Center, Jamaica, New York*To whom correspondence should be addressed: Kashif Aziz, 9155 97th street, Jamaica, New York, 11421; Tel: +19293509197, +923464910784, E-mail: kashifaziz927@gmail.com06 6 2018 2018 17 526 530 23 5 2018 05 6 2018 Copyright © 2018 Aziz et al.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.This article is available from http://www.excli.de/vol17/Aziz_06062018_proof.pdfAvelumab is an anti-PD-L1 (programmed death-ligand 1) immune checkpoint inhibitor (ICIs) and the monoclonal antibody that constitutes a major development in the immunotherapy of cancer. In 2017, The European Medicine Agency (EMA) approved it as an orphan drug for treatment of gastric cancer. Avelumab has recently been approved in the United States, Europe and Japan for treatment of metastatic Merkel cell carcinoma (MCC). Avelumab inhibits the interaction of Programmed cell death protein 1 (PD-1) on immune cells with PD-L1 on tumor cells, thus banishing immunosuppressive signals and leading to enhanced immune cell activation. Here we are revealing a case of the patient with metastatic gastric cancer receiving avelumab with the development of undesirable endocrinopathies during the course of treatment. We suggested that patients receiving avelumab immunotherapy should be monitored for signs and symptoms of thyroiditis, hypothyroidism and adrenal insufficiency, which may require immediate attention and supportive treatment by immunosuppression and respective hormone replacement.\n\navelumabhypothyroidismhypoadrenalismendocrinopathiesImmune Check Point InhibitorsPd-L1\n==== Body\nIntroduction\nProgrammed cell death protein 1 (also known as PD-1) is a cell surface receptor that plays a significant role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis in antigen-specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (Francisco et al., 2010[2]; Fife and Pauken, 2011[1]). A new class of drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used for varying success to treat some types of cancer (Syn et al., 2017[12]). Avelumab is a whole monoclonal antibody of isotype IgG1 that binds to the programmed death ligand 1 (PD-L1) and therefore inhibits binding to its receptor the PD-1. Formation of a PD-1/PD-L1 receptor/ligand complex leads to inhibition of CD8+ T cells, and therefore inhibition of an immune-related reaction. Immunotherapy aims at ceasing this immune blockage by blocking those receptor-ligand pairs (Joseph et al., 2018[6]). The most common serious adverse reactions to avelumab are immune-mediated adverse reactions (irAEs) which includes rash, pneumonitis, hepatitis, colitis, endocrinopathies, and nephritis as well as life-threatening infusion reactions (Hamid et al., 2013[4]). Hereby we present a case of hypothyroidism and adrenal insufficiency induced by Avelumab (PD-L1 inhibitor) in a 69-year- old patient with metastatic gastric cancer.\n\nCase Report\nA 69-year male presented to us with the recurrence of gastric cancer with pancreatic metastasis. He received 6 cycles of Taxotere, Cisplatima, and 5FU (TCF), a TCF chemotherapy regimen which includes Docetaxel, carboplatin, and 5-fluorouracil. He did not show any response to these medications. After that, he entered into a clinical trial with avelumab which is a PD-L1 inhibitor. After three months of starting avelumab, the patient started to complain of resting tachycardia. He had deranged thyroid function tests (TFT) indicating thyrotoxicosis and treated with tapazole 5 mg every other day for resting tachycardia. Subsequently, being 6 weeks on tapazole, his TFT and heart rates improved. Later, on seven months of treatment (15 cycles) the patient was complaining of fatigue, nausea, vomiting, found hypotensive (blood pressure=93/61 mm HG) and hyponatremia. At that time his relevant blood work-up was given in Table 1(Tab. 1).\n\nMRI, abdomen showed adrenal cortical atrophy. After getting the results of his blood tests and imaging, diagnosis of hypothyroidism and adrenal insufficiency were made and the patient was admitted to the hospital and started on hydrocortisone 20 mg in am and 10 mg in pm. Tapazole was stopped initially and later started on levothyroxine 50 mcg which titrated up to 88 mcg. Patient symptoms improved with this treatment.\n\nDiscussion\nImmune evasion is an emerging hallmark of cancer, and oncologists have long sought to connect the power of the immune system to treat cancer (Hanahan and Weinberg, 2011[5]). In the last 5 years, inhibition of 2 immune checkpoints, PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have significantly changed the landscape for immunotherapy. PD-1 is an immune checkpoint receptor expressed on activated T cells. When bound by PD-L1, PD-1 causes T-cell exhaustion and a favorable environment for tumor growth (Topalian et al., 2015[14]). Immune checkpoint inhibitors (ICIs) that block the programmed death 1 axis (PD-L1, PD-1) are important treatment options in various tumor types. Avelumab also functions as an immune checkpoint inhibitor and has recently been approved in the United States, Europe and Japan for the treatment of metastatic Merkel cell carcinoma (MCC) (Shirley, 2018[9]). Common treatment-related adverse events (TRAEs) with anti-PD-L1/PD-1 agents include low-grade fatigue, pruritus and rash. In addition, potentially serious irAEs, such as high-grade pneumonitis or autoimmune-like side effects, occur in a minority of patients (Postow et al., 2015[8]; Spain et al., 2016[11]; Weber et al., 2015[15]). The exact mechanism of PD-L1 induced endocrinopathies is not known. We suggest that cell lytic properties of this immunotherapeutic agent cause thyroiditis, and eventually lead to hypothyroidism and possible adrenalitis leading to hypoadrenalism. In some cases hypophysitis was also property, but not in our patient. On review of the literature, we found 4 studies and trials regarding the use, safety, and immune-related adverse events by the use of avelumab and other immune checkpoints inhibitors. These are shown in Table 2(Tab. 2) (References in Table 2: Kelly et al., 2018[7]; Hahn et al., 2017[3]; Sosa et al., 2018[10]; Sznol et al., 2017[13]) below. \n\nConclusion\nPatients receiving avelumab and other PD-1/PD-L1 inhibitors should be monitored for signs and symptoms of immune-mediated adverse events. With the exception of immune-mediated endocrinopathies, most immune-mediated adverse events can be treated with immunosuppression with corticosteroids. For endocrinopathies like hypothyroidism, thyroiditis, adrenal insufficiency and hypophysitis we have to monitor hormone levels and continuous respective hormone replacement.\n\nFinancial interests\nNone declared.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nTable 1 Relevant blood tests and their results\nTable 2 Review of literature regarding the use, safety, and immune related adverse events (irAEs) by the use of avelumab and other immune checkpoint inhibitors\n==== Refs\n1 Fife BT Pauken KE The role of the PD-1 pathway in autoimmunity and peripheral tolerance Ann N Y Acad Sci 2011 1217 45–59 21276005 \n2 Francisco LM Sage PT Sharpe AH The PD-1 pathway in tolerance and autoimmunity Immunol Rev 2010 236 219–42 20636820 \n3 Hahn AW Gill DM Agarwal N Maughan BL PD-1 checkpoint inhibition: Toxicities and management Urol Oncol 2017 35 701 707 28889921 \n4 Hamid O Robert C Daud A Hodi FS Hwu WJ Kefford R Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma N Engl J Med 2013 369 134–44 23724846 \n5 Hanahan D Weinberg RA Hallmarks of cancer: the next generation Cell 2011 144 646 674 21376230 \n6 Joseph J Zobniw C Davis J Anderson J Trinh VA Avelumab: a review of its application in metastatic Merkel cell carcinoma Ann Pharmacother 2018 Epub ahead of print \n7 Kelly K Infante JR Taylor MH Patel MR Wong DJ Iannotti N Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials Cancer 2018 124 2010 2017 29469949 \n8 Postow MA Callahan MK Wolchok JD Immune checkpoint blockade in cancer therapy J Clin Oncol 2015 33 1974 1982 25605845 \n9 Shirley M Avelumab: A review in metastatic Merkel cell carcinoma Target Oncol 2018 Epub ahead of print \n10 Sosa A Lopez Cadena E Simon Olive C Karachaliou N Rosell R Clinical assessment of immune-related adverse events Therap Adv Med Oncol 2018 10 1 11 \n11 Spain L Diem S Larkin J Management of toxicities of immune checkpoint inhibitors Cancer Treat Rev 2016 44 51 60 26874776 \n12 Syn NL Teng MWL Mok TSK Soo RA De-novo and acquired resistance to immune checkpoint targeting Lancet Oncol 2017 18 e731–41 29208439 \n13 Sznol M Postow MA Davies MJ Pavlick AC Plimack ER Shaheen M Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management Cancer Treat Rev 2017 58 70 76 28689073 \n14 Topalian SL Drake CG Pardoll DM Immune checkpoint blockade: a common denominator approach to cancer therapy Cancer Cell 2015 27 450–61 25858804 \n15 Weber JS Yang JC Atkins MB Disis ML Toxicities of immuno-therapy for the practitioner J Clin Oncol 2015 33 2092 2099 25918278\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1611-2156",
"issue": "17()",
"journal": "EXCLI journal",
"keywords": "Immune Check Point Inhibitors; Pd-L1; avelumab; endocrinopathies; hypoadrenalism; hypothyroidism",
"medline_ta": "EXCLI J",
"mesh_terms": null,
"nlm_unique_id": "101299402",
"other_id": null,
"pages": "526-530",
"pmc": null,
"pmid": "30034316",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "25858804;29616562;25605845;20636820;21276005;21376230;29799096;23724846;28689073;29469949;26874776;28889921;25918278;29208439",
"title": "Avelumab inducing hypothyroidism and hypoadrenalism: A case report and review of literature.",
"title_normalized": "avelumab inducing hypothyroidism and hypoadrenalism a case report and review of literature"
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"companynumb": "US-ACCORD-071516",
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"activesubstancename": "DOCETAXEL"
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{
"abstract": "The addition of the new protease inhibitors (PIs) to peg-interferon (IFN) and ribavirin (RBV), approved for chronic hepatitis C, has clearly improved sustained virological response (SVR) rates although several adverse events have been reported with this regimens, including mild hematological toxicity. Moreover, severe pancytopenia and aplastic anemia during triple therapy with telaprevir has recently been described in seven patients. We report here two cases of severe agranulocytosis/aplastic anemia using boceprevir or simeprevir in interferon-based combination and 2 additional cases of severe myelosupression in IFN-free therapy with sofosbuvir and simeprevir plus RBV. Our observations suggest that PIs could have a sort of class-effect in developing severe hematologic toxicity or, at least, an additive interaction with other potentially myelotoxic agents such as IFN or RBV that are used in the classical regimens against HCV. Unfortunately, the mechanisms behind this phenomenon are currently unknown. In conclusion, given the lifethreatening character of these complications, close monitoring is mandatory in patients under PIs based therapy to promptly detect serious hematological toxicities and to carefully evaluate treatment discontinuation. Prospective studies assessing the usefulness of RBV in the era of new IFN-free combinations are needed.",
"affiliations": "Department of Clinical Hematology, Hospital del Mar, Barcelona, Spain.;Liver Unit, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.;Liver Unit, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.;Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.;Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.;Department of Clinical Hematology, Hospital del Mar, Barcelona, Spain.;Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.;Department of Clinical Hematology, Hospital del Mar, Barcelona, Spain.;Liver Unit, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.",
"authors": "Senín|Alicia|A|;Broquetas|Teresa|T|;Cañete|Nuria|N|;Lens|Sabela|S|;Londoño|María-Carlota|MC|;Ferraro|Mariana|M|;Forns|Xavier|X|;Salar|Antonio|A|;Carrión|Jose A|JA|",
"chemical_list": "D000998:Antiviral Agents; D011480:Protease Inhibitors; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D000069616:Simeprevir",
"country": "Mexico",
"delete": false,
"doi": "10.5604/16652681.1231593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "16(2)",
"journal": "Annals of hepatology",
"keywords": "Anemia; Hepatitis; Toxicity and protease.",
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D000998:Antiviral Agents; D001855:Bone Marrow Diseases; D001856:Bone Marrow Examination; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D006526:Hepatitis C; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011392:Proline; D011480:Protease Inhibitors; D012307:Risk Factors; D012720:Severity of Illness Index; D000069616:Simeprevir; D016896:Treatment Outcome",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "312-317",
"pmc": null,
"pmid": "28233734",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aplastic Anemia and Severe Myelosuppression with Boceprevir or Simeprevir-Containing Hepatitis C Virus Treatment.",
"title_normalized": "aplastic anemia and severe myelosuppression with boceprevir or simeprevir containing hepatitis c virus treatment"
} | [
{
"companynumb": "ES-JNJFOC-20170308874",
"fulfillexpeditecriteria": "1",
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{
"abstract": "Invasive fungal infections (IFI) represent one of the most aggressive infectious complications among hematopoietic cell transplantation (HCT) recipients. Aspergillosis is the most frequent cause of IFI in allogeneic HCT (allo-HCT), with most of the cases involving the respiratory tract. Other infrequent and usually more aggressive forms of invasive aspergillosis include hepatic, neurological, and gastrointestinal (GI). We report herein a case of GI aspergillosis diagnosed in a living patient, off all systemic immunosuppression after an allo-HCT, who had undergone a permanent colostomy because of colon carcinoma 35 years before hematological diagnosis.",
"affiliations": "Department of Hematology, Vall d'Hebron Hospital, Barcelona, Spain.",
"authors": "Mora|D|D|;Barba|P|P|;Ruiz|I|I|;Castillo|N|N|;Aizpurua|M|M|;Roselló|E|E|;Bosch|F|F|;Valcárcel|D|D|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12082",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "15(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D017809:Fatal Outcome; D005260:Female; D005767:Gastrointestinal Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D012307:Risk Factors; D013997:Time Factors; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "E107-10",
"pmc": null,
"pmid": "23581249",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Primary gastrointestinal aspergillosis 6 months after allogeneic hematopoietic cell transplantation: a case report.",
"title_normalized": "primary gastrointestinal aspergillosis 6 months after allogeneic hematopoietic cell transplantation a case report"
} | [
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"companynumb": "ES-PFIZER INC-2018269289",
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"activesubstancename": "VORICONAZOLE"
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"abstract": "Acute fibrinous and organizing pneumonia (AFOP) is rare in patients with systemic lupus erythematosus (SLE). We herein report a case of AFOP with SLE and hemophagocytic syndrome. Early-phase high-resolution computed tomography showed a fine granular lung pattern. A pathological examination revealed AFOP. An immunohistological examination revealed numerous CD163+ and fewer CD68+ macrophages present in the lung tissue and in alveolar spaces as well, including fibrin balls, the interstitium, and bronchial walls. Pneumonia and thrombocytopenia worsened during high-dose steroid therapy, plasma exchange, and intravenous immunoglobulin administration. The addition of intravenous cyclophosphamide successfully ameliorated the symptoms and radiographic lesions. Therefore, this therapy may be useful for treating severe AFOP.",
"affiliations": "Department of Rheumatology, Shimane University Faculty of Medicine, Japan.;Department of Rheumatology, Shimane University Faculty of Medicine, Japan.;Department of Rheumatology, Shimane University Faculty of Medicine, Japan.;Department of Rheumatology, Shimane University Faculty of Medicine, Japan.;Department of Rheumatology, Shimane University Faculty of Medicine, Japan.;Department of Surgical Pathology, Shimane University Faculty of Medicine, Japan.;Internal Medicine III, Shimane University Faculty of Medicine, Japan.;Organ Pathology, Shimane University Faculty of Medicine, Japan.;Respiratory Medicine & Medical Oncology, Shimane University Faculty of Medicine, Japan.;Respiratory Medicine & Medical Oncology, Shimane University Faculty of Medicine, Japan.;Thoracic Surgery, Shimane University Faculty of Medicine, Japan.;Department of Rheumatology, Shimane University Faculty of Medicine, Japan.",
"authors": "Taira|Mariko|M|;Matsumura|Takeshi|T|;Sumita|Yoshiko|Y|;Moriyama|Mayuko|M|;Kondo|Masahiro|M|;Ishikawa|Noriyoshi|N|;Wada|Yasuko|Y|;Nagase|Mamiko|M|;Nishikawa|Emiko|E|;Tsubata|Yukari|Y|;Kishimoto|Koji|K|;Murakawa|Yohko|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7184-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34433711\n10.2169/internalmedicine.7184-21\nCase Report\nA Rare Case of Acute Fibrinous and Organizing Pneumonia Associated with Systemic Lupus Erythematosus and Autoimmune-associated Hemophagocytic Syndrome: The Involvement of CD163-positive Macrophages\nTaira Mariko 1\nMatsumura Takeshi 1\nSumita Yoshiko 1\nMoriyama Mayuko 1\nKondo Masahiro 1\nIshikawa Noriyoshi 2\nWada Yasuko 3\nNagase Mamiko 4\nNishikawa Emiko 5\nTsubata Yukari 5\nKishimoto Koji 6\nMurakawa Yohko 17\n1 Department of Rheumatology, Shimane University Faculty of Medicine, Japan\n2 Department of Surgical Pathology, Shimane University Faculty of Medicine, Japan\n3 Internal Medicine III, Shimane University Faculty of Medicine, Japan\n4 Organ Pathology, Shimane University Faculty of Medicine, Japan\n5 Respiratory Medicine & Medical Oncology, Shimane University Faculty of Medicine, Japan\n6 Thoracic Surgery, Shimane University Faculty of Medicine, Japan\n7 General Treatment Center for Intractable Diseases, Shimane University Faculty of Medicine, Japan\nCorrespondence to Dr. Yohko Murakawa, murakawa@med.shimane-u.ac.jp\n\n24 8 2021\n15 2 2022\n61 4 559565\n28 1 2021\n2 7 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nAcute fibrinous and organizing pneumonia (AFOP) is rare in patients with systemic lupus erythematosus (SLE). We herein report a case of AFOP with SLE and hemophagocytic syndrome. Early-phase high-resolution computed tomography showed a fine granular lung pattern. A pathological examination revealed AFOP. An immunohistological examination revealed numerous CD163+ and fewer CD68+ macrophages present in the lung tissue and in alveolar spaces as well, including fibrin balls, the interstitium, and bronchial walls. Pneumonia and thrombocytopenia worsened during high-dose steroid therapy, plasma exchange, and intravenous immunoglobulin administration. The addition of intravenous cyclophosphamide successfully ameliorated the symptoms and radiographic lesions. Therefore, this therapy may be useful for treating severe AFOP.\n\nacute fibrinous and organizing pneumonia\nautoimmune-associated hemophagocytic syndrome\nsystemic lupus erythematosus\nrheumatic disease\nCD163 positive macrophages\nintravenous cyclophosphamide\n==== Body\npmcIntroduction\n\nAcute fibrinous and organizing pneumonia (AFOP) is a relatively newly recognized histopathological manifestation presenting with fibrin “balls” within the alveolar spaces and organizing pneumonia, featuring fibrin-associated, loose, intraluminal connective tissue within the alveolar ducts and bronchioles. AFOP does not meet the classic histological criteria for diffuse alveolar damage, bronchiolitis obliterans with organizing pneumonia, or eosinophilic pneumonia (1). AFOP may be idiopathic or develop secondary to a variety of lung injuries (2) and other conditions, including drug-taking, environmental insults, infection, transplantation, and autoimmune diseases (3).\n\nSeveral cases of AFOP associated with rheumatic diseases have been reported (1-11), but only one has been linked to systemic lupus erythematosus (SLE) (11); although this case was treated successfully (11), the prognosis of AFOP associated with rheumatic diseases is not always good (1,4,5), and the optimal treatment remains unclear.\n\nWe herein report a case of AFOP associated with SLE and autoimmune-associated hemophagocytic syndrome (AAHS) that worsened during initial high-dose prednisolone (PSL) therapy, including intravenous methylprednisolone (IV MP), plasma exchange, and massive intravenous immunoglobulin (IVIG) administration. However, intravascular pulsed cyclophosphamide (IV CYC) therapy was successful. Our case also indicated that CD163+ cells, previously indicated to be M2 anti-inflammatory macrophages (12), are provably involved in AFOP with SLE.\n\nCase Report\n\nA 25-year-old woman was admitted to Shimane University Hospital with a fever, cough, and erythema of the face and extremities. Five years earlier, she had been diagnosed with histiocytic necrotizing lymphadenitis and been initially treated with PSL at 30 mg/day. The dose was gradually reduced and maintained at 3 mg/day for several years. She had presented with a productive cough in the past two months and facial erythema after her visit to Thailand in the past month before her hospital admission.\n\nA laboratory examination revealed proteinuria. She was first examined at the Department of Respiratory Medicine and then consulted the Department of Rheumatology. On admission, her body temperature was 36.8°C. Her heart and breathing rates were normal. Her percutaneous oxygen saturation [as revealed by pulse oximetry (SpO2)] on room air was 97%. She presented with erythema on her face and extremities, oral ulcers, and cervical and inguinal lymphadenopathy. Auscultation revealed a few right-side-dominant coarse crackles.\n\nA urinalysis revealed proteinuria, hematuria, hyaline, and cellular casts. The urinary protein excretion level was 7.1 g/day. Blood tests revealed progressive pancytopenia from the day of admission to day 4, the day of transfer to the Department of Rheumatology with the following findings: white blood cells: 4,140 to 2,320 /μL of blood, hemoglobin (Hgb): 9.2 to 8.6 g/dL, and platelets: 166,000 to 75,000 /μL of blood. Hypoalbuminemia and elevated levels of lactate dehydrogenase (445 IU/L, normal 100-215 IU/L), ferritin (796 ng/mL, normal 5-120 ng/mL), soluble interleukin 2 receptor (1,332 U/mL, normal 144-518 U/mL), and KL-6 (591 U/mL, normal ＜500 U/mL) were detected. The total bilirubin levels and renal function were within normal ranges. Complements CH50, C3, and C4 were decreased to 10.5 U/mL, 26 mg/dL, and 6.9 mg/dL respectively; the levels of C1q-circulating immune complexes were elevated (5.3 μg/mL, normal ＜2.9 μg/mL). According to an immunofluorescence test, her antinuclear antibody status was found to be positive (1:320; homogeneous and speckled type). Antibodies to dsDNA (96.2 IU/mL, normal ≤12.0 IU/mL), Sm (11.7, normal ≤10), U1RNP (12.7, normal ≤10), SS-A (≥500, normal ≤10) and PAIgG (180 ng/107 platelets, normal ≤25 ng/107 platelets) were also evident, but direct Coombs test, lupus anticoagulants, anti-cardiolipin IgG, and anti-cardiolipin-beta2 glycoprotein I complex, anti-SS-B, and anti-glomerular basement antibodies were not detected. She was diagnosed with SLE because she met both the 1997 revised American College of Rheumatology criteria and the 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) classification criteria.\n\nA blood gas analysis (BGA) on room air revealed a pH of 7.415, an arterial carbon dioxide partial pressure (PaCO2) of 38.5 mmHg, an arterial oxygen partial pressure (PaO2) of 81.8 mmHg, an HCO3- level of 24.1 mEq/L, and a base excess of 0.1 mmol/L. Chest computed tomography (CT) revealed diffuse, finely granular shadows in both lungs (Fig. 1). An infection assessment was extensively conducted because of her travel history and excluded by negative results on the interferon-γ release assay for tuberculosis, the virus separating test, other blood or urinary infection markers (such as beta-D-glucan, fungal antigens, antibodies against viruses, chlamydiae, and mycoplasma), cultures of sputum and gastric juice, and polymerase chain reaction. The angiotensin-converting enzyme levels were within the normal limits.\n\nFigure 1. A chest CT scan obtained on admission and before treatment. Diffuse finely granular shadows are evident in both lungs.\n\nBronchofiberscopy and bronchoalveolar lavage (BAL) performed on the day of admission revealed lymphocytosis with a reduced CD4/8 ratio and small amounts of bleeding but findings that were inconsistent with diffuse alveolar hemorrhage. A transbronchial lung biopsy revealed no specific findings.\n\nA videothoracoscopic lung biopsy was also performed because the patient had traveled abroad, and the possibility of microorganisms had to be excluded. The biopsy specimens obtained on day 3 revealed intra-alveolar fibrin balls in the alveolar spaces, an air space filling pattern with neutrophils, foam cells, an inflammatory exudate, and organizing pneumonia (Fig. 2). No alveolar hemorrhage or infectious disease was observed. The patient was diagnosed with AFOP associated with SLE.\n\nFigure 2. Videothoracoscopically derived lung biopsy specimens revealed fibrin balls within the alveolar spaces, foamy cells, leucocytes, an inflammatory exudate, and organizing pneumonia. Hematoxylin and Eosin staining: (a) 100× and (b) 400×. Immunohistochemistry with (c) anti-CD68 or (d) anti-CD163 mouse monoclonal antibody, followed by biotinylated anti-mouse IgG, avidinbiotin-peroxidase complex, and color developed with diaminobenzidine tetrahydrochloride (brown). Nuclei were counterstained with hematoxylin (blue). Control mouse IgG stained exudate weakly, but not cells (not shown).\n\nAn immunohistochemical examination later revealed increased numbers of macrophage linear cells; numerous CD163+ cells and a smaller number of CD 68+ cells were observed everywhere in her lung tissue and in alveolar spaces, including fibrin balls, the interstitium, and bronchial walls (Fig. 2c, d). Antibodies against IgG, C1q, or C3 were used for immunostaining, but these deposits were not detected, except for a small granular deposit of IgG in one vessel.\n\nThe patient's body temperature increased to 40 °C on day 3 accompanied by worsening pancytopenia, elevated ferritin levels, and worsening liver function tests. A bone marrow examination performed on the same day revealed the presence of hemophagocytic cells. The patient was also diagnosed with autoimmune-associated hemophagocytic syndrome (AAHS). We initiated IV MP 1,000 mg/day for 3 days followed by 1.5 mg/kg/day of PSL. Despite high-dose steroidal therapy, anemia (Hgb 7.9 g/dL), the thrombocytopenia (37,000 /μL), hyperferritinemia, and liver function worsened.\n\nWe performed plasma exchange on days 7 and 8 for the temporary reduction of cytokines causing AAHS, followed by 400 mg/kg/day IVIG for 5 days, because immune-related thrombocytopenia (17,000 /μL) might be involved under conditions of hemoptysis. However, while the platelet count improved by more than 50,000 /μL, it decreased again, and platelet transfusion did not increase the platelet count as expected. Her serum LDH also remained high, which may have been caused by AAHS. Furthermore, she required supplemental oxygen to treat hypoxia, and the lung lesions evident on CT worsened on day 13 (Fig. 3b). We administered IV CYC (750 mg) to treat respiratory symptoms and uncontrolled AAHS. Her respiratory and other symptoms and laboratory data improved.\n\nFigure 3. CT changes on hospital days (a) 1, (b) 13, and (c) 74. (b) The pulmonary manifestations worsened on day 13 despite high-dose prednisolone therapy, including intravenous pulsing, plasma exchange, and massive intravenous immunoglobulin administration. (c) Only slight granular shadows remained on day 74.\n\nA renal biopsy examined after the platelet counts improved on day 65 revealed lupus nephritis type III-S (A/C) +V (International Society of Nephrology/Renal Pathology Society 2003 classification) with granular deposits of IgG, C1q, and C3.\n\nCYC was changed to tacrolimus after the third course due to concerns about the patient's fertility and neutropenia caused by CYC. We also investigated the effect of tacrolimus on improving proteinuria caused by type V lupus nephritis. The dose of tacrolimus was increased by measuring the blood concentrations, although the approved dosage for lupus nephritis is below 3 mg/day in Japan. Only slight granular shadows were evident on CT on day 74 (Fig. 3c), and her proteinuria improved. The patient's clinical course is shown in Fig. 4.\n\nFigure 4. The clinical course. anti-ds DNA Ab: anti-double-stranded DNA antibody, BAL: bronchoalveolar lavage, BM: bone marrow, IV CYC: intravascular cyclophosphamide pulse, IVIG: massive intravenous immunoglobulin administration, IV MP: intravenous methylprednisolone pulse, PSL: prednisolone\n\nDiscussion\n\nAFOP was first reported as a histological pattern by Beasley et al. and was evident in the present clinical setting. AFOP does not meet the classic histological criteria for diffuse alveolar damage, bronchiolitis obliterans with organizing pneumonia, or eosinophilic pneumonia (1). The predominant histological features of AFOP are as follows: (i) organizing intra-alveolar fibrin, (ii) organizing pneumonia, and (iii) a patchy distribution. The minor features are as follows: (i) interstitial changes with acute and/or chronic inflammation, type 2 pneumocyte hyperplasia, and/or alveolar septal expansion with myxoid connective tissue, (ii) interstitial inflammation and (typically mild-to-moderate) expansion, and/or (iii) interstitial changes primarily confined to areas adjacent to the intra-alveolar fibrin balls (the intervening lung tissue exhibits only minimal changes). Pertinent negative observations are as follows: (i) hyaline membranes are not apparent, (ii) eosinophils are inconspicuous or absent, (iii) extensive bronchopneumonia and/or abscess formation is absent, and (iv) granulomatous inflammation is absent (1).\n\nAFOP associated with rheumatic diseases has been reported (Table). No specific autoantibodies related to AFOP were detected. Anti-SSA/Ro antibody was observed in three cases (#7, #8, #12); however, the proportion of the antibody may be observed usualy in rheumatic diseases. Cases #9 and #10 possessed anti-EJ antisynthetase antibody (9,10). Therefore, this rare antibody may be associated with AFOP in some patients with anti-EJ antibody-positive antisynthetase syndrome; however, other pathologic patterns may be more frequent (12 nonspecific interstitial pneumonia and 3 unclassifiable interstitial pneumonia have been reported) (10,13). No autoantibody associated with AFOP has been found in other rheumatic diseases.\n\nTable. Acute Fibrinous and Organizing Pneumonia Associated with Rheumatic Diseases.\n\n\tRheumatic diseases\tAge\nSex\tSymptoms\tAutoantibodies\tRadiographic findings\tTherapy\tOutcome\tReferences\t\n1\tPolymyositis\t78\nF\tDyspnea\tNot described\tBilateral reticulonodular\tCS\tDeath unrelated cause\t1\t\n2\tAnkylosing spondylitis\t55\nM\tCough, dyspnea, hemoptysis\tNot described\tBilateral perihilar air-space\tAntibiotics\tImproved\t\t\n3\tPossible fibromyalgia\t58\nF\tFever, arthralgia\tNot described\tConsistent with atypical pneumonia\tAntibiotics\tImproved\t\t\n4\tDermatomyositis\t14\nF\tDyspnea\tANA\tExtensive parenchymal process with patchy densities prominent in both lower lobes\tAntibiotics, CS, cyclosporine, IV CYC, ventilation\tDeath respiratoly failure\t2\t\n5\tUndifferentiated connective tissue disease\t39\nF\tCough, fever, dyspnea Raynaud’s phenomenon, sicca syndrome (normal salivary gland biopsy), boot and gloves neuropathic pain\tp-ANCA, anti-TPO, anti-TBG\tDiffuse GGA, with foci of parenchymal densification\tCS, IV CYC, later IV MP ventilation\tDeath respiratoly failure, pulmonary hemorrhage\t5\t\n6\tCollagen vascular disease-like condition\t47\nM\tJoint pain and stiffness, myalgia, dry cough, and dyspnea\tANA\tDiffuse reticular abnormalities in both lower lobes, associated with a GGA\tCS, AZA, ventilation\tImproved\t6\t\n7\tPrimary Sjögren's syndrome\t75\nF\tDyspnea, wheezing, productive cough dry skin, arthritis, rash and pulmonary hypertension\tanti-SS-A\nanti-SS-B\tBilateral multi-lobar areas of consolidation\tCS\tImproved\t7\t\n8\tPrimary Sjögren's syndrome\t60\nF\tFever, dyspnea, dry cough\tANA anti-SS-A\tBilateral diffuse multiple solitary nodules admixed with patchy areas of GGA\tCS\tImproved\t8\t\n9\tAntisynthetase syndrome\t34\nM\tDry cough, dyspnea on exertion necrotizing myopathy\tanti-EJ\tBilateral patchy infiltrates predominantly in the lower lobes\tCS, IVIG, MMF\tImproved\t9\t\n10\tAntisynthetase syndrome\t66\nF\tPruritic rash, myalgia, productive cough,\tAtypical pANCA, anti-EJ\tPathy peripheral airspase consolidation including foci of central lucency\tCS (only initial use of MMF and AZA by intolerance)\tImproved\t10\t\n11\tSystemic lupus erythematosus, anti-phospholipid syndrome\t47\nM\tDyspnea, productive cough, hemoptysis\tANA, anti-dsDNA, anti-Sm anti-phospholipid\tPeripheral and peribronchiolar areas of consolidation, maximal in the superior segments of the lower lobes with subpleural sparing in several areas\tCS, oral CYC\tImproved\t11\t\n12\tSystemic lupus erythematosus\t25\nF\tFever, cough, erythema, nephritis, pancytopenia hemophagocytosis\tANA, anti-dsDNA, anti-Sm anti-U1RNP, anti-SS-A, PAIgG\tDiffuse granular shadows\tIV MP, CS, PE, IVIG, IV CYC\tImproved\tPresent case\t\nANA: anti-nuclear antibody, AZA: azathioprine, CS: corticosteroid, CYC: cyclophosphamide, GGA: ground-glass attenuation, IV CYC: intravenous cyclophosphamide, IVIG: intravenous immunoglobulin, IV MP; intravenous methyl-prednisolone pulse, MMF: mycophenolate mofetil, PAIgG: platelet-associated immunoglobulin-G, PE: plasma exchange, TGB: thyroxin binding globulin, TPO: thyroid peroxidase\n\nThe radiographic CT patterns also varied, exhibiting multifocal patchy opacities, diffuse multiple (but solitary) nodules, peribronchiolar areas of consolidation, nodular shadows, or fine granular shadows (such as those in our case). The lung locations also varied from diffuse to lower lobe dominance. A pathological examination is thus essential.\n\nPulmonary parenchymal manifestations of SLE include alveolar hemorrhage, acute lupus pneumonitis, and chronic interstitial pneumonitis, but these conditions, especially the acute forms, are relatively rare (14,15). In the present case, chest CT revealed diffuse granular shadows, causing us to suspect acute lupus pneumonitis, but intense respiratory distress did not develop. The findings of BAL differed from those of alveolar hemorrhage. Owing to the history of the patient's travel abroad, we intensively checked for microorganisms but found none. The patient was ultimately diagnosed based on the histopathological findings of the lung.\n\nThe etiology and mechanisms of AFOP in SLE or other rheumatic diseases have not yet been proven. In the patient, deposition of immune complexes of IgG, C3, and C1q in glomeruli with hypocomplinemia, elevated immune complexes, and anti-dsDNA was observed, which were not detected in lung specimens. It is possible that the cytokines involved in AAHS also cause AFOP. Hematoxylin-eosin staining of lung specimens revealed neutrophils and foam cells, which are activated macrophages laden with lipids, in air spaces. Immunohistochemical examinations with antibodies against CD68 and CD163 were performed to detect macrophages; the former is expressed on pro-inflammatory M1 macrophages, while the latter is expressed on anti-inflammatory M2 macrophages (16). CD163+ cell numbers were significantly increased, and CD68+ cells were observed in relatively smaller numbers but increased in CD68+ cells in the normal lung reported elsewhere, where these cells were scattered in the alveolar spaces (17). Both macrophages were observed everywhere in her lung tissue, in alveolar spaces, including fibrin balls, the interstitium, and bronchial walls. A higher ratio of density of CD163+ to CD68+ macrophages has also been reported in nonspecific interstitial pneumonia and cryptogenic organizing pneumonia (17). In the AFOP case we reported, the increase in these cells seemed larger and the distribution wider than the interstitial pneumonia reported previously (17). The CD163+ M2 macrophage-dominant increase has been previously demonstrated in AAHS (15). Systemic macrophage activation and related cytokines may reflect both hemophagocytosis and AFOP in our case. The patient's laboratory data and symptoms reflecting AAHS activity in the present case paralleled pulmonary symptoms. M2 macrophages are also known as producers of TGF-β, which may cause fibrin balls as well as fibrosis. Thus, macrophage activation in the lung or other tissues may be related to AFOP, although its involvement was not clear in other cases reported previously. Further careful observation of AFOP in rheumatic cases is needed to determine its etiology.\n\nNo optimal treatment for AFOP associated with SLE or other rheumatic diseases has yet been established. Cases #2 and #3 of Table did not require immunosuppressive therapies but improved with antibiotics, suggesting that an infection may have been in play. Of the other patients, 4 of 10 improved when corticosteroids alone were administered (#1, #7, #8, #10), and the other 6 received corticosteroids and immunosuppressants. Seven of 10 patients improved, and the other 3 died. Case #4 received intensive mPSL-pulsing and IVIG (2 g/kg) therapies followed by IV CYC but died 2 weeks after admission (4). Case #5 with undifferentiated connective tissue disease developed respiratory failure caused by pulmonary hemorrhaging, despite treatment with a high dose of corticosteroid (IV MP) and IV CYC and required ventilatory support in the intensive-care unit (6). Only one case of AFOP with SLE (#11) has been reported. Hariri et al. described a 47-year-old man with AFOP associated with SLE who was successfully treated with prednisone 60 mg daily for 4-6 weeks, CYC 100 mg daily, and anticoagulation therapy (11). In our patient, only the second case of SLE associated with AFOP, the addition of IV CYC to prior IV MP, plasma exchange, or IVIG was effective. The addition of IV CYC might affect AAHS, which may indirectly affect AFOP. High-dose steroid, IV MP, or plasma exchange may be effective for AFOP; however, it was difficult for our patient to wait for the effects on both respiratory and blood conditions. Unfortunately, cases #4 and #5 died despite treatment with CYC. The discrepancy between these cases and CYC-effective patients (#10 and the present case) is not clear. The differences may depend on underlying autoimmune diseases, timing of CYC introduction, or disease severity in each patient. Identifying which case requires CYC may be important. More documentation of cases of AFOP with rheumatic diseases is needed.\n\nOurs is the second reported case of SLE with AFOP. The AFOP radiographic patterns vary, as described in this manuscript, and differ from those in a previous report (11). A lung biopsy is required to diagnose AFOP. Further research on more patients is required to establish safe and effective therapies for AFOP associated with rheumatic diseases.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nThe authors would like to thank the patient for consenting to this case report. The authors also thank Prof. Takeshi Isobe, Respiratory Medicine & Medical Oncology, Faculty of Medicine, Shimane University, for his valuable advice and Dr. Mitsuhiro Tada, who was part of the same department, for conducting the bronchoscopic examinations.\n==== Refs\n1. Beasley MB , Franks TJ , Galvin JR , Gochuico B , Travis WD . Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 126 : 1064-1070, 2002.12204055\n2. Vasu TS , Cavallazzi R , Hirani A , Marik PE . A 64-year-old male with fever and persistent lung infiltrate. Respir Care 54 : 1263-1265, 2009.19712502\n3. Arnaud D , Surani Z , Vakil A , Varon J , Surani S . Acute fibrinous and organizing pneumonia: a case report and review of the literature. Am J Case Rep 18 : 1242-1246, 2017.29170364\n4. Prahalad S , Bohnsack JF , Maloney CG , Leslie KO . Fatal acute fibrinous and organizing pneumonia in a child with juvenile dermatomyositis. J Pediatr 146 : 289-292, 2005.15689928\n5. Valim V , Rocha RH , Couto RB , Paixão TS , Serrano EV . Acute fibrinous and organizing pneumonia and undifferentiated connective tissue disease: a case report. Case Report Rheumatol 2012 : 549298, 2012.\n6. Balduin R , Giacometti C , Saccarola L , et al . Acute fibrinous and organizing pneumonia in a patient with collagen vascular disease“stigma”. Sarcoidosis Vasc Diffuse Lung Dis 24 : 78-80, 2007.18069424\n7. Fasanya A , Gandhi V , DiCarlo C , Thirumala R . Acute fibrinous and organizing pneumonia in a patient with Sjögren's syndrome. Respir Med Case Rep 20 : 28-30, 2017.27896062\n8. Wang Y , Zhao S , Du G , et al . Acute fibrinous and organizing pneumonia as initial presentation of primary Sjögren's syndrome: a case report and literature review. Clin Rheumatol 37 : 2001-2005, 2018.29717396\n9. Kashif M , Arya D , Niazi M , Khaja M . A rare case of necrotizing myopathy and fibrinous and organizing pneumonia with anti-EJ antisynthetase syndrome and SSA antibodies. Am J Case Rep 18 : 448-453, 2017.28439062\n10. Sauter JL , Butnor KJ . Expanding the spectrum of pulmonary histopathological manifestations of anti-synthetase syndrome: anti-EJ-associated acute fibrinous and organizing pneumonia. Histopathology 65 : 581-582, 2014.24660769\n11. Hariri LP , Unizony S , Stone J , et al . Acute fibrinous and organizing pneumonia in systemic lupus erythematosus: a case report and review of the literature. Pathol Int 60 : 755-759, 2010.20946526\n12. Do T , Tan R , Bennett M , et al . MicroRNA networks associated with active systemic juvenile idiopathic arthritis regulate CD163 expression and anti-inflammatory functions in macrophages through two distinct mechanisms. J Leuk Biol 103 : 71-85, 2018.\n13. Sasano H , Hagiwara E , Kitamura H , et al . Long-term clinical course of anti-glycyl tRNA synthetase (anti-EJ) antibody-related interstitial lung disease pathologically proven by surgical lung biopsy. BMC Pul Med 16 : 168, 2016.\n14. Keane MP , Lynch JP 3rd . Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax 55 : 159-166, 2000.10639536\n15. Murakawa Y , Taira M . Pulmonary manifestations of systemic lupus erythematosus. Riumachi-ka (Rheumatology). Forthcoming(in Japanese).\n16. Crayne CB , Albeituni S , Nichols KE , Cron RQ . Immunology of macrophage activation syndrome. Front Immunol 10 : 119, 2019.30774631\n17. Yamashita M , Saito R , Yasuhira S , et al . Distinct profiles of CD163-positive macrophages in idiopathic interstitial pneumonias. J Immunol Res 4 : 2018:1436236, 2018.\n\n",
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"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "CD163 positive macrophages; acute fibrinous and organizing pneumonia; autoimmune-associated hemophagocytic syndrome; intravenous cyclophosphamide; rheumatic disease; systemic lupus erythematosus",
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"pmid": "34433711",
"pubdate": "2021-08-24",
"publication_types": "D016428:Journal Article",
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"title": "A Rare Case of Acute Fibrinous and Organizing Pneumonia Associated with Systemic Lupus Erythematosus and Autoimmune-associated Hemophagocytic Syndrome: The Involvement of CD163-positive Macrophages.",
"title_normalized": "a rare case of acute fibrinous and organizing pneumonia associated with systemic lupus erythematosus and autoimmune associated hemophagocytic syndrome the involvement of cd163 positive macrophages"
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"abstract": "A 20-year-old man presented with recurrent syncope and abnormal electrocardiogram (ECG). His evaluation revealed a prolonged QT interval >600 milliseconds, witnessed torsades de pointes (TdP), and dilated cardiomyopathy. At his initial admission, an ICD was implanted and atrial pacing at 80 beats per minute suppressed ventricular arrhythmias. The patient was readmitted with device infection and recurrent TdP leading to intubation. This led to the discovery of a hitherto unrevealed loperamide abuse and his cardiac arrhythmias and LV dysfunction were determined to be related to large doses of loperamide. Following abstinence, his ejection fraction and ECG returned to normal.",
"affiliations": "St. Vincent Medical Group, Indianapolis, Indiana, USA.;St. Vincent Medical Group, Indianapolis, Indiana, USA.;St. Vincent Medical Group, Indianapolis, Indiana, USA.;St. Vincent Medical Group, Indianapolis, Indiana, USA. bjpadani@stvincent.org.",
"authors": "Vaughn|Patricia|P|;Solik|Michelle M K|MM|;Bagga|Shiv|S|;Padanilam|Benzy J|BJ|",
"chemical_list": "D000930:Antidiarrheals; D008139:Loperamide",
