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"abstract": "We report a case of right atrial metastasis in a 66-year-old female patient with breast cancer. The patient presented with palpitation and dyspnea after long-term endocrine therapy. A large echo-dense mass was found in the right atrium after the examination. In order to relieve the symptoms, the patient underwent a resection of the atrial lesion, and the pathology confirmed that it was metastatic breast cancer. Next-generation sequencing (NGS) of the entire exon was taken to explore the gene expression of the metastatic lesion. Forty-eighty genes were identified with mutations, and the mutations of ATM and ESR1 were considered to be associated with the development and metastasis of breast cancer in this case.",
"affiliations": "Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.;Department of Hematology and Oncology, Beijing Tsinghua Changgung Hospital, Beijing 100010, China.;Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.",
"authors": "Xu|Fengrui|F|;Wang|Xiaodi|X|;Jiang|Zefei|Z|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/atm.2019.09.36",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2305-5839",
"issue": "7(22)",
"journal": "Annals of translational medicine",
"keywords": "Atrium metastasis; breast cancer; next-generation sequencing (NGS)",
"medline_ta": "Ann Transl Med",
"mesh_terms": null,
"nlm_unique_id": "101617978",
"other_id": null,
"pages": "702",
"pmc": null,
"pmid": "31930103",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
"references": "17693068;30099774;24126323;24185510;24398047;15899620;8223737;14998838;21163893;30601740;17061036;15811617;29971271",
"title": "A right atrium metastasis of breast cancer after long-term endocrine therapy.",
"title_normalized": "a right atrium metastasis of breast cancer after long term endocrine therapy"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-232625",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FULVESTRANT"
},
"dru... |
{
"abstract": "Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin.\n\n\n\nA disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism.\n\n\n\nAmong 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine.\n\n\n\nThis study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.",
"affiliations": "Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.;Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.;Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.;Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.;Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.;Centre for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, Québec, Canada.;Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.",
"authors": "Pacheco-Paez|Tatiana|T|0000-0001-7801-7062;Montastruc|François|F|0000-0001-7056-8126;Rousseau|Vanessa|V|;Chebane|Leila|L|;Lapeyre-Mestre|Maryse|M|;Renoux|Christel|C|;Montastruc|Jean-Louis|JL|0000-0001-6341-6001",
"chemical_list": "D004364:Pharmaceutical Preparations; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1002/mds.27876",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-3185",
"issue": "35(1)",
"journal": "Movement disorders : official journal of the Movement Disorder Society",
"keywords": "adverse drug reactions; drug safety; gabapentin; gabapentinoids; parkinsonism; pregabalin",
"medline_ta": "Mov Disord",
"mesh_terms": "D000368:Aged; D001499:Bayes Theorem; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders; D004364:Pharmaceutical Preparations; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "8610688",
"other_id": null,
"pages": "176-180",
"pmc": null,
"pmid": "31633228",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Parkinsonism associated with gabapentinoid drugs: A pharmacoepidemiologic study.",
"title_normalized": "parkinsonism associated with gabapentinoid drugs a pharmacoepidemiologic study"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1059376",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": "1",
... |
{
"abstract": "A 79-year-old man with chronic lymphocytic leukaemia presented with fever and a widespread vesicular rash on 19 November 2014. The patient had not been under immunosuppressive regime for 6 months. He had received a shingles vaccine on 14th October and developed flu-like symptoms after 2 weeks. Intravenous antimicrobial therapy including aciclovir was started. He remained stable with no evidence of systemic involvement. On day 5, he developed respiratory and renal failure that required transfer to intensive care unit. Vesicle fluid, bronchoalveolar lavage and plasma were positive for varicella zoster virus by PCR. Slight clinical improvement allowed extubation on day 16. He subsequently deteriorated and died on day 25. Multiorgan failure was considered the immediate cause of death whereas disseminated varicella zoster infection was stated in the medical certificate as the other condition leading to this outcome. Varicella zoster Oka vaccine strain was detected in vesicle fluid, using PCR.",
"affiliations": "Royal Infirmary of Edinburgh, Edinburgh, UK.;Borders General Hospital, Melrose, UK.;Great Ormond St Hospital for Children, London, UK.;Department of Medical Virology, Royal Infirmary of Edinburgh, Edinburgh, UK.;Great Ormond St Hospital for Children, London, UK.;Royal Infirmary of Edinburgh, Edinburgh, UK.",
"authors": "Costa|E|E|;Buxton|J|J|;Brown|J|J|;Templeton|K E|KE|;Breuer|J|J|;Johannessen|I|I|",
"chemical_list": "D053061:Herpes Zoster Vaccine; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D017809:Fatal Outcome; D006562:Herpes Zoster; D053061:Herpes Zoster Vaccine; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D051437:Renal Insufficiency; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27147629",
"pubdate": "2016-05-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23982221;24687808;26865048;12388706;25237196;24983077;17416267;25452596;25916341",
"title": "Fatal disseminated varicella zoster infection following zoster vaccination in an immunocompromised patient.",
"title_normalized": "fatal disseminated varicella zoster infection following zoster vaccination in an immunocompromised patient"
} | [
{
"companynumb": "GB-TEVA-671895ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "On the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab.\n\n\n\nTen days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary.\n\n\n\nCerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause.\n\n\n\nSuspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities.\n\n\n\nDespite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response.\n\n\n\nThis case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.",
"affiliations": "Department of Hepatology and Gastroenterology.;Department of Hepatology and Gastroenterology.;Department of Diagnostic and Interventional Radiology, Charité University Medicine Berlin.;Department of Hepatology and Gastroenterology.;Department of Hepatology and Gastroenterology.;Department of Neurology, Charité University Medicine Berlin, Berlin.;Department of Hepatology and Gastroenterology.;Department of Hepatology and Gastroenterology.",
"authors": "Özdirik|Burcin|B|0000-0002-8885-737;Jost-Brinkmann|Fabian|F|;Savic|Lynn Jeanette|LJ|;Mohr|Raphael|R|;Tacke|Frank|F|;Ploner|Christoph J|CJ|;Roderburg|Christoph|C|;Müller|Tobias|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000068258:Bevacizumab; C000594389:atezolizumab; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026377",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34128898\nMD-D-21-02522\n10.1097/MD.0000000000026377\n26377\n5700\nResearch Article\nClinical Case Report\nAtezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma\nCase report and literature review\nÖzdirik Burcin MD a∗\nJost-Brinkmann Fabian MD a\nSavic Lynn Jeanette MD bc\nMohr Raphael MD a\nTacke Frank MD a\nPloner Christoph J. MD d\nRoderburg Christoph MD ae\nMüller Tobias MD a\nSaranathan. Maya\na Department of Hepatology and Gastroenterology\nb Department of Diagnostic and Interventional Radiology, Charité University Medicine Berlin\nc Berlin Institute of Health (BIH)\nd Department of Neurology, Charité University Medicine Berlin, Berlin\ne Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.\n∗ Correspondence: Burcin Özdirik, Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany (e-mail: burcin.oezdirik@charite.de).\n18 6 2021\n18 6 2021\n100 24 e263778 4 2021\n23 5 2021\n2 6 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nIntroduction:\n\nOn the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab.\n\nPatient concerns:\n\nTen days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary.\n\nDiagnosis:\n\nCerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause.\n\nIntervention:\n\nSuspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities.\n\nOutcome:\n\nDespite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response.\n\nConclusion:\n\nThis case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.\n\nKeywords\n\natezolizumab\nbevacizumab\ncase report\nencephalitis\nhepatocellular carcinoma\nimmune checkpoint-inhibitor\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nHepatocellular carcinoma (HCC) is the most frequent primary liver cancer, representing the fifth most common cancer worldwide.[1,2] The development of HCC is associated with chronic liver disease in up to 90% of cases.[2] The most frequent risk factors include chronic viral hepatitis (types B and C), alcohol intake, metabolic disease, and aflatoxin exposure.[3] HCCs are commonly classified according to the Barcelona Clinic of Liver Cancer (BCLC) staging system, which stratifies HCC into 5 different classes (BCLC 0 and A–D) based on the degree of liver dysfunction, tumor burden, and performance status.[2,3] While in patients with early tumor stages (BCLC A, B), surgical resection, orthotopic liver transplantation, or ablative therapies might offer a curative approach, approximately 50% of patients are diagnosed with locally advanced or metastatic disease and, therefore, are not eligible for these potentially curative treatments.[2,4] In case of advanced disease, systemic therapy is recommended by current guidelines.[4]\n\nFor the last decade, sorafenib, a multireceptor tyrosine-kinase inhibitor targeting predominantly vascular endothelial growth factor receptor (VEGFR) 2 and Raf kinase inhibition was considered standard of care for first-line systemic treatment of HCC.[5,6] On the basis of the results of the REFLECT-trial using a non-inferiority endpoint design, lenvatinib, another multireceptor tyrosine-kinase inhibitor, was recently approved as an alternative to sorafenib for first-line therapy.[7] The rather poor efficacy but important toxic profile of both agents led to further studies, mainly involving immunotherapies with immune checkpoint inhibitors (ICIs). In this context, the multicenter phase III study IMBRAVE 150 compared the efficacy of a combination of atezolizumab as well as bevacizumab with sorafenib in patients with advanced HCC. The combination therapy could improve all oncological endpoints (overall survival, progression-free survival, overall response rate). In addition, the combination of atezolizumab and bevacizumab was significantly less toxic compared with sorafenib.[8]\n\nThe most common side effects of this combination were loss of appetite, hypertension, fatigue, rash, and gastrointestinal symptoms. Nevertheless, treatment with ICI may entail immune-related adverse events (irAE) by creating an exaggerated inflammatory response, as blocking the T-cell inhibitory programmed cell death ligand 1 (PD-L1) pathway carries the risk of inducing or exaggerating autoimmune diseases. Such irAEs include dermatological, gastrointestinal, hepatological, endocrine, or rheumatological toxicities as well as pneumonitis.[9] Up to now, only few case reports and small case series have reported central nervous system complications such as encephalitis and encephalopathy.[10–14]\n\nHere, we report one of the first cases of severe encephalitis after treatment with atezolizumab and bevacizumab for advanced HCC that was successfully treated by high-dose steroids, plasmapheresis, and drug discontinuation.\n\n2 Case presentation\n\nA 70-year-old female patient without pre-existing conditions was diagnosed with multifocal hepatocellular carcinoma with macrovascular invasion into the right portal vein in March 2020. Routine ultrasound examination of her hepatitis C induced liver cirrhosis revealed multiple HCC foci in segments V, VI, VII, and I (Fig. 1).\n\nFigure 1 Multifocal hepatocellular carcinoma with macrovascular invasion into the right portal vein in axial abdominal CT- and MR-imaging during the course of treatment. Tumor lesions are indicated by yellow arrows. (A) Axial contrast-enhanced magnetic resonance imaging (MRI) (venous phase) demonstrates multifocal hepatocellular carcinoma with macrovascular invasion into the right portal vein at initial diagnosis in March 2020. (B) Axial contrast-enhanced computed tomography (CT)-scan (venous phase) displays a progression in size 1 week after initial diagnosis. (C) Axial contrast-enhanced CT-scan (venous phase) displays a progression in size of multifocal hepatocellular carcinoma 2 weeks after 1 cycle of atezolizumab/bevacizumab.\n\nFurther clinical work-up, including magnetic resonance imaging (MRI) and computer tomography (CT)-scan of the chest, did not reveal extrahepatic tumor manifestation except lymph node invasion (portocaval, paraaortal). Liver function was well preserved [Child-Pugh-Score A, model of End-stage liver disease (MELD) 6]; therefore, a tumor stage of BCLC C was assigned. Serum level of alfa-fetoprotein (AFP) was 430 U/mL. As results from the IMBRAVE-150 trial showed superiority over sorafenib with regard to progression-free survival and tumor response, we initiated treatment with atezolizumab (fix dose of 1200 mg over 2 hours) and bevacizumab (15 mg/kg over 90 minutes).[15] Initial administration was well tolerated without any signs of acute toxicity.\n\nTen days later, the patient presented herself in our emergency room with previous episodes of impaired cognition and language, somnolence, emesis, and dyspnea, along with severe deterioration of her general condition. Neurological examination at initial presentation did not show any abnormalities except for a blurred orientation to time. Laboratory testing revealed slightly elevated inflammatory markers [C-reactive protein (CRP) 54 mg/dL (<5 mg/dL), leucocytes 3.08/nL (4–10/nL), lymphocytes 0.34/nL (1.10–4.50/nL), sodium 130 mmol/L (135–145 mmol/L), thyroid-stimulating hormone (TSH) 0.20 mU/L (0.27–4.20 mU/L), fT3 1.79 U/L (2–4.40 U/L), ALT 61 U/l (<31 U/L), AST 92 U/L (<35 U/L)]. No clinical or laboratory signs of hepatic encephalopathy were present [ammonia 31 μmol/L (21–71 μmol/L)]. Blood, urine, and sputum cultures did not identify any pathogen. COVID 19 and influenza A and B were negative. A cranial CT-scan did not show any signs of bleeding or ischemia. Chest x-ray did not reveal any pathological findings.\n\nIn this clinical setting, we initiated treatment with methylprednisolone 100 mg/day (1 mg/kg) accompanied by an anti-infective therapy regime with ceftriaxone, amoxicillin, and acyclovir as long as the laboratory results were in progress. We initially suspected atezolizumab-related hypophysitis due to low TSH and fT3 levels combined with progressive somnolence and hyponatremia. Further clinical work-up, including cranial MRI with gadobutrol, did not reveal any abnormal findings, displaying no signs of cerebral metastases, bleeding, ischemia, or inflammation with particular regard to the pituitary gland. Moreover, initial endocrine tests, including cortisol, Insulin-like growth factor 1, luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone levels were unremarkable, displaying no signs of hypophysitis.\n\nThe clinical condition of the patient deteriorated with recurrent fever episodes, adynamia, and somnolence. Cerebral spinal fluid (CSF) analysis on day 4 (3 days after treatment initiation with methylprednisolone) revealed an elevated leucocyte count (179/μL) and increased protein level (5494 mg/dL) (Table 1).\n\nTable 1 Results of cerebrospinal fluid analysis during high-dose prednisolone treatment.\n\nDays after initial presentation, d\t1\t2\t3\t4–7\t8\t9–12\t13\t14–21\t22–27\t32–37\t38–45\t\nPrednisolone, mg\t100\t100\t100\t150\t150\t1000\t1000\t60\t50\t40\t30\t\nPlasmapheresis\t\t\t\tSession 1,2,3\t\t\t\t\t\t\t\t\nCell count, cells/μL\t\t\t179\t\t34\t\t4\t\t\t\t\t\nProtein level, mg/L\t\t\t5494\t\t2097\t\t825\t\t\t\t\t\nLactate, mg/dL\t\t\t56\t\t43\t\t32\t\t\t\t\t\nGlucose, mg/dL\t\t\t71\t\t72\t\t64\t\t\t\t\t\n\nCSF cytology showed no tumor cells. Further CSF work-up showed no signs of an infectious (bacterial, viral, or fungal), autoimmune or paraneoplastic inflammation of the central nervous system, rendering an atezolizumab-associated encephalitis likely (detailed analysis is listed in Table 2).\n\nTable 2 Cerebrospinal fluid and serum analysis results.\n\nInfectious parameters\tResult\tParaneoplastic and autoimmune parameters\tResult\t\nHerpes simplex-1/2 DNA\tNegative\tVoltage-gated-potassium antibody\tNegative\t\nHuman herpesvirus-6 DNA\tNegative\tAnti-Hu antibody\tNegative\t\nVaricella-zoster-virus IgM, G\tNegative\tAnti-Yo antibody\tNegative\t\nCytomegalovirus DNA\tNegative\tAnti-Ri antibody\tNegative\t\nAdenovirus DNA\tNegative\tN-methyl-d-aspartate antibody\tNegative\t\nEnterovirus RNA\tNegative\tAmphyphysin antibody\tNegative\t\nJohn Cunnigham virus DNA\tNegative\tAnti-CV2 antibody\tNegative\t\nCryptococcal antigen\tNegative\tAquaporin 4 antibody\tNegative\t\nRickettsia IgG/IgM\tNegative\tContactin-associated-protein-like-2 antibody\tNegative\t\nEhrlichia chaffeensis DNA\tNegative\tDPP-like protein 6 antibody\tNegative\t\nBorrellia burgdorferi Ig M, G\tNegative\tDopamin-2-antibody\tNegative\t\nTreponoma pallidum Ig M, G\tNegative\tGAD65 antibody\tNegative\t\nE coli DNA\tNegative\tGABA-B-receptors\tNegative\t\nListeria DNA\tNegative\tAMPAR1 and 2 antibodies\tNegative\t\nNeisseria DNA\tNegative\tLGl1 antibody\tNegative\t\nStreptococcus aglatiae DNA\tNegative\tMyelin antibodies\tNegative\t\nStreptococcus pneumonia DNA\tNegative\t\t\t\n\nOn day 5, the patient's general condition deteriorated with progressive respiratory failure. A subsequent CT-scan revealed bilateral infiltrations of the lung and pleural effusions, indicating aspiration pneumonia. Thus, the patient was admitted to the intensive care unit, where she was mechanically ventilated. Anti-infective therapy was escalated to piperacillin and tazobactam. Subsequently, we decided to start treatment with plasmapheresis, following the recommendations of the guidelines for ICI-associated adverse events (AEs) by the American society of clinical oncology.[16] After 3 sessions of plasmaphereses, serum levels of Creatine-kinase (CK) and myoglobin (initially CK 1700 U/L, myoglobin 1600 U/L) returned to normal. Moreover, the dose of methylprednisolone was increased up to 150 mg per day (1.5 mg/kg/day) and 2 days later up to 200 mg/day (2 mg/kg/day).\n\nOn day 8, CSF analysis revealed a decrease in cell count and protein level. The patient's cognition was still severely impaired and she was even unable to follow simple instructions. Thus, steroid pulse therapy with 1 g methylprednisolone for 5 days was initiated, leading to further remission of clinical symptoms (patient could follow easy instructions) and CSF cell count (Table 1, Fig. 2).\n\nFigure 2 Cerebrospinal fluid (CSF) cell count and protein levels during treatment with prednisolone and plasmapheresis. The graph displays CSF cell count and protein levels during course of treatment with prednisolone and plasmapheresis. Initially, prednisolone 100 mg/day (1 mg/kg) was administered intravenously and later increased up to 150 mg/day intravenously. When CSF analysis on day 8 did not reveal liquor remission, the dose was increased up to 1000 mg/day. Complete liquor remission was achieved on day 13.\n\nNeurological examination still revealed areflexia and a reduced tone in all 4 extremities. Electromyography (EMG) on day 10 demonstrated a motor neuropathy with axonal and proximal demyelinating component, suggesting a critical illness myopathy possibly accompanied by immune-mediated polyradiculoneuropathy.\n\nIn the following days, a CT-scan of the chest indicated a resolution of infiltrations parallel to clinical improvement. Nevertheless, several weaning attempts failed, probably due to persistent muscle weakness. Therefore, we performed dilatative tracheostomy on day 15. Afterwards, communication with the patient improved considerably. She started to follow commands correctly, still not being able to mobilize on her own. Motor examination of the extremities revealed a decreased tone, proximal and distal muscle weakness, and areflexia. Twenty-one days days after initial presentation, the patient was transferred to a weaning rehabilitation clinic. Decannulation could be performed after 42 days when sufficient spontaneous breathing was possible. After 2 months, the patient started to masticate and swallow. Active mobilization was still not possible, as she still suffered from severe critical illness neuropathy. At this time-point, the patient's general condition deteriorated again due to progressive liver cancer disease. After discontinuation of atezolizumab/bevacizumab treatment after initial administration and under consideration of the patient's will and her poor general condition, no new HCC treatment approaches were initiated. Seventy-six days after initial treatment with atezolizumab/bevacizumab, the patient died due to multiorgan failure.\n\n3 Discussion and conclusion\n\nICIs are a mainstay in the treatment of many cancers including HCC. The principle of ICI treatment is to overcome immune tolerance against the tumor, which is mediated by specific inhibitory molecules such as PD-1, the PD-1 ligand (PDL-1), or cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Once activated, they repress the T-cell response against cancer cells. In turn, antibodies against these immune checkpoints might activate the immune system to re-recognize these tumor cells as foreign.[17] Atezolizumab blocks the PD-1/PD-L1 signaling by selectively binding to PD-L1, enabling the inhibition of effector T-cells with induction of tumor cell death.[18,19] Nevertheless, despite a well-tolerability and manageable safety profile, ICI treatment goes along with a risk for irAEs. In a Ib study on the toxicity of atezolizumab and bevacizumab in advanced HCC, Lee et al reported 12 patients (12%) who required systemic corticosteroids within 30 days of an irAE with atezolizumab. These patients developed pneumonitis, colitis, drug-induced liver injury, and an increase in liver enzymes.[20] Moreover, the expert group around Pishvaian et al even described a case of encephalitis, but did not report further clinical details.[21] Besides this case, to our knowledge, only a few cases of encephalitis following treatment with atezolizumab have been published (Table 3).\n\nTable 3 Summary of characteristics of previously reported atezolizumab-induced encephalitis cases.\n\n\tSex, age\tPrimary tumor\tAgent, dose\tTime to onset\tInitial symptoms\tCSF\tcMRI\tTreatment\tOutcome\t\n[10]\tF, 59\tbladder\tAtezolizumab1200 mg\t12 days\tConfusion, fatigue, spastic tremors, emesis\tIncreased cell count and protein levels\tIsolated frontal lobe metastasis, no other pathological findings\tDexamethasone 40 mg/day (10 mg every 6 h)\tResidual upper extremity weakness 4/5; death after 1 month after discharge due to progressive disease\t\n[11]\tM, 78\tlung\tAtezolizumab1200 mg\t13 days\tConfusion, fever, somnolence, nuchal rigidity\tIncreased cell count and protein levels. On day 22 remission in CSF\tNo pathological findings\t1 g methyl-prednisolone\tDischarge after 58 days; well orientated, able to communicate and to sit down\t\n[12]\tF, 53\tcervix\tAtezolizumab 1200 mg; bevacizumab (15 mg/kg)\t13 days\tAltered mental, status headache, meningeal signs\tIncreased cell count, protein and glucose levels\tDiffuse leptomeningeal enhancement\tDexamethasone 18 mg/day (6 mg every 8 h)\tDischarge after 35 days to hospice; well-orientated, able to sit and communicate. Motor examination showed decreased tone, proximal and distal muscle weakness, preserved reflexes\t\n[13]\tF, 48\tlung\tAtezolizumab 1200 mg\t13 days\tFever, psychomotor slow-down, memory impairment, aphasia\tIncreased cell count, elevated protein and glucose level\tPachy- and leptomeningeal enhancement\tMethylprednisolone 1 g/d for 3 days, then 1 mg/kg per day for 1 month followed by a very gradual decrease\tComplete resolution of neurological symptoms and brain MRI abnormalities after 9 mo\t\n[14]\tM, 49\tbladder\tAtezolizumab 1200 mg\tN.a.\tAltered mental status, stupor, generalized tonic-clonic seizures\tIncreased cell count\tDiffuse leptomeningeal enhancement\tDexamethasone, intravenous immunoglobulin\tDeath due to septic shock and multiorgan failure\t\n\nIn summary, including our patient, the majority of patients were female (n = 4; 67%) with a mean age of 64 years (range 48–78). Primary tumor localizations were the lung (n = 2), bladder (n = 2), and the cervix (n = 1). Similar to our case, patients presented within 10 to 13 days after treatment initiation with altered mental status, confusion, and in 2 cases with meningeal signs. CSF cell count and protein levels were elevated in all patients during the course of disease, while no signs of an infectious, autoimmune, or paraneoplastic cause could be found (Table 2). In 3 reported cases, leptomeningeal enhancement was detected in MRI.[12–14] According to Laserna et al,[12] these findings were associated with a prolonged clinical course. In our case, pathological findings in imaging were absent. Moreover, duration of neurological alterations was longer than in previously reported cases which may be influenced by multiple factors: First, our patient developed aspiration pneumonia that required mechanical ventilation, which led to enhanced muscle weakness and prolonged weaning duration. Second, in line with the case reported by Laserna et al,[12] our patient most likely suffered from critical illness myopathy and immune-mediated polyradiculoneuropathy as indicated by clinical findings (weakness, partial areflexia, reduced tone) and EMG analysis. Third, as bevacizumab further enhances atezolizumab's efficacy by reversing VEGF-mediated immunosuppression to promote T-cell infiltration into the tumor, more severe AEs in combination with bevacizumab compared with atezolizumab monotherapy can be assumed. In line with Kim et al,[22] in our case, a rapid clinical improvement started approximately 26 days after atezolizumab/bevacizumab administration, which is plausible as the half-life of atezolizumab is 27 days.\n\nTreatment of serious irAEs includes stopping the ICI agent and temporary immunosuppression with steroids or other agents such as intravenous immunoglobulins, plasmapheresis, or even infliximab or rituximab. The former might suppress autoimmune T-cell activity and the latter might help neutralizing the ICIs.[16,23] In 50% of the reported cases, steroid dose up to 1 g/day was administered. In line, as no immediate clinical and CSF improvement was achieved, we escalated our therapy regime up to 1 g/day. In contrast to the reported cases, we started treatment with plasmapheresis for 3 days. As simultaneous steroid pulse therapy was performed, it is difficult to evaluate the therapeutic effect of plasmapheresis. However, CK and myoglobin levels decreased drastically. Therefore, in line with Möhn et al,[24] we suggest a low threshold for therapy options such as intravenous immunoglobulins or plasmapheresis, as encephalitis is a highly relevant and serious complication. Consequently, the establishment of specific algorithms incorporating predictors is highly desirable in order to select optimal treatment strategies with regard to dosage and agents (steroid, infliximab, IVIG, rituximab, plasmapheresis) of immunosuppressive therapy.\n\nTo prevent irAE, it is important to identify risk factors for the development. Patients with pre-existing neurological autoimmune disorders probably represent a high-risk group. Garcia et al reported about 14 patients (including 8 patients with a previous history of multiple sclerosis) developing multiple sclerosis after treatment with pembrolizumab and nivolumab. All patients presented with rapid neurological disease progression and required medical intervention.[24,25] In contrast, none of the patients known to us (neither our case patient nor the previously reported patients) suffered from a neurological disease before the initiation of treatment.\n\nAnother important aspect is the question, whether the occurrence of irAE correlates with the antitumor effect of ICI therapy. Our patient presented with further tumor progression 2 weeks after 1 cycle of atezolizumab and bevacizumab (Fig. 1). As treatment was immediately discontinued in all reported cases, it is difficult to evaluate treatment response. Nevertheless, in none of the reported cases, a remarkable treatment response was demonstrated. Therefore, future research should explore further risk factors to reduce irAE and to maximize the benefit of immunotherapy among patients.\n\n4 Conclusion\n\nWe describe the clinical course of a patient with advanced HCC developing life-threatening encephalitis after only 1 cycle of atezolizumab and bevacizumab, which resulted in remission after rapid immunosuppressive treatment. In this regard, establishment of specific algorithms incorporating predictors is highly desirable in order to select optimal treatment strategies of immunosuppressive therapy with regard to dosage and agents (steroid, infliximab, IVIG, rituximab, plasmapheresis). Moreover, there is an unmet need for clinical trials to identify risk factors for developing irAE after atezolizumab and bevacizumab treatment in patients with HCC as well as preventive measures in respect to toxicity of this efficacious combination therapy.\n\nAuthor contributions\n\nConceptualization: Burcin Özdirik, Fabian Jost-Brinkmann, Frank Tacke, Christoph J. Ploner, Tobias Müller.\n\nData curation: Burcin Özdirik, Fabian Jost-Brinkmann.\n\nSupervision: Christoph J. Ploner, Christoph Roderburg, Tobias Müller.\n\nVisualization: Lynn Jeanette Savic.\n\nWriting – original draft: Burcin Özdirik, Fabian Jost-Brinkmann, Tobias Müller.\n\nWriting – review & editing: Burcin Özdirik, Fabian Jost-Brinkmann, Lynn Jeanette Savic, Raphael Mohr, Frank Tacke, Christoph J. Ploner, Christoph Roderburg, Tobias Müller.\n\nAbbreviations: AE = adverse events, AFP = alfa-fetoprotein, BCLC = Barcelona Clinic of Liver Cancer, CK = creatine-kinase, CRP = C-reactive protein, CSF = cerebrospinal fluid, CT = computer tomography, CTCAE = Common Terminology Criteria for Adverse Events, CTLA-04 = cytotoxic T-lymphocyte-associated protein 4, EMG = electromyography, HCC = hepatocellular carcinoma, HCV = hepatitis C-virus, irAE = immune-related adverse events, MELD = Model of End-stage liver disease, MRI = magnetic resonance imaging, PDGFR = platelet-derived growth factor receptor, PD-L1 = programmed cell death ligand 1, TKI = tyrosine.kinas inhibitor, TSH = thyroid-stimulating hormone, VEGF = vascular endothelial growth factor, VEGFR = vascular endothelial growth factor receptor.\n\nHow to cite this article: Özdirik B, Jost-Brinkmann F, Savic LJ, Mohr R, Tacke F, Ploner CJ, Roderburg C, Müller T. Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review. Medicine. 2021;100:24(e26377).\n\nL.J.S. is a participant in the BIH-Charité Junior Clinician Scientist. Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health.\n\nThis research received no external funding.\n\nWritten informed consent has been obtained from the patients’ spouse to publish this paper.\n\nInstitutional Review Board Statement is not applicable, as informed consent of the patients’ spouse is available.\n\nThe authors declare no conflict of interest.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nCSF = cerebrospinal fluid, F = female, IRAE = immune-related adverse event, M = male, NA = not applicable.\n==== Refs\nReferences\n\n[1] Fujiwara N Friedman SL Goossens N Hoshida Y . Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68 :526–49.28989095\n[2] Forner A Reig M Bruix J . Hepatocellular carcinoma. Lancet 2018;391 :1301–14.29307467\n[3] EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56 :908–43.22424438\n[4] EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69 :182–236.29628281\n[5] Cheng AL Kang YK Chen Z . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10 :25–34.19095497\n[6] Llovet JM Ricci S Mazzaferro V . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359 :378–90.18650514\n[7] Kudo M Finn RS Qin S . Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391 :1163–73.29433850\n[8] Finn RS Qin S Ikeda M . Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382 :1894–905.32402160\n[9] König D Läubli H . Mechanisms of immune-related complications in cancer patients treated with immune checkpoint inhibitors. Pharmacology 2020;28 :01–14.\n[10] Levine JJ Somer RA Hosoya H . Atezolizumab-induced encephalitis in metastatic bladder cancer: a case report and review of the literature. Clin Genitourin Cancer 2017;15 :e847–9.28372981\n[11] Arakawa M Yamazaki M Toda Y . Atezolizumab-induced encephalitis in metastatic lung cancer: a case report and literature review. eNeurol Sci 2018;14 :49–50.\n[12] Laserna A Tummala S Patel N El Hamouda DEM Gutiérrez C . Atezolizumab-related encephalitis in the intensive care unit: case report and review of the literature. SAGE Open Med Case Rep 2018;6 : 2050313X18792422.\n[13] Robert L Langner-Lemercier S Angibaud A . Immune-related encephalitis in two patients treated with immune checkpoint inhibitor. Clin Lung Cancer 2020;21 :e474–7.32299770\n[14] Kim A Keam B Cheun H Lee ST Gook HS Han MK . Immune-checkpoint-inhibitor-induced severe autoimmune encephalitis treated by steroid and intravenous immunoglobulin. J Clin Neurol 2019;15 :259–61.30877699\n[15] Cheng AL Ikeda M Galle P . IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) and bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol 2019;30 :mdz446.\n[16] Brahmer JR Lacchetti C Schneider BJ . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36 :1714–68.29442540\n[17] El Dika I Khalil DN Abou-Alfa GK . Immune checkpoint inhibitors for hepatocellular carcinoma. Cancer 2019;125 :3312–9.31290997\n[18] Gunturi A McDermott DF . Nivolumab for the treatment of cancer. Expert Opin Investig Drugs 2015;24 :253–60.\n[19] Huppert LA Gordan JD Kelley RK . Checkpoint inhibitors for the treatment of advanced hepatocellular carcinoma. Clin Liver Dis 2020;15 :53–8.\n[20] Lee MS Hsu CH He AR . Clinical safety, tolerability and adverse events of special interest in a phase IB study of atezolizumab and bevacizumab. EASL HCC summit; Lisbon, Portugal 2019.\n[21] Hsu CH Lee MS Ryoo BY . Clinical safety, tolerability and adverse events of special interest in a phase IB study of atezolizumab and bevacizumab. Manila: APASL; 2019.\n[22] Stroh M Winter H Marchand M . Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther 2017;102 :305–12.27981577\n[23] Postow MA Sidlow R Hellmann MD . Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378 :158–68.29320654\n[24] Möhn N Beutel G Gutzmer R . Neurological immune related adverse events associated with nivolumab, ipilimumab, and pembrolizumab therapy-review of the literature and future outlook. J Clin Med 2019;8 :\n[25] Zimmer L Goldinger SM Hofmann L . Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60 :210–25.27084345\n\n",
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"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular; D004660:Encephalitis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D010956:Plasmapheresis; D011239:Prednisolone",
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"title": "Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review.",
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"abstract": "BACKGROUND\nTubulointerstitial nephritis and uveitis syndrome is a rare lymphocyte-related oculorenal inflammatory disease presumed to be associated with drug use and infectious agents. Toxoplasma gondii is one of such pathogens that could exhibit encephalitis, meningitis, and uveitis in immunocompromised or in some immunocompetent individuals. If the immunoglobulin M of Toxoplasma is positive on screening, the interpretation of the result is not simple, especially when immunoglobulin M stays positive persistently.\n\n\nMETHODS\nA 34-year-old Asian male developed fever, headache, and lymphadenopathy with tenderness, which was initially diagnosed as meningitis. Antibiotics were started, and diclofenac sodium was used for the fever. Although his symptoms were alleviated in a week by the treatment, gradual decline in renal function was noted, prompting a renal biopsy that indicated acute granulomatous interstitial nephritis. A week later, tenderness in both eyes with blurred vision appeared and revealed iritis and keratic precipitations in both eyes; hence, the diagnosis of acute tubulointerstitial nephritis and bilateral uveitis syndrome was made. Toxoplasma gondii-specific immunoglobulin G and immunoglobulin M titers were both positive. Although we could not rule out recent infection of Toxoplasma gondii, which may cause uveitis initially, Toxoplasma immunoglobulin G avidity test indicated a distant infection, which allowed us to rule out meningitis and uveitis as responsible for the complication of recent Toxoplasma gondii infection. Drug-induced lymphocyte stimulation test, or lymphocyte transformation test of diclofenac sodium, was solely positive among the tested drugs. Uveitis was alleviated only with ophthalmic steroid, and renal function returned to normal without administration of systemic steroid.\n\n\nCONCLUSIONS\nWe experienced a case of diclofenac-induced tubulointerstitial nephritis and uveitis syndrome. In ruling out infections, Toxoplasma immunoglobulin M was persistently positive, and Toxoplasma immunoglobulin G avidity test indicated a \"distant\" infection. From these two results, we ruled out recent infection. However, it should be noted that \"distant\" infection indicated by commercial immunoglobulin G avidity is still a multiplex profile consisting of reinfection, reactivation, and latent infection. Narrowing down the infection profile of Toxoplasma is challenging in some cases. Therefore, careful diagnosis and extended follow-up of such patients are needed.",
"affiliations": "Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan. ooya.yoshihiro.cw@mail.hosp.go.jp.;Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan.;Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan.;Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan.;Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan.;Department of Internal Medicine, Seikeikai Chiba Medical Center, Chiba City, Chiba, 260-0842, Japan.;Department of Ophthalmology, National Hospital Organization Chibahigashi National Hospital, Chiba City, Chiba, 260-8712, Japan.;Department of Pathology, National Hospital Organization Chibahigashi National Hospital, Chiba City, Chiba, 260-8712, Japan.;Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba, 260-8712, Japan.",
"authors": "Oya|Yoshihiro|Y|http://orcid.org/0000-0002-7645-598X;Futami|Hidekazu|H|;Nakazawa|Takuya|T|;Ishijima|Kazuyuki|K|;Umemiya|Keiko|K|;Takizawa|Fumiyoshi|F|;Imai|Naoki|N|;Kitamura|Hiroshi|H|;Matsumura|Ryutaro|R|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2909\n10.1186/s13256-021-02909-z\nCase Report\nTubulointerstitial nephritis and uveitis syndrome following meningitis and systemic lymphadenopathy with persistent Toxoplasma immunoglobulin M: a case report\nhttp://orcid.org/0000-0002-7645-598X\nOya Yoshihiro ooya.yoshihiro.cw@mail.hosp.go.jp\n\n12\nFutami Hidekazu futami.hidekazu.re@mail.hosp.go.jp\n\n1\nNakazawa Takuya nakazawa.takuya.te@mail.hosp.go.jp\n\n1\nIshijima Kazuyuki ishijima.kazuyuki.dv@mail.hosp.go.jp\n\n1\nUmemiya Keiko umemiya.keiko.pw@mail.hosp.go.jp\n\n1\nTakizawa Fumiyoshi fmytak.fmytak@sweet.ocn.ne.jp\n\n5\nImai Naoki imai.naoki.ng@mail.hosp.go.jp\n\n3\nKitamura Hiroshi kitamura.hiroshi.kw@mail.hosp.go.jp\n\n4\nMatsumura Ryutaro matsumura.ryutaro.hm@mail.hosp.go.jp\n\n1\n1 grid.416698.4 Department of Rheumatology, Allergy and Clinical Immunology, National Hospital Organization Chibahigashi National Hospital, 673 Nitona-cho, Chuou-ku, Chiba City, Chiba 260-8712 Japan\n2 grid.416698.4 Laboratory of Autoimmune diseases, Department of Clinical Research, National Hospital Organization Chibahigashi National Hospital, Chiba City, Chiba 260-8712 Japan\n3 grid.416698.4 Department of Ophthalmology, National Hospital Organization Chibahigashi National Hospital, Chiba City, Chiba 260-8712 Japan\n4 grid.416698.4 Department of Pathology, National Hospital Organization Chibahigashi National Hospital, Chiba City, Chiba 260-8712 Japan\n5 Department of Internal Medicine, Seikeikai Chiba Medical Center, Chiba City, Chiba 260-0842 Japan\n23 9 2021\n23 9 2021\n2021\n15 48214 9 2020\n17 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nTubulointerstitial nephritis and uveitis syndrome is a rare lymphocyte-related oculorenal inflammatory disease presumed to be associated with drug use and infectious agents. Toxoplasma gondii is one of such pathogens that could exhibit encephalitis, meningitis, and uveitis in immunocompromised or in some immunocompetent individuals. If the immunoglobulin M of Toxoplasma is positive on screening, the interpretation of the result is not simple, especially when immunoglobulin M stays positive persistently.\n\nCase presentation\n\nA 34-year-old Asian male developed fever, headache, and lymphadenopathy with tenderness, which was initially diagnosed as meningitis. Antibiotics were started, and diclofenac sodium was used for the fever. Although his symptoms were alleviated in a week by the treatment, gradual decline in renal function was noted, prompting a renal biopsy that indicated acute granulomatous interstitial nephritis. A week later, tenderness in both eyes with blurred vision appeared and revealed iritis and keratic precipitations in both eyes; hence, the diagnosis of acute tubulointerstitial nephritis and bilateral uveitis syndrome was made. Toxoplasma gondii-specific immunoglobulin G and immunoglobulin M titers were both positive. Although we could not rule out recent infection of Toxoplasma gondii, which may cause uveitis initially, Toxoplasma immunoglobulin G avidity test indicated a distant infection, which allowed us to rule out meningitis and uveitis as responsible for the complication of recent Toxoplasma gondii infection. Drug-induced lymphocyte stimulation test, or lymphocyte transformation test of diclofenac sodium, was solely positive among the tested drugs. Uveitis was alleviated only with ophthalmic steroid, and renal function returned to normal without administration of systemic steroid.\n\nConclusions\n\nWe experienced a case of diclofenac-induced tubulointerstitial nephritis and uveitis syndrome. In ruling out infections, Toxoplasma immunoglobulin M was persistently positive, and Toxoplasma immunoglobulin G avidity test indicated a “distant” infection. From these two results, we ruled out recent infection. However, it should be noted that “distant” infection indicated by commercial immunoglobulin G avidity is still a multiplex profile consisting of reinfection, reactivation, and latent infection. Narrowing down the infection profile of Toxoplasma is challenging in some cases. Therefore, careful diagnosis and extended follow-up of such patients are needed.\n\nKeywords\n\nPersistent immunoglobulin M (IgM)\nDrug-induced lymphocyte stimulation test (DLST)\nLymphocyte transformation test (LTT)\nTubulointerstitial nephritis and uveitis (TINU) syndrome\nToxoplasma gondii\nIgG avidity test\nStrain-specific diagnosis\nMeningitis\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nTubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal multisystemic autoimmune disease that may occur in response to various environmental triggers, including drugs and microbial pathogens [1]. Since TINU syndrome was first described by Dobrin in 1975 [2], only about 200 cases have been recorded until 2018 [1]. Matsumoto has identified a total of 102 Japanese cases from literature in the period between 1977 and 2013 [3]. Patients with TINU syndrome can present with systemic symptoms (fever, fatigue, malaise, asthenia, or headache), uveitis (bilateral eye pain, redness, blurred vision, or photophobia), and tubulointerstitial nephritis (rise in serum creatinine and urinary protein). Noncaseating granulomata were found in 13% of renal biopsy specimen [4].\n\nToxoplasma gondii is an intracellular protozoan parasite with worldwide distribution that infects more than one-third of the global population [5]. The clinical presentation of this parasite varies from asymptomatic in healthy individuals to neurological symptoms (encephalitis [6], meningitis), ocular symptoms (uveitis, such as posterior uveitis) [6, 7], myocarditis, pneumonitis, or opportunistic infections mostly in immunocompromised hosts. Although the renal manifestation of Toxoplasma infection is not frequent [8–10], Toxoplasma infection is listed as a differential diagnosis of acute tubulointerstitial nephritis (TIN) [11] or of granulomatous interstitial nephritis [10]. Even in immunocompetent hosts, some (10–15%) [12–15] individuals develop acute systemic manifestations. Most frequent symptoms are lymph node enlargement (94.6%), asthenia (86.5%), headache (70.3%), and fever (67.6%). Retinochoroiditis (10.8%) is also present in the analysis of 37 immunocompetent adults with acute acquired toxoplasmosis [16]. The severity of subacute toxoplasmosis of the primary infection may vary depending on the virulence of the strain or the amount of inoculum [17]. Although most of the symptoms in immunocompetent adults are self-limited and last from a few weeks to months [16, 18], life-threatening pneumonia or death has also been reported [19].\n\nThe prevalence of recent infection of Toxoplasma in immunocompetent adults is best studied with pregnant women. Primary infection at early pregnancy is well known to cause congenital toxoplasmosis. The positive rate of both immunoglobulin G (IgG) and immunoglobulin M (IgM) specific to Toxoplasma gondii in pregnant women varies worldwide: New Zealand, South Korea, USA 0.1–0.5%, Japan 1.0–1.5% [20, 21], or 3.8% [22], Africa, and Eastern Mediterranean 2–5% [21]. To make matters more complicated, Toxoplasma IgM can persist for several months [23–27] or years [28] after the acute phase of primary infection (recent infection). Toxoplasma IgG avidity test is a key tool to distinguish “true” recent infection from distant infection, widely used for the screening of pregnant women. Among the initially screened IgM-positive pregnant women, as much as 59% (in Brazil) [29], 56% (in Turkey) [30], and 71.4% (in Japan) [31, 32] of them are reported to have a higher titer of IgG avidity, indicating distant infections of more than 5 months before [33]. This high frequency of persistent IgM in the initially screened IgM-positive population is one of the reasons for the lack of reliability in serological tests of Toxoplasma [34].