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"keywords": "Implantable Cardioverter Defibrillator (ICD); Loperamide; Narcotic withdrawal; QT prolongation; Torsades de Pointes (TdP)",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D000200:Action Potentials; D000930:Antidiarrheals; D002311:Cardiomyopathy, Dilated; D004562:Electrocardiography; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D008139:Loperamide; D008297:Male; D009293:Opioid-Related Disorders; D011237:Predictive Value of Tests; D016171:Torsades de Pointes; D055815:Young Adult",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electrocardiographic Abnormalities, Malignant Ventricular Arrhythmias, and Cardiomyopathy Associated With Loperamide Abuse.",
"title_normalized": "electrocardiographic abnormalities malignant ventricular arrhythmias and cardiomyopathy associated with loperamide abuse"
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"abstract": "A female patient with electroclinical and neuroradiological features compatible with Rasmussen syndrome developed a particular clinical and EEG pattern. As the seizures were refractory to valproate at 750 mg/kg/day, oxcarbazepine (OXC) at 30 mg/kg/day was added. Seizures became more frequent and on neurological examination, no hemiparesis was detected. The interictal EEG showed focal spikes and diffuse paroxysms in the right fronto-temporal regions. Brain MRI revealed right hemiatrophy, mainly at the Sylvian fissure. After initiating OXC daily, brief absence seizures, lasting less than 20 seconds and associated with bilateral and synchronous 2.5-3-Hz spike-and-waves compatible with typical absences, were observed. OXC was discontinued and the typical absences disappeared. Treatment with intravenous gammaglobulin was started. At the last control visit, at nine years of age, no absence seizures were observed either by the parents or on the EEG recording. Our patient who met the diagnostic criteria for Rasmussen syndrome presented with absence seizures that may have been induced by OXC. The absence seizures disappeared after OXC was discontinued.",
"affiliations": "Department of Neurology, Hospital de Pediatría \"Prof Dr Juan P Garrahan\", Buenos Aires.;Department of Neurology, Hospital de Pediatría \"Victor J. Vilela\", Rosario, Argentina.;Department of Neurology, Hospital de Pediatría \"Prof Dr Juan P Garrahan\", Buenos Aires.;Department of Neurology, Hospital de Pediatría \"Prof Dr Juan P Garrahan\", Buenos Aires.",
"authors": "Caraballo|Roberto H|RH|;Cachia|Pedro|P|;Valenzuela|Gabriela Reyes|GR|;Calvo|Agustin|A|",
"chemical_list": "D000927:Anticonvulsants; D000078330:Oxcarbazepine",
"country": "France",
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"doi": "10.1684/epd.2019.1035",
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"issue": "21(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "Rasmussen syndrome; absences; epilepsia partialis continua; oxcarbazepine",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D004569:Electroencephalography; D004660:Encephalitis; D005260:Female; D006801:Humans; D000078330:Oxcarbazepine; D012640:Seizures",
"nlm_unique_id": "100891853",
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"title": "Rasmussen syndrome: absence seizures may be induced by oxcarbazepine.",
"title_normalized": "rasmussen syndrome absence seizures may be induced by oxcarbazepine"
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"abstract": "Therapy related acute lymphoblastic leukemia (t-ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t-B-ALL cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t-B-ALL cases with a pre-B cell immunophenotype. Ph + t-B-ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t-B-ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t-B-ALL have been described in the literature. In the current study, three of four cases with Ph + t-B-ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t-B-ALL and prior radiation exposure.",
"affiliations": "Department of Pathology, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Pathology, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Medicine, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Pathology, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Pathology, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Pathology, Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.",
"authors": "Matnani|Rahul|R|;Parekh|Vishwas|V|;Borate|Uma|U|;Brazelton|Jason|J|;Reddy|Vishnu|V|;Peker|Deniz|D|",
"chemical_list": "C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase",
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"issue": "65(10)",
"journal": "Pathology international",
"keywords": "B-ALL; MLL; Philadelphia chromosome; therapy-related",
"medline_ta": "Pathol Int",
"mesh_terms": "D000368:Aged; D001943:Breast Neoplasms; D002880:Chromosomes, Human, Pair 11; D020732:Cytogenetic Analysis; D005260:Female; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014178:Translocation, Genetic",
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"publication_types": "D016428:Journal Article",
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"title": "Therapy-related B-lymphoblastic leukemia associated with Philadelphia chromosome and MLL rearrangement: Single institution experience and the review of the literature.",
"title_normalized": "therapy related b lymphoblastic leukemia associated with philadelphia chromosome and mll rearrangement single institution experience and the review of the literature"
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"drugadditional"... |
{
"abstract": "Somatostatin Analogues (SSAs) are used to treat Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and acromegaly. Side effects of SAAs usually include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. Exocrine Pancreatic Insufficiency (EPI) is often misdiagnosed as disease progression or failure to SAAs or diagnosed after a delay in patients receiving SAAs. We present our experience with EPI developing in patients following use of SAAs.\n\n\n\nWe reviewed chart and pharmacy records of 110 GEP-NETs patients who received SSAs. Data was collected including demographics, pathology, stage, dose/duration of long and short-acting SA, use of antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI) or H2 blockers). Laboratory data include chromogranin-A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) or fecal elastase test (FE). EPI was defined by a FE below normal level OR by a reduction of ≥ 21.2% or steatorrhea on QFFT. Patients who were identified to develop EPI were treated with pancreatic exocrine replacement therapy (PERT).\n\n\n\nAmong, 110 GEP-NETs patients, 104 received LA Octreotide and 6 Somatuline Depot Injection. Of these, 23 received short-acting SSA for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. QFFT confirmed EPI in 19, 11 based on clinical symptoms, and 16 had sample error or refusal to collect specimen. CTCAE 4.0 grades of EPI were: grade 2(69%), grade 3(22%) and grade 4(9%). Median time to development of EPI was 12 months (95%CI 3 - 23). Except 1, all patients received PERT either with concomitant PPI (13) or later if no improvement with PERT (6) and 2 on H2 blockers. 37% of the patients had improvement in EPI within 4-8 weeks. Deficiency of vitamins and trace elements was found in 11 of 19 patients, who received supplementation.\n\n\n\nOur experience constitutes the first and the largest study addressing EPI as a rare but serious complication of chronic use of SAAs. Although SAAs are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to EPI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SAAs, such as EPI, can improve not only diarrhea and weight loss in these patients but also can reduce cost of using short-acting SAAs and antidiarrheal.",
"affiliations": "Department of Medical Oncology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra and Feinstein Institute for Medical Research, USA.;Tufts Medical Center, Boston, MA, USA.;Tufts Medical Center, Boston, MA, USA.;Tufts Medical Center, Boston, MA, USA.;Tufts Medical Center, Boston, MA, USA.",
"authors": "Saif|Muhammad Wasif|MW|;Romano|Alicia|A|;Smith|Melissa H|MH|;Patel|Rachana|R|;Relias|Valerie|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "3(2)",
"journal": "Cancer medicine journal",
"keywords": "Chronic pancreatitis; Clinical studies; Exocrine pancreatic insufficiency; Gastric surgery; Gastroenteropancreatic neuroendocrine tumors (GEP-NET); Lanreotide; Pancreatic neoplasms; Pancreatic surgery; Risk factors; Somatostatin",
"medline_ta": "Cancer Med J",
"mesh_terms": null,
"nlm_unique_id": "101744997",
"other_id": null,
"pages": "75-84",
"pmc": null,
"pmid": "32405630",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "29782352;2883060;20662741;2437563;2884879;8132133;2895501;24307787;25014687;1371938;29923433;19704057;7827373;7661155;3513542;2690316;2121494;27355335",
"title": "Chronic Use of Long-Acting Somatostatin Analogues (SSAs) and Exocrine Pancreatic Insufficiency (EPI) in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): An Under-recognized Adverse Effect.",
"title_normalized": "chronic use of long acting somatostatin analogues ssas and exocrine pancreatic insufficiency epi in patients with gastroenteropancreatic neuroendocrine tumors gep nets an under recognized adverse effect"
} | [
{
"companynumb": "US-IPSEN BIOPHARMACEUTICALS, INC.-2020-08975",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LANREOTIDE ACETATE"
},
"d... |
{
"abstract": "Cardiopulmonary bypass, the extreme of non-obstetric surgery during pregnancy, presents unique challenges to minimize maternal and fetal risk. We present our experience with a woman who was diagnosed with a left atrial myxoma following an ischemic cerebrovascular accident. We discuss clinical management specific to cardiopulmonary bypass during pregnancy and delivery in the context of a multidisciplinary team approach. We recommend using intermittent Doppler ultrasound as a non-invasive real-time assessment of uteroplacental perfusion during non-obstetric surgery in pregnancy. Monitoring of perfusion facilitates active feedback for appropriate in utero resuscitation in these cases.",
"affiliations": "University of Wisconsin School of Medicine and Public Health, Department of OB/GYN, Division of Maternal Fetal Medicine, Madison, WI, USA.;Madison Anesthesiology Consultants, LLP, Madison, WI, USA.;University of Wisconsin School of Medicine and Public Health, Department of OB/GYN, Division of Maternal Fetal Medicine, Madison, WI, USA.;University of Wisconsin School of Medicine and Public Health, Department of OB/GYN, Division of Maternal Fetal Medicine, Madison, WI, USA. Electronic address: iruretagoyen@wisc.edu.",
"authors": "Mandel|D C|DC|;Pryde|P G|PG|;Shah|D M|DM|;Iruretagoyena|J I|JI|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "27()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Cardiac myxoma; Cardiopulmonary bypass; Fetal Doppler; Pregnancy",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D002315:Cardiopulmonary Bypass; D005260:Female; D005323:Fetal Monitoring; D006801:Humans; D021041:Placental Circulation; D011247:Pregnancy; D018608:Ultrasonography, Doppler",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "75-80",
"pmc": null,
"pmid": "27021885",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Doppler ultrasound in the management of uteroplacental perfusion during cardiopulmonary bypass in pregnancy.",
"title_normalized": "use of doppler ultrasound in the management of uteroplacental perfusion during cardiopulmonary bypass in pregnancy"
} | [
{
"companynumb": "US-BAYER-2016-215914",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Renal lymphatic abnormalities are rare, and the understanding of pathophysiology involving renal lymphatics is limited. Symptoms can include hypertension, hematuria, proteinuria, chyluria, and abdominal and lumbar pain. Imaging techniques specific to the renal lymphatics have not been clarified. We review the intrahospital imaging evaluation/workup and clinical course of a 6-year-old male who presented to our institution with a large perirenal cyst. His presentation presented a diagnostic and management challenge. The cyst was determined to be lymphatic in origin and required multiple interventional radiology and surgical procedures for management.",
"affiliations": "Section of Interventional Radiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Hematology/Oncology, and Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Section of Interventional Radiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.;Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.",
"authors": "Desai|Sudhen B|SB|;Sun|Raphael C|RC|;Johnson|Brittany L|BL|;Rialon|Kristy L|KL|;Iacobas|Ionela|I|;Kukreja|Kamlesh U|KU|;Schady|Deborah A|DA|;Phung|Thuy|T|;Sanvitha|Sridhar|S|;Naik-Mathuria|Bindi J|BJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/lrb.2020.0004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-6851",
"issue": "18(6)",
"journal": "Lymphatic research and biology",
"keywords": "Rapamycin; lymphangiectasia; lymphangiography; pediatric; renal cyst",
"medline_ta": "Lymphat Res Biol",
"mesh_terms": "D002648:Child; D003560:Cysts; D006801:Humans; D007668:Kidney; D008202:Lymphangioma; D008208:Lymphatic System; D042601:Lymphatic Vessels; D008297:Male",
"nlm_unique_id": "101163587",
"other_id": null,
"pages": "572-578",
"pmc": null,
"pmid": "32589505",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal Lymphangiectasia in a Pediatric Patient.",
"title_normalized": "renal lymphangiectasia in a pediatric patient"
} | [
{
"companynumb": "US-MYLANLABS-2021M1003543",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "Laminaria are cervical dilators inserted for several days preceding second-trimester abortions and other uterine procedures. Our patient was intubated after a life-threatening anaphylactic reaction to laminaria prior to her surgical abortion. Abortions with laminaria dilators are frequently performed outpatient across the United States. Due to stigma, increasing restrictions, and forced closure of family planning clinics, these procedures are often obtained covertly and remotely. Patients may present obtunded, in shock, without records or proxy, and with no external evidence of the allergen's location or continued presence. Emergency and critical care physicians may consider this etiology in obtunded women with anaphylaxis who are responding poorly to standard care.",
"affiliations": "University of Rochester, Department of Obstetrics and Gynecology, Rochester, NY, USA.;University of Rochester, Department of Emergency Medicine, Rochester, NY, USA. Electronic address: research@kylebarbour.org.;University of Rochester, Department of Obstetrics and Gynecology, Rochester, NY, USA.;University of Rochester, Department of Obstetrics and Gynecology, Rochester, NY, USA.",
"authors": "McQuade|Miriam|M|;Barbour|Kyle|K|;Betstadt|Sarah|S|;Harrington|Amy|A|",
"chemical_list": "D000021:Abortifacient Agents, Steroidal; D015735:Mifepristone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.158409",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "38(1)",
"journal": "The American journal of emergency medicine",
"keywords": "Abortion; Anaphylaxis; Complications; Dilators; Intubation; Laminaria",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000021:Abortifacient Agents, Steroidal; D000028:Abortion, Induced; D000328:Adult; D000707:Anaphylaxis; D002584:Cervix Uteri; D003422:Critical Care; D004106:Dilatation; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007442:Intubation, Intratracheal; D007795:Laminaria; D015735:Mifepristone; D011247:Pregnancy; D011262:Pregnancy Trimester, Second",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "163.e1-163.e2",
"pmc": null,
"pmid": "31477354",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intubation and intensive care after laminaria anaphylaxis in second-trimester abortion.",
"title_normalized": "intubation and intensive care after laminaria anaphylaxis in second trimester abortion"
} | [
{
"companynumb": "US-PFIZER INC-2019562421",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAmiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5-15% and is correlated to dosage, age of the patient, and preexisting lung disease.\n\n\nMETHODS\nA 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved.\n\n\nCONCLUSIONS\nAPT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a 'ground-glass' appearance appreciated on HRCT are more definitive than chest x-ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of amiodarone in areas of previous inflammation. Those undergoing major cardiothoracic surgery are known to be predisposed to APT. Some elements require consideration: a baseline pulmonary function test (PFT) did not exist prior. APT would manifest a restrictive pattern of PFTs. In APT diffusing capacity (DLCO) is generally >20 percent from baseline. A DLCO was not done in this patient. Therefore, not every type of interstitial lung disease could be ruled out. Key features support a clinical diagnosis: (1) new dyspnea, (2) exclusion of lung infection, (3) exclusion of heart failure, (4) new radiographic features, (5) improvement with withdrawal of amiodarone. Our case illustrates consideration of APT in patients who have extensive use of amiodarone and new onset dyspnea.",
"affiliations": "Department of Internal Medicine, St. Mary's Medical Center, University of California, Los Angeles, Long Beach, CA, USA.;Department of Internal Medicine, St. Mary's Medical Center, University of California, Los Angeles, Long Beach, CA, USA.;Department of Internal Medicine, St. Mary's Medical Center, University of California, Los Angeles, Long Beach, CA, USA.;Charles R. Drew University of Medicine and Science, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.;Department of Internal Medicine, St. Mary's Medical Center, University of California, Los Angeles, Long Beach, CA, USA.",
"authors": "Sweidan|Alexander J|AJ|;Singh|Navneet K|NK|;Dang|Natasha|N|;Lam|Vinh|V|;Datta|Jyoti|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4137/CCRep.S39809",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1179-5476",
"issue": "9()",
"journal": "Clinical medicine insights. Case reports",
"keywords": "amiodarone; amiodarone induced; drug induced; ground glass; honeycombing; idiopathic; interstitial lung disease; postcardiac surgery; pulmonary fibrosis; pulmonary toxicity",
"medline_ta": "Clin Med Insights Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101531893",
"other_id": null,
"pages": "91-94",
"pmc": null,
"pmid": "27773995",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "20623129;21704281;18689579;9869825;15331188;15331187;17878423;17765636;2399310;15331184;12576397;3286141;22529166;19399307;2364524",
"title": "Amiodarone-Induced Pulmonary Toxicity - A Frequently Missed Complication.",
"title_normalized": "amiodarone induced pulmonary toxicity a frequently missed complication"
} | [
{
"companynumb": "US-ZYDUS-012844",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "BACKGROUND\nAmong locally advanced gastric cancer (LAGC) patients, poor response to initial neoadjuvant chemotherapy (NAC) is associated with unfavorable outcomes; however, changing the postoperative therapy regimen in this group of patients is unclear. We compared the poor responders who continued the original protocols with that of patients who switched treatment after NAC plus D2 gastrectomy.\n\n\nMETHODS\nOur study included LAGC patients who achieved tumor regression grade 3 according to the American Joint Committee on Cancer/College of American Pathologists system, after NAC, between December 2006 and December 2017 at our institution. Outcomes were overall survival (OS), progression-free survival (PFS), and adverse events during postoperative treatment. The propensity score matching method was used to match patients.\n\n\nRESULTS\nOverall, 160 patients were enrolled in the final analysis set, including 21 switched cases and 139 non-switched cases. A 1:2 matched cohort (21 switching vs. 42 non-switching) was generated to eliminate all confounding factors. No statistical differences were observed in OS and PFS, either in the whole patients (OS: log-rank p = 0.804; PFS: log-rank p = 0.943) or in the matched cohort (OS: log-rank p = 0.907; PFS: log-rank p = 0.670) between the two groups. Patients with changed regimens had a significantly higher rate of peripheral neurotoxicity (p = 0.045). Contrarily, a lower rate of overall adverse events was observed in the non-switching group with marginal significance (p = 0.069).\n\n\nCONCLUSIONS\nAdjusting to a non-cross-resistant regimen only by post-NAC pathological evaluation may not be sufficient for designing an effective treatment route for LAGC poor responders. Treatment change required a more scrutinized clinical track, which involved a multifaceted assessment.",
"affiliations": "Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China. ziyu_li@hsc.pku.edu.cn.;Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China. jijiafu@hsc.pku.edu.cn.",
"authors": "Liu|Zining|Z|;Wang|Yinkui|Y|;Shan|Fei|F|;Ying|Xiangji|X|;Zhang|Yan|Y|;Li|Shuangxi|S|;Jia|Yongning|Y|;Miao|Rulin|R|;Xue|Kan|K|;Li|Zhemin|Z|;Li|Ziyu|Z|;Ji|Jiafu|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-021-10087-x",
"fulltext": "\n==== Front\nAnn Surg Oncol\nAnn Surg Oncol\nAnnals of Surgical Oncology\n1068-9265\n1534-4681\nSpringer International Publishing Cham\n\n34327603\n10087\n10.1245/s10434-021-10087-x\nGastrointestinal Oncology\nTreatment Switch in Poor Responders with Locally Advanced Gastric Cancer After Neoadjuvant Chemotherapy\nLiu Zining MD\nWang Yinkui MD\nShan Fei MD\nYing Xiangji MPH\nZhang Yan MPH\nLi Shuangxi MD\nJia Yongning MD\nMiao Rulin MD\nXue Kan MD\nLi Zhemin MD\nLi Ziyu MD, PhD ziyu_li@hsc.pku.edu.cn\n\nJi Jiafu MD, PhD jijiafu@hsc.pku.edu.cn\n\ngrid.412474.0 0000 0001 0027 0586 Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China\n29 7 2021\n29 7 2021\n2021\n28 13 88928907\n25 1 2021\n10 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nAmong locally advanced gastric cancer (LAGC) patients, poor response to initial neoadjuvant chemotherapy (NAC) is associated with unfavorable outcomes; however, changing the postoperative therapy regimen in this group of patients is unclear. We compared the poor responders who continued the original protocols with that of patients who switched treatment after NAC plus D2 gastrectomy.\n\nMethods\n\nOur study included LAGC patients who achieved tumor regression grade 3 according to the American Joint Committee on Cancer/College of American Pathologists system, after NAC, between December 2006 and December 2017 at our institution. Outcomes were overall survival (OS), progression-free survival (PFS), and adverse events during postoperative treatment. The propensity score matching method was used to match patients.\n\nResults\n\nOverall, 160 patients were enrolled in the final analysis set, including 21 switched cases and 139 non-switched cases. A 1:2 matched cohort (21 switching vs. 42 non-switching) was generated to eliminate all confounding factors. No statistical differences were observed in OS and PFS, either in the whole patients (OS: log-rank p = 0.804; PFS: log-rank p = 0.943) or in the matched cohort (OS: log-rank p = 0.907; PFS: log-rank p = 0.670) between the two groups. Patients with changed regimens had a significantly higher rate of peripheral neurotoxicity (p = 0.045). Contrarily, a lower rate of overall adverse events was observed in the non-switching group with marginal significance (p = 0.069).\n\nConclusion\n\nAdjusting to a non-cross-resistant regimen only by post-NAC pathological evaluation may not be sufficient for designing an effective treatment route for LAGC poor responders. Treatment change required a more scrutinized clinical track, which involved a multifaceted assessment.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1245/s10434-021-10087-x.\n\nBeijing Municipal Health CommissionDFL20181103 ZYLX201701 issue-copyright-statement© Society of Surgical Oncology 2021\n==== Body\npmcPerioperative chemotherapy (PEC) and neoadjuvant chemotherapy (NAC) have been broadly practiced in patients with locally advanced gastric cancer (LAGC) for over 10 years in Europe, North America, and, most recently, China.1–3 These regions all have one feature in common: over two-thirds of patients are detected at an advanced stage of cancer during their first visit.4 For most LAGC patients, NAC improves tumor resectability and reinforces the effects of therapeutic surgery.5\n\nThe effects of NAC on a tumor can be histopathologically evaluated using pathological tumor regression grading (TRG) systems. Generally, patients with a poor pathological response after NAC are usually graded with a higher post-therapy pathological (yp) TNM stage as a result of lower chemosensitivity leading to significantly lower survival outcomes.6–8 Despite the application of several different standards for TRG assessment, most of these criteria achieved similar predictive values.9\n\nHowever, although the PEC and NAC protocols have been updated over the years, a large proportion of patients respond unsatisfactorily to NAC. The rate of poor responders (Mandard TRG 4–5) in the MAGIC, OE05, and FLOT4 trials was 43%, 80%, and 38%, respectively.10–12 Therefore, current advances in PEC and NAC, including searching for more effective protocols, reducing toxicity, standardizing dosage, and treatment duration would benefit responders but may not significantly impact outcomes for those who are inherently less chemosensitive. On the other hand, current guidelines for NAC do not have clear recommendations for regimen adaptation when a poor post-NAC response is observed. The restricted available drug selections reduce the merit of NAC in LAGC.13–15 Few studies have evaluated if adjuvant therapy should be adapted to the pathological response.16\n\nThe current study investigates the efficacy of a non-cross-resistant drug for LAGC patients who were evaluated pathologically as poor responders after NAC treatment. A propensity score matching (PSM) analysis was utilized to reduce potentially confusing factors and enable the comparison of survival outcomes.\n\nMethods\n\nPatients\n\nData from a prospective database of all patients who started NAC at the Peking University Cancer Hospital and Institute were searched between 1 December 2006 and 1 December 2017. Study inclusion criteria included (1) a proven diagnosis of gastric adenocarcinoma with poor response according to postoperative pathology using the American Joint Committee on Cancer/College of American Pathologists (AJCC/CAP) system;8 (2) no signs of distant metastasis at first visit; (3) patients had undergone adjuvant chemotherapy (AC) after surgery; and (4) curative gastrectomy was performed. The exclusion criteria were (1) patients received fewer than two cycles of NAC or fewer than three cycles of AC; (2) patients received reduced regimens of AC compared with NAC; (3) patients used more than one NAC treatment protocol; (4) patients received radiotherapy, targeted therapy, or immune therapy before relapse; (5) patients received hyperthermia intraperitoneal chemotherapy; (6) patients with R1/R2 resection, or suspected of having metastasis or recurrence before completion of three cycles of postoperative treatment; (7) patients with D0/D1/D1 plus lymphadenectomy; and (8) death within 3 months following curative surgery (see Fig. 1).Fig. 1 Patient enrolment and propensity score matching process. NAC neoadjuvant chemotherapy, AC adjuvant chemotherapy, TRG tumor regression grade, ECF epirubicin, cisplatin, and 5-fluorouracil, BMI body mass index, ECOG Eastern Cooperative Oncology Group, ASA American Society of Anesthesiologists, LVI lymphovascular invasion\n\nRegimen and Radical Surgery\n\nThe determination of clinical stages, design for treatment route, preoperative assessment, and prompt intervention for adverse events (AEs) were managed by the multidisciplinary team (MDT). Clinical stages were defined by abdominal computed tomography (CT) scan and/or endoscopic ultrasound (EUS) and/or pretherapeutic laparoscopic exploration. All patients used paclitaxel plus 5-fluorouracil arms or cisplatin plus 5-fluorouracil arms as preoperative or postoperative treatments. Regimens, including oxaliplatin plus S-1 (SOX), oxaliplatin plus capecitabine (CapeOX), oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX), cisplatin plus S-1 (CS), paclitaxel plus capecitabine (PX), and paclitaxel plus S-1 (PS), are summarized in electronic supplementary Table S1. To assess the duration of treatment, 2-week protocols were recalculated as 3-week protocols to enable direct comparisons between regimens. Dosage reductions or cessation occurred if severe AEs were observed during chemotherapy, as determined by the MDT members. After two to three cycles of chemotherapy, the antitumor effect was evaluated using CT scans. The therapy was prematurely terminated in cases of disease progression, with a curative gastrectomy being immediately performed. Otherwise, gastrectomy or continued NAC was considered after obtaining informed consent and approval from each patient. Subtotal or total gastrectomy plus D2 lymphadenectomy was performed according to the Japanese Gastric Cancer Association (JGCA) guidelines.17\n\nData Collection\n\nPatient characteristics, including age, body mass index (BMI), sex, American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group (ECOG) performance status, tumor location, tumor diameter (on short axis), differentiation grade, vascular involvement, post-therapy pathological (yp) TNM stage according to the 8th AJCC guidelines, type of gastrectomy, severe complications classified as Clavien–Dindo grades III–IV, Borrmann type, duration of NAC, and duration of AC were all recorded.18,19 Chemotherapy-related toxicities observed were systematically and routinely documented according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, including leukopenia, anemia, thrombocytopenia, hepatotoxicity, digestive tract disorders (including nausea, vomiting, and diarrhea), and chemotherapy-induced peripheral neuropathy (CIPN).20\n\nHistopathology Analysis\n\nAll pathological examinations were undertaken by two experienced gastrointestinal pathologists who were blinded to the group assignment. All enrolled patients were classified as poor responders (TRG 3) based on the National Comprehensive Cancer Network (NCCN) guidelines.21\n\nFollow-Up\n\nPatients were followed-up regularly via physical examination, radiological examination, endoscopic examination, and laboratory examination, or telephone call when visits were not possible. These examinations were performed quarterly during the first 2 years, then every 6 months until the fifth year. After 5 years, consultation and follow-ups occurred annually.\n\nPropensity Score Matching (PSM)\n\nExamination of the baseline characteristics revealed significant or marginal differences in data, such as tumor size, AC duration, and tumor location. between the groups. To exclude known clinical risk factors and to calibrate the baseline, a 1:2 ratio of PSM was performed to match patients using the R ‘MatchIt’ package (R version 3.6.2; The R Foundation for Statistical Computing).22 All relevant confounding covariates were incorporated into the matching process, including age, BMI, sex, ASA score, ECOG score, tumor diameter, NAC duration, AC duration, tumor location, types of resection, yp TNM stage, differentiation, histological type, lymphovascular invasion (LVI), Borrmann type, and severe complications. The logit option was used to build a logistic regression model and the optimal matching option was used. To avoid overinflation and reduce variance, matching was not undertaken with replacement. A detailed patient selection method and the distribution of propensity score before and after PSM are shown in Figs. 1 and 2, respectively.Fig. 2 Pre-matching and post-matching information. a Propensity score distribution in the LTG and OTG groups before PSM application and after matching. b Love plot demonstrating the value of the standardized difference for each covariate included in the propensity score before and after matching. The value of the blue circular dots (after matching) did not exceed the absolute value of 0.20 (shown as a dashed line), suggesting a well-balanced distribution for all covariates after matching. PSM propensity score matching, BMI body mass index, ECOG Eastern Cooperative Oncology Group, ASA American Society of Anesthesiologists, NAC neoadjuvant chemotherapy, AC adjuvant chemotherapy\n\nStatistical Analysis\n\nThe independent t-test and the Chi-square test were used to analyze baseline differences either in the pre-match or post-match cohorts. We used a standardized mean difference (SMD) to define the matching efficacy. An SMD of <0.20 was taken as successful propensity matching between the groups.23 The relationships between clinical and pathological factors and long-term progression-free survival (PFS) and overall survival (OS) were assessed using univariate log-rank tests. Univariate and multivariate Cox regression analysis was applied to identify the prognostic factors of OS and PFS. Tumor or treatment characteristics that achieved a p value <0.10 in univariate analysis were included in the multivariate analysis. For all analyses, p < 0.05 was considered statistically significant. Testing for trends can be applied based on various statistical hypotheses when necessary. Statistical analyses were performed using SE STATA (Stata Statistical Software, release 15.1; Stata Corp LLC, College Station, TX, USA).\n\nResults\n\nPatient characteristics and the PSM process\n\nThe patient selection process is displayed in Fig. 1. A total of 160 patients with a TRG 3 diagnosis after more than two cycles of NAC followed by a curative gastrectomy plus D2 lymphadenectomy were identified. There were 21 patients with modified treatments, including 16 patients who changed from platinum/fluoropyrimidine to paclitaxel/fluoropyrimidine, and 5 patients who changed from paclitaxel/fluoropyrimidine to platinum/fluoropyrimidine regimens. A total of 139 patients remained on their original protocols: 132 participants were included in the platinum/fluoropyrimidine arm and 7 participants were included in the paclitaxel/fluoropyrimidine arm. The demographic and histopathological features have been summarized in Table 1, to minimize potential biases and to increase the comparability of groups.Table 1. Demographic and clinicopathologic characteristics in the non-switching and switching groups before and after propensity score matching\n\n\tUnmatched cohort\t\tMatched cohort\t\nNon-switching group\n[n = 139]\tSwitching group\n[n = 21]\tSMD\tp-value\t\tNon-switching group\n[n = 42]\tSwitching group\n[n = 21]\tSMD\tp-Value\t\nPropensity score\t0.11 ± 0.11\t0.25 ± 0.15\t1.070\t<0.001\t\t0.23 ± 0.14\t0.25 ± 0.15\t0.172\t0.517\t\nAge, years\t58.82 ± 10.39\t55.71 ± 8.04\t0.334\t0.192\t\t55.05 ± 9.81\t55.71 ± 8.04\t0.074\t0.789\t\nSex, female\t33 (23.74)\t6 (28.57)\t0.110\t0.835\t\t12 (28.57)\t6 (28.57)\t<0.001\t1.000\t\nBMI, kg/m2\t23.27 ± 3.15\t24.26 ± 3.22\t0.313\t0.180\t\t23.86 ± 3.22\t24.26 ± 3.22\t0.126\t0.640\t\nECOG\t\t\t0.254\t0.700\t\t\t\t0.103\t0.924\t\n 0\t92 (66.19)\t15 (71.43)\t\t\t\t28 (66.67)\t15 (71.43)\t\t\t\n 1\t43 (30.94)\t6 (28.57)\t\t\t\t14 (33.33)\t6 (28.57)\t\t\t\n 2\t4 (2.88)\t0 (0.00)\t\t\t\t0 (0.00)\t0 (0.00)\t\t\t\nASA classification\t\t\t0.221\t0.679\t\t\t\t0.078\t0.960\t\n 1\t23 (16.55)\t2 (9.57)\t\t\t\t3 (7.14)\t2 (9.52)\t\t\t\n 2\t101 (72.66)\t17 (80.95)\t\t\t\t36 (85.71)\t17 (80.95)\t\t\t\n 3\t15 (10.79)\t2 (9.52)\t\t\t\t3 (7.14)\t2 (9.52)\t\t\t\nDiameter, cm\t3.29 ± 2.36\t4.50 ± 3.73\t0.388\t0.047\t\t4.09 ± 3.12\t4.50 ± 3.73\t0.119\t0.640\t\nNAC duration\t\t\t0.045\t1.000\t\t\t\t0.049\t1.000\t\n 2 cycles\t83 (59.71)\t13 (61.90)\t\t\t\t15 (35.71)\t8 (38.10)\t\t\t\n >2 cycles\t56 (40.29)\t8 (38.10)\t\t\t\t27 (64.29)\t13 (61.90)\t\t\t\nAC duration\t\t\t0.518\t0.061\t\t\t\t<0.001\t1.000\t\n 3–4 cycles\t74 (53.24)\t6 (28.57)\t\t\t\t12 (28.57)\t6 (28.57)\t\t\t\n 5–6 cycles\t65 (46.76)\t15 (71.43)\t\t\t\t30 (71.43)\t15 (71.43)\t\t\t\nTumor location\t\t\t0.520\t0.107\t\t\t\t0.085\t0.951\t\n Proximal\t57 (41.01)\t4 (19.50)\t\t\t\t9 (21.43)\t4 (19.05)\t\t\t\n Distal\t73 (52.52)\t14 (66.67)\t\t\t\t28 (66.67)\t14 (66.67)\t\t\t\n Whole\t9 (6.47)\t3 (14.29)\t\t\t\t5 (11.90)\t3 (14.29)\t\t\t\nResection\t\t\t0.015\t1.000\t\t\t\t0.049\t1.000\t\n Subtotal\t85 (61.15)\t13 (61.90)\t\t\t\t25 (59.52)\t13 (61.90)\t\t\t\n Total\t54 (38.85)\t8 (38.10)\t\t\t\t16 (40.48)\t8 (38.10)\t\t\t\nypT stage\t\t\t0.317\t0.737\t\t\t\t0.112\t0.915\t\n 1\t5 (3.60)\t0 (0.00)\t\t\t\t0 (0.00)\t0 (0.00)\t\t\t\n 2\t17 (12.23)\t2 (9.52)\t\t\t\t3 (7.14)\t2 (9.52)\t\t\t\n 3\t30 (21.58)\t6 (28.57)\t\t\t\t11 (26.19)\t6 (28.57)\t\t\t\n 4\t87 (62.59)\t13 (61.90)\t\t\t\t28 (66.67)\t13 (61.90)\t\t\t\nypN stage\t\t\t0.585\t0.182\t\t\t\t0.460\t0.441\t\n 0\t43 (30.94)\t2 (9.52)\t\t\t\t9 (21.43)\t2 (9.52)\t\t\t\n 1\t21 (15.11)\t5 (23.81)\t\t\t\t5 (11.90)\t5 (23.81)\t\t\t\n 2\t34 (24.46)\t5 (23.81)\t\t\t\t12 (28.57)\t5 (23.81)\t\t\t\n 3\t41 (29.50)\t9 (42.86)\t\t\t\t16 (38.10)\t9 (42.86)\t\t\t\nyp stage\t\t\t0.496\t0.244\t\t\t\t0.055\t1.000\t\n 1\t13 (9.35)\t0 (0.00)\t\t\t\t0 (0.00)\t0 (0.00)\t\t\t\n 2\t41 (29.50)\t5 (23.81)\t\t\t\t11 (26.19)\t5 (23.81)\t\t\t\n 3\t85 (61.15)\t16 (76.19)\t\t\t\t31 (73.81)\t16 (76.19)\t\t\t\nDifferentiation\t\t\t0.238\t0.469\t\t\t\t0.116\t0.912\t\n Well–moderate\t48 (34.53)\t5 (23.81)\t\t\t\t8 (19.05)\t5 (23.81)\t\t\t\n Poor\t91 (65.47)\t16 (76.19)\t\t\t\t34 (80.95)\t16 (76.19)\t\t\t\nHistology\t\t\t0.182\t0.611\t\t\t\t<0.001\t1.000\t\n Adenocarcinoma\t116 (83.45)\t16 (76.19)\t\t\t\t32 (76.19)\t16 (76.19)\t\t\t\n Mucinous or signet-ring\t23 (16.55)\t5 (23.81)\t\t\t\t10 (23.81)\t5 (23.81)\t\t\t\n LVI\t60 (43.17)\t12 (57.14)\t0.282\t0.335\t\t22 (52.38)\t12 (57.14)\t0.096\t0.929\t\nBorrmann type\t\t\t0.345\t0.250\t\t\t\t0.225\t0.693\t\n 2\t13 (9.35)\t3 (14.29)\t\t\t\t4 (9.52)\t3 (14.29)\t\t\t\n 3\t118 (84.89)\t15 (71.43)\t\t\t\t34 (80.95)\t15 (71.43)\t\t\t\n 4\t8 (5.76)\t3 (14.29)\t\t\t\t4 (9.52)\t3 (14.29)\t\t\t\nSevere complications\t20 (14.39)\t3 (14.29)\t0.003\t1.000\t\t6 (14.29)\t3 (14.29)\t<0.001\t1.000\t\nData in parentheses are expressed as percentages\n\nBMI body mass index, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, NAC neoadjuvant chemotherapy, SMD standardized mean difference, LVI lymphovascular invasion, AC adjuvant chemotherapy\n\nResults from the 1:2 PSM process, as described in the Methods section, are shown in Fig. 1. The propensity score suggests there were no biases in the matched groups (0.229 ± 0.138 vs. 0.254 ± 0.148, SMD 0.172, p = 0.517). Following PSM, a cohort of 21 patients who switched treatment and 42 matched non-switching patients were defined (see Table 1). After the PSM protocol, we ensured that most confounders were within 0.20 SMD, except for Borrmann type (SMD 0.225, p = 0.693) and ypN stage (SMD 0.460, p = 0.441). ypN stage was not as balanced as other covariates because the yp TNM stage was regarded as the only surrogate factor for tumor staging (SMD 0.055, p = 1.000).\n\nTreatment switching effects on long-term outcomes\n\nThe median overall follow-up time was 73.3 months (45.0–99.0), with no difference between the switching and non-switching groups, either in the pre-matched cohort (switching vs. non-switching: 72 vs. 74, p = 0.824) or in the post-matched cohort (switching vs. non-switching: 72 vs. 73, p = 0.787). Comparing the survival curves for whole patients, the 5-year OS was 48.15% in the switching group and 53.08% in the non-switching group (see Fig. 3a), while the 5-year PFS was 35.92% in the switching group and 44.75% in the non-switching group (Fig. 3b). There was no significant difference in either OS (log-rank p = 0.804) or PFS (log-rank p = 0.943). Similarly, within the post-matched cohort, switching treatment was associated with no significantly different outcomes compared with the non-switching group (OS: log-rank p = 0.907; PFS: log-rank p = 0.670), as shown in Fig. 3c and d.Fig. 3 Kaplan–Meier survival plot of overall and progression-free survival before and after propensity score matching. a, b Survival curve of overall and progression-free survival in whole patients. c, d Survival curve of overall and progression-free survival after matching. Numbers at the bottom of the graphs indicate patients at risk. The p-value represents the log-rank test.\n\nAn exploratory subgroup analysis was conducted to analyze the survival benefit in the cohort before and after PSM, respectively (electronic supplementary Fig. S1; Fig. 4). The OS and PFS outcomes were comparable between the switching and non-switching groups in most subgroups. A significant survival benefit could only be found in the ypT<4 subgroup among the whole patients (electronic supplementary Fig. S1b), in which the 5-year PFS was 18.75% in the switching group, compared with 68.86% in the non-switching group (hazard ratio [HR] 3.28, 95% confidence interval [CI] 1.25–8.56; p = 0.016). In the corresponding PSM cohort, the 5-year PFS was 63.49% in the non-switching group, with no statistical significance between groups (HR 1.91, 95% CI 0.58–6.28; p = 0.287). Kaplan–Meier plots of OS and PFS for ypT<4 patients before and after PSM are presented in electronic supplementary Fig. S2.Fig. 4 Subgroup analysis of a OS in the matched cohort, and b PFS in the matched cohort. OS overall survival, PSM propensity score matching, PFS progression-free survival, BMI body mass index, ECOG Eastern Cooperative Oncology Group, ASA American Society of Anesthesiologists, NACT neoadjuvant chemotherapy, AC adjuvant chemotherapy\n\nRisk Factors for Patient Survival\n\nThe prognostic value of all the recorded clinicopathological factors was evaluated using univariate and multivariate Cox regression analysis. Among 160 patients, the univariate analysis indicated that the variables of tumor diameter >5 cm, non-distal location, total gastrectomy, advanced ypTNM stage, poorer histological subtype, LVI, and Borrmann type IV were correlated with an unfavorable prognosis, both for OS and PFS, while those with higher ECOG score were correlated only for PFS (see Table 2). When candidate prognostic factors were subjected to multivariate models, only ypTNM stage was identified as an independent prognostic factor in both OS (III vs. I/II: HR 3.04, 95% CI 1.56–5.94; p = 0.001) and PFS (III vs. I/II: HR 2.85, 95% CI 1.52–5.33; p = 0.001). On the other hand, Bormann type IV independently predicted poorer OS (HR 3.51, 95% CI 1.73–7.11; p = 0.043) but not PFS (HR 1.64, 95% CI 0.72–3.73; p = 0.238) [see Table 2].Table 2. Univariate and multivariate analyses of prognostic factors\n\n\tOS\tPFS\t\nUnivariate HR (95% CI)\tp-value\tMultivariate HR (95% CI)\tp-value\tUnivariate HR\n(95% CI)\tp-value\tMultivariate HR\n(95% CI)\tp-value\t\nAge >60 years\t1.43 (0.91–2.23)\t0.121\t\t\t1.33 (0.88–2.01)\t0.182\t\t\t\nSex, female\t1.16 (0.69–1.95)\t0.570\t\t\t0.84 (0.51–1.39)\t0.497\t\t\t\nBMI >25 kg/m2\t0.70 (0.43–1.16)\t0.166\t\t\t0.70 (0.44–1.11)\t0.131\t\t\t\nECOG >0\t1.36 (0.86–2.15)\t0.189\t\t\t1.45 (0.95–2.21)\t0.086\t1.32 (0.83–2.10)\t0.237\t\nASA classification\t\n 1\t1.00\t\t\t\t\t\t\t\t\n 2\t0.89 (0.49–1.64)\t0.717\t\t\t1.09 (0.60–1.99)\t0.760\t\t\t\n 3\t0.87 (0.37–2.03)\t0.744\t\t\t0.98 (0.43–2.24)\t0.961\t\t\t\nDiameter, cm\t2.74 (1.59–4.72)\t<0.001\t1.24 (0.65–2.37)\t0.507\t3.45 (2.07–5.78)\t<0.001\t1.70 (0.93–3.11)\t0.082\t\nNAC duration, >2 cycles\t1.26 (0.79–2.01)\t0.334\t\t\t1.13 (0.74–1.73)\t0.568\t\t\t\nAC duration, >4 cycles\t0.85 (0.54–1.32)\t0.463\t\t\t0.92 (0.61v1.39)\t0.684\t\t\t\nTumor location, distal vs. others\t1.87 (1.19–2.95)\t0.006\t1.37 (0.74–2.56)\t0.316\t\t\t1.53 (0.88–2.67)\t0.131\t\nTotal gastrectomy\t1.88 (1.20–2.95)\t0.006\t1.19 (0.62–2.29)\t0.603\t2.09 (1.38–3.16)\t0.001\t1.11 (0.62–1.98)\t0.731\t\nypT4 stage\t2.16 (1.27–3.66)\t0.004\t\t\t2.22 (1.37–3.59)\t0.001\t\t\t\nypN+ stage\t3.01 (1.62–5.58)\t<0.001\t\t\t3.53 (1.95–6.37)\t<0.001\t\t\t\nypTNM stage III\t3.77 (2.11–6.75)\t<0.001\t3.04 (1.56–5.94)\t0.001\t4.26 (2.47–7.34)\t<0.001\t2.85 (1.52–5.33)\t0.001\t\nPoor differentiation\t0.98 (0.61–1.57)\t0.933\t\t\t0.363 (0.79–1.92)\t0.363\t\t\t\nMucinous or signet-ring cells\t1.74 (1.02–2.95)\t0.041\t1.32 (0.75–2.33)\t0.337\t1.59 (0.97–2.62)\t0.068\t1.30 (0.76–2.22)\t0.338\t\nLVI\t2.13 (1.35–3.35)\t0.001\t1.09 (0.64–1.88)\t0.742\t2.60 (1.70–3.99)\t<0.001\t1.45 (0.88–2.40)\t0.148\t\nBorrmann type IV\t3.51 (1.73–7.11)\t<0.001\t2.40 (1.03–5.60)\t0.043\t2.96 (1.47–5.97)\t0.002\t1.64 (0.72–3.73)\t0.238\t\nSevere complications\t1.54 (0.87–2.70)\t0.135\t\t\t1.43 (0.84–2.43)\t0.182\t\t\t\nSwitching treatment\t0.92 (0.47–1.79)\t0.805\t\t\t0.98 (0.53–1.80)\t0.944\t\t\t\nBMI body mass index, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, PFS progression-free survival, OS overall survival, NAC neoadjuvant chemotherapy, CI confidence interval, AC adjuvant chemotherapy, LVI lymphovascular invasion\n\nAdverse Events\n\nThe major AEs recorded during chemotherapy for the matched cohort are listed in Table 3. No deaths related to chemotherapy were observed. The overall rate of AEs was 95.24% in the non-switching group, marginally higher than the 80.95% rate in the switching group (p = 0.069). Nevertheless, the grade 3/4 AE rates were comparable in the two groups (non-switching vs. switching: 30.95% vs. 28.57%, p = 0.846). Although incidences between the two matched groups were comparable, in each AE subclass there were three tiers, including leukopenia, anemia, thrombocytopenia, hepatotoxicity, digestive tract disorders, and neurotoxicity. The global rate of neurotoxicity was found to be significantly higher in treatment-switched patients (non-switchers vs. switchers: 19.05% vs. 42.86%, p = 0.045). On the other hand, there was no significant difference in the frequency of any types of AEs that occurred in the whole patients, whether stratified by CTCAE or not (Table 4).Table 3. Adverse events of adjuvant chemotherapy in patients in the switching or non-switching treatment groups after propensity score matching, based on CTCAE v4.0\n\nAdverse events\tNon-switching group [n = 42] (%)\tSwitching group [n = 21] (%)\tp-value\n(grade 0 vs. >0)\tp-valuea\t\nLeukopenia\t\t\t0.160\t0.279\t\n Grade 0\t9 (21.43)\t8 (38.10)\t\t\t\n Grade 1/2\t21 (50.00)\t8 (38.10)\t\t\t\n Grade 3/4\t12 (28.57)\t5 (23.81)\t\t\t\nAnemia\t\t\t0.711\t0.714\t\n Grade 0\t26 (61.90)\t14 (66.67)\t\t\t\n Grade 1/2\t16 (38.10)\t7 (33.33)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nThrombocytopenia\t\t\t1.000\t1.000\t\n Grade 0\t36 (85.71)\t18 (85.71)\t\t\t\n Grade 1/2\t6 (14.29)\t3 (14.29)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nHepatotoxicity\t\t\t0.466\t0.470\t\n Grade 0\t24 (57.14)\t14 (66.67)\t\t\t\n Grade 1/2\t18 (42.86)\t7 (33.33)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nDigestive tract disorders\t\t\t0.475\t0.478\t\n Grade 0\t18 (42.86)\t11 (52.38)\t\t\t\n Grade 1/2\t24 (57.14)\t10 (47.62)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nNeurotoxicity\t\t\t0.045\t0.063\t\n Grade 0\t34 (80.95)\t12 (57.14)\t\t\t\n Grade 1/2\t7 (16.67)\t8 (38.10)\t\t\t\n Grade 3/4\t1 (2.38)\t1 (4.76)\t\t\t\nAdverse outcomes, in total\t\t\t0.069\t0.299\t\n Grade 0\t2 (4.76)\t4 (19.05)\t\t\t\n Grade 1/2\t27 (64.29)\t11 (52.38)\t\t\t\n Grade 3/4\t13 (30.95)\t6 (28.57)\t\t\t\nCTCAE Common Terminology Criteria for Adverse Events\n\naChi-square test for linear trend applied across ordered categories\n\nTable 4. Adverse events of adjuvant chemotherapy in patients in the switching or non-switching treatment groups (in whole patients), based on CTCAE v4.0\n\nAdverse events\tNon-switching group [n = 139] (%)\tSwitching group [n = 21] (%)\tp-value\n(grade 0 vs. >0)\tp-valuea\t\nLeukopenia\t\t\t0.310\t0.529\t\n Grade 0\t38 (27.34)\t8 (38.10)\t\t\t\n Grade 1/2\t68 (48.92)\t8 (38.10)\t\t\t\n Grade 3/4\t33 (23.74)\t5 (23.81)\t\t\t\nAnemia\t\t\t0.773\t0.773\t\n Grade 0\t97 (69.78)\t14 (66.67)\t\t\t\n Grade 1/2\t42 (30.22)\t7 (33.33)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nThrombocytopenia\t\t\t0.521\t0.202\t\n Grade 0\t102 (73.38)\t18 (85.71)\t\t\t\n Grade 1/2\t34 (24.46)\t3 (14.29)\t\t\t\n Grade 3/4\t3 (2.16)\t0 (0.00)\t\t\t\nHepatotoxicity\t\t\t0.429\t0.430\t\n Grade 0\t104 (74.82)\t14 (66.67)\t\t\t\n Grade 1/2\t35 (25.18)\t7 (33.33)\t\t\t\n Grade 3/4\t0 (0.00)\t0 (0.00)\t\t\t\nDigestive tract disorders\t\t\t0.149\t0.120\t\n Grade 0\t50 (35.97)\t11 (52.38)\t\t\t\n Grade 1/2\t85 (61.15)\t10 (47.62)\t\t\t\n Grade 3/4\t4 (2.88)\t0 (0.00)\t\t\t\nNeurotoxicity\t\t\t0.168\t0.101\t\n Grade 0\t100 (71.94)\t12 (57.14)\t\t\t\n Grade 1/2\t38 (27.34)\t8 (38.10)\t\t\t\n Grade 3/4\t1 (0.72)\t1 (4.76)\t\t\t\nAdverse outcomes in total\t\t\t0.138\t0.419\t\n Grade 0\t12 (8.63)\t4 (19.05)\t\t\t\n Grade 1/2\t86 (61.87)\t11 (52.38)\t\t\t\n Grade 3/4\t41 (29.50)\t6 (28.57)\t\t\t\nCTCAE common terminology criteria for adverse events\n\naChi-square test for linear trend applied across ordered categories\n\nDiscussion\n\nFollowing the conclusion of the MAGIC trial, with the accumulation of clinical benefit data,2,11,24,25 PEC gradually became standardized in Western countries and parts of East Asia.13–15 Despite the lack of large-scale phase III clinical research in China, the perioperative treatment modality revealed a prominent interim outcome in the RESOLVE trial (NCT01534546), with the perioperative SOX arm shown to be superior to the postoperative XELOX arm in 3-year disease-free survival (DFS) in LAGC patients undergoing D2 gastrectomy.26 Even though preoperative chemotherapy is responsive and more tolerable in most LAGC patients, and can enhance the resectability,5 approximately one-third of patients still tend to manifest poor or even no response after NAC, as measured using different TRG systems.9,10,27 Furthermore, there are still concerns as to whether the TRG can accurately reflect the NAC efficacies, as the shrinkage of primary tumor bed may occur simultaneously, challenging the identification of the original tumorous borders and volumes.28 These unresolved outcomes make the postoperative treatment of patients with a poor response following NAC difficult to predict—almost a ‘trial and error’ approach.