\n\nIn the diagnosis of an autoimmune disease, differential diagnosis of dozens of systemic diseases including infections are required. Some infections are difficult to exclude because of symptoms similar to a suspected autoimmune disease. A combination of TINU syndrome and Toxoplasma gondii infection is one of them. If the IgM of Toxoplasma-specific antibody is present, the diagnostic processes become more challenging. Such cases might be misdiagnosed as TINU syndrome with coexisting active toxoplasmosis, or underdiagnosed as just toxoplasmosis. Differential diagnosis of TINU syndrome and interpretations of Toxoplasma serological tests in immunocompetent hosts will be discussed. The chances of encountering this combination might not be so rare considering the worldwide prevalence of Toxoplasma gondii.\n\nCase presentation\n\nA 34-year-old Japanese male with a medical history of gastric ulcer for 20 years, regular use of esomeprazole for the last 3 years, no known allergies, and no family history of kidney or eye disease presented to his local emergency department with complaints of having 2 days of 40 ℃ fever, headache, myalgia, general fatigue, and vomiting. These symptoms developed 2 days after an incised finger wound with a small amount of bleeding due to an injury during his sewage plumber work. A rapid test for influenza A and B antigens was negative; owing to concern for bacterial infection, he was started on amoxicillin and ibuprofen. His symptoms did not improve for 5 days, and he was referred to the neurology department of another hospital on day 6 of illness. On admission, he was alert. The headache and neck pain were triggered by his movement. His temperature was 38.5 °C, heart rate 88 beats/minute, and blood pressure 133/69 mmHg. Although the finger exhibited no redness, swelling, or abscess formation, physical examination revealed bilateral cervical and inguinal lymphadenopathy with tenderness. As meningeal irritation signs, neck stiffness was positive, and Kernig sign was positive at 60 degrees. No other neurological deficits were noted. White blood cell (WBC) count was 8200/mm3, with 70% neutrophils, 12.5% lymphocytes, 6.0% eosinophils, and 9.3% monocytes. Serum creatinine (Cre) was 0.91 mg/dL (80 μmol/L), and blood urea was 6.0 mg/dL (2.1 mmol/L). Erythrocyte sedimentation rate was 55 mm/hour, and serum C-reactive protein (CRP) was 11.58 mg/dL. Urine was negative for glucose and protein, the sediment contained < 1 white cell and < 1 red cell per high-power field, and two blood cultures were negative. Computed tomography (CT) scan of the brain did not identify any source of fever. A lumbar puncture was also performed in the neurology department. His cerebrospinal fluid (CSF) was clear and colorless. Initial pressure was high at 235 mmH2O. CSF cell count was 1 × 106 cells/L (1/μL) without red blood cells, glucose level was 3.66 mmol/L (66 mg/dL) [plasma glucose level 5.55 mmol/L (100 mg/dL)], and protein level was 0.31 g/L (31 mg/dL); no organisms were observed on Gram stain. No bacterial growth was detected in bottles of CSF and in bottles of blood. Then, treatment with oral levofloxacin 500 mg/day was initiated on day 6 of illness. Nonsteroidal antiinflammatory agents/drugs (NSAIDs), that is, diclofenac sodium suppositories 25 mg, were also administered three times a day for a week until remission of high fever on day 13 of illness (Fig. 2c). After the initiation of the treatment, contrary to the improvement of the inflammatory findings and parameters, kidney function deteriorated. Serum CRP levels were 11.58, 9.01, and 0.67 mg/dL, and serum Cre levels were 0.98, 1.28, and 2.74 mg/dL on day 6, 9, and 17 of illness, respectively. WBC count was 10,600/mm3, with mild elevated 12.5% eosinophil (reference value < 6.0%) on day 11. There was no skin eruption on extremities. Levofloxacin and esomeprazole were discontinued on day 17, and rapid reduction of kidney function prompted a transfer to our hospital on day 20 of illness for further evaluation and management (Fig. 2a,b). On admission, he had no fever and no complaints. There was no weight increase or pretibial pitting edema. The finger cut had healed without any scars or redness, and bilateral cervical and inguinal lymphadenopathy had diminished with little tenderness. Laboratory studies showed a WBC count of 10,000/mm3, with 60% neutrophil, 25% lymphocytes, 8.0% eosinophils, and 4.0% monocytes. Erythrocyte sedimentation rate was 22 mm/hour, serum CRP was 0.85 mg/dL, serum Cre was 2.09 mg/dL (185 umol/L), blood urea was 27.3 mg/dL (9.4 mmol/L), serum beta-2-microglobulin was 3.8 mg/L (reference value < 2.0 mg/L), urinary beta-2-microglobulin was 1589 ug/L (reference value < 229 ug/L), and urinary N-acetyl-β-d-glucosaminidase (NAG) was 7.9 IU/L (reference value < 6.9 IU/L). The results of laboratory tests showed that the levels of sodium, potassium, chloride, calcium, total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and uric acid were normal. IgG was 1073 mg/dL, immunoglobulin A (IgA) was 129 mg/dL, and IgM was 78 mg/dL. Urine remained negative for glucose and protein, and the sediment contained 0–1 white cell and 0–1 red cell per high-power field. Serum cystatin C measurement was 1.79 mg/L (reference value 0.57–1.01 mg/L), and glomerular filtration rate (GFR) was 61 mL/min/m2. His fractional excretion of sodium (FeNa) was elevated to 2.1% (reference value < 1%). Renal sonography revealed normal level in resistance index.\n\nA percutaneous renal biopsy performed on day 22 of illness revealed focal or belt-like distribution of numerous mononuclear cell infiltrates in the interstitium, associated with focal tubular atrophy, tubulointerstitial edema, and mild tubulitis. The moderate diffuse interstitial inflammation was composed of lymphocytes and eosinophils with mild fibrosis (Fig. 1b). Four interstitial granulomas composed of lymphocyte, plasma cell, macrophage, epithelioid cells, and multinucleated giant cells were identified (Fig. 1a). Glomerular and vascular structures were well preserved. Immunofluorescence showed no evidence of IgG, IgA, IgM, or immune complex deposition. Acid-fast staining for Mycobacterium was negative, and Grocott staining for detection of fungi was also negative. Angiotensin-converting enzyme (ACE) level was normal (11.4 U/L) (reference value 8.3–21.4 U/L). Chest X-ray and computed tomography did not reveal any abnormal masses, or mediastinum or hilar lymphadenopathy in the lung. Gallium scintigraphy did not show any abnormal accumulations. Saxon test results were normal (5.10 g/2 minutes) (reference value > 2.00 g/2 minutes). Anti-neutrophil cytoplasmic antibody (ANCA), MPO-ANCA, PR3-ANCA, anti-nuclear antibody (ANA), anti-SS-A/SS-B, anti-beta-2GPI, anti-RNP, anti-Sm, anti-dsDNA, anti-ssDNA, anti-Scl70, and anti-glomerular basement membrane (anti-GBM) antibodies were negative. IgG4 was at a normal level, soluble IL-2 receptor was 1050 U/mL (reference value 157–474 U/mL), and IgG-, IgA-, and IgM-specific antibodies against Chlamydia did not indicate a recent infection. Serologies for human immunodeficiency viruses (HIVs) 1 and 2, hepatitis B, and hepatitis C were negative. Anti-Treponema pallidum was negative, Epstein–Barr (EBV), mumps, and cytomegalovirus (CMV) serologies were not compatible with acute infection. According to these findings, we diagnosed the patient with granulomatous interstitial nephritis.Fig. 1 Renal biopsy. a Light microscopy of the renal biopsy (periodic acid–Schiff stain) revealed normal glomerulus with formation of interstitial granulomas indicated by arrow heads. Granulomas were composed of lymphocytes, plasma cells, macrophages, epithelioid cells, and multinucleated giant cells. Bar = 100 μm. b Magnified picture of marked area in a, revealing a focal distribution of mononuclear cell infiltrates in the interstitium, associated with focal tubular atrophy, with tubulointerstitial edema as indicated by black arrow head, and with mild tubulitis with intraepithelial lymphocytes, as indicated by white arrow heads. The moderate diffuse interstitial inflammation is composed of lymphocytes and eosinophils. Bar = 50 μm\n\nOn day 29 of illness, eye pain, conjunctival hyperemia, tenderness, photophobia, and blurred vision appeared in both eyes. Best-corrected visual acuity (BCVA) was 1.2 in the right eye and 1.5 in the left eye. Intraocular pressures were normal (right 11 mmHg/left 14 mmHg) with deep anterior chamber. Slit-lamp examination revealed iritis and keratic precipitation (corneal endothelial inflammatory precipitates/deposits) in both eyes. Anterior chamber cells were 1+ right and 0.5+ left. Dilated fundoscopic examination revealed that retina and vitreous body had nonspecific findings. No fever and no lymphadenopathy were observed. Hence, the diagnosis of acute tubulointerstitial nephritis and bilateral uveitis (TINU) syndrome was made, and ophthalmic steroid therapy was initiated (Fig. 2b, c). Symptoms of uveitis, eye pain, redness, and blurred vision disappeared in 1 week. Keratic precipitations were reduced in 1 week, and disappeared in 2 weeks. His serum Cre level gradually improved to 1.29 mg/dL on day 44 of illness without any systemic medical interventions, and systemic steroid therapy was not provided throughout the course of the disease. Mild elevation of eosinophils was also gradually improved. Percentage of peripheral eosinophils/total WBC count were 8.0%/10000, 11.6 %/6700, and 5.0%/7600 on day 20, 24, and 44 of illness, respectively.Fig. 2. Summary of clinical course. a: Symptoms related to meningitis are shown. CRP levels are shown in the line chart. The x-axis shows day of illness (nonlinear scale). Onset of fever is defined as day 0 of illness. Key days are shown in the bottom line; day 6: initiation of diclofenac sodium; day 17: peak day of serum Cre (red line); day 29: development of uveitis (blue line); day 44: date of discharge; day 71: restart of esomeprazole; day 239: second sampling of IgG avidity test. The same time scale is shared by a, b, c, and d. b: Symptoms related to TIN and uveitis are shown. Serum Cre and percent peripheral eosinophils of the total WBC counts (eosinophils %) are shown in the line chart. ★: Renal biopsy was performed on day 22 of illness. c Duration of each administered drug is shown with rectangles. The patient had been administered esomeprazole for 3 years on day 0. The results of lymphocyte transformation test (LTT)/drug-induced lymphocyte stimulation test (DLST) (performed on day 37 of illness) are shown in parenthesis on the right side. The drug positive for LTT/ DLST is shown in bold line. d Values of Toxoplasma gondii-specific IgG, IgM, and IgG avidity along with the clinical course are shown in a table. The positions of the days of illness are adjusted to match the time scale of a, b, and c. High IgG avidity indicate a distant infection of more than 5 months before. IgG avidity test of day 20 (cryopreserved serum) and day 239 were performed together on day 239\n\nTo rule out toxoplasmosis, which could also develop into lymphadenopathy, meningitis, and uveitis, Toxoplasma-specific IgG and IgM titers were evaluated on day 37 of illness, and revealed to be both positive 219 IU/mL (reference value < 6 U/mL) and 4.2 IE/mL (reference value < 0.8 U/mL) respectively. He had a dog for a pet, but not a cat. Despite the positivity of Toxoplasma IgM antibody, the bilateral uveitis responded well to the ophthalmic steroid therapy, lymphadenopathy disappeared,and no signs of meningitis was observed. We decided that antimicrobial therapy was not needed, and he was discharged on day 44 of illness. Drug-induced lymphocyte stimulation test (DLST) or lymphocyte transformation test (LTT), performed by a commercially based clinical diagnostic testing service (SRL, Inc., Tokyo, Japan), confirmed that the patient had a negative stimulation index (SI) score for levofloxacin, esomeprazole, ceftriaxone, and amoxicillin, while he had a high SI score exclusively for diclofenac sodium of 207% (reference value < 180%).\n\nAfter discharge, uveitis recurrence was not detected, and ophthalmic steroid was terminated after 2 months of use. However, the titer of IgM of Toxoplasma remained at a high level for an additional 6 months; we were not sure whether Toxoplasma infection was implicated in this TINU syndrome (Fig. 2d). To address the question, Toxoplasma IgG avidity test was performed with serum sample of day 20 of illness stocked in freezer, and with fresh serum sample from day 239 of illness. The test was performed by a laboratory company (SRL) using Platelia (TM) TOXO IgG AVIDITY (Bio-Rad) according to the manufacturer’s protocol. In brief, optical density (OD) indicating Toxoplasma IgG in serum was measured by enzyme-linked immunosorbent assay (ELISA) after dissociating the link between antibody and antigen. Urea was used as the dissociating agent. Target antigen of the ELISA was purified from Toxoplasma gondii RH strain. Avidity Index (AI) was measured by the ratio of OD(dissociating agent treated) to OD(dissociating agent untreated). IgG AI of the above samples was 0.62 (day 20) and 0.66 (day 239) (reference value: low AI < 0.4, mid 0.4 ≤ AI < 0.5, high 0.5 ≤ AI), indicating a chronologically distant infection of more than 5 months before fever onset. Hence, we determined that the pathogenesis of TINU syndrome in our case was not implicated with a recent infection of Toxoplasma.\n\nNo recurrence of renal dysfunction was observed in the 18 months of follow-up; serum Cre levels were 1.21, 1.03, and 1.04 mg/dL on day 71, 92, and 239 of illness, respectively. Urinary beta-2-microglobulin was reduced to 234 μg/L (reference value < 229 μg/L) on day 204 of illness. HLA typing showed HLA-A3101, HLA-A3303, HLA-B4002, HLA-B4403, HLA-DR0802, HLA-DR1302. HLA-DQB1 0302, and HLA-DQB1 0604, none of which was reported to have strong association with TINU syndrome.\n\nDiscussion\n\nTo diagnose TINU syndrome, differential diagnosis of infections and dozens of other systemic diseases are required. Among infections, Toxoplasma gondii is a pathogen with considerable prevalence on a global scale. Since IgM of Toxoplasma is known to persist in many cases [32], the chances of encountering patients with TINU syndrome with Toxoplasma IgM like our patient might not be so rare. Our case illustrates the difficulties in determining the pathogenic contribution of Toxoplasma gondii in a case of lymphadenopathy and meningitis followed by TINU syndrome. IgG avidity test seemed to rule out recent infection of Toxoplasma and led us to conclude that TINU syndrome in our case was not implicated with a recent infection of Toxoplasma. However, this process of interpretation may not be enough for a precise understanding of the infection profile of Toxoplasma in similar situations. The limitations of current commercial serological tests are also discussed here.\n\nDiagnosis of TINU syndrome\n\nA T-cell-mediated mechanism has been postulated for pathogenesis of TINU syndrome [1, 4, 35]. On analysis of kidney biopsy specimens from drug-induced tubulointerstitial nephritis (TIN), oligoclonal proliferation of drug-antigen-specific T cells was detected by staining of specific T-cell receptor beta-chain variable-region (TCR Vβ) [36]. The oligoclonal immune response is also reproduced in vitro with peripheral blood mononuclear cells from the same patients [36]. Also in TINU syndrome, under the same scenario, the proliferation of antigen-specific T cells initiates the adaptive immune response, which activates the humoral response with B cells. This process, delayed-type hypersensitivity reactions of type IV, causes immunopathologic damage to the uvea and renal interstitium [1]. Autoantibodies against modified CRP (mCRP) is proposed to be a marker for distinguishing TINU syndrome from drug-induced TIN [37, 38]. mCRP is presumed to be one of the common target autoantigens in renal and ocular tissues [37–39]. To demonstrate antigen-specific T cells, an in vitro assay called lymphocyte transformation test (LTT), or drug-induced lymphocyte stimulation test (DLST) is utilized as a useful diagnostic procedure for drug-induced TIN [40–43] and for TINU syndrome [44]. However, the sensitivity of this test for the detection of causative agents of drug hypersensitivity reactions is not adequate in some drugs (such as anti-tuberculosis drugs) [45]. Though the results of LTT/DLST may not be absolute [41, 42, 44, 46], we considered that our case was drug-induced TINU syndrome caused by diclofenac sodium. Diclofenac sodium was administered 5 days before the increment of serum Cre and 3 weeks before the development of uveitis, suggesting it is chronologically reasonable to infer that TIN and uveitis were both induced from diclofenac sodium. LTT/ DLST was performed as described by Pichler et al. [40]. In brief, 0.20 × 106 whole peripheral lymphocytes were stimulated with titrated density of medicine in culture medium (complete RPMI1640 medium), together with separately prepared serum from the same patient. Cultures were started in triplicate. After 72 hours, [3H] thymidine was added and cultured for an additional 24 hours, and the thymidine uptakes were counted from the harvested cells.\n\nThe major histologic changes of tubulointerstitial nephritis (TIN) are interstitial edema and intraepithelial infiltration of inflammatory cells in renal tubules, accompanied with destruction of tubular basement membranes (TBM), called tubulitis [47]. The infiltrated cells consist of T lymphocytes, monocytes, eosinophils, and plasma cells [43].\n\nIn a review of 40 renal biopsies of patients with granulomatous formation (37 of them are TIN), sarcoidosis was present in 50% of the patients, and drug-induced TIN was present in 18% [48]. In an area where infection is a more likely etiology, microbial pathogens such as Mycobacterium, tuberculosis, fungi, bacteria, spirochetes, and parasites (Leishmania, Toxoplasma) are associated with granulomatous TIN [48]. ANCA-associated vasculitis, Crohn’s disease, and TINU syndrome can also cause granulomatous formation in renal interstitium [43, 48]. Histological findings of tubulitis are classified into three groups by immunohistochemistry [47]: (1) negative for antibodies and immune deposits [49, 50]; (2) positive staining of immune complexes along the TBM that sometimes associates with complement [51]; and (3) linear staining of the TBM, usually with IgG and complement. The third group is known as anti-tubular basement membrane (anti-TBM) disease [52, 53].\n\nDetailed diagnostic criteria for TINU syndrome were developed by John T. H. Mandeville and James T. Rosenbaum [4]. These criteria adopt a probabilistic approach to the diagnosis using the presented clinical features [1]. Based on the criteria, our patient is diagnosed as “definite” TINU syndrome (Table 1). As is noted in the criteria, the diagnosis of TINU syndrome requires the presence of both acute TIN and uveitis, without other systemic diseases that can cause TIN and uveitis. The important differential diagnosis suggested by the combination of fever, lymphadenopathy, anterior bilateral uveitis, and granulomatous interstitial nephritis is as follows; sarcoidosis, Sjogren’s syndrome, systemic lupus erythematosus, granulomatous with polyangiitis (GPA), Behcet’s syndrome, Epstein–Barr virus–associated infectious mononucleosis, tuberculosis, bacterial/fungal infections, toxoplasmosis, and histoplasmosis [4, 54].Table 1 Diagnostic criteria for tubulointerstitial nephritis and uveitis syndrome\n\nThe diagnosis of TINU syndrome requires the presence of both acute interstitial nephritis (AIN) and uveitis, without other known systemic diseases that can cause either interstitial nephritis or uveitis\t\nCases are categorized further as “definite,” “probable,” or “possible” on the basis of (1) the diagnostic criteria for AIN as defined below and (2) the clinical characteristics of uveitis as defined below\t\nDefinite TINU syndrome\t\n• AIN diagnosed histopathologically or clinically (complete criteria) and typical uveitis\t\nProbable TINU syndrome\t\n• AIN diagnosed histopathologically and atypical uveitis\t\n or\t\n• AIN diagnosed clinically (incomplete criteria) and typical uveitis\t\nPossible TINU syndrome\t\n• AIN diagnosed clinically (incomplete criteria) and atypical uveitis\t\nDiagnostic criteria for acute interstitial nephritis\t\n• Histopathologic diagnosis: renal biopsy consistent with tubulointerstitial nephritis\t\n• Clinical diagnosis:a presence of the following criteria (a case is considered to have “complete criteria” if the three factors listed below are present; a case is considered to have “incomplete criteria” if fewer than three factors listed below are present):\t\n 1. Abnormal renal function (elevated serum creatinine or decreased creatinine clearance)\t\n 2. Abnormal urinalysis: increased beta-2 microglobulin, low-grade proteinuria [a level below that seen in patients with nephrotic syndrome (2+ or less on a semiquantitative test, or a spot urinary protein-to-urinary creatinine ratio of < 3, or < 3.0 g protein/24 hours in an adult or < 3.5 g protein/1.73 m2/24 hours in a child)], urinary eosinophils, pyuria or hematuria without infection, urinary white cell casts, or normoglycemic glucosuria\t\n 3. A systemic illness lasting > 2 weeks, characterized by a combination of the following symptoms and laboratory findings:\t\n a. Signs and symptoms: fever, weight loss, anorexia, malaise, fatigue, rash, abdominal or flank pain, arthralgia, or myalgia\t\n b. Laboratory findings: evidence of anemia, abnormal liver function, eosinophilia, or Westergren erythrocyte sedimentation rate > 40 mm/hour\t\nUveitis characteristics\t\n• Typical\t\n 1. Bilateral anterior uveitis with or without intermediate uveitis or posterior uveitis\t\n 2. Onset of uveitis ≤ 2 months before or ≤ 12 months after AIN\t\n• Atypical\t\n 1. Unilateral anterior uveitis or intermediate uveitis or posterior uveitis or a combination of these categories\t\n 2. Onset of uveitis > 2 months before or > 12 months after AIN\t\naIf atypical clinical features are present, or if the renal disease does not improve after 6 weeks with appropriate therapy, a renal biopsy is recommended\n\nFor complete explanation of this criteria, please see full reference [4]. AIN, acute interstitial nephritis\n\nDistinction of sarcoidosis from TINU syndrome is particularly difficult [1]. In 736 patients of sarcoidosis, the percentage of renal involvement (renal sarcoidosis) was only 0.7% [55]. Another retrospective analysis of 47 patients with renal sarcoidosis reported that 90% of them had intrathoracic lesions, 66% had proteinuria, and 55% had increased ACE [56]. The lymph node enlargement in sarcoidosis is typically firm, nontender, and freely movable [57]. As opposed to this clinical phenotype, our case had lymphadenopathy with tenderness and did not have hilar lymphadenopathy, proteinuria, elevated ACE, and other findings such as hepatomegaly, nephrocalcinosis, or nephrolithiasis on CT scan and on Gallium scintigraphy. Moreover, uveitis, lymphadenopathy, and TIN activity in our case were appreciably alleviated without using systemic steroid in the 18 months of follow-up, which is contrasting to the high relapse rate of renal sarcoidosis even after strong steroid therapy [56]. This clinical presentation made drug-induced TINU syndrome more likely than renal sarcoidosis. Long-term follow-up would be needed to confirm this presumptive diagnosis.\n\nThe first TINU syndrome cases were described as “Acute eosinophilic interstitial nephritis with uveitis” by Dobrin [2]. From this description, one can infer that eosinophils may play a certain role in the pathogenesis of TINU syndrome. Eosinophilia is included in the diagnostic criteria of TINU syndrome as one of the manifestations of acute interstitial nephritis [4]. Systemic eosinophilia is reported in 17% of TINU syndrome patients (21 of 122 cases) [4]. Mild elevations of eosinophils were observed also in our case. Interestingly, the level of peripheral eosinophils showed two peaks in the clinical course. These peaks were noticed when reviewing the data retrospectively. The first peak was recorded in parallel with the upregulation of serum Cre, or the development of TIN. The second peak was recorded around 4–5 days before the development of uveitis. These fluctuations of eosinophils might reflect the pathogenesis of TINU syndrome. Whether peripheral eosinophils can be used as a prognostic or activation marker of TINU syndrome symptoms should be investigated.\n\nTINU syndrome is probably an underdiagnosed disorder [4]. TINU syndrome would not have been diagnosed if the association of interstitial nephritis and uveitis were not clinically evident, or if one of the symptoms had resolved by the time other symptoms developed. TINU syndrome cases are diagnosed in 0.2–2% of patients attending specialist uveitis services [58], and in 0.4% (n = 15/3830) of uveitis patients in Japan [59]. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU syndrome. Larger datasets from renal literatures also suggest that most cases of TINU syndrome are caused by drug-induced hypersensitivity reaction [58]. Contrary to the differential diagnosis described in the above paragraph, specific infective agents reported as being possibly associated with TINU syndrome include tuberculosis [60], EBV [61–63], herpes zoster reactivation [63], systemic toxoplasmosis [8], and generalized lymphadenopathy [8].\n\nA review summarizing 133 TINU syndrome cases noted that the main drugs proposed as risk factors for TINU syndrome are nonsteroidal antiinflammatory agents (18%) and antibiotics (24%) [4]. There is a case of levofloxacin-related anterior uveitis, vitritis, and macular edema that required oral prednisone to return to baseline vision in an adult female [64]. The most common causative drug for uveitis is bisphosphonate, which is employed in the treatment of osteoporosis or of dystrophic disease involving the skeletal system. Bisphosphonates have been associated with uveitis, nonspecific conjunctivitis, episcleritis, and scleritis. Several antibiotics have been causally linked to uveitis, most notably rifabutin, sulfonamides, and fluoroquinolones. Sulfonamide-associated uveitis develops quickly, often as fast as 8 days [64]. Esomeprazole, a proton pump inhibitor (PPI), was resumed 2 months after discontinuation, without any complications thereafter. This indicates that esomeprazole had little effect on the pathogenesis of our TINU syndrome, although PPIs are common causative drugs for drug-induced TIN, like antibiotics and NSAIDs [65, 66]. Increased pH in stomach helps the survival of tachyzoites of Toxoplasma gondii [67]. In the view of susceptibility to ingested infectious agents, the high pH may make it difficult to completely deny the contribution of esomeprazole to pathogenesis.\n\nTIN and uveitis symptoms are not always concurrent. The review summarizing 133 TINU syndrome cases noted that ocular symptoms were concurrent with systemic symptoms in only 15% of cases; in 21% of cases, uveitis occurred before systemic symptoms, occurring up to 2 months beforehand; in 65% of cases, uveitis occurred after systemic symptoms with a median of 3 months, up to 14 months [4, 58]. Based on the study, eye pain and redness were observed in 41% (n = 55/133), blurred vision in 10.5% (n = 14/133), anterior uveitis in 73% (n = 97/133), and keratic precipitation in 9.8% (n = 13/133) of the TINU syndrome cases [4]. Another review summarizing 2619 uveitis cases reported that viral infections were seen in 8.6% (n = 226/2619) and parasitic infections in 7.5% of cases (n = 198/2619), most of which were Toxoplasma infection (n = 173) [68]. Most viral infection-related uveitis anatomically localized in the anterior (81%, n = 183/226), whereas most parasitic infection-related uveitis localized in the posterior part (77%, n = 153/198). This suggests that the bilateral anterior uveitis observed in our case was more likely to be TINU syndrome or viral infection related rather than parasitic infection related.\n\nUrinary beta-2-microglobulin is widely used as an interstitial damage marker. In our case, it was highly elevated in the acute phase and gradually reduced to a normal level in parallel with remission of the illness. Consistent with our case, a review reported that urinary beta-2-microglobulin levels were elevated in all cases of tested TINU syndrome (100%, n = 37/37) and persisted for months [4]. Persistent histological change was reported in the two tested cases even at second biopsy 9 months after the first diagnosis of TINU syndrome [69]. They suggest a requirement of immunosuppressive therapy in selected TINU syndrome patients [69]. Urine TNFα and IL-9 levels are proposed to be good biomarkers to improve the prebiopsy diagnosis for acute interstitial nephritis [70], because TINU syndrome is thought to be a lymphocyte-mediated immune response [1].\n\nInterpretation of Toxoplasma serology\n\nThe second most common cause of encephalitis deaths in the USA is Toxoplasma gondii, following herpesvirus [6]. A common cause of uveitis in immunocompetent hosts is Toxoplasma gondii. As many as 2% of Toxoplasma-infected patients exhibit ocular toxoplasmosis, which can be present either in the context of recently acquired infection (recent infection) or of reactivated disease as retinochoroiditis [71]. Retinochoroiditis scarring has been considered as a finding of congenital infection, but is increasingly recognized as a result of acquired recent infection [72]. Therefore, clinicians have a good chance of seeing an immunocompetent patient with subacute Toxoplasma infections. However, medical literature related to acquired toxoplasmosis in immunocompetent patients is not enough [16], probably because acquired toxoplasmosis has been considered to be basically self-limiting.\n\nIgG avidity test of Toxoplasma was originally developed by Hedman and his associates in Finland [73]. Maturation of antibody affinity to target antigen occurs in the weeks or months after the primary infection. IgG avidity is initially low in the first 3 months (may remain to be low for 1 year), and achieves a higher level in the late phase of (distant) infection (4–5 months) [34]. IgG avidity is necessary as confirmatory testing to distinguish the recent infection of Toxoplasma from patients with persistent IgM or false positive IgM [32]. In our case, although positivity of IgG and IgM of Toxoplasma was obtained, we only periodically monitored the level of IgG and IgM. Despite the lack of headache, fever, and uveitis, the persisting IgM confused our interpretation of the serological results, and urged us to perform IgG avidity of Toxoplasma. The test is still in the research phase and not covered by health insurance in Japan. The IgG avidity test performed on the frozen sample of day 20 of illness indicated a distant infection. Therefore, complication of a recent infection of Toxoplasma on his pathogenesis was excluded accordingly.\n\nA limitation of our investigation is that commercial Toxoplasma IgM and IgG tests cannot distinguish different strains of Toxoplasma gondii. Although reinfection of Toxoplasma gondii does not basically occur in immune-competent hosts except in some rare case reports [74–78], this may be true exclusively for the same strain. There are several strains in Toxoplasma gondii with different virulence, and prevalence varies depending on geographical factors [79, 80]. Contrary to the accepted notion above, a reinfection experiment in sheep model demonstrated that reinfection of a different strain of Toxoplasma gondii on preimmune sheep with the preceding infection does occur [81]. There is a case report of human reinfection by a different strain of Toxoplasma that was not protected by the immunity of the preceding strain of Toxoplasma [82] (Fig. 3a, lower right). The authors and others [83–86] also confirmed that acquired immunity against a preceding strain of Toxoplasma may not protect against reinfection by another strain, based on mouse model experiments. Although there is no evidence of increased risk of Toxoplasma infection for plumbers who are frequently exposed to sewage water [87], oocysts are persistent and prevalent in water, soil, and foods [88]. Also, vegetarians and certain occupations such as farmers are significantly more associated with Toxoplasma IgM seropositivity [89].Fig. 3 Toxoplasma serology tests in primary infection, reactivation, and in reinfection. a The transmission of Toxoplasma gondii to immunocompetent humans (intermediate host) occurs by ingestion of oocysts, normally via contaminated food or water. Infection can also occur via consumption of undercooked meat or raw meat containing tissue cysts with bradyzoites. The majority of cases (85–90%) are asymptomatic, but around 10–15% of the infected individuals develop systemic symptoms [12–15]. In either case, chronic (distant) infection can persist for the life of the hosts. If the hosts become immunodeficient or immune-suppressed, bradyzoites reactivate, which causes cerebral or ocular toxoplasmosis. If primary infection occurs during pregnancy, parasites can also infect the fetus by congenital transmission. Typical Toxoplasma serological changes of primary infection in immunocompetent patients are shown in b. The first isotype antibody to appear in the very early phase of the primary infection is IgM, followed by the appearance of IgG, which is required for confirmation of the infection. Toxoplasma IgG avidity test is a critical tool to distinguish recent infection from distant infection in pregnant women, because IgM of Toxoplasma is known to persist in many cases of distant infection [29–32] (persistent IgM is marked with * in this figure). However, congenital transmission also occurs in distant/latent infected host when the host becomes immunodeficient (a, lower left) or reinfected with different strains of Toxoplasma gondii (a: lower right). In such cases, commercial IgG avidities give high-level results even before the onset of reactivation or reinfection, because the hosts have been distantly/latently infected. Therefore, clinicians cannot interpret IgG avidity test as they do in primary infection. Clinically symptomatic phases are highlighted in yellow. Blue dot line indicates the “distant infection” profile, which consists of three infection profiles: latent infection, reactivation, and reinfection. Different strains of Toxoplasma gondii are described as oocysts-2 or tissue cysts-2. Representative changes of Toxoplasma gondii serology in reactivation and in reinfection are shown in c and d. In d, distinctive serological changes of reinfection from serum of reactivation are written in red letter. IgG, IgM, IgA, Toxoplasma gondii-specific IgG, IgM, IgA; Inf, infection; Pos, positive; Neg, negative; Pos/higher, positive or higher level; v.e, very early phase of infection. Recent infection is highlighted in pink, and distant infection is highlighted in light blue. This figure is modified from Vera Lucia Pereira-Chioccola et al. [15] and O Villard et al. [93]. Ref A-K, reference group A–K; Ref. A: [90, 91], Ref. B: [96], Ref. C: [74–77, 78(p), 82(p), 94, 96]; p, presumed cases; Ref. D: [91], Ref. E: [91], Ref. F: [93], Ref. G: [74, 77, 82, 94], Ref. H: [74, 76, 77], Ref. I: [74, 91, 96], Ref. J: [74, 76, 77], Ref. K: [17, 93], Ref. L: [17]\n\nBesides reinfection, recurrence or reactivation of the primary infection is another type of “distant” Toxoplasma infection profile. Reactivation mostly occurs in immunosuppressed conditions [15]. Reactivation causes cerebral, ocular, or congenital toxoplasmosis [90, 91] (Fig. 3a, lower left). A retrospective serological analysis found that, among 217 cases of serologically positive ocular toxoplasmosis, only 3.2% were in recent primary infection profile, while 68.2% were in a distant (chronic) infection profile based on IgG avidity test [92]. Direct detection of Toxoplasma gondii is basically required for the confirmation of reactivated toxoplasmosis. For the detection, bioassay of suspected biological materials in laboratory mice or PCR tests targeting gene sequences of Toxoplasma are utilized [5]. Thus, the initial serological results of our case (positive IgG and IgM) indicate any of the following profiles: (1) recent primary infection; (2) latent/distant infection of primary infection (with persistent IgM); (3) recent infection of a different strain (reinfection); or (4) recurrence/reactivation of latent infection. The following serological results and the high IgG avidity in our case excluded the possibility of (1) recent primary infection. However, high titer and high avidity IgG generated by distant/preceding infections might mask the detection of low avidity IgG generated by a recent infection with a different strain. Therefore, the “distant” infection indicated by commercial IgG avidity test is still a multiplex profile consisting of (3) reinfection, (4) reactivation, and (2) latent infection [93]. Ranges of distant infection are described as light blue rectangle at left side in Fig. 3a.\n\nThe positivity of serum Toxoplasma IgA is reported to be a proof of reinfection and not of reactivation [74, 77, 82, 94]. In primary infection, Toxoplasma IgA appears shortly after IgM and persists for some time (usually 6–7 months) [95]. Reappearance of Toxoplasma IgM in previously infected patients is another serological marker of reinfection and not of reactivation [74, 91, 96], although this rule is applicable only in the absence of persistent IgM. However, reappearance of IgM is not always detected in reinfection-presumed cases [75–77]. Increased IgG of Toxoplasma observed at reinfection [74, 76, 77] or at reactivation [93] should be interpreted carefully, because such a rise is also observed in a delayed serological response to antigens after treatment of toxoplasmosis [97]. Serological variations in each infection profile are summarized in tables in Fig. 3b–d.\n\nEvaluation of Toxoplasma IgA was not performed in our case. PCR detection from suspected biological materials was not attempted. The fact that the patient was not immunodeficient or immune-suppressed suggested that (4) reactivation was not likely. No remarkable change in Toxoplasma IgG throughout the clinical course suggested that (2) latent/distant infection was more likely than (3) reinfection or (4) reactivation. On the other hand, our case fortunately satisfied the diagnostic criteria for TINU syndrome. Based on the whole clinical course, we were able to interpret the serological results of Toxoplasma as (2) latent infection rather than (3) reinfection. It should be noted that making this diagnosis in the middle of the course was difficult. Protein microarray survey has identified a number of target antigens for IgG and IgM, from serum of Toxoplasma-infected patients [98]. Several efforts to identify strain-specific antigens [80, 83, 99–101] or stage-specific antigens [102–104] that enable more specific serotyping of Toxoplasma gondii have been reported. Future development of serological examination of Toxoplasma should facilitate the clinical diagnosis of autoimmune diseases such as TINU syndrome.\n\nConclusion\n\nThis case illustrates the difficulty in determining the infection profile of Toxoplasma gondii in the diagnosis of TINU syndrome. Performing the IgG avidity test in a timely manner is recommended to determine the chronological assessment of the putative Toxoplasma gondii infection. However, these serological examinations still have limitations in their precise determination of the infection profile. Therefore, careful monitoring and extended follow-up of such patients are critical.\n\nAbbreviations\n\nTINU syndrome Tubulointerstitial nephritis and uveitis syndrome\n\nDLST Drug-induced lymphocyte stimulation test\n\nLTT Lymphocyte transformation test\n\nTBM Tubular basement membranes\n\nBCVA Best-corrected visual acuity\n\nKP Keratic precipitation\n\nNSAID Nonsteroidal antiinflammatory agent/drug\n\nCRP C-reactive protein\n\nCre Creatinine\n\nCT Computed tomography\n\nCSF Cerebrospinal fluid\n\nWBC White blood cell\n\nNAG N-acetyl-β-d-glucosaminidase\n\nGFR Glomerular filtration rate\n\nFeNa Fractional excretion of sodium\n\nACE Angiotensin-converting enzyme\n\nANCA Anti-neutrophil cytoplasmic antibody\n\nANA Anti-nuclear antibody\n\nGBM Glomerular basement membrane\n\nEBV Epstein–Barr virus\n\nCMV Cytomegalovirus\n\nSI Stimulation index\n\nHLA Human leukocyte antigen\n\nAcknowledgements\n\nThe authors thank Dr. Hiroshi Arai (neurologist) for taking care of the patient and providing clinical information.\n\nAuthors’ contributions\n\nYO, HF, TN KI, FT, NI, HK, and RM evaluated the patient clinically, and revised the manuscript. KU managed clinical samples. NI made the ophthalmological diagnosis and cared for the patient. HK made the pathological diagnosis and contributed microscopic pictures. YO reviewed the literature and prepared the manuscript. RM provided substantial contributions to the design of the manuscript, revising it critically for important intellectual content, and obtained final approval of the version to be published. All authors read and approved the final manuscript.\n\nFunding\n\nThere are no funding details to be declared.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article because no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this article. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nNone.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Clive DM Vanguri VK The syndrome of tubulointerstitial nephritis with uveitis (TINU) Am J Kidney Dis 2018 72 1 118 128 10.1053/j.ajkd.2017.11.013 29429748\n2. Dobrin RS Vernier RL Fish AL Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome Am J Med 1975 59 3 325 333 10.1016/0002-9343(75)90390-3 1163543\n3. Matsumoto K Fukunari K Ikeda Y Miyazono M Kishi T Matsumoto R Fukuda M Uchiumi S Yoshizaki M Nonaka Y Kanaya A A report of an adult case of tubulointerstitial nephritis and uveitis (TINU) syndrome, with a review of 102 Japanese cases Am J Case Rep. 2015 16 119 123 10.12659/AJCR.892788 25725230\n4. 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Dzitko K Staczek P Gatkowska J Dlugonska H Toxoplasma gondii: serological recognition of reinfection Exp Parasitol 2006 112 2 134 137 10.1016/j.exppara.2005.09.010 16289467\n84. Dao A Fortier B Soete M Plenat F Dubremetz JF Successful reinfection of chronically infected mice by a different Toxoplasma gondii genotype Int J Parasitol 2001 31 1 63 65 10.1016/s0020-7519(00)00151-x 11165272\n85. Araujo F Slifer T Kim S Chronic infection with Toxoplasma gondii does not prevent acute disease or colonization of the brain with tissue cysts following reinfection with different strains of the parasite J Parasitol 1997 83 3 521 522 10.2307/3284421 9194838\n86. Franco PS da Silva NM de Barbosa BF de Gomes AO Ietta F Shwab EK Su C Mineo JR Ferro EAV Calomys callosus chronically infected by Toxoplasma gondii clonal type II strain and reinfected by Brazilian strains is not able to prevent vertical transmission Front Microbiol 2015 6 181 10.3389/fmicb.2015.00181 25806028\n87. Alvarado-Esquivel C Liesenfeld O Márquez-Conde JA Estrada-Martínez S Dubey JP Seroepidemiology of infection with Toxoplasma gondii in workers occupationally exposed to water, sewage, and soil in Durango, Mexico J Parasitol. 2010 96 5 847 850 10.1645/GE-2453.1 20950091\n88. Shapiro K Bahia-Oliveira L Dixon B Dumetre A de Wit LA VanWormer E Villena I Environmental transmission of Toxoplasma gondii: oocysts in water, soil and food Food Waterborne Parasitol. 2019 15 e00049 10.1016/j.fawpar.2019.e00049 32095620\n89. Zhou Q Wang Q Shen H Zhang Y Zhang S Li X Acharya G Seroepidemiological map of Toxoplasma gondii infection and associated risk factors in preconception period in china: a nationwide cross-sectional study J Obstet Gynaecol Res 2018 44 6 1134 1139 10.1111/jog.13638 29673005\n90. Desmonts G Couvreur J Thulliez P Congenital toxoplasmosis. 5 cases of mother-to-child transmission of pre-pregnancy infection Presse Med 1990 19 31 1445 1449 2146635\n91. Gláucia MQA Vasconcelos-Santos DV Carellos EVM Romanelli RMC Vitor RWA Carneiro ACAV Januario JN Congenital toxoplasmosis from a chronically infected woman with reactivation of retinochoroiditis during pregnancy J Pediatr (Rio J) 2009 86 1 85 88 10.2223/JPED.1948 19918624\n92. Greigert V Pfaff AW Sauer A Filisetti D Candolfi E Villard O Biological diagnosis of ocular toxoplasmosis: a nine-year retrospective observational study mSphere. 2019 4 5 00636 719 10.1128/mSphere.00636-19\n93. Villard O Cimon B L'Ollivier C Fricker-Hidalgo H Godineau N Houze S Paris L Pelloux H Villena I Candolfi E Serological diagnosis of Toxoplasma gondii infection: recommendations from the French National Reference Center for Toxoplasmosis Diagn Microbiol Infect Dis 2016 84 1 22 33 10.1016/j.diagmicrobio.2015.09.009 26458281\n94. Hegab SM Al-Mutawa SA Immunopathogenesis of toxoplasmosis Clin Exp Med 2003 3 2 84 105 10.1007/s10238-003-0011-2 14598184\n95. Sensini A Toxoplasma gondii infection in pregnancy: opportunities and pitfalls of serological diagnosis Clin Microbiol Infect 2006 12 6 504 512 10.1111/j.1469-0691.2006.01444.x 16700697\n96. Hashiguchi J Onozawa M Naka T Hatanaka KC Shiratori S Sugita J Fujimoto K Matsuno Y Teshima T Re-infection of Toxoplasma gondii after HSCT presenting lymphadenopathy resembling recurrence of lymphoma Transpl Infect Dis 2018 20 3 12892 10.1111/tid.12892\n97. Saso A Bamford A Grewal K Noori M Hatcher J D'Arco F Guy E Lyall H Fifteen-minute consultation: management of the infant born to a mother with toxoplasmosis in pregnancy Arch Dis Child Educ Pract Ed 2020 105 5 262 269 10.1136/archdischild-2018-316603 32071105\n98. Liang L Dökaya M Juarez S Caner A Jasinskas A Tan X Hajagos BE Bradley PJ Korkmaz M Gürüz Y Felgner PL Davies DH Identification of potential serodiagnostic and subunit vaccine antigens by antibody profiling of toxoplasmosis cases in Turkey Mol Cell Proteom 2011 10 7 M110.006916 10.1074/mcp.M110.006916\n99. Kong JT Grigg ME Uyetake L Parmley S Boothroyd JC Serotyping of Toxoplasma gondii infections in humans using synthetic peptides J Infect Dis 2003 187 9 1484 1495 10.1086/374647 12717631\n100. Xiao J Buka SL Cannon TD Suzuki Y Viscidi RP Torrey EF Yolken RH Serological pattern consistent with infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult offspring Microbes Infect 2009 11 13 1011 1018 10.1016/j.micinf.2009.07.007 19638313\n101. Sun X Huijun Lu Jia B Chang Z Peng S Yin J Chen Q Jiang N A comparative study of Toxoplasma gondii seroprevalence in three healthy Chinese populations detected using native and recombinant antigens Parasit Vectors 2013 6 1 241 10.1186/1756-3305-6-241 23958280\n102. Appleford PJ Smith JE Strain and stage specific variation in Toxoplasma gondii antigens Int J Parasitol 2000 30 11 1187 1191 10.1016/S0020-7519(00)00109-0 11027786\n103. Kasper LH Ware PL Recognition and characterization of stage-specific oocyst/sporozoite antigens of Toxoplasma gondii by human antisera J Clin Invest 1985 75 1570 10.1172/JCI111862 2581998\n104. Santana SS Gebrim LC Carvalho FR Barros HS Barros PC Pajuaba ACAM Messina V Possenti A Cherchi S Reiche EMV Navarro IT Garcia JL Pozio E Mineo TWP Spano F Mineo JR CCp5A protein from Toxoplasma gondii as a serological marker of oocyst-driven infections in humans and domestic animals Front Microbiol 2015 24 6 1305 10.3389/fmicb.2015.01305\n\n",
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"journal": "Journal of medical case reports",
"keywords": "Drug-induced lymphocyte stimulation test (DLST); IgG avidity test; Lymphocyte transformation test (LTT); Meningitis; Persistent immunoglobulin M (IgM); Strain-specific diagnosis; Toxoplasma gondii; Tubulointerstitial nephritis and uveitis (TINU) syndrome",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D006801:Humans; D007075:Immunoglobulin M; D000072281:Lymphadenopathy; D008297:Male; D008581:Meningitis; D009395:Nephritis, Interstitial; D014122:Toxoplasma; D014605:Uveitis",
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"pubdate": "2021-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Tubulointerstitial nephritis and uveitis syndrome following meningitis and systemic lymphadenopathy with persistent Toxoplasma immunoglobulin M: a case report.",
"title_normalized": "tubulointerstitial nephritis and uveitis syndrome following meningitis and systemic lymphadenopathy with persistent toxoplasma immunoglobulin m a case report"
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"abstract": "Here we describe a unique case of clozapine-associated hypothermia during initial titration of this medication in an acute inpatient psychiatry setting. Only a handful of cases on this topic have been published. We discuss possible pharmacologic mechanisms supporting or refuting the propensity of clozapine to induce hypothermia, as well as risk factors for clozapine-induced hypothermia, and a comparison to clozapine-induced hyperthermia.\n\n\n\nA 70 year-old African American female with treatment-refractory schizoaffective disorder developed hypothermia with a nadir temperature of 89 °F (31.7 °C) after 7 days on clozapine, on a total dose of 50 mg twice daily. Accompanying symptoms included bradycardia, hypotension, QTc prolongation, tachypnea, hypoxemia, and an absence of shivering. The patient was transferred to the ICU, and rewarmed within 10 h with the discontinuation of her clozapine, ziprasidone, and carvedilol. Broad spectrum antibiotics were initiated, but discontinued shortly after, as the patient had no leukocytosis, and blood cultures were negative.\n\n\n\nWhile hypoglycemia, hypothyroidism, sepsis, and stroke were effectively ruled out, alternative drug-disease (including chronic kidney disease), and drug-drug interactions were considered possible contributing features. Benzodiazepines, valproic acid, ziprasidone, and the numerous antihypertensive agents the patient was taking were considered as either primary or compounding factors for hypothermia. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale.\n\n\n\nClozapine-induced hypothermia may occur more commonly than clinicians believe. Practitioners should be cognizant of this potentially fatal phenomenon, and monitor for temperature dysregulations while on clozapine, especially during initial titration, in those with multiple comorbid factors, and on additional medications that may contribute to hypothermia.",
"affiliations": "Department of Pharmacy, University of Alabama at Birmingham Medical Center, JT1728 619 19th Street South, Birmingham, AL, 35249, USA. bradleyburk@uabmc.edu.;Department of Pharmacy, University of Alabama at Birmingham Medical Center, JT1728 619 19th Street South, Birmingham, AL, 35249, USA.;Chattanooga College, 5600 Brainerd Road, Chattanooga, TN, 37415, USA.",
"authors": "Burk|Bradley G|BG|0000-0002-2681-3785;Ward|Alex H|AH|;Clark|Brooke|B|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
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"doi": "10.1186/s12888-020-02695-w",
"fulltext": "\n==== Front\nBMC Psychiatry\nBMC Psychiatry\nBMC Psychiatry\n1471-244X BioMed Central London \n\n2695\n10.1186/s12888-020-02695-w\nCase Report\nA case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations\nhttp://orcid.org/0000-0002-2681-3785Burk Bradley G. bradleyburk@uabmc.edu 1 Ward Alex H. ahward@uabmc.edu 1 Clark Brooke brooke.clark@mlh.org 2 1 grid.413019.e0000 0000 8951 5123Department of Pharmacy, University of Alabama at Birmingham Medical Center, JT1728 619 19th Street South, Birmingham, AL 35249 USA \n2 Chattanooga College, 5600 Brainerd Road, Chattanooga, TN 37415 USA \n9 6 2020 \n9 6 2020 \n2020 \n20 29011 3 2020 27 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nHere we describe a unique case of clozapine-associated hypothermia during initial titration of this medication in an acute inpatient psychiatry setting. Only a handful of cases on this topic have been published. We discuss possible pharmacologic mechanisms supporting or refuting the propensity of clozapine to induce hypothermia, as well as risk factors for clozapine-induced hypothermia, and a comparison to clozapine-induced hyperthermia.\n\nCase presentation\nA 70 year-old African American female with treatment-refractory schizoaffective disorder developed hypothermia with a nadir temperature of 89 °F (31.7 °C) after 7 days on clozapine, on a total dose of 50 mg twice daily. Accompanying symptoms included bradycardia, hypotension, QTc prolongation, tachypnea, hypoxemia, and an absence of shivering. The patient was transferred to the ICU, and rewarmed within 10 h with the discontinuation of her clozapine, ziprasidone, and carvedilol. Broad spectrum antibiotics were initiated, but discontinued shortly after, as the patient had no leukocytosis, and blood cultures were negative.\n\nDiscussion\nWhile hypoglycemia, hypothyroidism, sepsis, and stroke were effectively ruled out, alternative drug-disease (including chronic kidney disease), and drug-drug interactions were considered possible contributing features. Benzodiazepines, valproic acid, ziprasidone, and the numerous antihypertensive agents the patient was taking were considered as either primary or compounding factors for hypothermia. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale.\n\nConclusions\nClozapine-induced hypothermia may occur more commonly than clinicians believe. Practitioners should be cognizant of this potentially fatal phenomenon, and monitor for temperature dysregulations while on clozapine, especially during initial titration, in those with multiple comorbid factors, and on additional medications that may contribute to hypothermia.\n\nKeywords\nClozapineHypothermiaTemperatureSchizophreniaSchizoaffectiveAntipsychoticissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nWhile it is well established that antipsychotics may induce hyperthermia (an often-recognized part of neuroleptic malignant syndrome), hypothermia from these agents may be vastly under-recognized and under-represented within medical literature [1]. It was with the advent of chlorpromazine in the 1950s that the first case report of phenothiazine-induced hypothermia was published [2]. In an older review of neuroleptic-induced temperature dysregulations using primarily first-generation agents in various species, the authors found these agents decreased body temperature in 321 of 651 studies, and increased it in 183 cases [3]. However, of the studies specifically in humans, temperature decreased in only 26 of 153 cases, and increased in 127 cases [3]. A lack of systematic reviews with newer antipsychotics has left a gap in knowledge.\n\nA publication from 2017 examined original case reports of possible antipsychotic-induced hypothermia [4]. The risk of hypothermia appears to be highest during the first 7 days of therapy, but may occur after the first dose [1, 4, 5]. Additional factors, such as advanced age, cold exposure, use of benzodiazepines, and hypothyroidism (subclinical), were also noted to predispose a patient on antipsychotics to hypothermia [1, 6]. Of the 57 case reports analyzed, 52% were with second-generation antipsychotics [4]. These second-generation antipsychotic-induced hypothermia cases were further investigated in a more recent review, which found olanzapine and risperidone to be the most common causes of hypothermia [7]. Based on the comparatively larger number of hypothermia reports to drug-monitoring agencies such as Food and Drug Administration (FDA) Medwatch and World Health Organization (WHO), these authors also concluded that the incidence of hypothermia is at least 10 times higher than is indicated by published literature [4, 6, 7]. Indeed, if one were to compare the 591 cases of hypothermia with second-generation antipsychotics reported to the FDA to the 34 published case reports, this estimate seems highly conceivable [7].\n\nAlthough one report speculated clozapine may be safely utilized in those with a history of hypothermia from alternative antipsychotics, newer reports suggests this may not be the case [8, 9]. Here we present a unique case of hypothermia occurring on initial titration of clozapine during an inpatient psychiatry admission. We also aim to provide clinicians with greater insight into clozapine-induced temperature dysregulations.\n\nCase presentation\nMs. P is a 70-year-old African-American female with a history of schizoaffective disorder (bipolar type), vascular dementia, hypertension, coronary artery disease, chronic heart failure, dissected ascending aortic aneurysm, and chronic kidney disease (CKD) admitted to inpatient psychiatry for symptoms of mania and delusions. Her hospital admission was complicated by profound hypertension, acute kidney injury, and an acute on chronic heart failure exacerbation.\n\nRecords indicated Ms. P was prescribed risperidone prior to her hospitalization, which was restarted upon admission at a dose of 1.5 mg daily, titrated to 4 mg daily and continued for 3 weeks. Her risperidone was subsequently switched to olanzapine 5 mg daily, which was titrated to dose of 20 mg daily and continued for 2 weeks, then later changed to ziprasidone 40 mg twice daily. Due to inadequate response to all of these agents, she was ultimately placed on clozapine for her refractory schizoaffective symptoms. At this time, she was kept on ziprasidone with anticipation of tapering off after titrating clozapine to an adequate dose. The clozapine was started at a dose of 12.5 mg twice daily, titrated up to 25 mg twice daily after six doses, then up to 50 mg twice daily after three doses. The patient’s medication list during hospitalization is located in Table 1.\nTable 1 Prescribed medications and corresponding doses Ms. P was taking at the time of hypothermia onset\n\nAspirin\n\n81 mg PO daily\n\n\tFerrous Sulfate\n\n650 mg PO TID\n\n\tClozapine\n\n50 mg PO BID\n\n\tMultivitamin\n\nPO daily\n\n\t\nAtorvastatin\n\n40 mg PO daily\n\n\tClonidine\n\n0.3 mg/24 h transdermal patch\n\n\tDivalproex Sodium ER\n\n1250 mg PO nightly\n\n\tDonepezil\n\n10 mg PO daily\n\n\t\nBrimonidine\n\n0.15% eye drops daily\n\n\tHeparin\n\n5000 units SQ TID\n\n\tDocusate\n\n200 mg PO daily\n\n\tTrazodone\n\n100 mg PO PRN HS\n\n\t\nAmlodipine\n\n10 mg PO daily\n\n\tHydralazine\n\n100 mg PO TID\n\n\tZiprasidone\n\n100 mg PO daily\n\n\tAcetaminophen\n\n650 mg PO PRN QID\n\n\t\nCarvedilol\n\n25 mg PO BID\n\n\tIsosorbide dinitrate\n\n60 mg PO BID\n\n\tLorazepam 1 mg PO TID\t\n\n\nOn day 50 of admission, Ms. P developed hypothermia, with a temperature of 90.8 °F (32.7 °C). By the next morning (day 7 of clozapine trial), she displayed hypoxemia (O2 saturation 88%), tachypnea, and worsening hypothermia (Fig. 1). While the patient had been intermittently bradycardic prior to this, her heart rate was lower during this event, ranging between 40 and 50 beats per minute. The patient displayed both hypotension as well as hypertension during this event, with blood pressure readings between 96 and 153 mmHg systolic and 39–75 mmHg diastolic. She appeared somnolent and confused at this time, and remarked that she was cold (and had cold extremities to touch); however, no shivering was noted on exam.\nFig. 1 Temperature (°F) log prior to and during hypothermic event\n\n\n\nDue to concerns for sepsis, Ms. P was transferred to the intensive care unit, where she became normothermic within approximately 10 h with the use of warming blankets, and the discontinuation of her clozapine, ziprasidone, and carvedilol. Laboratory values were remarkable for elevated procalcitonin (0.61 ng/mL), hypoxemia, and hypercapnia, while other values were within normal limits (Table 2). Broad-spectrum antibiotics were initiated, but were discontinued after 3 days as the patient had no leukocytosis, and blood cultures were negative. Her electrocardiogram was significant for bradycardia with vagally mediated pauses, and a prolonged QTc (505 milliseconds), but no Osborn J-waves were apparent. An echocardiogram conducted did not find any valvular vegetation, but noted a reduced ejection fraction of 49% (baseline 55%). A prior CT of the head within the previous 4 months displayed chronic lacunar infarcts within the left thalamus and right centrum semiovale, but no acute abnormalities or changes. A repeat CT scan was not performed during her hypothermic episode.\nTable 2 Laboratory test results performed at time of hypothermia onset\n\nSodium\n\n142 mMol/L\n\n\tSerum Creatinine\n\n1.5 mg/dL (H)\n\n\tBicarbonate\n\n30 mMol/L\n\n\tMagnesium\n\n2.3 mg/dL\n\n\tPotassium\n\n4.2 mMol/L\n\n\tChloride\n\n103 mMol/L\n\n\tAmylase\n\n50 units/L\n\n\t\nPhosphate\n\n3.7 mg/dL\n\n\tCalcium\n\n8.8 mg/dL\n\n\tBUN\n\n38 mg/dL (H)\n\n\tRBC\n\n2.83 × 106/cmm (L)\n\n\tHemoglobin\n\n8.3 g/dL (L)\n\n\tHematocrit\n\n25% (L)\n\n\tUrinalysis\n\nNEG\n\n\t\nWBC\n\n4.42 × 103/cmm\n\n\tMCV\n\n89 fL\n\n\tPlatelets\n\n94.2 × 103/cmm (L)\n\n\tAlbumin\n\n3.3 g/dL (L)\n\n\tTSH\n\n4.62 mInt-units/mL\n\n\tFree T4\n\n0.66 ng/dL\n\n\tBlood cultures\n\nNEG\n\n\t\nGlucose\n\n70 mg/dL\n\n\tProcalcitonin\n\n0.61 ng/mL (H)\n\n\tTroponin\n\n< 0.030 ng/mL\n\n\tAlk Phos\n\n96 units/L\n\n\tAST\n\n29 units/L\n\n\tALT\n\n43 units/L\n\n\tViral Panel\n\nNEG\n\n\t\n\n\nDiscussion\nOther considerations of secondary hypothermia included hypothyroidism, hypoglycemia, stroke, and sepsis. However, as indicated in Table 2, the patient’s thyroid stimulating hormone (TSH) and blood glucose drawn at the time of the hypothermic episode were within normal limits. As the patient did not present with leukocytosis and all blood cultures and viral panels returned negative, sepsis was ruled out as a likely cause of the hypothermia. Although altered mental status was noted, stroke was excluded, as neurologic exam was grossly normal. In addition, while we recognize antihypertensives as a potential cause, secondary to their ability to inhibit vasoconstriction and shivering, we do not believe these were the sole reason behind her hypothermia. Rather, these agents might have compounded the effects brought on by clozapine. Our rationale may be supported by the fact that the patient had not received two of her carvedilol doses before the hypothermic episode secondary to bradycardia, and because Ms. P had been on the majority of these antihypertensives (save isosorbide dinitrate) for a prolonged period prior to this hypothermia episode.\n\nAlternative drug-disease interactions must also be considered a risk factor for hypothermia in this patient. Clozapine (along with all other antipsychotics) possesses a black box warning for all-cause mortality in those with dementia. This risk appears to be consistent even for those specifically with vascular dementia [10]. It is evident based on the current data that those with dementia are more highly susceptible to the adverse effects (possibly including hypothermia) of antipsychotics. Acute heart failure exacerbations may also precipitate hypothermic events, secondary to inadequate oxygen delivery in the body, and may have been a causative factor in our patient [11]. However, the inverse of this might also be true, as hypothermia may induce or exacerbate heart failure [12]. The patient’s history of CKD should also be taken into account. While the manufacturer lists no specific dose adjustments for clozapine in those with renal dysfunction, only 0.55% is recovered within the urine unchanged, with 48.5% excreted as non-pharmacologically active metabolites [13]. Dose reductions of clozapine may be a necessity in those with renal dysfunction.\n\nMs. P was taking additional psychotropics aside from clozapine, all of which have case reports of hypothermia, or are thought to magnify the risk of hypothermia (Table 1). Although the literature appears varied, divalproex may significantly increase the levels of clozapine [14, 15]. While divalproex was the primary agent considered to have caused hypothermia in some of the available reports, it should be noted that data exists on hypothermic resolution after antipsychotic cessation in the presence of continued divalproex use [16]. As previously stated, our patient was kept on divalproex, with no further episodes of hypothermia during her stay, leading us to rule out divalproex as the sole cause of her hypothermia. Although cases of using ziprasidone safely in those with a history of hypothermia exist, other cases portray ziprasidone-induced hypothermia occurring even after 3 years on this medication [17]. Thus, we cannot fully rule out ziprasidone as a potential cause of hypothermia in our patient. Benzodiazepines, such as the lorazepam prescribed to our patient, are thought to inhibit the preoptic nucleus, preventing vasoconstriction and shivering [18]. Because nearly 80% of case reports denote hypothermia generally occurs after drug initiation or dose increases, we considered clozapine as the most likely cause in our patient [1, 7]. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale for determining the probability of an adverse drug reaction (scoring “yes” on questions 1, 2, 3, 5, and 10) [19].\n\nIt should be acknowledged that Ms. P has never had pharmacogenomic testing performed. Owing to the fact that clozapine is highly metabolized by cytochrome P450 (CYP) 1A2 and CYP2D6, we cannot discount that a genetic polymorphism placed this patient at increased risk for hypothermia secondary to higher than intended levels. As depicted in Table 1, the patient was not on any medications known to inhibit CYP1A2 or CYP2D6. A clozapine level was not performed at the time of hypothermia to determine if the level was supratherapeutic. Also of interest, pharmacokinetic and pharmacodynamic processes are altered in hypothermia. CYP450 metabolizing enzymes (including CYP3A4 and CYP2D6) are noted to be less active during hypothermia, leading to decreased clearance of the medications they metabolize [20]. Though unclear, it is possible the effects of a medication leading to hypothermia may be amplified in such an environment, if that particular medication is metabolized through a CYP450 pathway.\n\nLiterature review\nOnly a handful of case reports on clozapine-induced hypothermia exist, with varying onset and doses depicted. Papazisis et al. described a 71-year old male individual with hypothermia and accompanying Osborn J-waves after a year on 300 mg/day of clozapine [21]. This patient was switched to quetiapine with no further incidence of hypothermia [21]. Pelechas et al. described a 61-year old male taking clozapine, diazepam, and haloperidol who developed hypothermia after an unknown period [22]. A more recently published case series reported a 65-year old male who developed mild hypothermia after 5 days of clozapine use, on a total dose of 50 mg/day, which subsided after discontinuing clozapine and switching to olanzapine [4]. These authors also reported a 59-year old female with hypothermia lasting more than 6 days while on clozapine, risperidone, and olanzapine [4]. The authors appear to attribute this case primarily to risperidone, as this agent was recently titrated, and because hypothermia persisted even after discontinuing the olanzapine and clozapine [4]. In a case of intentional overdose on 3.5 g of clozapine (concentration 2183 ng/mL), the patient was noted to have a temperature of 91.6 °F (33.1 °C) upon admission [23].\n\nWe extracted data on clozapine and hypothermia from the FDA Adverse Event Reporting System (Table 3) [24]. Data from 1990 to 2019 demonstrated 109 separate cases of individuals experiencing hypothermia while taking clozapine. Clozapine was the primary suspect in 83 of these cases. The majority of cases were considered serious, and 21 patients died after exposure. Schizophrenia was by in large the most common indication for use of clozapine. Table 3 provides information on the onset of hypothermia after initiation of clozapine. While the single largest percentage of cases occurred within the first month (~ 27%), it is important to note that the majority of cases happened within 1 year of being on this medication, and even after 10 years on clozapine. However, it is unknown as to whether or not cases occurring later in therapy happened after any dose increases. Of those with clozapine-induced hypothermia, 60% were male. Middle to advanced age appeared more highly correlated with clozapine-induced hypothermia (63% for ages 40+, with 25.8% aged 60+), with the average age of 46 years. Haloperidol, antidepressants (any), valproic acid, olanzapine, and benzodiazepines (or any “z” drugs), were among the top co-prescribed medications for those with clozapine-induced hypothermia (9.2, 11, 11, 12, and 17.4% respectively). When co-administered with clozapine, event reporters considered valproic acid a suspect of hypothermia in 4 (15.4%) cases, benzodiazepines were considered suspects in 5 (19.2%) cases, while olanzapine was considered a suspect in 8 (30.7%) cases. Interestingly, the demographics and characteristics within Table 3 fit relatively closely with those depicted in a publication from Windfuhr et al., wherein the incidence of sudden unexplained death (SUD) from antipsychotics was examined [25]. In this paper, the authors found that older male patients were slightly more at risk of SUD (58% vs. 42% female), with other risk factors including clozapine, benzodiazepines, cardiovascular disease, and a diagnosis of dementia [25]. This correlation may point to hypothermia as a potential cause of SUD from antipsychotics.\nTable 3 Demographics & Characteristic Features of Clozapine-Induced Hyper- and Hypothermia\n\nDemographics & Characteristic Features\tClozapine-Induced Fever\tClozapine-Induced Hypothermia\t\nOnset\t< 1 month appears to be greatest risk, but may occur at any time or with dose increases [24–26]\t\nDose Related\tUnlikely, but risk possibly increased with overdose [23, 24]\t\nTitration Related\tPossibly (dose increases > 50 mg/week) [27, 28]\tUnknown\t\nConcomitant Medication(s) Which May Increase Risk\tValproic acid, additional antipsychotics [28, 29]\tValproic acid, benzodiazepines, additional antipsychotics [24]\t\nSex Category\tMale>female (~ 1.5:1) [24]\t\nAge (years)\tAverage age ~ 41\n\n(~ 70% are 40+, with ~ 5.4% being 60+) [24, 27]\n\n\tAverage age ~ 46\n\n(~ 63% are 40+, with ~ 25.8% being 60+) [24]\n\n\t\nSeen on Rechallenge\tPossibly, but uncommon [27, 28]\tUnknown\t\n\n\nIn a 2007 review, van Marum et al. found 524 cases of hyperthermia during antipsychotic use reported to the WHO international database for Adverse Drug Reactions [1]. This was surprisingly similar to the number of hypothermia cases reported (n = 480). The incidence of NMS from antipsychotics in recent studies ranges from 0.01–0.02%, while earlier studies reported incidences between 0.2–3.23% [29, 30]. This decline in incidence may represent an increased awareness by practitioners. NMS caused by antipsychotics has been postulated to be secondary to potent D2 antagonism, and thus considered more common with the first-generation antipsychotics; although this remains uncertain, as virtually every antipsychotic has had case reports depicting NMS [30]. Even in the absence of frank NMS, some antipsychotics have been noted to cause fever, with clozapine being the most notable. In reference to clozapine, fever is most commonly seen within the first 3 weeks of therapy, and has a very wide reported incidence (0.5–55%) [26, 30, 31]. While clozapine-induced fevers are generally noted to be transient (lasting between 2 and 4 days on average) and benign, they may necessitate discontinuation, or at the very least further investigation to rule out alternative pathophysiology [26, 27, 32]. In the instance where clozapine is restarted after discontinuation, case reports determine it is well-tolerated with no further episodes of fever; however, Chung et al. found 1 out of 7 patients (14.3%) had fever on rechallenge [28, 33]. It is unclear if fever from clozapine is related to dose or the rate of titration, though it has been noted to occur with titration rates of > 50 mg/week, and when given concomitantly with valproic acid [28, 31]. Studies have demonstrated that the pro-inflammatory cytokine interleukin-6 may have a specific role in mediating clozapine-induced fevers [31].\n\nLess well known, the pathophysiology behind antipsychotic-induced hypothermia appears complex, and multiple mechanisms have been proposed. Clozapine possesses a unique pharmacologic profile that encompasses activity on numerous receptors, including antagonistic effects on D2, D3, alpha-1, 5-HT2A/C, and M3, and partial agonistic effects on 5-HT1A. N-desmethylclozapine (NDMC), unlike its parent compound, possesses D2 and D3 partial agonistic effects, as well as M3 agonism [34, 35]. Table 4 summarizes literature on mice (or rat) studies conducted with various unique compounds possessing similar or opposite effects as clozapine on these receptors. Intrinsic efficacy of clozapine on D1 receptors appears to show it may be an agonist, rather than antagonist, at this receptor [54]. If this were true, it would suggest D1 agonism as a cause of hypothermia. Mitigation of clozapine-induced hypothermia by the D1 antagonist SCH-23390 supports this hypothesis [37]. Antagonistic effects on D2 do not support clozapine-induced hypothermia, but may be supported by the agonistic effects of NDMC on this receptor, as the D2 agonist bromocriptine has been shown to produce hypothermia in mice [34, 38, 39]. Similarly, hypothermic effects by norclozapine have been mimicked by the D2/3 agonist (+)-7-OH-DPAT, and blocked by the D3-selectve antagonist (+/−)-S 11566 in rats [40]. However, studies in D3 knockout mice have indicated that this effect may not be secondary to D3 agonism [41]. 5-HT2A/C antagonism corroborates potential hypothermic effects from clozapine, as agonists of this receptor (MK-212 and DOI) have been shown to reverse the hypothermic effects of chlorpromazine and haloperidol (antagonists of this receptor) [47]. Conversely, because clozapine is thought to possess 5-HT7 inverse agonist properties, the hypothermic effects seen with the selective 5HT7 receptor agonist LP-44 may disprove any implication of this receptor [50]. Minimal data exists on the effects of M3-selective agonists on temperature dysregulation, but if one were to consider the hyperthermic effects of M3 antagonists such as hyoscine, then it may stand to reason that the opposite effects potentially induce hypothermia [52]. Inhibition of compensatory responses to hypothermic reactions, such as shivering and vasoconstriction, through the peripheral alpha-1 antagonistic properties of clozapine should also be considered as an exacerbating, or possibly primary, factor [43]. Lastly, it has been shown that all antipsychotics increase neurotensin levels within the rodent brain [55, 56]. Central agonistic effects of neurotensin induce hypothermia, while peripheral effects may induce hypotension [55, 56]. Given that clozapine and NDMC bind to a multitude of receptors, it is possible that no single mechanism is responsible, but rather may be caused by an interplay of activity tilting the balance in favor of hypothermia. However, because other antipsychotics not possessing the same receptor profile as clozapine or NDMC have been noted to cause hypothermia, a reasonable assumption would be the commonality of 5HT2A antagonism or neurotensin-1 augmentation amongst these agents as the primary pathophysiology.\nTable 4 Receptor/Ligand Data Supporting or Refuting Propensity of Clozapine & NDMC to Induce Hypothermia\n\nReceptor\tAuthor, year\tConclusions\t\nD1\tOgren SO, 1988 [36]\n\nSalmi P, 1994 [37]\n\n\tThe D1/2 receptor agonist apomorphine and the D2 agonist pergolide induced hypothermia in rats, which was prevented by the use of sulpiride, a D2 antagonist.\t\nHypothermia produced by clozapine was fully antagonized by the selective D1 receptor antagonist SCH-23390.\t\nD2\tZarrindast MR, 1989 [38]\n\nBoulay D, 1999 [39]\n\n\tBromocriptine, a D2 agonist, caused dose-dependent decreases in the core body temperature of mice. This effect was mitigated by pretreatment with sulpiride\t\nThe preferential D2/3 receptor agonists 7-OH-DPAT and PD 128907 induced hypothermia in D2 (+/+) mice, but not in D2 knockout mice.\t\nD3\tMillan MJ, 1995 [40]\n\nPerachon S, 2000 [41]\n\nVarty GB, 1998 [42]\n\n\tSimilar to (+)-7-OH-DPAT, clozapine dose-dependently elicited hypothermia in rats. The D3-selective antagonist (+/−)-S 11566 blocked clozapine-induced hypothermia.\t\n(+)-7-OH-DPAT was effective in inducing hypothermia in both D3 (+/+) and D3 knockout mice, suggesting the D3 receptor is not responsible for hypothermia.\t\nRaclopride (D2/3 antagonist) blocked (+)-7-OH-DPAT induced hypothermia.\t\nAlpha-1\tBoschi G, 1987 [43]\tPhenothiazines, butyrophenones, and benzamides (alpha-1 antagonists) injected intraperitoneally demonstrated induced-hypothermia, whereas intracerebovascular administration did not. The administration of phenylephrine (alpha-1 agonist) attenuated hypothermia.\t\n5HT1A\tGudelsky GA, 1986 [44]\n\nAbdel-Fattah AF, 1995 [45]\n\nNeves G, 2008 [46]\n\n\tThe 5HT1A agonist 8-OH-DPAT induced dose-related decreased in temperature in rats.\t\nPindolol, a 5HT1A antagonist, suppressed tryptophan (serotonin precursor) induced hypothermia in pargyline-treated mice.\t\nThe hypothermia produced by the N-phenylpiperazine derivatives LASSBio-579 and LASSBio-581 was diminished by the 5-HT1A antagonist WAY 100635.\t\n5HT2A/C\tYamada J, 1995 [47]\n\nMurphy TJ, 2019 [48]\n\nGudelsky GA, 1986 [44]\n\n\tThe centrally acting 5HT2A/C agonist I-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) strongly inhibited haloperidol and chlorpromazine-induced hypothermia.\t\nThe selective 5HT2C agonist WAY-163909 inhibited ketamine-induced hypothermia, whereas DOI did not.\t\nMK-212 (5HT2 agonist) induced hyperthermia, while mianserin (5HT2 antagonist) blocked hyperthermia caused by MK-212 in rats.\t\n5HT7\tHedlund PB, 2010 [49]\n\nNaumenko VS, 2011 [50]\n\n\tLP-211 (5HT7 selective agonist) induced hypothermia in 5HT7 (+/+) mice, but not 5HT7 receptor knockout mice.\t\nThe selective 5HT7 receptor antagonist SB 269970 inhibited centrally administered LP-44 (5HT7 agonist) induced hypothermia. Intraperitoneal administration of LP-44 did not induce hypothermia.\t\nM3\tBlack CE, 2001 [51]\n\nGolding JF, 2018 [52]\n\n\tM3 antagonism via hyoscine hydrobromide may induce hyperthermia through decreased skin conductance and vasoconstriction, reducing heat loss and sweating.\t\nNeurotensin-1 receptor (NTS-1)\tFeifel D, 2010 [53]\tPD149163, a selective, brain-penetrating, NT1 receptor agonist produced hypothermia in rats.\t\n\n\nConclusions\nClinicians should be cognizant of the risk of hypothermia from clozapine, which can be severe or even fatal. Frequent temperature monitoring should be performed during initiation and titration of an antipsychotic, especially in those with comorbid CKD or dementia, or concomitantly taking benzodiazepines, valproic acid, or additional antipsychotics. This effect requires additional investigation, as multiple pharmacologic mechanisms are proposed.\n\nAbbreviations\nCKDChronic kidney disease\n\nFDAFood and Drug Administration\n\nWHOWorld Health Organization\n\nCYP450Cytochrome P450\n\nNMSNeuroleptic malignant syndrome\n\nNDMCN-desmethylclozapine\n\nTSHThyroid stimulating hormone\n\nSUDSudden unexpected death\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe express gratitude to the presented patient and their family.\n\nAuthors’ contributions\nBB and AW were all involved in the medication therapy management and assessment of the patient. BB wrote the first draft of the manuscript. BB, AW, and BC contributed in the preparation of the manuscript and have approved the final version of the manuscript.\n\nFunding\nThere was no source of funding.\n\nAvailability of data and materials\nData sharing is not applicable to this article, as this is a single-patient case report. No datasets besides those reported in the article were generated during the current study.\n\nEthics approval and consent to participate\nOur institutional review board granted consent for publication of encrypted information in this case.\n\nConsent for publication\nWritten informed consent for publication of this case report was obtained from the deceased patient’s family. A copy of the signed written consent to publish is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. van Marum RJ Wegewijs MA Loonen AJ Hypothermia following antipsychotic drug use Eur J Clin Pharmacol 2007 63 6 627 631 17401555 \n2. Dundee JW Mesham PR Scott WE Chlorpromazine and the production of hypothermia Anaesthesia. 1954 9 4 296 302 13207699 \n3. Clark WG Lipton JM Changes in body temperature after administration of amino acids, peptides, dopamine, neuroleptics and related agents: II Neurosci Biobehav Rev 1985 9 2 299 371 2861591 \n4. Zonnenberg C Bueno-de-Mesquita JM Ramlal D Hypothermia due to antipsychotic medication: a systematic review Front Psychiatry 2017 8 165 28936184 \n5. 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A registry-based observational cohort study J Am Med Dir Assoc 2019 20 3 323 329 30824220 \n11. Omar HR Guglin M Hypothermia is an independent predictor of short and intermediate term mortality in acute systolic heart failure: insights from the ESCAPE trial Int J Cardiol 2016 220 729 733 27393856 \n12. Danzl DF Pozos RS Accidental hypothermia N Engl J Med 1994 331 26 1756 1760 7984198 \n13. Sheehan JJ Sliwa JK Amatniek JC Atypical antipsychotic metabolism and excretion Curr Drug Metab 2010 11 6 516 525 20540690 \n14. Hommers L Scharl M Hefner G Comedication of Valproic acid is associated with increased metabolism of clozapine J Clin Psychopharmacol 2018 38 3 188 192 29620699 \n15. Rajkumar AP Poonkuzhali B Kuruvilla A Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia Int Clin Psychopharmacol 2013 28 1 50 56 23104241 \n16. 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Electrocardiographic manifestations in three psychiatric patients with hypothermia - case report. Hell J Cardiol. 2016;8:267–70.\n23. Thomas L Pollak PT Delayed recovery associated with persistent serum concentrations after clozapine overdose J Emerg Med 2003 25 1 61 66 12865111 \n24. FDA Adverse Event Reporting System (FAERS) Public Dashboard. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers. Accessed 11/10/19.\n25. Windfuhr K Turnbull P While D The incidence and associated risk factors for sudden unexplained death in psychiatric in-patients in England and Wales J Psychopharmacol 2011 25 11 1533 1542 20952453 \n26. Novartis Pharmaceuticals. Clozaril (clozapine) package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019758s062lbl.pdf. Accessed 12/2/19.\n27. Lowe CM Grube RR Scates AC Characterization and clinical management of clozapine-induced fever Ann Pharmacother 2007 41 10 1700 1704 17785616 \n28. Pui-yin Chung J Shiu-yin Chong C Chung KF The incidence and characteristics of clozapine- induced fever in a local psychiatric unit in Hong Kong Can J Psychiatr 2008 53 12 857 862 \n29. Berman BD Neuroleptic malignant syndrome: a review for neurohospitalists Neurohospitalist. 2011 1 1 41 47 23983836 \n30. Ware MR, Feller DB, Hall KL. Neuroleptic malignant syndrome: diagnosis and management. Prim Care Companion CNS Disord. 2018;20(1).\n31. Hung YP Wang CS Yen CN Role of cytokine changes in clozapine-induced fever: a cohort prospective study Psychiatry Clin Neurosci 2017 71 6 395 402 28106314 \n32. Kohen I Afzal N Hussain S Manu P Increases in C-reactive protein may predict recurrence of clozapine-induced fever Ann Pharmacother 2009 43 1 143 146 19126823 \n33. Bruno V Valiente-Gómez A Alcoverro O Clozapine and fever: a case of continued therapy with clozapine Clin Neuropharmacol 2015 38 4 151 153 26166236 \n34. Burstein ES Ma J Wong S Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist J Pharmacol Exp Ther 2005 315 3 1278 1287 16135699 \n35. Weiner DM Meltzer HY Veinbergs I The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine Psychopharmacology 2004 177 1–2 207 216 15258717 \n36. Ogren SO Fuxe K Apomorphine & pergolide induce hypothermia by stimulation of dopamine D-2 receptors Acta Physiol Scand 1988 133 1 91 95 3067517 \n37. Salmi P Karlsson T Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat Eur J Pharmacol 1994 253 1–2 67 73 7912199 \n38. Zarrindast MR Bromocriptine-induced hypothermia: D-2 receptor involvement Arch Int Pharmacodyn Ther 1989 298 38 49 2569299 \n39. 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Evidence for opposing roles of 5-HT2 and 5-HT1A receptors Neuropharmacology. 1986 25 12 1307 1313 2951611 \n45. Abdel-Fattah AF Matsumoto K El-Hady KA 5-HT1A and 5-HT2 receptors mediate hypo- and hyperthermic effects of tryptophan in pargyline-pretreated rats Pharmacol Biochem Behav 1995 52 2 379 384 8577805 \n46. Neves G Kliemann M Betti AH Serotonergic neurotransmission mediates hypothermia induced by the N-phenylpiperazine antipsychotic prototypes LASSBio-579 and LASSBio-581 Pharmacol Biochem Behav 2008 89 1 23 30 18082872 \n47. Yamada J Sugimoto Y Horisaka K Serotonin2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice Biol Pharm Bull 1995 18 11 1580 1583 8593484 \n48. Murphy TJ Murnane KS The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice Eur J Pharmacol 2019 842 255 261 30412729 \n49. Hedlund PB Leopoldo M Caccia S LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor Neurosci Lett 2010 481 1 12 16 20600619 \n50. Naumenko VS Kondaurova EM Popova NK On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor Neuropharmacology. 2011 61 8 1360 1365 21884711 \n51. Black CE Huang N Neligan PC Effect of nicotine on vasoconstrictor and vasodilator responses in human skin vasculature Am J Physiol Regul Integr Comp Physiol 2001 281 4 R1097 R1104 11557615 \n52. Golding JF Wesnes KA Leaker BR The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function Br J Clin Pharmacol 2018 84 7 1535 1543 29522648 \n53. Feifel D Goldenberg J Melendez G The acute and subchronic effects of a brain-penetrating, neurotensin1 receptor agonist on feeding, body weight and temperature Neuropharmacology. 2010 58 1 195 198 19596358 \n54. Ahlenius S Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs Pharmacol Toxicol 1999 84 5 193 196 10361974 \n55. Vadnie CA Ayers-Ringler J Oliveros A Antipsychotic-like effects of a neurotensin receptor type 1 agonist Behav Brain Res 2016 305 8 17 26909848 \n56. Prange AJ Jr Nemeroff CB The manifold actions of neurotensin: a first synthesis Ann N Y Acad Sci 1982 400 368 375 6132578\n\n",
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"title": "A case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations.",
"title_normalized": "a case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine induced temperature dysregulations"
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"abstract": "A young woman on chronic corticosteroid treatment for systemic lupus erythematosus developed a myasthenia-like syndrome 7 weeks after starting chloroquine therapy. Discontinuation of chloroquine allowed symptomatic and immunological remission within 6 months. Ocular symptoms reappeared following a second short course of chloroquine. A motor-point biopsy revealed a vacuolar myopathy with membranous bodies in intramuscular nerves. We discuss the possible role of chloroquine in the pathogenesis of a myasthenia-like syndrome.",
"affiliations": "Department of Neurology, Istituto Neurologico C. Besta, Milan, Italy.",
"authors": "Sghirlanzoni|A|A|;Mantegazza|R|R|;Mora|M|M|;Pareyson|D|D|;Cornelio|F|F|",
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"title": "Chloroquine myopathy and myasthenia-like syndrome.",
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nAutoenucleation has long been described in the literature, dating back as far as the 4th century AD. Within a 3-month period, two patients were admitted to our hospital after autoenucleation. A comprehensive review of the literature was performed to identify trends in, risk factors for, and potential life-threatening complications of autoenucleation.\n\n\nRESULTS\nTwo adult Caucasian men were transferred from outside hospitals after autoenucleation. One patient's urine tested positive for methamphetamines, and the second patient had a history of schizophrenia. In both cases, imaging of the head and orbits was performed to rule out secondary sequelae after self-enucleation. Patient one did not have any intracranial abnormalities. Patient 2 had a head computed tomography scan that showed a left internal carotid artery dissection, subarachnoid hemorrhage, and basal ganglia/thalamic stroke. Review of the literature revealed that almost all cases were associated with underlying mental illness and/or a history of drug abuse.\n\n\nCONCLUSIONS\nAutoenucleation occurs more frequently in patients with psychiatric illness or drug abuse. It can be a devastating injury, not only locally, but neurologically. Ophthalmologists should be aware of the potentially life-threatening consequences of autoenucleation.",
"affiliations": "aDepartment of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma bDepartment of Ophthalmology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts cDepartment of Ophthalmology and Visual Sciences dDepartment of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.",
"authors": "Gauger|Elizabeth H|EH|;Sobel|Rachel K|RK|;Allen|Richard C|RC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICU.0000000000000184",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-8738",
"issue": "26(5)",
"journal": "Current opinion in ophthalmology",
"keywords": null,
"medline_ta": "Curr Opin Ophthalmol",
"mesh_terms": "D000328:Adult; D015353:Eye Enucleation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012307:Risk Factors; D019966:Substance-Related Disorders; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9011108",
"other_id": null,
"pages": "429-38",
"pmc": null,
"pmid": "26163777",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complications and outcomes after autoenucleation.",
"title_normalized": "complications and outcomes after autoenucleation"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-15-00166",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"dru... |
{
"abstract": "BACKGROUND\nPregnancy is an important issue for many women with systemic lupus erythematosus (SLE). This study examined maternal and fetal outcomes among SLE women with or without a history of lupus nephritis (LN).\n\n\nMETHODS\nWe retrospectively analyzed 98 pregnancies in 57 women previously diagnosed with SLE who gave birth at our hospital.\n\n\nRESULTS\nThere were 44 pregnancies in women with a history of LN and 54 pregnancies in those without. Fetal loss was observed in 16.1% of SLE pregnancies when excluding induced abortion, and preeclampsia and SLE flare were observed in 12.2 and 6.1% of SLE pregnancies, respectively. No significant differences were evident between women with or without LN in rate of fetal loss, preeclampsia or SLE flare. Women with a history of LN exhibited a significantly shorter duration of gestation (37.0 weeks vs. 38.4 weeks, P = 0.006) and lower birth weight (2484 g vs. 2746 g, P = 0.007) than those without LN. Multivariate analysis revealed glucocorticoid dose but not history of LN, as an independent risk factor for preterm delivery and low birth weight.\n\n\nCONCLUSIONS\nThis study was unable to conclude that a history of LN predicted pregnancy outcomes among SLE women. Instead, a higher dose of glucocorticoid at conception was unexpectedly associated with preterm delivery and low birth weight. Further studies are awaited to verify the relationship.",
"affiliations": "Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan. hikeuchi@gunma-u.ac.jp.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.;Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, Japan.;Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, Japan.;Department of Nephrology, Rheumatology, Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.",
"authors": "Oishi|Yuko|Y|;Ikeuchi|Hidekazu|H|https://orcid.org/0000-0002-0768-7090;Hamatani|Hiroko|H|https://orcid.org/0000-0001-7727-6986;Nakasatomi|Masao|M|;Sakairi|Toru|T|https://orcid.org/0000-0003-2804-485X;Kaneko|Yoriaki|Y|;Maeshima|Akito|A|;Iwase|Akira|A|;Hiromura|Keiju|K|https://orcid.org/0000-0002-9490-8364",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-020-02017-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "25(8)",
"journal": "Clinical and experimental nephrology",
"keywords": "Lupus nephritis; Pregnancy; Preterm birth; Systemic lupus erythematosus",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": null,
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "835-843",
"pmc": null,
"pmid": "34165663",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "22439065;14528505",
"title": "Pregnancy outcomes in patients with systemic lupus erythematosus with or without a history of lupus nephritis.",
"title_normalized": "pregnancy outcomes in patients with systemic lupus erythematosus with or without a history of lupus nephritis"
} | [
{
"companynumb": "JP-ASTELLAS-2022JP008296",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIneffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide.\n\n\nMETHODS\nForty-three patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low probability of benefit from such therapy. The response to treatment was assessed after 16 weeks.\n\n\nRESULTS\nNeutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8).\n\n\nCONCLUSIONS\nLenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.",
"affiliations": "Department of Interdisciplinary Oncology, University of South Florida and the H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA. listaf@moffitt.usf.edu",
"authors": "List|Alan|A|;Kurtin|Sandy|S|;Roe|Denise J|DJ|;Buresh|Andrew|A|;Mahadevan|Daruka|D|;Fuchs|Deborah|D|;Rimsza|Lisa|L|;Heaton|Ruth|R|;Knight|Robert|R|;Zeldis|Jerome B|JB|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa041668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "352(6)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory; D020533:Angiogenesis Inhibitors; D001853:Bone Marrow; D005260:Female; D017353:Gene Deletion; D006410:Hematopoiesis; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D009503:Neutropenia; D013792:Thalidomide; D013921:Thrombocytopenia",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "549-57",
"pmc": null,
"pmid": "15703420",
"pubdate": "2005-02-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Efficacy of lenalidomide in myelodysplastic syndromes.",
"title_normalized": "efficacy of lenalidomide in myelodysplastic syndromes"
} | [
{
"companynumb": "US-AMGEN-USASP2020089509",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Linear IgA disease is an autoimmune subepidermal bullous disease in which linear IgA deposits are found at the basement membrane zone. It is classically idiopathic but may be drug induced. We report on a patient with drug induced linear IgA disease who exhibited certain unusual and interesting clinical features including isomorphic Koebner response, annular blister of the nipples and local insulin sensitivity. To the best of our knowledge, these clinical features have not yet been reported in linear IgA disease.",
"affiliations": "Department of Dermatology, Combined Military Hospital, Lahore, Pakistan.",
"authors": "Rashid Dar|Nasser|N|;Raza|Naeem|N|",
"chemical_list": "D000890:Anti-Infective Agents; D007070:Immunoglobulin A; D018727:Muscarinic Antagonists; D008795:Metronidazole; D002086:Butylscopolammonium Bromide",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "16(4)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D001327:Autoimmune Diseases; D002086:Butylscopolammonium Bromide; D003875:Drug Eruptions; D006801:Humans; D007070:Immunoglobulin A; D007333:Insulin Resistance; D008297:Male; D008795:Metronidazole; D018727:Muscarinic Antagonists; D009558:Nipples; D012872:Skin Diseases, Vesiculobullous",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "215-7",