\n\nIntuitively, a poor TRG, or little regression in the pathologic specimen, would suggest ineffective neoadjuvant treatment. It is theoretically posited that NAC enables monitoring chemotherapy responses at an early stage, potentially conferring time and flexibility to switch therapies for poor responders; however, as selections of first-line therapies for LAGC are scarce, this strategy does not provide much of an advantage. Only fluorouracil plus platinum- and/or taxane-based regimens have been proven to be effective in PEC settings according to ESMO and NCCN guidelines.14,15 That is, if a patient has received 5-fluorouracil/leucovorin, oxaliplatin, docetaxel (FLOT) as preoperative treatment, then any non-cross-resistant chemotherapy is currently unwarranted.\n\nWang et al. retrospectively reviewed 12 patients with treatment modifications (from oxaliplatin to taxane-based protocols), compared with 24 deliberately matched control cases who retained the original treatment protocols. All patients received an oxaliplatin plus 5-fluorouracil-based regimen as preoperative treatment but were reported to show minimal responses for NAC, with a graded histologic regression (GHR) <50%. The OS outcomes were not significantly improved in the modified group. Although the study tested the hypothesis that poor responders with stage III LGAC (AJCC 7th edition) are a potentially beneficial group for changing treatments, the data did not confirm this outcome. No further studies with larger sample sizes have committed to confirm this hypothesis as yet.\n\nHowever, in the current study, the treatment-switched strategy showed no statistically significant survival improvement, either in whole patients or in a stringent PSM cohort. The subgroup analysis, except for the ypT<4 category, did not reveal any merit or disadvantages in treatment switching. The tolerance of treatment switching was globally comparable between the two treating strategies, although the derived marginal significance (p = 0.069) might deserve further investigations as the treatment duration has been well-matched in the PSM cohort. In contrast, the rate of CIPN was significantly higher in the treatment-switched group after PSM. This result could be because 62% of patients in the treatment-switched group received oxaliplatin/docetaxel sequential therapy. Although CIPN patterns do share similarities, it is known that recovery from CIPN is delayed in oxaliplatin compared with paclitaxel, always requiring 2–3 months following cessation of therapy.29 The recovery period overlapped with the timeline between the completion of NAC and the initiation of AC. The coincident timing window could have resulted in treatment-switched patients being treated with two types of neurotoxic agents.30\n\nAs for the ypT<4 subclass, we found a global strength of PFS benefit in non-switching patients before PSM. Although this statistical significance did not persist in PFS after PSM and in the OS analysis, a clear trend of survival inferiority can be found in the switching group, with only 26.79% 5-year OS and 18.75% 5-year PFS (electronic supplementary Fig. S2). In these eight patients, comprising of five patients with ypN3 status (including four patients with ypN3b status and one patient with ypN3a status), all ypN3 (62.50%) patients confronted recurrence and all four N3b (50.00%) patients suffered death due to tumor metastasis. Compared with the non-switching group, with only 17.31% of ypN3 patients in the ypT<4 subcategory, there was a significantly higher proportion of ypN3 patients in the switching group (62.50% vs. 17.31%, p = 0.005). As the size of the subgroup was quite small, the influence of the confounders cannot be neglected. Therefore, the unequal distribution of ypN status should be the most likely reason for these survival differences in the ypT<4 subgroup because the lymph node metastasis is most prognostic for gastric cancer, as advocated by the current dataset (Table 2). Nonetheless, all our results obtained thus far showed that a second non-cross-resistant regimen such as AC did not result in either a better survival outcome or increased tolerance in NAC poor responders.\n\nSimilarly, in breast cancer (BC), von Minckwitz et al. investigated clinical outcomes when switching to non-cross-resistant chemotherapy in patients who did not respond to the initial induced chemotherapy. The interim evaluation was performed by sonography after two cycles of TAC (docetaxel, doxorubicin, and cyclophosphamide). Patients with no change in tumor size after the initial treatment were randomized to (1) use an additional four cycles of TAC, or (2) switch to a non-cross-resistant NX regimen (vinorelbine and capecitabine). The final pathological response showed no significant difference between these two treatment protocols, but fewer toxic effects were observed in the treatment switch group, unlike ultrasonography for BC, which proved to have satisfactory diagnostic accuracy in superficial soft tissue tumors. Current diagnostic efficacies in post-treatment assessment for LAGC, either CT or EUS, show that baseline gastrointestinal tract tumors are often unmeasurable according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, resulting in insufficiently quantified comparisons in many studies.31–33 Consequently, there is currently a lack of consensus on reliable post-treatment evaluations for LAGC in the absence of pathology data.34 Moreover, unlike BC, which has a relatively better grade of differentiation and slower metastasis tendencies, gastrointestinal tumors are more invasive and are not always chemosensitive. As a result, timely surgery for resectable LAGC is an important factor in managing patients’ survival outcomes.35 Therefore, treatment using NAC is undertaken with greater caution in LAGC patients as D2 surgery presents better outcome opportunities and consideration of alternative chemotherapy protocols occurs post-surgery. More recently, in the field of treating BC, results from the CREATE-X trial showed that the addition of capecitabine has a statistically significant survival advantage in human epidermal growth factor receptor 2 (HER2)-negative residual invasive BC patients with no pathologic complete response after NAC. In the subgroup analysis within that study, patients who did not use 5-fluorouracil as an NAC regimen had a statistical benefit in DFS with the inclusion of capecitabine, based on original postoperative protocols (capecitabine group vs. control: HR 0.63, 95% CI 0.63–0.99).36 The successful design of the CREATE-X trial was due to the discriminatory molecular-based subtyping method, where patients with potential benefit were enriched due to the wide range and number of regimen selections for treating BC.\n\nAlthough the treatment of LAGC has evolved into the era of precision medicine, chemotherapy is still the principal strategy in preoperative clinical settings, simply because there is currently no evidence to support the use of biologically targeted drugs and anti-angiogenic compounds that can statistically improve patients’ survival prognosis.37,38 The effectiveness of molecular classifications for GC still needs to be validated in large, population-based, prospective datasets.39 Nonetheless, according to The Cancer Genome Atlas (TCGA) molecular subclassification, patients with mismatch repair (MMR) deficiency or microsatellite high instability (MSI-H) status show a better prognosis but lower chemosensitivity compared with MSI-low (MSS) patients.40 This tentative conclusion has been confirmed by post hoc analysis of data from the MAGIC and CLASSIC trials.41,42 The consensus of current experience on MSI (and other TCGA subtypes) provides significant, important guidelines for treating post-NAC poor responders. Not only does it help to avoid unnecessary chemotherapy but it also offers a cost-effective clinical strategy for those patients unable to afford the high price of genetic testing, especially for the first round of chemotherapy.43 Importantly, the current study indicates that a treatment-switched strategy based only on a histopathological assessment is not a valid protocol for non-responders.\n\nAs NAC and PEC for LAGC have become widespread across the Western world and are gradually being popularized in East Asia, patients who do not respond to chemotherapy remain a challenge in LAGC treatment. These patients may potentially have their treatments augmented by linking with specific histological or molecular subclassifications. To investigate whether poorly responsive patients can benefit from changing treatments or including additional agents (supplemental to the original plan), a prospective study that ‘enriches’ the intent-to-treat population is necessary so that we can learn from the success of the CREATE-X trial.44\n\nSome limitations of this study need to be considered. First, our study was limited by the retrospective nature of the analysis, and all confounding factors could not be varied or controlled. The application of stringent selection criteria, together with a PSM method to minimize the systemic and statistical bias, were two compensatory factors employed to overcome this inherent limitation. Second, our treatment-switched group was restricted to interchanging between paclitaxel and oxaliplatin in dual-drug protocols. Additional chemotherapy agents were consequently not included; for example, from doublet XELOX to triplet FLOT, and similar sequential management protocols. The number of patients with additional chemotherapy in our initial dataset is quite small, all of whom either did not complete sufficient cycles of treatment or due to other excluded reasons. Third, the threshold for switching treatments was based on evaluations using the AJCC/CAP TRG system. As miscellaneous TRG systems for gastric cancer are available globally, derived with different principles, different layers, and different cut-off values, whether the recommended AJCC/CAP system by the Chinese Society of Clinical Oncology is valid to ascertain those patients who need a treatment switch needs further investigation.13\n\nConclusion\n\nThe results from the current study demonstrate that within the guidelines for recommended chemotherapeutic drugs in a perioperative setting for LAGC, treatment switch strategies based on a post-NAC pathological evaluation offer no benefits, either in short-term tolerance or long-term survival, in comparison with patients who did not switch. However, these conclusions warrant further investigations, using a larger sample database, together with a finer selection of patients using non-cross-resistant regimens as post-NAC treatment in any future prospective studies.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.SUPPLEMENTARY FIG. S1 Subgroup analysis of (a) overall survival in the entire cohort, and (b) progression-free survival in the entire cohort. SUPPLEMENTARY FIG. S2 Kaplan–Meier survival plot of overall survival (OS) and progression-free survival (PFS) before and after PSM in the ypT<4 subclass. Survival curve of OS and PFS (a, b) in whole patients, and (c, d) after matching. Numbers at the bottom indicate patients at risk. The p-value represents the log-rank test. (ZIP 1769 kb)\n\nAcknowledgment\n\nNone.\n\nFunding\n\nThis work was funded by Beijing Municipal Health Commission (DFL20181103, ZYLX201701)\n\nWith\n\nDISCLOSURE\n\nZining Liu, Yinkui Wang, Fei Shan, Xiangji Ying, Yan Zhang, Shuangxi Li, Yongning Jia, Rulin Miao, Kan Xue, Zhemin Li, Ziyu Li, and Jiafu Ji declare there are no potential commercial conflicts of interests.\n\nData Sharing Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors upon reasonable request. Requests to access the datasets should be directed to Ziyu Li (ziyu_li@hsc.pku.edu.cn).\n\nHuman Rights Statement\n\nThis study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).\n\nInformed Consent\n\nThis study was approved by the Ethics Committee of Beijing Cancer Hospital (NO. 2019YJZ26) and informed consent was received from all patients.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nZining Liu and Yinkui Wang contributed equally to this work.\n==== Refs\nReferences\n\n1. Cunningham D Allum WH Stenning SP Thompson JN Van de Velde CJH Nicolson M Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med. 2006 355 1 11 20 10.1056/NEJMoa055531 16822992\n2. 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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D006801:Humans; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D013274:Stomach Neoplasms",
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"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "28664909;24109590;23323004;33392098;25079317;21444866;32663120;31807528;27776843;30885279;20925139;31553110;29727332;27664260;27342689;28241187;24595801;21490451;25157992;27697982;1598671;28292272;27298411;31230156;16822992;28094848;28784312;31427088;28758147;32007193;28564564",
"title": "Treatment Switch in Poor Responders with Locally Advanced Gastric Cancer After Neoadjuvant Chemotherapy.",
"title_normalized": "treatment switch in poor responders with locally advanced gastric cancer after neoadjuvant chemotherapy"
} | [
{
"companynumb": "CN-ROCHE-2974666",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nPNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children.\n\n\nMETHODS\nHere, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy.\n\n\nRESULTS\nThe patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years.\n\n\nCONCLUSIONS\nIt is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation.",
"affiliations": "Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Dermatology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Dermatology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Dermatology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatric Oncology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatric Pulmonology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatrics, Catharina Hospital, Eindhoven, The Netherlands.;Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.",
"authors": "Fidder|Sander A R|SAR|;Bolling|Marieke C|MC|;Diercks|Gilles F H|GFH|;Pas|Hendri H|HH|;Hooimeijer|Louise H L|LHL|;Bungener|Laura B|LB|;Willemse|Brigitte W M|BWM|;Scheenstra|Rene|R|;Stapelbroek|Janneke M|JM|;van der Doef|Hubert P J|HPJ|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.14023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(6)",
"journal": "Pediatric transplantation",
"keywords": "PTLD; antibodies; children; intestine transplant; liver; malignancy; organ transplantation; paraneoplastic pemphigus",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e14023",
"pmc": null,
"pmid": "34014017",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation.",
"title_normalized": "paraneoplastic pemphigus associated with post transplant lymphoproliferative disorder after small bowel transplantation"
} | [
{
"companynumb": "NL-ASTELLAS-2018US026032",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures, and generalized anxiety disorder in many countries. Supported by case reports and a few studies there is an ongoing debate on PRG's potential to cause addictive behaviors. Considering that PRG is currently under investigation for the treatment of benzodiazepine dependence and withdrawal as well as relapse prevention in alcohol dependence, assessment of PRG's abuse and dependence potential is indispensable. We report the case of a 38-year-old female patient with borderline personality disorder and past alcohol abuse who developed PRG abuse. The patient took up to 800 mg PRG per day, initially administered to treat unspecific anxiety, and experienced euphoric feelings after PRG intake. In the further course, she increased the daily PRG dosage and consulted other physicians to receive additional PRG prescriptions. During reduction of PRG, the patient developed a moderate withdrawal syndrome with vegetative symptoms. Because of the early detection of the developing PRG abuse (4 months after first application of PRG), the development of PRG dependence was prevented. This case illustrates the possibility of PRG to trigger the development of addictive behaviors and should encourage physicians to be very careful when administering PRG to patients with current or past substance-related disorders.",
"affiliations": "From the Department of Psychiatry and Psychotherapy III, University Hospital of Ulm, Ulm University, Ulm, Germany. maximilian.gahr@uni-ulm.de",
"authors": "Gahr|Maximilian|M|;Franke|Beate|B|;Freudenmann|Roland W|RW|;Kölle|Markus A|MA|;Schönfeldt-Lecuona|Carlos|C|",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0b013e3182872718",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "7(2)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D000437:Alcoholism; D000700:Analgesics; D001008:Anxiety Disorders; D016739:Behavior, Addictive; D001883:Borderline Personality Disorder; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000069583:Pregabalin; D013375:Substance Withdrawal Syndrome; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "147-9",
"pmc": null,
"pmid": "23519046",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Concerns about pregabalin: further experience with its potential of causing addictive behaviors.",
"title_normalized": "concerns about pregabalin further experience with its potential of causing addictive behaviors"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2021-05378",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"druga... |
{
"abstract": "BACKGROUND\nUse of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure.\n\n\nOBJECTIVE\nWhat are the patient characteristics and clinical settings in which DOAC treatment failure manifests?\n\n\nMETHODS\nWe searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019.\n\n\nMETHODS\nInformation on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure.\n\n\nRESULTS\nOur search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%).\n\n\nCONCLUSIONS\nOur analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non-Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis.",
"affiliations": "Department of Internal Medicine, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI.;Department of Cardiology, University of Toledo Medical Center, Toledo, OH; and.;Department of Cardiology, Detroit Medical Center, John D. Dingell VA Medical Center, Wayne State University School of Medicine, Detroit, MI.",
"authors": "Kajy|Marvin|M|;Mathew|Anil|A|;Ramappa|Preeti|P|",
"chemical_list": "D000925:Anticoagulants; D011728:Pyridones; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000001083",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "28(1)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D001281:Atrial Fibrillation; D000069604:Dabigatran; D006801:Humans; D011728:Pyridones; D000069552:Rivaroxaban; D020521:Stroke; D017211:Treatment Failure",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e87-e95",
"pmc": null,
"pmid": "31599766",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment Failures of Direct Oral Anticoagulants.",
"title_normalized": "treatment failures of direct oral anticoagulants"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-00105",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drug... |
{
"abstract": "OBJECTIVE\nHuman papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer.\n\n\nMETHODS\n106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed.\n\n\nRESULTS\n63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval [CI]: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P=.021) and especially HPV-/p16- (55.8%; 95% CI: 33.46-78.14; P=.002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P=.270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV-/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16-: 68.8%; 95%CI: 47.44-90.16; P=.138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio [HR] 0.22; 95% CI: 0.09-0.53; P<.001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33-16.82; P=.016, and HPV+/p16+ vs HPV-/p16-: HR 6.40; 95% CI: 2.23-18.35; P<.001), whereas local relapse dramatically influenced OS.\n\n\nCONCLUSIONS\nOur data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS.",
"affiliations": "Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: sabine.mai@umm.de.;Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.;Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.;Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.;Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.;Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.",
"authors": "Mai|Sabine|S|;Welzel|Grit|G|;Ottstadt|Martine|M|;Lohr|Frank|F|;Severa|Sebastin|S|;Prigge|Elena-Sophie|ES|;Wentzensen|Nicolas|N|;Trunk|Marcus J|MJ|;Wenz|Frederik|F|;von Knebel-Doeberitz|Magnus|M|;Reuschenbach|Miriam|M|",
"chemical_list": "D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D016685:Mitomycin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "93(4)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D009367:Neoplasm Staging; D027383:Papillomaviridae; D030361:Papillomavirus Infections; D011379:Prognosis; D012189:Retrospective Studies; D012737:Sex Factors; D016019:Survival Analysis; D013997:Time Factors",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "819-27",
"pmc": null,
"pmid": "26530750",
"pubdate": "2015-11-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prognostic Relevance of HPV Infection and p16 Overexpression in Squamous Cell Anal Cancer.",
"title_normalized": "prognostic relevance of hpv infection and p16 overexpression in squamous cell anal cancer"
} | [
{
"companynumb": "DE-FRESENIUS KABI-FK201600605",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by impaired clearance of low-density lipoprotein cholesterol. Given limitations in pharmacologic therapy and the significant morbidity and mortality associated with this disease, liver transplantation may be offered to select homozygous FH patients in childhood in an effort to slow progression of atherosclerotic cardiovascular disease. In rare cases, domino liver transplantation can be performed, transplanting the livers of patients with various metabolic disorders into elderly recipients whose projected survival precludes prolonged waiting on the transplant list. Herein, we report a case of domino liver transplantation using the liver of a 14-year-old boy with homozygous FH into a 65-year-old man with primary sclerosing cholangitis and cirrhosis who developed rapidly progressive atherosclerotic cardiovascular disease involving the arteries of his proximal bilateral lower extremities, carotid arteries and superior mesenteric artery.",
"affiliations": "Division of Cardiovascular Medicine, Department of Internal Medicine, 1500 E. Medical Center Dr, Ann Arbor, MI, USA. Electronic address: jgolbus@med.umich.edu.;Division of Cardiovascular Medicine, Department of Internal Medicine, 1500 E. Medical Center Dr, Ann Arbor, MI, USA.;Division of Gastroenterology, Department of Internal Medicine, 1500 E. Medical Center Dr, Ann Arbor, MI, USA.;Division of Cardiovascular Medicine, Department of Internal Medicine, 1500 E. Medical Center Dr, Ann Arbor, MI, USA.",
"authors": "Golbus|Jessica R|JR|;Farhat|Linda|L|;Fontana|Robert J|RJ|;Rubenfire|Melvyn|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2017.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "11(5)",
"journal": "Journal of clinical lipidology",
"keywords": "Atherosclerotic cardiovascular disease; Familial hypercholesterolemia; Homozygous familial hypercholesterolemia",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000293:Adolescent; D000368:Aged; D050197:Atherosclerosis; D015209:Cholangitis, Sclerosing; D018450:Disease Progression; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "1284-1288",
"pmc": null,
"pmid": "28807459",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia.",
"title_normalized": "rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-029697",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCurrent guidelines recommend unfractionated heparin (UFH) or low-molecular-weight heparin plus an oral anticoagulant for the prevention of thromboembolism in patients undergoing electric cardioversion of atrial fibrillation (AF). Selective factor Xa inhibitors, such as fondaparinux, which has a favourable benefit-risk profile in the prevention and treatment of venous thromboembolism and the management of acute coronary syndromes, have not been systematically evaluated in this setting.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of fondaparinux versus standard treatment in patients undergoing echocardiographically-guided cardioversion of AF.\n\n\nMETHODS\nIn this multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study, patients with AF undergoing electric cardioversion following transoesophageal echocardiography (TEE) were randomized to fondaparinux or standard therapy (UFH plus vitamin K antagonist [VKA]). Patients showing an atrial thrombus in the first TEE (clot-positive) were randomized to treatment with fondaparinux or standard care for 4 weeks before cardioversion.\n\n\nRESULTS\nThe primary endpoint (combined rate of cerebral neurological events, systemic thromboembolism, all-cause death and major bleeding events) occurred in 3 of 174 (1.7%) patients on fondaparinux and 2 of 170 (1.2%) patients on UFH+VKA. The rate of thrombus disappearance among clot-positive patients was higher in the fondaparinux arm (11 of 14; 78.6%) than in the UFH+VKA arm (7 of 14; 50.0%). Incidences of adverse events were similar (45.4% with fondaparinux and 46.5% with UFH+VKA).\n\n\nCONCLUSIONS\nIn this pilot study in patients with TEE-guided cardioversion, the use of fondaparinux appeared to be well tolerated, with similar efficacy to UFH+VKA. Furthermore, a trend to greater thrombus resolution was observed.",
"affiliations": "Saint-Antoine university and medical school, université Pierre et Marie Curie, CHU Saint-Antoine, department of cardiology, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France. Electronic address: ariel.cohen@sat.aphp.fr.;Hospital Bielefeld centre, department of cardiology and internal intensive care, Bielefeld, Germany.;René-Descartes university, Georges-Pompidou European hospital, arrhythmia department, Paris, France.;Heart centre, Freiburg university, cardiology and angiology I, Freiburg, Germany.;Institute of heart and vessels Louis-Mathieu, department of cardiology, Vandœuvre-les-Nancy, France.;Winicker Norimed GmbH, Nuremberg, Germany.;GlaxoSmithKline, Germany.;St-Marien hospital Bonn Venusberg, department of internal medicine, Bonn, Germany. Electronic address: heyder.omran@marien-hospital-bonn.de.",
"authors": "Cohen|Ariel|A|;Stellbrink|Christoph|C|;Le Heuzey|Jean-Yves|JY|;Faber|Thomas|T|;Aliot|Etienne|E|;Banik|Norbert|N|;Kropff|Stefan|S|;Omran|Heyder|H|;|||",
"chemical_list": "D000925:Anticoagulants; D011134:Polysaccharides; D005170:Factor X; D000077425:Fondaparinux",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1875-2128",
"issue": "108(2)",
"journal": "Archives of cardiovascular diseases",
"keywords": "Anticoagulant; Atrial fibrillation; Cardioversion; Cardioversion électrique; Fibrillation atriale; Fondaparinux; Thrombosis; Échocardiographie transœsophagienne",
"medline_ta": "Arch Cardiovasc Dis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017548:Echocardiography, Transesophageal; D004554:Electric Countershock; D005170:Factor X; D005260:Female; D000077425:Fondaparinux; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011134:Polysaccharides; D025321:Surgery, Computer-Assisted; D013923:Thromboembolism",
"nlm_unique_id": "101465655",
"other_id": null,
"pages": "122-31",
"pmc": null,
"pmid": "25684570",
"pubdate": "2015-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "SAfety of Fondaparinux in transoesophageal echocardiography-guided Electric cardioversion of Atrial Fibrillation (SAFE-AF) study: a pilot study.",
"title_normalized": "safety of fondaparinux in transoesophageal echocardiography guided electric cardioversion of atrial fibrillation safe af study a pilot study"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1117844",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FONDAPARINUX"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRapidly progressive interstitial lung disease (RPILD) associated with the anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5ab+) dermatomyositis (DM) is a rare but life-threatening condition despite immunosuppressive treatment. We report the case of a 44-year-old woman who was diagnosed with severe RPILD associated with anti-MDA5ab+ DM 1 week before her admission in the intensive care unit. The patient underwent a successful double-lung transplant after she failed treatment with immunosuppressive therapy, including tofacitinib. At 1-year follow-up, she had experienced no relapse of the disease.\n\n\nMETHODS\nThis case includes a patient recently diagnosed with RPILD for whom no treatment showed efficacy, including glucocorticoids, cyclophosphamide, plasma exchanges, tofacitinib, and tacrolimus. She was placed under mechanical ventilation and venovenous extracorporeal membrane oxygenation 2 weeks after diagnosis in a bridge-to-transplant process. She was successfully transplanted 20 days later after having been registered on the French National Lung Transplant Waiting List with high priority. One year after surgery, her pulmonary function tests were good, and she showed no sign of relapse of anti-MDA5ab+ DM.\n\n\nCONCLUSIONS\nLung transplantation can be a life-saving procedure in RPILD related to anti-MDA5ab+ DM. High-emergency allocation priority on the transplant list reduced the time between diagnosis and surgery. Patients without comorbidities should be promptly referred to specialized centers to rapidly assess the feasibility of transplantation in this context.",
"affiliations": "Réanimation Polyvalente, Hôpital Foch, Suresnes, France.;Réanimation Polyvalente, Hôpital Foch, Suresnes, France. Electronic address: m.neuville@hopital-foch.com.;Sorbonne Université, Médecine Intensive Réanimation, Hôpital Tenon, Paris, France.;Chirurgie Thoracique, Hôpital Foch, Suresnes, France.;Chirurgie Thoracique, Hôpital Foch, Suresnes, France.;Unité de Soins Intensifs Respiratoires, Hôpital Foch, Suresnes, France.;Pneumologie, Hôpital Foch, Suresnes, France.;Département d'Anesthésie, Hôpital Foch, Suresnes, France.;Département de Médecine interne et Immunologie Clinique, Hôpital Pitié-Salpêtrière, Paris, France.;Réanimation Polyvalente, Hôpital Foch, Suresnes, France.;Réanimation Polyvalente, Hôpital Foch, Suresnes, France.",
"authors": "Marchiset|Antoine|A|;Neuville|Mathilde|M|;Voiriot|Guillaume|G|;De Wolf|Julien|J|;Glorion|Matthieu|M|;Parquin|François|F|;Roux|Antoine|A|;Guen|Morgan Le|ML|;Allenbach|Yves|Y|;Zuber|Benjamin|B|;Cerf|Charles|C|;|||",
"chemical_list": "D001323:Autoantibodies; D000072640:Interferon-Induced Helicase, IFIH1",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.08.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2613-2615",
"pmc": null,
"pmid": "34511249",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-Emergency Lung Transplantation for Interstitial Lung Disease Associated With Anti-MDA5 Dermatomyositis: A Case Report.",
"title_normalized": "high emergency lung transplantation for interstitial lung disease associated with anti mda5 dermatomyositis a case report"
} | [
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"companynumb": "FR-AUROBINDO-AUR-APL-2021-052362",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"actiondrug": "6",
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"activesubstancename": "PREDNISONE"
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"abstract": "BACKGROUND\nAlthough the national HIV control programme in Uganda has a well-established system for monitoring disease progression and treatment outcomes, monitoring of adverse drug reactions (ADRs) is inadequate. In order to address under-reporting of ADRs, the National Pharmacovigilance Centre, in collaboration with the HIV control programme, piloted a targeted spontaneous reporting (TSR) system as a complementary method to traditional spontaneous reporting.\n\n\nMETHODS\nFrom April 2012 to March 2014, all cases of suspected renal toxicity in 10,225 patients on tenofovir-based regimens were monitored in the regional pharmacovigilance centres of Masaka and Mbale. The identification of renal toxicity was performed using serum creatinine, urinalysis, and other signs and symptoms of kidney injury.\n\n\nRESULTS\nThere was one suspected renal toxicity reported for every 200 patients on a tenofovir-based regimen. Some of the serious reactions reported were death in two cases and bone demineralisation in five patients. Most of patients had been on treatment for 2 years. Those that had been on tenofovir for more than 4 years had raised serum creatinine levels, emphasising the importance of monitoring for the risk of renal damage for longer. We also found that the reporting rate of suspected ADRs for all medicines in the two sites increased almost fivefold during the implementation period.\n\n\nCONCLUSIONS\nAlthough the occurrence of suspected tenofovir renal toxicity of HIV patients is low, there is need to monitor those at risk so as to prevent irreversible kidney injury. TSR can complement spontaneous reporting for collecting safety data on particular drugs and increase ADR reporting rates.",
"affiliations": "National Pharmacovigilance Centre, National Drug Authority, P.O. Box 23096, Kampala, Uganda, hbyomire@nda.or.ug.",
"authors": "Ndagije|Helen|H|;Nambasa|Victoria|V|;Namagala|Elizabeth|E|;Nassali|Huldah|H|;Kajungu|Dan|D|;Sematiko|Gordon|G|;Olsson|Sten|S|;Pal|Shanthi|S|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-015-0277-9",
"fulltext": "\n==== Front\nDrug Saf\nDrug Saf\nDrug Safety\n0114-5916\n1179-1942\nSpringer International Publishing Cham\n\n25749663\n277\n10.1007/s40264-015-0277-9\nOriginal Research Article\nTargeted Spontaneous Reporting of Suspected Renal Toxicity in Patients Undergoing Highly Active Anti-Retroviral Therapy in Two Public Health Facilities in Uganda\nNdagije Helen hbyomire@nda.or.ug\n\n1\nNambasa Victoria 1\nNamagala Elizabeth 2\nNassali Huldah 1\nKajungu Dan 3\nSematiko Gordon 1\nOlsson Sten 4\nPal Shanthi 5\n1 National Pharmacovigilance Centre, National Drug Authority, P.O. Box 23096, Kampala, Uganda\n2 STD/AIDS Control Program, Ministry of Health, Kampala, Uganda\n3 Institute of Health and Society (IRSS), Universite Catholique de Louvain, Brussels, Belgium\n4 World Health Organization Collaborating Centre for International Drug Monitoring, Uppsala, Sweden\n5 Essential Medicines and Health Products Quality Assurance and Safety of Medicines World Health Organisation, Geneva, Switzerland\n7 3 2015\n7 3 2015\n2015\n38 4 395408\n© The Author(s) 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nBackground\n\nAlthough the national HIV control programme in Uganda has a well-established system for monitoring disease progression and treatment outcomes, monitoring of adverse drug reactions (ADRs) is inadequate. In order to address under-reporting of ADRs, the National Pharmacovigilance Centre, in collaboration with the HIV control programme, piloted a targeted spontaneous reporting (TSR) system as a complementary method to traditional spontaneous reporting.\n\nMethods\n\nFrom April 2012 to March 2014, all cases of suspected renal toxicity in 10,225 patients on tenofovir-based regimens were monitored in the regional pharmacovigilance centres of Masaka and Mbale. The identification of renal toxicity was performed using serum creatinine, urinalysis, and other signs and symptoms of kidney injury.\n\nResults\n\nThere was one suspected renal toxicity reported for every 200 patients on a tenofovir-based regimen. Some of the serious reactions reported were death in two cases and bone demineralisation in five patients. Most of patients had been on treatment for 2 years. Those that had been on tenofovir for more than 4 years had raised serum creatinine levels, emphasising the importance of monitoring for the risk of renal damage for longer. We also found that the reporting rate of suspected ADRs for all medicines in the two sites increased almost fivefold during the implementation period.\n\nConclusion\n\nAlthough the occurrence of suspected tenofovir renal toxicity of HIV patients is low, there is need to monitor those at risk so as to prevent irreversible kidney injury. TSR can complement spontaneous reporting for collecting safety data on particular drugs and increase ADR reporting rates.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s40264-015-0277-9) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© Springer International Publishing Switzerland 2015\n==== Body\nKey Points\n\nThe targeted spontaneous reporting methodology can increase reporting of suspected adverse reactions to a drug.\t\nAlthough the occurrence of renal toxicity associated with tenofovir is low, in a resource-limited setting where there is rapid scale-up of treatment and patients are initiated on a tenofovir regimen without initial screening, a monitoring programme for those that may develop renal toxicity should be put in place to encourage evidence-based decision making for improved patient safety.\t\nHaving adopted and leveraged on existing structures in the STD/AIDS Control Program, a platform for collaboration with the National Pharmacovigilance Centre was created, hence strengthening pharmacovigilance activities.\t\n\nIntroduction\n\nUganda is a resource-limited country with a high disease burden. Communicable diseases namely malaria, tuberculosis (TB) and HIV/AIDS account for 54 % of the total burden of disease [1]. Access to essential medicines for treating common diseases such as malaria, pneumonia, HIV, and diabetes mellitus at facility level is reported at 50–68 % according to a survey conducted by the Ministry of Health in 2008 [2]. In order to address the high disease burden, the Ministry of Health is focused on rapidly expanding access to essential medicines through implementation of public health programmes and targeting the major communicable and non-communicable diseases. This increased access to medicines is expected to increase the number of people at risk of developing adverse drug reactions (ADRs).\n\nThe World Health Organization (WHO) Programme for International Drug Monitoring, recognises a reporting rate of over 200 suspected ADRs per million inhabitants/year, sent at least once a quarter from a national pharmacovigilance centre as good performance [3]. With more than 10 million Individual Case Safety Reports (ICSR) submitted from member countries of this WHO programme, VigiBase® is one of the sources of international safety data [4]. Analysis of the spontaneous reports in VigiBase® over a decade between the year 2000 and 2009 revealed that high-income countries had high reporting rates ranging from between 3 and 613 reports per million inhabitants per year while low-income countries had the lowest range at 0–21 [5]. Despite recognition of the occurrence and burden of ADRs and the need to report them, several studies show that there is widespread under-reporting of ADRs to spontaneous reporting systems, including serious or severe ADRs [6–9]. The 2014 reporting rate from Uganda in VigiBase® corresponds to 20 reports per million inhabitants [10, 11]. A study conducted to assess pharmacovigilance systems in sub-Saharan Africa indicated that in Uganda, public health programmes do not routinely collect and share ADR data with the National Pharmacovigilance Centre (NPC) [12].\n\nAs of September 2013, the national STD/AIDS Control Program (ACP) had distributed antiretroviral (ARV) medicines to over 570,573 HIV-infected persons [13]. The HIV/AIDS 2013 Progress Report [13] showed that cotrimoxazole was dispensed to over 800,000 persons living with HIV whether ARV active or naive. Although, this program has a well-established system for monitoring HIV prevalence, incidence, numbers on treatment and treatment outcomes, monitoring of ADRs due to ARVs is still inadequate.\n\nIn order to address under-reporting of ADRs due to ARVs, the NPC, in collaboration with the national ACP piloted the targeted spontaneous reporting (TSR) approach as a complementary method to the traditional spontaneous reporting method. TSR (sometimes called stimulated reporting) is a variant of spontaneous reporting that focuses on capturing ADRs in a well-defined group of patients on treatment [14]. The WHO developed this TSR methodology in 2010 in three countries including Uganda with support from the Monitoring Medicines Project under the seventh framework programme (FP-7) of the European Commission. Following a training workshop on this new methodology, Uganda adapted TSR to monitor renal toxicity among HIV patients on tenofovir-based regimens. TSR was the method chosen because it held the promise of a comprehensive monitoring method that was affordable and feasible in healthcare settings with limited human and financial resources. TSR was considered likely to build on the gains that had already been achieved by the existing efforts in promoting the role of pharmacovigilance as a best practice that improves the quality of care.