"pmc": null,
"pmid": "19111146",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug induced linear IgA disease with unusual features: Koebner phenomenon, local insulin sensitivity and annular blister of the nipples.",
"title_normalized": "drug induced linear iga disease with unusual features koebner phenomenon local insulin sensitivity and annular blister of the nipples"
} | [
{
"companynumb": "PK-PFIZER INC-2015380883",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatitis B virus (HBV) reactivation has been reported in B-cell lymphoma patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative and hepatitis B core antibody [HBcAb]-positive). This study aimed to assess HBV reactivation and hepatitis occurrence in diffuse large B-cell lymphoma (DLBCL) patients with resolved hepatitis B receiving rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients to identify risk factors for HBV reactivation and hepatitis occurrence and to analyze whether HBV reactivation and hepatitis affect the survival of DLBCL patients with resolved hepatitis B.\n\n\nMETHODS\nWe reviewed the clinical data of 278 patients with DLBCL treated with rituximab-containing therapy between January 2004 and May 2008 at Sun Yat-sen University Cancer Center, China. Predictive factors for HBV reactivation, hepatitis development, and survival were examined by univariate analysis using the chi-square or Fisher's exact test and by multivariate analysis using the Cox regression model.\n\n\nRESULTS\nAmong the 278 patients, 165 were HBsAg-negative. Among these 165 patients, 6 (10.9%) of 55 HBcAb-positive (resolved HBV infection) patients experienced HBV reactivation compared with none (0%) of 110 HBcAb-negative patients (P = 0.001). Patients with resolved hepatitis B had a higher hepatitis occurrence rate than HBsAg-negative/HBcAb-negative patients (21.8% vs. 8.2%, P = 0.013). HBcAb positivity and elevated baseline alanine aminotransferase (ALT) levels were independent risk factors for hepatitis. Among the 55 patients with resolved hepatitis B, patients with elevated baseline serum ALT or aspartate aminotransferase (AST) levels were more likely to develop hepatitis than those with normal serum ALT or AST levels (P = 0.037, P = 0.005, respectively). An elevated baseline AST level was an independent risk factor for hepatitis in these patients. Six patients with HBV reactivation recovered after immediate antiviral therapy, and chemotherapy was continued. HBcAb positivity, HBV reactivation, or hepatitis did not negatively affect the survival of DLBCL patients.\n\n\nCONCLUSIONS\nDLBCL patients with resolved hepatitis B may have a higher risk of developing HBV reactivation and hepatitis than HBsAg-negative/HBcAb-negative patients. Close monitoring and prompt antiviral therapy are required in these patients.",
"affiliations": "Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. chenkl@sysucc.org.cn.;Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Radiotherapy Department, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, Guangdong, P. R. China. huanghui765@hotmail.com.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. raohl@sysucc.org.cn.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. guoying@sysucc.org.cn.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. huanghq@sysucc.org.cn.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA. liazhang@mdanderson.org.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. shaojy@sysucc.org.cn.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. linty@sysucc.org.cn.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. jiangwq@sysucc.org.cn.;Lymphoma and Myeloma Center, Institute of Hematology and Blood Diseases Hospital, Tianjin, P. R. China. zoudehui72@163.com.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. huliyang90@126.com.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. m1_031495@yahoo.com.;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. caiqq@sysucc.org.cn.",
"authors": "Chen|Kai-Lin|KL|;Chen|Jie|J|;Rao|Hui-Lan|HL|;Guo|Ying|Y|;Huang|Hui-Qiang|HQ|;Zhang|Liang|L|;Shao|Jian-Yong|JY|;Lin|Tong-Yu|TY|;Jiang|Wen-Qi|WQ|;Zou|De-Hui|DH|;Hu|Li-Yang|LY|;Wirian|Michael Lucas|ML|;Cai|Qing-Qing|QQ|",
"chemical_list": "D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1186/s40880-015-0015-9",
"fulltext": "\n==== Front\nChin J CancerChin J CancerChinese Journal of Cancer1000-467X1944-446XBioMed Central London 1510.1186/s40880-015-0015-9Original ArticleHepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival Chen Kai-Lin chenkl@sysucc.org.cn Chen Jie huanghui765@hotmail.com Rao Hui-Lan raohl@sysucc.org.cn Guo Ying guoying@sysucc.org.cn Huang Hui-Qiang huanghq@sysucc.org.cn Zhang Liang liazhang@mdanderson.org Shao Jian-Yong shaojy@sysucc.org.cn Lin Tong-Yu linty@sysucc.org.cn Jiang Wen-Qi jiangwq@sysucc.org.cn Zou De-Hui zoudehui72@163.com Hu Li-Yang huliyang90@126.com Wirian Michael Lucas m1_031495@yahoo.com Cai Qing-Qing caiqq@sysucc.org.cn Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060 Guangdong P. R. China Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Radiotherapy Department, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120 Guangdong P. R. China Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060 Guangdong P. R. China Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060 Guangdong P. R. China Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, 510060 Guangdong P. R. China Lymphoma and Myeloma Center, Institute of Hematology and Blood Diseases Hospital, Tianjin, P. R. China State Key Lab of Experimental Method of Hematology, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin, 300020 P. R. China 28 5 2015 28 5 2015 2015 34 1817 9 2014 22 1 2015 © Chen et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nHepatitis B virus (HBV) reactivation has been reported in B-cell lymphoma patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative and hepatitis B core antibody [HBcAb]-positive). This study aimed to assess HBV reactivation and hepatitis occurrence in diffuse large B-cell lymphoma (DLBCL) patients with resolved hepatitis B receiving rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients to identify risk factors for HBV reactivation and hepatitis occurrence and to analyze whether HBV reactivation and hepatitis affect the survival of DLBCL patients with resolved hepatitis B.\n\nMethods\nWe reviewed the clinical data of 278 patients with DLBCL treated with rituximab-containing therapy between January 2004 and May 2008 at Sun Yat-sen University Cancer Center, China. Predictive factors for HBV reactivation, hepatitis development, and survival were examined by univariate analysis using the chi-square or Fisher’s exact test and by multivariate analysis using the Cox regression model.\n\nResults\nAmong the 278 patients, 165 were HBsAg-negative. Among these 165 patients, 6 (10.9%) of 55 HBcAb-positive (resolved HBV infection) patients experienced HBV reactivation compared with none (0%) of 110 HBcAb-negative patients (P = 0.001). Patients with resolved hepatitis B had a higher hepatitis occurrence rate than HBsAg-negative/HBcAb-negative patients (21.8% vs. 8.2%, P = 0.013). HBcAb positivity and elevated baseline alanine aminotransferase (ALT) levels were independent risk factors for hepatitis. Among the 55 patients with resolved hepatitis B, patients with elevated baseline serum ALT or aspartate aminotransferase (AST) levels were more likely to develop hepatitis than those with normal serum ALT or AST levels (P = 0.037, P = 0.005, respectively). An elevated baseline AST level was an independent risk factor for hepatitis in these patients. Six patients with HBV reactivation recovered after immediate antiviral therapy, and chemotherapy was continued. HBcAb positivity, HBV reactivation, or hepatitis did not negatively affect the survival of DLBCL patients.\n\nConclusions\nDLBCL patients with resolved hepatitis B may have a higher risk of developing HBV reactivation and hepatitis than HBsAg-negative/HBcAb-negative patients. Close monitoring and prompt antiviral therapy are required in these patients.\n\nKeywords\nDiffuse large B-cell lymphomaHepatitisHepatitis B virus reactivationResolved hepatitis Bissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHepatitis B virus (HBV) infection is a serious global public health problem. It is common in China and other parts of Southeast Asia as well as in the Western Pacific regions [1]. HBV reactivation is a well-recognized complication in cancer patients with chronic HBV infection undergoing immunosuppressive or cytotoxic chemotherapy.\n\nRituximab is a chimeric mouse/human anti-CD20 monoclonal antibody. Rituximab in combination with cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine, and prednisone (R-CHOP) is the current standard chemotherapy regimen for diffuse large B-cell lymphoma (DLBCL) [2,3]. Recent evidence has shown that HBV reactivation is associated with the use of rituximab [4]. Without prophylaxis, hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab-containing therapy show a high incidence of HBV reactivation and HBV-related liver failure and death [5-7]. Antiviral prophylaxis is therefore currently recommended for these patients [8]. HBV reactivation can also be observed in lymphoma patients with resolved HBV infection (HBsAg-negative and hepatitis B core antibody [HBcAb]- and/or hepatitis B surface antigen antibody [HBsAb]-positive) during the course of rituximab-containing therapy and may prove to be fatal [4,7,9-13]. The data on the incidence of HBV reactivation and its risk factors as well as the effects of HBV reactivation and hepatitis on the survival of HBsAg-negative DLBCL patients after rituximab-containing therapy are limited in China.\n\nThis retrospective study therefore aimed to determine the occurrence rates of HBV reactivation and hepatitis in DLBCL patients with resolved hepatitis B compared with HBsAg-negative/HBcAb-negative patients, to identify risk factors for HBV reactivation and hepatitis in HBsAg-negative patients and patients with resolved hepatitis B, and to analyze whether HBV reactivation or hepatitis could affect the survival of patients with resolved hepatitis B after rituximab-containing therapy.\n\nMethods\nPatient selection\nBetween January 2004 and May 2008, patients diagnosed with CD20+ DLBCL who were treated with rituximab-containing chemotherapy at Sun Yat-sen University Cancer Center, China were screened for this study. Their HBsAg status was determined before they were administered anticancer therapy.\n\nPatients who were negative for HBsAg underwent HBV serology tests, including those for HBsAb, hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), and HBcAb. In addition, HBV serology, HBV DNA, and liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin [TB] levels) were tested before each chemotherapy cycle and at least every 3 months during the follow-up period. HBsAg or HBV DNA tests were performed if abnormal liver function was observed or if hepatitis was suspected. Patients enrolled in this study had no evidence of hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus, hepatitis E virus, or human immunodeficiency virus infection and had adequate available clinical information and follow-up data. The exclusion criteria were the coexistence of another type of lymphoma, associated chronic inflammation, and a previous malignancy or second primary tumor. Hepatitis serology was tested for all patients before they started chemotherapy. HBV DNA was tested using a polymerase chain reaction assay (ABI 7900; Applied Biosystems, Foster City, CA, USA). The lower detection limit for HBV DNA was 100 IU/mL.\n\nThis study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center. Informed consent for the collection of medical information was obtained from all patients at their first visit. All pathologic specimens were reviewed and reclassified according to the World Health Organization (WHO) criteria for pathological diagnosis [14].\n\nDefinitions\nHepatitis and HBV reactivation have been defined previously [15,16]. Hepatitis was defined as a 3-fold or greater increase in serum ALT levels that exceeds the upper limit of normal (ULN) or as an absolute increase in ALT levels to >100 U/L. The ULN of ALT in our hospital is 40 U/L. Hepatitis was attributed to HBV reactivation when there was evidence of HBsAg seroreversion (reappearance of HBsAg), with an increase in HBV DNA levels compared with baseline, in the absence of clinical or laboratory features of acute infection with HAV, HCV, or other systemic infections.\n\nThe international prognosis index (IPI) included five factors: age (≤60 years vs. >60 years), lactate dehydrogenase (LDH) value (≤245 U/mL vs. >245 U/mL), Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0–1 vs. >1), Ann Arbor stage (I/II vs. III/IV), and the number of extranodal involvements (0–1 vs. >1). IPI scores were separated based on the number of factors present [17].\n\nStatistical analysis\nOverall survival (OS) was measured from the date of diagnosis to the date of death from any cause or to the date of the last follow-up visit. Variables were examined for associations with hepatitis or HBV reactivation by univariate analysis using χ2 or Fisher’s exact test. Multivariate logistic regression analysis was performed to identify predictors of hepatitis or HBV reactivation. Survival curves were drawn by the Kaplan–Meier method and compared using the log-rank test. The prognostic importance of factors was analyzed using the Cox regression model [18]. Multivariate analysis was carried out using a forward stepwise procedure. Factors with a P value < 0.2 in the univariate analysis were incorporated into the multivariate analysis. Statistical significance was defined as P < 0.05 (two-tailed). Statistical analyses were performed with PASW version 18.0 software (IBM, Armonk, NY, USA).\n\nResults\nPatient characteristics\nBetween January 2004 and May 2008, 278 DLBCL patients were treated with rituximab-containing chemotherapy (Figure 1). Among them, 165 were negative for HBsAg. Of these 165 patients, 55 (33.3%) were positive for HBcAb, 80 (48.5%) were positive for HBsAb, and 150 (90.9%) were negative for HBeAb. All patients were negative for HBV DNA before rituximab-containing therapy. The HBsAg-negative patients were predominantly males, with a median age of 54 years (range, 8–83 years). Most of these patients had a favorable PS, no bulky mass, no evidence of B symptoms, no liver, spleen, or bone marrow involvement, and normal liver function. There were no significant differences in the baseline characteristics between HBcAb-positive and -negative patients, except for the positive rate of HBsAb (94.5% vs. 25.5%, P < 0.001). The median age was 56 years (range, 8 to 83 years) for HBcAb-negative patients and 58 years (range, 18 to 79 years) for HBcAb-positive patients (P = 0.798). The median number of rituximab-containing chemotherapy cycles was 4 (range, 1 to 8) for HBcAb-negative patients and 4 (range, 1 to 7) for HBcAb-positive patients (P = 0.343). The detailed clinical characteristics are listed in Table 1.Figure 1 Hepatitis B virus (HBV) status and hepatitis outcome in 278 hepatitis B surface antigen (HBsAg)-negative patients with CD20+ diffuse large B-cell lymphoma (DLBCL). HBeAb, hepatitis B e antibody; HBsAb, hepatitis B surface antibody.\n\nTable 1 \nBaseline clinical characteristics according to HBcAb status in HBsAg-negative DLBCL patients\n\n\n\nCharacteristic\n\t\nHBcAb-negative [cases (%)]\n\t\nHBcAb-positive [cases (%)]\n\t\nP\nvalue\n\t\nTotal\t110\t55\t\t\nSex\t\t\t0.434\t\n Male\t67 (60.9)\t30 (54.5)\t\n Female\t43 (39.1)\t25 (45.5)\t\nECOG PS\t\t\t0.525\t\n 0–1\t96 (87.3)\t46 (83.6)\t\n ≥2\t14 (12.7)\t9 (16.4)\t\nBulky mass\t\t\t0.619\t\n Yes\t28 (25.5)\t16 (29.1)\t\n No\t82 (74.5)\t39 (70.9)\t\nB symptoms\t\t\t0.448\t\n −\t80 (72.7)\t43 (78.2)\t\n +\t30 (27.3)\t12 (21.8)\t\nAnn Arbor stage†\n\t\t\t0.698\t\n I–II\t52 (47.3)\t28 (50.9)\t\n III-IV\t57 (51.8)\t27 (49.1)\t\nLiver involvement\t\t\t0.720\t\n −\t104 (94.5)\t53 (96.4)\t\n +\t6 (5.5)\t2 (3.6)\t\nIPI score†\n\t\t\t0.851\t\n 0–1\t48 (43.6)\t21 (38.2)\t\n 2\t28 (25.4)\t17 (30.9)\t\n 3\t23 (20.9)\t11 (20.0)\t\n 4-5\t10 (9.1)\t6 (10.9)\t\nALT\t\t\t0.874\t\n ≤40 U/L\t95 (86.4)\t47 (85.5)\t\n >40 U/L\t15 (13.6)\t8 (14.5)\t\nAST\t\t\t0.863\t\n ≤45 U/L\t97 (88.2)\t49 (89.1)\t\n >45 U/L\t13 (11.8)\t6 (10.9)\t\nTB\t\t\t0.852\t\n ≤20.5 μmol/L\t99 (90.0)\t50 (90.9)\t\n >20.5 μmol/L\t11 (10.0)\t5 (9.1)\t\nLDH\t\t\t0.910\t\n ≤245 U/mL\t67 (60.9)\t33 (60.0)\t\n >245 U/mL\t43 (39.1)\t22 (40.0)\t\nHBsAb\t\t\t<0.001\t\n –\t82 (74.5)\t3 (5.5)\t\n +\t28 (25.5)\t52 (94.5)\t\nHBeAb\t\t\t0.251\t\n –\t102 (92.7)\t48 (87.3)\t\n +\t8 (7.3)\t7 (12.7)\t\nHBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; LDH, lactate dehydrogenase; HBsAb, hepatitis B surface antibody; HBeAb, hepatitis B e antibody. †The information of Ann Arbor stage and IPI were available for 164 patients.\n\n\n\nHBV reactivation rate and its risk factors in DLBCL patients with resolved hepatitis B after rituximab-containing chemotherapy\nOverall, 6 patients developed HBV reactivation after rituximab-containing chemotherapy, and they all had resolved HBV infection. Among the 110 HBsAg-negative/HBcAb-negative patients, 9 developed hepatitis, but none were associated with HBV reactivation (Figure 1). Univariate analysis showed that HBsAg-negative/HBcAb-positive patients had a greater likelihood of developing HBV reactivation than HBsAg-negative/HBcAb-negative patients (10.9% vs. 0%, P = 0.001). There were no significant difference between patients with and without HBV reactivation in terms of age, sex, ECOG PS, Ann Arbor disease stage, bulky mass presence, B symptoms, IPI score, liver, spleen, extranodal site, or bone marrow involvement, and ALT, AST, TB, or LDH levels (all P > 0.05) (Table 2). Among the 55 patients with resolved hepatitis B, there were no significant differences between patients with and without HBV reactivation in terms of the above mentioned variables (all P > 0.05).Table 2 \nUnivariate analysis of potential risk factors for HBV reactivation in HBsAg-negative DLBCL patients\n\n\n\nFactor\n\t\nWithout HBV reactivation [cases (%)]\n\t\nWith HBV reactivation [cases (%)]\n\t\nP\nvalue\n\t\nTotal\t159\t6\t\t\nHBcAb\t\t\t0.001\t\n –\t110 (69.2)\t0 (0)\t\t\n +\t49 (30.8)\t6 (100.0)\t\t\nAge (years)\t\t\t0.237\t\n ≤60\t65 (40.9)\t4 (66.7)\t\t\n >60\t94 (59.1)\t2 (33.3)\t\t\nSex\t\t\t1.000\t\n Female\t66 (41.5)\t2 (33.3)\t\t\n Male\t93 (58.5)\t4 (66.7)\t\t\nECOG PS\t\t\t1.000\t\n 0–1\t137 (86.2)\t5 (83.3)\t\t\n ≥2\t22 (13.8)\t1 (16.7)\t\t\nBulky mass\t\t\t0.343\t\n Yes\t115 (72.3)\t6 (100.0)\t\t\n No\t44 (27.7)\t0 (0)\t\t\nB symptoms\t\t\t1.000\t\n –\t118 (74.2)\t5 (83.3)\t\t\n +\t41 (25.8)\t1 (16.7)\t\t\nAnn Arbor stage†\n\t\t\t0.211\t\n I–II\t79 (49.7)\t1 (16.7)\t\t\n III-IV\t79 (49.7)\t5 (83.3)\t\t\nLiver involvement\t\t\t1.000\t\n –\t151 (95.0)\t6 (100.0)\t\t\n +\t8 (5.0)\t0 (0)\t\t\nSpleen involvement\t\t\t0.441\t\n –\t145 (91.2)\t5 (83.3)\t\t\n +\t14 (8.8)\t1 (16.7)\t\t\nInvolved extranodal sites\t\t\t0.627\t\n <2\t122 (76.7)\t4 (66.7)\t\t\n ≥2\t37 (23.3)\t2 (33.3)\t\t\nBone marrow involvement\t\t\t1.000\t\n –\t148 (93.1)\t6 (100.0)\t\t\n +\t11 (6.9)\t0 (0)\t\t\nIPI score†\n\t\t\t0.402\t\n 0–1\t68 (42.8)\t1 (16.7)\t\t\n 2–5\t90 (56.6)\t5 (83.3)\t\t\nHBeAb\t\t\t0.094\t\n –\t146 (91.8)\t4 (66.7)\t\t\n +\t13 (8.2)\t2 (33.3)\t\t\nALT\t\t\t0.597\t\n ≤40 U/L\t136 (85.5)\t6 (100.0)\t\t\n >40 U/L\t23 (14.5)\t0 (0)\t\t\nAST\t\t\t0.526\t\n ≤45 U/L\t141 (88.7)\t5 (83.3)\t\t\n >45 U/L\t18 (11.3)\t1 (16.7)\t\t\nTB\t\t\t0.463\t\n ≤20.5 μmol/L\t144 (90.6)\t5 (83.3)\t\t\n >20.5 μmol/L\t15 (9.4)\t1 (16.7)\t\t\nLDH\t\t\t0.681\t\n ≤245 U/mL\t97 (61.0)\t3 (50.0)\t\t\n >245 U/mL\t62 (39.0)\t3 (50.0)\t\t\nHBV, hepatitis B virus. Other footnotes as in Table 1.\n\n\n\nHepatitis rate and its risk factors in DLBCL patients with resolved hepatitis B after rituximab-containing chemotherapy\nHepatitis was observed in 21 (12.7%) of the 165 HBsAg-negative CD20+ DLBCL patients, 6 of whom had HBV-related hepatitis. Other possible causes of hepatitis were chemotherapy (n = 7), tumor progression (n = 4), heart failure (n = 1), infection (n = 2), and septic shock (n = 1). For the 3 HBsAg-, HBcAb-, and HBsAb-negative patients, the possible causes of hepatitis were chemotherapy (n = 2) and tumor progression (n = 1). Univariate analysis identified a higher incidence of hepatitis in the HBcAb-positive group compared with the HBcAb-negative group (21.8% vs. 8.2%, P = 0.013). Moreover, patients with elevated serum ALT levels at baseline were more likely to develop hepatitis than those with normal serum ALT levels (30.4% vs. 9.9%, P = 0.013). The risk of hepatitis was also higher in patients with elevated serum AST levels at baseline than in those with normal serum AST levels (31.6% vs. 10.3%, P = 0.019). The univariate analysis results of potential prognostic factors associated with hepatitis are shown in Table 3. Multivariate logistic regression analysis revealed that HBcAb positivity and elevated serum ALT levels at baseline were independently associated with the development of hepatitis in HBsAg-negative DLBCL patients (both P < 0.05) (Table 4).Table 3 \nUnivariate analysis of potential prognostic factors associated with hepatitis in HBsAg-negative DLBCL patients\n\n\n\nFactor\n\t\nWithout hepatitis [cases (%)]\n\t\nWith hepatitis [cases (%)]\n\t\nP\nvalue\n\t\nTotal\t144\t21\t\t\nHBcAb\t\t\t0.013\t\n –\t101 (70.1)\t9 (42.9)\t\t\n +\t43 (29.9)\t12 (57.1)\t\t\nHBeAb\t\t\t1.000\t\n –\t131 (91.0)\t19 (90.5)\t\t\n +\t13 (9.0)\t2 (9.5)\t\t\nAge (years)\t\t\t0.399\t\n ≤60\t62 (43.1)\t7 (33.3)\t\t\n >60\t82 (56.9)\t14 (66.7)\t\t\nSex\t\t\t0.756\t\n Female\t60 (41.7)\t8 (38.1)\t\t\n Male\t84 (58.3)\t13 (61.9)\t\t\nECOG PS\t\t\t0.500\t\n 0–1\t125 (86.8)\t17 (81.0)\t\t\n ≥2\t19 (13.2)\t4 (19.0)\t\t\nB symptoms\t\t\t0.726\t\n −\t108 (75.0)\t15 (71.4)\t\t\n +\t36 (25.0)\t6 (28.6)\t\t\nAnn Arbor stage†\n\t\t\t0.129\t\n I–II\t73 (50.7)\t7 (33.3)\t\t\n III-IV\t70 (48.6)\t14 (66.7)\t\t\nLiver involvement\t\t\t0.598\t\n −\t136 (94.4)\t21 (100)\t\t\n +\t8 (5.6)\t0 (0)\t\t\nSpleen involvement\t\t\t1.000\t\n −\t131 (91.0)\t19 (90.5)\t\t\n +\t13 (9.0)\t2 (9.5)\t\t\nInvolved extranodal sites\t\t\t0.586\t\n <2\t111 (77.1)\t15 (71.4)\t\t\n ≥2\t33 (22.9)\t6 (28.6)\t\t\nBone marrow involvement\t\t\t1.000\t\n −\t134 (93.1)\t20 (95.2)\t\t\n +\t10 (6.9)\t1 (4.8)\t\t\nIPI score†\n\t\t\t0.180\t\n 0–1\t63 (43.8)\t6 (28.6)\t\t\n 2–5\t80 (55.8)\t15 (71.4)\t\t\nALT\t\t\t0.013\t\n ≤40 U/L\t128 (88.9)\t14 (66.7)\t\t\n >40 U/L\t16 (11.1)\t7 (33.3)\t\t\nAST\t\t\t0.019\t\n ≤45 U/L\t131 (91.0)\t15 (71.4)\t\t\n >45 U/L\t13 (9.0)\t6 (28.6)\t\t\nTB\t\t\t0.696\t\n ≤20.5 μmol/L\t129 (89.6)\t20 (95.2)\t\t\n >20.5 μmol/L\t15 (10.4)\t1 (4.8)\t\t\nLDH\t\t\t0.728\t\n ≤245 U/mL\t88 (61.1)\t12 (57.1)\t\t\n >245 U/mL\t56 (38.9)\t9 (42.9)\t\t\nFootnotes as in Table 1.\n\nTable 4 \nMultivariate analysis of potential risk factors associated with hepatitis in HBsAg-negative DLBCL patients\n\n\n\nVariate\n\t\nOR\n\t\n95% CI\n\t\nP\nvalue\n\t\nHBcAb (+)\t3.27\t1.25-8.59\t0.016\t\nALT (>40 U/L)\t4.22\t1.43-12.49\t0.009\t\nAST(>45 U/L)\tNA\tNA\t0.129\t\nOR, odds ratio; CI, confidence interval; NA, not applicable. Other abbreviations as in Table 1.\n\n\n\nFor the 55 patients with resolved hepatitis B, 22 (40%) had elevated serum ALT levels during the chemotherapy and follow-up period, and 12 (21.8%) experienced hepatitis. The possible causes of hepatitis were HBV-related disease (n = 6), chemotherapy (n = 1), tumor progression (n = 2), heart failure (n = 1), and infection (n = 2). Patients with elevated serum ALT or AST levels at baseline were more likely to develop hepatitis than those with normal serum ALT or AST levels (P = 0.037 and P = 0.005, respectively). The univariate analysis results of potential prognostic factors associated with hepatitis in patients with resolved hepatitis B are shown in Table 5. Multivariate logistic regression analysis revealed that elevated serum AST levels at baseline were independently associated with the development of hepatitis in DLBCL patients with resolved hepatitis B (odds ratio [OR] = 10.25, 95% confidence interval [CI] = 1.60–21.73, P = 0.014).Table 5 \nUnivariate analysis of potential prognostic factors associated with hepatitis in DLBCL patients with resolved hepatitis B\n\n\n\nFactor\n\t\nWithout hepatitis [cases (%)]\n\t\nWith hepatitis [cases (%)]\n\t\nP\nvalue\n\t\nTotal\t43\t12\t\t\nHBeAb\t\t\t0.639\t\n –\t38 (88.4)\t10 (83.3)\t\t\n +\t5 (11.6)\t2 (16.7)\t\t\nAge (years)\t\t\t0.831\t\n ≤60\t23 (53.5)\t6 (50.0)\t\t\n >60\t20 (46.5)\t6 (50.0)\t\t\nSex\t\t\t0.340\t\n Female\t21 (48.8)\t4 (33.3)\t\t\n Male\t22 (51.2)\t8(66.7)\t\t\nECOG PS\t\t\t0.974\t\n 0–1\t36 (83.7)\t10 (83.3)\t\t\n ≥2\t7 (16.3)\t2 (16.7)\t\t\nB symptoms\t\t\t0.763\t\n −\t34 (79.1)\t9 (75.0)\t\t\n +\t9 (20.9)\t3 (25.0)\t\t\nAnn Arbor stage\t\t\t0.168\t\n I–II\t24 (55.8)\t4 (33.3)\t\t\n III-IV\t19 (44.2)\t8 (66.7)\t\t\nLiver involvement\t\t\t0.447\t\n −\t41 (95.3)\t12 (100)\t\t\n +\t2 (4.7)\t0 (0)\t\t\nSpleen involvement\t\t\t0.873\t\n −\t40 (93.0)\t11 (91.7)\t\t\n +\t3 (7.0)\t1 (8.3)\t\t\nInvolved extranodal sites\t\t\t0.275\t\n <2\t35 (81.4)\t8 (66.7)\t\t\n ≥2\t8 (18.6)\t4 (33.3)\t\t\nBone marrow involvement\t\t\t0.594\t\n −\t42 (97.7)\t12 (100.0)\t\t\n +\t1 (2.3)\t0 (0.0)\t\t\nIPI score\t\t\t0.288\t\n 0–1\t18 (41.9)\t3 (25.0)\t\t\n 2–5\t25 (58.1)\t9 (75.0)\t\t\nALT\t\t\t0.037\t\n ≤40 U/L\t39 (90.7)\t8 (66.7)\t\t\n >40 U/L\t4 (9.3)\t4 (33.3)\t\t\nAST\t\t\t0.005\t\n ≤45 U/L\t41 (95.3)\t8 (66.7)\t\t\n >45 U/L\t2 (4.7)\t4 (33.3)\t\t\nTB\t\t\t0.918\t\n ≤20.5 μmol/L\t39 (90.7)\t11 (91.7)\t\t\n >20.5 μmol/L\t4 (9.3)\t1 (8.3)\t\t\nLDH\t\t\t0.894\t\n ≤245 U/mL\t26 (60.5)\t7 (58.3)\t\t\n >245 U/mL\t17 (39.5)\t5 (41.7)\t\t\nAbbreviations as in Table 1.\n\n\n\nDetails of 6 patients who developed HBV reactivation\nDetails of the patients who developed HBV reactivation are shown in Table 6. Most of these patients were males, were older (>60 years), and had bulky masses, advanced Ann Arbor stage, and HBsAb positivity at baseline. No patient showed detectable serum HBV DNA levels at baseline. Most of the patients had normal liver function at baseline, except for Patients 1 and 2. None of the patients received antiviral prophylaxis.Table 6 \nDetails and outcomes of 6 HBsAg-negative/HBcAb-positive DLBCL patients who developed HBV reactivation after rituximab-containing chemotherapy\n\n\n\nPatient no.\n\t\nAge (years)\n\t\nSex\n\t\nBaseline\n\t\nR-CHOP cycles\n\t\nInterval between last cycle and HBV reactivation (days)\n\t\nAt diagnosis of HBV reactivation\n\t\nOutcome\n\t\n\nIPI\n\t\nStage\n\t\nHBeAb\n\t\nALT (U/L)\n\t\nAST (U/L)\n\t\nTB (μmol/L)\n\t\nPeak HBV DNA (IU/mL)\n\t\nPeak ALT (U/L)\n\t\nPeak AST (U/L)\n\t\nPeak TB (μmol/L)\n\t\n1\t65\tMale\t4\t3\t+\t18.0\t68.2\t8.9\t5\t42\t1.72 × 107\n\t333.1\t285.8\t69.0\tAlive and well\t\n2\t21\tMale\t3\t3\t-\t22.0\t27.0\t36.6\t2\t24\t8.60 × 103\n\t107.6\t60.2\t47.1\tDied of lymphoma\t\n3\t69\tFemale\t2\t3\t-\t21.0\t25.0\t9.4\t6\t23\t1.80 × 105\n\t230.8\t120.1\t11.0\tAlive and well\t\n4\t70\tMale\t3\t3\t-\t10.0\t29.0\t11.1\t7\t98\t4.76 × 106\n\t239.0\t174.0\t8.1\tDied of lymphoma\t\n5\t26\tFemale\t2\t3\t+\t10.0\t15.0\t6.4\t2\t27\t9.28 × 106\n\t106.0\t89.0\t7.8\tAlive and well\t\n6\t68\tMale\t1\t1\t-\t25.0\t35.0\t7.0\t6\t29\t4.47 × 104\n\t219.2\t204.5\t11.3\tAlive and well\t\nR-CHOP, cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine, and prednisone regimen. Other abbreviations as in Tables 1 and 2.\n\n\n\nHBV reactivation was more likely to occur after an average of 5 R-CHOP cycles (range, 2–7 cycles) at a median interval of 27 days (range, 24–98 days). Antiviral drug administration was immediately started after HBV DNA detection. Three patients developed severe hepatitis. Hepatoprotective drugs were used when necessary, and HBV reactivation was managed with lamivudine (100 mg/day). Rituximab-containing chemotherapy was continued after serum HBV DNA became undetectable and liver function had improved.\n\nSurvival of DLBCL patients with resolved hepatitis B after rituximab-containing chemotherapy\nAmong patients with resolved hepatitis B, the median follow-up duration was 61 (1–93) months, the median 1-year OS rate was 85.2% (95% CI, 75.8%–100.0%), the 3-year OS rate was 79.5% (95% CI, 68.7%–90.2%), and the 5-year OS rate was 75.7% (95% CI, 64.1%–87.2%). Among these patients, no significant difference was observed in OS between patients with and without HBV reactivation (66.7% [95% CI, 29.0%–100%] vs. 73.2% [95% CI, 59.9%–86.5%], P = 0.682) (Figure 2A) or between patients with and without hepatitis (75.0% [95% CI, 50.5%–99.5%] vs. 71.4% [95% CI, 56.5%–86.3%], P = 0.927) (Figure 2B). OS was similar in patients with resolved hepatitis B and HBsAg-negative/HBcAb-negative patients (75.7% [95% CI, 64.1%–87.2%] vs. 68.5% [95% CI, 57.8%–76.2%], P = 0.274) (Figure 2C). Among HBsAg-negative patients, no significant difference was observed in OS between patients with and without HBV reactivation (66.7% vs. 70.2%, P = 0.908) or between patients with and without hepatitis (75.2% vs. 71.3%, P = 0.512).Figure 2 Overall survival (OS) curves for DLBCL patients. A, the trends of OS curves for patients with or without HBV reactivation during rituximab-containing chemotherapy were similar. B, the trends of OS curves for patients with or without hepatitis were similar. C, the trends of OS curves for patients with resolved hepatitis B and HBsAg-negative/HBcAb-negative patients were also similar. Abbreviations as in Figure 1.\n\n\n\nDiscussion\nThis study demonstrated that CD20+ DLBCL patients with resolved HBV infection had a significantly higher risk of HBV reactivation and hepatitis compared with HBsAg-negative/HBcAb-negative patients after rituximab-containing chemotherapy. Baseline HBcAb positivity and elevated baseline serum ALT levels were independent risk factors for hepatitis in HBsAg-negative patients. An elevated baseline AST level was an independent risk factor for hepatitis in patients with resolved hepatitis B. HBV reactivation could be managed with prompt antiviral therapy followed by the continuation of chemotherapy. HBcAb positivity, HBV reactivation, or hepatitis did not negatively affect patient survival.\n\nSeveral studies have consistently demonstrated that the incidence of HBV infection is higher in patients with B-cell lymphoma than in the general population [19-22]. Chronic HBV infection was considered to be associated with lymphomagenesis [23], especially for B-cell lymphoma [24]. In this study, 33.3% (55/165) of patients had resolved HBV infection, which was consistent with the 20%–40% incidence reported in endemic areas [25]. The incidence of HBV reactivation was 3.6% (6/165) in HBsAg-negative patients in this study, but was reported as high as 80% (12/15) in HBsAg-positive lymphoma patients receiving rituximab-containing chemotherapy without prophylaxis [5].\n\nCompared with HBsAg-negative/HBcAb-negative patients, HBsAg-negative/HBcAb-positive patients had a greater likelihood of developing HBV reactivation (10.9% vs. 0%, P = 0.001). However, Hui et al. [9] found no significant difference between the two groups in a study of non-Hodgkin’s lymphoma and Hodgkin lymphoma patients, of whom only 20.1% (49/244) received R-CHOP therapy. The incidence of HBV reactivation varied from 2.3% to 23.8% of patients with resolved HBV infection [4,10-13]. The reasons for this discrepancy remain to be elucidated. However, treatment intensity, patient characteristics, and geographic HBV differences may be responsible. Among the patients with resolved hepatitis B, no significant risk factors for HBV reactivation were found. Prospective studies with larger sample sizes are required to investigate the risk factors for resolved hepatitis B.\n\nHepatitis can be caused by a range of factors, including tumor progression, drug-related factors, heart failure, and severe sepsis. In this study, hepatitis was caused by HBV reactivation in 28.5% (6/21) of patients, and HBV reactivation was accompanied by hepatitis in all of the 6 patients, given that HBV reactivation often causes a disease flare that leads to liver dysfunction. However, HBV reactivation can also be transient and clinically silent if the viral load is low [26]; thus, HBV reactivation can also occur in the absence of hepatitis [27,28].\n\nResolved hepatitis B involves interaction between the virus and the immune system. A variety of mechanisms may be involved. Low-level HBV virus replication is the main cause of resolved HBV infection. Other causes include HBV gene mutation, HBV integration into the host chromosome, HBV infection of peripheral mononuclear cells, host immune response abnormalities, and interference by other viral infection. Persistent HBV infection can promote liver disease, thereby leading to hepatitis and cirrhosis [29].\n\nALT is primarily localized in the liver, with lower enzymatic activities found in skeletal muscle and heart tissues. AST is localized in heart, brain, skeletal muscle, and liver tissues. Damaged hepatocytes release their contents, including ALT and AST, into the extracellular space [30]. Serum ALT or AST levels are generally considered sensitive indicators of liver cell injury. However, in addition to HBV infection, elevated baseline serum ALT levels can be caused by various other factors, including tumor progression, fatty liver, and diabetes [31]. In contrast to our results, Yeo et al. [4] found that all the patients who developed HBV reactivation had normal baseline serum ALT levels and that the incidence of hepatitis was similar in HBsAg-negative/HBcAb-negative patients and in patients with resolved HBV infection. However, 53.7% (43/80) of patients in that study were treated without rituximab. Further studies are therefore needed to clarify the relationship between elevated baseline serum ALT levels and the hepatitis risk, as well as the possible mechanisms involved.\n\nAmong the 55 HBcAb-positive patients in our study, 8 (14.5%) had elevated baseline serum ALT levels. During the chemotherapy and follow-up period, 22 (40%) of the 55 patients had elevated serum ALT levels. Data on the proportion of HBcAb-positive patients with elevated serum ALT levels were limited. In a study by Yeo et al. [4], the incidence of elevated serum ALT levels in HBcAb-positive patients was 19.6% during chemotherapy. The reasons for these differences remain unclear. However, differences in patient characteristics and treatment intensities may be responsible. Therefore, there is no obvious association between HBcAb-positive patients and ALT levels, and further studies are warranted.\n\nSeveral studies demonstrated that rituximab obviously improved outcomes in patients with B-cell lymphoma [2,3]. However, rituximab has been reported to increase the HBV reactivation rate in patients with chronic HBV infection or resolved HBV infection. Although HBV infection control is mediated mainly by HBV-specific cytotoxic T lymphocytes, B lymphocytes are still required for antigen presentation. Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that alters the activity of T lymphocytes and destroys B lymphocytes, resulting in the failure of antigen presentation and the subsequent expansion of HBV infection in hepatocytes [32,33]. HBV-related hepatitis during rituximab-containing chemotherapy can be severe and fatal [34-36].\n\nAccording to previous data and our experience, HBV-related hepatitis often develops after 5 or 6 cycles of chemotherapy at an interval of 1 to 13 months after chemotherapy. Antiviral drugs successfully controlled HBV reactivation in most patients, although 2 elderly patients (ages 77 and 84 years) developed fatal HBV-related disease [4,13,37]. In this study, it was reasonable for such patients to undergo close monitoring of HBV serology, HBV DNA, and liver function before each chemotherapy cycle and at least every 3 months during the follow-up period; this is consistent with the monitoring frequency of 1–3 months recommended by the latest European Association for the Study of the Liver (EASL) Clinical Practice Guidelines [8] and the consensus on the management of lymphoma with HBV infection in China [38]. In addition, in this study, HBsAg and HBV DNA testing was performed in the event of abnormal liver function or suspected hepatitis. Lamivudine successfully controlled HBV reactivation in all 6 affected patients. Prophylactic agents thus may not be recommended for HBsAg-negative/HBcAb-positive patients if close monitoring of HBV DNA is guaranteed.\n\nHowever, regular monitoring may not be suitable for all patients. Some experts recommend prophylaxis with antiviral drugs in all HBsAg-negative/HBcAb-positive patients who receive rituximab-containing regimens for hematologic malignancies with a high risk of HBV reactivation and/or if close monitoring of HBV DNA is not guaranteed [8]. Lamivudine is widely used for prophylaxis; however, its efficacy is hampered by the development of viral mutations that result in drug resistance [39]. The prophylactic entecavir was found to be effective and associated with minimal resistance in lymphoma patients with resolved hepatitis B [40], but its long-term use is expensive. More large-scale studies or meta-analyses are required to identify host and viral factors that can help to predict the occurrence of HBV-related hepatitis and thus allow the design of individualized strategies for preventing HBV-related hepatitis. Different approaches based on cost-effectiveness, particularly in HBV-endemic areas, could be used for patients with different risk levels, and antiviral prophylaxis should be continued indefinitely.\n\nIn HBsAg-positive patients with non-Hodgkin’s lymphoma, the HBV reactivation-associated mortality was 30%–50% without antiviral prophylaxis [5]. The HBV-related morbidity and overall mortality remained high in lymphoma patients treated with antiviral prophylaxis [41]. In this study, OS was similar in HBsAg-negative/HBcAb-positive patients and HBsAg-negative/HBcAb-negative patients after rituximab-containing chemotherapy. Moreover, no significant difference was observed in OS between patients with and without HBV reactivation or between patients with and without hepatitis. Fukushima et al. [11] found similar survival rates in HBcAb-positive or HBcAb-negative patients, although their study included other types of lymphoma in addition to DLBCL, and 26.4% (19/72) of patients had not received rituximab-containing therapy. In addition, DLBCL is a heterogeneous disorder with varied clinical outcomes. Hsu et al. [28] also demonstrated that resolved HBV infection with HBV reactivation was associated with low OS and progression-free survival rates, although the differences were not significant. Further studies are needed to determine the impact of HBV reactivation on the clinical outcomes of lymphoma patients.\n\nOur study had several key points. First, all patients had newly diagnosed DLBCL and received rituximab-containing therapy. Second, we compared the incidence of HBV reactivation or hepatitis between HBcAb-positive and HBcAb-negative patients and identified risk factors for the occurrence of HBV reactivation and hepatitis in HBsAg-negative patients and patients with resolved hepatitis B. Third, we analyzed the effects of HBcAb positivity, HBV reactivation, and hepatitis on survival, which are currently unknown. Furthermore, South China is a highly endemic HBV area, and this is the first to confirm these findings in the southern Chinese population in the largest cancer center in South China.\n\nHowever, this study was limited by its retrospective nature. First, the assignment of rituximab-containing chemotherapy was not randomized in HBcAb-positive or HBcAb-negative patients but was instead based on the consideration of individual patients, leading to inevitable bias in terms of which patients received rituximab. Second, this study was limited to the analysis of patients from a single institute. All of the patients were Chinese, and our findings therefore must be confirmed in patients from other parts of Asia and in other ethnic groups.\n\nConclusions\nIn conclusion, this study clearly indicates that patients with resolved hepatitis B are at a higher risk of developing HBV reactivation and hepatitis after rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients. Close monitoring of HBV DNA levels and liver function and prompt antiviral therapy are required in these patients. Prospective studies including more patients are required to confirm our findings and to determine the most effective monitoring and therapeutic strategies.\n\nKai-Lin Chen and Jie Chen contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nQC designed research; QC, KC, JC, and DZ performed research and analyzed data; QC and KC wrote the article; YG helped to analyze data; HR, HH, LZ, JS, TL, and WJ conceived study and provided clinical data; LH and MW helped to collect data. All authors read and approved the final manuscript.\n\nThis work was supported by the National Natural Science Foundation of China (No. 81372883, No. 81001052), the Science and Technology Planning Project of Guangdong Province, China (No. 2011B031800222), the Young Talents Project of Sun Yat-sen University Cancer Center (to QC), the Young Talents Project of Sun Yat-sen University (to QC), the Natural Science Foundation of Guangdong Province, China (No. 8151008901000043), and the Sister Institution Network Fund of MD Anderson Cancer Center (to HR). This research was also partly supported by the NIH through MD Anderson’s Cancer Center Support Grant (No. CA016672).\n==== Refs\nReferences\n1. Lee WM Hepatitis B virus infection N Engl J Med 1997 337 1733 45 10.1056/NEJM199712113372406 9392700 \n2. Coiffier B Lepage E Briere J Herbrecht R Tilly H Bouabdallah R CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 2002 346 235 42 10.1056/NEJMoa011795 11807147 \n3. Pfreundschuh M Trumper L Osterborg A Pettengell R Trneny M Imrie K CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by MabThera International Trial (MInT) Group Lancet Oncol 2006 7 379 91 10.1016/S1470-2045(06)70664-7 16648042 \n4. Yeo W Chan TC Leung NW Lam WY Mo FK Chu MT Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab J Clin Oncol 2009 27 605 11 10.1200/JCO.2008.18.0182 19075267 \n5. Shih LN Sheu JC Wang JT Huang GT Yang PM Lee HS Serum hepatitis B virus DNA in healthy HBsAg-negative Chinese adults evaluated by polymerase chain reaction J Med Virol 1990 32 257 60 10.1002/jmv.1890320412 2081972 \n6. Evens AM Jovanovic BD Su YC Raisch DW Ganger D Belknap SM Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports Ann Oncol 2011 22 1170 80 10.1093/annonc/mdq583 21115603 \n7. Pei SN Chen CH Lee CM Wang MC Ma MC Hu TH Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients Ann Hematol 2010 89 255 62 10.1007/s00277-009-0806-7 19697028 \n8. European Association For The Study Of The Liver EASL clinical practice guidelines: management of chronic hepatitis B virus infection J Hepatol 2012 57 167 85 10.1016/j.jhep.2012.02.010 22436845 \n9. Hui CK Cheung WW Zhang HY Au WY Yueng YH Leung AY Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy Gastroenterology 2006 131 59 68 10.1053/j.gastro.2006.04.015 16831590 \n10. Koo YX Tay M Teh YE Teng D Tan DS Tan IB Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis Ann Hematol 2011 90 1219 23 10.1007/s00277-011-1241-0 21520001 \n11. Fukushima N Mizuta T Tanaka M Yokoo M Ide M Hisatomi T Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier Ann Oncol 2009 20 2013 7 10.1093/annonc/mdp230 19561036 \n12. Ji D Cao J Hong X Li J Wang J Chen F Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/HBcAb-positive: a multicenter retrospective study Eur J Haematol 2010 85 243 50 10.1111/j.1600-0609.2010.01474.x 20491883 \n13. Matsue K Kimura S Takanashi Y Iwama K Fujiwara H Yamakura M Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma Cancer 2010 116 4769 76 10.1002/cncr.25253 20597091 \n14. Swerdlow SHCE Harris NL Jaffe ES Stein H Thiele J World health organization classification of tumours of the haematopoietic and lymphoid tissues 2008 Pileri SA IARC Press \n15. Yeo W Chan PK Ho WM Zee B Lam KC Lei KI Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy J Clin Oncol 2004 22 927 34 10.1200/JCO.2004.05.161 14990649 \n16. Lok AS Liang RH Chiu EK Wong KL Chan TK Todd D Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study Gastroenterology 1991 100 182 8 1983820 \n17. Ziepert M Hasenclever D Kuhnt E Glass B Schmitz N Pfreundschuh M Standard international prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era J Clin Oncol 2010 28 2373 80 10.1200/JCO.2009.26.2493 20385988 \n18. Cox DR Regression models and life tables J R Stat Soc B 1972 34 187 220 \n19. Marcucci F Mele A Spada E Candido A Bianco E Pulsoni A High prevalence of hepatitis B virus infection in B-cell non-Hodgkin’s lymphoma Haematologica 2006 91 554 7 16585021 \n20. Wang F Xu RH Han B Shi YX Luo HY Jiang WQ High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers Cancer 2007 109 1360 4 10.1002/cncr.22549 17326056 \n21. Kim JH Bang YJ Park BJ Yoo T Kim CW Kim TY Hepatitis B virus infection and B-cell non-Hodgkin’s lymphoma in a hepatitis B endemic area: a case–control study Jpn J Cancer Res 2002 93 471 7 10.1111/j.1349-7006.2002.tb01280.x 12036441 \n22. Qin XT Lu Y Chen XQ Xu HP Fan HJ Correlation of hepatitis B virus infection to non-Hodgkin’s lymphoma Chin J Cancer 2007 26 294 7 \n23. Engels EA Cho ER Jee SH Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study Lancet Oncol 2010 11 827 34 10.1016/S1470-2045(10)70167-4 20688564 \n24. Wang F Yuan S Teng KY Garcia-Prieto C Luo HY Zeng MS High hepatitis B virus infection in B-cell lymphoma tissue and its potential clinical relevance Eur J Cancer Prev 2012 21 261 7 10.1097/CEJ.0b013e3283498e87 22433629 \n25. Marzano A Angelucci E Andreone P Brunetto M Bruno R Burra P Prophylaxis and treatment of hepatitis B in immunocompromised patients Dig Liver Dis 2007 39 397 408 10.1016/j.dld.2006.12.017 17382608 \n26. Hoofnagle JH Reactivation of hepatitis B Hepatology 2009 49 S156 65 10.1002/hep.22945 19399803 \n27. Li HR Huang JJ Guo HQ Zhang X Xie Y Zhu HL Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy J Viral Hepat 2011 18 877 83 10.1111/j.1365-2893.2010.01386.x 21054683 \n28. Hsu C Tsou HH Lin SJ Wang MC Yao M Hwang WL Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study Hepatology 2014 59 2092 100 10.1002/hep.26718 24002804 \n29. Chemin I Jeantet D Kay A Trepo C Role of silent hepatitis B virus in chronic hepatitis B surface antigen(−) liver disease Antiviral Res 2001 52 117 23 10.1016/S0166-3542(01)00176-0 11672821 \n30. Ozer J Ratner M Shaw M Bailey W Schomaker S The current state of serum biomarkers of hepatotoxicity Toxicology 2008 245 194 205 10.1016/j.tox.2007.11.021 18291570 \n31. Clark JM Brancati FL Diehl AM The prevalence and etiology of elevated aminotransferase levels in the United States Am J Gastroenterol 2003 98 960 7 10.1111/j.1572-0241.2003.07486.x 12809815 \n32. Stasi R Del Poeta G Stipa E Evangelista ML Trawinska MM Cooper N Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura Blood 2007 110 2924 30 10.1182/blood-2007-02-068999 17548576 \n33. Dai MS Chao TY Kao WY Shyu RY Liu TM Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP Ann Hematol 2004 83 769 74 10.1007/s00277-004-0899-y 15338194 \n34. Tsutsumi Y Kanamori H Mori A Tanaka J Asaka M Imamura M Reactivation of hepatitis B virus with rituximab Expert Opin Drug Saf 2005 4 599 608 10.1517/14740338.4.3.599 15934864 \n35. Sarrecchia C Cappelli A Aiello P HBV reactivation with fatal fulminating hepatitis during rituximab treatment in a subject negative for HBsAg and positive for HBsAb and HBcAb J Infect Chemother 2005 11 189 91 10.1007/s10156-005-0385-Z 16133710 \n36. Li YH He YF Wang FH Lin XB Xia ZJ Sun XF Clinical analysis of liver damage of 116 malignant lymphoma patients with chronic HBV infection after cytotoxic chemotherapy Chin J Cancer 2005 24 1507 9 \n37. Koo YX Tan DS Tan IB Tao M Chow WC Lim ST Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy Cancer 2010 116 115 21 19899164 \n38. Chinese Society of Hematology, CMA, Committee of Malignant Lymphoma, Chinese Anti-cancer Association, Chinese Society of Hepatology, CMA Consensus on the management of lymphoma with HBV infection Zhonghua Xue Ye Xue Za Zhi 2013 34 988 93 24294861 \n39. Lok AS Lai CL Leung N Yao GB Cui ZY Schiff ER Long-term safety of lamivudine treatment in patients with chronic hepatitis B Gastroenterology 2003 125 1714 22 10.1053/j.gastro.2003.09.033 14724824 \n40. Huang YH Hsiao LT Hong YC Chiou TJ Yu YB Gau JP Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B J Clin Oncol 2013 31 2765 72 10.1200/JCO.2012.48.5938 23775967 \n41. Kumagai K Takagi T Nakamura S Sawada U Kura Y Kodama F Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan Ann Oncol 1997 8 Suppl 1 107 9 10.1093/annonc/8.suppl_1.S107 9187442\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1944-446X",
"issue": "34(5)",
"journal": "Chinese journal of cancer",
"keywords": null,
"medline_ta": "Chin J Cancer",
"mesh_terms": "D002681:China; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009026:Mortality; D011379:Prognosis; D012307:Risk Factors; D000069283:Rituximab; D014775:Virus Activation",
"nlm_unique_id": "101498232",
"other_id": null,
"pages": "225-34",
"pmc": null,
"pmid": "26058465",
"pubdate": "2015-05-28",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19899164;19697028;20385988;20491883;20688564;20597091;21115603;21520001;21054683;22433629;22436845;23775967;24294861;9392700;9187442;24002804;15338194;15934864;16133710;16351802;16585021;16648042;16831590;17355794;17326056;17382608;17548576;18291570;19075267;11672821;11807147;12036441;12809815;14724824;14990649;1983820;2081972;19399803;19561036",
"title": "Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival.",
"title_normalized": "hepatitis b virus reactivation and hepatitis in diffuse large b cell lymphoma patients with resolved hepatitis b receiving rituximab containing chemotherapy risk factors and survival"
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"abstract": "There is increasing interest in developing more nuanced methods for managing aggression and violence in long-term psychiatric inpatient settings. However, the dearth of controlled studies has, at times, hampered presentation of viable options. Following the publication of guidelines developed in the California State Hospital forensic system, the authors present a group of 7 cases illustrating different approaches to violence management, including pharmacological, psychotherapeutic, and environmental interventions.",
"affiliations": "1California Department of State Hospitals (DSH),Sacramento,California,USA.;1California Department of State Hospitals (DSH),Sacramento,California,USA.;2Department of State Hospitals (DSH)-Metropolitan,Norwalk,California.;1California Department of State Hospitals (DSH),Sacramento,California,USA.;1California Department of State Hospitals (DSH),Sacramento,California,USA.",
"authors": "Dardashti|Laura J|LJ|;O'Day|Jennifer A|JA|;Barsom|Michael W|MW|;Schwartz|Eric H|EH|;Proctor|George J|GJ|",
"chemical_list": "D014150:Antipsychotic Agents",
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"issue": "20(3)",
"journal": "CNS spectrums",
"keywords": "Forensic; in-patient; psychiatry; state hospital; treatment; violence",
"medline_ta": "CNS Spectr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D002140:California; D005260:Female; D005555:Forensic Psychiatry; D017408:Guidelines as Topic; D006778:Hospitals, Psychiatric; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia; D014754:Violence; D055815:Young Adult",
"nlm_unique_id": "9702877",
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"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Illustrative cases to support the Cal-VAT guidelines.",
"title_normalized": "illustrative cases to support the cal vat guidelines"
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"abstract": "Rhabdomyolysis is defined as a pathological condition of skeletal muscle cell damage leading to the release of toxic intracellular components into the circulation. Several factors may lead to rhabdomyolysis. Fenofibrate is a fibric acid derivative agent that is used in the treatment of hyperlipidaemia. Although several case reports of rhabdomyolysis have been reported due to the combination of statin and fenofibrate, fenofibrate alone rarely causes rhabdomyolysis. When administering fenofibrate in chronic renal failure, dose should be adjusted. Here, we report a case with fenofibrate-induced rhabdomyolysis in a patient with chronic renal failure.",
"affiliations": "Department of Nephrology, University of Yuzuncu Yil, Van, Turkey. yaseminsoyoral@yahoo.com",
"authors": "Soyoral|Yasemin Usul|YU|;Canbaz|Esra Turan|ET|;Erdur|Mehmet Fatih|MF|;Emre|Habib|H|;Begenik|Huseyin|H|;Erkoc|Reha|R|",
"chemical_list": "D000960:Hypolipidemic Agents; D011345:Fenofibrate",
"country": "Pakistan",
"delete": false,
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"issue": "62(8)",
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"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D005260:Female; D011345:Fenofibrate; D006801:Humans; D000960:Hypolipidemic Agents; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D012206:Rhabdomyolysis",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fenofibrate-induced rhabdomyolysis in a patient with stage 4 chronic renal failure due to diabetes mellitus.",
"title_normalized": "fenofibrate induced rhabdomyolysis in a patient with stage 4 chronic renal failure due to diabetes mellitus"
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"abstract": "Microangiopathic hemolytic anemia and thrombocytopenia (MAHA-T) is a rare complication of acute pancreatitis (AP). Treatment with therapeutic plasma exchange (TPE) is used at many centers. The natural history of this disease is not well understood. We report a case of acute pancreatitis induced MAHA-T with end organ dysfunction and a normal ADAMTS13 level. Following three TPEs, the patient's clinical status, blood counts and hemolytic markers stabilized. Improvement occurred even after TPE was discontinued. The optimal management of AP-induced MAHA-T is poorly understood. Many centres are reporting good outcomes with the early initiation of TPE. MAHA-T associated with acute pancreatitis is often treated with early initiation of TPE. However, the value of TPE in altering the natural history of the condition is not well understood. Further study is required to understand the role of ADAMTS13 testing to guide treatment, and the role of TPE in management.",
"affiliations": "Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. kevhill@toh.ca.;Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.;Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.;Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.;Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.",
"authors": "Hill|Kevin M|KM|http://orcid.org/0000-0001-9570-5270;Moorman|Danielle|D|;Mack|Jonathan|J|;Gonsalves|Carol|C|;Khalife|Roy|R|",
"chemical_list": "D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human",
"country": "Netherlands",
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"doi": "10.1007/s11239-019-01946-2",
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"issn_linking": "0929-5305",
"issue": "49(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Acute pancreatitis; Hemolytic anemia; MAHA; TTP; Therapeutic plasma exchange",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000071120:ADAMTS13 Protein; D000743:Anemia, Hemolytic; D005260:Female; D006801:Humans; D008875:Middle Aged; D010195:Pancreatitis; D010951:Plasma Exchange; D013921:Thrombocytopenia",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "159-163",
"pmc": null,
"pmid": "31493291",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9820399;14014893;9807681;21716116;10765912;15538566;22233953;28416509;2289666;24678155;12018906;12630759;15069598;1467404;20178726;17606444;27987277;26905311;25119611;8203364;22536085;19892300;7668225;21903475;9587572;2062330;21886987;30374015;19036107;567425;26183157;27868334;28189178;28904486;11034007;19008177",
"title": "A case of acute pancreatitis-induced microangiopathic hemolytic anemia with thrombocytopenia.",
"title_normalized": "a case of acute pancreatitis induced microangiopathic hemolytic anemia with thrombocytopenia"
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... |
{
"abstract": "OBJECTIVE\nThis report describes a 64-year-old woman with recurrent hypercalcemia. Her laboratory evaluation was consistent with milk-alkali syndrome. It was eventually discovered that the source of the excessive calcium consumption was nicotine-replacement chewing gum and carbonated water.\n\n\nMETHODS\nAn extensive literature search was performed to see if milk-alkali syndrome due to nicotine-replacement gum and carbonated water has been previously reported.\n\n\nRESULTS\nNo prior report describing the association of milk alkali syndrome with nicotine-replacement gum and carbonated water was found.\n\n\nCONCLUSIONS\nWe present a unique case of milk-alkali syndrome due to nicotine-replacement gum and carbonated water. It serves as a lesson to evaluate other sources besides calcium supplements as the cause of excessive calcium intake.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona.",
"authors": "Swanson|Christine M|CM|;Mackey|Patricia A|PA|;Westphal|Sydney A|SA|;Argueta|Rodolfo|R|",
"chemical_list": "D061545:Carbonated Water; D002638:Chewing Gum; D018722:Nicotinic Agonists; D009538:Nicotine; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.4158/EP13080.CR",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-891X",
"issue": "19(6)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000279:Administration, Cutaneous; D002118:Calcium; D061545:Carbonated Water; D002638:Chewing Gum; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D008875:Middle Aged; D009538:Nicotine; D018722:Nicotinic Agonists",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "142-4",
"pmc": null,
"pmid": "23807522",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nicotine-substitute gum-induced milk alkali syndrome: a look at unexpected sources of calcium.",
"title_normalized": "nicotine substitute gum induced milk alkali syndrome a look at unexpected sources of calcium"
} | [
{
"companynumb": "US-ACTAVIS-2014-19002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Myoclonic status epilepticus or mixed absence-myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006; Crespel et al., 2013). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013). We present the video-EEG of a 24-year-old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures (1)].",
"affiliations": "Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier Research Unit URCMA (Unité de recherche sur les comportements et mouvements anormaux), INSERM, U661, Montpellier, France.;Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier Research Unit URCMA (Unité de recherche sur les comportements et mouvements anormaux), INSERM, U661, Montpellier, France.",
"authors": "Gélisse|Philippe|P|;Crespel|Arielle|A|",
"chemical_list": "D000927:Anticonvulsants; D002998:Clonazepam; D014635:Valproic Acid; D010076:Oxazepam",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2014.0719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "17(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "absence seizure; juvenile myoclonic epilepsy; status epilepticus",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000927:Anticonvulsants; D001714:Bipolar Disorder; D002389:Catatonia; D002998:Clonazepam; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D020190:Myoclonic Epilepsy, Juvenile; D010076:Oxazepam; D013226:Status Epilepticus; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "95-6",
"pmc": null,
"pmid": "25644293",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy.",
"title_normalized": "mixed myoclonic absence status epilepticus in juvenile myoclonic epilepsy"
} | [
{
"companynumb": "FR-ACTAVIS-2015-15999",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance.\n\n\n\nWe performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests.\n\n\n\nOur test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results).\n\n\n\nWe developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.",
"affiliations": "Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany. Electronic address: andreas.benesic@med.uni-muenchen.de.;Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany.;Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany.;Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany.;Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität Munich, Germany.;Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany.",
"authors": "Benesic|Andreas|A|;Rotter|Isabelle|I|;Dragoi|Diana|D|;Weber|Sabine|S|;Leitl|Alexandra||;Buchholtz|Marie-Luise|ML|;Gerbes|Alexander L|AL|",
"chemical_list": "D007770:L-Lactate Dehydrogenase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2018.04.049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "16(9)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Antibiotic; Diagnostic; Nonsteroidal Anti-inflammatory; Pain Reliever",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002470:Cell Survival; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D003584:Cytological Techniques; D003955:Diagnostic Tests, Routine; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005858:Germany; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D012680:Sensitivity and Specificity; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1488-1494.e5",
"pmc": null,
"pmid": "29723689",
"pubdate": "2018-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury.",
"title_normalized": "development and validation of a test to identify drugs that cause idiosyncratic drug induced liver injury"
} | [
{
"companynumb": "PHHY2018DE010331",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditional": nul... |
{
"abstract": "We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.",
"affiliations": "Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.;Department of Hematology, Tokyo Women's Medical University, Japan.",
"authors": "Watanabe|Aya|A|;Shiseki|Masayuki|M|;Oishi|Megumi|M|;Kobayashi|Maya|M|;Oshima|Shoko|S|;Osanai|Satoko|S|;Ryuzaki|Michiko|M|;Izuka|Yuki|Y|;Tanaka|Norina|N|;Ishiyama|Midori|M|;Shinohara|Akihito|A|;Kazama|Hiroshi|H|;Hagiwara|Shotaro|S|;Yoshinaga|Kentaro|K|;Tanaka|Junji|J|",
"chemical_list": "D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6387-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33775998\n10.2169/internalmedicine.6387-20\nCase Report\nSuccessful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports\nWatanabe Aya 1\nShiseki Masayuki 1\nOishi Megumi 1\nKobayashi Maya 1\nOshima Shoko 1\nOsanai Satoko 1\nRyuzaki Michiko 1\nIzuka Yuki 1\nTanaka Norina 1\nIshiyama Midori 1\nShinohara Akihito 1\nKazama Hiroshi 1\nHagiwara Shotaro 1\nYoshinaga Kentaro 1\nTanaka Junji 1\n1 Department of Hematology, Tokyo Women's Medical University, Japan\nCorrespondence to Dr. Masayuki Shiseki, shisekim@twmu.ac.jp\n\n29 3 2021\n1 9 2021\n60 17 28592862\n25 9 2020\n2 2 2021\nCopyright © 2021 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/).\nWe herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.\n\nthrombotic thrombocytopenic purpura\nautoimmune hepatitis\nimmune thrombocytopenia\nrituximab\nADAMTS13\n==== Body\npmcIntroduction\n\nThrombotic thrombocytopenic purpura (TTP) is a rare but severe clinical condition characterized by thrombocytopenia, hemolytic anemia, and damage of vital organs, including the kidneys and central nervous system. The pathological condition of TTP is based on thrombotic microangiopathy owing to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency. In most cases, acquired autoantibody against ADAMTS13 plays a central role in TTP development (1). Plasma exchange (PE) with corticosteroids is a standard treatment procedure for acquired TTP. TTP is occasionally complicated by other autoimmune disorders such as systemic lupus erythematosus (2). We experienced two TTP cases complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. Both patients achieved a sufficient and sustained response after being treated with rituximab.\n\nCase Reports\n\nCase 1\n\nA 65-year-old man with autoimmune hepatitis (AIH) was admitted to our hospital because of consciousness disturbance with severe thrombocytopenia. Five years prior to admission, he had undergone comprehensive examinations because of elevated serum aspartate aminotransferase and alanine aminotransferase (ALT) levels, elevated serum IgG level, and positive reaction for antinuclear antibody (ANA) without any evidence of hepatitis B and C virus infection. A histopathological analysis of liver tissue specimens indicated chronic hepatitis with lymphoid cell aggregation in the portal vein area. Eventually, a diagnosis of AIH was made. Prednisolone (PSL) of 30 mg/day was initiated, and his liver function improved. The dose of PSL was gradually decreased, and subsequently, a maintenance dose (10 mg/day) was continuously administered until admission.\n\nAt admission, laboratory data demonstrated severe thrombocytopenia (9×109/L), anemia (Hb 6.7 g/dL), high serum lactate dehydrogenase (LDH) (2,041 U/L, normal range, 119-229 U/L), increased total bilirubin (3.5 mg/dL) and indirect bilirubin (3.0 mg/dL), and undetectable serum haptoglobin with appearance of red cell fragmentation on the blood film, indicating thrombotic microangiopathy. The disease status of AIH was considered to be stable because the ALT level was in the normal range (30 U/L). The serum IgG level was almost normal (1,719 mg/dL, normal range, 870-1,700 mg/dL), and the titer of ANA was increased (1:160). The immature platelet fraction (IPF) was 5.3%. Disseminated intravascular coagulation (DIC) was ruled out because of findings of coagulation tests of PT (12.0 sec, control 11.2 sec), APTT (28.6 sec, control 32.5 sec), fibrinogen (441 mg/dL) and FDP (10.5 μg/mL). Renal insufficiency and fever were observed, leading to the clinical diagnosis of TTP. PE was initiated immediately with a maintenance dose of PSL (10 mg/day) for AIH (Figure A). The diagnosis of TTP was then confirmed according to decreased serum ADAMTS13 activity (<1%) with a high titer of inhibitor for ADAMTS13 (11.0 BU/mL). The platelet count increased to 50×109/L on day 3 from PE initiation. The PSL dose was not increased, because an objective response was obtained. However, an interruption of PE on day 4 resulted in a decreased platelet count to 25×109/L again on day 5. Although we reinitiated PE every day with an increased dose of PSL of 60 mg/day (1 mg/kg/day), the platelet count did not increase. Therefore, high-dose methylprednisolone (1 g/day) was administered for 3 days. In addition, rituximab (375 mg/m2) was administered once a week for 4 times from day 14. Before rituximab treatment, off-label rituximab use for TTP was approved by the institutional committee for the evaluation of unapproved, contraindicated, and off-label drug use. Written informed consent was obtained from the patient before rituximab use. The platelet count increased gradually and normalized on day 35. We continued PE every day until day 21, and then, on alternate days until day 40. The activity of ADAMTS13 recovered with a decreased inhibitor titer. The PSL dose was tapered gradually, and PSL of 10 mg/day was administered continuously. Corticosteroid, PE, and rituximab therapies were tolerable, and there were no significant toxicities resulting in any treatment interruption. The platelet count was still maintained within the normal range at the last follow-up date, 6 months after the TTP diagnosis. The disease status of AIH also remained stable without an elevation of ALT (23 U/L) under maintenance therapy of PSL (10 mg/day). The serum IgG level decreased to 937 mg/dL, and the ANA titer decreased to the normal range (1:40).\n\nFigure. Clinical courses of Case 1 (A) and Case 2 (B) after the initiation of plasma exchange (PE). The solid line shows the platelet count (×1010 /L). The dotted line shows the serum ADAMTS13 activity (%). The vertical bars in graphs show the titers of inhibitor for ADAMTS13 (BU/mL). The inverted triangles show rituximab (375 mg/m2). The arrows show PE. Plt: platelet, PSL: prednisolone, mPSL: methylprednisolone\n\nCase 2\n\nA 33-year-old woman who had been diagnosed with immune thrombocytopenic purpura (ITP) at 13 years of age was admitted to our hospital because of the sudden appearance of severe purpura and worsening of thrombocytopenia with a platelet count of 5×109/L. When she was 13 years old, multiple petechia appeared on her legs, and a blood test revealed thrombocytopenia (platelet count 3×109/L). A diagnosis of ITP was made according to a bone marrow analysis of megakaryocytic hyperplasia without any dysplastic features and a high serum level of platelet-associated immunoglobulins (PAIgG) (42.4 ng/107cells, normal range, <27.6 ng/107cells) at another hospital, and PSL was initiated for ITP treatment. She first visited our hospital at 19 years of age. Treatment for ITP by PSL (4-30 mg/day) had been continued. Until 4 days before admission, her platelet count had been kept over 100×109/L with a maintenance dose of PSL (4 mg/day).\n\nAt admission, she had slight anemia (Hb 11.4 g/dL), an increase of total bilirubin (2.4 mg/dL), indirect bilirubin (2.4 mg/dL) and serum LDH (838 U/L) with normal serum ALT (18 U/L) and creatinine (0.43 mg/dL). IPF increased (14.1%) and the reticulocyte count was in the normal range (8×1010/L). The PSL dose was increased to 60 mg/day, since an exacerbation of ITP was suspected. However, no objective response was obtained. On the 6th hospital day, she had fever, and the laboratory data showed anemia (Hb 5.4 g/dL), an elevated serum LDH level (1,140 U/L), total bilirubin (2.4 mg/dL), and indirect bilirubin (2.3 mg/dL), and an undetectable serum haptoglobin level with the appearance of red cell fragmentation on peripheral blood film, indicating thrombotic microangiopathy. Therefore, a clinical diagnosis of TTP was made. Blood coagulation tests, including PT (10.7 sec, control 11.0 sec), APTT (20.9 sec, control 33.7), fibrinogen (276 mg/dL), and FDP (10.9 μg/mL), showed no definite evidence of DIC. PE was initiated with high-dose methylprednisolone of 1 g/day for 3 days followed by 500 mg/day for 3 days, and tapered doses, and then, her platelet count increased gradually (Figure B). Later, the diagnosis of TTP was confirmed due to a decreased serum ADAMTS13 activity (<5%) with a high titer of inhibitor for ADAMTS13 (1.1 BU/mL). After the cessation of PE, her platelet count decreased again on day 6 from PE initiation. Therefore, we restarted PE and rituximab (375 mg/m2) was introduced on day 10. Before rituximab treatment, off-label rituximab use for TTP was approved by the institutional committee for the evaluation of unapproved, contraindicated, and off-label drug use. Written informed consent was obtained from the patient before rituximab use. Rituximab was administered once a week for 4 times, and then, the platelet count and the ADAMTS13 activity increased, while the inhibitor concentration decreased. The serum haptoglobin increased to detectable level (95 mg/dL) on day 21. The platelet count was stable after PE cessation. The corticosteroid dose gradually decreased and eventually stopped at one year from TTP diagnosis. No significant adverse events which required treatment interruption. The platelet count has remained in the normal range for 6 years without any treatment including corticosteroids, thus suggesting that rituximab was effective for not only TTP, but also for ITP.\n\nDiscussion\n\nThere are few reports describing TTP complicated by AIH or ITP (3,4). It remains unclear whether there are differences in the clinical courses and outcomes between TTP patients with or without other autoimmune disorders. Letchumanan et al. (5) showed higher mortality rates and a longer time to achieve complete remission in TTP patients with SLE than those without SLE. Patients with autoimmune disorders often receive corticosteroid therapy. The optimal corticosteroid dose for treatment has yet to be established in TTP patients complicated by autoimmune disorders, especially those who already received corticosteroids at the time that TTP is first diagnosed.\n\nA sufficient objective response was not achieved by PE and corticosteroids in the two patients described in the present report. In addition, the titer of ADAMTS13 inhibitor increased during PE and corticosteroid treatment. Rituximab, a humanized anti-CD20 monoclonal antibody, could be effective for TTP via different mechanisms from corticosteroid and/or PE. Rituximab may reduce autoantibody production by decreasing the number of B-lymphocytes, similar to other autoantibody-mediated disorders such as ITP. In the present two cases, the ADAMTS13 inhibitor decreased after rituximab administration. Rituximab is effective for the treatment of TTP refractory to PE and corticosteroid therapy (6) and also effective for the treatment of TTP associated with SLE refractory to them (7). The frontline use of rituximab for TTP remains controversial. In certain conditions, including cases complicated by autoimmune disorders, the early or frontline introduction of rituximab for TTP treatment may improve the clinical outcomes of such patients.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Scully M , Hunt BJ , Benjamin S , et al . Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 158 : 323-335, 2012.22624596\n2. Roriz M , Landais M , Desprez J , et al . Risk factors for autoimmune diseases development after thrombotic thrombocytopenic purpura. Medicine (Baltimore) 94 : e1598, 2015.26496263\n3. Shimizu M , Nomura S , Ishii K , et al . The significance of ADAMTS13 in a patient with thrombotic thrombocytopenic purpura complicated autoimmune hepatitis. Thromb Haemost 101 : 599-600, 2009.19277430\n4. Al-Husban N , Al-Kuran O . Post-partum thrombotic thrombocytopenic purpura (TTP) in a patient with known idiopathic (immune) thrombocytopenic purpura: a case report and review of the literature. J Med Case Rep 12 : 147, 2018.29855343\n5. Letchumanan P , Ng HJ , Lee LH , Thumboo J . A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford) 48 : 399-403, 2009.19202160\n6. Joly BS , Coppo P , Veyradier A . Thrombotic thrombocytopenic purpura. Blood 129 : 2836-2846, 2017.28416507\n7. Niewold TB , Alpert D , Scanzello CR , Paget SA . Rituximab treatment of thrombotic thrombocytopenic purpura in the setting of connective tissue disease. J Rheumatol 33 : 1194-1196, 2006.16755668\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "ADAMTS13; autoimmune hepatitis; immune thrombocytopenia; rituximab; thrombotic thrombocytopenic purpura",
"medline_ta": "Intern Med",
"mesh_terms": "D006801:Humans; D010951:Plasma Exchange; D016553:Purpura, Thrombocytopenic, Idiopathic; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence; D000069283:Rituximab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2859-2862",
"pmc": null,
"pmid": "33775998",
"pubdate": "2021-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19277430;19202160;29855343;26496263;28416507;22624596;16755668",
"title": "Successful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports.",
"title_normalized": "successful rituximab treatment in thrombotic thrombocytopenic purpura patients complicated by other autoimmune disorders two case reports"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1073840",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Tubulointerstitial nephritis (TIN) presents histopathologically as tubulitis and oedema/inflammation and fibrosis, affecting the renal tubules and interstitium with relative sparing of the glomeruli and vasculature. It can be acute or chronic or acute on chronic and has a wide range of etiologies. In this article, we report a case of a 44-year male who presented with acute TIN, associated with the use of diclofenac at therapeutic doses, that resolved with treatment but later progressed to chronic TIN after the patient resumed diclofenac therapy. The case is discussed in the context of literature regarding the nephrotoxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Key Words: Nonsteroidal anti-inflammatory drugs, Acute kidney injury, Tubulointerstitial nephritis.",
"affiliations": "Department of Internal Medicine, Izmir University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey.;Department of Pathology, Izmir University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey.;Department of Nephrology, Mugla Sitki Kocman University, School of Medicine, Mugla, Turkey.",
"authors": "Ozalp|Faruk Recep|FR|;Karadeniz|Tugba|T|;Alp|Alper|A|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.29271/jcpsp.2021.02.228",
"fulltext": null,
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"issn_linking": "1022-386X",
"issue": "31(2)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D058186:Acute Kidney Injury; D005355:Fibrosis; D006801:Humans; D008297:Male; D009395:Nephritis, Interstitial",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "228-231",
"pmc": null,
"pmid": "33645197",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An Old Enemy: Still Nephrotoxic.",
"title_normalized": "an old enemy still nephrotoxic"
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"abstract": "The association between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is rare and has never been treated with an arginine vasopressin receptor antagonist. We report a unique case of SIADH associated with ibuprofen use and successfully treated with tolvaptan. A 76-year-old man came to our observation because of lumbar pain and epigastric discomfort. He was taking ibuprofen orally 400 mg bid as an analgesic treatment. Laboratory tests showed low levels of sodium (116 mmol/L) and chloride; a diagnosis of SIADH was formulated and ibuprofen was stopped immediately. Imaging tests allowed to rule out the presence of malignancies or cerebral and lung diseases. Slightly hypertonic saline infusion was administered for 3 days without significant sodium improvement; therefore, tolvaptan was started at the initial dose of 7.5 mg daily, doubled after 5 days. After 8 days of treatment the patient showed progressive increase of sodium levels up to normal values. In the following weeks tolvaptan was prescribed at progressively titrated dosage to full suspension; afterwards the sodium levels remained normal without any type of treatment.",
"affiliations": "Clinic of Internal Medicine 1, Department of Internal Medicine, University of Genoa School of Medicine, Viale Benedetto XV, 6, 16132 Genoa, Italy.",
"authors": "Artom|Nathan|N|;Oddo|Silvia|S|;Pende|Aldo|A|;Ottonello|Luciano|L|;Giusti|Massimo|M|;Dallegri|Franco|F|",
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"doi": "10.1155/2013/818259",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIM.ENDOCRINOLOGYCase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2013/818259Case ReportSyndrome of Inappropriate Antidiuretic Hormone Secretion and Ibuprofen, a Rare Association to Be Considered: Role of Tolvaptan Artom Nathan \n1\n*Oddo Silvia \n2\n0000-0002-3804-918XPende Aldo \n1\n0000-0002-0709-5298Ottonello Luciano \n1\nGiusti Massimo \n2\nDallegri Franco \n1\n1Clinic of Internal Medicine 1, Department of Internal Medicine, University of Genoa School of Medicine, Viale Benedetto XV, 6, 16132 Genoa, Italy2Division of Endocrinology, Department of Endocrinological and Metabolic Sciences, University of Genoa School of Medicine, Genoa, Italy*Nathan Artom: nat.artom@hotmail.itAcademic Editors: I. Broom, M. Demura, H. Kang, and T. Nagase\n\n2013 2 6 2013 2013 81825913 3 2013 15 5 2013 Copyright © 2013 Nathan Artom et al.2013This 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.The association between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is rare and has never been treated with an arginine vasopressin receptor antagonist. We report a unique case of SIADH associated with ibuprofen use and successfully treated with tolvaptan. A 76-year-old man came to our observation because of lumbar pain and epigastric discomfort. He was taking ibuprofen orally 400 mg bid as an analgesic treatment. Laboratory tests showed low levels of sodium (116 mmol/L) and chloride; a diagnosis of SIADH was formulated and ibuprofen was stopped immediately. Imaging tests allowed to rule out the presence of malignancies or cerebral and lung diseases. Slightly hypertonic saline infusion was administered for 3 days without significant sodium improvement; therefore, tolvaptan was started at the initial dose of 7.5 mg daily, doubled after 5 days. After 8 days of treatment the patient showed progressive increase of sodium levels up to normal values. In the following weeks tolvaptan was prescribed at progressively titrated dosage to full suspension; afterwards the sodium levels remained normal without any type of treatment.\n==== Body\n1. Introduction\nHyponatremia is the most frequent electrolyte abnormality in hospitalized patients and is associated with a greatly increased morbidity and mortality; in this context the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of hyponatremia [1]. \n\nThe diagnostic criteria for the diagnosis of SIADH are hypoosmolality (plasma osmolality <280 mOsm/kg, or plasma sodium concentration <134 mmol/L); inappropriate urinary osmolality concentration (Uosm >100 mOsm/kg) for hyponatremia; elevated urinary sodium (>40 mmol/L), with normal dietary salt and water intake; patient's normovolemia; exclusion of hypothyroidism, diuretic treatment, and glucocorticoid deficiency [2]. The most common causes of SIADH are malignancies, pulmonary disorders, central nervous system disorders, and medications. \n\nUsual therapeutic options in hyponatremic patients with SIADH consist of fluid restriction (less than 800–1200 mL daily), hypertonic saline solution, furosemide with oral salt supplementation, oral urea, and demeclocycline. The choice of the therapeutic strategy depends on the symptoms of the patient, the acute or chronic onset, and the severity of hyponatremia [2]. Tolvaptan is a new drug that targets the mechanism of the disorder: it is an orally active, selective, nonpeptide antagonist that blocks arginine vasopressin (AVP) binding to V2 receptors of the distal nephron and consequently induces the excretion of electrolyte-free water without changes in the level of sodium excretion [3]. \n\nThe two most important studies reporting tolvaptan treatment of normovolemic or hypervolemic hyponatremia are the SALT and the EVEREST trials [3, 4]. In patients with normovolemic or hypervolemic hyponatremia, the SALT study showed that tolvaptan treatment significantly increased the serum sodium levels on days 4 and 30 of the study [3]. In patients hospitalized for heart failure, the EVEREST study showed that tolvaptan treatment had no effects on long-term mortality or heart failure-related morbidity [4].\n\nOur report describes a case of severe SIADH due to a nonsteroidal anti-inflammatory drug (NSAID), the first reported in literature treated with an oral AVP-receptor antagonist.\n\n2. Case Report\nA 76-year-old Caucasian man came to our observation because of lumbar pain and epigastric discomfort. He was taking ibuprofen orally 400 mg bid as an analgesic treatment for 1 month. About his clinical history, 1 year before the admission, he had suffered from acute coronary syndrome during an episode of atrial tachyfibrillation treated with percutaneous transluminal coronary angioplasty and stenting, and subsequently a biologic prosthetic mitral valve had been implanted due to severe mitral insufficiency. He was on regular treatment with warfarin, atorvastatin, and bisoprolol tablets. At the admission to our ward we stopped ibuprofen. He demonstrated a state of mild confusion and irritability. Laboratory tests showed sodium 116 mmol/L and chloride 84 mmol/L; hepatic and renal tests, as well as the other routine blood tests, were normal, with uric acid 2.5 mg/dL and urea 37 mg/dL. Duration of hyponatremia was unknown. The patient appeared clinically normovolemic (blood pressure 126/76 mmHg without orthostatic hypotension, heart rate 86 bpm) and showed no signs of heart or renal failure. We performed thyroid function tests and measurement of urinary cortisol excretion that resulted normal. After the evidence of low plasma osmolality (252 mOsm/L), high Uosm (561 mOsm/L), and high urinary sodium (160 mmol/L), a diagnosis of SIADH was formulated. To determine the etiopathogenesis of the syndrome, we performed brain MR, total body CT scan, radionuclide bone scan, serologic tests for Chlamydia, Legionella, and Mycoplasma: all tests resulted normal.\n\nWe started infusion of a slightly hypertonic saline solution (1.2% at a rate of 60 mL per h) for 3 days without significant sodium changes; since the patient was taking warfarin and therefore we could not prepare immediately a central iv line to allow the infusion of a more hypertonic solution (3% saline), we decided to treat the patient with tolvaptan, an oral AVP V2 receptor antagonist, initially at the dosage of 7.5 mg daily, checking plasmatic sodium level every 6 hours, and after 5 days at the dosage of 15 mg daily. The patient was encouraged to drink water if he felt thirsty. The changes of sodium level associated with the treatment are presented in Figure 1. After 8 days of treatment the patient showed progressive increase of sodium levels up to normal values and fully recovered clinically. In the following weeks tolvaptan was prescribed at progressively titrated dosage to full suspension (at day 40); afterwards the sodium levels remained normal without any type of treatment.\n\nOur diagnostic conclusion was drug-induced SIADH, due to the use of ibuprofen, with a complete recovery of normal sodium levels induced by the treatment with a V2 receptor antagonist.\n\n3. Discussion\nSIADH is the most frequent cause of euvolemic hyponatremia, a condition characterized by increased morbidity and mortality [1]. Despite being described more than 50 years ago, the management of SIADH is still controversial [5]; in addition in recent years a new therapeutic option, the AVP receptor antagonists, also known as aquaretics or vaptans, was introduced [6].\n\nDrugs are a common cause of SIADH and in particular the various groups of antidepressants are frequently involved in this important electrolyte disturbance [7]. Our patient showed a severe hyponatremia after a prolonged use of ibuprofen, a less common inducer of SIADH. NSAIDs exert their pharmacological effects through the inhibition of the synthesis of prostaglandins [8]: at the kidney level prostaglandins are involved in the modulation of both glomerular filtration rate and tubular sodium reabsorption. In healthy hydrated individuals renal prostaglandins do not exert a major role in sodium and water homeostasis but in conditions such as chronic heart failure, cirrhosis, chronic nephropathy, and hypovolemic states, NSAIDs decrease renal blood flow and glomerular filtration rate significantly [9]. In addition these drugs can reduce water excretion by specifically potentiating the renal effects of AVP, although at the central level prostaglandin inhibition may suppress AVP secretion [7]. Our patient did not show any evidence of either hemodynamic impairment or decrease of renal function, apparently presenting a condition of pure inappropriate AVP secretion.\n\nTraditional approaches to hyponatremia management in SIADH patients are limited by the challenge of compliance, barriers in the practicality of fluid restriction, and risk of serious neurological adverse effects or worsening congestion in patients with hypervolemia, both related to saline infusion. Lithium and demeclocycline have also been proposed to correct hyponatremia, but their use is limited by adverse effects, particularly nephrotoxicity. In this context the antagonists of AVP receptors are a new opportunity and a drug of this class, tolvaptan, was recently approved by EMEA for the oral treatment of hyponatremia due to SIADH in the European Union [10, 11]. AVP binds to 3 different receptors: V1a receptors are present on vascular smooth muscle cells, V1b are detected in the anterior pituitary and pancreas modulating ACTH and insulin release, and V2 receptors are detected in the principal cells of the renal collecting duct [12]. Tolvaptan is a specific oral antagonist of V2 receptors inducing an increase in solute-free water excretion, with minimal-to-no effect on electrolyte excretion, termed the “aquaresis effect” [12]: it has been evaluated in patients with both euvolemic and hypervolemic hyponatremia [10].\n\nOur patient was not treated with fluid restriction because sodium levels were too low (recommended water consumption should have been close to 0 mL) [6]: we started with a slightly hypertonic saline solution which did not induce any significant change in hyponatremia and, after 3 days, we decided to begin tolvaptan. At the dosage of 7.5 mg daily tolvaptan induced an increase of 9 mmol/L in serum sodium levels after 24 hours and 11 mmol/L after 48 hours; in the subsequent days, with an increased dosage for tolvaptan of 15 mg daily, the sodium improvement was less marked with the achievement of normal values (>135 mmol/L) after 13 days of treatment. The drug was very well tolerated without any evidence of osmotic demyelination syndrome. \n\nThe dose of tolvaptan was quite low compared to the doses used in both the SALT trials and the EVEREST trial [4]: we decided to start with a daily dose of 7.5 mg of tolvaptan, only doubling it after a few days. We obtained a very good response after the first administration of tolvaptan (plus the suspension of ibuprofen) and therefore we did not increase the drug to the suggested daily doses of 30–60 mg. However, after the significant initial increase in sodium levels, we experienced some difficulties in reaching normal values (7 days to arrive at 130 mmol/L, 13 days to arrive at 135 mmol/L): therefore we maintained the drug for a longer period with respect to the SALT population [10]. Recently Meyer et al. administered tolvaptan in a severe hyponatremia (108 mmol/L) induced by the antidepressant venlafaxine, obtaining a more rapid, and possibly dangerous, rise in sodium levels (to 131 mmol/L in 2 days) [20]. A possible explanation of these discrepancies could be related to the complex effects of a NSAID to renal functions, not only in terms of potentiation of the AVP effects but also in terms of independent effects on glomerular filtration rate and tubular sodium reabsorption [21]. \n\nIn all cases of SIADH, such as those evaluated in the SALT-1 and SALT-2 trials, tolvaptan was superior to placebo in increasing serum sodium levels, usually with a good tolerability and safety; additional clinical benefits of tolvaptan were represented by the lack of need for fluid restriction and by the improvement of physical and mental symptoms [10]. Possible decreases in morbidity and mortality remain to be evaluated by future clinical trials. Recently another evaluation of the data of the SALT-1 and SALT-2 trials allowed Dasta et al. to demonstrate that tolvaptan use is associated with a shorter length of hospital stay than placebo among patients with SIADH; considering the drug cost for inpatients therapy, tolvaptan was associated with a significant estimated mean hospital cost reduction in the United States [22].\n\nIn the available literature the correlation between NSAIDs and SIADH is anecdotal [13–19]. Table 1 shows a summary of the case reports. Most cases of NSAID-induced SIADH were caused by ibuprofen: they were usually characterized by severe hyponatremia (sodium <120 mmol/L) and most of the times treated with fluid restriction. No reported case was probably treated with hypertonic saline. Some of those cases are only associated with hyponatremia, and it is not reported whether hyponatremia is in the context of a SIADH diagnosis. Moreover cases of NSAID-induced SIADH, treated with tolvaptan, are not reported in the literature. \n\nOur contribution shows the importance of investigating the use of the NSAIDs in the pharmacological anamnesis of SIADH patients and how tolvaptan can be a good strategy in NSAID-induced SIADH. \n\nDisclosure\nSilvia Oddo is involved in the Otsuka Hyponatremia Registry. The other authors have nothing to disclose.\n\nFigure 1 Time course of serum sodium levels during tolvaptan treatment. \n\nTable 1 Published cases of NSAID-induced SIADH.\n\nAuthors\tReference\tNo. of pts.\tInitial sodium levels (mmol/L)\tTherapy\tDrug involved\t\nTemple et al. \t[13]\t2\t131–134\tMannitol/fluid restriction\tSalicylate\t\nBlum and Aviram\t[14]\t1\t115\tFluid restriction\tIbuprofen\t\nDunn et al.\t[15]\t2\t118\n118\tFluid restriction\nFluid restriction\tIbuprofen\nDiclofenac\t\nPetersson et al.\t[16]\t2\t119\n120\tHypertonic saline\nIsotonic saline/fluid restriction\tPiroxicam\nDiclofenac\t\nCheung et al.\t[17]\t1\t116\tFluid restriction\tNabumetone/diclofenac\t\nRault \t[18]\t1\t125\tIsotonic saline\tIbuprofen\t\nShimada et al. \t[19]\t1 \n(twice)\t118\n104\tFluid restriction\tMetamizole\nPropyphenazone\n==== Refs\n1 Hannon MJ Thompson CJ The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences European Journal of Endocrinology 2010 162 1 S5 S12 2-s2.0-77953646715 20164214 \n2 Peri A Pirozzi N Parenti G Festuccia F Menè P Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Journal of Endocrinological Investigation 2010 33 9 671 682 2-s2.0-78751690075 20935451 \n3 Schrier RW Gross P Gheorghiade M Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia The New England Journal of Medicine 2006 355 20 2099 2112 2-s2.0-33751005260 17105757 \n4 Decaux G Soupart A Vassart G Non-peptide arginine-vasopressin antagonists: the vaptans The Lancet 2008 371 9624 1624 1632 2-s2.0-43049146180 \n5 Hoorn EJ Bouloux P-M Burst V Perspectives on the management of hyponatraemia secondary to SIADH across Europe Best Practice & Research Clinical Endocrinology & Metabolism 2012 26 Supplement 1 S27 S32 22469248 \n6 Peri A Combe C Considerations regarding the management of hyponatraemia secondary to SIADH Best Practice & Research Clinical Endocrinology & Metabolism 2012 26 Supplement 1 S16 S26 22469247 \n7 Liamis G Milionis H Elisaf M A review of drug-induced hyponatremia American Journal of Kidney Diseases 2008 52 1 144 153 2-s2.0-45449087534 18468754 \n8 FitzGerald GA Patrono C The coxibs, selective inhibitors of cyclooxygenase-2 The New England Journal of Medicine 2001 345 6 433 442 2-s2.0-0035833502 11496855 \n9 Ducobu J Dupont P Inhibition of prostaglandins in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) Presse Medicale 1983 12 20 1279 1282 2-s2.0-0020520801 \n10 Verbalis JG Adler S Schrier RW Berl T Zhao Q Czerwiec FS Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion European Journal of Endocrinology 2011 164 5 725 732 2-s2.0-79953267031 21317283 \n11 Rajendran R Grossman A Kar P Vasopressin receptor antagonist in the treatment of the syndrome of inappropriate antidiuretic hormone in general hospital practice Endocrine Journal 2012 59 10 903 909 22785335 \n12 Bulloch MN Pinner NA Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia Expert Review of Clinical Pharmacology 2010 3 5 601 612 2-s2.0-77956825642 22111741 \n13 Temple AR George DJ Done AK Thompson JA Salicylate poisoning complicated by fluid retention Clinical Toxicology 1976 9 1 61 68 2-s2.0-0017177993 1277769 \n14 Blum M Aviram A Ibuprofen induced hyponatremia Rheumatology and Rehabilitation 1980 19 4 258 259 2-s2.0-0019226205 7209292 \n15 Dunn AM Buckley BM Axford JS Berry H Non-steroidal anti-inflammatory drugs and the kidney British Medical Journal 1986 293 6540 202 203 2-s2.0-0022568814 3089448 \n16 Petersson I Nilsson G Hansson BG Hedner T Water intoxication associated with non-steroidal anti-inflammatory drug therapy Acta Medica Scandinavica 1987 221 2 221 223 2-s2.0-0023257578 3591460 \n17 Cheung NT Coley S Sheeran T Situnayake RD Syndrome of inappropriate secretion of antidiuretic hormone induced by diclofenac British Medical Journal 1992 306 6871 p. 186 2-s2.0-0027049336 \n18 Rault RM Case report: hyponatremia associated with nonsteroidal antiinflammatory drugs American Journal of the Medical Sciences 1993 305 5 318 320 2-s2.0-0027273741 8484392 \n19 Shimada T Higashi K Kimura K Shido T Tomita K Syndrome of inappropriate antidiuresis seen twice in eight years Endocrine Journal 1995 42 2 163 169 2-s2.0-0029048794 7627260 \n20 Meyer I Frank D Janssens U A case of venlafaxine-induced syndrome of inappropriate ADH secretion (SIADH)-treatment with tolvaptan Dtsch Med Wochenschr 2012 137 21 1096 1099 22588654 \n21 Vane JR Bakhle YS Botting RM Cyclooxygenases 1 and 2 Annual Review of Pharmacology and Toxicology 1998 38 97 120 2-s2.0-0031777185 \n22 Dasta JF Chiong JR Christian R Evaluation of costs associated with tolvaptan-mediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials Hospital Practice 2012 40 1 7 14\n\n",