\n\nAlthough tenofovir had formerly been recommended as part of the alternative first-line ARV therapy (ART) regimen in the national guidelines and is now the preferred first-line regimen, little was known about its toxicity profile in the Ugandan population. Several studies on the use of tenofovir by patients with mild renal dysfunction or for longer durations indicated that it might be associated with renal toxicity [15–18]. In vitro studies also suggested a higher risk than has been observed in patients [19]. Patient populations are heterogeneous and treatment is complicated by the coadministration of tenofovir with other drugs that may enhance renal toxicity. Monitoring patients on a tenofovir-based regimen for a possible increased risk of renal dysfunction is therefore crucial. However, this is not always done due to a lack of laboratory facilities, inadequate knowledge for monitoring and work overload, especially in resource-limited settings. Failure to monitor patients to identify those who may be at risk of developing renal toxicity may result in significant deterioration in kidney function over a number of years as well as other complications.\n\nThe TSR method was adapted and piloted in the ACP among patients on tenofovir-based ART regimens seeking care from the two regional pharmacovigilance centres of Masaka and Mbale Regional Referral hospitals and their catchment health facilities. The purpose of this study was to pilot TSR using the example of renal toxicity to tenofovir in adults and to enhance pharmacovigilance within the ACP.\n\nMethodology\n\nImplementation Design\n\nThis was a pilot using TSR methodology to capture ADRs for HIV-positive clients who were initiated on tenofovir-based regimens. The Uganda health delivery system is comprised of the following levels:national referral\n\nregional referral\n\ndistrict or general hospital\n\nhealth centre IV (Serves a county, should be able to admit patients having a senior medical officer and another doctor as well as a theatre for carrying out emergency operations)\n\nhealth centre III (Found in sub-county, runs an out-patient clinic, treating common diseases and offering antenatal care. Its led by a senior clinical officer and has a functioning laboratory)\n\nhealth centre II (serves a few thousand people, led by a registered nurse, runs an out-patient clinic treating common diseases and offering antenatal care)\n\nhealth centre I (structured as village health teams and working as a link between the community and the health facilities).\n\nHealth services are also provided in the private sector by for-profit health providers, not-for-profit healthcare facilities and traditional/complimentary medicine providers. As of June 2014, the Ministry of Health had accredited 1,572 public and private health facilities countrywide to offer ART services. The health workers involved in ART service delivery range from doctors, clinical officers, registered nurses and midwives to nursing assistants. The NPC has leveraged on the expertise in the national and regional referral hospitals and has designated these as regional pharmacovigilance centres. Two focal persons were appointed by the hospitals to coordinate activities in the region including the lower public health facilities.\n\nSite Selection\n\nFrom April 2012 to March 2014, all cases of suspected renal toxicity in patients on tenofovir-based regimens were monitored in the two regional pharmacovigilance centres of Masaka and Mbale. The population in the study sites had been estimated at about 20,000 HIV-positive patients on ART.\n\nMonitoring of the Tenofovir-Based Regimen\n\nFor the pilot study, cases of suspected renal toxicity in patients on tenofovir-based regimens were targeted and monitored. Health workers in the pilot facilities were trained to monitor for signs and symptoms of tenofovir renal toxicity in all patients that were initiating or were already on tenofovir-based regimens. The laboratory tests carried out were serum creatinine and urinalysis (including proteinuria and glycosuria) as per the recommendations in the national guidelines for monitoring tenofovir at the various levels of health service delivery [20–22]. The 2014 national ART guidelines recommend carrying out urinalysis for monitoring of patients initiated on ART at baseline and thereafter every 6 months or as required [20]. They further recommend carrying out serum creatinine and/or blood urea to monitor renal function for patients on tenofovir every 6 months at district and regional referral hospitals.\n\nThe measurement parameters were the basis for the case definition and any patient that presented with any one out-of-range parameter was considered for suspected renal toxicity. To simplify monitoring of patients at the pilot sites, a job aid was developed to guide health workers on the frequency of carrying out laboratory tests and on how to identify and report suspected cases. Signs and symptoms suggesting renal toxicity were described in the job aid (see Electronic Supplementary Material 1). Changes from the baseline parameters even in the absence of cardinal symptoms of renal insufficiency would trigger adverse reaction reporting.\n\nTraining and Support Supervision for the Targeted Spontaneous Reporting (TSR) Methodology\n\nThe health professionals managing patients were trained on the TSR methodology and renal toxicity monitoring as well as any other safety concerns. To supplement the training, support supervision was conducted regularly and involved personnel from both the NPC and the ACP. During support supervision, review meetings with the pharmacovigilance centre focal persons were held and strategies for strengthening pharmacovigilance in the hospitals were reviewed. Mentoring in ART care with focal facility personnel was also done.\n\nData Collection\n\nBased on the case definition and the national guidelines, health workers reported suspected ADRs using the national form (see Electronic Supplementary Material 2). Completed reports were then relayed to the regional pharmacovigilance coordinator who entered them into the web-based case management system VigiFlow™ [23]. The NPC staff and the ACP focal person held regular meetings to assess causal relationships. The assessors assigned a score to the components and factors considered in establishing the causal relationships between tenofovirand the adverse events such as temporal sequence, alternative causes, confirmation by objective evidence and challenge and re-challenge with the drug. Each question was answered positive (yes), negative (no), or unknown or inapplicable (do not know).The likelihood of tenofovir being related to renal toxicity was assessed using the Naranjo algorithm [24]. The suspected ADR was then assigned to a category from the total score as follows: definite ≥9, probable 5–8, possible 1–4, doubtful ≤0. A descriptive summary of data on renal toxicity was created and is presented in Sect. 3.3.\n\nEthical Considerations\n\nADR monitoring and reporting is a routine clinical care activity. Health workers were required to report the reactions that they observe and those reported by the patients. Informed consent was not individually taken from each patient as the ADR form is confidential and was treated as such by the NPC. Ethical clearance was sought from the Uganda National Council for Science and Technology (Ref: HS 1136), which provides ethics research clearance at the national level in accordance to the World Medical Association Helsinki Declaration. Approval for the pilot was obtained from National Drug Authority and the ACP to conduct this pilot study.\n\nResults\n\nBackground to the Sites\n\nA total of 10,225 patients were on tenofovir-based regimens in the two pilot sites in the 24 months of the pilot implementation. A majority of these patients were from the Masaka region as presented in Table 1.Table 1 Patients on the tenofovir-based regimen among the study sites\n\nStudy site\tNumber of patients on tenofovir\t\nMasaka Region\t\n Masaka Regional Referral hospital\t2,637\t\n TASO Masaka\t1,759\t\n Villa Maria hospital\t1,700\t\n Lyantonde hospital\t740\t\n Kalungu Health Centre IV\t63\t\n Kitovu hospital\t40\t\n Bukulula Health Centre IV\t348\t\nSubtotal\t7,287\t\nMbale Region\t\n Mbale Regional Referral hospital\t950\t\n TASO Tororo\t1,615\t\n St. Antony hospital Tororo\t158\t\n Bududa hospital\t215\t\nSub-total\t2,938\t\nTotal\t10,225\t\n\nDemographics of the Suspected Renal Toxicity Cases\n\nFifty-three (0.52 % of the exposed cases) of the suspected renal toxicities were reported to the NPC, of which 23 (43.4 %) were males. The median age of these patients was 43 years [interquartile range (IQR) 33–51] and the median body weight was 55 kg (IQR 47–62). Patients had been on tenofovir-based regimen for a median duration of 24 months (IQR 12–36). All patients that had been on a tenofovir regimen for more than 4 years had raised creatinine levels.\n\nThe majority (60 %) of this cohort of patients were on the tenofovir/lamivudine/nevirapine (TDF/3TC/NVP) combination, while 35 % were on tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) and the remaining 5 % were on the ritonavir-boosted lopinavir in combination with TDF/3TC.\n\nPresenting Signs and Symptoms for the Suspected Renal Toxicity\n\nOf the 53 cases with suspected renal toxicities, six (11 %) presented with bilateral pedal oedema, four with facial puffiness and five with bone demineralisation, which was confirmed by X-ray. Eleven (21 %) cases had out-of-range urinalysis, and the results are summarised in Table 2 along with other observed signs and symptoms of suspected renal toxicity. All of the patients that presented with glycosuria also had proteinuria. Two out of every three patients on a tenofovir-based regimen whose protein levels were tested (n = 38) had a positive result. Haematuria found in one patient out of the 53 reported cases was not expected. None of the patients in this study presented with hyperglycaemia.Table 2 Summary of presenting signs and symptoms of suspected renal toxicity\n\nParameter\tNumber of patients (%)\tTotal (N)\t\nIncreased creatinine (>1.2 g/dL)\t43 (81)\t53\t\nCreatinine clearance >90 mL/min\t43 (100)\t43\t\nCreatinine levels not provided\t10 (19)\t53\t\nProteinuria\t25 (66)\t38\t\nGlycosuria and proteinuria\t11 (44)\t25\t\nBone demineralisation\t5 (9)\t53\t\nBilateral pitting pedal oedema\t6 (11)\t53\t\nFacial puffiness\t4 (8)\t53\t\n\nTwenty-one patients were changed to a non-tenofovir-based regimen and their urine parameters and creatinine clearance improved thereafter. Tenofovir was substituted with zidovudine in six of these cases and the other 15 cases were substituted with abacavir. Two of those cases changed to abacavir had co-morbidities of both hypertension and diabetes, whereas two of the cases changed to zidovudine also had hypertension. A 45-year-old male, who had been on a tenofovir-based regimen for 5 years and presented with increased serum creatinine, glycosuria and proteinuria, was the only case with hypertension that was monitored without a regimen change as the signs and symptoms of renal damage resolved thereafter. Other co-morbidities reported included one case of lipodystrophy and one case of Kaposi’s sarcoma. The laboratory findings for one case were consistent with Fanconi syndrome (i.e. hypouricaemia, hypokalaemia, generalised aminoaciduria and proteinuria).\n\nAbout 80 % of the cases tested had a raised serum creatinine level. A raised serum creatinine and calculated creatinine clearance of <90 mL/min (calculated with the Cockroft and Gault formula) was reported in all 43 patients that had a serum creatinine test performed and this is presented in detail in Table 3.Table 3 Characteristics of the patients with suspected renal toxicity\n\nAge\tSex\tDuration on ART (months)\tRegimen\tConcomitant drugs\tPresenting symptom/signs\tOutcome and remarks\tSerum creatinine (mg/dL)\tCreatinine clearance (mL/min)\tRegimen change\t\n43\tF\t5\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine\tExpected but not serious\t1.36\t52.0\tNo\t\n30\tF\t12\tTDF/3TC/NVP\tCotrimoxazole\tIncreased serum creatinine glucose: nil\n\nProteins: +\n\n\tLife-threatening but expected\t1.47\t58.2\tNo\t\n51\tM\t5\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine\tExpected but not serious; urinalysis has been normal since May 2014\t1.47\t47\tNo\t\n62\tM\t12\tTDF/3TC/NVP\tNone reported\tUrine RBCs: nil\n\nPus cells: +\n\nEpithelial cells: ++\n\nUrine protein: ++\n\nGlucose: nil.\n\n\tReaction expected and was life-threatening. Improved\t1.52\t32.8\tChanged from TDF to AZT\t\n64\tM\t6\tTDF/3TC/EFV\tCotrimoxazole\tRaised serum creatinine\n\nUrine protein: +\n\nUrea: 8.3 mg/dL\n\n\tCotrimoxazole stopped due to neutropenia. Patient improved. Reaction expected\t1.35\t54.4\tChanged from TDF to ABC\t\n62\tF\t84\tTDF/3TC/NVP\tNone reported\tRaised serum creatinine\n\nUrine protein: +++\n\nGlucose: +\n\n\tReaction was serious but expected\t1.36\t37.2\tNo\t\n30\tF\t4\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine levels\n\nGlucose: nil\n\nProteins: nil\n\n\tReaction was expected but not life-threatening. Patient recovered\t1.75\t37.5\tNo\t\n45\tM\t19\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine\tReaction was expected but not life-threatening. Patient recovered\t1.42\t60\tNo\t\n42\tF\t6\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine\tNo co-morbidities reported, patient died\t1.80\t71.0\tNo\t\n68\tM\t10\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine\tReaction was expected but not life-threatening. Patient recovered\t1.57\t57.0\tNo\t\n52\tM\t9\tTDF/3TC/EFV\tCotrimoxazole\tRaised serum creatinine\tReaction was expected and life-threatening but resolved\t1.47\t53.0\tNo\t\n41\tF\t\tTDF/3TC/lopinavir\tDapsone\tGeneralised oedema, progressive anuria\tDapsone has an effect on renal function. The patient was allergic to cotrimoxazole. The reaction was expected and life-threatening but it resolved\t2.3\t21.0\tTDF changed to AZT\t\n28\tM\t24\tTDF/3TC/EFV\tNone reported\tRenal tubular necrosis, raised serum creatinine\n\nUrine glucose: nil\n\nProteins: +\n\n\tGood viral suppression at 381 copies\n\nPatient recovered. Reaction was expected\n\n\tActual results not seen\t\tTDF changed to ABC\t\n33\tM\t12\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine\tReaction was expected. Patient has normal urinalysis\tResults not seen\t\tNo\t\n38\tF\t48\tTDF/3TC/EFV\tCotrimoxazole\tRaised serum creatinine\tAZT had been changed to TDF after 2 months of treatment. Follow-up urinalysis on TDF regimen indicated protein +. The reaction was expected and serious\t2.57\t27.0\tNo\t\n29\tF\t24\tTDF/3TC/NVP\tIbuprofen for 5 days and vitamin B complex for 2 weeks\tIncreased creatinine: 1.65 mg/dL. Follow-up value was 1.3 mg/dL\tThe patient was reported to also have lumbago. Reaction was serious and expected but resolved\t1.65\t58.0\tNo\t\n37\tM\t84\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine\tVery poor adherence with very poor immunological outcome. The suspected renal abnormality is also resolving\t10.91\t6.2\tNo\t\n45\tM\t36\tTDF/3TC/NVP\tCarvedilol, spironolactone\tOedema, polyuria, raised serum creatinine protein 3+ and a known hypertensive\tReaction expected and patient is recovering\t4.6\t24.4\tTDF changed to AZT\t\n42\tF\t84\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine: 1.3 then 1.1 mg/dL\tReaction expected and patient is recovering\t1.3\t51.6\tNo\t\n49\tF\t48\tTDF/3TC/NVP\tCotrimoxazole\tNeuropathy and increased creatinine\n\nGlucose: nil\n\nProteins: +\n\n\tReaction expected and patient recovered\t10.0\t7.2\tTDF changed to ABC\t\n61\tM\t36\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine\tReaction expected and patient recovered\tResults not seen\t\tNo\t\n33\tM\t12\tTDF/3TC\tAtazanavir\tIncrease creatinine, facial puffiness, high urea level\n\nGlucose: nil\n\nProtein: nil\n\n\tReaction expected and patient recovered\t10.9\t10.6\tNo\t\n55\tM\t\tTDF/3TC/NVP\tNone reported\tRaised serum creatinine\n\nGlucose: nil\n\nProteins: nil\n\n\tReaction expected and patient recovered\t1.5\t44.2\tNo\t\n47\tF\t24\tTDF/3TC/NVP\tInsulin\tIncreased serum creatinine\n\nGlucose: +\n\nProteins: +\n\n\tKnown to be hypertensive and have diabetes mellitus. Reaction expected and patient recovering\tResults not seen\t\tTDF changed to ABC\t\n49\tM\t12\tTDF/3TC\tAlluvia and cotrimoxazole\tIncreased creatinine levels\n\nGlucose: nil\n\nProteins: nil\n\n\tHistory of TB treatment immediately before starting ART. Reaction expected and patient recovering\t1.66\t27.8\tNo\t\n53\tM\t12\tTDF/3TC/NVP\tCotrimoxazole\tFacial puffiness, increased serum creatinine\n\nProteinuria: +++\n\nGlucose: +\n\n\tSigns of treatment failure. The reaction was expected\tResults not seen\t\tTDF withdrawn, changed to ABC\t\n50\tF\t24\tTDF/3TC/NVP\tNone reported\tIncreased creatinine\n\nGlucose: nil\n\nProteins: +\n\n\tHad lactic acidosis with high LDH levels. Reaction expected\tResults not seen\t\tNo\t\n48 \tF\t5\tTDF/3TC\tEFV\tIncreased creatinine levels\tReaction expected and patient recovering\t1.76\t30.7\tNo\t\n29\tF\t36\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine levels\n\nUrea: 51 mg/dL\n\n\tReaction expected and patient recovering\t1.74\t47.8\tNo\t\n28\tF\t24\tTDF/3TC/NVP\tCotrimoxazole\tRaised serum creatinine, proteinuria\n\nUrine protein: 3+++\n\nGlucose: nil\n\n\tReaction expected and patient recovered\t1.43\t58.3\tChanged from TDF to AZT regimen\t\n25\tF\t12\tTDF/3TC/NVP\tCotrimoxazole\tFanconi syndrome\n\nUrine protein: 3+++\n\nUrine glucose: +\n\nRandom blood sugar: 6.1 mmol\n\n\tRaised amylase, raised AST. Outcome is not yet known, patient still being monitored\t1.79\t34.0\tART stopped\t\n22\tF\t48\tTDF/3TC/EFV\tCotrimoxazole\tRaised serum creatinine\tUrinalysis was normal during follow-up. Reaction expected and patient recovering\t1.45\t36.0\tNo\t\n52\tM\t2\tTDF/3TC/EFV\tCotrimoxazole\tRaised creatinine\n\nGlucose: nil\n\nProteins: nil\n\n\tHad a Kaposi’s sarcoma lesion as well. Urinalysis results returned to normal. Reaction expected and patient recovering\t1.30\t54.3\tFrom NVP to EFV\t\n45\tM\t60\tTDF/3TC/NVP\tCaptopril, nifedipine\tIncreased creatinine, known hypertension\n\nGlucose: +\n\nProteins: +\n\n\tKnown hypertensive. Reaction expected and patient recovering\t1.79\t61.9\tNo\t\n38\tF\t24\tTDF/3TC/EFV\tAtorvastatin\tIncreased serum creatinine\tStarted ART (AZT/3TC/EFV) in 2006, substituted AZT with TDF due to lipodystrophy\n\nReaction expected and patient recovered. Serum creatinine reduced to 1.39 mg/dL\n\n\t1.43\t53.4\tNo\t\n31\tF\t24\tTDF/3TC/NVP\tNifedipine, atenolol\tRenal tubular necrosis, raised serum creatinine\n\nGlucose: nil\n\nProtein: +\n\n\tRight-sided hemiparesis of a known hypertensive\n\nReaction expected and patient recovered\n\n\t4.28\t14.1\tFrom TDF to ABC\t\n56\tF\t66\tTDF/3TC/NVP\tCotrimoxazole\tFacial puffiness, easy fatigue, raised creatinine levels\n\nUrea: 240 mg/dL\n\n\tReaction expected and patient recovering\t7.26\t7.7\tChanged TDF to ABC\t\n56\tM\t24\tTDF/3TC/NVP\tCotrimoxazole\tRaised creatinine, urea (92 mg/dL)\n\nGlucose: +\n\nProteins: ++\n\n\tPatient had pancytopaenia and he died\t3.15\t17.2\tNo\t\n44\tF\t24\tTDF/3TC\tNVP\tFacial puffiness, increased creatinine levels\tNot known\tResults not seen\t\tNo\t\n40\tM\t2\tTDF/3TC/NVP\tNone reported\tRenal toxicity with bilateral pedal oedema\n\nGlucose: +\n\nProteins: +\n\n\tHad a history of TB of the kidneys. Reaction was expected\t16.52\t3.9\tDrug stopped\t\n39\tM\t48\tTDF/3TC/NVP\tCotrimoxazole\tIncreased creatinine\tReaction was expected and the patient recovered\tResults not seen\t\tTDF substituted for ABC\t\n+ (30–100 mg/dl), ++ (100–300 mg/dl), +++ (300–1000 mg/dl), ++++ (>1000 mg/dl) define measured level of protein/glucose\n\n3TC lamivudine, ABC abacavir, ART antiretroviral therapy, AZT zidovudine, EFV efavirenz, F female, HTN hypertension, LDH lactate dehydrogenase, M male, NVP nevirapine, RBCs red blood cells, TB tuberculosis, TDF tenofovir\n\nOne in every five cases of suspected renal toxicity did not have a result for serum creatinine. The characteristics of the ten patients whose serum creatinine results could not be established are listed in Table 4. Six of the ten cases had their regimen changed, mainly because of bone demineralisation, and two patients died.Table 4 Characteristics of patients for whom serum creatinine was not performed\n\nAge\tSex\tART regimen\tDuration on ART (months)\tConcomitant drugs\tPresenting symptom/signs\tOutcome and remarks\t\n30\tF\tTDF/3TC/EFV\t48\tCiprofloxacin 500 mg\tBlood in urine\n\nUrine protein: + (30 g/dL)\n\nWhite blood cells: 2+\n\nGlucose: nil\n\nUrinary tract infection that did not improve on ciprofloxacin 500 mg twice daily for 1 week\n\n\tRegimen changed from TDF to ABC and the patient recovered\t\n29\tM\tTDF/3TC/NVP\t1.2\tDapsone, prednisone\tBilateral pedal oedema\n\nUrine protein: 3+\n\nRed blood cells: 2+\n\nPus cells: 2+\n\n\tPatient died\t\n52\tF\tTDF/3TC/NVP\t28\tCotrimoxazole, ciprofloxacin 500 mg\tUrine protein: 2++\n\nPus cells: ++\n\nEpithelial cells: ++\n\nCD4: 15\n\n\tPatient improved on ciprofloxacin 500 mg. Regimen was maintained\t\n47\tF\tTDF/3TC/NVP\t36\tAnti-TB drugs for 6 months\tParaesthesia of both limbs\n\nGlucose: ++\n\nProtein: ++\n\nPale\n\n\tHad just completed TB treatment 1 week ago, TDF was changed to ABC and recovered\t\n38\tM\tTDF/3TC/EFV\t1\tNone\tBilateral pedal oedema\n\nAnaemia (haemoglobin 6.6 g/dL)\n\nProtein: +\n\nUltrasound revealed bilateral hydronephrosis\n\n\tPatient died\t\n34\tM\tFirst on AZT/3TC/NVP, then TDF/3TC/NVP\t24\tCotrimoxazole\tBone demineralisation on left head of femur\n\nGlucose: nil\n\nProteins: nil\n\n\tDeveloped hyperpigmentation of the nails and was substituted to TDF on request\t\n43\tF\tTDF/NVP/3TC\t36\tNone\tBone demineralisation\n\nGlucose: +\n\nProteins: ++\n\n\tTDF substituted with ABC and recovered\t\n46\tF\tTDF/3TC/NVP\t24\tNone\tSevere bone pains and unstable gait\tOutcome and new regimen could not be readily established\t\n60\tF\tTDF/3TC/NVP\t5\tCotrimoxazole\tOsteomalacia, reduced bone density of femur\n\nGlucose: nil\n\nProteins: +\n\n\tTDF substituted with AZT\t\n39\tF\tTDF/3TC/EFV\t12\tCotrimoxazole\tBone demineralisation\n\nReduced bone density of the right and left femur\n\nGlucose: nil\n\nProteins: nil\n\n\tTDF substituted to ABC and recovered\t\n+ (30–100 mg/dl), ++ or 2+ (100–300 mg/dl), 3+ (300–1000 mg/dl), 4+ (>1000 mg/dl) define measured level of protein/glucose\n\n3TC lamivudine, ABC abacavir, ART antiretroviral therapy, AZT zidovudine, EFV efavirenz, F female, M male, NVP nevirapine, TB tuberculosis, TDF tenofovir\n\nCausality Assessment\n\nThe majority (80 %) of the suspected renal toxicity cases were classified as probable and the rest were possibly related to tenofovir. None of the causality assessment grading belonged to the extreme categories of doubtful and definite.\n\nReporting Trends for Suspected Adverse Drug Reactions\n\nDuring the time of the pilot, there was an increase in the overall number of ADR reports that VigiBase® submitted to the national pharmacovigilance system compared with the previous years (shown in Fig. 1) and also specifically from the annual number of reports collected in the two study sites of Mbale and Masaka (seen in Table 5 with comparisons before and after the TSR pilot period). The reports collected is about five times more than the pre-study period.Fig. 1 Number of individual case safety reports (ICSRs) from Uganda in VigiBase® per year\n\nTable 5 Comparison of suspected adverse drug reaction reports collected from the study sites with the overall adverse drug reaction reports\n\nSource of reports\tPeriod\t\nBefore TSR pilot study\tAfter start of TSR\t\n2010\t2011\tTotal\t2012\t2013\t2014\tTotal\t\nStudy sites\t17\t27\t44\t142\t46\t181\t369\t\nUganda VigiBase® reports\t60\t518\t578\t42\t239\t687\t968\t\nPercentage\t\t\t8 % (44/578)\t\t\t\t38 % (369/968)\t\nTSR targeted spontaneous reporting\n\nDiscussion\n\nBackground to the Study\n\nThis pilot was implemented to establish the feasibility and positive effects that may accrue from a targeted spontaneous reporting methodology in resource-limited settings. In the ACP, the TSR was adapted to monitor the safety of patients on HIV treatment by focusing on suspected renal toxicity related to the use of tenofovir.\n\nSummary of Findings\n\nIn our study, there was one suspected renal toxicity reported in every 200 patients on a tenofovir-based regimen. Among the serious reactions reported were the death of two patients and bone demineralisation, also known as osteomalacia, which occurred in five patients. Further assessment of the causality relationship revealed that these reports were probably or possibly but not definitely related to tenofovir. The median duration of treatment for the patients in this cohort was 2 years. However, all 13 (100 %) patients that had been on the tenofovir regimen for more than 4 years had raised creatinine levels. This group of patients emphasises the importance of monitoring for the risk of renal damage the longer patients are on tenofovir. We also found out that the reporting rate of suspected ADRs to all medicines in the two selected sites increased almost five-fold during the implementation of the TSR methodology.\n\nSuspected Adverse Reactions Associated with Tenofovir\n\nTenofovir is a drug that is widely used for treatment of HIV infections in Uganda as more than half of the patients on ART in the two targeted study sites had it as part of their regimen [20].\n\nBased on the case definition, the findings from this pilot support the presenting signs and symptoms of renal toxicity associated with tenofovir that are not different from that reported in the literature [16, 17]. According to the manufacturer, adverse reactions with a suspected relationship with tenofovir are classified as either uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000) [25]. Increased serum creatinine was uncommon and renal failure, osteomalacia, lipodystrophy and angioedema were considered to be rare in the European Summary of Product Characteristics.\n\nFrom our cases, proteinuria, glycosuria, raised serum creatinine and bone demineralisation are characteristics of tenofovir-induced kidney injury. Use of proteinuria and glycosuria to screen for tenofovir-induced kidney injury seems to be a very useful approach that should be emphasised and for which cost effectiveness ought to be studied further, especially for long-term monitoring of patients in resource-limited settings. Patients who had proteinuria diagnosed with dipstick, their regimens subsequently changed had a positive treatment outcome similar to other studies [16].\n\nSince the main target for tenofovir toxicity is the proximal tubule, the presence of tubular proteinuria would be the most sensitive test for detecting proximal tubular dysfunction. However, it was not possible to measure tubular proteinuria in this pilot. The dipstick analysis used in this pilot primarily detected albuminuria, which is insensitive for low molecular weight proteinuria characteristic of tenofovir toxicity. The alternative tests for assessing proximal tubular function were to measure fractional excretion of phosphates and glycosuria, which are also established markers of proximal tubule dysfunction and are easy to screen for but are less sensitive tests than tubular protein excretion. Glycosuria was found in 11 of the patients, who also had proteinuria, while bone demineralization was found in five patients, which points to proximal tubular dysfunction [16, 25, 26].\n\nIn studies [27, 28], serum creatinine >1.2 g/dL with calculated creatinine clearance <90 mL/min was reported in more than 80 % of the cases. This is consistent with findings of a study of more than 1,000 HIV-infected patients on tenofovir which identified 1 % whose serum creatinine increased to >120 g/dL [29]. The SCOLTA (Surveillance Cohort Long-Term Toxicity Antiretroviral) study of 754 HIV-infected, tenofovir-treated patients found a 2.5 % incidence of creatinine elevations more than 1.5 times the upper limit of normal in a mean follow-up of 19.5 months, similar to the monitoring period of the patients in this pilot [29].\n\nAchievement of the TSR Pilot\n\nThe project piloted TSR as a methodology for enhancing ADR reporting in the ACP in Uganda. It was specifically targeting patients who developed renal toxicity after taking tenofovir. This initiative was the first of its kind in Uganda and in sub-Saharan Africa.\n\nThe pilot was established on the basis of collaboration with a public health programme and the NPC, which ensured ownership and division of activities according to the comparative advantage of each participating entity. The healthcare providers identified with the activity mostly because of the involvement of the ACP.\n\nAs a result of this collaboration, the ACP incorporated ADR reporting in its training manuals for ART. Also, pharmacovigilance reports from ART sites are incorporated into the national quarterly ART report. This has increased the number of spontaneous reports from public health facilities. It has increased visibility of the NPC activities by opening communication lines with all public health system programmes through sharing of reports, feedback meetings, case review meetings and joint training of healthcare providers.\n\nThe pilot was observational with no exclusion and inclusion criteria for those monitored. Patients were monitored in the routine clinical setting where risk factors and gaps in care were observed and studied. In the case of lifelong treatment such as ART, reporting lasts a lifetime as well [14]. The fivefold increase in the reporting rate compared to the pre-study period suggests that the TSR methodology addresses the problem of under-reporting that is seen with the traditional Ugandan spontaneous reporting.\n\nThrough joint support supervision activities, the NDA and NPC were able to identify gaps in health service provision. The point in case is the Ministry of Health ART guidelines which were not clear to health workers regarding monitoring patients on tenofovir. The NPC noted that health workers were opting for more expensive tests such as serum creatinine for monitoring tenofovir instead of a urine dipstick which is a cheaper alternative.\n\nThis pilot had a capacity-building component in terms of training, mentorship and feedback on the quality of care provided at the health facilities. This motivated health workers to provide better services and also to report suspected adverse reactions. At the pilot close-out dissemination meeting, stakeholders were particularly impressed by the feedback presented to them about the quality of reports as analysed by the NPC. Stakeholders requested that the TSR method of monitoring safety be rolled out to other parts of the country.\n\nChallenges and Limitations of the TSR Pilot\n\nHIV treatment is a rapidly evolving field whose guidelines keep changing. The recommendations for ART and preventing mother to child transmission (PMTCT) kept changing as the policies and guidelines changed. As a result, the planned TSR roll-out for PMTCT services has not yet been carried out.\n\nAssessment of the cases was difficult because some reports did not have baseline tests for renal function at the start of therapy. The dipstick analysis used in this pilot detected primarily albuminuria and is insensitive for low molecular weight proteinuria characteristic of tenofovir toxicity. Ideally, proteinuria should be assessed by formal measurement of the urine protein-to-creatinine ratio (P:C) or albumin-to-creatinine ratio (A:C). This was not possible in this study because the pilot used dipstick testing for detecting proteinuria and hence absolute urine protein values were not obtained. The lack of baseline laboratory tests in some reported cases makes it difficult to attribute the findings to tenofovir renal toxicity since it was not possible to rule out the existence of renal disease before tenofovir regimens had been started.\n\nMonitoring for ADRs was initially viewed as an extra activity stretching the programme’s logistics and resources. The NPC at one point provided some supplies and gave incentives to those involved in the project. Health workers viewed the programme as research that comes with added work since they already have a heavy workload from their usual work and so expected allowances. The joint support supervision encouraged the health workers and contributed to their change of attitude and the quality of patient care started improving.\n\nRecommendations\n\nUse of targeted surveillance monitoring strategies increases the number of reports and can help to identify risks that are associated with specific treatment in public health programmes. This plays an important role in signal detection. The role of co-morbidities such as hypertension and diabetes in this case also needs to be further studied as the TSR is rolled out. The numbers in this study were too small to come to a meaningful conclusion regarding their relationship to tenofovir-associated renal toxicity. The cost effectiveness of using these simple tests should also be further studied, especially in resource-limited settings.\n\nPharmacovigilance should be integrated into public health systems as a routine activity. However, there is still the need to plan for pharmacovigilance activities and resources such as having a focal person at the health facility level, especially where there are high patient loads, and a regional focal person to coordinate pharmacovigilance activities within the regions. In order to improve ADR reporting, the reporting of pharmacovigilance activities in Uganda needs to be simplified and harmonised with the current electronic reporting systems for the public health programmes and the health management information systems. Advocacy for integration should be enhanced by the relevant stakeholders and continuous information sharing. For successful implementation, involvement of different stakeholders is key because the issues encountered are better handled by a multi-disciplinary approach.\n\nConclusion\n\nThis pilot revealed that the incidence of suspected adverse events that are possibly related to the use of tenofovir-based regimens in HIV treatment is one report in 200 patients. We also found that the reporting rate of suspected ADRs to all medicines in the two selected sites increased almost fivefold during the implementation of the TSR methodology.\n\nTargeted spontaneous reporting as a surveillance method can complement spontaneous reporting since it comes with the advantages of an increased reporting rate and the possibility of calculating the incidence of the ADR in question. In resource-limited settings, a successful monitoring programme for the safety of medicines used in public health programmes can be implemented and a specific question of interest can be answered in a specific population. This encourages use of evidence-based decision making for a better-quality patient care programme.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary material 1 (PDF 737 kb)\n\nSupplementary material 2 (PDF 1523 kb)\n\nThe authors wish to thank all the staff of the National Pharmacovigilance Centre, especially Angela Bonabana and Christine Naluswata, for their work in data collection. Special thanks also goes to the doctors, nurses, pharmacists, pharmacy technicians, counsellors and all of the health workers at the ART and PMTCT clinics in the Masaka and Mbale Regional Referral Hospitals.\n\nFunding and conflict of interest\n\nThe study was supported in part with funds from the Research Directorate of the European Commission under the seventh framework programme (grant number 223566) and United Nations Innnovative Financing to Shape Markets for HIV/AIDS, Malaria and Tuberculosis (UNITAID). Helen Ndagije, Victoria Nambasa, Elizabeth Namagala, Huldah Nassali, Dan Kajungu, Gordon Sematiko, Sten Olsson and Shanthi Pal have no conflicts of interest that are directly relevant to the content of this study.\n\nTheme issue\n\nThis article is part of a theme issue co-edited by Elliot G. Brown, Shanthi Pal and Sten Olsson. No external funding was used to support the publication of this theme issue.\n==== Refs\nReferences\n\n1. Government of Uganda, Ministry of Health. 2010. Health sector strategic plan III 2010/11-2014/15. http://www.health.go.ug/docs/HSSP_III_2010.pdf. Accessed 28 Oct 2014.\n2. Government of Uganda, Ministry of Health, December 2008. Access to and use of medicines by households in Uganda: report of a survey conducted 2008. http://www.afro.who.int/en/downloads/doc_download/5722-uganda-access-to-and-use-of-medecines-by-households.html. Accessed 26 Dec 2014.\n3. WHO Collaborating Centre for International Drug Monitoring, Reporting trends. Uppsala, Sweden. Updated 2014 Nov 25. http://who-umc.org/graphics/28351.gif. Accessed 30 Dec 2014.\n4. Lindquist M VigiBase, the WHO global ICSR database system: basic facts Drug Inf J. 2008 42 5 409 419\n5. Aagaard L Strandell J Melskens L Petersen PSG Hansen EH Global patterns of adverse drug reactions over a decade: analyses of spontaneous reports to VigiBase™ Drug Saf 2012 35 12 1171 1182 10.1007/BF03262002 23072620\n6. Kiguba R Karamagi C Waako P Ndagije HB Bird SM Recognition and reporting of suspected adverse drug reactions by surveyed healthcare professionals in Uganda: key determinants BMJ Open 2014 4 11 e005869 10.1136/bmjopen-2014-005869 25421337\n7. Lazarou J Pomeranz B Corey PN Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies JAMA 1998 279 1200 1205 10.1001/jama.279.15.1200 9555760\n8. Gurwitz JH Field TS Avorn J McCormick D Jain S Eckler M Incidence and preventability of adverse drug events in nursing homes Am J Med 2000 109 2 87 94 10.1016/S0002-9343(00)00451-4 10967148\n9. Hazell L Shakir SA Under reporting of adverse drug reactions: a systematic review Drug Saf 2006 29 5 385 396 10.2165/00002018-200629050-00003 16689555\n10. WHO Collaborating Centre for International Drug Monitoring, VigiLyze, Search and Analyse VigiBase, The WHO Global Database of Individual Case Safety Reports (ICSRs). Uppsala, Sweden. Updated 2014 Dec 11. https://vigilyze.who-umc.org. Accessed 30 Dec 2014.\n11. Uganda Bureau of Statistics, 2014 Census Population [Internet]. Kampala; p. 6. Available from: http://unstats.un.org/unsd/demographic/sources/census/2010_PHC/Uganda/UGA-2014-11.pdf. Accessed 26 Dec 2014.\n12. Strengthening Pharmaceutical Systems (SPS) Program. Safety of medicine in sub-Saharan Africa: assessment of pharma-covigilance systems and their performance. Submitted to the US Agency for International Development by the Strengthening Pharmaceutical Systems (SPS) Program. Arlington: Management Sciences for Health; 2011. http://apps.who.int/medicinedocs/documents/s19152en/s19152en.pdf. Accessed 26 Dec 2014.\n13. Uganda STD/AIDS Control Programme. HIV and AIDS Uganda country progress report; 2013. Kampala; 2014. http://www.unaids.org/sites/default/files/country/documents/UGA_narrative_report2014.pdf. Accessed 26 Dec 2014.\n14. Pal SN Duncombe C Falzon D Olsson S WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems Drug Saf 2013 36 2 75 81 10.1007/s40264-012-0014-6 23329541\n15. Chua AC Llorin RM Lai K Cavailler P Law H Renal safety of tenofovir containing antiretroviral regimen in a Singapore cohort AIDS Res Ther. 2012 9 1 19 10.1186/1742-6405-9-19 22703627\n16. Fernandez-Fernandez B Montoya-Ferrer A Sanz AB Sanchez-Niño MD Izquierdo MC Poveda J Tenofovir nephrotoxicity: 2011 update AIDS Res Treat. 2011 2011 354908 21716719\n17. Cooper RD Wiebe N Smith N Keiser P Naicker S Tonelli M Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients Clin Infect Dis 2010 51 5 496 505 10.1086/655681 20673002\n18. Mulenga LB Kruse G Lakhi S Cantrell RA Reid SE Zulu I Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia AIDS. 2008 22 14 1821 1827 10.1097/QAD.0b013e328307a051 18753939\n19. Vidal F Domingo JC Guallar J Saumoy M Cordobilla B Sánchez De La Rosa R In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells Antimicrob Agents Chemother 2006 50 11 3824 3832 10.1128/AAC.00437-06 16940060\n20. Ministry of Health, Uganda. The Integrated National Guidelines on Antiretroviral Therapy, Prevention of mother to child transmission of HIV and infant & young child feeding. 1st ed. Kampala; 2011. http://www.emtct-iatt.org/wp-content/uploads/2014/05/GL_Integrated-National-Guidelines-on-ART-PMTCT-and-IYCF-June-2011-MOH-Uganda_0.pdf. Accessed 16 Feb 2015.\n21. Gupta SK Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system AIDS Patient Care STDS. 2008 22 2 99 103 10.1089/apc.2007.0052 18260800\n22. Romo FT Aziz M Livak B Huesgen E Colton B Renal function recovery and HIV viral suppression following tenofovir discontinuation for renal impairment J AIDS Clin Res 2014 5 379 26097776\n23. Olsson S The role of the WHO programme on international drug monitoring in coordinating worldwide drug safety efforts Drug Saf 1998 19 1 1 10 10.2165/00002018-199819010-00001 9673854\n24. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508\n25. Europeans Medicines Agency. Tenofovir summary of product characteristics. 2002. p. 1–183. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000419/WC500051737.pdf. Accessed 8 Jan 2015.\n26. Hall AM Hendry BM Nitsch D Connolly JO Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence Am J Kidney Dis 2011 57 5 773 780 10.1053/j.ajkd.2011.01.022 21435764\n27. Scherzer R Estrella M Li Y Choi AI Deeks SG Grunfeld C Association of tenofovir exposure with kidney disease risk in HIV infection AIDS. 2012 26 7 867 875 10.1097/QAD.0b013e328351f68f 22313955\n28. Madeddu G Bonfanti P De Socio GV Carradori S Grosso C Marconi P Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project Biomed Pharmacother 2008 62 1 6 11 10.1016/j.biopha.2007.04.008 17574807\n29. Jones R Stebbing J Nelson M Moyle G Bower M Mandalia S Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study J Acquir Immune Defic Syndr 2004 37 4 1489 1495 10.1097/01.qai.0000138983.45235.02 15602127\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0114-5916",
"issue": "38(4)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000369:Aged, 80 and over; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D010865:Pilot Projects; D014454:Uganda; D055815:Young Adult",
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"pages": "395-408",
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"pmid": "25749663",
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"title": "Targeted spontaneous reporting of suspected renal toxicity in patients undergoing highly active anti-retroviral therapy in two public health facilities in Uganda.",
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"abstract": "Febrile infection-related epilepsy syndrome (FIRES) is a devastating immune inflammatory-mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8-year-old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non-recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune-inflammatory etiology can reasonably be hypothesized.",
"affiliations": "Intensive Care Unit, Meyer Children's Hospital, Florence, Italy.;Nephrology Department, Meyer Children's Hospital, University of Florence, Florence, Italy.;Paediatric Neurology Unit, Meyer Children's Hospital, University of Florence, Florence, Italy.",
"authors": "L'Erario|Manuela|M|;Roperto|Rosa Maria|RM|;Rosati|Anna|A|https://orcid.org/0000-0002-8754-7214",