"fulltext_license": "CC BY",
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"nlm_unique_id": "101576457",
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"pages": "818259",
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"pmid": "23819075",
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"title": "Syndrome of inappropriate antidiuretic hormone secretion and Ibuprofen, a rare association to be considered: role of tolvaptan.",
"title_normalized": "syndrome of inappropriate antidiuretic hormone secretion and ibuprofen a rare association to be considered role of tolvaptan"
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"abstract": "OBJECTIVE\nTo report a case of neurologic adverse effects that developed during concomitant treatment with ciprofloxacin, nonsteroidal antiinflammatory drugs (NSAIDs), and chloroquine. Possible mechanisms for a drug interaction are discussed.\n\n\nMETHODS\nA 68-year-old woman who was receiving chronic treatment with NSAIDs and chloroquine developed dizziness, anxiety, and tremors when ciprofloxacin 500 mg twice daily was begun for Salmonella osteitis. When she discontinued the antirheumatic treatment, there was a prompt relief of symptoms. After indomethacin was reintroduced, the patient developed signs and symptoms of peripheral neuropathy, which partially subsided when ciprofloxacin was discontinued.\n\n\nCONCLUSIONS\nEnhanced neurologic adverse effects of ciprofloxacin when taken together with NSAIDs or chloroquine may result from reduced effects of gamma-aminobutyric acid. An alternative explanation could be that NSAIDs and chloroquine impair the elimination of ciprofloxacin, thereby contributing to toxic concentrations of the antibiotic.\n\n\nCONCLUSIONS\nThe possibility of interactions between ciprofloxacin and antirheumatic drugs should be considered.",
"affiliations": "Department of Infectious Diseases, Lund University Hospital, Sweden.",
"authors": "Rollof|J|J|;Vinge|E|E|",
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"issue": "27(9)",
"journal": "The Annals of pharmacotherapy",
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"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002738:Chloroquine; D002939:Ciprofloxacin; D004244:Dizziness; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D010523:Peripheral Nervous System Diseases; D013575:Syncope",
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"references": null,
"title": "Neurologic adverse effects during concomitant treatment with ciprofloxacin, NSAIDS, and chloroquine: possible drug interaction.",
"title_normalized": "neurologic adverse effects during concomitant treatment with ciprofloxacin nsaids and chloroquine possible drug interaction"
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"abstract": "Direct oral anticoagulants can potentially provide a more convenient oral alternative for the management of left ventricular thrombi than Warfarin. These medications do not require frequent monitoring and have less drug-drug interactions. Randomized controlled trials are needed to further demonstrate their efficacy and safety in this setting.",
"affiliations": "Division of Cardiology, Department of Internal Medicine Wayne State University/Detroit Medical Center Detroit Michigan.;Department of Internal Medicine Wayne State university/Detroit Medical Center Detroit Michigan.;Department of Internal Medicine Wayne State university/Detroit Medical Center Detroit Michigan.;Department of Internal Medicine Wayne State university/Detroit Medical Center Detroit Michigan.;Division of Interventional Cardiology Wayne State University/Detroit Medical Center Detroit Michigan.;Division of Cardiology, Department of Internal Medicine Wayne State University/Detroit Medical Center Detroit Michigan.;Division of Cardiology, Department of Internal Medicine Wayne State University/Detroit Medical Center Detroit Michigan.",
"authors": "Shokr|Mohamed|M|;Ahmed|Abdelrahman|A|0000-0001-9285-7535;Abubakar|Hossam|H|;Sayedahmad|Ziad|Z|;Rashed|Ahmed|A|;Afonso|Luis|L|;Cardozo|Shaun|S|",
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"country": "England",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1917CCR31917Case ReportCase ReportsUse of direct oral anticoagulants in the treatment of left ventricular thrombi: A tertiary center experience and review of the literature SHOKR et al.Shokr Mohamed \n1\nAhmed Abdelrahman http://orcid.org/0000-0001-9285-7535amahmed@med.wayne.edu \n2\nAbubakar Hossam \n2\nSayedahmad Ziad \n2\nRashed Ahmed \n3\nAfonso Luis \n1\nCardozo Shaun \n1\n\n1 \nDivision of Cardiology, Department of Internal Medicine\nWayne State University/Detroit Medical Center\nDetroit\nMichigan\n\n2 \nDepartment of Internal Medicine\nWayne State university/Detroit Medical Center\nDetroit\nMichigan\n\n3 \nDivision of Interventional Cardiology\nWayne State University/Detroit Medical Center\nDetroit\nMichigan\n* Correspondence\n\nAbdelrahman Ahmed, Department of Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, MI.\n\nEmail: amahmed@med.wayne.edu\n22 11 2018 1 2019 7 1 10.1002/ccr3.2019.7.issue-1135 142 16 2 2018 06 10 2018 16 10 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nDirect oral anticoagulants can potentially provide a more convenient oral alternative for the management of left ventricular thrombi than Warfarin. These medications do not require frequent monitoring and have less drug‐drug interactions. Randomized controlled trials are needed to further demonstrate their efficacy and safety in this setting.\n\nApixabandirect oral anticoagulantsDOACsleft ventricular thrombusRivaroxabanthrombolysis source-schema-version-number2.0component-idccr31917cover-dateJanuary 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:15.01.2019\n\n\nShokr \nM \n, \nAhmed \nA \n, \nAbubakar \nH \n, et al. Use of direct oral anticoagulants in the treatment of left ventricular thrombi: A tertiary center experience and review of the literature . Clin Case Rep . 2019 ;7 :135 –142 . 10.1002/ccr3.1917\n==== Body\n1 BACKGROUND\nLeft ventricular thrombus (LVT) is a common complication following acute myocardial infarction (AMI) with potential for significant morbidity and mortality. While it complicates different forms of cardiomyopathies and coagulopathies; the most commonly encountered clinical scenario for LVT remains ST‐elevation myocardial infarction (STEMI), particularly anterior STEMI. The incidence of LVT has been declining with the evolvement of the treatment of acute myocardial infarction. It ranges between 2.9% and 15.2% in the era of primary PCI as opposed to 40% and 28% in the prethrombolytic and thrombolytic eras, respectively. The decreased incidence is attributed to earlier reperfusion and aggressive use of antiplatelet and antithrombin therapy.1 LVT is associated with a significant risk of systemic embolism. In the prethrombolytic era, ischemic embolic stroke complicated 0.8%‐5.5% of anterior STEMI with LVT being the most likely origin especially with postmortem studies showing that 46% of acute myocardial infarction (MI) patients had LVT.2, 3 A meta‐analysis of 11 studies concluded that the risk of embolization with echocardiography‐demonstrated LV thrombi after anterior MI is five times higher compared to patients without evidence of thrombi on echocardiography.4 Development of LV thrombus is related to Virchow's triad of stasis, endothelial injury, and hypercoagulable state. These components are commonly present following MI, especially anterior MI.2 Other factors that increase risk of thrombus formation are advanced age, high levels of C‐reactive protein, presence of apical aneurysm, and low ejection fraction.5\n\n\nOral anticoagulation with Warfarin is the currently recommended and most evidence‐based therapy. We report our tertiary center experience with the use of Rivaroxaban and Apixaban for treatment of patients with LVT.\n\n2 CASES\n2.1 Case 1\nA 70‐year‐old man with history of hypertension and diabetes mellitus (DM) presented with chest pain due to anterolateral STEMI for which he underwent percutaneous coronary intervention (PCI) of the left circumflex (LCX) with a drug‐eluting stent. There was a chronic total occlusion of the left anterior descending (LAD) as well. A transthoracic echocardiogram (TTE) revealed an ejection fraction (EF) of 10%‐15% with akinetic septum, mid to apical anterior and lateral walls; dyskinetic apex and an echodensity measuring 38 × 18 mm at its greatest dimension suggestive of a thrombus (Figure 1A). HAS BLED score was 1. He was discharged on Aspirin, Clopidogrel, and Rivaroxaban (15 mg daily for 3 weeks then 20 mg daily). A TTE 3 months later revealed resolution of the previously seen LVT and improvement in EF to 35% (Figure 1B).\n\nFigure 1 A, Apical four chamber view showing the LV thrombus of case one. B, Resolution of the thrombus after three months of anticoagulation with Rivaroxaban\n\n2.2 Case 2\nA 63‐year‐old male with history of gout presented with shortness of breath and chest pain. He was found to have new‐onset heart failure due to a completed anterior myocardial infarction for which he underwent PCI to LAD and first diagonal with drug‐eluting stents preceded by rotational atherectomy. TTE showed an EF of 10% with severe akinesia of the apex; anterior, anterolateral, and mid to distal anteroseptal walls with a 12 × 9 mm thin layered mural thrombus. He received intravenous heparin for 7 days while inpatient. HAS BLED score was 1. He was started on Aspirin and Clopidogrel. Due to concerns of compliance with Warfarin, he was discharged on Rivaroxaban 20 mg daily instead. A TTE 4 months later showed resolution of the LVT.\n\n2.3 Case 3\nA 58‐year‐old man with history of DM, presented with shortness of breath due to new‐onset heart failure secondary to a completed anterior infarction. He underwent PCI to the right coronary artery (RCA) with drug‐eluting stents in the proximal and mid portions. A TTE showed an EF of 10% and a large 18 × 8 mm nonmobile apical thrombus. HAS BLED score was 2 He was discharged on 20 mg of Rivaroxaban in addition to Aspirin and Clopidogrel. A TTE, 3 months later, showed complete resolution of the previously reported thrombus.\n\n2.4 Case 4\nA 69‐year‐old man with history of ischemic cardiomyopathy presented with acute dyspnea. TTE showed a left ventricular (LV) ejection fraction of 10% with global hypokinesis and a 11 × 13 mm apical LVT. HAS BLED score was 3. He was discharged on Aspirin, Clopidogrel, and Rivaroxaban 20 mg daily which he stopped 40 days later for gastrointestinal bleeding secondary to vascular malformations; however, a follow‐up TTE performed 6 months later showed complete resolution of the LVT.\n\n2.5 Case 5\nA 60‐year‐old male with no past medical history presented with shortness of breath and lower extremity edema due to decompensated heart failure following a completed anterior myocardial infarction. TTE showed an EF of 10%‐15%, global hypokinesis and a 19 × 12 mm left ventricular apical thrombus (Figure 2A). HAS BLED score was 0. Due to compliance concerns, he was started on Apixaban 5 mg twice daily following 2 days of intravenous heparin. In addition, he was also discharged on Aspirin and Clopidogrel. He discontinued the medication one month later; however, a follow‐up TTE 4 months from the diagnosis showed complete resolution of the thrombus (Figure 2B).\n\nFigure 2 A, Apical four chamber view showing the LV thrombus of case five. B, Resolution of the thrombus after four months of anticoagulation with Apixaban\n\n2.6 Case 6\nA 28‐year‐old female with history of hypertension presented with worsening shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, and bilateral leg swelling of 1‐week duration. TTE showed global hypokinesia, bilateral ventricular enlargement with an EF of 10%‐15% and a large echodensity in the apical inferolateral aspect of the left ventricle measuring 36 mm × 15 mm consistent with a thrombus. HAS BLED score was 1. Due to compliance concerns, Apixaban 5 mg twice daily was started instead of Warfarin. In addition, he continued to take Aspirin. Complete resolution of the LV thrombus was noted on TTE 10 months later.\n\n2.7 Case 7\nA 68‐year‐old male with history of nonischemic cardiomyopathy (NICM) and stroke presented with shortness of breath due to decompensated heart failure. TTE revealed an EF of 25%, and an 8 mm pedunculated apical echodensity consistent with a thrombus. HAS BLED score was 3. Due to patient's reluctance to comply with Warfarin, Apixaban 2.5 mg twice daily was started. He also continued Aspirin and Clopidogrel for his previous stroke. Two months later, follow‐up TTE revealed resolution of the thrombus.\n\n2.8 Case 8\nA 62‐year‐old male with past history of alcohol abuse presented with sub‐sternal chest pain due to an anetroseptal STEMI for which he had PCI to mid‐LAD with a drug‐eluting stent. TTE showed an EF of 15%‐20%, akinesis of the mid‐anterior wall, anteroseptal wall and apex in addition to two echogenic masses attached to the LV apex consistent with LV thrombi with the larger measuring 20 mm × 12 mm. HAS BLED score was 1. Apixaban 5 mg twice daily was started, in addition to Aspirin and Ticagrelor. Seven months later, a follow‐up TTE showed resolution of the thrombi.\n\n3 RESULTS\nDiagnosis of LVT was confirmed by the interpretation of one cardiologist in each patient. Out of the eight patients reported in this series, seven were males. The mean age was 59.7 years and the mean time until thrombus resolution was 4.8 months. Six patients (75%) had underlying ischemic heart disease and 50% of LVT developed in the setting of acute STEMI. Only three patients were on antiplatelet therapy prior to developing the LVT. All patients continued on DOACs with antiplatelet therapy (87.5% received dual antiplatelet therapy and only one patient received Aspirin alone) after LVT was diagnosed. Despite the increased bleeding risk with combined anticoagulation and dual antiplatelet therapy (Triple therapy),6 there was only one case were Rivaroxaban was stopped after 6 weeks due to GI bleeding related to arteriovenous malformations. In patients who received Rivaroxaban, 75% received the dosing for nonvalvular AF (20 mg daily if the creatinine clearance is >50 mL/min) and one patient received the DVT/PE dosing at the provider's discretion. In patients who received Apixaban, nonvalvular AF doses were used.7\n\n\n4 DISCUSSION\nThe diagnosis of left ventricular thrombosis can be established by cardiac imaging with transthoracic echocardiography (TTE) being the preferred screening modality.8 The role of the direct oral anticoagulants (DOACs) Apixaban and Rivaroxaban in preventing strokes in atrial fibrillation (AF) patients has been established as reflected in the 2014 guidelines by the American Heart Association/American Stroke Association (AHA/ASA) which recommend either Warfarin or Apixaban for recurrent stroke prevention in AF patients (Class I; Level of Evidence A) with Rivaroxaban designated a Class IIa indication (Level of Evidence B). However, Warfarin, a vitamin K antagonist (VKA) remains the drug of choice in patients with acute MI complicated by LVT (Class I; Level of Evidence C). Low‐molecular‐weight Heparin (LMWH), dabigatran, Rivaroxaban, or Apixaban for 3 months are to be considered as alternatives in this setting when patients are intolerant to VKA therapy because of adverse events that are nonhemorrhagic in nature (Class IIb; Level of Evidence C).6, 9, 10 It is recommended that anticoagulation is initiated as soon as LVT is detected.11\n\n\nWarfarin remains the first‐line choice because of the lack of studies demonstrating the efficacy and safety of DOACs in this cohort of patients. It affects the anticoagulation cascade at multiple steps and carries the advantage of effective reversal in case of bleeding. However, it poses a challenge to both clinicians and patients and its use is declining in favor of DOACs because of its narrow therapeutic index, the need for constant monitoring, dietary restrictions, and extensive drug‐drug interactions.12 DOACs are currently used for various indications including prevention of stroke and systemic embolism in nonvalvular atrial fibrillation (AF), venous thromboembolism (VTE) prophylaxis in major orthopedic surgery, treatment of acute VTE and prevention of recurrent VTE.13\n\n\nRecently, several case reports of successful resolution of LV thrombi DOACs were published. To our knowledge, this is the largest case series to date documenting the effectiveness of these medications in treating LVT. Apixaban and Rivaroxaban are two factor Xa (FXa) inhibitors approved for anticoagulation in the United States.6 Their rapid onset and offset make bridging therapy unnecessary which is a convenient peri‐procedural option.14 In contrast to VKAs, FXa can potentially prevent de novo thrombi and resolve established ones by directly inhibiting free and thrombus‐associated FXa. They reduce the generation of clot‐induced fibrinopeptide A in a similar fashion to hirudin; a potent inhibitor of thrombin.15\n\n\nRivaroxaban was approved for the treatment of nonvalvular atrial fibrillation, deep venous thrombosis, and pulmonary embolism. It has the added advantage of loosening the plasma fibrin network by modifying it to thicker fibers and larger pores, therefore allowing for greater flow permeation through the clots, rendering them more sensitive to fibrinolytics.16 In patients with recent STEMI, combined use of Rivaroxaban and antiplatelets reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Despite the increase in major bleeding compared to placebo, fatal bleeding was not significantly increased.17 There is increasing evidence questioning the efficacy of VKA to resolve large intracardiac thrombi. Of note, left atrial appendage (LAA) thrombi persisted in 40% of patients undergoing VKA treatment.18 Kawano et al reported successful resolution a right atrial thrombus after failure of Warfarin.19\n\n\nApixaban is characterized by rapid absorption, more than 50% bioavailability, time to peak activity of 2.5‐4 hours, a half‐life of 12 hours (Warfarin is 40 hours) and 25% renal excretion. Moreover, it has predictable pharmacokinetics and can be administered with fixed doses without the need for regular monitoring which makes it a more attractive option for patients and health care providers alike.12, 20\n\n\nMany studies support the efficacy of these agents in thrombolysis but no randomized trial specifically examined their use in LVT treatment. The Apixaban Versus Acetylsalicylic acid to Prevent Stroke (AVERROES) trial compared Apixaban versus Aspirin in nonvalvular AF patients who were not suitable candidates for Warfarin treatment and was terminated early due to the strong evidence of Apixaban superiority over Aspirin.6 Patients in this trial were followed up for a mean of 1.1 years. Fifty‐one patients in the Apixaban arm developed stroke or systemic embolism compared to 113 in the Aspirin arm (HR 0.45; 95% CI, 0.32‐0.62). Both medications showed comparable risk of major bleeding (1.4%) (1.2%; HR with Apixaban, 1.13; 95% CI, 0.74‐1.75).6 Apixaban efficacy and side effects were well studied against Warfarin mainly in patients with atrial fibrillation. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial was a double‐blind study that randomly assigned patients to receive either Warfarin or Apixaban with a sample size of 18 201 patients. In this study, Apixaban decreased the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11% compared to Warfarin. It was also associated with lower rates of gastrointestinal bleeding and lower bleeding rates across age‐groups.21 Makrides CA demonstrated that short‐duration Rivaroxaban at a low dose (15 mg/d) in combination with a dual antiplatelet therapy (DAPT) was effective for the treatment of left ventricular (LV) thrombus in patients with acute coronary syndromes and drug‐eluting stent implantation, and at low to intermediate bleeding risk.22 Resolution of LVT can be confirmed by follow‐up TTE.2 The exact time for resolution of the thrombus varies in each patient. A study of 29 patients suffering from LVT after MI demonstrated the resolution of thrombus in 34% of the patients within 6 months of starting treatment.23 The 2014 AHA/ASA guidelines recommend for a duration of treatment with oral anticoagulants for 3 months while the European Society of Cardiology 2017 STEMI guidelines recommend a longer duration of treatment up to 6 months.6, 11 Based on this, a follow‐up TTE every 3 to 6 months is a reasonable recommendation.\n\nReview of the literature demonstrates different doses of DOACs implemented in the management of LVT. Full dose of anticoagulation (5 mg BID for Apixaban and 20 mg daily for Rivaroxaban) and low doses (2.5 mg BID for Apixaban and 15 mg daily for Rivaroxaban) have been used. We have also used different doses in our patients because of the lack of evidence at that time (Table 1). However, in the setting of dual antiplatelet therapy (DAPT), DOACs increase the risk of bleeding.24 Therefore, it is recommended that low doses of DOACs are to be used when combined with low dose Aspirin and Clopidogrel.25\n\n\nTable 1 Comparison between PubMed‐reported cases between 2012 and 2017 and our 8 cases\n\nCase\tAge\t\nGender\n\nM: male\n\nF: female\n\tEtiology\tSize (mm)\tHAS‐BLED\tAntiplatelets/Anticoagulants prior to diagnosis\t\nDOAC\n\nDose & duration\n\t\nPostdiagnosis\n\nAntiplatelets/anticoagulants\n\tComplications\tFollow‐up echo\t\nCase 1\t70\tM\tSTEMI\t38 × 18\t1\tNone\tRivaroxaban 15 mg twice daily for 3 wk then 20 mg daily for 3 mo\tAspirin + Clopidogrel\tNone\t3 mo later → resolution\t\nCase 2\t63\tM\tSTEMI\t12 × 9\t1\tNone\tRivaroxaban 20 mg daily for 4 mo\t\nHeparin (10 d)\n\nAspirin +Clopidogrel\n\tNone\t4 mo later → resolution\t\nCase 3\t58\tM\tSTEMI\t18 × 8\t2\tNone\tRivaroxaban 20 mg daily for 3 mo\t\nHeparin (4 d)\n\nAspirin+ Clopidogrel\n\tNone\tResolution after 3 mo\t\nCase 4\t69\tM\tIschemic cardiomyopathy\t11 × 13\t3\tAspirin + Clopidogrel\tRivaroxaban 20 mg daily for 6 mo\tAspirin + Clopidogrel\t\nAfter 6 wk → GI bleed (AV malformation)\n\nSwitched to ASA/Clopidogrel\n\t5 mo later → resolution\t\nCase 5\t60\tM\tIschemic cardiomyopathy\t19 × 12\t0\tNone\tApixaban 5 mg twice a day for 4 mo\tAspirin + Clopidogrel\tNone\t4 mo later → resolution\t\nCase 6\t28\tF\tNonischemic cardiomyopathy\t36 × 15\t1\tAspirin\tApixaban 5 mg twice a day for 10 mo\tAspirin\tNone\t10 mo later → resolution\t\nCase 7\t68\tM\tNonischemic cardiomyopathy\t8\t3\tAspirin + Clopidogrel\tApixaban 2.5 mg twice a day for 2 mo\tAspirin + Clopidogrel\tNone\t2 mo later → resolution\t\nCase 8\t62\tM\tSTEMI\tTwo masses ,the largest measuring 12 × 20\t1\tNone\tApixaban 5 mg twice a day for 7 mo\tAspirin + Ticagrelor\t\t7 mo later → resolution\t\nMakrides22\n\t52\tM\tSTEMI\tN/A\t1\tNone\t\n15 mg\n\n3 mo\n\tAspirin + Clopidogrel\tNone\tResolution after 1 mo\t\nMakrides22\n\t75\tM\tSTEMI\tN/A\t2\tNone\t\n15 mg\n\n3 mo\n\tAspirin + Prasugrel (switched to Clopidogrel)\tNone\tResolution after 1 mo\t\nMakrides22\n\t69\tF\tSTEMI\tN/A\t2\tNone\t\n15 mg\n\n3 mo\n\tAspirin + Ticagrelor (switched to Clopidogrel)\tNone\tResolution after 2 wk\t\nPadilla Pérez et al29\n\t78\tM\tDilated cardio‐myopathy\tN/A\tNA\tNone\t\n15 mg\n\n1 mo\n\tNone\tNone\t1 mo (resolution)\t\nAzizi et al30\n\t54\tM\tSTEMI\tN/A\t1\tNone\t\n20 mg\n\n1 mo\n\tAspirin, Prasugrel (switched to Clopidogrel)\tNone\t1 mo (resolution )\t\nLas Casas et al31\n\t61\tM\tChaga's disease\t12.39 × 25.95\tNA\tAspirin + Clopidogrel + Warfarin\t\n20 mg\n\n20 mo\n\tNone\tNone\tResolution after 40 d\t\nNakasuka et al16\n\t42\tM\tTachy‐cardia induced cardio‐myopathy\t20 × 10\tNA\tNone\t\n15 mg\n\n7 d\n\t\nHeparin+Warfarin (5 d)\n\nSwitched to Rivaroxaban\n\tNone\t7 d (resolution)\t\nMaki et al32\n\t21\tF\tProtein C deficiency\t26 × 20\tNA\tNone\t\n15 mg\n\n2.8 y\n\t\nHeparin (6 d)\n\nWarfarin (4 d)\n\nArgatroban (2 d )\n\tNone\tResolution, 24 d from initial treatment\t\nJamal et al33\n\t39\tM\tSTEMI\tN/A\tNA\tNone\t\n20 mg\n\n6 wk\n\tAspirin + Clopidogrel\tNone\tResolution after 5 wk\t\nDi Nisioet al34\n\t52\tM\tCancer related thrombosis\t30\tNA\tNone\t15 mg daily for 3 wk, followed by 20 mg daily for 4 mo\tAspirin + Clopidogrel\tNone\t4 mo (40% size reduction)\t\nJohn Wiley & Sons, LtdDespite the encouraging data that support the use of DOACs in prevention of thromboembolism, they have a few disadvantages. They are more expensive than Warfarin. Apixaban in particular requires adjusting the dose for age, weight, and kidney function. Patients who meet two of the following three criteria (a) age >80; (b) weight less than 60 kg; (c) creatinine level more than 1.5, must receive 2.5 mg two times a day, which is half the usual dose.12 The fact that these agents do not require monitoring is an advantage but can make it difficult to assess patients' adherence to treatment.\n\nMajor bleeding has been a potential complication noted with the use of anticoagulants. In a meta‐analysis of nine studies involving 51 533 patients, the mean pooled rates of any major bleeding, major GI bleeding, and intracranial hemorrhage (ICH) with Rivaroxaban were 3.32 (95% CI 2.28‐4.25); 2.41, (95% CI 1.25‐3.56) and 0.40 (95% CI 0.17‐0.74) events/100 patient‐years, respectively. Despite significant heterogeneity among those studies, the pooled rates of major bleeding were still low and consistent with those reported in ROCKET AF trial.26, 27 In our study, only one patient suffered from GI bleeding requiring blood transfusion 2 months after starting Rivaroxaban. The patient had an episode of melena 8 months prior to starting Rivaroxaban and endoscopy at that time showed duodenal arteriovenous malformations, so it is difficult to link this episode entirely to Rivaroxaban use. Rivaroxaban was discontinued, and the patient remained on Aspirin and Clopidogrel and an echo, 4 months later, revealed resolution of the thrombus. We included eight case reports from the literature where patients received DOACs for LVT with no reported GI bleeding. Other advantages for DOACs over Warfarin include fewer drug interactions with some antimicrobial, antifungal, and antiviral medications that involve CYP3A4 and Pgp metabolic pathways.28\n\n\nOur cases add to the body of evidence supporting the efficacy of DOACs in treating LV thrombi. However, this case series is not without its limitations. First, it demonstrated the role of DOACs in only eight patients. Second, the timing of follow‐up echocardiographic examinations was not standardized which makes it difficult to ascertain the exact timing of thrombus resolution in our patients.\n\nTable 1 combines all the reported cases in the literature compared to our case series.\n\nCONFLICT OF INTEREST\nThe primary author has no disclosures.\n\nAUTHOR CONTRIBUTIONS\nMS: drafted the first version of the manuscript particularly the Rivaroxaban discussion, acquisition of clinical images. AA: wrote the discussion about Apixaban, reviewed flow of information in the manuscript, analyzed patient data, critically analyzed the manuscript, and responded to reviewers comments. HA: analyzed and collected patient data. ZS: analyzed and collected patient data. AR: involved in critical revision of manuscript for intellectual content. LA: involved in critical revision of manuscript for intellectual content. SC: involved in critical revision of manuscript for intellectual content.\n==== Refs\nREFERENCES\n1 \n\nDriesman \nA \n, \nHyder \nO \n, \nLang \nC \n, \nStockwell \nP \n, \nPoppas \nA \n, \nDawn Abbott \nJ \n. Incidence and predictors of left ventricular thrombus after primary percutaneous coronary intervention for anterior ST‐segment elevation myocardial infarction . Clin Cardiol . 2015 ;38 (10 ):590 ‐597 .26417910 \n2 \n\nStokman \nPJ \n, \nNandra \nCS \n, \nAsinger \nRW \n. Left ventricular thrombus . 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Circ Res . 2012 ;111 (8 ):1069 ‐1078 .23023509 \n16 \n\nNakasuka \nK \n, \nIto \nS \n, \nNoda \nT \n, et al., Resolution of left ventricular thrombus secondary to tachycardia‐induced heart failure with rivaroxaban . Case Rep Med . 2014 ;2014 :1 ‐5 .\n17 \n\nRuff \nCT \n, \nGiugliano \nRP \n, \nBraunwald \nE \n, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta‐analysis of randomised trials . Lancet . 2014 ;383 (9921 ):955 ‐962 .24315724 \n18 \n\nHammerstingl \nC \n, \nPötzsch \nB \n, \nNickenig \nG \n. Resolution of giant left atrial appendage thrombus with rivaroxaban . Thromb Haemost . 2013 ;109 :583 ‐584 .23348106 \n19 \n\nMega \nJL \n, \nBraunwald \nE \n, \nMurphy \nSA \n, et al. Rivaroxaban in patients stabilized after a ST‐segment elevation myocardial infarction: results from the ATLAS ACS‐2–TIMI‐51 Trial (anti‐Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome‐thrombolysis in myocardial infarction‐51) . J Am Coll Cardiol . 2013 ;61 (18 ):1853 ‐1859 .23500262 \n20 \n\nHanley \nCM \n, \nKowey \nPR \n. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? \nJ Thorac Dis . 2015 ;7 (2 ):165 .25713732 \n21 \n\nGranger \nCB \n, \nAlexander \nJH \n, \nMcMurray \nJ \n, et al. Apixaban versus warfarin in patients with atrial fibrillation . N Engl J Med . 2011 ;365 (11 ):981 ‐992 .21870978 \n22 \n\nMakrides \nCA \n. Resolution of left ventricular postinfarction thrombi in patients undergoing percutaneous coronary intervention using rivaroxaban in addition to dual antiplatelet therapy . BMJ Case Rep . 2016 ;2016 .\n23 \n\nKeren \nA \n, \nGoldberg \nS \n, \nGottlieb \nS \n, et al. Natural history of left ventricular thrombi: their appearance and resolution in the posthospitalization period of acute myocardial infarction . J Am Coll Cardiol . 1990 ;15 (4 ):790 ‐800 .2307788 \n24 \n\nDewilde \n\n\nWJ \n, \nOirbans \n, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention . Lancet . 2013 ;381 :1107 ‐1115 .23415013 \n25 \n\nLip \nG \n, \nWindecker \nS \n, \nHuber \nK \n, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia‐Pacific Heart Rhythm Society (APHRS) . Eur Heart J . 2014 ;35 (45 ):3155 ‐3179 .25154388 \n26 \n\nWeeda \nER \n, \nWhite \nCM \n, \nPeacock \nWF \n, \nColeman \nCI \n. Rates of major bleeding with rivaroxaban in real‐world studies of nonvalvular atrial fibrillation patients: a meta‐analysis . Curr Med Res Opin . 2016 ;32 (6 ):1117 ‐1120 .26934003 \n27 \n\nPatel \nMR \n, \nMahaffey \nKW \n, \nGarg \nJ \n, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation . N Engl J Med . 2011 ;365 (10 ):883 ‐891 .21830957 \n28 \n\nLee \nLH \n. DOACs – advances and limitations in real world . Thromb J . 2016 ;14 (1 ):17 .27766043 \n29 \n\nPadilla Pérez \nM \n, \nSalas Bravo \nD \n, \nGarcelán Trigo \nJA \n, et al. Resolution of left ventricular thrombus by rivaroxaban . Future Cardiol . 2014 ;10 (3 ):333 ‐336 .24976470 \n30 \n\nAzizi \nA \n, et al. Rivaroxaban dissolves postinfarction left ventricular thrombus . Cardiovasc Med . 2016 ;19 :25 ‐27 .\n31 \n\nLas Casas \nAA \n, \nBorges \nM \n, \nMelo‐Souza \nSE \n. Rivaroxaban for treatment of intraventricular thrombus in Chagas disease . J Cardiol Cases . 2016 ;13 (3 ):75 ‐77 .30546610 \n32 \n\nMaki \nH \n, \nNishiyama \nM \n, \nShirakawa \nM \n. Simultaneous left ventricular and deep vein thrombi caused by protein C deficiency . Case Rep Med . 2017 ;2017 :1 ‐4 .\n33 \n\nJamal \nN \n, \nBapumia \nM \n. Dual antiplatelet agents and Rivaroxaban for massive intracoronary thrombus in STEMI . Clin Case Rep . 2015 ;3 (11 ):927 ‐931 .26576274 \n34 \n\nDi Nisio \nM \n, \nCarella \nC \n, \nNatoli \nC \n, et al. Rivaroxaban for cancer‐associated cardiac thrombosis . Am J Med . 2015 ;128 (10 ):e43 –e44 .\n\n",
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"title": "Use of direct oral anticoagulants in the treatment of left ventricular thrombi: A tertiary center experience and review of the literature.",
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"abstract": "Primary squamous cell carcinoma (SCC) of the pancreas is a rare tumor and associated with poor prognosis. The diagnosis and optimal management of patients is still a matter of debate and not well-defined. Limited chemotherapy protocols, radiotherapy and surgical resection of the tumor were proposed for the management of patients suffering from SCC of the pancreas.\nIn this report, we introduced a 57-year-old man who was diagnosed with SCC of the pancreas along with liver metastasis. The patient underwent surgical resection and several adjuvant systemic chemotherapies including fluorouracil and taxane based regimens which were led to the 13- month overall survival.\nAlthough, the patients died from underlying tumor, the survival time before death was one of the longest time/period reported.",
"affiliations": "Department of Clinical Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.;Department of Internal Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Department of Clinical Pharmacy, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.;Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Department of Clinical Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.",
"authors": "Farokhi|Pegah|P|;Sadeghi|Alireza|A|;Moghaddas|Azadeh|A|;Heidarpour|Mitra|M|;Dinari|Saman|S|",
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"fulltext": "\n==== Front\nCaspian J Intern Med\nCaspian J Intern Med\nCJIM\nCaspian Journal of Internal Medicine\n2008-6164\n2008-6172\nBabol University of Medical Sciences Babol, Iran\n\n10.22088/cjim.12.0.407\nCase Report\nPrimary Squamous Cell Carcinoma, a Rare Pathological Report of Pancreatic Cancer\nFarokhi Pegah 1\nSadeghi Alireza MD 2\nMoghaddas Azadeh PharmD, 3*\nHeidarpour Mitra MD 4\nDinari Saman 1\n1 Department of Clinical Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran\n2 Department of Internal Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran\n3 Department of Clinical Pharmacy, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran\n4 Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran\n* Correspondence: Azadeh Moghaddas, Department of Clinical Pharmacy, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail: azadeh_moghaddas@yahoo.com, Tel: 0098 3137927074, Fax: 0098 3137927074\n2021\n12 Suppl 2 S407S412\n15 4 2020\n2 9 2020\n3 10 2020\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground:\n\nPrimary squamous cell carcinoma (SCC) of the pancreas is a rare tumor and associated with poor prognosis. The diagnosis and optimal management of patients is still a matter of debate and not well-defined. Limited chemotherapy protocols, radiotherapy and surgical resection of the tumor were proposed for the management of patients suffering from SCC of the pancreas.\n\nCase Presentation:\n\nIn this report, we introduced a 57-year-old man who was diagnosed with SCC of the pancreas along with liver metastasis. The patient underwent surgical resection and several adjuvant systemic chemotherapies including fluorouracil and taxane based regimens which were led to the 13- month overall survival.\n\nConclusion:\n\nAlthough, the patients died from underlying tumor, the survival time before death was one of the longest time/period reported.\n\nKey Words\n\nPrimary squamous cell\nCarcinoma\nPancreatic cancer\nSurvival\nChemotherapy\n==== Body\npmcPancreatic cancer, generally refers to a ductal adenocarcinoma of the pancreas, is categorized as a highly aggressive tumor and estimated to become the second leading cause of cancer-related deaths by 2030 (1). Exocrine elements are responsible for more than 95 percent of malignant neoplasms of the pancreas while adenocarcinoma represented approximately 85 percent of all pancreatic neoplasms. Of the several subtypes of ductal adenocarcinoma, mostly have a similar poor long-term prognosis. The more distinct term \"exocrine pancreatic neoplasms\" compose all tumors that are caused by the pancreatic ductal, acinar cells and their stem cells (2). Squamous cell carcinoma (SCC) is a subtype of ductal carcinoma, a non-endocrine part. It is one of the rare subtypes of pancreatic malignancy that correlates with poor prognosis. It is accounting for 0.5-2% of all malignancy of the pancreas (3). The diagnosis and optimal management of SCC of pancreas remains poorly defined. There is no available standard treatment protocol or guidelines for the management of SCC of pancreas mainly due to the rarity of the disease. Surgical resection, chemotherapy, and radiation were proposed as therapeutic approaches (2). Herein, a case of advanced SCC of the pancreatic with liver metastasis was reported. The patient underwent surgical resection followed by adjuvant chemotherapy by fluorouracil and taxane-based regimens.\n\nCase presentation\n\nA 57yearold man, with a known case of hypertension, was admitted at the emergency room of Milad hospital, Isfahan, Iran, in June 2018, with chief complaints of right abdominal pain (epigastric pain radiating to back and shoulder), vomiting, weight loss (more than 10 kg over the last 6 months) and weakness.\n\nHe had no history of smoking or alcohol consumption. The primary physical examination had tenderness in his left upper abdomen and paleness in the face. Initial investigations at the emergency room revealed that his baseline serum amylase (15.59 IU/l), lipase (17.16 U/l) and other routine laboratory test were within normal limits. However, the serum levels of carbohydrate antigen (CA) 19–9 (112.7IU/mL, reference: 0–37IU/mL) and CA-125 (239.3IU/mL, reference: 0–40IU/mL) were elevated.\n\nAn upper gastrointestinal endoscopy had no major finding except an ignorable mucosal swelling. However, in ultrasonography investigation, hypoechoic and heterogeneous mass with size 66*71 cm in the head of the pancreas, and porta hepatitis mass suspicious to lymphadenopathy involvement have been detected. Abdominal and pelvic computed tomography (CT) has been considered for confirming the diagnosis and heterogeneous enhancing mass lesion measured 8.8x1.6.8.x1 cm in the pancreas’s head (figure 1) was reported accordingly. In addition, the mass displaced superior mesenteric vein (SMV), dilated the pancreatic duct and intra and extrahepatic bile duct (common bile duct was 20 mm in diameter).\n\nFigure 1 Computed tomography image showing an 8.8 x1.6.8 x1 cm mass in the head of pancreas\n\nFor further evaluation, patient was sent to oncology clinic of Omid Hospital, Isfahan, Iran affiliated to Isfahan University of Medical Sciences, specialized for the treatment of cancer patients. At first, the patient referred to surgical oncologist and due to tumor confirmation, the surgeon decided to perform tumor resection and tumor biopsy gathering during open pancreatomy surgery. Adenosquamous carcinoma, pancreatoblastoma and metastatic SCC from another primary site were contemplated as differential diagnosis.\n\nAfter surgery, the resected sample from the operating room including part of gastric and intestine tissue in the length of 36 cm and pancreas tissue in the 7*8*9 mm dimension were sent for histopathological evaluation. In microscopic examination, there was evidence of tumor cells with high nucleus- cytoplasm ratio, large nuclei, well-defined nucleus and pleomorphism. Highly mitotic activity with atypical mitosis and granular eosinophilic cytoplasm was also observed (figure 2). In addition, immunohistochemical (IHC) staining revealed that the samples were positive for CK5/6 and P63 markers, sensitive markers for squamous differentiation, which had confirmed our diagnosis (Figure 3). The patient was diagnosed as a case of poorly differentiated (basaloid) squamous cell carcinoma of pancreas, a rare condition, which arises from the pancreatic duct. All surgical margins including bile duct/choledochal surgical were free of tumor invasion. Although, 2 out of 6 resected lymph nodes were involved by tumor invasion and evidence of vascular invasion was seen, the invasion of the superior mesenteric artery (SMA) could not be assessed. The staging was confirmed as stage 2b (T3N1M0). Extensive workup was performed to evaluate other primary sources and metastatic disease did not indicate any head and neck malignancy.\n\nFigure 2 Markedly pleomorphic tumor cells in diffuse sheets showed clouds of squamous cells with keratin pearls displaying in the hemorrhagic necrotic tissue (hematoxylin and eosin staining, magnification, x200)\n\nThe patient tolerated the chemotherapy regimen well except a mild nausea and vomiting episode which was managed by 80 mg granisetron intravenously (IV). Vital signs, liver and renal functions were normal, and the patient was hemodynamically stable. The Eastern Cooperative Oncology Group (ECOG) performance status of patient was 1. The oncologist considered the adjuvant chemotherapy with a combination of 5-fluorouracil (5-FU) continuously infused over 120 h at a dose of 800 mg/m2/day in normal saline 1 liter on D1 through D5. Cisplatin (60 mg/m2) infused for 2h on D1. The treatment protocol was repeated every 3 weeks. After 3 chemotherapy cycles, the oncologist repeated the CT scan to evaluate the chemotherapy tumor’s response in the patient. The CT scan revealed no evidence of tumor’s shrinkage and there was a new metastatic lesion in the liver measured up to 40 mm. Furthermore, the patient’s chemotherapy regimen was change to 8 courses of FOLFIRI regimen (including irinotecan 180 mg/m2 IV on day 1 and leucovorin 400 mg/m2 over 2 h IV on D1 followed by 5-FU 400 mg/m2 IV bolus on day 1, then 5-FU 2400 mg/m2 as a 46-h continuous infusion. The treatment protocol was repeated every 2 weeks.\n\nAfter 8 course FOLFIRI chemotherapy completion, again the patient underwent the follow-up CT scan showed increase in size of liver metastasis and appearance of new pulmonary nodules lesion in the patient’s lung. The disease was considered progressive one. As the third line treatment, the patient received 125 mg/m2 protein-bound paclitaxel, nab-paclitaxel, IV followed by 1 g/m2 gemcitabine IV on days 1,8,15 repeated every 28 days. The treatment was considered to continue until unacceptable toxicity or evidence of disease progression. Premedication consisted of standard antiemetic drugs. After 2 cycles of chemotherapy, follow-up CT scan revealed that the patient’s condition was stable. The patient had less than one-month progression-free disease (PFS) time and he finally died after 13 months from tumor’s diagnosis time (Overall survival (OS): approximately 13 months).\n\nFigure 3 Histological finding showed a positive result for immunohistochemistry staining A, P63 marker B, CK5/6 marker (magnification, x400)\n\nDiscussion\n\nSquamous cell carcinoma of the pancreas is a rare condition, responsible for 0.5 to 2% of all exocrine pancreatic tumors, and has not been well described since the 1940s. There are several hypothesis for identifying the origin of the tumor: 1- capability of malignant changing of bipotential primitive cell that is differentiated into either squamous or glandular carcinoma; 2- malignant transformation of squamous metaplasia of the ductal epithelium; 3-preexisting adenocarcinoma that transforms into SCC; 4-a transformation of atypical squamous cell into malignant cell (4, 5).The SCC clinical presentation of pancreas is similar to adenocarcinoma. Anorexia, weight loss, abdominal pain, nausea, vomiting, and obstructive jaundice are frequent complaints in patients present with pancreatic malignancy (6, 7).\n\nThe diagnosis of SCC of pancreas is a matter of exclusion and must be made after excluding metastases from another possible primary SCC (8). To establish a diagnosis of SCC in the pancreas, tumor enhancement on contrast CT, and tumor blush patterns on angiography, endoscopic retrograde cholangiopancreatography, and positron emission tomography-computed tomography scan (PET-CT scan) can be helpful (9). Recently, there has been a consensus on utilizing endosonography-guided fine needle aspiration (EUS-FNA) for diagnosing of SCC of the pancreas (10). Zhang et al. in 2018 reported a case of SCC of pancreas who was diagnosed by EUS-FNA. They also performed 18F-fluorodeoxyglucose (18F-FDG) PET/CT examination showed high 18F-FDG accumulation in pancreas for diagnosis and for the first time follow-up (10). The other similar reports also applied PET/CT examination for cancer detection (3). PET/CT has been noted to be a highly sensitive and accurate method for detecting pancreatic cancer. The reported sensitivity ranges from 78% to 95%, and accuracy from 64% to 91% (11). From past time, CT scans are often used to diagnose pancreatic cancer clearly and even have the ability to detect affected lymph nodes and near or distant organs. Furthermore, the cancer diagnosis of our patients was based on whole body CT examination (12). Off note, performing PET/CT is an inaccessible and expensive procedure and it limits to more complicated cases for diagnosis in our country. The rarity of SCC of pancreas made difficulties in meticulous diagnosis in clinical setting. Although, the data reported from the histopathological examination of our patient were in contrary with previous studies with cloud of squamous cells that had a positive response to P63 and CK5/6 markers staining. Adenosquamous carcinoma, another rare exocrine pancreatic neoplasm, should be usually considered in the differential diagnosis of SCC in which at least 30% malignant squamous cell carcinoma mixed with ductal adenocarcinoma (13). No evidence of ductal adenocarcinoma was seen in the histopathological examination of our patient’s sample.\n\nAs it was performed in our patient, curative resection of tumor is highly recommended in pancreatic cancer to enhance the patient’s median OS in operable condition. Previous reports have noted 7-month median OS in 8 patients with pancreatic SCC undergoing curative surgical resection (14, 15). Brown et al. (28) indicated a median OS of 7 months (range 616 months) for patients who underwent curative resection and a recently published systematic review and pooled survival analysis by NtanasisStathopoulos et al. demonstrated a median OS of 7 months in 54 patients with pancreatic SCC. This report is the largest pool data analysis in the term of pancreatic SCC till now (16).\n\nThey showed that operable cases had significantly better OS when compared with nonoperable cases (10 months versus 4 months, respectively) (3). Also, in this pool analysis, the patients’ median age at diagnosis was 63 years (range 33-80 years); the majority (61.1%) of cases were males; abdominal pain (77.8%) and weight loss (57.4%) were the most common chief complaints. Most of the patients were nonsmokers (77.8%) and non-alcoholic (70.4%). Most of the tumors were located in head of the pancreas (52.9%) followed by the tail (21.6%) and body (5.9%). The clinical feature and demographic characteristics of our patient was in contrary with other cases analyzed in pool data analyses. In our report, 13 months OS was seen from the patient’s diagnosis until the patient’ death which was one of the largest survival times ever been reported (17).\n\nOverall survival in patients who refuse treatment is dismal and has been reported as short as 3 months (3). However, there was no consensus on selecting the best therapeutic approaches. The cure rate for pancreatic cancer is very low at 7%, which makes the disease a real treatment challenge. Surgical resection is considered as the only potentially curative treatment and stage I, IIA and IIB pancreatic cancers are regarded resectable (3). Adjuvant radiotherapy and chemotherapy are usually accompanied with surgical therapeutic options. Among adjuvant chemotherapy regimen, the combination of cisplatin and 5-FU has shown promising results in terms of survival and the response rate in all types of pancreatic cancer and other SCC cancer originated from the other parts of body such as esophagus or head and neck. Aurelllo et al. reported more than 3-month OS with 2 cycles of cisplatin and 5-FU combination as adjuvant therapy in patients with pancreatic SCC (18). As a second-line treatment, the FOLFIRI regimen with manageable toxicity and notable efficacy has been suggested in platinum resistance pancreatic cancer with up to 6.6 months’ OS and 3.2-month PFS (8). The selection of chemotherapy regimens in our case was based on previous suggested chemotherapy and the oncologist preference and experiences. Combination of cisplatin and 5-FU as a first option and FOLFIRI regimen as an alternative were considered in the treatment of our case.\n\nIn Frank et al.’s study, maintenance FOLFIRI regimen after induction with FOLFIRINOX resulted in 11 months PFS and 46 months OS (17). Moreover, FOLFIRI has demonstrated efficacy in squamous cell carcinoma of esophagus (19). However, our patient clinical response was not acceptable by administering the suggestive alternative chemotherapy regimen FOFIRI.\n\nAccording to several reports, gemcitabine-based chemotherapy including gemcitabine and carboplatin, oxaliplatin, 5-FU, and paclitaxel has been recommended as one of the therapeutic options in SCC pancreatic cancer (3, 15, 20). In addition, the new pharmaceutical form of paclitaxel such as nanoparticle albumin-bound paclitaxel or albumin‑free nanosomal paclitaxel lipid suspension in combination with gemcitabine has demonstrated significant efficacy in the treatment of pancreas cancer (3). By considering the new recommendation, we chose the combination of gemcitabine and nab-paclitaxel as the third-line treatment in our patients that led to stabilize disease progression and to the increase of OS of patients up to 13 months. Majumdar et al. administered nanosomal paclitaxel suspension in combination with gemcitabine for patients with SCC of the pancreas that resulted in more than 1-year OS while it had manageable toxicity (3). According to these reports, a newer pharmaceutical dosage form of paclitaxel and gemcitabine could be considered as a feasible and safe therapeutic option for patients with SCC of the pancreas.\n\nOther reports in regard with the use of new emerging monoclonal antibodies such as cetuximab have failed to demonstrate a defensible efficacy in the treatment of another part of body SCC origin including head and neck cancer (21), skin cancer (23) and metastatic esophageal SCC. Even based on the published meta-analysis in 2020, not only did not cetuximab give rise to increasing survival of pancreatic SCC but also would exacerbate toxicity profile of adjuvant regimen (24). Furthermore, there is still the urging of requirement to develop the new chemotherapy regimens and introduce new therapeutic agents which have the potential to prolong the survival time of patients suffering from pancreatic SCC as a rare condition.\n\nIn conclusion, SCC of pancreas is a rare condition with a poor prognosis. Up to now, there is no determined treatment available for pancreatic SCC. This case report shows that the combination of nab-paclitaxel formulation and gemcitabine can be a potential treatment option for the treatment of locally advanced SCC of pancreatic head after failure in the treatment with other chemotherapy regimens. Nevertheless, new treatment modalities are needed to improve the prognosis of patients with pancreatic SCC.\n\nAcknowledgments\n\nThe authors are grateful to the patient and their family for their cooperation.\n\nConflict of interests:\n\nThe authors have no competing interests.\n==== Refs\nReferences\n\n1 Rahib L Smith BD Aizenberg R Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States Cancer Res 2014 74 2913 21 24840647\n2 Kodavatiganti R Campbell F Hashmi A Gollins SW Primary squamous cell carcinoma of the pancreas: a case report and review of the literature J Med Case Rep 2012 6 295 22973995\n3 Majumdar SKD Muduly DK Mishra S Management of primary squamous cell carcinoma of the pancreas with a nanosomal paclitaxel lipid suspension-based regimen: A case report Mol Clin Oncol 2019 10 430 4 30931112\n4 Mercke C Albertsson M Hambraeus G Cisplatin and 5-Fu combined with radiotherapy and surgery in the treatment of squamous cell carcinoma of the esophagus palliative effects and tumor response Acta Oncol 1991 30 617 22 1716448\n5 Khansur T Allred C Little D Anand V Cisplatin and 5-fluorouracil for metastatic squamous cell carcinoma from unknown primary Cancer Invest 1995 13 263 6 7743377\n6 Ando N Kato H Igaki H A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907) Ann Surg Oncol 2012 19 68 74 21879261\n7 Li Z Zhang P Ma Q Wang D Zhou T Cisplatin-based chemoradiotherapy with 5-fluorouracil or pemetrexed in patients with locally advanced, unresectable esophageal squamous cell carcinoma: A retrospective analysis Mol Clin Oncol 2017 6 743 7 28515926\n8 Neuzillet C Hentic O Rousseau B Rebours V Bengrine-Lefèvre L Bonnetain F FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts World J Gastroenterol 2012 18 4533 41 22969226\n9 Zaniboni A Aitini E Barni S FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study Cancer Chemother Pharmacol 2012 69 1641 5 22576338\n10 Zhang G Cheng ZZ Xu GH Primary squamous cell carcinoma of the pancreas with effective comprehensive treatment: A case report and literature review Medicine 2018 97 e12253 30313026\n11 Wang XY Yang F Jin C Fu DL Utility of PET/CT in diagnosis, staging, assessment of resectability and metabolic response of pancreatic cancer World J Gastroenterol 2014 20 15580 9 25400441\n12 Delbeke D Pinson CW Pancreatic tumors: role of imaging in the diagnosis, staging, and treatment J Hepatobiliary Pancreat Surg 2004 11 4 10 15747028\n13 Madura JA Jarman BT Doherty MG Yum MN Howard TJ Adenosquamous carcinoma of the pancreas Arch Surg 1999 134 599 603 10367867\n14 Serafini F Rosemurgy A Carey L Squamous cell carcinoma of the pancreas Am J Gastroenterol 1996 91 2621 2 8947003\n15 Brijbassie A Stelow E Shami VM Squamous cell carcinoma of the pancreas: A case report and review of literature Gastroenterology Res 2014 7 102 4 27785278\n16 Brown HA Dotto J Robert M Salem RR Squamous cell carcinoma of the pancreas J Clin Gastroenterol 2005 39 915 9 16208119\n17 Ntanasis-Stathopoulos I Tsilimigras DI GeorgiadouD Squamous cell carcinoma of the pancreas: A systematic review and pooled survival analysis Eur J Cancer 2017 79 193 204 28511147\n18 Aurello P Petrucciani N D’Angelo F Squamous cell carcinoma of the pancreas presenting with upper gastrointestinal bleeding Am Surg 2012 78 E284e5\n19 Franck C Canbay A Malfertheiner P Venerito M Maintenance therapy with FOLFIRI after FOLFIRINOX for advanced pancreatic ductal adenocarcinoma: a retrospective single-center analysis J Oncol 2019 2019 5832309 31885579\n20 Wang X Wang X Huang J Irinotecan plus fluorouracil‐based regimen as second or third‐line chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma Thoracic Cancer 2016 7 246 50 27042229\n21 Abedi SH Ahmadzadeh A Mohammad Alizadeh AH Pancreatic squamous cell carcinoma Case Rep Gastroenterol 2017 11 219 24 28559781\n22 Merlano M Occelli M Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck Ther Clin Risk Manag 2007 3 871 6 18473010\n23 Trodello C Higgins S Ahadiat O Cetuximab as a component of multimodality treatment of high-risk cutaneous squamous cell carcinoma: a retrospective analysis from a single tertiary academic medical center Dermatol Surg 2019 45 254 67 30672860\n24 Huang ZH Ma XW Zhang J Cetuximab for esophageal cancer: an updated meta-analysis of randomized controlled trials BMC Cancer 2018 18 1170 30477458\n\n",
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"issue": "12(Suppl 2)",
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"keywords": "Carcinoma; Chemotherapy; Pancreatic cancer; Primary squamous cell; Survival",
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"abstract": "Acute generalised exanthematous pustulosis (AGEP) is a rare cutaneous eruption, most often caused by commonly used antibiotics. It is characterised by an acute onset of non-follicular sterile pustular rash and erythema within hours or days of drug exposure and usually resolves spontaneously within 1-2 weeks once the drug is discontinued. Haemodynamic involvement in the form of shock is rare. Here, we present a severe case of AGEP, manifesting with systemic involvement and haemodynamic instability resulting in shock with multiorgan dysfunction. The associated drugs were erythromycin and fluconazole with a possible combined effect of these two drugs that resulted in systemic involvement. Our patient improved markedly, both haemodynamically and dermatologically, after discontinuation of the drugs and with systemic steroid therapy.",
"affiliations": "Department of Internal Medicine, Cooper University Hospital, Camden, New Jersey, USA.;Department of Internal Medicine, Cooper University Hospital, Camden, New Jersey, USA.;Department of Internal Medicine, Cooper University Hospital, Cherry Hill, New Jersey, USA.",
"authors": "Jakkidi|Manisha|M|;Basmadjian|Carine|C|;Roy|Satyajeet|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D004917:Erythromycin; D015725:Fluconazole; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220612",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22061210.1136/bcr-2017-220612Rare Disease15061523Male51-70 yearsWhiteUSA/CanadaCase ReportAn illusion of septic shock: acute generalised exanthematous pustulosis with multiorgan dysfunction Jakkidi Manisha 1Basmadjian Carine 1Roy Satyajeet 21 Department of Internal Medicine, Cooper University Hospital, Camden, New Jersey, USA2 Department of Internal Medicine, Cooper University Hospital, Cherry Hill, New Jersey, USACorrespondence to Dr Manisha Jakkidi, manishareddy989@gmail.com2017 2 8 2017 2 8 2017 2017 bcr201722061213 7 2017 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This 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/Acute generalised exanthematous pustulosis (AGEP) is a rare cutaneous eruption, most often caused by commonly used antibiotics. It is characterised by an acute onset of non-follicular sterile pustular rash and erythema within hours or days of drug exposure and usually resolves spontaneously within 1–2 weeks once the drug is discontinued. Haemodynamic involvement in the form of shock is rare. Here, we present a severe case of AGEP, manifesting with systemic involvement and haemodynamic instability resulting in shock with multiorgan dysfunction. The associated drugs were erythromycin and fluconazole with a possible combined effect of these two drugs that resulted in systemic involvement. Our patient improved markedly, both haemodynamically and dermatologically, after discontinuation of the drugs and with systemic steroid therapy.\n\ndermatologycontraindications and precautionsskindrug interactionsspecial-featureunlocked\n==== Body\nBackground \nAcute generalised exanthematous pustulosis (AGEP) is a rare condition which presents with rapid onset of several non-follicular sterile pustules occurring diffusely on an oedematous and erythematous background.1 2 Systemic manifestations are typically restricted to fever and leucocytosis. Reversible mild hepatic and kidney injury have been reported in some cases.1 3 AGEP is caused by drugs in 90% of the cases3 and spontaneously resolves rapidly after the offending agent has been discontinued. Topical steroids are used for symptom relief and systemic steroids have been used in atypical severe presentations with systemic involvement.4 5 Here, we describe a unique case of erythromycin and fluconazole induced severe form of AGEP presenting with shock requiring vasopressors and multiorgan dysfunction requiring CVVHD. Despite prompt discontinuation of the offending agent, patient's condition continued to deteriorate until systemic steroids were initiated.\n\nCase presentation \nA 61-year-old man with morbid obesity, Chronic Obstructive Pulmonary Disease, hypertension and type 2 diabetes mellitus was admitted to the hospital for a 1-week history of acute onset rapidly progressive diffusely erythematous rash within the deep folds of his pannus and in the intertriginous areas. He never had this type of rash previously. The rash was refractory to over-the-counter topical nystatin therapy which the patient had used at home for 5 days prior to admission. On initial presentation, the rash was suspicious for candidal intertrigo based on the appearance of the rash and presence of risk factors (obesity, DM). Erythrasma was also high on the differential diagnosis based on coral red florescence noted with woods lamp, appearance of the rash and presence of risk factors (obesity and DM). As such the patient was started empirically on oral erythromycin and oral fluconazole for possible erythrasma and candidal intertrigo since the rash was extensive. Within 3 days, the patient's rash spread diffusely across his trunk and extremities to form erythematous morbilliform papules which coalesced to form plaques (figures 1 and 2). Within 12 hours of noticeably worsening rash, the patient acutely decompensated, became short of breath and developed metabolic and respiratory acidosis, requiring transfer to the intensive care unit. He was initially started on BiPAP, however, due to increasing somnolence he was intubated. He was noted to be hypotensive, not responsive to intravenous fluid resuscitation. Patient was started on vasopressor support with norepinephrine. He also developed shock liver and acute kidney failure requiring CVVHD.\n\nFigure 1 Erythematous, oedematous morbilliform papules and plaques in the axilla.\n\nFigure 2 Non-follicular pustules on an erythematous base with focal areas of desquamation on the trunk.\n\nInvestigations \nInvestigations included Complete Blood Count which revealed neutrophilic leucocytosis (white blood cell 31.10× 109/L), Basic Metabolic Profile and Arterial Blood Gas Analysis which showed acute kidney failure (creatinine of 3.06 mg/dL, hyperkalaemia of 6.3 mmol/L and phosphorus of 7.0 mg/dL), metabolic and respiratory acidosis. Liver Function Tests were consistent with shock liver (AST of 4902 units/mL and an ALT of 3073 units/mL). Infectious workup was negative and included—CXR which was normal. CT chest/abdomen and pelvis failed to reveal any focal signs of infection. Blood and urine culture were negative for any bacterial, fungal growth. Superficial wound culture grew Streptococcus agalactiae, rare Proteus mirabilis, rare Klebsiella and coagulase-negative Staphylococcus—polymicrobial growth which was expected of a skin swab. Skin biopsy was performed which later showed diffuse spongiosis, as well as numerous subcorneal pustules filled with a mixed inflammatory infiltrate, predominately consisting of neutrophils, with some associated lymphocytes, establishing a diagnosis of AGEP (figures 3 and 4).\n\nFigure 3 Skin biopsy showing subcorneal pustule.\n\nFigure 4 Skin biopsy showing subcorneal neutrophils and spongiosis.\n\nDifferential diagnosis \nOther differentials included septic shock, pustular psoriasis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). While these differential diagnoses were possible, they were less likely. A comprehensive evaluation, including a thorough physical examination, CXR, CT scan, blood and urine cultures did not reveal any infectious aetiology, making Septic Shock less likely. Although the clinical manifestations of AGEP and pustular psoriasis are similar and at times can be difficult to distinguish, it was less likely to be pustular psoriasis for several reasons. Aside from the classic skin biopsy findings described above, the abrupt onset, short duration and rapid improvement after drug withdrawal support AGEP compared with a prolonged duration with quiescence and recurrence over the course of years in pustular psoriasis. Additionally, the patient had no evidence of arthritis, nor did he have a personal or family history of psoriasis, which would be more consistent with pustular psoriasis. Finally, this was less likely to be TEN or SJS as well there was no mucous membrane involvement in our patient, as well as the latency period between drug exposure and clinical manifestations is often prolonged in these syndromes compared with AGEP.\n\nTreatment \nErythromycin and fluconazole were immediately discontinued on acute decompensation. Due to concern for septic shock initially, he was started on broad spectrum antibiotics, with vancomycin, meropenem and micafungin. However, when the infectious workup was negative, antibiotics were discontinued. With suspicion of AGEP, he was treated with methylprednisolone 80 mg every 8 hours for 3 days and eventual slow taper on oral steroids.\n\nOutcome and follow-up\nThe patient had marked improvement in both haemodynamics and rash once started on steroids. He no longer required vasopressor agents and was extubated on day 3 of methylprednisolone. He required 4 days of CVVHD and had complete recovery of both kidney and liver function. He was maintained on oral prednisone with slow taper for 2 weeks.\n\nDiscussion \nAGEP is a relatively rare cutaneous condition provoked by drugs mainly by anti-infective agents, less commonly by infections3 4 and sometimes the cause remains unclear. It is believed to be a T-cell mediated neutrophilic inflammation and the histological hallmark is a spongiform subcorneal/intraepidermal pustule. The rash typically starts in the intertriginous area, as seen in our patient, or the face and rapidly spreads to involve the rest of the body. Systemic manifestations are typically just limited to include fever and neutrophilic leucocytosis and organ involvement is rare. In a few patients, mild hepatic and kidney dysfunction has been reported.1 3 6 Our case of AGEP was an atypical presentation with severe systemic involvement leading to haemodynamic instability and multiorgan dysfunction, thereby giving an illusion of septic shock. Macrolides are a known causative agent and there has been a case report of fluconazole causing AGEP as well. However, to the best of our knowledge, there have been only a few reported cases of AGEP with such severe presentation and none of these cases were associated with the use of erythromycin and fluconazole.7 8 In most of the severe presentations, vancomycin was the culprit medication.7 8 It is possible that the combined effect of erythromycin and fluconazole which are both hepatically metabolised and alter each other's metabolism leading to increased drug levels resulted in the drug reaction being severe with systemic involvement as an affect.\n\nOther differentials to consider would be pustular psoriasis, SJS and TEN. The patient had no history of psoriasis and the concern for SJS and TEN was low based on the history, lack of mucosal involvement and the timing of the drug eruption within a few days of the antibiotics. The diagnosis was more in favour of AGEP which was later confirmed by the biopsy results.\n\nTreatment of AGEP involves prompt removal of the offending agent which typically leads to improvement in symptoms within a few days. Topical steroids can be used for symptom relief. Systemic steroids are not indicated, but have been used in rare cases with severe presentations such as in our case, but currently there is not enough data to support the use of systemic steroids to reduce the duration of the symptoms and early recovery.4 5 9 10\n\nLearning points\nAcute generalised exanthematous pustulosis (AGEP) is a rare cutaneous drug eruption, which can be severe and mimic septic shock. It should be suspected in patients being managed for septic shock with negative infectious workup, where the patient's condition continues to deteriorate while on anti-infective agents.\n\nThe case illustrated empiric use of anti-infective agents on suspicion of infection, but the infectious workup was negative. This lays emphasis on being cautious while using antibiotics without confirmation of infection.\n\nSeveral medications have been known to cause AGEP, but it is unclear as to which factors contribute to its severity.\n\nOur patient had pre-existing conditions of morbid obesity, COPD, hypertension and type 2 diabetes mellitus. However, so far no relation of AGEP to the above mentioned comorbidities has been described in the literature.\n\nDiscontinuation of the culprit agent might not always result in clinical improvement, especially in severe cases and there might be a role for systemic steroids to promote early clinical recovery\n\nContributors: MJ conceived, designed, wrote the summary, background,discussion and edited the entire manuscript. CB contributed the case presentation, Investigations, treatment and follow-up part of the manuscript. SR provided intellectual input, drafting and critical revision of the final manuscript. MJ is the overall guarantor of the final manuscript.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences \n1 Sidoroff A , Halevy S , Bavinck JN , et al \nAcute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern . J Cutan Pathol \n2001 ;28 :113 –9 . 10.1034/j.1600-0560.2001.028003113.x 11168761 \n2 Sidoroff A , Dunant A , Viboud C , et al \nRisk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR) . Br J Dermatol \n2007 ;157 :989 –96 . 10.1111/j.1365-2133.2007.08156.x 17854366 \n3 Roujeau JC , Bioulac-Sage P , Bourseau C , et al \nAcute generalized exanthematous pustulosis. analysis of 63 cases . Arch Dermatol \n1991 ;127 :1333 –8 .1832534 \n4 Choi MJ , Kim HS , Park HJ , et al \nClinicopathologic manifestations of 36 korean patients with acute generalized exanthematous pustulosis: a case series and review of the literature . Ann Dermatol \n2010 ;22 :163 –9 . 10.5021/ad.2010.22.2.163 20548906 \n5 Lee HY , Chou D , Pang SM , et al \nAcute generalized exanthematous pustulosis: analysis of cases managed in a tertiary hospital in Singapore . Int J Dermatol \n2010 ;49 :507 –12 . 10.1111/j.1365-4632.2010.04313.x 20534083 \n6 Speeckaert MM , Speeckaert R , Lambert J , et al \nAcute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts . Eur J Dermatol \n2010 ;20 :425 –33 . 10.1684/ejd.2010.0932 20542841 \n7 Mawri S , Jain T , Shah J , et al \nVancomycin-induced acute generalized exanthematous pustulosis (AGEP) masquerading septic shock-an unusual presentation of a rare disease . J Intensive Care \n2015 ;3 :47 \n10.1186/s40560-015-0114-3 26561525 \n8 Mohyuddin GR , Al Asad M , Scratchko L , et al \nAcute generalized exanthematous pustulosis with multiple organ dysfunction syndrome . Am J Crit Care \n2013 ;22 :270 –3 . 10.4037/ajcc2013987 23635939 \n9 Chang SL , Huang YH , Yang CH , et al \nClinical manifestations and characteristics of patients with acute generalized exanthematous pustulosis in Asia . Acta Derm Venereol \n2008 ;88 :363 –5 . 10.2340/00015555-0438 18709306 \n10 Szatkowski J , Schwartz RA \nAcute generalized exanthematous pustulosis (AGEP): A review and update . J Am Acad Dermatol \n2015 ;73 :843 –8 . 10.1016/j.jaad.2015.07.017 26354880\n\n",
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"keywords": "contraindications and precautions; dermatology; drug interactions; skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D056150:Acute Generalized Exanthematous Pustulosis; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D003937:Diagnosis, Differential; D004917:Erythromycin; D015725:Fluconazole; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009102:Multiple Organ Failure",
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"title": "An illusion of septic shock: acute generalised exanthematous pustulosis with multiorgan dysfunction.",
"title_normalized": "an illusion of septic shock acute generalised exanthematous pustulosis with multiorgan dysfunction"
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"abstract": "OBJECTIVE\nBased on previous studies revealing acid-suppression medication as a risk factor for food allergy tolerance induction, we aimed to establish the importance of those findings in patients undergoing oral immunotherapy (OIT).\nWe describe a case series of four patients who underwent milk OIT with a concomitant use of proton pump inhibitor (PPI) medication and who developed anaphylaxis after a known, previously tolerated dose of milk.\n\n\nCONCLUSIONS\nPPIs may act as a cofactor in patients undergoing OIT, triggering adverse reactions, irrespective of the PPI used or the dosage. It would be necessary to separate the administration of drug from food intake.Since OIT is a new form of treatment, long-term adverse events arising from PPI treatment and other possible triggers are still uncertain. Consequently, monitoring of patient must be prolonged over time. Additional investigations on the influence of different drugs in OIT maintenance phase are required.",
"affiliations": "Department of Pediatric Gastroenterology, Severo Ochoa University Hospital, Leganés, Madrid, Spain; mgarciavega6@gmail.com.;Department of Pediatric Pneumology, Gregorio Marañón University Hospital, Madrid, Spain.;Department of Pediatric Allergology, Severo Ochoa University Hospital, Leganés, Madrid, Spain.;Department of Pediatric Allergology, Severo Ochoa University Hospital, Leganés, Madrid, Spain.;Department of Pediatric Gastroenterology, Severo Ochoa University Hospital, Leganés, Madrid, Spain.;Department of Pediatric Allergology, Severo Ochoa University Hospital, Leganés, Madrid, Spain.;Department of Pediatric Allergology, Severo Ochoa University Hospital, Leganés, Madrid, Spain.",
"authors": "Vega|Marta García|MG|;Alonso|Sara Bellón|SB|;España|Amelia Pérez|AP|;Teruel|Sergio José Quevedo|SJQ|;Fernández|Sonia Fernández|SF|;Bermejo|Teresa Bracamonte|TB|;Zudaire|Luis Echeverría|LE|",
"chemical_list": "D054328:Proton Pump Inhibitors",
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"issn_linking": "0301-0546",
"issue": "49(3)",
"journal": "Allergologia et immunopathologia",
"keywords": "adverse reaction; anaphylaxis; cofactor; food allergy; oral immunotherapy; proton pump inhibitors",
"medline_ta": "Allergol Immunopathol (Madr)",
"mesh_terms": "D000707:Anaphylaxis; D000818:Animals; D002648:Child; D003888:Desensitization, Immunologic; D057765:Eosinophilic Esophagitis; D005260:Female; D005512:Food Hypersensitivity; D005756:Gastritis; D006801:Humans; D008297:Male; D008892:Milk; D054328:Proton Pump Inhibitors",
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"references": null,
"title": "Treatment with proton pump inhibitors as a cofactor in adverse reactions of patients undergoing oral food immunotherapy.",
"title_normalized": "treatment with proton pump inhibitors as a cofactor in adverse reactions of patients undergoing oral food immunotherapy"
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"abstract": "A 65-year-old man with multiple lymphadenopathy presented to our hospital and was diagnosed with StageIVA blastoid-variant mantle cell lymphoma (MCL), with a Ki-67 index of 93%. Partial response was achieved after four courses of CHASER (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab) chemotherapy, and complete response was achieved after autologous stem cell transplantation (ASCT). Six months after ASCT, the MCL relapsed with occurrence of tumors one on the left upper arm and one in the cerebrum, which were proved to be resistant to the conventional chemotherapy and progressed rapidly. These tumors disappeared with scarring following the local irradiation (45 Gy). However, the unirradiated regions became enlarged. The bulky abdominal lesion was treated with local irradiation (41 Gy) combined with 560 mg of ibrutinib but still resulted in progressive disease 1 month after initiating the ibrutinib treatment. Finally, the patient died 5 months post-relapse. The prognosis of patients with blastoid-variant MCL with high Ki-67 index is extremely poor. Furthermore, the risk of central nervous system (CNS) involvement is very high. Therefore, ibrutinib maintenance therapy post ASCT might be a treatment option to prevent CNS involvement. Further efforts might be needed to improve the outcomes of blastoid-variant MCL with a high Ki-67 index.",
"affiliations": "Department of Hematology, Oita Kouseiren Tsurumi Hospital.;Department of Hematology, Oita Kouseiren Tsurumi Hospital.;Department of Diagnostic Pathology, Oita Kouseiren Tsurumi Hospital.;Department of Clinical Laboratory, Oita Kouseiren Tsurumi Hospital.;Department of Hematology, Oita Kouseiren Tsurumi Hospital.;Department of Hematology, Oita Kouseiren Tsurumi Hospital.;Department of Radiation Oncology, Oita Kouseiren Tsurumi Hospital.;Department of Hematology, Oita Kouseiren Tsurumi Hospital.",
"authors": "Nakamura|Kyoko|K|;Saburi|Masuho|M|;Kondo|Yoshiyuki|Y|;Soga|Yasuhiro|Y|;Itani|Kazuhito|K|;Kohno|Kazuhiro|K|;Otsuka|Makoto|M|;Nakayama|Toshiyuki|T|",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "Japan",
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"issue": "60(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Autologous stem cell transplantation; Blastoid variant; Ibrutinib; Mantle cell lymphoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000225:Adenine; D000368:Aged; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D014182:Transplantation, Autologous",
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"references": null,
"title": "Ibrutinib therapy for a blastoid variant mantle cell lymphoma patient with early extranodal relapse after autologous stem cell transplantation.",
"title_normalized": "ibrutinib therapy for a blastoid variant mantle cell lymphoma patient with early extranodal relapse after autologous stem cell transplantation"
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"abstract": "Pregnancy of unknown location presents a diagnostic challenge, in rare occasions leading to the diagnosis of malignancy. We describe a case of β-hCG-secreting nongestational primary gastric choriocarcinoma presenting as a pregnancy of unknown location.\n\n\n\nA 37-year-old woman, gravida 4 para 3013, presented with several days of vaginal bleeding and rising β-hCG level without ultrasound localization of pregnancy. The diagnosis of pregnancy of unknown location was made and methotrexate administered at a β-hCG level of 7,779 milli-international units/mL. A 40% decrease in β-hCG level was noted between days 4 and 7. One week later, an inappropriate β-hCG level rise to 10,937 milli-international units/mL was noted, prompting a second dose of methotrexate and computed tomography imaging, leading to the discovery of gastric and liver lesions. Pathology from gastric biopsies revealed nongestational choriocarcinoma. The patient was treated with chemotherapy, with death from cardiac arrest 7 months after diagnosis.\n\n\n\nMalignancies that can secrete β-hCG include gestational trophoblastic disease, gonadal and extragonadal germ cell tumors, and malignancies with choriocarcinoma differentiation. Although ectopic pregnancy compromises approximately 2% of first-trimester pregnancy, gestational trophoblastic neoplasia and gestational choriocarcinoma can be seen in 1 of 1,500 and 1 of 20,000 pregnancies, respectively. When β-hCG levels do not fall appropriately in women undergoing medical management for pregnancy of unknown location, ectopic β-hCG secretion by a malignancy must be considered.",
"affiliations": "Departments of Obstetrics and Gynecology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.",
"authors": "Larish|Alyssa|A|;Kumar|Amanika|A|;Kerr|Sarah|S|;Langstraat|Carrie|C|",
"chemical_list": "D018997:Chorionic Gonadotropin, beta Subunit, Human",
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"mesh_terms": "D000328:Adult; D031954:Choriocarcinoma, Non-gestational; D018997:Chorionic Gonadotropin, beta Subunit, Human; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D013274:Stomach Neoplasms; D014592:Uterine Hemorrhage",
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"title": "Primary Gastric Choriocarcinoma Presenting as a Pregnancy of Unknown Location.",
"title_normalized": "primary gastric choriocarcinoma presenting as a pregnancy of unknown location"
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"abstract": "Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m(2) for 3 days) and LDARAC (10 mg/m(2) q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients.",
"affiliations": "Department of Hematology of Nantes, France.",
"authors": "Harousseau|J L|JL|;Huguet|F|F|;Reiffers|J|J|;Collombat|P|P|;Kohser|P|P|;Prise|P L|PL|;Souteyrand|P|P|;Hurteloup|P|P|",
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"title": "Oral idarubicin and low dose cytarabine as the initial treatment of acute myeloid leukemia in elderly patients.",
"title_normalized": "oral idarubicin and low dose cytarabine as the initial treatment of acute myeloid leukemia in elderly patients"
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{
"abstract": "Immune-mediated necrotising myopathy is a subtype of idiopathic inflammatory myopathy characterised by muscle fibre necrosis without significant inflammatory infiltrate. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) myopathy is seen in 6%-10% of idiopathic inflammatory myopathy and is diagnosed in the context of elevated serum creatine kinase levels, proximal muscle weakness and anti-HMGCR autoantibodies. We recently encountered a 61-year-old man with anti-HMGCR myopathy with an atypical skin manifestation, partially responsive to triple therapy with steroids, intravenous immunoglobulin (IVIG) and rituximab. To our knowledge, there have been only four reported cases of skin rash associated with anti-HMGCR myopathy. Our case demonstrates the importance of recognising atypical manifestations of anti-HMGCR myopathy. Early addition of IVIG and rituximab is also critical in patients not responding to steroid monotherapy. Delay in achieving remission leads to prolonged steroid use, lower likelihood of beginning physical therapy and overall worse clinical outcomes.",
"affiliations": "Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA rahulkarnagovind@gmail.com.;Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.;Pathology, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.;Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.",
"authors": "Karna|Rahul|R|http://orcid.org/0000-0002-6775-0776;Singh|Richa|R|;Marshall|Cody|C|;Johnston|Alexandra|A|",
"chemical_list": "D003067:Coenzymes; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243728",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(9)",
"journal": "BMJ case reports",
"keywords": "muscle disease; rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003067:Coenzymes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases; D009220:Myositis; D010088:Oxidoreductases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34544705",
"pubdate": "2021-09-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical presentation of anti-HMGCR myopathy.",
"title_normalized": "atypical presentation of anti hmgcr myopathy"
} | [
{
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"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
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... |
{
"abstract": "A term baby with neonatal convulsions secondary to birth asphyxia was given i.v. phenytoin via a cannula in the dorsum of the hand at 17 h of age. She developed a blue discolouration in the tissues surrounding the i.v. site. The infusion was aborted but the discolouration gradually spread to the rest of the hand. Twenty hours later, improvement could be detected although a blister appeared near the i.v. site. A further attempt two days later to administer phenytoin via an i.v. cannula sited in the left foot was aborted after the appearance of a similar reaction.",
"affiliations": "Basildon Hospital, Essex, UK.",
"authors": "Sharief|N|N|;Goonasekera|C|C|",
"chemical_list": "D010672:Phenytoin",
"country": "Norway",
"delete": false,
"doi": "10.1111/j.1651-2227.1994.tb18288.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "83(11)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": null,
"medline_ta": "Acta Paediatr",
"mesh_terms": "D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006230:Hand Injuries; D006801:Humans; D007231:Infant, Newborn; D007275:Injections, Intravenous; D010672:Phenytoin; D012640:Seizures; D017695:Soft Tissue Injuries",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "1218-9",
"pmc": null,
"pmid": "7841742",
"pubdate": "1994-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Soft tissue injury associated with intravenous phenytoin in a neonate.",
"title_normalized": "soft tissue injury associated with intravenous phenytoin in a neonate"
} | [
{
"companynumb": "GB-PFIZER INC-2015389755",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
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... |
{
"abstract": "Sickle cell disease(SCD) is a disorder of red cells resulting from the co-inheritance of haemoglobin S (HbS) with another abnormal haemoglobin. The diagnosis of acute leukaemia is uncommon in our patients with sickle cell disease more so the patients have high morbidity and mortality due to the sickling process. Acute leukemia is a malignant clonal disorder of haemopoietic precursor cells resulting in accumulation of immature blood cells in the bone marrow and blood. The objective of the case series was to highlight the challenges of diagnosis and management of SCD patients with acute leukaemia, the importance of peripheral blood film review and propound a possible risk factor.\nRecords of 58 patients diagnosed and managed for acute leukaemia over a 7 year period at the University College Hospital, Ibadan were reviewed. The diagnosis of acute leukaemia was based on clinical features in addition to peripheral and bone marrow smears findings. Microsoft excel version 2013 was used for statistical analysis.\nFive (8.6%) of the patients with acute leukaemia also had sickle cell disease: 3 males and 2 females were described. Recurrent fever and anaemia were the most consistent presenting features in the patients. All the patients were not on any routine medications meant for SCD patients and had poor history of clinic attendance prior to the diagnosis of acute leukaemia. The diagnosis of acute leukaemia was not made until the patients were seen by a haematologist. The principal tool of diagnosis in all the patients was peripheral blood film review. Two patients were discharged against medical advice. The treatment period ranged between one month and one year in the remaining three patients.\nSCD patients are not exempted from developing acute leukaemias and the diagnoses of the two conditions overwhelms the social and economic support of patients and care givers. The study also underscores the relevance of high level of suspicion and prompt review of peripheral blood film of SCD patients particularly when patients present with unremitting symptoms associated with anaemia and fever.",
"affiliations": "Haematology Department, Central Laboratory, Synlab Nigeria Limited, Lagos.;Department of Haematology, College of Medicine, University of Ibadan, Nigeria.;Department of Haematology, College of Medicine, University of Ibadan, Nigeria.;Department of Haematology, College of Medicine, University of Ibadan, Nigeria.;Department of Haematology, College of Medicine, University of Ibadan, Nigeria.",
"authors": "Aworanti|Oladapo W|OW|;Fasola|Foluke A|FA|;Kotila|Taiwo R|TR|;Olaniyi|John A|JA|;Brown|Biobele J|BJ|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.4314/ahs.v20i3.36",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1680-6905",
"issue": "20(3)",
"journal": "African health sciences",
"keywords": "Acute leukaemia; anaemia; sickle cell disease",
"medline_ta": "Afr Health Sci",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000740:Anemia; D000755:Anemia, Sickle Cell; D002648:Child; D002675:Child, Preschool; D005260:Female; D005334:Fever; D006801:Humans; D007938:Leukemia; D008297:Male; D009549:Nigeria; D055815:Young Adult",
"nlm_unique_id": "101149451",
"other_id": null,
"pages": "1304-1312",
"pmc": null,
"pmid": "33402979",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15055307;28830890;2672962;28588742;10975379;8988912;22614769;22084346;23103089;27325377;31371806",
"title": "Acute leukemia in sickle cell disease patients in a tertiary health facility in Nigeria: a case series.",
"title_normalized": "acute leukemia in sickle cell disease patients in a tertiary health facility in nigeria a case series"
} | [
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"companynumb": "NG-BAXTER-2020BAX022673",
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"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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{
"abstract": "Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a recently described entity so far exclusively in East Asian children. AESD diagnosis is based on clinicoradiologic criteria, often without pleocytic CSF and characterized by hyperglycemia and transaminasemia. Here, we present the first case of human herpesvirus 7-related AESD in an immunocompetent child >2 years old and of Caucasian origin.",
"affiliations": "From the Department of Pediatrics, Thriasio General Hospital.;From the Department of Pediatrics, Thriasio General Hospital.;2nd Department of Pediatrics, Athens Medical Center.;Second Pediatric Department, School of Medicine, University of Athens.;Department of Diagnostics, Hellenic Pasteur Institute.;Department of Radiodiagnostics, Thriasio General Hospital.;Department of Radiodiagnostics, Athens Medical Center, Athens, Greece.;2nd Department of Pediatrics, Athens Medical Center.;Department of Diagnostics, Hellenic Pasteur Institute.;Second Pediatric Department, School of Medicine, University of Athens.",
"authors": "Syridou|Garyfallia|G|;Drikos|Ioannis|I|;Kapetanakis|Minas|M|;Vartzelis|Giorgos|G|;Horefti|Elina|E|;Triantafylou|Evagelia|E|;Bodozoglou|Nikolaos|N|;Zarganis|Diagoras|D|;Mentis|Andreas|A|;Tsolia|Maria|M|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000002557",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "39(2)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000367:Age Factors; D015415:Biomarkers; D001927:Brain Diseases; D002648:Child; D038524:Diffusion Magnetic Resonance Imaging; D004198:Disease Susceptibility; D005260:Female; D016199:Herpesvirus 7, Human; D006801:Humans; D016133:Polymerase Chain Reaction; D019349:Roseolovirus Infections; D012640:Seizures; D063189:Symptom Assessment",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "170-172",
"pmc": null,
"pmid": "31929436",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Human Herpesvirus 7-Related Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion.",
"title_normalized": "human herpesvirus 7 related acute encephalopathy with biphasic seizures and late reduced diffusion"
} | [
{
"companynumb": "GR-SLATE RUN PHARMACEUTICALS-20GR000349",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
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"activesubstancename": "MIDAZOLAM"
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"drugadditional":... |
{
"abstract": "Neurological manifestation of Takayasu's Arteritis (TA) in pregnancy presenting as convulsive syncope is extremely rare, and poses a serious diagnostic dilemma due to other vast causes of fits in pregnancy.\nWe aimed to present and shed more light on a case of TA with convulsive syncope in pregnancy refractory to anticonvulsants for seven weeks, and review the literature on the management of TA in pregnancy.\nA gravida 4 para 3+0 at 28 weeks of amenorrhea presented with repeated episodes of the sudden loss of consciousness, followed by a fall and jerking of the limbs. These were refractory to anticonvulsants that she had used for seven weeks. Physical examination revealed undetectable pulse and blood pressure (BP) in the upper limbs but elevated BP in the lower limbs. Further investigations confirmed TA and she improved on steroids and antihypertensives.\nThis case typically describes the unexpected presentation of TA with convulsive syncope. It calls for meticulous clinical assessment of epileptic seizures in pregnancy to avoid a late diagnosis of TA and its potential poor outcomes.",
"affiliations": "Department of Obstetrics and Gynecology, Lacor Hospital, Gulu, Uganda.;Department of Obstetrics and Gynecology, Lacor Hospital, Gulu, Uganda.;Department of Pediatrics and Neurology, Lacor Hospital, Gulu, Uganda.;Department of Obstetrics and Gynecology, Lacor Hospital, Gulu, Uganda.;Department of Internal Medicine, Gulu University, Gulu, Uganda.",
"authors": "Alobo|Gasthony|G|;Nahurira|Violah|V|;Omona|Venice|V|;Bayo|Pontius|P|;Olum|Sam|S|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.4314/ahs.v21i2.46",