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"fulltext": "\n==== Front\nEpilepsia Open\nEpilepsia Open\n10.1002/(ISSN)2470-9239\nEPI4\nEpilepsia Open\n2470-9239\nJohn Wiley and Sons Inc. Hoboken\n\n34596364\n10.1002/epi4.12545\nEPI412545\nShort Research Article\nShort Research Articles\nSevoflurane as bridge therapy for plasma exchange and Anakinra in febrile infection–related epilepsy syndrome\nL’ERARIO et al.\nL’Erario Manuela 1\nRoperto Rosa Maria 2\nRosati Anna https://orcid.org/0000-0002-8754-7214\n3 anna.rosati@meyer.it\n\n1 Intensive Care Unit Meyer Children’s Hospital Florence Italy\n2 Nephrology Department Meyer Children’s Hospital University of Florence Florence Italy\n3 Paediatric Neurology Unit Meyer Children’s Hospital University of Florence Florence Italy\n* Correspondence\nAnna Rosati, Paediatric Neurology Unit, Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, Firenze 50139, Italy.\nEmail: anna.rosati@meyer.it\n\n20 10 2021\n12 2021\n6 4 10.1002/epi4.v6.4 788792\n31 7 2021\n23 3 2021\n28 9 2021\n© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.\nhttps://creativecommons.org/licenses/by/4.0/ 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.\n\nAbstract\n\nFebrile infection–related epilepsy syndrome (FIRES) is a devastating immune inflammatory–mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8‐year‐old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non‐recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune‐inflammatory etiology can reasonably be hypothesized.\n\nchildren\nFIRES\nNORSE\nplasma exchange\nrefractory status epilepticus\nsevoflurane\nsource-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:01.12.2021\nL’Erario M , Roperto RM , Rosati A . Sevoflurane as bridge therapy for plasma exchange and Anakinra in febrile infection–related epilepsy syndrome. Epilepsia Open. 2021;6 :e12545. 10.1002/epi4.12545\n==== Body\npmc Key Points\n\nSevoflurane such as isoflurane should also be considered in treating refractory convulsive status epilepticus in children.\n\nSevoflurane as bridge therapy for plasma exchange and anakinra in treating convulsive status epilepticus of presumed or ascertained autoimmune‐inflammatory etiology.\n\nLower concentration, a shorter anesthesia induction time and benzodiazepine co‐administration could reduce sevoflurane toxicity and enhance its efficacy.\n\n1 INTRODUCTION\n\nFebrile infection–related epilepsy syndrome (FIRES), which has now been classified as a subset of new‐onset refractory status epilepticus (NORSE), is a devastating epileptic encephalopathy that typically begins with a mild nonspecific febrile illness in an otherwise healthy individual. 1 Twenty‐four hours to two weeks after a febrile episode, seizures appear and evolve into a prolonged super‐refractory status epilepticus (SRSE) which may continue for months. 2\n\nBilateral and multifocal seizure onset with autonomic features and a strong tendency to evolve into bilateral tonic‐clonic seizures is commonly observed. Specific EEG patterns have been recognized in patients with FIRES. 3 Common sequels are drug‐resistant epilepsy, cognitive impairment, and psychosis. The etiology is unknown. An underlying inflammatory or immune mechanism, however, has been hypothesized based on seizure appearance after a febrile episode and the evidence of intrathecal overproduction of proinflammatory cytokines and chemokines. 4 Based on its hypothesized autoimmune etiology, patients with suspected FIRES are generally treated with intravenous corticosteroids, immunoglobulins, plasma exchange, and immunotherapy. 5 , 6 , 7 , 8 Several treatments, including ketogenic diet, hypothermia, vagus nerve stimulation, and cannabidiol have been reported and proposed for the treatment of FIRES but no records exist on the use and efficacy of inhaled anesthetics. 5 , 6 , 9 Increasing evidence indicates anakinra, an IL‐1 receptor antagonist, as a safe and efficacious therapy in FIRES. 10 Anakinra efficacy has also been reported in improving recovery and long‐term outcomes; its early administration has therefore recently been recommended in children with suspected FIRES. 10 The efficacy of inhalational anesthetics has been reported in the treatment of RCSE. 11 Isoflurane is the only inhaled anesthetic recommended and is preferred over desflurane, xenon, and sevoflurane because of its higher rate of tolerability and hypothetical lower toxicity. 11 Sevoflurane is a halogenated inhaled anesthetic with rapid onset and short‐lasting activity, with proven efficacy and safety for both the induction and maintenance of general anesthesia. 12 In comparison with older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more rapid uptake and induction than the 'older' inhalational agents, improved control of depth of anesthesia, and faster elimination and recovery. 12\n\nHere we report a case of an 8‐year‐old boy with FIRES in whom inhalation anesthesia with sevoflurane as bridge therapy for immunosuppressive treatment with plasma exchange and anakinra was effective and safe in controlling a prolonged SRSE.\n\n2 CASE REPORT\n\nAn otherwise healthy 8‐year‐old boy with a recent febrile status was transferred to the pediatric iIntensive‐care unit (PICU) of Meyer Children's Hospital from a second‐level hospital due to a coma status and recurrent focal motor seizures. Blood and cerebrospinal fluid exams were unremarkable, and a clear infective etiology was not identified. Previously the patient had been unsuccessfully treated with endorectal diazepam and intravenous benzodiazepines, phenytoin and phenobarbital. Upon admission to our hospital, the patient was intubated and underwent continuous video‐electroencephalography (EEG) monitoring which recorded right and left focal motor seizures and secondarily generalized seizures fulfilling the criteria for refractory SE. 1 , 2\n\nThe patient was therefore enrolled in a national multicenter randomized sequential trial approved by the Italian Medicines Agency (EudraCT number 2013‐004396‐12; ClinicalTrial.gov identification number: NCT02431663) and randomized to ketamine (KE) (study arm). 13 As per protocol, KE was started and the dose was rapidly increased up to 100 mcg/kg/min. Only transitory EEG suppression‐burst (SB) patterns were recorded during the 3 mg/kg KE bolus administration at each infusion velocity increment. Due to KE inefficacy, midazolam (MDZ) up to 12 mcg/kg/min, propofol (PR) up to 4 mg/kg/h, and thiopental (TPS) up to 5 mg/kg/h (control arm) were also administered as per protocol. A transitory reduction of seizure frequency without SB pattern appearance was obtained only with high doses of MDZ, and not with PR and TPS. Several anti‐seizure medications (intravenous lacosamide, levetiracetam and valproic acid, and topiramate and carbamazepine per os) were administered together with ketogenic diet with no substantial changes in seizure frequency and EEG features (Figure 1). Based on the seizure type and frequency, ranging from 20 to 35 per hour, EEG and clinical features, a diagnosis of FIRES was made. Status epilepticus remained unchanged despite 5 days of intravenous corticosteroids (1 g/day) and 2 days of intravenous immunoglobulins (2 g/day). Because of the refractoriness of SE, we opted for re‐administered conventional anesthetics (MDZ, PR, and TPS) and MDZ at a dosage up to 20 mcg/kg/min, thus obtaining only a transitory reduction of seizure frequency. After 29 days of prolonged SRSE, having received written informed consent by the parents, 3.5% sevoflurane (MAC 1) through a closed circuit was started. For the first time since the beginning of the seizures, a stable EEG SB pattern and resolution of SE was achieved (Figure 1). As soon as sevoflurane inhalation was reduced (MAC 0.6), focal motor seizures reappeared. Sevoflurane was increased to the previous dosage (MAC 1) in association with five‐day plasma exchange therapy. Combined therapy with sevoflurane and plasma exchange (1.5 PV) was then efficacious to reach a stable EEG SB pattern and SRSE control. No major sevoflurane‐related adverse events, such as hypotension requiring vasopressors, were observed with the exception of a transitory mild metabolic acidosis. Only a few (2 to 4 per day) minor focal motor seizures re‐occurred after the withdrawal of sevoflurane and plasma exchange. Seven days after sevoflurane and plasma exchange had been discontinued, anakinra at the dosage of 100 mg b.i.d. was started in association with PHT, PB, topiramate and lorazepam (Figure 1). Due to the poor mental status of the patient and in order to begin ventilator weaning, a tracheostomy was necessary. The patient was transferred to the Neurology Department following 68 days of intensive care. After another 12 days, he was discharged from the hospital and sent home with 2 to 4 focal motor seizures a week and in a minimally conscious state. The first brain MRI report, performed at one week from seizure onset, was normal. At one month from seizure onset, mild cerebral atrophy and hippocampal sclerosis was observed; after six months, MRI showed moderate to severe cortical‐subcortical atrophy.\n\nFIGURE 1 EEG features (figure above) and treatments (figure below) during the 68 days in ICU from May 25 to July 29. EEG features, ictal EEG pattern (to the left), suppression‐burst pattern (at the center) and interictal EEG activity after status epilepticus resolution (to the right). Treatments: IV Ig, intravenous immunoglobulin; KE, ketamine; LCS, lacosamide; LZP, lorazepam; MDZ, midazolam; PB, phenobarbital; PE, plasma exchange; PHT, phenytoin; PR, propofol; Sevo, sevoflurane; TPM, topiramate; TPS, thiopental; VPA, valproate\n\n3 DISCUSSION\n\nIn our case, inhaled anesthesia with sevoflurane combined with plasma exchange was effective in controlling a prolonged SRSE with no adverse events. An EEG SB pattern was only achieved with sevoflurane, and SRSE resolution was obtained when plasma exchange therapy was added, thus confirming the efficacy of immunotherapy in FIRES. The low blood solubility and high lipid solubility of sevoflurane are responsible for its rapid distribution in the cerebral tissue and its scarce elimination through plasma exchange, unlike the most commonly used intravenous anesthetics. 12 These pharmacokinetic features make sevoflurane particularly interesting in treating SE in which plasma exchange is indicated.\n\nIsoflurane is the only volatile anesthetic recommended in the treatment of RCSE. 11 It is preferred to desflurane, xenon, and sevoflurane because it has a higher rate of tolerability and hypothetical lower toxicity. 11 In fact, electroencephalogram abnormalities and epileptiform patterns have been observed in children undergoing sevoflurane mask anesthesia induction, both in healthy children and in children with epilepsy. 14 Some studies showed that lower sevoflurane concentration during anesthesia induction and shorter induction time could reduce the occurrence of epileptic discharge. 15 Kreuzer et al showed that anesthesia induction with 6% sevoflurane in children was accompanied by reduced epileptiform activity when compared to the administration of 8% sevoflurane. 15 Benzodiazepine premedication has been considered responsible for the absence of epileptiform EEG changes during sevoflurane anesthesia. 16\n\nRecent experimental studies suggest that volatile anesthetics have a neuroprotective effect when the brain is undergoing ischemia, yet they display neurotoxicity under normal brain conditions when administered during early or late development stages. 17\n\nWe report administering sevoflurane for an extremely severe epileptic episode of prolonged SRSE. It was administered along with MDZ and lorazepam. Both the ischemic condition together with the paired administration of benzodiazepines may have contributed to the reduction of its toxicity and may have enhanced its efficacy. 18\n\nIn our case, anakinra was efficacious in maintaining seizure control after sevoflurane withdrawal, thus supporting its efficacy in FIRES. 10\n\nThe brain MRI revealed a diffuse cortical‐subcortical brain atrophy, as is often reported in FIRES patients. 19 Whether brain atrophy is due to prolonged intractable seizures or the disease entity itself is still uncertain.\n\nWe suggest that sevoflurane as bridge therapy for immunosuppressive treatment could be taken into consideration early in those children with SE in which an autoimmune‐inflammatory etiology may be reasonably hypothesized.\n\nCONFLICT OF INTEREST\n\nThe authors have disclosed that they do not have any potential conflicts of interest. The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n\nACKNOWLEDGEMENTS\n\nThe authors thank the EEG technicians Francesca Piras, Elisa Nacci and Debora Di Maina for their technical support on EEG recordings.\n==== Refs\nREFERENCES\n\n1 Hirsch LJ , Gaspard N , van Baalen A , Nabbout R , Demeret S , Loddenkemper T , et al Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions. Epilepsia. 2018;59 :739–44.29399791\n2 Gaspard N , Hirsch LJ , Sculier C , Loddenkemper T , van Baalen A , Lancrenon J , et al New‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia. 2018;59 :745–52.29476535\n3 Farias‐Moeller R , Bartolini L , Staso K , Schreiber JM , Carpenter JL . Early ictal and interictal patterns in FIRES: the sparks before the blaze. Epilepsia. 2017;58 :1340–8.28555777\n4 Kothur K , Bandodkar S , Wienholt L , Chu S , Pope A , Gill D , et al Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus. Epilepsia. 2019;60 :1678–88.31283843\n5 Hon KL , Leung AKC , Torres AR . Febrile Infection‐Related Epilepsy Syndrome (FIRES): an overview of treatment and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2018;12 :128–35.29745347\n6 Sakuma H , Horino A , Kuki I . Neurocritical care and target immunotherapy for febrile infection‐related epilepsy syndrome. Biomed J. 2020;43 :205–10.32330681\n7 Kenney‐Jung DL , Vezzani A , Kahoud RJ , LaFrance‐Corey RG , Ho M‐L , Muskardin TW , et al Febrile infection‐related epilepsy syndrome treated with anakinra. Ann Neurol. 2016;80 :939–45.27770579\n8 Dilena R , Mauri E , Aronica E , Bernasconi P , Bana C , Cappelletti C , et al Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection‐related epilepsy syndrome. Epilepsia Open. 2019;4 :344–50.31168503\n9 Serino D , Santarone ME , Caputo D , Fusco L . Febrile infection‐related epilepsy syndrome (FIRES): prevalence, impact and management strategies. Neuropsychiatr Dis Treat. 2019;15 :1897–903.31371963\n10 Koh S , Wirrell E , Vezzani A , Nabbout R , Muscal E , Kaliakatsos M , et al Proposal to optimize evaluation and treatment of Febrile infection‐related epilepsy syndrome (FIRES): a report from FIRES workshop. Epilepsia Open. 2021;6 :62–72.33681649\n11 Zeiler FA , Zeiler KJ , Teitelbaum J , Gillman LM , West M . Modern inhalational anesthetics for refractory status epilepticus. Can J Neurol Sci. 2015;42 :106–15.25572922\n12 Behne M , Wilke HJ , Harder S . Clinical pharmacokinetics of sevoflurane. Clin Pharmacokinet. 1999;36 :13–26.\n13 Rosati A , Ilvento L , L'Erario M , De Masi S , Biggeri A , Fabbro G , et al Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open‐label, non‐profit trial (KETASER01). BMJ Open. 2016;6 :e011565.\n14 Brioni JD , Varughese S , Ahmed R , Bein B . A clinical review of inhalation anesthesia with sevoflurane: from early research to emerging topics. J Anesth. 2017;31 :764–78.28585095\n15 Constant I , Seeman R , Murat I . Sevoflurane and epileptiform EEG changes. Paediatr Anaesth. 2005;15 :266–74.15787916\n16 Kreuzer I , Osthaus WA , Schultz A , Schultz B . Influence of the sevoflurane concentration on the occurrence of epileptiform EEG patterns. PLoS One. 2014;9 :e89191.24586585\n17 Nieminen K , Westerèn‐Punnonen S , Kokki H , Yppärilä H , Hyvärinen A , Partanen J , et al Sevoflurane anaesthesia in children after induction of anaesthesia with midazolam and thiopental does not cause epileptiform EEG. Br J Anaesth. 2002;89 :853–6.12453929\n18 Neag MA , Mitre AO , Catinean A , Mitre CI . An overview on the mechanisms of neuroprotection and neurotoxicity of isoflurane and sevoflurane in experimental studies. Brain Res Bull. 2020;165 :281–9.33080307\n19 Culleton S , Talenti G , Kaliakatsos M , Pujar S , D'Arco F . The spectrum of neuroimaging findings in febrile infection‐related epilepsy syndrome (FIRES): a literature review. Epilepsia. 2019;60 :585–92.30854647\n\n",
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"keywords": "FIRES; NORSE; children; plasma exchange; refractory status epilepticus; sevoflurane",
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"title": "Sevoflurane as bridge therapy for plasma exchange and Anakinra in febrile infection-related epilepsy syndrome.",
"title_normalized": "sevoflurane as bridge therapy for plasma exchange and anakinra in febrile infection related epilepsy syndrome"
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"abstract": "Dextromethorphan (DM) may have ketamine-like rapid-acting, treatment-resistant, and conventional antidepressant effects.1,2 This reports our initial experience with DM in unipolar Major Depressive Disorder (MDD). A patient with treatment-resistant MDD (failing adequate trials of citalopram and vortioxetine) with loss of antidepressant response (to fluoxetine and bupropion) twice experienced a rapid-acting antidepressant effect within 48 hours of DM administration and lasting 7 days, sustained up to 20 days with daily administration, then gradually developing labile loss of antidepressant response over the ensuing 7 days. Upon full relapse in DSM-5 MDD while taking 600 mg/day of the strong CYP2D6 inhibitor bupropion XL, a 300 mg oral loading dose of DM was given, followed by 60 mg po bid after an additional dose-finding period, without side effects. DM exhibited a ketamine-like rapid-acting antidepressant effect, thought to be mediated by mTOR activation (related to NMDA PCP site antagonism, sigma-1 and beta adrenergic receptor stimulation) and 5HTT inhibition, resulting in AMPA receptor trafficking, and dendritogenesis, spinogenesis, synaptogenesis, and increased neuronal survival (related to NMDA antagonism and sigma-1 and mTOR signaling). This report appears to be the first report of a rapid-acting effect in unipolar MDD and adds to antidepressant effects observed in the retrospective chart review of 77 patients with Bipolar II Disorder (Kelly and Lieberman 2014). If replicated, there is some reason to think that the administration of other agents with DM, such as lithium or D-cycloserine, might prolong the duration of the rapid-antidepressant effect.",
"affiliations": "Dr. Edward C. Lauterbach, MD, Professor Emeritus of Psychiatry and Neurology, Mercer University School of Medicine, Macon, Georgia, USA.",
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"title": "Treatment Resistant Depression with Loss of Antidepressant Response: Rapid-Acting Antidepressant Action of Dextromethorphan, A Possible Treatment Bridging Molecule.",
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"abstract": "Listeria monocytogenes is the third most frequent cause of bacterial meningitis and has a predilection for elderly patients and the immunosuppressed. A small number of patients with Listeria monocytogenes meningoencephalitis have previously been reported to experience stroke-like symptoms that were attributed to microabscess formation and the mass effect of collections of infection in the brain. These infections led to temporary neurological deficits that resolved with antimicrobial treatment, rather than to true strokes with permanent neurological deficits. This report discusses the case of an 80- year-old male, who was immunosuppressed with mesalazine for the treatment of Crohn's disease, and who went on to develop Listeria monocytogenes meningoencephalitis. 1 week into his admission, for antibiotic therapy, the patient began to experience new onset right upper limb weakness, nystagmus and past pointing. These symptoms were initially thought to be a complication of the infection. However, subsequent diffusion-weighted MRI revealed that the patient had more likely suffered an acute ischaemic event and a contrast-enhanced MRI performed later could not detect any abscess or large infective focus in a region that could explain the symptoms. This case report highlights the fact that ischaemic and infective pathologists may coexist in immunosuppressed Listeria patients and that clinical signs and symptoms should guide the use of appropriate imaging modalities such as MRI to clarify differentials so that ischaemia is not mistaken for the more common stroke mimic caused by infection in these patients.",
"affiliations": "East Kest Hospitals University NHS Trust, Margate, United Kingdom.;East Kest Hospitals University NHS Trust, Margate, United Kingdom.;East Kest Hospitals University NHS Trust, Margate, United Kingdom.;East Kest Hospitals University NHS Trust, Margate, United Kingdom.",
"authors": "Deen|Surrin S|SS|0000-0002-6206-7337;Boyes|Jennifer|J|;Oyewole|Bankole|B|;Bahk|Anna|A|;Thomas|George|G|;Gunathilagan|Gunaratnam|G|",
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"fulltext": "\n==== Front\nBJR Case Rep\nBritish Institute of Radiology\nbjrcr\nBJR | case reports\n2055-7159 The British Institute of Radiology. \n\nBJRCR-D-19-00068\n10.1259/bjrcr.20190068\nCase Report\nbjrcrBJRCRneuroNeuroradiologymriMRIAcute ischaemic stroke in Listeria monocytogenes meningoencephalitis\nIschaemic stroke in Listeria meningoencephalitis.Deen et alhttp://orcid.org/0000-0002-6206-7337Deen Surrin S. MBBS1,2ssd32@cam.ac.uk Boyes Jennifer 2jennifer.boyes1@nhs.net Oyewole Bankole 2bankole.oyewole@nhs.net Bahk Anna 2annabahk@nhs.net Thomas George 2gthomas3@nhs.net Gunathilagan Gunaratnam 2,3g.gunathilagan@nhs.net 1 Department of Radiology, University of Cambridge, Cambridge, United Kingdom\n2 East Kest Hospitals University NHS Trust, Margate, United Kingdom\n3 School of Medical Education, King's College London, London, United Kingdom\nAddress correspondence to: Dr Surrin S. Deen. E-mail: ssd32@cam.ac.uk\n3 2020 \n12 2 2020 \n6 1 2019006809 7 2019 08 9 2019 13 9 2019 © 2020 The Authors. Published by the British Institute of Radiology2020The AuthorsThis is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.Listeria monocytogenes is the third most frequent cause of bacterial meningitis and has a predilection for elderly patients and the immunosuppressed. A small number of patients with Listeria monocytogenes meningoencephalitis have previously been reported to experience stroke-like symptoms that were attributed to microabscess formation and the mass effect of collections of infection in the brain. These infections led to temporary neurological deficits that resolved with antimicrobial treatment, rather than to true strokes with permanent neurological deficits. This report discusses the case of an 80- year-old male, who was immunosuppressed with mesalazine for the treatment of Crohn’s disease, and who went on to develop Listeria monocytogenes meningoencephalitis. 1 week into his admission, for antibiotic therapy, the patient began to experience new onset right upper limb weakness, nystagmus and past pointing. These symptoms were initially thought to be a complication of the infection. However, subsequent diffusion-weighted MRI revealed that the patient had more likely suffered an acute ischaemic event and a contrast-enhanced MRI performed later could not detect any abscess or large infective focus in a region that could explain the symptoms. This case report highlights the fact that ischaemic and infective pathologists may coexist in immunosuppressed Listeria patients and that clinical signs and symptoms should guide the use of appropriate imaging modalities such as MRI to clarify differentials so that ischaemia is not mistaken for the more common stroke mimic caused by infection in these patients.\n==== Body\nClinical presentation\nAn 80-year-old male presented to the emergency department with fever and confusion. He had a background of Crohn’s disease, diabetes mellitus type II, atrial fibrillation and hypertension. For these conditions, he took mesalazine 1.5 g three times a day, insulin injections, bisoprolol 1.25 mg once daily and rivaroxaban 20 mg once daily. He was assessed by the emergency physicians and found to have pain on neck flexion. Blood tests revealed raised serum C-reactive protein and a CT of the head showed age-related changes but no acute abnormalities. Blood cultures were taken and a lumbar puncture was performed for cerebrospinal fluid sampling. The patient then began empirical treatment for a presumed diagnosis of bacterial meningitis and his mesalazine use was put on hold. Cerebrospinal fluid polymerase chain reaction analysis later revealed the presence of Listeria monocytogenes and after discussion with the hospital microbiologist, antibiotic treatment was changed to a 6-week course of intravenous amoxicillin. 2 days later, the patient’s blood culture results also confirmed Listeria monocytogenes growth. The features of meningism began to gradually improve with amoxicillin treatment but on day 7 of admission, the patient developed new right upper limb numbness, nystagmus and past pointing on the right side.\n\nDifferential diagnosis\nInitially, it was thought that the most likely cause for the patient’s new neurological symptoms was progression of his infection. This suspicion was based off previous literature describing abscess formation as the most common source of stroke-like symptoms in immunosuppressed Listeria monocytogenes meningoencephalitis patients.1–4 A true stroke was also considered as a possibility at this point, but ischaemia was felt to be less likely due to the patient’s anticoagulation with rivaroxaban and a lack of any reports that the clinical team could identify describing an ischaemic stroke occurring simultaneously with active Listeria meningoencephalitis infection. Imaging was nevertheless performed to assess for progression of infection, ischaemic or haemorrhagic stroke\n\nInvestigation/Imaging findings\nCT of the head after the development of limb numbness, nystagmus and past pointing, showed no changes compared to the CT imaging from 1 week earlier at admission. MRI of the head was therefore performed, but diagnostic quality was limited due to agitation and movement by the patient, diffusion-weighted imaging (DWI) however revealed a small hyperintensity in the left occipital lobe white matter adjacent to the lateral ventricle. This is shown in Figure 1.\n\nFigure 1. (a) DWI showing a small left occipital lesion (arrow); (b) ADC map does not depict a clear lesion corresponding to that seen on DWI. ADC, apparent diffusion coefficient; DWI, diffusion-weightedimaging.\n\nAfter detection of this small occipital lesion, a repeat MRI was performed under mild benzodiazepine sedation and with contrast, which showed high signal in the dependent regions within each lateral ventricle, likely representing ventriculitis related to the Listeria meningoencephalitis. The small focus of high DWI signal was again seen in the left occipital lobe, adjacent to the medial aspect of the occipital horn of the left lateral ventricle. On the apparent diffusion coefficient map, this lesion was of low signal, in keeping with a small focal infarct in the area. There was a normal craniocervical junction region, moderate generalized atrophy and severe periventricular and corona radiata deep white matter microangiopathic changes. There was no convincing focus of intracranial haemorrhage and nothing to suggest haemorrhagic transformation of the small left occipital infarct. Post-contrast, there were no signs of intracranial abscess or empyema and no evidence of a space-occupying lesion. The dural venous sinuses were patent and there were no significant findings identified involving the arterial tree at the level of the circle of Willis. The MRI slices showing the occipital lesion are displayed in Figure 2.\n\nFigure 2. Repeat MRI images under sedation (a) DWI image showing a small left occipital lesion (arrow); (b) ADC map showing a small area of low ADC (arrow) corresponding to the lesion on DWI; (c) T2 weighted image showing no significant changes in the region of the lesion; (d) post-contrast image showing no contrast uptake or ring-enhancement at the site of the lesion. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging.\n\nCT angiogram of the carotids was performed after the MRI confirming stroke but did not find any source of emboli in the carotids. There was no significant stenosis, aneurysm or occlusion detected in any major blood vessel, although some calcification was noted at the proximal internal carotid artery on the left and within the distal vertebral artery on the right. The appearance of the CT angiogram is shown in Figure 3.\n\nFigure 3. The patient’s CT angiogram of (a) the carotids showing no significant stenosis and (b) the intracranial blood vessels.\n\nTreatment, outcome and follow-up\nThe patient’s stroke was treated by pausing rivaroxaban and initiating anti platelet therapy with 300 mg of aspirin once daily. After 2 weeks, he was restarted on rivaroxaban and the aspirin was permanently stopped. He spent a total of 38 days in hospital and during this time he also underwent stroke physiotherapy treatment. He was then discharged home and had a follow-up appointment with a stroke consultant in an outpatient clinic three months later. At the follow-up clinic, he still had some residual stroke symptoms that affected his mobility and acted as further confirmation of a true ischaemic event due to the symptom persistence at this time. He required the assistance of Zimmer frame to mobilize and had a Tinetti balance score of 19/28, indicating he now had a moderate falls risk. He also required support from arm rests and rails to facilitate his transfers but was independent with his self-care, including dressing and washing. He also reported that his Crohn’s disease was not fully controlled at the time of follow-up but was due to see a gastroenterologist for adjustment of this treatment.\n\nDiscussion\nListeria monocytogenes meningoencephalitis has a higher prevalence in the elderly and in patients who are immunocompromised.5,6 Particularly, in the immunosuppressed there can be sufficient accumulation of bacteria to create an abscess that has a mass effect on the CNS and causes focal neurological signs and symptoms.7,8 When abscess formation occurs, eradication of the organism becomes more difficult. Early recognition and treatment of Listeria monocytogenes meningoencephalitis is therefore important to avoid progression in the immunosuppressed.\n\nThe presentation of progressive Listeria monocytogenes meningoencephalitis can mimic stroke and cases of stroke mimics have been reported in immunosuppression caused by chronic lymphocytic leukaemia and chronic lymphocytic leukaemia treatment,2 in lung cancer with chemotherapy treatment,3 in a rheumatoid arthritis patient taking methotrexate and prednisolone4 and in a patient taking immunosuppressive therapy for Horton’s arthritis.1\n\nThe authors of this case report have not been able to identify a published example of stroke symptoms developing in any Listeria monocytogenes meningoencephalitis patient, immunosuppressed for Crohn’s, or to identify any other report of a true ischaemic stroke occurring during an episode of active Listeria monocytogenes meningoencephalitis infection. Nevertheless, in the case presented here a histological diagnosis of stroke was not established and previous studies have shown that ischemic complications of CNS infection may be associated with vasculitic thrombotic infarction, such as commonly occurs in tuberculosis9 or rarely in other infections.10 A cardioembolic source for the infarction was also unsupported by any bacteremia or known valvular disease and the possibility of early microabscess formation cannot be completely excluded based on the imaging and clinical findings presented here alone. This patient, however, represents an example of the clinical dilemmas faced when concomitant episodes suggestive of acute cerebral infarct and Listeria monocytogenes meningoencephalitis occur and demonstrates how the combination of diffusion weighted and contrast enhanced MRI can be used in an attempt to clarify the diagnoses.\n\nThe ability to differentiate neurological deficits caused by infection from those caused by ischaemia is clinically important as the treatments for each condition is different and delays in diagnosis, especially of ischaemic stroke, are associated with higher morbidity. The appearance of ischaemic stroke on DWI depends on timing after the event. Following a stroke there is an initial hyperintensity on DWI and then a decrease in signal towards the later phases. In CNS infection there can be a centrally located restriction in diffusion and more significant restriction of diffusion peripherally if there is an abscess wall present. With contrast-enhanced MRI on the other hand, infarcted nervous tissue does not typically show enhancement; however, infection can demonstrate enhancement both centrally and peripherally in the form of an outer ring.\n\nCases like this should serve as a reminder to clinicians to consider the possibility of two simultaneous and different pathophysiologies, resulting in symptoms that could otherwise be attributed to only one disease. The more common scenario is for Listeria monocytogenes meningoencephalitis to cause a stroke mimic but the possibility of a true stroke should never be overlooked as stroke is a condition which, if missed or incorrectly attributed to a mimic, could result in severe disability or even death. In the future, the early use of diffusion-weighted and contrast-enhanced MRI, when CT head results are non-diagnostic, should always be considered in Listeria monocytogenes meningoencephalitis patients who develop stroke-like symptoms including those who are immunosuppressed.\n\nLearning points\nStroke-like symptoms in Listeria monocytogenes meningoencephalitis may present in immunocompromised patients due to progression of infection and the mass effect of abscess formation.\n\nIt is also possible for stroke-like symptoms presenting in immunosuppressed Listeria monocytogenes meningoencephalitis patients to represent true cerebral infarct.\n\nDiffusion-weighted MRI and contrast-enhanced MRI can help differentiate infective from ischaemic causes of neurological deficit in Listeria monocytogenes meningoencephalitis patients and should be considered early in the clinical work-up.\n\nAcknowledgment: The authors would like to acknowledge support for this work from the stroke unit and radiology department of Queen Elizabeth the Queen Mother Hospital and from the Education Centre of East Kent Hospitals University NHS Foundation Trust and King’s College London School of Medicine.\n\nInformed consent statement: Written informed consent was obtained from the patient for the publication of all the clinical information and images discussed in this article.\n==== Refs\nREFERENCES\n1. Peterlana D , Cozzio S , Bonifatti DM , WJIJoM S \nStroke-like manifestations in a patient with Listeria monocytogenes abscess and Horton’s arteritis\n. 2014 ; 64 –8\n.\n2. Bajkó Z , Bălaşa R , Maier S , Moţăţăianu A , Treabă A , Macarie I , et al \nListeria monocytogenes meningoencephalitis mimicking stroke in a patient with chronic lymphocytic leukemia\n. Neurol Ther \n2013 ; 2 (1-2 ): 63 –70\n. doi: 10.1007/s40120-013-0009-y 26000217 \n3. Marini S , Caruso A , Falcini M , Palumbo P , Pantoni L , LJJoCN P \nListeria monocytogenes brainstem infection (rhombencephalitis) mimicking ischemic stroke\n. J Clin Neurosci \n2014 ; 21 : 2006 –8\n. doi: 10.1016/j.jocn.2014.03.021 24961733 \n4. Karunaratne K , Bertoni M , Balogun I , Hargroves D , TJPn W \nThe right diagnosis but the wrong pathway?\n\nListeria meningitis mimicking stroke \n2016 ; 16 : 220 –2\n.\n5. Mylonakis E , Hohmann EL , Calderwood S \nCentral nervous system infection with Listeria monocytogenes. 33 years' experience at a general Hospital and review of 776 episodes from the literature\n. 1998 ; 77 : 313 –36\n.\n6. Aouaj Y , Spanjaard L , Van Leeuwen N , Dankert JJE \nInfection. Listeria monocytogenes meningitis: serotype distribution and patient characteristics in the Netherlands\n. 2002 ; 128 : 405 –9\n.\n7. Bartt R \neditor Listeria and atypical presentations of Listeria in the central nervous system : Seminars in neurology . 333 Seventh Avenue, New : Copyright© 2000 by Thieme Medical Publishers, Inc. ; 2000 .\n8. Cone LA , Leung MM , Byrd RG , Annunziata GM , Lam RY , Herman BK \nMultiple cerebral abscesses because of Listeria monocytogenes: three case reports and a literature review of supratentorial listerial brain abscess(es\n. Surg Neurol \n2003 ; 59 : 320 –8\n. doi: 10.1016/S0090-3019(03)00056-9 12748019 \n9. M-LS T , Viswanathan S , Rahmat K , Nor HM , Kadir KAA , Goh KJ , et al \nCerebral infarction pattern in tuberculous meningitis\n. 2016 ; 6 : 38802 .\n10. Lim CCT , Lee KE , Lee WL , Tambyah PA , Lee CC , Sitoh YY , et al \nNipah virus encephalitis: serial Mr study of an emerging disease\n. Radiology \n2002 ; 222 : 219 –26\n. doi: 10.1148/radiol.2221010499 11756729\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-7159",
"issue": "6(1)",
"journal": "BJR case reports",
"keywords": null,
"medline_ta": "BJR Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101684132",
"other_id": null,
"pages": "20190068",
"pmc": null,
"pmid": "32201611",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "12113484;26819187;12748019;24961733;9772921;26000217;27958312;11756729",
"title": "Acute ischaemic stroke in Listeria monocytogenes meningoencephalitis.",
"title_normalized": "acute ischaemic stroke in listeria monocytogenes meningoencephalitis"
} | [
{
"companynumb": "GB-ALLERGAN-2014373US",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "1",
"... |
{
"abstract": "Management of metastatic malignant melanoma is challenging. Although several new systemic therapies for metastatic malignant melanoma have recently been developed, some patients still also require radiation therapy (RT) for palliative care. However, the safety and efficacy of combining use of novel drugs with RT remain unclear. Here, we report treating a patient with rapidly growing malignant melanoma with a programmed cell death protein 1 (PD-1) inhibitor and a BRAF inhibitor together with 60 Gy of hypofractionated RT without severe adverse effects. The tumor within the radiation field exhibited a more marked response than that outside it. A combination of RT with an anti-PD-1 antibody or a BRAF inhibitor may, therefore, be a useful and tolerable approach to treating metastatic BRAF-mutant melanoma.",
"affiliations": "Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.;Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.;Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.;Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.;Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.;Division of Radiation Oncology, Department of Radiation Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047 Japan.",
"authors": "Ueki|Kazuhito|K|0000-0002-3562-2593;Kosaka|Yasuhiro|Y|;Kimino|Genki|G|;Imagumbai|Toshiyuki|T|;Takayama|Kenji|K|;Kokubo|Masaki|M|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-016-0260-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "5(4)",
"journal": "International cancer conference journal",
"keywords": "Anti-PD-1 antibody; BRAF; Hypofractionated radiation therapy; Melanoma",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "214-218",
"pmc": null,
"pmid": "31149457",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "10348291;15342808;16636135;21295875;21639808;22658127;23462419;23650406;24192487;2424880;24743051;24985732;25399552;25527358;25578781;25762352;25795410;25873177;26027431;26433823",
"title": "Treatment of malignant melanoma with nivolumab and vemurafenib combined with hypofractionated radiation therapy.",
"title_normalized": "treatment of malignant melanoma with nivolumab and vemurafenib combined with hypofractionated radiation therapy"
} | [
{
"companynumb": "JP-ROCHE-1678990",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "To clarify the correlation between preeclampsia and parity and to identify protective factors against preeclampsia in multiparous women with systemic lupus erythematosus (SLE).\nWe conducted a single-center, retrospective chart review study of 85 pregnant women. We used multiple logistic regression analysis to assess the association between parity and preeclampsia in women with SLE, and described the detailed clinical courses and management of four women with a history of severe preeclampsia and of a woman who experienced preeclampsia during her latest pregnancy.\nMultiparity was significantly associated with a low risk of preeclampsia (adjusted odds ratio: 0.08; 95% confidence interval: 0.01-0.95). One multiparous woman without a history of preeclampsia developed preeclampsia during her latest pregnancy; she had critical risk factors for preeclampsia, including chronic kidney disease and hypertension, and was not administered aspirin. In contrast, four multiparous women with a history of severe preeclampsia received adequate medications; they did not develop recurrent preeclampsia and delivered live newborns.\nMultiparity and maintenance therapy for SLE before and during pregnancy and preventive treatment for preeclampsia may improve outcomes in subsequent pregnancies.",
"affiliations": "Department of Obstetrics, National Center for Child Health and Development, Tokyo, Japan.;Division of Maternal Medicine, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Department of Obstetrics, National Center for Child Health and Development, Tokyo, Japan.;Department of Obstetrics, National Center for Child Health and Development, Tokyo, Japan.;Division of Maternal Medicine, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Maeda|Yuto|Y|;Kaneko|Kayoko|K|;Ogawa|Kohei|K|;Sago|Haruhiko|H|;Murashima|Atsuko|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14397595.2020.1830466",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "31(4)",
"journal": "Modern rheumatology",
"keywords": "Aspirin; parity; pre-eclampsia; pregnancy; systemic lupus erythematosus",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006973:Hypertension; D015994:Incidence; D007231:Infant, Newborn; D008180:Lupus Erythematosus, Systemic; D016017:Odds Ratio; D010298:Parity; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D012189:Retrospective Studies; D012306:Risk; D012307:Risk Factors",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "843-848",
"pmc": null,
"pmid": "32990121",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The effect of parity, history of preeclampsia, and pregnancy care on the incidence of subsequent preeclampsia in multiparous women with SLE.",
"title_normalized": "the effect of parity history of preeclampsia and pregnancy care on the incidence of subsequent preeclampsia in multiparous women with sle"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-16971",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"druga... |
{
"abstract": "BACKGROUND\nWith the introduction of the Kidney Allocation System in the United States in December 2014, transplant centers can list eligible B blood type recipients for A2 organ offers. There have been no prior reports of ABO incompatible A2 to B deceased donor kidney transplantation in human immunodeficiency virus-positive (HIV+) recipients to guide clinicians on enrolling or performing A2 to B transplantations in HIV+ candidates. We are the first to report a case of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results.\n\n\nRESULTS\nWe describe an HIV+ 39-year-old African American man with end-stage renal disease who underwent A2 to B blood type incompatible deceased donor kidney transplantation. Prior to transplantation, he had an undetectable HIV viral load. The patient was unsensitized, with his most recent anti-A titer data being 1:2 IgG and 1:32 IgG/IgM. Induction therapy of basiliximab and methylprednisolone was followed by a postoperative regimen of plasma exchange, intravenous immunoglobulin, and rituximab with maintenance on tacrolimus, mycophenolate mofetil, and prednisone. He had delayed graft function without rejection on allograft biopsy. Nadir serum creatinine was 2.0 mg/dL. He continued to have an undetectable viral load on the same antiretroviral therapy adjusted for renal function.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results, suggesting that A2 donor kidneys may be considered for transplantation into HIV+ B-blood type wait list candidates.",
"affiliations": "Department of General Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address: rachel.forbes@vanderbilt.edu.;Department of General Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Department of Internal Medicine, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Department of General Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Department of Internal Medicine, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Department of General Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.",
"authors": "Forbes|R C|RC|;DeMers|A|A|;Concepcion|B P|BP|;Moore|D R|DR|;Schaefer|H M|HM|;Shaffer|D|D|",
"chemical_list": "D000017:ABO Blood-Group System",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2016.11.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D001787:Blood Group Incompatibility; D051799:Delayed Graft Function; D015658:HIV Infections; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D014019:Tissue Donors; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "206-209",
"pmc": null,
"pmid": "28104138",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A2 to B Blood Type Incompatible Deceased Donor Kidney Transplantation in a Recipient Infected with the Human Immunodeficiency Virus: A Case Report.",
"title_normalized": "a2 to b blood type incompatible deceased donor kidney transplantation in a recipient infected with the human immunodeficiency virus a case report"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP004621",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional... |
{
"abstract": "Erythema annulare centrifugum (EAC) is a rare erythema characterized by erythematous and urticarial papules or annular plaques that enlarges centrifugally. The lesions usually involve the thighs and the legs. Several disorders are occasionally associated with EAC, infections, including mycoses, bacteria, or viruses and drugs have also been regarded as possible causes of this eruption. We present a 42-year-old dark-skinned woman affected by recurrent EAC that appeared secondary to influenza type A (H1N1). Histopathology showed a superficial form of EAC. In our case, a previous cytomegalovirus and Epstein-Barr virus (EBV) infection were identified and no underlying other diseases were found. Clarithromycin with calcipotriol betamethasone treatment was temporarily efficacious. In the last 3 years, the lesions started to appear every 2 weeks and tended to regress with local treatment after a variable period. We believe that the latent cytomegalovirus and the reactivity induced by EBV combined with influenza can determine, in our case, a cell mediate cutaneous immune response, which leads to the peculiar inflammatory disease known as EAC.",
"affiliations": "Dermatology Unit of Asti's Hospital, Cardinal Massaia Hospital, Asti, Italy.;Skinlab, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.;Skinlab, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.;Skinlab, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.",
"authors": "Ena|Luca|L|;Mazzarello|Vittorio|V|;Ferrari|Marco|M|;Ena|Pasquale|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512869",
"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567\nS. 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\n10.1159/000512869\ncde-0013-0134\nSingle Case\nRecurrent Erythema Annulare Centrifugum due to Influenza Type A\nEna Luca ab\nMazzarello Vittorio b\nFerrari Marco bc*\nEna Pasquale bd\naDermatology Unit of Asti's Hospital, Cardinal Massaia Hospital, Asti, Italy\nbSkinlab, Department of Biomedical Sciences, University of Sassari, Sassari, Italy\ncDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy\ndPrivate Practitioner, Sassari, Italy\n*Marco Ferrari, Skinlab, Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, IT–07100 Sassari (Italy), dr.marcoferrari@gmail.com\nJan-Apr 2021\n18 2 2021\n18 2 2021\n13 1 134140\n15 6 2020\n8 11 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis 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.\nErythema annulare centrifugum (EAC) is a rare erythema characterized by erythematous and urticarial papules or annular plaques that enlarges centrifugally. The lesions usually involve the thighs and the legs. Several disorders are occasionally associated with EAC, infections, including mycoses, bacteria, or viruses and drugs have also been regarded as possible causes of this eruption. We present a 42-year-old dark-skinned woman affected by recurrent EAC that appeared secondary to influenza type A (H1N1). Histopathology showed a superficial form of EAC. In our case, a previous cytomegalovirus and Epstein-Barr virus (EBV) infection were identified and no underlying other diseases were found. Clarithromycin with calcipotriol betamethasone treatment was temporarily efficacious. In the last 3 years, the lesions started to appear every 2 weeks and tended to regress with local treatment after a variable period. We believe that the latent cytomegalovirus and the reactivity induced by EBV combined with influenza can determine, in our case, a cell mediate cutaneous immune response, which leads to the peculiar inflammatory disease known as EAC.\n\nKeywords\n\nErythema annulare centrifugum\nInfluenza\nParacetamol\nCytomegalovirus\nCell-mediate immunity\n==== Body\nIntroduction\n\nErythema annulare centrifugum (EAC) is a reactive disorder that appears as urticarial-like papules and erythematous plaques with crusts or vesicles that enlarge by peripheral extension with central clearing, resulting in annular or polycyclic appearance. EAC is a relatively rare inflammatory disorder described by Darier in the annular erythema's group. EAC secondary to influenza A in a dark-skinned woman was never described in this condition. Infectious diseases, drug use, systemic diseases, autoimmune disorders, and internal malignancies are occasionally associated [1].\n\nCase Presentation\n\nA 42-year-old native Indian woman was referred to our department in October 2016 with a 6-month history of a relapsing, mild itchy eruption involving the legs and abdomen. This eruption was concomitant with seasonal influenza (cough, fever, and fatigue), lasting for 6 weeks, treated with paracetamol 1,000 mg/day and sometimes tripolidine. She was otherwise healthy and had no lymphadenopathy. Physical examination revealed several erythematous and violaceus annular plaques, measuring from 2 to 10 cm in diameter, with a thick central area and a centrifugal spread on forearms, lower abdomen, buttocks, thighs, and lower legs. The lesions were located symmetrically in the inguinal and upper-exterior regions of the thighs. Some of these plaques presented an erythematous edge and peripheral scaling (Fig. 1a, b). Routine blood investigation revealed a moderate neutrophilic leukocytosis (13.5 × 103/mm3: 4.50–12.5), hypercholesterolemia, and increase of C-reactive protein (19.64 mg/L: 0.0–5.0). Serological tests for Borrelia burgdorferi, HIV, hepatitis viruses A, B, C, anti-streptolysin title, and syphilis serology were negative. Furthermore, IgG anti-cytomegalovirus (CMV) (463.0 AU/mL: >15 AU/mL), VCA-EBV IgG Ab, and varicella zoster were positive. IgM anti-cytomegalovirus, anti-gad, and anti-IA antibodies were negative. Laboratory tests were negative for fungi and bacteria. Stool exam for bacteria and parasites and search of Helicobacter pylori were negative. Thyroid function tests and immunology laboratory test to measure ENA panel and immunoglobulins were negative. Tuberculin test was moderately positive. A chest X-ray and mammogram showed no abnormalities. Gynecological examination, transvaginal ultrasound, and PAP test were negative. Histopathologic examination of a skin biopsy revealed an intense dermal perivascular lymphohistiocytic infiltration with a “sleeve-like” arrangement. There was edema of the papillary dermis, hyperkeratosis, and focal epidermal spongiosis (Fig. 2a, b). Direct skin immunofluorescence test and PCR for CMV-DNA in biopsy specimen results were negative. Clinic-pathological findings were consistent with the diagnosis of a superficial form of EAC. Anti-CMV IgG antibodies remained elevated, and previous therapy with antihistamines and topical corticosteroids was not effective. Treatment with clarithromycin 500 mg/day and topical calcipotriol/betamethasone for 6 weeks resulted in temporary regression of the annular lesions. The course of the disease was chronic and recurrent over 3 years. Annular and discoid-shaped lesions that did not exceed 3 cm in diameter, on the lower limbs and thighs, reappeared about every 2 weeks during the summer, fall, and winter (Fig. 1c). These lesions disappeared with the same topical treatment, while similar annular skin changes occurred in the adjacent areas. No relapses occurred after 6 months of follow-up.\n\nDiscussion\n\nThe diagnosis of EAC was based on the suggestive figurate erythema and histopathological pattern. This disorder is rare and usually occurs on the proximal extremities, thighs, arms, or trunk and clears up by itself in variable time duration. EAC can mimic nummular eczema, annular granuloma, erythema multiforme, erythema marginatum, cutaneous B-cell lymphoma, annular sarcoidosis, cutaneous lupus erythematosus, erythema gyratum repens, tinea corporis, mycosis fungoides, and figurate psoriasis. A superficial and a deep type histopathologic variant have been described. In the superficial variant of EAC, infiltrates of histiocytes, lymphocytes, and rarely eosinophils are present around vessels of superficial plexus. The infiltrate, with tight aggregate around the vessels, is known as “coat-sleeve” [2]. The etiology and pathogenesis are unknown and this condition is interpreted as a hypersensitivity reaction to different causes, including viral infections. For these reasons, a full physical examination and laboratory investigations should exclude associated malignancies. EAC has been associated with many infections, particularly dermatophytoses, Candida spp., but also viruses (EBV, poxvirus, HIV, and HVZ), parasites, pediculosis pubis, and bacteria [3]. The interaction between latent CMV infection and influenza is not defined. In our case, the subtype A/H1N1 influenza virus may be regarded a possible pathogenic agent in the onset of the eruption. During that time in Italy, this type of virus was mainly responsible for influenza [4], even with serious cases. We also believe that the triggering of the erythematous lesions can be a cutaneous hypersensitivity reaction due to the prolonged action of influenza virus. EAC was associated with herpes zoster, considering this cutaneous eruption is due to an alteration of the local immunity known as Wolf's isotopic response [5]. Varicella zoster DNA was not found in the skin of the described case, suggesting that the EAC took place not as a direct consequence of local viral infection, but through a type IV immune reaction to the herpes virus. This mechanism could explain a similar action with the release of cytokines from the cutaneous immune system stimulated from the influenza virus and, secondly, from CMV. Macular-papular rashes, cutaneous vasculitis, and Gianotti-Crosti syndrome rarely occur in patients with influenza viruses [6]. A pityriasis rosea that developed after the H1N1 vaccination would demonstrate the role of the immune response of the skin to virus antigens [7]. Reactive EAC associated with various infections tends to resolve spontaneously within a few weeks, while in cases with underlying malignancy, the lesions either do not disappear spontaneously or reappear after a short time. However, a patient with a variant form of EAC showed relapse during many years for no apparent reason [8, 9]. The therapeutic validity of macrolides, especially clarithromycin, was demonstrated in cases of idiopathic EAC [10] and clarithromycin resulted in efficacy also in our challenging case. EAC secondary to influenza A in a dark-skinned woman was never described in this condition. Paracetamol and tripolidine taken during viral infection are not pharmacological concausal molecules [11] like triggering EAC (Table 1). However, we cannot exclude that paracetamol may have had an initial role in the pathogenesis of a superficial perivascular EAC-like dermatitis. In conclusion, in our patient, the genesis and the marked recurrence of EAC may be secondary to influenza and a possible individual predisposition of the dark skin. We believe that the latent cytomegalovirus and reactivity induced by EBV, combined with influenza virus, can determine a cell-mediate immunity response of the skin, related to a molecular change miming viral epitopes. Hypothetically, anti-influenza therapy such as paracetamol can amplify the immune-mediated cellular response to flu viruses. This hypersensitivity reaction leads to the peculiar inflammatory disease known as EAC.\n\nStatement of Ethics\n\nWritten informed consent to publish this case (including images) was obtained from the patient. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare. The authors alone are responsible for the content and writing of the paper.\n\nFunding Sources\n\nThe authors did not receive any funding.\n\nAuthor Contributions\n\nLuca Ena: conception and design, interpretation of the data, drafting, final approval. Marco Ferrari: acquisition, analysis, and interpretation of the data; revision; final approval. Vittorio Mazzarello, Pasquale Ena: conception and design, acquisition and interpretation of data, revision, final approval.\n\nFig. 1 a, b Clinical presentation of multiple erythematous and violaceous annular plaques involving the forearm and lower abdomen. Some lesions presented a peripheral scaling with an “active” border. c Clinical presentation of a recurrence on the thigh showing multiple and smaller annular lesions.\n\nFig. 2 a, b Histopathological findings of the biopsy showed a moderately intense superficial perivascular lymphohistiocytic infiltrate with epidermal hyperplasia, hyperkeratosis, focal spongiosis, and parakeratosis. Sometimes the perivascular infiltration in the upper dermis results in a “sleeve-like” appearance. Hematoxylin and eosin stain, original magnification: ×4 (a), ×10 (b).\n\nTable 1 Conditions observed in association with erythema annulare centrifugum\n\nDiseases\tDrugs\t\nTinea\tAmitriptyline\t\nRheumatoid arthritis\tCimetidine\t\nS. of Sjögren\tFinasteride\t\nThyroiditis\tEtizolam\t\nPregnancy\tAldactone\t\nCancer (thyroid, ovarian)\tGold Thiomalate\t\nInfluenza\tAceclofenac\t\nHerpes zoster\tImmunotherapy agent\t\n\tUstekinumab\t\n\tChloroquine\t\n\tHydroxychloroquine\n==== Refs\nReferences\n\n1 Kim DH Lee JH Lee JY Park YM Erythema Annulare Centrifugum: Analysis of Associated Diseases and Clinical Outcomes according to Histopathologic Classification Ann Dermatol 2016 4 28 (2) 257 9 27081281\n2 Baglieri F Scuderi G Erythema annulare centrifugum: a “deep type” figurate eruption G Ital Dermatol Venereol 2012 2 147 (1) 129 31 22370579\n3 McDaniel B Cook C Erythema Annulare Centrifugum Stat Pearls 2020 Treasure Island (FL) Stat Pearls Publishing\n4 Mid-season risk assessment: seasonal influenza 2015–2016 in the EU/EEA countries ECDC 2016 8 Feb\n5 Ohmori S Sugita K Ikenouchi-Sugita A Nakamura M Erythema annulare centrifugum associated with herpes zoster J UOEH 2012 9 34 (3) 225 9 23035341\n6 Piérard GE [Image of the month: rash of H1N1 influenza] Rev Med Liege 2012 12 67 (12) 612 3 23342869\n7 Chen JF Chiang CP Chen YF Wang WM Pityriasis rosea following influenza (H1N1) vaccination J Chin Med Assoc 2011 6 74 (6) 280 2 21621174\n8 Molina GE Danesh MJ Foreman RK Kroshinsky D A 78-Year-Old Female with a Diffuse Pruritic Rash and Palmoplantar Desquamation Dermatopathology (Basel) 2020 1 6 (4) 241 5 32083061\n9 Mandel VD Ferrari B Manfredini M Giusti F Pellacani G Annually recurring erythema annulare centrifugum: a case report J Med Case Reports 2015 10 9 (1) 236\n10 Sardana K Chugh S Mahajan K An observational study of the efficacy of azithromycin in erythema annulare centrifugum Clin Exp Dermatol 2018 4 43 (3) 296 9 29297941\n11 Meena D Chauhan P Hazarika N Kansal NK Gupta A Aceclofenac-Induced Erythema Annulare Centrifugum Indian J Dermatol 2018 Jan-Feb 63 (1) 70 2 29527030\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "13(1)",
"journal": "Case reports in dermatology",
"keywords": "Cell-mediate immunity; Cytomegalovirus; Erythema annulare centrifugum; Influenza; Paracetamol",
"medline_ta": "Case Rep Dermatol",
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"references": "27081281;21621174;26496986;29297941;32083061;23035341;23342869;29527030;22370579",
"title": "Recurrent Erythema Annulare Centrifugum due to Influenza Type A.",
"title_normalized": "recurrent erythema annulare centrifugum due to influenza type a"
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"abstract": "Further to recent data indicating that patients with vascular dementia (VaD) show a cholinergic deficit, we aimed to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effects on the symptoms of VaD. Patients aged 65-80, with a diagnosis of dementia and probable VaD, received rivastigmine 3-6 mg/day (n=8) or cardioaspirin (n=8) in an open study for 22 months. At 22 months, patients treated with rivastigmine showed significant improvements in executive function and behavioural symptoms (both p<0.05 vs. both baseline and control group), which were reflected in reduced caregiver stress (p<0.05 vs. baseline and controls). Baseline scores of global response, cognition, word fluency and activities of daily living were maintained in patients receiving rivastigmine, and there was no increase in benzodiazepine or neuroleptic intake. In contrast, the control group showed no improvements in any domain, and significant deterioration in global response and executive function (both p<0.05 vs. baseline and rivastigmine group). Side effects in both groups were tolerable and there were no study withdrawals. Long-term rivastigmine treatment appeared to be safe and effective in this patient population. In particular, improvements in domains particularly relevant to this condition were observed. These benefits may reflect the drug's dual inhibitory effects on the cholinergic system, and its particular activity in frontal areas of the brain. A large, double-blind study of rivastigmine in patients with VaD would be worthwhile.",
"affiliations": "Dipartimento di Fisiologia e Patologia, Università degli Studi di Trieste, Trieste, Italy. moretti@univ.trieste.it",
"authors": "Moretti|Rita|R|;Torre|Paola|P|;Antonello|Rodolfo M|RM|;Cazzato|Giuseppe|G|;Bava|Antonio|A|",
"chemical_list": "D002219:Carbamates; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D000068836:Rivastigmine",
"country": "Netherlands",
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"issue": "203-204()",
"journal": "Journal of the neurological sciences",
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"medline_ta": "J Neurol Sci",
"mesh_terms": "D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D001519:Behavior; D002219:Carbamates; D017028:Caregivers; D002800:Cholinesterase Inhibitors; D015140:Dementia, Vascular; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents; D009483:Neuropsychological Tests; D048448:Phenylcarbamates; D011569:Psychiatric Status Rating Scales; D000068836:Rivastigmine; D013315:Stress, Psychological; D016896:Treatment Outcome",
"nlm_unique_id": "0375403",
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"pages": "141-6",
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"pmid": "12417373",
"pubdate": "2002-11-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
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"title": "Rivastigmine in subcortical vascular dementia: an open 22-month study.",
"title_normalized": "rivastigmine in subcortical vascular dementia an open 22 month study"
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"abstract": "Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients' time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet's reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.",
"affiliations": "Endocrinology, Diabetes & Metabolism, Orlando VA Healthcare System, Orlando, Florida, USA.;Endocrinology, Diabetes & Metabolism, Orlando VA Healthcare System, Orlando, Florida, USA.",
"authors": "O'Callaghan|Sondra|S|;Yau|Hanford|H|",
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"fulltext": "\n==== Front\nEndocr Connect\nEndocr Connect\nEC\nEndocrine Connections\n2049-3614 Bioscientifica Ltd Bristol \n\n33289687\n10.1530/EC-20-0487\nEC-20-0487\nReview\nTreatment of malignancy-associated hypercalcemia with cinacalcet: a paradigm shift\nS O’Callaghan and H YauTreating malignancy associated hypercalcemiaO’Callaghan Sondra 1 Yau Hanford 1 1 Endocrinology, Diabetes & Metabolism, Orlando VA Healthcare System, Orlando, Florida, USA\nCorrespondence should be addressed to S O’Callaghan or H Yau: acorporeal@comcast.net or hanfordyau@gmail.com\n1 2021 \n03 12 2020 \n10 1 R13 R24\n24 11 2020 03 12 2020 © 2021 The authors2021The authorsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients’ time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet’s reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.\n\nKeywords\nhypercalcemiamalignancyparathyroid hormone-related peptidehumoral\n==== Body\nIntroduction\nMalignancy-associated hypercalcemia (MAH) has long been described in medical literature and has posed a therapeutic conundrum. Over decades, this form of hypercalcemia has eluded conventional therapies, in that, it responds only temporarily and often is refractory. Clinically, for the patient it negatively impacts quality of life, and patients can succumb to hypercalcemic crisis. Indeed, MAH not uncommonly, constitutes a metabolic oncologic emergency (1, 2).\n\nMalignancy-associated hypercalcemia is the second most common cause of hypercalcemia in the general population and the most common cause of hypercalcemia among patients in the inpatient setting. Incidence has been reported at 15 cases per 100,000 annually, and approximately 20–30% of patients with cancer develop MAH (3). The clinical symptomatology of hypercalcemia depends on the degree of elevation of calcium. The patient may be asymptomatic, has few constitutional symptoms, or may develop neurovascular symptoms resulting in a state of metabolic emergency (1).\n\nSurvival\nHistorically, once MAH presents, up to 50% of patients die in an average of 30 days, and up to 75% die within 3 months (4, 5). It has been suggested that therapy for hypercalcemia is interim, with no effect on survival; this has been observed over time (4, 6). Despite advances in therapeutics, survival after diagnosis of MAH has not changed over the decades. In the 1980s, patients with bone metastases from breast cancer were observed to survive about 3 months after the onset of hypercalcemia (7). Median survival in patients with squamous cell carcinoma and hypercalcemia was 17–64 days (8, 9). In a series of patients with parathyroid hormone-related peptide (PTH-RP) mediated hypercalcemia associated with solid organ malignancy, the median survival was 52 days (10). A 2017 study revealed similar survival rates with the cohort having median survival of 40 days (11). Neither degree of elevation of hypercalcemia nor degree of elevation of PTH-RP has shown an associated change in survival (10). This recapitulates early studies showing that the absolute level of calcium is not a good prognosticator, but the mere presence of hypercalcemia portends poor prognosis (6).\n\nSurvival may be impacted by controlling the calcium level, to the extent that patients whose calcium is normal or near-normal are not succumbing to hypercalcemia-related complications (e.g. cardiac arrhythmias) as a cause of death. It is thought that controlling calcium can increase quality of life, reduce morbidity, and give time for targeted cancer therapy to be implemented (12). Ramos et al. showed that after MAH was diagnosed, there was a lengthened survival in those patients whose calcium normalized and were subsequently able to receive chemotherapy (11). Nonetheless, their study confirmed that for patients developing MAH, there remains dismal prognosis. Specifically looking at effects on morbidity and mortality, bisphosphonate therapy has brought about no change in these parameters (13). Ling et al. confirm this, observing that patients died within 2 months, while some who received bisphosphonate died within 3 months of developing hypercalcemia (14). They noted that tumor type, time from tumor diagnosis to hypercalcemia, nor level of serum calcium impacted survival. It has also been observed that there is no difference in survival in patients treated with different anti-hypercalcemic agents (5).\n\nHistoric and current observations continue to confirm that MAH portends a poor prognosis (8). In fact, a bedside prognostic score has been developed and used in studies evaluating hypercalcemia as an independent prognostic factor (9, 15). Certainly, newer targeted anti-cancer therapies may extend overall survival in cancer patients and can lengthen progression time to malignancy-associated complications such as bone metastases and/or hypercalcemia. There are currently no studies describing the impact of newer, targeted anti-cancer therapies and their impact on MAH and survival. Is it possible that if hypercalcemia is normalized, patients can experience fewer morbidities (those that relate to hypercalcemia) and have extended survival simply because they can continue with targeted anti-cancer therapies?\n\nHistorical perspective of classification and pathophysiology\nIn 1941, Albright proposed that tumors be tested for parathyroid hormone (PTH), as it seemed a hormone causing PTH-like effects were produced from tumors (16). Since this hormone early on was thought to be PTH, the process was termed ectopic PTH syndrome. Still in the 1970s, more studies showed that tumors can secrete a hormone other than PTH which exerts PTH-like effects (17, 18). Though this PTH-like substance remained elusive for decades, it had been concluded that the prior known ‘ectopic PTH syndrome’ was very rare (<1% of cases), as most cases of MAH had no detectable PTH (3, 19, 20). As these cases continued to be described, the term ‘pseudo-hyperparathyroidism’ was given in lieu of ectopic PTH syndrome. To describe the process more accurately, more than 30 years after Albright’s supposition, the term ‘humoral hypercalcemia of malignancy’ (HHM) was proposed (21).\n\nResearchers postulated that there were many factors that drive MAH, including bone resorption by local tumor growth, substances causing bone resorption, and renal effects of PTH-like factors (22, 23, 24). Previously, it was estimated that PTH-like factors were produced by at least 75–80% of solid tumors associated with hypercalcemia (23); the current estimate remains at -80% (3).\n\nCurrent perspective of classification and pathophysiology\nVarious pathophysiologic mechanisms have been found to be responsible for MAH. Overall, general mechanisms are osteolytic and humoral (Table 1). Mechanisms within these two main states are further considered briefly.\nTable 1 General mechanisms of malignancy-associated hypercalcemia.\n\nOsteolytic\tHumoral\t\n↑ Bone resorption\t↑ PTH-RP\t\nLocal destruction by metastasis\t↑ PTH\t\nHumoral factors\t↑ 1,25(OH)2D3\t\n1,25(OH)2D3, 1,25-dihydroxy vitamin D3; PTH, parathyroid hormone; PTH-RP, parathyroid hormone-related peptide.\n\n\n\n\nHumoral hypercalcemia of malignancy (HHM)\nMost cases of MAH are driven by means which are humoral (3). The mechanism is most frequently via tumor secretion of PTH-RP, and/or other humoral factors. Most often, it is observed in cancers involving solid tumors (without bone metastases), but it can manifest in a variety of cancers.\n\nAnother mechanism that can drive HHM is the elevation of 1,25-dihydroxy vitamin D (1,25(OH)2D3), leading to increased absorption of calcium. This is mainly seen in hematologic cancers like lymphomas, and it has been reported in ovarian dysgerminomas (3, 25, 26, 27).\n\nTrue ectopic PTH secretion by tumors is the least common mechanism to drive HHM; there have been cases reported in neuroendocrine tumors (3, 20).\n\nSpecifically speaking to cases of HHM driven by PTH-RP, it was first commonly observed in cancers involving solid tumors but without bone metastases. Bone metastases had long been described in breast cancer, yet without production of PTH-RP. However, HHM has been described coincident with bone metastases, and a PTH-like peptide was identified in breast cancer cells in (28, 29, 30). Furthermore, the first report of expression of the PTH-RP gene and the production of PTH-RP has been documented in multiple myeloma with marked elevation of serum calcium, evidence that a humoral component can also contribute to the skeletal complications and hypercalcemia in myeloma (31). Of note, patients with normocalcemic states have been found to have tumors expressing PTH-RP, suggesting that levels in circulation may not have been high enough to achieve and maintain a hypercalcemic state (32). There can be overlap in the way tumor activity results in a hypercalcemic state (Fig. 1).\nFigure 1 Intersecting and independent etiologies of HHM. Parathyroid hormone (PTH); parathyroid hormone-related peptide (PTH-RP). 1,25-dihydroxy vitamin D (1,25(OH)2D3).\n\n\n\n\nOsteolytic\nOther factors that can drive MAH are osteolytic. Osteoclast-mediated destruction and osteosclerosis due to impaired/increased osteoblastic activity are the predominant forces contributing to the formation of bone lesions. Hypercalcemia can develop when the predominant force is osteoclastic, and hypocalcemia can develop due to calcium sequestration when the driving force is osteoblastic. Although cancers can exhibit predominantly increased resorption or formation of bone, a mixed picture is not uncommonly observed (33, 34, 35). Increased resorption and impaired formation are driven by local factors and humoral tumor factors produced by the tumor. Bone metastases themselves ultimately can destroy bone locally and exert mass effect. Thus, another mechanism for MAH is explained by local osteolytic effects resulting in hypercalcemia, seen mainly in cancers with significant skeletal lysis and/or increased resorption like breast cancer and multiple myeloma, respectively.\n\nPTH-RP in perspective\nParathyroid hormone-related peptide is in many tissues and is involved in normal physiology (36, 37). In normal states, PTH-RP is not elevated. In a pathologic state like HHM, PTH-RP is produced and secreted in excess, therefore, it was proposed that PTH-RP could serve as a tumor marker (38).\n\nBefore its actual identification, this PTH-like protein from tumor extracts was described as having multiple times the biologic activity of PTH, being a different form of PTH, and working in concert with other substances resulting in hypercalcemia (17, 39). In the 1980s, parathyroid hormone-like proteins identified in breast (30) and lung cancers displayed homology to PTH, yet with greater biologic activity (40, 41). This increased effect on bone and renal activity can explain the development of hypercalcemia above the threshold of the body’s capability to maintain normal calcium homeostasis and can account for the relative severity and acuity of MAH compared with PTH-mediated hypercalcemia. Researchers reported a PTH-like protein that can stimulate adenylate cyclase in the renal cortices (30, 42) and promote calcium retention consistent with the clinical manifestations of HHM, pointing to the kidney as a major therapeutic target for this disease state (42).\n\nHistorically, the PTH-RP assays were developed and used in labs for research purposes. Currently, commercial labs have developed and offer PTH-RP testing, though there is currently great need for standardization and improvement in specificity, sensitivity, and analytic precision due to the various isoforms of the molecule (43).\n\nHomology of PTH to PTH-RP as well as their genetic homology\nParathyroid hormone-related protein purified from lung and breast cancer cell lines was cloned; an amino acid sequence with homology to human PTH was observed (30, 40, 41), explaining its PTH-like effects. Considering the homology of PTH and PTH-RP, it was inferred that there was homology in the genes encoding them (40). In 1989, the human PTH-RP gene was characterized (44), structurally confirming the relatedness of the PTH-RP and PTH genes (chromosome 12 and 11, respectively) and showing that three distinct PTH-like proteins are products of the PTH-RP gene. Knowing the structural and genetic similarities of PTH and PTH-RP, it comes as no surprise that there are similarities and overlap in their functional activities relating to calcium homeostasis.\n\nThe type 1 parathyroid hormone receptor (PTH1R)\nBased on review of prior and ongoing studies, it was surmised in 1989 that the hormone driving MAH acted on PTH target cells at the PTH receptor (19). It is now known that PTH and PTH-RP share the PTH1R to evoke their physiologic actions. After a very elegant literature review discussing the interaction and contribution of PTH1R and the calcium-sensing receptor (CaSR) signaling pathway to the development and perpetuation of breast cancer bone metastases, Yang suggested that future therapeutic modalities target those agents that can influence PTH-RP, the PTH1R, and CaSR signaling pathways (45).\n\nThe calcium-sensing receptor\nThe CaSR on the surface of the parathyroid gland chief cell is the principal regulator of PTH synthesis, secretion, and gene expression by mediating the inhibitory action of calcium (36). In the calcitonin-secreting C-cells of the thyroid, it mediates the stimulatory action of high calcium on calcitonin secretion. Cinacalcet is a calcimimetic that directly lowers PTH levels by increasing the sensitivity of the CaSR to extracellular calcium. In 1998, the first therapeutic use of this novel agent was described in a patient with parathyroid carcinoma and hypercalcemia (46) resulting in a reduction in calcium and PTH levels. Despite disease progression resulting in PTH increases, calcium remained stable with various dosage adjustments. It has been suggested that cinacalcet may potentially be useful in cancers with ectopic production of PTH (20, 47). Review of studies up to 2001, suggested a physiologic relationship between the CaSR and the secretion of PTH-RP (37); a relationship on which to focus future therapy.\n\nPharmacotherapy for MAH\nReducing tumor burden, can reduce or control calcium at least temporarily (17). This can be by surgical or chemotherapeutic means. Targeted cancer treatment, when successful, can slow progression to a state of hypercalcemia.\n\nCertainly, reducing exogenous influences on calcium burden are paramount. This can be achieved by removing calcium supplements orally, parenterally, and in dialysate. Low calcium or calcium-free dialysate is effective in hypercalcemic crisis when initial treatments fail, or in the setting of fluid overload or renal failure (48). Discontinuation of agents that raise serum calcium (e.g. thiazides or lithium) reduces calcium burden otherwise imposed by the hypercalcemic state. Avoiding immobility and volume depletion and employing volume expansion with isotonic saline where necessary is helpful. Hydration and diuresis with a loop diuretic, directly increasing calcium excretion, have been used to lower serum calcium. However, this is not a safe option in all patients, and it can lead to dehydration with rebound hypercalcemia.\n\nIt was thought that long- term management of MAH needed to focus on development of agents targeting bone resorption (39). Some early agents employed to lower calcium were found to be unsafe, are no longer in use, and will not be discussed. For 30 years, bisphosphonates were the focus of studies and were the mainstay of therapy for MAH. In 1977 etidronate was the first diphosphate used to treat hypercalcemia. It slowed bone resorption, thereby affecting calcium metabolism to reduce serum levels. Working similarly was pamidronate, which was approved 14 years later (1991); pamidronate became the first bisphosphonate specifically indicated for treatment of MAH. The next bisphosphonate approved for MAH was zolendronate (2001). These agents are dosed intravenously (IV) in clinic or hospital settings. It can take a few days to see a reduction in calcium levels, and this reduction is temporary.\n\nDenosumab came to market in 2010 as the first novel agent in 30 years targeted at inhibiting bone resorption. It is a human MAB that binds to and inhibits the receptor activator of nuclear factor kappa-B ligand (RANKL), the primary mediator of bone resorption, via activation of osteoclasts. Employing denosumab, Hu et al. observed a 70% response rate (response = calcium level <2.8 mmol/L) for patients with MAH, and the median duration of response was 9 days (49). The longest duration was 104 days. It is promising that this agent can, in some cases, bring about a longer period of lowered calcium levels.\n\nGlucocorticoids can be effective in cases of HHM where overproduction of 1,25(OH)2D3 predominantly drives hypercalcemia. Calcitonin lowers blood calcium by promoting calcium incorporation into bone, however, the effects are minimal and transient.\n\nHistorically, the only treatment for hypercalcemia in patients with renal failure was dialysis (50). Currently, denosumab can be used without need for dosage adjustment in renal failure. Cinacalcet, though not indicated for treatment of MAH, can safely reduce calcium levels in renal failure or renal-compromised patients. Therefore, safety in this population is established.\n\nCinacalcet was approved for use in 2004 and is indicated for patients with secondary hyperparathyroidism with chronic kidney disease on dialysis, hypercalcemia in patients with parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Considering the shared homology of PTH and PTH-RP and given cinacalcet’s current role in controlling PTH-mediated hypercalcemia, Can there be a key role for cinacalcet in treating other hypercalcemic states, especially those driven by PTH-RP? It had been suggested that MAH refractory to bisphosphonate therapy can be treated with denosumab (51). It is now proposed that cinacalcet can be used as adjunctive therapy in HHM (and possibly other forms of MAH) successfully and safely over the long-term.\n\nCases of cinacalcet-treated MAH\nThe Netherlands\nOne of the first cases using cinacalcet in MAH was described in 2012 by Bech (52) and colleagues. In this case, efficacy of cinacalcet as a suppressor of PTH-RP production was explored. A 57 -year-old male with stage cT4N3M1b squamous cell lung carcinoma developed severe, recurrent MAH. On presentation, the patient had symptomatic hypercalcemia with the following laboratory values: PTH <1.0 pmol/L (1.3–6.8 pmol/L), PTH-RP 5.8 pmol/L or 55 ng/L (<0.6 pmol/L or 6 ng/L), and calcium 4.5 mmol/L (routine clinical chemistry assays Roche Diagnostics). The patient was administered normal saline, calcitonin, and pamidronate over 2 weeks. These measures achieved a calcium of 2.8 mmol/L which increased to 4.4 mmol/L after 2 weeks. For the next 5 days, normal saline was resumed along with calcitonin and a single dose of zolendronate. Nonetheless, the calcium and PTH-RP were 3.5 mmol/L and 13.3 pmol/L (125 ng/L), respectively.\n\nAt this point, with the patient’s consent, cinacalcet was started and continued for 15 days while chemotherapy with carboplatin and gemcitabine was initiated. During this first cycle, the calcium dropped to a hypocalcemic level, and PTH-RP came down. Cinacalcet was discontinued, bringing about a rise in PTH from undetectable to 5.1 pmol/L with a normalization of serum calcium. There were three more cycles of combination chemotherapy without cinacalcet. After the fourth cycle, the calcium rose to 3.5 mmol/L. The patient was hospitalized, and cinacalcet was started along with hydration and a dose of zolendronate. Calcium improved to 3.0 mmol/L, and the patient was discharged on the cinacalcet. Hospitalization was required after 9 days, and a dose of zolendronate was given. Due to disease progression, the patient succumbed to his illness after 2 weeks. It was concluded that about 71% of the variance in serum calcium correlated with PTH-RP levels and that PTH-RP reduction may be a result of cinacalcet use.\n\nUnited States of America\nSternlicht & Glezerman report a case of metastatic renal cell carcinoma in 2013 (53). Laboratory reference ranges provided are PTH-RP 14–27 pg/mL (14–27 ng/L) and PTH 12–88 pg/mL (1.3–9.3 pmol/L). After bisphosphonate and denosumab therapy, the calcium was 14.2 mg/dL (3.6 mmol/L), PTH 10 pg/mL (1.1 pmol/L), and PTH-RP 114 pg/mL (114 ng/L). Cinacalcet was started and titrated, and at 10 weeks calcium improved to 10.1 mg/dL (2.5 mmol/L) with PTH-RP 159 pg/mL (159 ng/L). Their theory is that cinacalcet may have a role in the treatment of MAH.\n\nNew Zealand\nA case presented by abstract at the Endocrine Society’s 97th Annual Meeting by Whitfield and Carroll (54) describes a 54- year-old female diagnosed with inoperable gastroenteropancreatic neuroendocrine tumor (GEP-NET). The tumor was treated with octreotide. Within 1 year, the calcium rose to 3.0 mmol/L (2.2–2.6 mmol/L) with PTH <0.6 pmol/L (1.5–6.0 pmol/L) and PTH-RP 3.3 pmol/L or 31 ng/L (0.0–1.5 pmol/L or 0–14 ng/L). Tumor embolization failed, and funded sunitinib therapy was unavailable. Three weekly infusions of zolendronate and normal saline failed to control calcium and its symptoms, therefore cinacalcet was initiated and titrated. The calcium improved to 2.9 mmol/L within 1 month and remained 2.5–2.9 mmol/L for 18 months (all the while patient remained on octreotide). The observation was that cinacalcet may be a useful therapeutic option for MAH.\n\nBelgium\nAnother case of a neuroendocrine (NET) tumor with hypercalcemia has been described by Valdes-Socin and colleagues in 2017 (55). A 52- year-old male presented with an unresectable, well-differentiated, metastatic pancreatic NET. Laboratory reference ranges provided are calcium 2.2–2.6 mmol/L and PTH 12–58 pg/mL (1.3–6.2 pmol/L).\n\nCalcium was 3.5 mmol/L with PTH <4 pg/mL (0.4 pmol/L); PTH-RP could not be measured. Several cycles of streptozotocin-adriamycin and FOLFOX (folinate, fluorouracil, oxaliplatin) were given. While the PTH level remained low at 19 pg/mL (2.0 pmol/L), the tumor mass and calcium level (2.6 mmol/L) improved. After 3 months, the calcium and PTH were 2.9 mmol/L and <2 pg/mL (0.2 pmol/L), respectively. Octreotide was given without clinical impact. Calcium had risen to 3.1 mmol/L and was refractory to saline fluids, diuretics, recombinant calcitonin, and zolendronate. Compassionate treatment with cinacalcet was initiated. Calcium levels responded down to 2.8 then 2.6 mmol/L over 3 months. Shortly thereafter, sunitinib was introduced. After 1 month of combined sunitinib-cinacalcet therapy, the calcium fell into the hypocalcemic range at 2.1 mmol/L with PTH 78 pg/mL (8.3 pmol/L). Cinacalcet was discontinued; sunitinib treatment was continued for 4 years with normal calcium levels.\n\nThe authors conclude that cinacalcet lowered calcium and improved clinical condition and that sunitinib contributed to lowering calcium.\n\nGreece\nAsonitis and colleagues (56) presented a case of a 69-year-old female with a 6-year history of infiltrating ductal and lobular mammary carcinoma with bone metastases. The patient received zolendronate and radioactive samarium due to thoracic, lumbar spine, and pelvic lesions. Of note, the zolendronate was given for bone metastases, not hypercalcemia, and the last dose had been given 2 years prior to presentation with hypercalcemia. Laboratory reference ranges provided are calcium 8.6–10.2 mg/dL (2.3–2.6 mmol/L) and PTH 8–76 pg/mL (8–76 ng/L).\n\nAt presentation, the calcium level was 15.2 mg/dL (3.8 mmol/L) with PTH 6.5 pg/mL (0.6 pmol/L). The PTH-RP could not be measured. Treatment consisted of normal saline, furosemide, and zolendronate. On day 2, the calcium was 12.9 mg/dL (3.2 mmol/L), and calcitonin and hydrocortisone were administered. On day 5, the calcium was 10.4 mg/dL (2.6 mmol/L), and the patient was discharged on methylprednisolone, furosemide, reduced calcium intake, and increased water intake. Five days later, denosumab was added due to a calcium level of 13.6 mg/dL (3.4 mmol/L). After 3 weeks, cinacalcet was added to the regimen, since the calcium plateaued at 13.3 mg/dL (3.3 mmol/L). By 2 weeks, the calcium level improved to 11.7 mg/dL (2.9 mmol/L), and the cinacalcet was titrated. At this point the denosumab was administered monthly. The calcium was normal (9.6 mg/dL (2.4 mmol/L)) after 3 weeks and remained normal for 1.5 months. To confirm efficacy, cinacalcet was held, resulting in a rise of calcium by 1.7 mg/dL (0.4 mmol/L). In total, the patient benefitted from stable calcium levels for 11 months with cinacalcet. The authors suggest that cinacalcet can be an effective therapeutic option for MAH.\n\nUnited States of America\nRecently, authors report a case of an 81 -year-old female suffering from non-small cell lung cancer (NSCLC) and recurrent bladder cancer with HHM refractory to traditional therapy (57). Laboratory reference ranges provided are calcium 8.5–10.1 mg/dL (2.1–2.5 mmol/L), PTH 18–85 pg/mL (1.9–9.0 pmol/L), and PTH-RP 0-2 pmol/L (<19 ng/L).\n\nThe NSCLC was showing progression, so nivolumab was started. Five weeks later the calcium started to rise (10.6 mg/dL (2.7 mmol/L)). Thereafter, due to progressive clinical deterioration, she was hospitalized with calcium 12.7 mg/dL (3.8 mmol/L), PTH <6 pg/mL (<0.7 pmol/L), and PTH-RP 3.3 pmol/L (31 ng/L). Treatment consisted of pamidronate and fluids. After 4 days, the calcium was 8.2 mg/dL (2.1 mmol/L). She was readmitted due to symptoms with calcium 11.1 md/dL (2.8 mmol/L), PTH 5.8 pg/mL (0.6 pmol/L), and PTH-RP 42 pmol/L (396 ng/L). Treatment consisted of zolendronate and fluids. Within 2 days the calcium was 8.7 mg/dL (2.2 pmol/L) with a rise to 10.1 mg/dL (2.5 mmol/L) in 3 days. Denosumab was given, but readmission was required in 3 days with a calcium of 11.1 mg/dL (2.8 mmol/L). After zolendronate and two doses of calcitonin were given, the calcium was 9.0 mg/dL (2.3 mmol/L). Cinacalcet was initiated and titrated. For nearly 2 months on cinacalcet monotherapy, she had no more hypercalcemia despite rises in the PTH-RP 143–>194 pmol/L (1,348–>1,829 ng/L). Nivolumab was discontinued due to disease progression, and the patient died in hospice care without further laboratory studies.\n\nOur case (United States of America)\nWe now present a case of HHM treated successfully with cinacalcet. Success being defined as normalization of calcium levels over many months without need for clinic or hospital administration of IV nor s.c. agent and no emergency department visits nor hospital admissions for hypercalcemia urgency or crisis.\n\nPerforming labs and reference ranges are provided as follows: Calcium 2.1–2.7 mmol/L, Orlando VA Health Care System, Orlando, Florida, USA; 1,25(OH)2 D3 43–173 pmol/L Quest Diagnostics, chromatography/mass spectrometry, Chantilly, Virginia, USA; 25 hydroxy vitamin D (25 (OH) D3) 75–250 nmol/L Quest Diagnostics, immunoassay, Chantilly, Virginia, USA; PTH-RP 14–27 ng/L Quest Diagnostics, immunoassay, Chantilly, Virginia, USA; PTH 1.5–6.8 pmol/L Quest Diagnostics, immunoassay, Chantilly, Virginia, USA. Adjusted calcium level was determined using the following equation: ((4-albumin) × 0.8) + serum calcium. All calcium levels referenced below are adjusted serum levels, as the patient’s albumin was low.\n\nA 71-year-old male had a past medical history significant for Von Hippel-Lindau syndrome and metastatic renal cell carcinoma (RCC). The RCC was found to have metastasized (16 years after initial nephrectomy) as evidenced by pulmonary masses, a large pancreatic mass replacing the tail, a right parotid mass, osseous lesions, and numerous hyperdense left renal lesions. Treatment with pazopanib was initiated shortly thereafter. The patient developed MAH 6 months into therapy. The calcium was 3.1 mmol/L with PTH 0.6 pmol/L, and 25 (OH) D3 142 nmol/L, therefore, MAH was presumed. The hypercalcemia responded to zolendronate 4 mg IV on two separate occasions over 11 months (calcium levels normal or slightly elevated) while the patient was able to receive targeted cancer therapy, with a change from pazopanib to nivolumab.\n\nUpon its return, the hypercalcemia at 3.0 mmol/L was refractory to three doses of denosumab 120 mg SC over 4 weeks. Nivolumab was discontinued due to kidney injury, and prednisone was started. At the time of his consultation with our Endocrinology service, the patient presented with a calcium of 3.7 mmol/L, PTH of 0.2 pmol/L, PTH-RP 47 ng/L, 1,25(OH)2 D3 238 pmol/L, and 25 (OH) D3 102 nmol/L. The patient received IV hydration 3 L over 6 h and IV methylprednisolone 40 mg once; he had just received the latest denosumab dose. Day 2, the patient received furosemide 40 mg IV and 1 L normal saline IV and was started on cinacalcet 30 mg by mouth (PO) daily. Four days later, the calcium improved to 3.3 mmol/L, and the cinacalcet was increased to 60 mg PO daily. One week after cinacalcet dose escalation, the calcium was 2.8 mmol/L. Due to the very favorable response and uncertainty as to whether this continued dose would incite hypocalcemia, the cinacalcet was reduced back to 30 mg PO daily. Seven days later the calcium had risen to 3.3 mmol/L; the cinacalcet was again increased to 60 mg PO daily. At this time targeted therapy with cabozantanib was started and was given off and on for 10 months. It had been placed on hold for various medical reasons. The calcium level remained normal for 3 months at which time it dropped to low normal at 2.1 mmol/L. Rather than de-escalating the cinacalcet dose by 50%, the dose was simply reduced to 45 mg PO daily. The calcium remained in the normal range for the next 9 months (with a goal to keep the calcium at the upper limits of normal, so as not to incite hypocalcemia), and the PTH normalized to 1.9 pmol/L. During this time the 1,25(OH)2 D3 normalized and then rose slightly above normal again.\n\nIn his 10th month of treatment with cinacalcet, the patient suffered an acute stroke and was hospitalized. During that time, his cinacalcet treatment was interrupted. Resultantly, his calcium rose to 3.6 mmol/L. Cinacalcet was resumed at 90 mg PO daily, and denosumab 120 mg SC was given. By 10 days, the calcium improved to 3.0 mmol/L, and another dose of denosumab 120 mg SC was given. The calcium normalized in 1 week and remained normal with a normal PTH on cinacalcet monotherapy until he succumbed to his disease 17 days later (Fig. 2).\nFigure 2 Parathyroid hormone (PTH). The dash line represents calcium response, and the bar denotes change in PTH.\n\n\n\n\nIt should be noted that the patient was started on prednisone for chronic kidney inflammation while on nivolumab. It was given off and on prior to and during the course of cinacalcet treatment. Considering the amount of time that the patient was on a stable dose of cinacalcet with normal calcium levels, it is our thought that the prednisone was not significantly influencing calcium levels. Furthermore, while targeted anti-tumor therapies had been on hold, the cinacalcet was, nonetheless, able to maintain normal calcium levels. While the PTH-RP came down to 29 ng/L, it was not profoundly elevated at any given time, and its improvement was only very slight. Therefore, it is postulated that for a given level of PTH-RP, there is not a correlation with the severity of hypercalcemia nor the cinacalcet dose required to achieve normocalcemia (Fig. 3). Changes in 25(OH) D3 were not noteworthy, while there was slight reduction in 1,25(OH)2 D3 (Table 2).\nFigure 3 Parathyroid hormone-related peptide (PTH-RP). The dash line represents calcium response, and the bar denotes change in PTH-RP.\n\n\nTable 2 Effects of cinacalcet treatment on pertinent biochemical parameters.\n\nParameters (normal range)\tDay 0 initiated cinacalcet 30 mg/day\tDay 4 ↑ cinacalcet 60 mg/day\tDay 11 ↓ cinacalcet 30 mg/day\tDay 18 ↑ cinacalcet 60 mg/day\tDay 110 ↓ cinacalcet 45 mg/day\tDay 260 stable cinacalcet 45 mg/day\tDay 305 stable cinacalcet 45 mg/day\tDay 335a restart cinacalcet 90 mg/day + denosumab\tDay 349b stable cinacalcet 90 mg/day\t\nCalcium (2.1–2.7 mmol/L)\t3.6\t3.3\t2.8\t3.3\t2.1\t2.4\t2.6\t3.6\t2.6\t\nPTH (1.5–6.8 pmol/L)\t0.2\t–\t0.3\t–\t–\t1.9\t–\t–\t–\t\nPTH-RP (14–27 ng/L)\t–\t–\t47\t–\t29\t32\t–\t–\t–\t\n25 (OH) D3 (75–250 nmol/L)\t102\t–\t–\t–\t72\t96\t–\t–\t–\t\n1,25(OH)2 D3 (43–173 pmol/L)\t238\t–\t–\t–\t216\t178\t–\t–\t–\t\naPatient was hospitalized for a stroke from day 306 to 334 and was off cinacalcet during this period. Cinacalcet was restarted along with one dose of s.c. denosumab 120 mg, bPatient deceased 11 days (day 360) after last lab draw.\n\n1, 25(OH)2 D3, 1, 25-dihydroxy vitamin D; 25(OH) D3, 25 hydroxy vitamin D; PTH, parathyroid hormone; PTH-RP, parathyroid hormone-related peptide.\n\n\n\n\nDiscussion\nOur patient acquired HHM that was refractory to bisphosphonate and denosumab therapy. As a result of treatment with cinacalcet, there was reduction in and normalization of calcium. As noted above, other cases show cinacalcet’s usefulness in the treatment of HHM. Given that the patients in these cases received multiple therapeutic agents to reduce calcium, it can be difficult to differentiate effects due to cinacalcet and those due to other agents. However, when hypercalcemia is refractory to all conventional modalities yet responds to the addition of cinacalcet, it follows that cinacalcet can serve as adjunctive therapy.\n\nIt is well described that the CaSR of the parafollicular C cells of the thyroid modulates calcitonin release in response to hypercalcemia (3). It is possible that this action could be a mechanism by which cinacalcet lowers calcium in HHM; Colloton describes reduction of PTH-RP-mediated calcium levels (accompanied by rise in calcitonin levels) with cinacalcet therapy (58). In our case, the PTH-RP levels did not show significant change, though the calcium showed dramatic response. Certainly, the CaSR’s influence on renal calcium disposition and osteoblast and osteoclast function can play a role in cinacalcet’s calcium lowering ability.\n\nThe patient in our case benefited from a eucalcemic state for nearly 1 year until he succumbed to his disease. It was observed that calcium levels start to respond to cinacalcet in 1 week with normalization of calcium by 2 weeks. While considering each of the cases reviewed here, it is important to note that each patient has variations in calcium homeostasis and in the disease states inciting the MAH and will thus respond differently even to the same cinacalcet dose. Great care should be taken in the monitoring and dosage adjustment of cinacalcet. It is proposed that a temporary drug holiday or a reduction in dose in the setting of hypocalcemia would be preferable to drug discontinuation. This reduces the chance of returning to a hypercalcemic state or a hypercalcemic urgency. Lab draws were more frequent with initiation of cinacalcet, for example within 1 week for the first draw and weekly draws until calcium levels are stable on a given dose. For our case there were a couple of instances of 3–4 weeks between blood draws, since the calcium was quite stable.\n\nReducing morbidity from MAH is important to patients in terms of their symptomatology, but it is equally important in terms of their required clinic visits and hospitalizations. While on oral cinacalcet monotherapy for his HHM, our patient remained eucalcemic, and no longer required clinic visits or hospitalizations specifically for treatment of hypercalcemia. Patients have many clinic encounters and hospitalizations resulting from disease treatment and progression of their primary disease; it follows that reducing the need for these encounters by controlling MAH becomes very meaningful to them.\n\nEarly on it was suggested that debulking tumor would favorably impact hypercalcemia regardless of the biochemical factors involved, because a debulked tumor could portend reduction of biochemical factors driving hypercalcemia (59). It follows that PTH-RP could be reduced with physical debulking or with targeted tumor therapy. Interestingly, our patient’s PTH-RP levels came down only slightly, with cinacalcet therapy; the significance of this is unknown. Even with only minimal reductions of PTH-RP and progression of cancer until the time of death, cinacalcet was able to achieve a eucalcemic state.\n\nConclusion\nEven as recent as 2014, it has been suggested that palliation of symptoms related to MAH is essential and clinically meaningful for patients, given the continued poor prognosis and high morbidity and mortality associated with MAH (49). Historically, agents have been temporizing and have not impacted patient survival. The ideal agent for long-term treatment of MAH that was hoped for in the early 1980s was an oral agent which maintains the serum calcium in the normal or near normal range (39). We suggest that cinacalcet can be that oral agent, reducing patients’ time in the hospital and clinic settings. It is well-tolerated and can maintain calcium levels in the normal range. This has a direct, major impact on morbidity. Treatment of MAH to this level of success can increase patient quality of life while targeted cancer therapies can work to improve survival. So far, this is the only agent to treat MAH suggested to favorably impact quality of life. Studies are needed to determine the possible impact of the achievement of eucalcemia on survival with MAH. While it is true that not all patients may respond, depending on the aggressiveness of the late stages of cancer, especially where death is imminent, it seems worthwhile to afford the possible benefit.\n\nCinacalcet is approved for secondary hyperparathyroidism, parathyroid carcinoma-associated hypercalcemia, and severe hypercalcemia associated with primary hyperparathyroidism. The use of cinacalcet is novel in the treatment of MAH/HHM; the case presented here responded successfully to this therapy (reduction of calcium levels to normal). First line agents for MAH historically have been IV or SC, and no agent had been uniformly safe and effective over a long period of time (23, 39). It is proposed here that oral cinacalcet can favorably influence calcium homeostasis safely over an extended period of time in the setting of HHM as adjunctive therapy or (in some cases) monotherapy. Given that there is often a humoral component to osteolytic MAH, it is postulated that cinacalcet could benefit patients regardless of the predominating etiology of MAH in any given case.\n\nGoals of future therapeutic modalities\nPrior to identifying PTH-RP or its receptor, it was postulated that blocking the humoral substance driving the hypercalcemia would be a possible therapeutic option (17). Recognizing the need to target renal resorption of calcium, it was suggested that drugs are needed to inhibit PTH or PTH-RP action or production, or that antibodies are needed to inhibit PTH-RP (19, 53, 60). Further research elucidating this interplay is warranted.\n\nGiven that these case reports showed improvement of calcium in MAH, there is promising evidence that cinacalcet can be employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Even though the exact mechanism of action for cinacalcet’s reduction in calcium in this setting is not entirely elucidated, we can still afford patients the possible benefit from it.\n\nDeclaration of interest\nThe published viewpoints are those of the individual authors and do not represent the official stance or statements of the respective academic and/or governmental agencies with which the authors are affiliated.\n\nFunding\nThis work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nAuthor contribution statement\nS O’Callaghan conceived of the idea and subject matter for this review article. S O’Callaghan and H Yau were responsible for the care of the patient presented in the case along with the acquisition, analysis, and interpretation of data. 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(10.3109/07357907.2015.1047506 )26068056 \n14 Ling PJ A’Hern RP Hardy JR Analysis of survival following treatment of tumor-induced hypercalcemia with intravenous pamidronate (APD)\n. British Journal of Cancer \n1995 \n72 \n206 –209\n. (10.1038/bjc.1995.304 )7599053 \n15 Penel N Dewas S Hoffman A Adenis A Cancer-associated hypercalcemia: validation of a bedside prognostic score\n. Supportive Care in Cancer \n2009 \n17 \n1133 –1135\n. (10.1007/s00520-009-0607-5 )19290550 \n16 Cabot RC Mallory TB Case records of the Massachusetts General Hospital: case 27461\n. New England Journal of Medicine \n1941 \n225 \n789 –791\n. (10.1056/NEJM194111132252007 )\n17 Powell D Singer FR Murray TM Minkin C Potts JT Jr Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases\n. New England Journal of Medicine \n1973 \n289 \n176 –181\n. (10.1056/NEJM197307262890403 )\n18 Sherwood LM Castleman B Case records of the Massachusetts General Hospital: case 15-1971-hypercalcemia with chronic pulmonary disease\n. New England Journal of Medicine \n1971 \n284 \n839 –847\n. (10.1056/NEJM197104152841508 )\n19 Martin TJ Suva LJ Parathyroid hormone-related protein in hypercalcaemia of malignancy\n. Clinical Endocrinology \n1989 \n31 \n631 –647\n. (10.1111/j.1365-2265.1989.tb01288.x )2697477 \n20 Vacher-Coponat H Opris A Denizot A Dussol B Berland Y Hypercalcaemia induced by excessive parathyroid hormone secretion in a patient with neuroendocrine tumor\n. Nephrology, Dialysis, Transplantation \n2005 \n20 \n2832 –2835\n. (10.1093/ndt/gfi065 )\n21 Martin TJ Atkins D Biochemical regulators of bone resorption and their significance in cancer\n. Essays in Medical Biochemistry \n1979 \n4 \n49 –82\n.\n22 Myers WPL Hypercalcemia in neoplastic disease\n. Archives of Surgery \n1960 \n80 \n308 –318\n. 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(10.1016/s0002-9440(1063343-3 )\n27 Hibi M Hara F Tomishige H Nishida Y Kato T Okumura N Hashimoto T Kato R 1,25-Dihydroxyvitamin D-mediated hypercalcemia in ovarian dysgerminoma\n. Pediatric Hematology and Oncology \n2008 \n25 \n73 –78\n. (10.1080/08880010701774033 )18231957 \n28 Grill V Ho P Body JJ Johanson N Lee SC Kukreja SC Moseley JM Martin TJ Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer\n. Journal of Clinical Endocrinology and Metabolism \n1991 \n73 \n1309 –1315\n. (10.1210/jcem-73-6-1309 )1955513 \n29 Soyfoo MS Brenner K Paesmans M Body JJ Non-malignant causes of hypercalcemia in cancer patients: a frequent and neglected occurrence\n. Supportive Care in Cancer \n2013 \n21 \n1415 –1419\n. (10.1007/s00520-012-1683-5 )23229654 \n30 Burtis WJ Wu T Bunch C Wysolmerski JJ Insoqna KL Weir EC Broadus AE Stewart AF Identification of a novel 17,000 dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy\n. Journal of Biological Chemistry \n1987 \n262 \n7151 –7156\n.\n31 Schneider HG Kartsogiannis V Zhou H Chou ST Martin TJ Grill V Parathyroid hormone-related protein mRNA and protein expression in multiple myeloma: a case report\n. Journal of Bone and Mineral Research \n1998 \n13 \n1640 –1643\n. (10.1359/jbmr.1998.13.10.1640 )9783553 \n32 Ralston SH Danks J Hayman J Fraser WD Stewart CS Martin TJ Parathyroid hormone-related protein of malignancy: immunohistochemical and biochemical studies in normocalcemic and hypercalcemic patients with cancer\n. Journal of Clinical Pathology \n1991 \n44 \n472 –476\n. (10.1136/jcp.44.6.472 )2066425 \n33 Roodman GD Mechanisms of bone metastasis\n. New England Journal of Medicine \n2004 \n350 \n1655 –1664\n. (10.1056/NEJMra030831 )\n34 Mundy GR Mechanisms of osteolytic bone destruction\n. Bone \n1991 \n12 (Supplement 1) S1 –S6\n. (10.1016/8756-3282(9190057-p )\n35 Body JJ Niepel D Tonini G Hypercalcemia and hypocalcemia: finding the balance\n. Supportive Care in Cancer \n2017 \n25 \n1639 –1649\n. (10.1007/s00520-016-3543-1 )28078478 \n36 Horwitz MJ Stewart AF Malignancy-associated hypercalcemia and medical management\n. In Endocrinology , 6th ed., Chapter 63, pp. 1198 –1209\n. Eds Jameson JL DeGroot LJ de Krester D Philadelphia: Saunders Elsevier, 2010 .\n37 Clemens TL Cormier S Eichinger A Endlich K Fiaschi-Taesch N Fischer E Friedman PA Karaplis AC Massfelder T Rossert J \nParathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets\n. British Journal of Pharmacology \n2001 \n134 \n1113 –1136\n. (10.1038/sj.bjp.0704378 )11704631 \n38 Martin TJ Grill V Hypercalcemia in cancer\n. Journal of Steroid Biochemistry and Molecular Biology \n1992 \n43 \n123 –129\n. (10.1016/0960-0760(9290196-p )\n39 Mundy GR Martin TJ The hypercalcemia of malignancy: pathogenesis and management\n. Metabolism: Clinical and Experimental \n1982 \n31 \n1247 –1277\n. (10.1016/0026-0495(8290012-9 )6755168 \n40 Moseley JM Kubota M Diefenbach-Jagger H Wettenhall REH Kemp BE Suva LJ Rodda CP Ebeling PR Hudson PJ Zajac JD Parathyroid hormone-related protein purified from a human lung cancer cell line\n. PNAS \n1987 \n84 \n5048 –5052\n. (10.1073/pnas.84.14.5048 )2885845 \n41 Suva LJ Winslow GA Wettenhall REH Hammonds RG Moseley JM Diefenbach-Jagger H Rodda CP Kemp BE Rodriguez H Chen EY A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression\n. Science \n1987 \n237 \n893 –896\n. (10.1126/science.3616618 )3616618 \n42 Kemp BE Moseley JM Rodda CP Ebeling PR Wettenhall REH Stapleton D Diefenbach-Jagger H Ure F Michelangeli VP Simmons HA Parathyroid hormone-related protein of malignancy: active synthetic fragments\n. Science \n1987 \n238 \n1568 –1570\n. (10.1126/science.3685995 )3685995 \n43 Naafs MAB Parathyroid hormone related peptide (PTHrP): a mini-review\n. Endocrinology and Metabolism International Journal \n2017 \n5 00139. (10.15406/emij.2017.05.00139 )\n44 Mangin M Ikeda K Dreyer BE Broadus AE Isolation and characterization of the human parathyroid hormone-like peptide gene\n. PNAS \n1989 \n86 \n2408 –2412\n. (10.1073/pnas.86.7.2408 )2928340 \n45 Yang Y Wang B PTH1R-CaSR cross talk: new treatment options for breast cancer osteolytic bone metastases\n. International Journal of Endocrinology \n2018 \n2018 \n7120979 . (10.1155/2018/7120979 )30151009 \n46 Collins MT Skarulis MC Bilezikian JP Silverberg SJ Spiegel AM Marx SJ Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent\n. Journal of Clinical Endocrinology and Metabolism \n1998 \n83 \n1083 –1088\n. (10.1210/jcem.83.4.4726 )9543122 \n47 Mirrakhimov AE Hypercalcemia of malignancy: an update on pathogenesis and management\n. North American Journal of Medical Sciences \n2015 \n7 \n483 –493\n. (10.4103/1947-2714.170600 )26713296 \n48 Kaiser W Biesenbach G Kramer R Zazqornik J Calcium free hemodialysis: an effective therapy in hypercalcemic crisis-report of 4 cases\n. Intensive Care Medicine \n1989 \n15 \n471 –474\n. (10.1007/BF00255605 )2600293 \n49 Hu MI Glezerman IG Leboulleux S Insogna K Gucalp R Misiorowski W Yu B Zorsky P Tosi D Bessudo A \nDenosumab for treatment of hypercalcemia of malignancy\n. Journal of Clinical Endocrinology and Metabolism \n2014 \n99 \n3144 –3152\n. (10.1210/jc.2014-1001 )24915117 \n50 Adami S Rossini M Hypercalcemia of malignancy: pathophysiology and treatment\n. Bone \n1992 \n13 (Supplement 1) S51 –S55\n. (10.1016/s8756-3282(0980010-0 )1581120 \n51 Thosani S Hu MI Denosumab: a new agent in the management of hypercalcemia of malignancy\n. Future Oncology \n2015 \n11 \n2865 –2871\n. (10.2217/fon.15.232 )26403973 \n52 Bech A Smolders K Telting D de Boer H Cinacalcet for hypercalcemia caused by pulmonary squamous cell carcinoma producing parathyroid hormone-related peptide\n. Case Reports in Oncology \n2012 \n5 \n1 –8\n. (10.1159/000335676 )22379470 \n53 Sternlicht H Glezerman IG Hypercalcemia of malignancy and new treatment options\n. Therapeutics and Clinical Risk Management \n2015 \n11 \n1779 –1788\n. (10.2147/TCRM.S83681 )26675713 \n54 Whitfield PL Carroll RW THR-319: Cinacalcet use in PTHrP-secreting GEP-NETs: a new management option for humoral hypercalcemia of malignancy?\n In Endocrine Society's 97th Annual Meeting and Expoo , March 5–8, San Diego, 2015 .\n55 Valdes-Socin H Almanza MR Fernandez-Ladreda MT Daele DV Polus M Chavez M Beckers A Use of Cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor\n. Archives of Endocrinology and Metabolism \n2017 \n61 \n506 –509\n. (10.1590/2359-3997000000291 )28977163 \n56 Asonitis N Kassi E Kokkinos M Giovanopoulos I Petychaki F Goqas H Hypercalcemia of malignancy treated with Cinacalcet\n. Endocrinology, Diabetes and Metabolism Case Reports \n2017 \n2017 170118. (10.1530/EDM-17-0118 )\n57 Sheehan M Tanimu S Tanimu Y Engel J Onitilo A Cinacalcet for the treatment of humoral hypercalcemia of malignancy: an introductory case report with a pathophysiologic and therapeutic review\n. Case Reports in Oncology \n2020 \n13 \n321 –329\n. (10.1159/000506100 )32308599 \n58 Colloton M Shatzen E Wiemann B Starnes C Scully S Henley C Martin D Cinacalcet attenuates hypercalcemia observed in mice bearing either rice H-500 Leydig cell or C26-DCT colon tumors\n. European Journal of Pharmacology \n2013 \n712 \n8 –15\n. (10.1016/j.ejphar.2013.04.013 )23623934 \n59 Perlia CP Gubisch NJ Wolter J Edelberg D Dederick MM Taylor 3rd SG Mithramycin treatment of hypercalcemia\n. Cancer \n1970 \n25 \n389 –394\n. (10.1002/1097-0142(197002)25:2<389::aid-cncr2820250217>3.0.co;2-x )5413510 \n60 Grill V Martin TJ Hypercalcemia of malignancy\n. Reviews in Endocrine and Metabolic Disorders \n2000 \n1 \n253 –263\n. (10.1023/a:1026597816193 )11706739\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "10(1)",
"journal": "Endocrine connections",
"keywords": "humoral; hypercalcemia; malignancy; parathyroid hormone-related peptide",
"medline_ta": "Endocr Connect",
"mesh_terms": null,
"nlm_unique_id": "101598413",
"other_id": null,
"pages": "R13-R24",
"pmc": null,
"pmid": "33289687",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Treatment of malignancy-associated hypercalcemia with cinacalcet: a paradigm shift.",
"title_normalized": "treatment of malignancy associated hypercalcemia with cinacalcet a paradigm shift"
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"abstract": "In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.",
"affiliations": "Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Inoue|Minako|M|;Okamura|Ken|K|;Kitaoka|Chie|C|;Kinoshita|Fumio|F|;Namitome|Ryo|R|;Nakamura|Udai|U|;Shiota|Masaki|M|;Goto|Kenichi|K|;Ohtsubo|Toshio|T|;Matsumura|Kiyoshi|K|;Oda|Yoshinao|Y|;Eto|Masatoshi|M|;Kitazono|Takanari|T|",
"chemical_list": "D000963:Antimetabolites; D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D008797:Metyrapone",
"country": "Japan",
"delete": false,
"doi": "10.1507/endocrj.EJ18-0025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-8959",
"issue": "65(7)",
"journal": "Endocrine journal",
"keywords": "Ectopic ACTH syndrome; Metyrapone; Pheochromocytoma; Positive feedback",
"medline_ta": "Endocr J",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000324:Adrenocorticotropic Hormone; D000963:Antimetabolites; D025461:Feedback, Physiological; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008797:Metyrapone; D008875:Middle Aged; D010673:Pheochromocytoma",
"nlm_unique_id": "9313485",
"other_id": null,
"pages": "755-767",
"pmc": null,
"pmid": "29760304",
"pubdate": "2018-07-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism.",
"title_normalized": "metyrapone responsive ectopic acth secreting pheochromocytoma with a vicious cycle via a glucocorticoid driven positive feedback mechanism"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-183176",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "OBJECTIVE\nA case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.\n\n\nMETHODS\nLesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.\n\n\nRESULTS\nThere was no recurrence of lesions at 3 months follow-up.\n\n\nCONCLUSIONS\nRadiotherapy is an effective form of cutaneous directed treatment for localized PTLD.",
"affiliations": "a Department of Dermatology , St. Vincent's University Hospital , Dublin , Ireland.;b Department of Histopathology , St. Vincent's University Hospital , Dublin , Ireland.;a Department of Dermatology , St. Vincent's University Hospital , Dublin , Ireland.",
"authors": "Murad|Aizuri|A|;Sheahan|Kieran|K|;Kirby|Brian|B|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2017.1341613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "29(2)",
"journal": "The Journal of dermatological treatment",
"keywords": "SCC-in-situ; liver transplant; post-transplant lymphoproliferative disorder",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D000368:Aged; D000903:Antibiotics, Antineoplastic; D001402:B-Lymphocytes; D002294:Carcinoma, Squamous Cell; D005500:Follow-Up Studies; D005720:Gamma Rays; D006801:Humans; D007150:Immunohistochemistry; D008105:Liver Cirrhosis, Biliary; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D009173:Mycophenolic Acid; D016559:Tacrolimus; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "168-169",
"pmc": null,
"pmid": "28604230",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) successfully treated with radiotherapy.",
"title_normalized": "primary cutaneous post liver transplant lymphoproliferative disorder ptld successfully treated with radiotherapy"
} | [
{
"companynumb": "IE-ROCHE-2090460",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "The novel coronavirus disease has brought the world to standstill with high infectivity and rapid transmission. The disease caused by novel coronavirus is termed as coronavirus disease 2019 (COVID-19). We present the case of a renal transplant patient who was infected with COVID-19 through community spread and presented with fever and gastrointestinal symptoms. Transplant recipients are particularly vulnerable because of the immunosuppressed state. These patients can shed a virus for a prolonged period and can have a higher load of the virus. There have been no COVID-19 cases transmitted through organ donation. Preinfection immunological impairment can aggravate the severity of the infection. The transplant team plays a crucial role in donor and recipient evaluation and guiding the timing of the transplant. Although specific published data are lacking with regard to transplant recipients, they should follow the same precautions as the general population, like avoiding nonessential travel and practice social distancing.",
"affiliations": "Adventist Medical Center, Hanford, CA, USA.;Ashland Bellefonte Cancer Center, Ashland, KY, USA.;Adventist Medical Center, Hanford, CA, USA.;Wise Health System, Decatur, TX, USA.;Great Plains Health, North Platte, NE, USA.;Interfaith Medical Center, Brooklyn, NY, USA.;Phoebe Putney Memorial Hospital, Albany, GA, USA.",
"authors": "Adapa|Sreedhar|S|0000-0001-5608-5654;Konala|Venu Madhav|VM|0000-0003-1953-8815;Naramala|Srikanth|S|0000-0003-1238-856X;Daggubati|Subba Rao|SR|;Koduri|Narayana Murty|NM|;Gayam|Vijay|V|0000-0001-5194-9134;Chenna|Avantika|A|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/2324709620949307",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620949307\n10.1177_2324709620949307\nCase Report\nCOVID-19 in Renal Transplant Patient Presenting With Active Typical Symptoms and Resolved Atypical Symptoms\nhttps://orcid.org/0000-0001-5608-5654Adapa Sreedhar MD, FACP, FASN1 https://orcid.org/0000-0003-1953-8815Konala Venu Madhav MD, FACP, CACP2 https://orcid.org/0000-0003-1238-856XNaramala Srikanth MD, FACR, CCD1 Daggubati Subba Rao MD3 Koduri Narayana Murty MD, MRCPsych4 https://orcid.org/0000-0001-5194-9134Gayam Vijay MD5 Chenna Avantika MD, FASN67 1 Adventist Medical Center, Hanford, CA, USA\n2 Ashland Bellefonte Cancer Center, Ashland, KY, USA\n3 Wise Health System, Decatur, TX, USA\n4 Great Plains Health, North Platte, NE, USA\n5 Interfaith Medical Center, Brooklyn, NY, USA\n6 Phoebe Putney Memorial Hospital, Albany, GA, USA\n7 Medical College of Georgia, Augusta, GA, USA\nSrikanth Naramala, MD, FACR, CCD, Department of Internal Medicine, Division of Rheumatology, Adventist Medical Center, 470 North Greenfield Avenue, Suite 305, Hanford, CA 93230, USA. Email: dr.srikanth83@gmail.com\n11 8 2020 \nJan-Dec 2020 \n8 23247096209493078 6 2020 18 7 2020 19 7 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The novel coronavirus disease has brought the world to standstill with high infectivity and rapid transmission. The disease caused by novel coronavirus is termed as coronavirus disease 2019 (COVID-19). We present the case of a renal transplant patient who was infected with COVID-19 through community spread and presented with fever and gastrointestinal symptoms. Transplant recipients are particularly vulnerable because of the immunosuppressed state. These patients can shed a virus for a prolonged period and can have a higher load of the virus. There have been no COVID-19 cases transmitted through organ donation. Preinfection immunological impairment can aggravate the severity of the infection. The transplant team plays a crucial role in donor and recipient evaluation and guiding the timing of the transplant. Although specific published data are lacking with regard to transplant recipients, they should follow the same precautions as the general population, like avoiding nonessential travel and practice social distancing.\n\ncoronavirusCOVID-19acute respiratory distress syndromerenal transplantcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe severe acute distress syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health concern and has infected more than 7 million people worldwide as of June 8, 2020.1 The disease caused by SARS-CoV-2 is termed as coronavirus disease 2019 (COVID-19). The SARS-CoV-2 is highly contagious and frequently involves patients with preexisting conditions. Transplant recipients are particularly vulnerable because of the immunosuppressed state and can develop opportunistic infections. COVID-19 is rapidly evolving, causing outbreaks and case clusters, and it has affected transplantation globally. We present a renal transplant patient who was infected with COVID-19 through community spread and presented with fever and gastrointestinal symptoms.\n\nCase Report\nA 61-year-old African American female with a history of end-stage renal disease due to adult polycystic kidney disease, s/p living-related kidney transplant in 2004 at an outside hospital, presented to the emergency room with fever for 5 days. She also had diarrhea and nausea, which had resolved by the time of presentation. The patient had nausea and diarrhea for 5 days. The diarrhea was nonbloody and watery, occurring about 4 to 5 times daily. The patient attended a funeral 10 days before her admission. She denied any history of cough, shortness of breath, chest pain, abdominal pain, vomiting, fatigue, myalgia, or headache. Symptoms started after attending a funeral in the city where several people had tested positive for COVID-19. Past medical history includes hypertension, gout, and histoplasmosis. Her home medications include tacrolimus 0.5 mg twice a day, mycophenolate mofetil (MMF) 250 mg twice a day, prednisone 5 mg daily, itraconazole 100 mg twice a day, allopurinol 100 mg daily, labetalol 100 mg twice a day, and hydralazine 100 mg 3 times a day.\n\nOn presentation, the patient was febrile with 103 °F, pulse rate 87 beats per minute, blood pressure 151/85 mm Hg, respiratory rate 24 breaths per minute, and oxygen saturation 92% to 97% on room air. Physical examination revealed that the patient was in respiratory distress with decreased breath sounds on the left side of the chest. The rest of the physical examination was unremarkable. The laboratory findings are summarized in Table 1. The patient’s baseline creatinine was 1.4 g/dL in the laboratory tests done in 2019. The urinalysis revealed 2+ protein, which was new, negative for blood and red blood cells. The chest X-ray revealed mild mid to lower lung infiltrate bilaterally, more significant on the left (Figure 1). The computed tomography (CT) scan of the chest with contrast revealed few scattered rounded ground glass and consolidative opacities seen within the lingula of the left lung and middle lobe right lung and segmental lung consolidation seen within the dependent portion of both lower lobes (Figure 2).\n\nTable 1. Summary of Laboratory Findings.\n\nParameters\tReference range\tAt admission\tAt discharge\t\nHemoglobin\t11-15 (g/dL)\t13.3\t12.4\t\nWBC\t4.5-11 (103/µL)\t4.7\t6.1\t\nLymphocytes\t22-48 (%)\t24.4\tN/A\t\nNeutrophils\t40-70 (%)\t67\tN/A\t\nSodium\t136-145 (mmol/L)\t135\t136\t\nPotassium\t3.5-5.1 (mmol/L)\t4.1\t4.1\t\nBicarbonate\t23-31 (mEq)\t21\t23\t\nBUN\t9.8-20.1 (mg/dL)\t13\t14\t\nCreatinine\t0.57-1.11 (mg/dL)\t1.3\t1.41\t\nMagnesium\t1.6-2.6 (mg/dL)\t1.6\tN/A\t\nCreatine kinase\t29-168 (U/L)\t83\tN/A\t\nFerritin\t30-400 (ng/mL)\t734.4\t1492.7\t\nC-reactive protein\t0-10 (mg/L)\t5.3\t6.5\t\nTacrolimus trough level\t5-20 (µg/L)\t7\tN/A\t\nCovid-19\tNAA/PCR\tPositive\tN/A\t\nAbbreviations: BUN, blood urea nitrogen; N/A, not available; NAA, nucleic acid amplification; PCR, polymerase chain reaction; WBC, white blood cells.\n\nFigure 1. Chest X-ray portable revealed mid to lower lung infiltrates bilaterally left greater than right.\n\nFigure 2. Computed tomography of the chest with contrast revealed few scattered rounded ground glass and consolidative opacities in the lingula of the left lung and middle lobe of the right lung along with segmental lung consolidation seen within the dependent portion of both lower lobes.\n\nThe patient was started on treatment with ceftriaxone and azithromycin for possible community-acquired pneumonia. The patient was started on intravenous fluids and antipyretics for fever. The patient’s MMF was held, tacrolimus and prednisone were continued. The COVID-19 testing done using polymerase chain reaction at the time of admission came positive. The patient needed only 2 to -3 L of oxygen for the first 2 days and no oxygen requirements after that. Her fever resolved. The patient was discharged after 5 days from the hospital. MMF was restarted and continued the same immunosuppressive regimen, before the hospital admission. The patient continues to do well after 2 weeks of discharge from the hospital.\n\nDiscussion\nCoronavirus disease 2019 (COVID-19) has become a global threat and is spreading at an alarming rate. The ailment from COVID-19 in transplant patients can be mild to severe. This group of patients can shed virus for longer period and can have increased viral load.2 Preinfection immunological impairment can aggravate the severity of the infection. These patients can also develop coinfections with bacteria, fungus, and opportunistic pathogens. The presentation in our patient was atypical with gastrointestinal symptoms, which is not a common presentation in COVID-19.\n\nTransplantation is a life-saving procedure for any end-stage organ damage, and in the event of COVID-19, the recipient and the transplant program faces many challenges that need individualized decisions. Review of literature did not report any COVID-19 transmission through organ donation.3 The SARS-CoV was detected in the liver and kidney on the autopsy reports, which, along with detection of SARS-CoV-2 in the blood of 15% cases, infers that virus can affect the organs.4 The clinical and laboratory screening of the donors should be done as COVID-19 has compelling community spread.3 SARS-CoV-2 real-time nucleic acid testing nasopharyngeal swab was included in the donor screening algorithms in many countries.3 Universal nucleic acid testing should be done in deceased and living donors.3 Prior studies have shown that the tissue viral loads and mortality were higher in patients with transplants who had severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) compared with immunocompetent individuals.3 In the setting of the pandemic, we should consider many factors like local health care utilization, weighing the risks and benefits of proceeding with the transplant, and exposing the patients to immunosuppression.\n\nThe chronic transplant recipients should limit their exposure by minimizing clinic visits and communicating with the transplant team either by telephone or through telemedicine visits. The members of the transplant care team should be educated on symptoms of COVID-19 and should report to the team if they experience any symptoms or self-isolate if they experience symptoms or had exposure. The members of the transplant team can be of increased risk of exposure when they travel to endemic areas to procure the organs, performing bronchoscopies on diseased donors, which are of exceptionally high risk, and getting exposed to asymptomatic patients who shed viruses.3 Appropriate personal protection equipment should be used to alleviate this risk.3\n\nManagement is challenging when a vaccine is not available. Prevention is the key by avoiding exposure, practicing social distancing, and controlling the transmission. The patients should be advised not to change their immunosuppressive medications without consulting with the transplant team to prevent rejection. Graft rejection will need hospital admission for the management that can result in an increased risk of exposure to COVID-19. The patients who are exposed to COVID-19 should seek guidance from the transplant team, quarantine themselves, and should be directed appropriately for testing if they develop symptoms. There is no evidence for prophylaxis for COVID-19 in transplant patients. Hydroxychloroquine is associated with side effects like visual disturbances, bone marrow depression, gastrointestinal symptoms, and QT interval prolongation, which can result in fatal arrhythmias.5 The transplant recipient who develops COVID-19 should be managed by the transplant team and might involve the temporary cessation of MMF or azathioprine on the background of calcineurin inhibitors (CNIs).6 In a study by Carbajo-Lozoya et al,7 tacrolimus inhibited the growth of human coronaviruses, including SARS-CoV.\n\nThe British Thoracic Society has issued guidance for transplant patients with symptoms compatible with COVID-19. All the patients should stop antiproliferative drugs like MMF or azathioprine and consider the reduction of CNIs. In the patients who do not require hospital admission, the patients should self-isolate, remotely monitored for any change of symptoms, and should not use high-dose steroids. In patients needing hospital admission or needing ventilator support, stopping CNIs and increasing steroid dose should be considered.8 The decision to increase the steroids should be a collaborative decision of intensivists and the transplant team. Other management issues like fluid administration, ventilator support, antibiotics, and antivirals should be in line with local and national guidance.8\n\nThere are many medications under trial for COVID-19, such as hydroxychloroquine, remdesivir, tocilizumab, and colchicine. Drug interactions should require very close attention. Information on adjusting immunosuppression and patient outcomes from prior case reports and series published on renal transplant patients with COVID-19 is discussed below and summarized in Table 2, which will help physicians in decision making in similar case scenarios.\n\nTable 2. Summary of Case Reports Published on Renal Transplant Patients With COVID-19.\n\nCase report\tAge in years/sex\tHome immunosuppression\tAge of transplant\tImmunosuppression modification\tOther treatments\tAKI (yes/no)\tCare in ICU (yes/no)\tOutcome\t\nZhu et al9\t52/Male\tTacrolimus, MMF, prednisone\t12 years\tDiscontinued all home immunosuppressive agents\nMethyl prednisone 40 mg oral daily\tIntravenous immunoglobulin (IVIG), interferon-α, biapenem\tNo\tNo\tDischarged\t\nGuillen et al10\t50/Male\tTacrolimus, everolimus, prednisone\t4 years\tDiscontinued tacrolimus, everolimus\tLopinavir + ritonavir, ceftaroline, meropenem, hydroxychloroquine, interferon-β\tYes\tYes\tUnknown\t\nGandolfini et al11\t75/Male\tTacrolimus, MMF, steroid\t10 years\tDiscontinued tacrolimus, MMF\nContinued steroids\tLopinavir + ritonavir, antibiotics\nHydroxychloroquine\tNo\tNo\tDeceased\t\nGandolfini et al11\t52/Male\tTacrolimus, MMF, steroid\t8 months\tDiscontinued tacrolimus, MMF\nContinued steroids\tDarunavir/cobicistat, antibiotics\nHydroxychloroquine, colchicine\tYes\tNo\tAlive\t\nHuang et al12\t58/Male\tMMF, steroids\t12 years\tDiscontinued MMF\nMethyl prednisone 80 mg oral daily started\tOseltamivir\nMoxifloxacin\nLopinavir + ritonavir\tNA\tYes\tDeceased\t\nNing et al13\t29/Male\tMMF, cyclosporine, methyl prednisone\t15 months\tContinued immunosuppression\tMoxifloxacin\nTrimethoprim-sulfamethoxazole, lopinavir + ritonavir\tNo\tNo\tDischarged\t\nChen et al14\t49/Male\tTacrolimus, MMF, prednisone\t7 years\tDiscontinued MMF, tacrolimus\nStarted on methyl prednisone 20 mg oral daily\tUmifenovir, ribavirin, IVIG, moxifloxacin\tNo\tYes\tDischarged\t\nSeminari et al15\t50/Male\tTacrolimus, MMF\t4 years\tContinued immunosuppression\tCeftriaxone\tNo\tNo\tDischarged\t\nMarx et al16\t58/Male\tBelatacept, MMF, prednisone\t3 years\tBelatacept, MMF discontinued\nLow-dose cyclosporine started\nPrednisone continued\tNo treatment\tYes\tNo\tDischarged\t\nArpali et al17\t28/Female\tTacrolimus, MMF, prednisone\t6 months\tContinued immunosuppression\tOseltamivir\tNo\tNo\tDischarged\t\nHsu et al18\t39/Male\tTacrolimus, MMF, prednisone\t3 years\tDiscontinued MMF, tacrolimus and prednisone continued\tHydroxychloroquine\nRemdesivir\tNo\tYes\tDischarged\t\nCheng et al19\t48/Male\tTacrolimus, MMF, prednisone\t11 years\tDiscontinued MMF and tacrolimus. Low-dose methyl prednisone started\tNo treatment\tNo\tNo\tDischarged\t\nCheng et al19\t65/Female\tTacrolimus, MMF, prednisone\t9 years\tDiscontinued MMF and tacrolimus. prednisone continued, later changed to methyl prednisone\tMoxifloxacin\nIVIG\nUmifenovir\tNo\tNo\tDischarged\t\nKim et al20\t36/Male\tTacrolimus, MMF, prednisone\t4 years\tDiscontinued MMF and tacrolimus. Started on methyl prednisone\tLopinavir + ritonavir\nHydroxychloroquine\tYes\tNo\tDischarged\t\nKim et al20\t56/Male\tTacrolimus, MMF, prednisone\t9 years\tDiscontinued MMF. tacrolimus and prednisone continued\tAzithromycin + hydroxychloroquine\tYes\tNo\tDischarged\t\nFontana et al21\t61/Male\tCyclosporine, prednisone\t15 years\tDiscontinued cyclosporine. methyl prednisone started\tHydroxychloroquine + azithromycin\nTocilizumab\nIVIG\nMeropenem\tYes\tNo\tDischarged\t\nBussalino et al22\t32/Male\tTacrolimus, MMF, prednisone\t2.5 years\tContinued on Tacrolimus, MMF with increase in dose of prednisone\tHydroxychloroquine\nOseltamivir\nCeftaroline\tYes\tNo\tDischarged\t\nWang et al23\t49/Male\tCyclosporine\nMMF\nPrednisone\t2 year\tContinued cyclosporine,\nMMF, prednisone\tLopinavir + ritonavir\nInterferon α-2b\nRibavirin\tYes\tNo\tDischarged\t\nAbbreviations: MMF, mycophenolate mofetil; ICU, intensive care unit.\n\nBartiromo et al24 has described the case of a 36-year-old renal transplant recipient who developed COVID-19 and was treated with hydroxychloroquine, ritonavir/lopinavir, along with a reduction of tacrolimus level. The patient developed abdominal pain, nausea, and vomiting, and tacrolimus trough levels were extremely high, 90.5 ng/mL, tacrolimus was discontinued and was managed only on steroids and discharged home.24\n\nIn a case series of 5 renal transplant patient with COVID-19, described by Zhang et al,25 all patients were on MMF, CNI, and prednisolone. MMF was stopped, and steroids, as well as CNI doses, were reduced in all patients. Four patients developed new-onset proteinuria. All patients had lung infiltrates and received antiretroviral therapy; none of them developed severe disease, needed intensive care unit (ICU) care, or needed intubation.25 Banerjee et al6 described 7 renal transplant patients with COVID-19 from London, all presenting with fever and respiratory symptoms. Two patients presented within 3 months of renal transplant, and 2 patients were managed on an outpatient basis. Four out of 5 needed ICU admission. One patient died, and 6 patients had immunosuppression modified. Alberici et al26 analyzed data from 20 renal transplant recipients with COVID-19. Most (95%) of these patients were on CNIs, 70% on MMF, 65% on glucocorticoids, and 10% on mammalian target of rapamycin (mTOR) inhibitor. All the immunosuppression was withdrawn. All patients have been treated with methylprednisolone 16 mg daily, 19 were treated with hydroxychloroquine and antivirals, and 6 patients received tocilizumab. Four patients needed ICU care, 6 developed acute kidney injury, and 1 among them needed dialysis. Unfortunately, 5 out of 20 patients died.26\n\nIn a single-center study by Akalin et al27 in New York, 36 adult kidney transplant recipients tested positive for COVID-19. The median age was 60 years, and the majority of them were male (26 patients, 72%). Most of them were African Americans and Hispanics at 39% and 42%, respectively. Ninety-four percent of the patients have hypertension, and 69% have diabetes. Thirty-five patients (97%) were receiving tacrolimus, 34 patients were receiving prednisone (94%), and 31 patients (86%) were receiving MMF. The presenting symptoms were fever (58%), cough (53%), dyspnea (44%), myalgias (36%), and diarrhea (22%). The hospital admission was needed in 28 patients out of which 27 patients’ radiographic findings were consistent with pneumonia. Antimetabolite was withdrawn in 86%, and tacrolimus was withdrawn in 21% of the patients. Hydroxychloroquine, azithromycin, leronlimab, tocilizumab, and high-dose glucocorticoids were used in 86%, 46%, 21%, 7%, and 7%, respectively. A total of 10 patients died (28%), 11 patients needed intubation (39%), renal replacement was needed in 6 patients (21%), and 10 patients were discharged.27\n\nIn a case series of 6 kidney transplant patients infected with COVID-19 pneumonia that were treated with tocilizumab, 4 patients died. All patients developed acute respiratory distress syndrome, and 2 of them needed continuous renal replacement therapy. Three of the 4 patients who died developed septic shock. The 2 patients who improved after tocilizumab treatment showed significant improvement in the lymphocyte count.28\n\nIn an experience from Spain evaluating the outcomes of COVID-19 in elderly (age >65 years) kidney transplant recipients, 4.9% (16 out of 324) were infected. One third of the patients developed renal dysfunction. mTOR inhibitors or MMF were discontinued on admission in all patients, and tacrolimus was withdrawn in 70% of the patients. The patients were primarily treated with a combination of azithromycin and hydroxychloroquine. Tocilizumab and antiretrovirals were given in a subset of patients. Short-term mortality in this study was 50% and is more pronounced in patients who had underlying cardiac disease, frail, and obese.29\n\nNair et al30 reported the clinical characteristics and outcomes of 10 kidney transplant recipients infected with COVID-19. Nine patients were hospitalized, and 1 patient was discharged home from the emergency room with no change in immunosuppression. Antimetabolites were stopped in all hospitalized patients. All hospitalized patients were treated with hydroxychloroquine and azithromycin. Five patients require ICU stay and developed acute kidney injury with one needing continuous renal replacement therapy. Mortality was 30% (3 patients) in this study.30\n\nHusain et al31 discussed the early outcomes of outpatient management of 41 kidney transplant recipients with COVID-19. COVID-19 was confirmed in 22 (54%) patients and suspected in 19 patients. Thirteen (32%) patients were hospitalized with a median time of 8 days from symptom onset. The majority of the patients were male, and the median age was 49 years. The main symptoms were fever (80%), cough (56%), and shortness of breath (36%). However, dyspnea was more significant in hospitalized patients (77%) than those treated as an outpatient. The median baseline creatinine was higher in hospitalized patients. Maintenance immunosuppression was similar in these patients, with 76% on CNIs and antimetabolites. The immunosuppressive regimen was reduced in 26 (63%) patients, with 82% in confirmed cases. Of the patients managed on an outpatient basis only, the improvement of the symptoms was seen at 12 days. There was no acute rejection noted during this limited follow-up (24 days) period in the patients with reduced immunosuppression.31\n\nConclusion\nThe kidney transplant recipients are at increased risk of developing infections secondary to their immunosuppressed state. Although specific published data are lacking, they should follow the same precautions as the general population, like avoiding nonessential travel and practice social distancing.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iDs: Sreedhar Adapa \nhttps://orcid.org/0000-0001-5608-5654\n\nVenu Madhav Konala \nhttps://orcid.org/0000-0003-1953-8815\n\nSrikanth Naramala \nhttps://orcid.org/0000-0003-1238-856X\n\nVijay Gayam \nhttps://orcid.org/0000-0001-5194-9134\n==== Refs\nReferences\n1 \nJohn Hopkins University and Medicine . Coronavirus Resource Center\n. Accessed June 8, 2020 \nhttps://coronavirus.jhu.edu/map.html\n2 \nFishman JA Grossi PA \nNovel coronavirus-19 (COVID-19) in the immunocompromised transplant recipient: #Flatteningthecurve\n. Am J Transplant . 2020 ;20 :1765 -1767\n.32233057 \n3 \nKumar D Manuel O Natori Y , et al\nCOVID-19: a global transplant perspective on successfully navigating a pandemic\n. Am J Transplant . 2020 ;20 :1773 -1779\n.32202064 \n4 \nKaul DR Mehta AK Wolfe CR Blumberg E Green M \nEbola virus disease: implications for solid organ transplantation\n. Am J Transplant . 2015 ;15 :5 -6\n.25510898 \n5 \nEljaaly K Alireza KH Alshehri S Al-Tawfiq JA \nHydroxychloroquine safety: a meta-analysis of randomized controlled trials\n. Travel Med Infect Dis . 2020 ;36 :101812 .\n6 \nBanerjee D Popoola J Shah S Ster IC Quan V Phanish M \nCOVID-19 infection in kidney transplant recipients\n. 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Am J Transplant . 2020 ;20 :1859 -1863\n.32181990 \n10 \nGuillen E Pineiro GJ Revuelta I , et al\nCase report of COVID-19 in a kidney transplant recipient: does immunosuppression alter the clinical presentation?\n\nAm J Transplant . 2020 ;20 :1875 -18784\n.32198834 \n11 \nGandolfini I Delsante M Fiaccadori E , et al\nCOVID-19 in kidney transplant recipients\n. Am J Transplant . 2020 ;20 :1941 -1943\n.32233067 \n12 \nHuang J Lin H Wu Y , et al\nCOVID-19 in post-transplantation patients—report of two cases\n. Am J Transplant . 2020 ;20 :1879 -1881\n.32243697 \n13 \nNing L Liu L Li W , et al\nNovel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: case report\n. Am J Transplant . 2020 ;20 :1864 -1868\n.32277555 \n14 \nChen S Yin Q Shi H , et al\nA familial cluster, including a kidney transplant recipient, of Coronavirus Disease 2019 (COVID-19) in Wuhan, China\n. 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Published online April 12, 2020. doi:10.1111/tid.13286 \n25 \nZhang H Chen Y Yuan Q , et al\nIdentification of kidney transplant recipients with coronavirus disease 2019\n. Eur Urol . 2020 ;77 :742 -747\n.32249089 \n26 \nAlberici F Delbarba E Manenti C , et al\nA single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia\n. Kidney Int . 2020 ;97 :1083 -1088\n.32354634 \n27 \nAkalin E Azzi Y Bartash R , et al\nCovid-19 and kidney transplantation\n. N Engl J Med . 2020 ;382 :2475 -2477\n.32329975 \n28 \nMella A Mingozzi S Gallo E , et al\nCase series of six kidney transplanted patients with COVID-19 pneumonia treated with tocilizumab\n. Transpl Infect Dis . Published online June 5, 2020. doi:10.1111/tid.13348 \n29 \nCrespo M Pérez-Sáez MJ Redondo-Pachón D , et al\nCOVID-19 in elderly kidney transplant recipients\n. Am J Transplant . Published online May 29, 2020. doi:10.1111/ajt.16096 \n30 \nNair V Jandovitz N Hirsch JS , et al\nCOVID-19 in kidney transplant recipients\n. Am J Transplant . 2020 ;20 :1819 -1825\n.32351040 \n31 \nHusain SA Dube G Morris H , et al\nEarly outcomes of outpatient management of kidney transplant recipients with coronavirus disease 2019\n. Clin J Am Soc Nephrol . Published online May 18, 2020. doi:10.2215/CJN.05170420\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "COVID-19; acute respiratory distress syndrome; coronavirus; renal transplant",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003967:Diarrhea; D005221:Fatigue; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D016377:Organ Transplantation; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D066027:Transplant Recipients",
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"title": "COVID-19 in Renal Transplant Patient Presenting With Active Typical Symptoms and Resolved Atypical Symptoms.",
"title_normalized": "covid 19 in renal transplant patient presenting with active typical symptoms and resolved atypical symptoms"
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"abstract": "A 70-year-old African American male with a history of hypertension, congestive heart failure, breast cancer status-post six rounds of doxorubicin/cyclophosphamide, and Parkinson's disease managed with carbidopa/levodopa presented to the emergency department with bilateral hearing loss and ataxia. The patient was admitted and evaluated for possible traumatic, oncological, and pharmacological etiologies. Further investigation revealed hypointensities along the cerebellar folia and basal cisterns on MRI in addition to the two-year history of progressive bilateral hearing loss and gait ataxia. In view of these findings, the patient was diagnosed with superficial siderosis and Parkinson's medications were discontinued. Superficial siderosis should be considered as a diagnosis in cases of bilateral hearing loss and ataxia in patients with history of anticoagulation and risk factors for prior cerebrovascular accidents or head trauma.",
"affiliations": "Department of Anatomical Sciences, St. George's University School of Medicine, St. George's, GRD.;Department of Anatomical Sciences, St. George's University, St. George's, GRD.;Departments of Neurosurgery and Structural & Cellular Biology, Tulane University & Ochsner Clinic Neurosurgery Program, Tulane University School of Medicine, New Orleans, USA.",
"authors": "Bordes|Stephen J|SJ|;Bang|Katrina E|KE|;Tubbs|R Shane|RS|",
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"doi": "10.7759/cureus.7307",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7307\nInternal Medicine\nNeurology\nSuperficial Siderosis Misdiagnosed As Parkinson’s Disease in a 70-year-old Male Breast Cancer Survivor\nMuacevic Alexander Adler John R Bordes Stephen J 1 Bang Katrina E 2 Tubbs R. Shane 32 \n1 \nDepartment of Anatomical Sciences, St. George's University School of Medicine, St. George's, GRD \n\n2 \nDepartment of Anatomical Sciences, St. George's University, St. George's, GRD \n\n3 \nDepartments of Neurosurgery and Structural & Cellular Biology, Tulane University & Ochsner Clinic Neurosurgery Program, Tulane University School of Medicine, New Orleans, USA \n\nStephen J. Bordes sbordes@sgu.edu\n18 3 2020 \n3 2020 \n12 3 e73073 3 2020 18 3 2020 Copyright © 2020, Bordes et al.2020Bordes 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/28837-superficial-siderosis-misdiagnosed-as-parkinsons-disease-in-a-70-year-old-male-breast-cancer-survivorA 70-year-old African American male with a history of hypertension, congestive heart failure, breast cancer status-post six rounds of doxorubicin/cyclophosphamide, and Parkinson’s disease managed with carbidopa/levodopa presented to the emergency department with bilateral hearing loss and ataxia. The patient was admitted and evaluated for possible traumatic, oncological, and pharmacological etiologies. Further investigation revealed hypointensities along the cerebellar folia and basal cisterns on MRI in addition to the two-year history of progressive bilateral hearing loss and gait ataxia. In view of these findings, the patient was diagnosed with superficial siderosis and Parkinson’s medications were discontinued. Superficial siderosis should be considered as a diagnosis in cases of bilateral hearing loss and ataxia in patients with history of anticoagulation and risk factors for prior cerebrovascular accidents or head trauma.\n\nsuperficial siderosisparkinson’s diseaseataxiabilateral hearing lossThe 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\nSuperficial siderosis is a rare neurological disease associated with chronic subpial deposition of hemosiderin throughout the brain and spinal cord due to recurrent episodes of subarachnoid hemorrhage [1-9]. Disease prevalence within the general population remains unclear, although population-based studies have reported a range of 0.21%-1.43% in patients aged over 55 years, with greater prevalence in those aged over 69 years [2,10]. The disease presents clinically as a triad of bilateral sensorineural hearing loss, ataxia, and myelopathy with pathognomonic findings of hypointensities along the brainstem, cerebellum, and spinal cord identified by multisequence MRI.\n\nIn view of the nonspecific sensorineural, neurological, and cerebrovascular findings associated with superficial siderosis combined with its low prevalence within the population, the disease can often be misdiagnosed or missed altogether. Herein, we present a case of superficial siderosis that was misdiagnosed and mistreated as Parkinson’s disease. We suggest that in order to avoid future misdiagnoses, superficial siderosis should be considered as a differential diagnosis for elderly patients, especially those on anticoagulation or with a history of brain trauma or injury, who present with bilateral sensorineural hearing loss and gait ataxia.\n\nCase presentation\nA 70-year-old African American man was admitted to the hospital with bilateral hearing loss and ataxia. The patient was initially brought in by his wife owing to concern for a potential traumatic brain injury, as he had hit his head on a metal gate three days previously while working on his farm. Upon further inquiries concerning history, the patient’s wife stated that his hearing and gait had progressively declined over the previous two years. The patient had first struggled with high pitched sounds, followed by both high- and low-pitched sounds. His wife noticed him sitting closer to his television, struggling to converse in loud settings, and asking others to repeat themselves more frequently. Both the patient and his wife attributed the initial hearing losses to old age.\n\nThe patient was diagnosed six years earlier at an outside facility with obstructive sleep apnea, hypertension, benign prostatic hyperplasia, and breast cancer. At that time, he underwent a bilateral mastectomy followed by six months of chemotherapy with doxorubicin and cyclophosphamide. He was subsequently diagnosed with deep vein thrombosis, pulmonary embolism, and congestive heart failure attributed to the chemotherapy. Long-term anticoagulation with warfarin was initiated. The remainder of his medications included lisinopril, metoprolol, amlodipine, tamsulosin, anastrozole, and tamoxifen. The patient followed up consistently with his primary physician and oncologist. At an appointment two years earlier, his gait was noted to be in decline with a tendency to lose balance, and his movements were slowed. He was inappropriately diagnosed with Parkinson’s disease, and carbidopa/levodopa therapy was initiated due to the similarity of physical manifestations between the patient’s presentation and the misdiagnosed movement disorder.\n\nPresently, exam findings on presentation were unremarkable with the exception of bilateral sensorineural hearing loss, ataxia, and 1+ pitting edema to the anterior tibia bilaterally. Weber testing showed no lateralization and Rinne testing revealed air conduction greater than bone conduction. The patient had no signs of trauma or infection to the external ear or tympanum bilaterally. There was no evidence of a bulging membrane. The light reflex was observed. Cranial nerves (CNs) II-XII were otherwise grossly intact. The patient’s gait was markedly ataxic and spastic with a tendency to fall. Romberg testing was negative. He did not exhibit a resting tremor or cogwheeling of the extremities. Head CT without contrast was ordered, which showed no acute intracranial abnormalities; however, old bilateral basal ganglia infarcts were noted. Twelve-lead ECG showed normal sinus rhythm with a first-degree atrioventricular block (Figure 1).\n\nFigure 1 Twelve-lead ECG\nHR: heart rate; A-V: atrioventricular; ECG: electrocardiogram; Ax; axis\n\nRemaining abbreviations cannot be expanded and refer to ECG waves and intervals.\n\nMultisequence brain MRI showed no signs of acute stroke; however, old blood products consistent with the hypointensity of hemosiderin were noted along the cerebellar folia and basal cisterns (Figure 2).\n\nFigure 2 Brain MRI\nAxial plane multisequence T1, T2, and FLAIR MRI showing the midbrain (A), pons (C-F), and cerebellum (G, H). Coronal plane T2-weighted MRI (B).\n\nHemosiderin hypointensities (black) noted along the cerebellar folia and basal cisterns in both coronal and axial planes (yellow arrows). Cranial nerve VIII (CN8) noted (white arrows).\n\nFLAIR, fluid-attenuated inversion recovery\n\n \n\n \n\nPeriventricular small vessel disease and parenchymal atrophy were also noted. Carotid artery and renal ultrasounds showed no evidence of occlusion, obstruction, plaque deposition, or hydronephrosis. Transthoracic echocardiography showed an ejection fraction of 60%, trivial mitral regurgitation, and physiological pulmonary regurgitation (Table 1). There was no sign of ventricular abnormality or dysfunction.\n\nTable 1 Transthoracic echocardiography results\nThe findings showed mild mitral annular calcification, trivial mitral regurgitation, normal left ventricle structure and function.\n\nTTE: transthoracic echocardiogram; EF: ejection fraction; LV: left ventricle; PW: posterior wall; FS: fractional shortening; EDV: end diastolic volume; ESV: end systolic volume; AO: aorta; LA: left atrium; MV: mitral valve; RAP: right atrial pressure; TR: tricuspid regurgitation; AV: aortic valve; RVSP: right ventricular systolic pressure; PV: pulmonic valve; LVOT: left ventricular outflow tract; VTI: velocity time integral; PASP: pulmonary artery systolic pressure\n\nEF Findings\tM-Mode/2D Measurements and Calculations\tDoppler Measurements and Calculations\t\nEF calculated\t60.2%\tLV diastolic dimension\t5.45 cm\tLV systolic dimension\t4.01 cm\tMV peak E-wave\t0.51 m/s\tAV peak velocity\t1.22 m/s\t\n \t \tLV PW diastolic\t1.02 cm\tLV volume systolic\t64.5 mL\tMV peak A-wave\t0.58 m/s\tAV peak gradient\t5.95 mmHg\t\n \t \tSeptum diastolic\t0.87 cm\tAO root dimension\t3.7 cm\tMV E/A ratio\t0.89\tEstimated RVSP\t22 mmHg\t\n \t \tLV volume diastolic\t162 mL\tLA/aorta\t0.86\tMV peak gradient\t1.06 mmHg\tPV peak velocity\t1.14 m/s\t\n \t \tLV FS\t26.42%\tLA dimension\t3.2 cm\tMV deceleration time\t197 ms\tPV peak gradient\t5.2 mmHg\t\n \t \tLV EDV/LV EDV index\t162 mL/69 m2\n\t \t \tMV E’ velocity\t0.06 m/s\tLVOT VTI\t13.5 cm\t\n \t \tLV ESV/LV ESV index\t64.5 mL/27 m2\n\t \t \tEstimated RAP\t10 mmHg\tEstimated PASP\t21.56 mmHg\t\n \t \t \t \t \t \tTR velocity\t1.70 m/s\t \t \t\n \t \t \t \t \t \tTR gradient\t11.56 mmHg\t \t \t\nInitial laboratory studies can be found in Table 2.\n\nTable 2 Laboratory results\nH: high value (above normal limits); L: low value (below normal limits); WBC: white blood cell count; RBC: red blood cell count; Hgb: hemoglobin; Hct: hematocrit; MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; RDW: red cell distribution width; PT: prothrombin time; INR: international normalized ratio; APTT: activated partial thromboplastin time; CO2: carbon dioxide; Est: estimated; HbA1c: hemoglobin A1c; LDL: low-density lipoprotein; HDL: high-density lipoprotein; THC: tetrahydrocannabinol; Ig: immunoglobulin; Ab: antibody; Ag: antigen; Gen: generation\n\nHematology\tChemistry\tUrine Analysis\tToxicology\tSerology\tCoagulation\t\nWBC\t5.4\tSodium\t143\tCollection type\tMidstream\tUrine opiates\tNegative <300 ng/mL\tSyphilis IgG/IgM Ab\tNonreactive\tPT\t14.8 H\t\nRBC\t4.35 L\tPotassium\t4.0\tColor\tYellow\tUrine barbiturates\tNegative <200 ng/mL\tHIV 1,2 Ag/Ab, 4thGen\tNonreactive\tINR\t1.2\t\nHgb\t13.5\tChloride\t102\tAppearance\tClear\tUrine phencyclidine\tNegative <25 ng/mL\tLyme Ab\tNonreactive\tAPTT\t28.3\t\nHct\t40.3 L\tCO2\n\t32\tUrine pH\t6.5\tUrine amphetamines\tNegative <1000 ng/mL\t \t\nMCV\t94\tBUN\t25 H\tSpecific gravity\t1.013\tUrine cocaine\tNegative <300 ng/mL\t \t\nMCH\t31.7\tCreatinine\t1.8 H\tProtein\tNegative\tUrine THC\tNegative <50 ng/mL\t \t\nMCHC\t33.6\tEst GFR\t37\tGlucose\tNegative\tPlasma/serum alcohol\t<0.010\t \t\nRDW\t12\tRandom glucose\t115\tOccult blood\tNegative\t \t\nPlatelet count\t211\tHbA1C\n\t5.5\tNitrite\tNegative\t \t\nImmature granulocyte, %\t0\tCalcium\t9.4\tBilirubin\tNegative\t \t\nNeutrophil, %\t54\tPhosphorus\t4.0\tAcetone\tNegative\t \t\nLymphocyte, %\t35\tMagnesium\t2.0\tLeukocyte esterase\tNegative\t \t\nMonocyte, %\t8 H\tCreatinine kinase\t226\tOsmolality\t414\t \t\nEosinophil, %\t2\tTroponin\t<0.30\tRandom creatinine\t130.2\t \t\nBasophil, %\t1\tTriglycerides\t147\tRandom sodium\t68\t \t\nNucleated RBC\t0\tCholesterol\t169\tRandom potassium\t30\t \t\nAbsolute neutrophils\t2.9\tLDL\t121 H\tRandom chloride\t31\t \t\n \tHDL\t34 L\tRandom urea nitrogen\t665\t \t\nL-Lactate\t1.8\t \t\nThe patient was found to have a kidney injury which was probably chronic and secondary to his hypertension. Elevated prothrombin time was attributable to warfarin; however, the international normalized ratio was subtherapeutic. First-degree atrioventricular block on ECG was attributed to beta-blocker compliance and the pedal edema to amlodipine, a dihydropyridine calcium-channel blocker. Neurology recommended a five-day trial of prednisone in case the symptoms were secondary to an autoimmune or inflammatory etiology; however, the patient exhibited no response and MRI results suggested an alternative diagnosis.\n\nThe patient was discharged following a negative stroke and traumatic head injury work-up with an outpatient audiogram appointment. At time of discharge and otolaryngology follow-up visit, the diagnosis was consistent with superficial siderosis. The patient did not meet Parkinson’s criteria, and he was instructed to discontinue carbidopa/levodopa.\n\nDiscussion\nSuperficial siderosis is a rare and frequently neglected cause of sensorineural hearing loss and progressive ataxia in the elderly [3,4,9]. It develops secondary to slow and repeated intracranial hemorrhages into the subarachnoid space, which result in chronic intra- and extracellular hemosiderin deposition in the subpial layers of the brain, spinal cord, and CNs [3,6,7,9]. Possible causes of these bleeds include intracranial tumors, head trauma, arteriovenous malformations, aneurysms, cervical root avulsion, neurosurgical procedures, brachial plexus injury, amyloid angiopathy, and chronic subdural hematomas [6-8]. Hemosiderin is most commonly found surrounding the brain stem, cerebellum, and basal cisterns as it pools in the posterior fossa, although superficial cortical deposition can be seen as well [1,5,9]. The diagnostic procedure of choice is T2 and susceptibility-weighted (SW) MRI, which visualizes paramagnetic blood products as hypointense [5,9]. T1 and gradient echo MRI are less sensitive in detecting blood products [5]. CT is not ideal for detecting hemosiderin, but these scans can be used to detect hemosiderin as hyperintense or to rule out other substances such as calcium that can appear as hypointense on T2 and SW MRI [9].\n\nSuperficial siderosis preferentially disturbs tissues with greater exposure to CSF and longer glial segments. This increases the rate of iron overload and subsequent lipid peroxidation of surrounding structures [3]. The condition has an atypical triad of impairment, which includes bilateral sensorineural hearing loss owing to the nature and long time course of CN VIII injury around the basal cisterns (Figure 2); gait ataxia due to involvement of the cerebellar folia and vermis (Figure 2); and myelopathy due to pyramidal tract involvement [3,8,9]. Other symptoms can include anosmia, which is often overlooked owing to the long CN I glial sheath; dementia due to cortical necrosis; cerebral atrophy; and declining executive function [3,9].\n\nHearing loss in this age group is often attributed to presbycusis, and further investigation is curtailed [4]. However, the presence of additional symptoms should raise a strong clinical suspicion for an alternative ongoing disease process. Differential diagnoses should include multiple sclerosis, autoimmune disease, neurosyphilis, Lyme disease, ototoxic pharmaceuticals (salicylates, aminoglycosides, platinum-based chemotherapeutic agents, etc.), and superficial siderosis [4,7]. It is less likely for Parkinson’s disease to be confused with siderosis. We recommend increasing suspicion for individuals on anticoagulation and individuals with prior head injuries.\n\nBleeding sources are identified in less than 50% of cases [4,9]. Management is approached stepwise, with a primary goal of stopping the bleeding, and secondary goals focused on chelation of hemosiderin deposits with lipid-soluble agents such as deferoxamine, deferiprone, and trientine. However, the risks often outweigh the benefits as symptomatic improvement can be negligible [7,8].\n\nConclusions\nSuperficial siderosis should be considered in any case of progressive bilateral sensorineural hearing loss and ataxia with or without additional accompanying symptoms, especially in individuals on long-term anticoagulation or those with prior head injuries. It is commonly misdiagnosed or underdiagnosed owing to its low frequency of occurrence in the general population. Treatment entails surgical correction of the hemorrhage, followed by iron chelation should benefits outweigh risks. We recommend increasing clinical sensitivity in order to decrease time to diagnosis and improve overall patient outcomes.\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 Prevalence and natural history of superficial siderosis a population-based study Stroke Pichler M Vemuri P Rabinstein AA 3210 3214 48 2017 29070715 \n2 Superficial siderosis in the general population Neurology Vernooij MW Ikram MA Hofman A Krestin GP Breteler MMB Van Der Lugt A 202 205 73 2009 19620607 \n3 Superficial siderosis of the meninges and its otolaryngologic connection: a series of five patients Otol Neurotol Kale SU Donaldson I West RJ Shehu A 90 95 24 2003 12544036 \n4 Superficial siderosis of the central nervous system: a neglected cause of sensorineural hearing loss Otolaryngol Neck Surg Parnes SM Weaver SA 69 77 107 1992 \n5 Susceptibility-weighted imaging of the brain: current utility and potential applications J Neuroimaging Robinson RJ Bhuta S 189 204 21 2011 \n6 Diagnostic and therapeutic challenges in superficial CNS siderosis Dan Med J Kondziella D Lindelof M Haziri D Larsen VA Kruse A 3 6 62 2015 https://www.ncbi.nlm.nih.gov/pubmed/26050830 \n7 Hearing loss and vertigo in superficial siderosis of the central nervous system Am J Otolaryngol Vibert D Häusler R Lövblad KO Schroth G 142 149 25 2004 14976664 \n8 Superficial siderosis: a case report and review of the literature Nat Clin Pract Neurol Levy M Turtzo C Llinas RH 54 58 3 2007 17205075 \n9 Superficial siderosis Neurology Kumar N Cohen-Gadol A Wright R Miller G Piepgras D Ahlskog J 1144 1152 66 2006 https://doi.org/10.1212/01.wnl.0000208510.76323.5b 16636229 \n10 Prevalence and natural history of superficial siderosis a population-based study Stroke Pichler M Vemuri P Rabinstein AA 3210 3214 48 2017 29070715\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(3)",
"journal": "Cureus",
"keywords": "ataxia; bilateral hearing loss; parkinson’s disease; superficial siderosis",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e7307",
"pmc": null,
"pmid": "32313748",
"pubdate": "2020-03-18",
"publication_types": "D002363:Case Reports",
"references": "19620607;26050830;16636229;14976664;1528605;17205075;21281380;12544036;29070715",
"title": "Superficial Siderosis Misdiagnosed As Parkinson's Disease in a 70-year-old Male Breast Cancer Survivor.",
"title_normalized": "superficial siderosis misdiagnosed as parkinson s disease in a 70 year old male breast cancer survivor"
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"abstract": "This case report describes the re-administration of abatacept to successfully reduce the articularsymptoms of a patient with rheumatoid arthritisduring the intensive phase of anti-tuberculous therapy. A 75-year-old man developed active pulmonary tuberculosis during the administration of abatacept for rheumatoid arthritis. The patient experienced a paradoxical reaction and exacerbation of rheumatoid arthritis that caused us to discontinue the abatacept. Later re-administration of abatacept along with anti-tuberculosis treatment led to well-controlled rheumatoid arthritis without exacerbation of the tuberculosis. This case shows that re-administration of abatacept may be much safer than TNF inhibitor to treat patients who are infected with mycobacteria during thetreatment of immunological diseases such asrheumatoid arthritiswith biological agents.",
"affiliations": "Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Kohnodai Hospital, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan.",
"authors": "Kawamoto|Hironori|H|;Takasaki|Jin|J|;Ishii|Satoru|S|;Suzuki|Manabu|M|;Morino|Eriko|E|;Naka|Go|G|;Iikura|Motoyasu|M|;Izumi|Shinyu|S|;Takeda|Yuichiro|Y|;Sugiyama|Haruhito|H|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30063-110.1016/j.rmcr.2017.04.013Case ReportRe-administration of abatacept for the control of articular symptoms of rheumatoid arthritis during anti-tuberculous therapy Kawamoto Hironori M.D.h5amm1212@yahoo.co.jpa∗Takasaki Jin bIshii Satoru bSuzuki Manabu bMorino Eriko bNaka Go bIikura Motoyasu bIzumi Shinyu bTakeda Yuichiro cSugiyama Haruhito ba Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japanb Division of Respiratory Diseases, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japanc Division of Respiratory Diseases, Department of Internal Medicine, Kohnodai Hospital, National Center for Global Health and Medicine, Tokyo, Japan∗ Corresponding author. Department of Respiratory Medicine, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.Department of Respiratory MedicineNational Center for Global Health and Medicine1-21-1 ToyamaShinjuku-kuTokyo162-8655Japan h5amm1212@yahoo.co.jp15 4 2017 2017 15 4 2017 21 147 150 21 2 2017 9 4 2017 10 4 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).This case report describes the re-administration of abatacept to successfully reduce the articularsymptoms of a patient with rheumatoid arthritisduring the intensive phase of anti-tuberculous therapy. A 75-year-old man developed active pulmonary tuberculosis during the administration of abatacept for rheumatoid arthritis. The patient experienced a paradoxical reaction and exacerbation of rheumatoid arthritis that caused us to discontinue the abatacept. Later re-administration of abatacept along with anti-tuberculosis treatment led to well-controlled rheumatoid arthritis without exacerbation of the tuberculosis. This case shows that re-administration of abatacept may be much safer than TNF inhibitor to treat patients who are infected with mycobacteria during thetreatment of immunological diseases such asrheumatoid arthritiswith biological agents.\n\nKeywords\nTuberculosisBiological agentAbataceptParadoxical reactionRheumatoid arthritis\n==== Body\n1 Introduction\nBiological agents such as abatacept are widely used in patients with moderate-to-severe active rheumatoid arthritis (RA). However, biological agents increase the risk of reactivation of the latent tuberculosis (TB) infection [1]. The American College of Rheumatology proposes that biological agents can be re-administered to patients with active TB after completion of anti-TB therapy [2]. The British Society of Rheumatology recommends that patients who are treated with biological agents should receive full anti-TB chemotherapy if clinically indicated [3].\n\nStopping treatment with biological agents increases the risk of exacerbating the disease attributable to the recovery of the biological agent-dependent inflammation. When RA patients are treated with biological agents that exacerbate pre-existing tuberculous lesions or cause the development of new lesions, this is termed a paradoxical reaction. Patients with a paradoxical reaction typically show fever, pulmonary infiltrates, and hypoxemia [4]. It is necessary to control the active TB as well as the RA in a paradoxical reaction.\n\nHere, we describe a RA patient who developed active TB during the initiation of abatacept, which is not an anti-tumor necrosis factor (TNF) agent, and whose RA and TB were successfully controlled by the re-administration of abatacept after anti-TB treatment.\n\n2 Case report\nA 75-year-old man was diagnosed as having RA 2 years ago because of polyarthralgia and increases in inflammatory reactions, rheumatoid factor and anti-cyclic citrullinated peptide antibody. At first, prednisolone (PSL) was prescribed at 5 mg per day, and salazosulfapyridine and methotrexate were added shortly thereafter because his RA was not under good control. After half a year, abatacept was also added because the above-mentioned medicines were still not enough to control the RA. After the addition of abatacept, his RA had been well controlled.\n\nTwo years later, he complained of a cough and slight fever. Laboratory data indicated increased inflammatory reaction, and a chest X-ray and computed tomography (CT) scan revealed consolidation in the right upper field lung (Fig. 1A and B). The patient's previous physician suspected bacterial pneumonia, discontinued the abatacept, and prescribed new quinolone antibiotics. However, the patient's pulmonary symptoms and laboratory data did not improve, and his RA was getting worse. Thereafter, Mycobacterium tuberculosis was confirmed by polymerase chain reaction and culture of his sputum. The isolated M. tuberculosis was susceptible to all anti-TB drugs. The result of a T-SPOT® TB test was indeterminable, and his C-reactive protein and matrix metalloproteinase 3 levels were elevated (Table 1).Fig. 1 (A) Chest X-ray shows consolidation in the right upper lung field and ground glass opacity in the bilateral lung bases. (B) Chest computed tomography shows emphysema, consolidation and granular shadows in the right upper lobe.\n\nFig. 1Table 1 Laboratory data on admission.\n\nTable 1Hematology\t\n White blood cells\t8170/μL\t\n Hemoglobin\t12.4 g/dL\t\n Platelets\t28.3 × 104/μL\t\nSerology\t\n Albumin\t3.4 g/dL\t\n AST\t19 U/L\t\n ALT\t18 U/L\t\n Creatinine\t0.78 mg/dL\t\n C-reactive protein\t6.3 mg/dL\t\n Hemoglobin A1c\t6%\t\nBiochemistry\t\n Anti-CCP antibody\t783.4\t\n MMP-3\t300.4\t\n RF\t228.3 IU/mL\t\nT-spot TB\tIndeterminable\t\nAST, aspartate aminotransferase; ALT, aspartate aminotransferase; CCP, cyclic citrullinated peptide; MMP-3, matrix metalloproteinase 3; RF, rheumatoid factor; TB, tuberculosis.\n\n\n\nAfter the diagnosis of TB, an anti-TB regimen comprising isoniazid, rifabutin, ethambutol and pyrazinamide was initiated. His cough improved although he still had a slight fever after the anti-TB regimen. On the 21st day of therapy, he experienced breathlessness, and oxygen at 2 L was necessary to maintain his blood oxygen level. A chest X-ray and CT scan showed progression of consolidation in the right upper field lung and new consolidation in the left upper field lung (Fig. 2A and B). A paradoxical reaction was suspected because consolidation in the pre-existing lesions had worsened and a new lesion appeared even though his clinical symptoms had improved with the anti-TB regimen. We added steroid pulse therapy (methylprednisolone at a daily dose of 1000 mg for 3 days) to the ongoing anti-TB therapy, after which his chest X-ray, oxygen saturation and RA symptoms immediately improved. After steroid pulse therapy, PSL 60 mg per day was used as steroid maintenance therapy. After steroid therapy for one month, almost all consolidations in the bilateral upper lung fields had disappeared (Fig. 3). We began to gradually taper the dose of PSL every week because his clinical course was uneventful.Fig. 2 (A) Chest X-ray shows exacerbation of the consolidation in the right upper lung field and the spread of consolidation to the left upper lung field. (B) Chest computed tomography shows the spread of consolidation in the bilateral lung lobes.\n\nFig. 2Fig. 3 Chest X-ray shows improvement of the consolidation in the bilateral lung fields.\n\nFig. 3\n\nWhen the PSL was reduced to 15 mg per day, he experienced exacerbation of left knee joint pain, and was no longer able to walk. His RA was thought to have recurred, so we increased the PSL to 20 mg per day. However, his symptoms were little improved. Because a high dose of PSL was needed to control his RA, we implemented a policy of re-administering abatacept to promote RA control.\n\nAfter re-administration of abatacept, his symptoms improved gradually, and we succeeded in reducing the PSL by 2.5 mg every two weeks. He was discharged under good control of RA with PSL at 10 mg per day and has continued to maintain a good clinical course after discharge (Fig. 4).Fig. 4 Clinical course of the patient's rheumatoid arthritis. The doses of prednisolone, the period of abatacept treatment, and changes in the patient's C-reactive protein and matrix metalloproteinase 3 values are shown. And clinical course of anti-tuberculosis treatment and Mycobacterium tuberculosis infection.\n\nFig. 4\n\nWith regard to TB, culture of his sputum was positive only once after admission. However, liver function disorder, a drug rash and bleary eyes occurred as adverse events. The anti-TB regimen was therefore changed to the combination of isoniazid, rifampicin and levofloxacin, with the ethambutol and pyrazinamide eliminated (Fig. 4). He is currently being treated with anti-TB therapy without relapse of his M. tuberculosis infection.\n\n3 Discussion\nKeane et al. [5] reported the onset of tuberculosis during the administration of TNF inhibitors or biological agents that are commonly used in a large number of RA patients. From 2004 to 2012 in Japan, the onset of TB during the administration of biological agents was reported in 408 patients, 13 of whom died [6]. Thus, tuberculosis treatment should be kept in mind when biological agents are administered.\n\nSome reports [7], [8] indicated that reinstitution of infliximab and adalimumab was effective in controlling bacteriological infection in cases in which paradoxical reaction was observed. One report showed that the group undergoing high doses of steroid or etanercept treatment during the first month had a significantly better negative bacterial infection rate than the group treated with usual medical treatment [9], and another report stated that reinstitution of infliximab resulted in good control of RA in addition to TB treatment [10]. Although the prevailing opinion is that treatment with biological agents should be stopped during active pulmonary tuberculosis, we would like to propose the possibility of administering a biological agent carefully along with TB treatment. However, further studies will be required to obtain evidence of the effectiveness of parallel treatment with biological agents and anti-TB medicine.\n\nCurrently, there are several biological agents for RA in the world. Biological agents except abatacept are contraindicated in patients with active pulmonary tuberculosis. In contrast, only abatacept is permitted to be carefully administered according to the medical package insert as the first new class agent for RA treatment because it has a fundamentally different mechanism of action than other anti-TNF therapies. The mechanism of action for abatacept selectively modulates the CD80/CD86-mediated CD28 costimulatory signal required for full T-cell activation and is a fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc (hinge, CH2, and CH3) protein of human IgG1 [11], [12]. Therefore, it is an immunomodulator and may affect the host response to opportunistic infections, including TB.\n\nTNF is an important cytokine for the formation of granulomas [13]. There is a report that TB infection caused by the administration of TNF inhibitors decreased the survival rate of TNF receptor knockout mice [14]. In mice with chronic TB infection, no significant difference was observed in survival rate or weight loss between the abatacept group and placebo. However, the group with TNF inhibited had a significantly shorter survival rate and lost more weight than the abatacept group [15]. The cause of these results remain unclear [15].\n\nThis reports highlights the possibility that re-administration of abatacept is much safer than a TNF inhibitor to treat patients infected with mycobacteria during the treatment of an immunological disease such as RA with biological agents. Additional clinical studies are need to establish the role of abatacept in the treatment of RA and other immunological diseases.\n==== Refs\nReferences\n1 Wallis R.S. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks Lancet Infect. Dis. 8 2008 601 611 18922482 \n2 Singh J.A. Furst D.E. Bharat A. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis Arthritis Care Res. 64 2012 625 639 \n3 Ding T. Ledingham J. Luqmani R. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies Rheumatology 49 2010 2217 2219 20837498 \n4 Carvalho A.C. De Iaco G. Saleri N. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients Clin. Infect. Dis. 42 2006 893 895 16477577 \n5 Keane J. Gershon S. Wise R.P. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent N. Engl. J. Med. 345 2001 1098 1104 11596589 \n6 Matsumoto T. Incidence and number of reported deaths due to tuberculosis during treatment with biologic agents in Japan J. Infect. Dis. Ther. 2 2014 4 \n7 Wallis R.S. van Vuuren C. Potgieter S. Adalimumab treatment of life-threatening tuberculosis Clin. Infect. Dis. 48 2009 1429 1432 19364287 \n8 Blackmore T.K. Manning L. Taylor W.J. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes Clin. Infect. Dis. 47 2008 e83 e85 18840076 \n9 Wallis R.S. Reconsidering adjuvant immunotherapy for tuberculosis Clin. Infect. Dis. 41 2005 201 208 15983916 \n10 Matsumoto T. Tanaka T. Kawase I. Infliximab for rheumatoid arthritis in a patient with tuberculosis N. Engl. J. Med. 355 2006 740 741 16914717 \n11 Kremer J.M. Dougados M. Emery P. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial Arthritis Rheum. 52 2005 2263 2271 16052582 \n12 Linsley P.S. Brady W. Urnes M. CTLA-4 is a second receptor for the B cell activation antigen B7 J. Exp. Med. 174 1991 561 569 1714933 \n13 Mapp P.I. Grootveld M.C. Blake D.R. Hypoxia, oxidative stress and rheumatoid arthritis Br. Med. Bull. 51 1995 419 436 7552073 \n14 Flynn J.L. Goldstein M.M. Chan J. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice Immunity 2 1995 561 572 7540941 \n15 Bigbee C.L. Gonchoroff D.G. Vratsanos G. Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice Arthritis Rheum. 56 2007 2557 2565 17665452\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "21()",
"journal": "Respiratory medicine case reports",
"keywords": "Abatacept; Biological agent; Paradoxical reaction; Rheumatoid arthritis; Tuberculosis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "147-150",
"pmc": null,
"pmid": "28507894",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "7540941;20837498;16052582;7552073;19364287;16914717;15983916;18922482;11596589;22473917;1714933;17665452;16477577;18840076",
"title": "Re-administration of abatacept for the control of articular symptoms of rheumatoid arthritis during anti-tuberculous therapy.",
"title_normalized": "re administration of abatacept for the control of articular symptoms of rheumatoid arthritis during anti tuberculous therapy"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-017359",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aims of the study were to analyze and classify reasons why retail pharmacies need to contact the pediatric emergency department (PED) for clarification on outpatient prescriptions generated using an electronic prescribing system and to categorize the severity of errors captured.\n\n\nMETHODS\nA retrospective chart review was conducted at a PED that cares for approximately 92,000 patients annually. All pharmacy callbacks documented in the electronic medical record between August 1, 2008 and July 31, 2009 were included. A datasheet was used to capture patient demographics (age, sex, race, insurance), prescriptions written, and reason for callback. Each call was then assigned a severity level, and time to respond to all calls was estimated. Frequencies were used to analyze the data.\n\n\nRESULTS\nA total of 731 errors for 695 callbacks were analyzed from 49,583 prescriptions written at discharge. The most common errors included administrative/insurance issues 342/731 (47%) and prescription writing errors 298/731 (41%). The errors were classified as insignificant (340/729 [47%]), problematic (288/729 [40%]), significant (77/729 [11%]), serious (12/729 [1.64%]), and severe (12/729 [1.64%]). Almost 96% of errant prescriptions were not able to be filled as originally written and required a change by the prescriber. These calls required approximately 127 hours to complete.\n\n\nCONCLUSIONS\nPrescription errors requiring a pharmacy callback are typically insignificant. However, 13.8% of callbacks about an error were considered significant, serious, or severe. Automated dose checking and verifying insurance coverage of prescribed medications should be considered essential components of prescription writing in a PED.",
"affiliations": "From the *Division of Pharmacy and †Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.",
"authors": "Caruso|Michelle C|MC|;Gittelman|Michael A|MA|;Widecan|Michelle L|ML|;Luria|Joseph W|JW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "31(6)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D011307:Drug Prescriptions; D057286:Electronic Health Records; D055695:Electronic Prescribing; D004636:Emergency Service, Hospital; D006776:Hospitals, Pediatric; D006784:Hospitals, Teaching; D006786:Hospitals, Urban; D006801:Humans; D057970:Inappropriate Prescribing; D007223:Infant; D019458:Insurance Coverage; D007356:Insurance, Pharmaceutical Services; D008508:Medication Errors; D009820:Ohio; D010351:Patient Discharge; D010607:Pharmacy Service, Hospital; D010818:Practice Patterns, Physicians'; D011306:Prescription Fees; D012189:Retrospective Studies; D013689:Telephone; D013997:Time Factors; D014193:Trauma Centers",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "403-8",
"pmc": null,
"pmid": "25996232",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric emergency department discharge prescriptions requiring pharmacy clarification.",
"title_normalized": "pediatric emergency department discharge prescriptions requiring pharmacy clarification"
} | [
{
"companynumb": "US-JNJFOC-20150702471",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
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