"fulltext": "\n==== Front\nAfr Health Sci\nAfr Health Sci\nAfrican Health Sciences\n1680-6905\n1729-0503\nMakerere Medical School Kampala, Uganda\n\njAFHS.v21.i2.pg852\n10.4314/ahs.v21i2.46\nArticles\nRefractory convulsive syncope in pregnancy: a rare presentation of Takayasu's arteritis - a case report and literature review\nAlobo Gasthony 12\nNahurira Violah 1\nOmona Venice 3\nBayo Pontius 1\nOlum Sam 4\n1 Department of Obstetrics and Gynecology, Lacor Hospital, Gulu, Uganda\n2 Department of Obstetrics and Gynecology, Lira University, Lira Uganda\n3 Department of Pediatrics and Neurology, Lacor Hospital, Gulu, Uganda\n4 Department of Internal Medicine, Gulu University, Gulu, Uganda\nCorresponding author: Gasthony Alobo, Lira University, BOX 1035 Lira, Uganda; Lecturer of obstetrics and gynecology; gasthonya@gmail.com\n6 2021\n21 2 852857\n© 2021 Alobo G et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee African Health Sciences. This is an Open Access article distributed under the terms of the Creative commons Attribution License (https://creativecommons.org/licenses/BY/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nNeurological manifestation of Takayasu's Arteritis (TA) in pregnancy presenting as convulsive syncope is extremely rare, and poses a serious diagnostic dilemma due to other vast causes of fits in pregnancy.\n\nObjective\n\nWe aimed to present and shed more light on a case of TA with convulsive syncope in pregnancy refractory to anticonvulsants for seven weeks, and review the literature on the management of TA in pregnancy.\n\nCase presentation\n\nA gravida 4 para 3+0 at 28 weeks of amenorrhea presented with repeated episodes of the sudden loss of consciousness, followed by a fall and jerking of the limbs. These were refractory to anticonvulsants that she had used for seven weeks. Physical examination revealed undetectable pulse and blood pressure (BP) in the upper limbs but elevated BP in the lower limbs. Further investigations confirmed TA and she improved on steroids and antihypertensives.\n\nConclusion\n\nThis case typically describes the unexpected presentation of TA with convulsive syncope. It calls for meticulous clinical assessment of epileptic seizures in pregnancy to avoid a late diagnosis of TA and its potential poor outcomes.\n\nTakayasu's Arteritis in pregnancy\nconvulsive syncope\ncase report\n==== Body\npmcBackground\n\nTakayasu's Arteritis (TA) is a rare chronic vasculitis of the large vessels, mainly the aorta and its branches 1. TA was named after Japanese Ophthalmologist Mikito Takayasu who together with his colleagues first described and reported a case of the disease in 19052. The vascular lesions are typically characterized by stenosis, occlusion, dilation, or aneurysm of the large arteries 3. It predominantly affects females within the reproductive age 4, 5. Patients with TA may be asymptomatic or present with signs and symptoms that result from lesions such as dizziness, claudication, reduced or absent peripheral pulses, hypertension and/or blood pressure discrepancies between the arms, or the arms and lower limbs 6–9.\n\nAlthough pregnancy does not have much effect on the progression of TA, the disease usually becomes apparent in the second and third trimesters. Pregnancy is also associated with alteration in cardiac and hematologic functions, therefore cardiovascular injury and thromboembolic events are feared complications of TA 10. There is a likelihood that such complications can result in poor maternal and fetal outcomes. Early diagnosis and prompt management of TA in pregnancy are therefore very important and this requires a multi-disciplinary approach involving obstetricians, rheumatologists, and cardiologists. However, in settings where TA is extremely rare, the diagnosis can be easily missed if the presentation is also unusual. Here we describe a 28-year old pregnant woman who was referred to our high-risk antenatal clinic (ANC) at Lacor Hospital in northern Uganda as a case of refractory convulsions in pregnancy.\n\nCase presentation\n\nA 28-year-old woman of African origin, gravida 4 para 3+0 at 28 weeks of amenorrhea was referred to Lacor Hospital from a nearby district hospital due to repeated episodes of loss of consciousness, collapse, and tonic jerking of the limbs. These symptoms had occurred over seven weeks and each would last for a few seconds only. She noted that these episodes were common on standing up just before making any steps. Her care-takers also reported associated incontinece of urine occasionally. She did not have any known chronic illness or contact with Tuberculosis. The past three pregnancies were unremarkable as she did not attend antenatal care clinics and delivered at home with the traditional birth attendant (TBA) due to socioeconomic reasons. During this fourth pregnancy, she had booked for ANC at the district hospital with support from a humanitarian organization. The booking blood pressure at 11 weeks was 125/85 mmHg (taken from the upper limbs). She was started on anticonvulsants; phenytoin 200 mg two times a day for 4 weeks then switched to sodium valproate 800 mg per day for 3 weeks but the symptoms remained unchanged.\n\nOn arrival at Lacor Hospital, the carotid, brachial, and radial pulses were undetectable and the BP in the upper limbs was unrecordable. The BP from the ankle was 160/100 and pulse rate of 84 beats/minute. Per Abdomen examination revealed a symphysio-fundal height corresponding to 28 weeks with a fetal heart rate of 140 beats/minute that was regular. The other physical examinations were unremarkable. Investigations done include; echocardiogram which revealed normal cardiac chambers and valves. The ejection fraction was 58.57%. A Doppler scan of the aortic arch, descending aorta to iliac artery and renal artery, and electroencephalography findings were normal. There was thickening of the common carotid artery (CCA) and subclavian artery (SCA) with a 50–60% stenosis on Doppler (Figures 1 and 2). Also, a reverse flow pattern was noted within the vertebral artery referred to as subclavian steal syndrome (Figure 3). The erythrocyte sedimentation rate (ESR) was 40 mm/1st hour. Antinuclear antibody (ANA) and C-reactive protein (CRP) tests were not avalable at our facility. There was no proteinuria on spot urine dipstick. An obstetric ultrasound scan revealed a single live intrauterine fetus with a heart rate of 138/minute, a normal amniotic fluid index (AFI 11 CM), and normal umbilical artery Doppler velocimetry.\n\nFig 1 Left subclavian artery Doppler of the patient\n\nFig 2 Right subclavian artery Doppler of the patient\n\nFig 3 Doppler ultrasound of the left vertebral artery showing reverse flow (subclavian steal syndrome)\n\nAfter reviewing the findings, we made a diagnosis of Takayasu's Arteritis with convulsive syncope. The patient was started on nifedipine 20 mg twice daily, with prednisolone 30 mg once a day; anticonvulsants were stopped. She was observed for one week on this treatment, the symptoms subsided and the ankle BP came down to 145/90 mmHg. The patient was discharged, and the dose of prednisolone tapered down to 10 mg daily over 4 weeks. She had a normal vaginal delivery at term to a male baby weighing 4.0kg. During the post-natal review, her BP was recorded as 115/75 mmHg and pulse of 80/minute in the upper limbs and she had no symptoms.\n\nDiscussion\n\nTakayasu's arteritis is a rare chronic granulomatous vasculitis of mainly the aorta and its branches. This can result in stenosis of the aortic arch, carotid, subclavian, iliac, or the abdominal aorta and renal arteries11. The patient presented here had involvement of the branches of the aortic arch only. TA is distributed worldwide but with the highest incidence in Japan, the eastern part of Asia, and India 12. The etiology of TA is largely unknown. However, autoimmunity, human leukocyte antigen (HLA – BW52, B40, DR2, DR4, DR7, DW3, DW12), and sex hormones have been postulated as plausible associations 13. Due to limited diagnostic modalities, we could not evaluate for the presence of these factors in the case described. Although chronic infectious diseases like tuberculosis (TB) have also been implicated as a possible trigger of TA 14, our patient did not give a history of any chronic illness likely to be TB. Pregnancy per se does not affect the progression of TA, but there are known maternal and fetal complications of TA. These complications result from narrowing of the aorta, aortic arch and its branches, and occasionally the pulmonary artery. The fetal complications include abortions, intrauterine growth restriction (IUGR), fetal death (FD), and rarely, placental abruption 15. Fetal complications are closely related to the reduced blood supply to the uterus from the narrowed abdominal aorta or iliac artery, and maternal cardiac insufficiency 16. This case did not have fetal complications and carried the pregnancy up to term; possibly due to non-stenosis of the aortic arch, abdominal aorta, and iliac vein. Nevertheless, it is recommended that all patients with TA in pregnancy should have a routine assessment of blood flow within the uterine and umbilical arteries 17.\n\nMaternal complications include hypertension, aortic regurgitation, and aneurysm 16, 18. These complications are common in the second and third trimesters and can result in serious maternal morbidity and mortality19. Hypertension that results from TA is aproteinuric” unless there is superimposed pre-eclampsia; like in the case described. The increase in BP results from abnormal function of the baroreceptors at the carotid and aortic arch, and inelastic stenosis of the arteries 20. With the exception of hypertension, we did not observe any serious maternal complications in our case. But in other case reports the following have been documented; congestive cardiac failure, stroke, pre-eclampsia, eclampsia, and sudden death 21.\n\nMaking a diagnosis of TA in pregnancy is usually challenging in settings where the disease is rare because of the low index of suspicion as was the case with our patient. Diagnosis is based on clinical presentation, imaging to demonstrate thickening with stenosis of the aorta and its branches, and laboratory markers of acute-phase reactants. The clinical manifestation in pregnancy may range from asymptomatic to alteration in blood pressures and pulses, myalgia, claudication, and fainting 8. This patient presented with loss of consciousness, collapse, and tonic convulsions. The differential diagnosis of this neurological manifestation in pregnancy is quite broad and can be misleading. In our case, this led to a misdiagnosis of epilepsy and unnecessarily prolonged use of anticonvulsants in pregnancy. It is recommended that BP in patients with TA should be measured in both upper and lower limbs to detect any discrepancies, in addition to checking for bruits. In a study by Comarmond C. et al, it was found that new-onset or worsening arterial hypertension was evident in 27% of pregnant women with TA, but they noted that this could be an underestimate because in a few patients there may be stenosis of the vessels supplying all the four extremities, giving a misleadingly low blood pressure recording 16.\n\nThe computed tomography (CT) and magnetic resonance imaging (MRI) angiography can detect vascular changes of TA at the earliest stage 22. However, the only readily available imaging modality in our setting was ultrasonography. Nevertheless, in resource-limited settings, Doppler ultrasonography can be useful in elucidating vascular stenosis from the thickening of the arterial walls. In some studies, the FDG-PET scan was found to have a sensitivity 70.1% and specificity of 77.2%23; but this is still limited in resource-constrained settings. Laboratory findings include raised ESR and CRP, positive ANA, and rheumatoid factor (RF) 24. Our patient had a raised ESR of 40 mm/1st hours. It should be noted that during pregnancy there is also increased ESR due to the higher fibrinogen levels and CRP with unknown mechanisms. Therefore, the acute phase response is not mostly helpful to exclude inflammatory ischemic symptoms from physiological changes. We were unable to perform a vessel biopsy in our case, but vascular histology may be important to distinguish TA from other forms of arteritis when findings are not clear-cut 25. We relied on clinical features and results from imaging to make a diagnosis of TA in our case after meeting the following criteria: age less than 40 years at presentation, reduced or absent pulses in the upper limbs, evidence of stenosis or occlusion of the major branches of the aorta, and systolic BP discrepancy in the limbs more than 10 mm Hg 26.\n\nThe medications used in our case were: nifedipine 40 mg/day which was adequate to control hypertension; and prednisolone 30 mg/day. The following medicines can also be used to control hypertension; alpha-methyldopa which is Class A; propranolol is safe up to the dose of 60 mg/day, above this dose it can cause IUGR and preterm birth (Class B); nifedipine dose higher than 60 mg/day is considered Class B as well 6. Although the current European League Against Rheumatism (EULAR) proposes a higher induction therapy for the treatment of vasculitis with an initial 1 mg/kg oral prednisolone (maximum 60 mg/day) for one month with subsequent tapering to 10–15 mg/day over some time 27, this dose may have adverse effects in pregnancy 10. There is evidence of good results with doses under 30 mg/day in active TA during pregnancy11. Patients who are resistant to steroids can benefit from immunomodulatory agents like infliximab, tocilizumab, leflunomide, and mycophenolate mofetil 28, 29. However, their safety in pregnancy is not well established and it is advisable to avoid using them unless the benefits outweigh the risks 28,29.\n\nOur patient had spontaneous vertex delivery. There is evidence to favor vaginal delivery, either spontaneous or assisted, in hemodynamically stable patients. Cesarean delivery is recommended in those who are having decompensated cardiac function or another obstetric indication 18. Anesthesia is considered safe in patients with TA, and epidural anesthesia is preferred30.\n\nOverall, neurological manifestations of TA are rare; even in the general population. Ischemia due to vascular stenosis initially presents with headache, dizziness, visual disturbance, transient ischemic attack, stroke, and very rarely convulsive syncope 18, 19. Convulsive syncope in pregnancy has not been reported; this could be the first case report. Our database searches with the following MeSH subheadings and Boolean operator (AND): “syncope” AND “convulsion” AND “Takayasu's arteritis” AND “pregnancy” yielded no results.\n\nConclusion\n\nTA in pregnancy presenting with convulsive syncope can pose a serious diagnostic dilemma. This may lead to misdiagnosis and unnecessary use of anticonvulsants. The unusual presentation that we have described here will help to shed more light on how TA can be differentiated from other causes of convulsions in pregnancy.\n\nAcknowledgments\n\nWe would like to thank all the staff of Lacor Hospital, Department of Obstetrics and Gynecology who participated in the management of this patient. Similarly, we are grateful to our patient who granted us consent to make a case presentation on her condition.\n\nAbbreviations\n\nANA: Anti-nuclear antibody; BP: Blood pressure; CCA: Common carotid artery; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; IUGR: Intrauterine growth restriction; SCA: Subclavian artery; TA: Takayasu's arteritis; TBA: Traditional birth attendant.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical clearance was provided by the Lacor Hospital Institutional Research Ethics Committee under the Mother-Child Health Lacor and South Sudan (Mo-CHeLaSS) project. We obtained written informed consent from the patient for making this case report. We have concealed the patient's identity except for the hospital's name and unique numbers that partly appear on the images.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this study are included in this published article.\n\nCompeting interests\n\nThe authors declare no conflict of interest.\n\nFunding\n\nWe did not receive any funding to develop this case report.\n\nAuthors' contribution\n\nVN and GA compiled the patient's history, physical examination, and management plan. VO reviewed the literature on diagnosis and treatment options. GA developed the concept and wrote the initial draft of the manuscript. SO, GA, VN, PB and VO did the final review of the manuscript before submission.\n==== Refs\n1 de Souza AWS de Carvalho JF Diagnostic and classification criteria of Takayasu arteritis Journal of Autoimmunity 2014 48 79 83 24461381\n2 Numano F The story of Takayasu arteritis Rheumatology 2002 41 1 103 106 11792888\n3 Kissin EY Merkel PA Diagnostic imaging in Takayasu arteritis Current Opinion in Rheumatology 2004 16 1 31 37 14673386\n4 Hall S Takayasu arteritis. A study of 32 North American patients Medicine 1985 64 2 89 99 2858047\n5 Wen D Du X Ma C-S Takayasu arteritis: diagnosis, treatment and prognosis International Reviews of Immunology 2012 31 6 462 473 23215768\n6 Maffei S Takayasu's arteritis: a review of the literature Internal and Emergency Medicine 2006 1 2 105 112 17111782\n7 Sise M The clinical spectrum of Takayasu's arteritis Surgery 1988 104 5 905 910 2903563\n8 Cong X-L Takayasu's arteritis: clinical features and outcomes of 125 patients in China Clinical Rheumatology 2010 29 9 973 981 20589520\n9 Park MC Clinical characteristics and outcomes of Takayasu's arteritis: analysis of 108 patients using standardized criteria for diagnosis, activity assessment, and angiographic classification Scandinavian Journal of Rheumatology 2005 34 4 284 292 16195161\n10 Lakhi NA Jones J Takayasu's arteritis in pregnancy complicated by peripartum aortic dissection Archives of Gynecology and Obstetrics 2010 282 1 103 106 20020151\n11 Serra R Updates in pathophysiology, diagnosis and management of Takayasu arteritis Annals of Vascular Surgery 2016 35 210 225 27238990\n12 Hall S Buchbinder R Takayasu's arteritis Rheumatic Diseases Clinics of North America 1990 16 2 411 422 1971727\n13 Saruhan-Direskeneli G Identification of multiple genetic susceptibility loci in Takayasu arteritis The American Journal of Human Genetics 2013 93 2 298 305 23830517\n14 Karadag O Assessment of latent tuberculosis infection in Takayasu arteritis with tuberculin skin test and Quantiferon-TB Gold test Rheumatology international 2010 30 11 1483 1487 20358203\n15 Seyahi E Takayasu arteritis: an update Current Opinion in Rheumatology 2017 29 1 51 56 27748689\n16 Comarmond C Takayasu arteritis and pregnancy Arthritis & Rheumatology 2015 67 12 3262 3269 26315109\n17 Alibaz-Oner F Direskeneli H Update on Takayasu's arteritis La Presse Médicale 2015 44 6 e259 e265 26033561\n18 Assad APL Maternal and neonatal outcomes in 89 patients with Takayasu arteritis (TA): comparison before and after the TA diagnosis The Journal of Rheumatology 2015 42 10 1861 1864 26329335\n19 Kraemer B A successful pregnancy in a patient with Takayasu's arteritis Hypertension in pregnancy 2008 27 3 247 252 18696353\n20 Sharma SK Sawhney S Rheumatic Diseases in Women and Children Current Perspectives 2014 JP Medical Ltd.\n21 NaliNi S Santa SA Takayasu arteritis with bilateral renal artery stenosis and left subclavian artery stenosis in pregnancy Journal of Clinical and Diagnostic Research: JCDR 2015 9 9 QD07\n22 Mavrogeni S The role of multimodality imaging in the evaluation of Takayasu arteritis Seminars in arthritis and rheumatism 2013 Elsevier\n23 Tezuka D Role of FDG PET-CT in Takayasu arteritis: sensitive detection of recurrences JACC: Cardiovascular Imaging 2012 5 4 422 429 22498333\n24 Nooshin D Ten-year investigation of clinical, laboratory and radiologic manifestations and complications in patients with Takayasu's arter itis in three university hospitals The Malaysian Journal of Medical Sciences: MJMS 2013 20 3 44 23966824\n25 Polachek A The fine line between Takayasu arteritis and giant cell arteritis Clinical Rheumatology 2015 34 4 721 727 25416136\n26 Arend WP The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis Arthritis & Rheumatism 1990 33 8 1129 1134 1975175\n27 Mukhtyar C EULAR recommendations for the management of primary small and medium vessel vasculitis Annals of the Rheumatic Diseases 2009 68 3 310 317 18413444\n28 Unizony S Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica Arthritis Care & Research 2012 64 11 1720 1729\n29 De Souza A Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study Scandinavian Journal of Rheumatology 2012 41 3 227 230 22400913\n30 Yoshida M Anesthetic management of a patient with Takayasu arteritis Anesthesia progress 2016 63 1 31 33 26866409\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1680-6905",
"issue": "21(2)",
"journal": "African health sciences",
"keywords": "Takayasu's Arteritis in pregnancy; case report; convulsive syncope",
"medline_ta": "Afr Health Sci",
"mesh_terms": null,
"nlm_unique_id": "101149451",
"other_id": null,
"pages": "852-857",
"pmc": null,
"pmid": "34795744",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "25416136;22498333;18413444;22400913;26329335;27238990;23215768;18696353;26500964;23966824;20020151;1971727;17111782;27748689;23830517;2858047;22920236;16195161;11792888;2903563;26033561;22674883;24461381;14673386;26315109;26866409;20358203;1975175;20589520",
"title": "Refractory convulsive syncope in pregnancy: a rare presentation of Takayasu's arteritis - a case report and literature review.",
"title_normalized": "refractory convulsive syncope in pregnancy a rare presentation of takayasu s arteritis a case report and literature review"
} | [
{
"companynumb": "UG-LUPIN PHARMACEUTICALS INC.-2021-26531",
"fulfillexpeditecriteria": "2",
"occurcountry": "UG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugaddi... |
{
"abstract": "We describe the challenges to treatment of leukemia in three cases of human immunodeficiency virus (HIV)-infected children with multiple infections and complications. Two of the three patients had acute myeloid leukemia and the other one acute lymphoblastic leukemia. Two of the patients were known with HIV infection; the third was diagnosed on admission. All patients received antiretroviral therapy with standard doses of lamivudine, stavudine and efavirenz or lopinavir/retonavir. All three were diagnosed with Mycobacterium tuberculosis on one or more occasions: pulmonary or miliary involvement or tuberculous meningitis. One patient developed spinal paraplegia and needed an urgent laminectomy. Later he recovered almost completely. The interaction between antiretroviral and antituberculosis treatments combined with chemotherapy, antibiotics and supportive care is not known. Despite the severity and the complexity of several associated diseases, the outcome of the patients was rewarding and encouraging.",
"affiliations": null,
"authors": "Stefan|D Cristina|DC|;Dippenaar|Anel|A|;De Bruin|Gerhard|G|;Uys|Ronelle|R|;van Toorn|Ronald|R|",
"chemical_list": "D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1093/tropej/fms007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0142-6338",
"issue": "58(6)",
"journal": "Journal of tropical pediatrics",
"keywords": null,
"medline_ta": "J Trop Pediatr",
"mesh_terms": "D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections; D006801:Humans; D007938:Leukemia; D008297:Male; D009169:Mycobacterium tuberculosis; D016896:Treatment Outcome; D014376:Tuberculosis; D019562:Viral Load",
"nlm_unique_id": "8010948",
"other_id": null,
"pages": "521-2",
"pmc": null,
"pmid": "22421805",
"pubdate": "2012-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Challenges to treatment of leukemia in HIV-positive children.",
"title_normalized": "challenges to treatment of leukemia in hiv positive children"
} | [
{
"companynumb": "ZA-CIPLA LTD.-2013US00458",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "STAVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease.\n\n\nMETHODS\nA 5-year-old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy.\n\n\nCONCLUSIONS\nPneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation.",
"affiliations": "Chair and Department of Radiology and Diagnostic Imaging, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland.",
"authors": "Laskowska|Katarzyna|K|;Burzyńska-Makuch|Małgorzata|M|;Krenska|Anna|A|;Kołtan|Sylwia|S|;Chrupek|Małgorzata|M|;Nawrocka|Elżbieta|E|;Lasek|Władysław|W|;Serafin|Zbigniew|Z|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.12659/pjr.882972",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1733-134X",
"issue": "77(2)",
"journal": "Polish journal of radiology",
"keywords": "computed tomography; graft-versus-host disease; pneumatosis cystoides intestinalis",
"medline_ta": "Pol J Radiol",
"mesh_terms": null,
"nlm_unique_id": "101175532",
"other_id": null,
"pages": "60-3",
"pmc": null,
"pmid": "22844311",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports",
"references": "2311891;10455375;2375647;6745722;6349056;8811375;14818407;18665358;22171137;19710000;3287869;409230;13752845;19034985",
"title": "Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases.",
"title_normalized": "pneumatosis cystoides interstitialis a complication of graft versus host disease a report of two cases"
} | [
{
"companynumb": "PL-ALKEM LABORATORIES LIMITED-PL-ALKEM-2022-03497",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Mycoplasma pneumoniae infection can present with a plethora of symptoms and result in a systemic vasculitis by activating a cascade of autoimmune reactions. In this case report, a young man without relevant past medical history was admitted to the hospital with diarrhea, abdominal pain and spiking fever. A CT-scan showed terminal ileitis. A 5-day broad spectrum antibiotic treatment (ciprofloxacin/clindamycin) did not result in any clinical improvement. On the contrary, the patient developed a cholestatic hepatitis, bilateral anterior uveitis and a dry cough. Extensive serological testing finally led to the diagnosis of a M. pneumoniae infection by paired serology (≥4-fold rise in IgG titer). In the diagnostic work-up, a PET-CT was performed and showed increased tracer uptake in the carotids and vertebral arteries, suggesting the diagnosis of vasculitis. After start of azithromycin and low-dose corticosteroids (0.5 mg/kg/day), a gradual clinical and biochemical improvement was observed. But subsequently, the patients relapsed and presented with an acute coronary syndrome. Coronary angiography revealed aneurysmatic deformation of the three coronary arteries, leading to the assumption of coronary vasculitis. Clinical improvement was achieved with high-dose corticosteroids (1 mg/kg/day). This case shows that M. pneumoniae is not merely a pulmonary infection, but that its primary symptoms can be diverse and misleading. All clinicians should be aware of its extrapulmonary manifestations.",
"affiliations": "Departement of Internal Medicine, Universitair Ziekenhuis, Gent, Belgium.;Department of Internal Medicine, Universitair Ziekenhuis Gent, Ghent, Belgium.;Department of Microbiology, AZ Maria Middelares, Ghent, Belgium.;Department of Cardiology, AZ Maria Middelares, Ghent, Belgium.;Department of Cardiology, AZ Maria Middelares, Ghent, Belgium.;Department of Gastroenteroly, AZ Maria Middelares, Ghent, Belgium.;Department of Gastroenteroly, AZ Maria Middelares, Ghent, Belgium.;Department of Gastroenteroly, AZ Maria Middelares, Ghent, Belgium.;Department of Rheumatology, AZ Maria Middelares, Ghent, Belgium.;Department of Cardiology, Universitair ziekenhuis Leuven, Leuven, Belgium.;Department of Gastroenteroly, AZ Maria Middelares, Ghent, Belgium.",
"authors": "Matthys|Imke|I|https://orcid.org/0000-0002-1434-4969;Borsboom|Daniel|D|https://orcid.org/0000-0001-5595-8433;Steyaert|Sophia|S|https://orcid.org/0000-0002-7028-3486;Vervloet|Delphine|D|https://orcid.org/0000-0003-4780-5247;Cornelis|Kristoff|K|https://orcid.org/0000-0001-6704-8410;Vanderstraeten|Erik|E|https://orcid.org/0000-0001-8540-6138;Kindt|Sébastien|S|https://orcid.org/0000-0002-4282-4230;Dewint|Pieter|P|https://orcid.org/0000-0002-1002-9822;Lambrecht|Valerie|V|;Sinnaeve|Peter|P|https://orcid.org/0000-0003-4716-5892;Van Steenkiste|Christophe|C|https://orcid.org/0000-0001-5167-744X",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D017963:Azithromycin",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2019.1578029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "75(3)",
"journal": "Acta clinica Belgica",
"keywords": "Mycoplasma pneumoniae; acute coronary syndrome; anterior uveitis; cholestatic hepatitis; vasculitis",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D015746:Abdominal Pain; D054058:Acute Coronary Syndrome; D000328:Adult; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002779:Cholestasis; D003323:Coronary Aneurysm; D003371:Cough; D003967:Diarrhea; D005334:Fever; D005938:Glucocorticoids; D006505:Hepatitis; D006801:Humans; D007079:Ileitis; D008297:Male; D009175:Mycoplasma Infections; D009177:Mycoplasma pneumoniae; D011019:Pneumonia, Mycoplasma; D012008:Recurrence; D014606:Uveitis, Anterior; D014657:Vasculitis",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "229-234",
"pmc": null,
"pmid": "30767713",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A plethora of manifestations following a Mycoplasma pneumoniae infection: a case report.",
"title_normalized": "a plethora of manifestations following a mycoplasma pneumoniae infection a case report"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-200734",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"dr... |
{
"abstract": "Pancreatic neuroendocrine tumors (panNETs) are a type of neuroendocrine tumor with 5-year overall survival rates of approximately 50% when metastasis is present at diagnosis. Tumor grade, as defined by Ki-67 proliferation index, influences overall survival, with low-grade tumors portending a better outcome than intermediate- and high-grade tumors. This case report follows the clinical course and management of a patient with an insulin-secreting metastatic panNET who died 10 years after diagnosis after a treatment course with regional therapy and multiple forms of cytotoxic and molecularly targeted agents. This report presents the various treatment options available for patients with insulin-secreting metastatic panNETs.",
"affiliations": "From the Division of Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, and Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill College of Medicine, Cornell University, New York, New York.;From the Division of Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, and Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill College of Medicine, Cornell University, New York, New York.",
"authors": "Giuroiu|Iulia|I|;Reidy-Lagunes|Diane|D|",
"chemical_list": "D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.6004/jnccn.2015.0021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "13(2)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D018450:Disease Progression; D017809:Fatal Outcome; D005500:Follow-Up Studies; D006801:Humans; D007328:Insulin; D000078790:Insulin Secretion; D007340:Insulinoma; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "139-44",
"pmc": null,
"pmid": "25691605",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metastatic insulinoma: current molecular and cytotoxic therapeutic approaches for metastatic well-differentiated panNETs.",
"title_normalized": "metastatic insulinoma current molecular and cytotoxic therapeutic approaches for metastatic well differentiated pannets"
} | [
{
"companynumb": "PHHY2015US031312",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"drugadditional": null,
"dru... |
{
"abstract": "The use of anesthetics has been linked to poor outcome in patients with status epilepticus (SE). This association, however, may be confounded, as anesthetics are mostly administered in patients with more severe SE and critical illnesses.\n\n\n\nTo minimize treatment-selection bias, we assessed the association between continuously administered intravenous anesthetic drugs (IVADs) and outcome in SE patients by a matched two-center study design.\n\n\n\nThis cohort study was performed at the Johns Hopkins Bayview Medical Center, Baltimore, MD, USA and the University Hospital Basel, Basel, Switzerland. All consecutive adult SE patients from 2005 to 2013 were included. Odds ratios (ORs) for death and unfavorable outcome (Glasgow Outcome Score [GOS] 1-3) associated with administration of IVADs were calculated. To account for confounding by known outcome determinants (age, level of consciousness, worst seizure type, acute/fatal etiology, mechanical ventilation, and SE duration), propensity score matching and coarsened exact matching were performed in addition to multivariable regression models.\n\n\n\nAmong 406 consecutive patients, 139 (34.2%) were treated with IVADs. Logistic regression analyses of the unmatched and matched cohorts revealed increased odds for death and unfavorable outcome in survivors who had received IVADs (unmatched: ORdeath = 3.13, 95% confidence interval [CI] 1.47-6.60 and ORGOS1-3 = 2.51, 95% CI 1.37-4.60; propensity score matched: ORdeath = 3.29, 95% CI 1.35-8.05 and ORGOS1-3 = 2.27, 95% CI 1.02-5.06; coarsened exact matched: ORdeath = 2.19, 95% CI 1.27-3.78 and ORGOS1-3 = 3.94, 95% CI 2.12-7.32).\n\n\n\nThe use of IVADs in SE is associated with death and unfavorable outcome in survivors independent of known confounders and using different statistical approaches. Randomized trials are needed to determine if these associations are biased by outcome predictors not yet identified and hence not accounted for in this study.",
"affiliations": "Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA. Raoul.Sutter@usb.ch.;Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland.;Clinic for Intensive Care Medicine, University Hospital Basel, Basel, Switzerland.;Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland.;Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland.;Clinic for Intensive Care Medicine, University Hospital Basel, Basel, Switzerland.;Division of Neurosciences Critical Care, Department of Anesthesiology, Critical Care Medicine and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.",
"authors": "Sutter|Raoul|R|0000-0002-6575-356X;De Marchis|Gian Marco|GM|;Semmlack|Saskia|S|;Fuhr|Peter|P|;Rüegg|Stephan|S|;Marsch|Stephan|S|;Ziai|Wendy C|WC|;Kaplan|Peter W|PW|",
"chemical_list": "D018686:Anesthetics, Intravenous",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40263-016-0389-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1172-7047",
"issue": "31(1)",
"journal": "CNS drugs",
"keywords": null,
"medline_ta": "CNS Drugs",
"mesh_terms": "D000368:Aged; D018686:Anesthetics, Intravenous; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "9431220",
"other_id": null,
"pages": "65-74",
"pmc": null,
"pmid": "27896706",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "17636063;19817823;22895985;14354021;24862385;18188092;18173905;16769951;26336950;27533350;23982031;23294049;11422324;15614126;24319039;22812603;18769858;25876118;26296517;9924914;15758590;20878265;18064739;23065689;9738086;19387871;19183752;17898231;22732291;12876241;14581659;23917849;16791671;22528274;25819797;25654177;19435569;20050893;11903460",
"title": "Anesthetics and Outcome in Status Epilepticus: A Matched Two-Center Cohort Study.",
"title_normalized": "anesthetics and outcome in status epilepticus a matched two center cohort study"
} | [
{
"companynumb": "US-UCBSA-2017006075",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThis open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.\n\n\nMETHODS\nOn day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m2 and 5-fluorouracil at a dose of 1000 mg/m2 /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m2 ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.\n\n\nRESULTS\nNine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses).\n\n\nCONCLUSIONS\nDuligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.",
"affiliations": "Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado.;King Albert II Institute, Medical Oncology Service, Saint-Luc University Clinic and Clinical and Experimental Research Institute (Pole MIRO), Catholic University of Louvain, Brussels, Belgium.;Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.;Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois.;King Albert II Institute, Medical Oncology Service, Saint-Luc University Clinic and Clinical and Experimental Research Institute (Pole MIRO), Catholic University of Louvain, Brussels, Belgium.;Genentech, South San Francisco, California.;Genentech, South San Francisco, California.;Genentech, South San Francisco, California.;Genentech, South San Francisco, California.;Genentech, South San Francisco, California.;Genentech, South San Francisco, California.;Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.",
"authors": "Jimeno|Antonio|A|;Machiels|Jean-Pascal|JP|;Wirth|Lori|L|;Specenier|Pol|P|;Seiwert|Tanguy Y|TY|;Mardjuadi|Feby|F|;Wang|Xiaodong|X|;Kapp|Amy V|AV|;Royer-Joo|Stephanie|S|;Penuel|Elicia|E|;McCall|Bruce|B|;Pirzkall|Andrea|A|;Clement|Paul M|PM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007074:Immunoglobulin G; C569960:MEHD7945A; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.30256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "122(24)",
"journal": "Cancer",
"keywords": "antibody; clinical trial; duligotuzumab; epidermal growth factor receptor (EGFR); human epidermal growth factor receptor 3 (HER3)",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3803-3811",
"pmc": null,
"pmid": "27525588",
"pubdate": "2016-12-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.",
"title_normalized": "phase ib study of duligotuzumab mehd7945a plus cisplatin 5 fluorouracil or carboplatin paclitaxel for first line treatment of recurrent metastatic squamous cell carcinoma of the head and neck"
} | [
{
"companynumb": "US-MYLANLABS-2017M1005741",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nthe analysis of therapeutic approach in patients with basic heart condition and amiodarone induced thyroid dysfunction--correlations with the evolution and prognosis.\n\n\nMETHODS\nThe study included 215 patients, 90 men and 125 women aged between 35 and 87, with different cardiac pathologies hospitalized in the Cardiology Clinic between 2004-2014, who received amiodarone treatment, in most cases for prophylaxis of various arrhythmias, both supraventricular and ventricular. During the evolution, these patients have developed amiodarone-induced thyroid dysfunction (hypo- or hyper function).\n\n\nCONCLUSIONS\nThe evaluation of thyroid function after starting treatment was performed in 187 patients (86.97%). Diagnosis of amiodarone-induced thyroid dysfunction was based on hormonal dosages of TSH, FT4 and FT3, endocrinological examination and thyroid ultrasound. Thyroid dysfunction treatment was initiated, depending on the situation, in all patients during the hospitalization. Treatment included anti thyroid drugs or hormones substitution and in some cases a minimal dose of prednisone.\n\n\nCONCLUSIONS\nThyroid dysfunction regardless of the type (with hypo- or hyper function) requires continuous changes of the cardiovascular treatment, and association, where appropriate, with thyroid dysfunction medication. In some cases the latter determines cardiovascular side effects, for instance corticotheraphy may become a factor of imbalance for the hemodynamic status of the patient (by fluid retention, increased blood pressure, hyper glycemia).",
"affiliations": "University of Medicine and Pharmacy Grigore T. Popa - Iaşi, Department of Medical Specialties (I).",
"authors": "Costache|Luliana|L|;Mogos|Voichiţa|V|;Preda|Cristina|C|;Vulpoi|Carmen|C|;Ungureanu|Maria-Christina|MC|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D014284:Triiodothyronine; D013972:Thyrotropin; D000638:Amiodarone; D013974:Thyroxine",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0048-7848",
"issue": "118(4)",
"journal": "Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi",
"keywords": null,
"medline_ta": "Rev Med Chir Soc Med Nat Iasi",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac; D015415:Biomarkers; D002309:Cardiology; D005260:Female; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D012383:Romania; D013959:Thyroid Diseases; D013971:Thyrotoxicosis; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine",
"nlm_unique_id": "0413735",
"other_id": null,
"pages": "959-64",
"pmc": null,
"pmid": "25581954",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapeutic particularities in amiodarone induced thyroid disorder in patients with underlying cardiac condition.",
"title_normalized": "therapeutic particularities in amiodarone induced thyroid disorder in patients with underlying cardiac condition"
} | [
{
"companynumb": "RO-PFIZER INC-2015181731",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Introduction: Transient-localized lesions of the splenium of the corpus callosum (SCC) have been described in various clinical conditions, some of them being attributed to the withdrawal of psychotropic drugs. The pathophysiology of the lesion reflects cytotoxic edema and reversible demyelination.Areas covered: The present article aimed at reviewing cases of transient SCC lesion exclusively related to changes in pharmacotherapy. It also reports the original case of a patient receiving a complex psychopharmacological therapy who developed a transient SCC lesion investigated by magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and pharmacogenetic profiling.Expert opinion: To date, only one review on the subject has been published, analyzing 22 cases of transient SCC lesion arising in epileptic patients on antiepileptic therapy. It hypothesized that the nature of the lesion is a cytotoxic edema and the cases described in the subsequent 14 years seem to support this hypothesis. The authors reported the case of an Italian-Egyptian patient who developed a transient SCC lesion after the rapid withdrawal of Carbamazepine and Lurasidone. The lesion completely disappeared from the MRI performed after 1 month. Patient's ethnic group and its pharmacogenetic profile were considered as possible causes of altered drug metabolism and, likely, of the SCC lesion.",
"affiliations": "Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, Neurology Unit, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Radiology, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, Milan, Italy.;Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, Neurology Unit, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.;Department of Mental Health, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.",
"authors": "Cirnigliaro|Giovanna|G|;Di Bernardo|Ilaria|I|;Caricasole|Valentina|V|;Piccoli|Eleonora|E|;Scaramelli|Barbara|B|;Pomati|Simone|S|;Villa|Chiara|C|;Pantoni|Leonardo|L|;Dell'Osso|Bernardo|B|",
"chemical_list": "D000927:Anticonvulsants; D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2020.1731472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "19(3)",
"journal": "Expert opinion on drug safety",
"keywords": "Pharmacological treatment; splenium of the corpus callosum; transient lesion",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D003337:Corpus Callosum; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D028761:Withholding Treatment",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "315-325",
"pmc": null,
"pmid": "32063066",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment-related transient splenial lesion of the Corpus Callosum in patients with neuropsychiatric disorders: a literature overview with a case report.",
"title_normalized": "treatment related transient splenial lesion of the corpus callosum in patients with neuropsychiatric disorders a literature overview with a case report"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "1",
"drugadministrati... |
{
"abstract": "Levetiracetam and topiramate are newer anticonvulsants, which is why international data on overdoses of these drugs are lacking. Only a few mild adverse reactions have been noted. These anticonvulsants have been the drug of choice for neurologists. Despite their wide usage, there is a dearth of literature on symptoms and signs of their toxicity. Presented here is the case of a 21-year-old female who overdosed twice on levetiracetam and topiramate. The woman was admitted and discharged after the first overdose. Ten days later, she took multiple tablets of both drugs and was seen again. Amazingly, the woman went home after the incident with no complications at all.",
"affiliations": "Emergency Department, Fujairah Hospital.;Emergency Department, Masafi Hospital.",
"authors": "Sarfaraz|Moaziz|M|;Syeda|Rana Hasan|RH|",
"chemical_list": "D000927:Anticonvulsants; D000931:Antidotes; D000077236:Topiramate; D002606:Charcoal; D005632:Fructose; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2016.01082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7831",
"issue": "11(2)",
"journal": "Drug discoveries & therapeutics",
"keywords": "Anticonvulsants; activated charcoal; gastrointestinal decontamination; seizures; toxicity",
"medline_ta": "Drug Discov Ther",
"mesh_terms": "D000927:Anticonvulsants; D000931:Antidotes; D002606:Charcoal; D062787:Drug Overdose; D005260:Female; D005632:Fructose; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D000077236:Topiramate; D055815:Young Adult",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "115-117",
"pmc": null,
"pmid": "28320983",
"pubdate": "2017-05-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levetiracetam and topiramate poisoning: Two overdoses on those drugs with no lasting effects.",
"title_normalized": "levetiracetam and topiramate poisoning two overdoses on those drugs with no lasting effects"
} | [
{
"companynumb": "AE-UCBSA-2017013292",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Infections are one of the most common causes of mortality in immunocompromised patients. In patients diagnosed with hematologic malignancies, treatment with stem cell transplants (SCT) or T-cell suppressing chemotherapy increases the risk of central nervous system (CNS) infections, of which toxoplasmosis is the most common. We report the case of a 63 year-old woman with chronic lymphocytic leukemia (CLL) that presented with gait instability and visual changes. Intracranial lesions were noted on initial neuro-imaging. A rapid decline in the patient's mental status warranted an urgent biopsy of the lesions that revealed tachyzoites consistent with toxoplasmosis. In the presence of diffuse brain lesions that lack a metastatic pattern or contrast enhancement, a common approach is to perform biopsy only after a battery of non-invasive testing. This diagnostic delay may take several days, exposing the patient to a rapidly fatal infection. This report illustrates the utility of early brain biopsy in high-risk patients with hematologic malignancies and CNS lesions.",
"affiliations": "Case Western Reserve Univerisity School of Medicine, 2109 Adelbert Rd, Cleveland, OH 44106, United States.;Case Western Reserve Univerisity School of Medicine, 2109 Adelbert Rd, Cleveland, OH 44106, United States.;Department of Neurosurgery, Neurological Institute, Cleveland Clinic Foundation, 9600 Euclid Ave, Cleveland, OH 44195, United States.;Department of Neurosurgery, Center for Neurological Restoration, Cleveland Clinic Foundation 9500 Euclid Ave, Cleveland, OH 44195, United States.;Department of Neurology, Neurological Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates. Electronic address: kuruvij@ccf.org.;Department of Infectious Disease, Respiratory Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, United States.;Department of Neurosurgery, Center for Neurological Restoration, Cleveland Clinic Foundation 9500 Euclid Ave, Cleveland, OH 44195, United States.",
"authors": "Xu|Jordan|J|;Nault|Rod J|RJ|;Maldonado-Naranjo|Andres|A|;Frizon|Leonardo A|LA|;John|Kuruvilla|K|;Holman|Katherine|K|;Nagel|Sean J|SJ|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2018.01.057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "50()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Chemotherapy; Disseminated cerebral toxoplasmosis; Immunosuppression; Leukemia",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D001706:Biopsy; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008875:Middle Aged; D009894:Opportunistic Infections; D016781:Toxoplasmosis, Cerebral",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "127-128",
"pmc": null,
"pmid": "29428267",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia.",
"title_normalized": "disseminated cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-PFIZER INC-2018141841",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "The treatment of paroxysmal supraventricular tachycardia (PSVT) in infancy with digitalis, adenosine triphosphate (ATP) and verapamil is reported. Treatment was successful in about 90% of the patients treated with ATP and verapamil and in 61--71% of the patients treated with digitalis (Lanatoside C). Verapamil terminated the tachycardia within 2 minutes of administration in most instances and ATP in less than 1 minute. Digitalis, however, took as long as 2 hours; it was therefore excluded as the drug of first choice in emergencies, and is better suited for treating patients with poor hemodynamics. Side effects with ATP are common but short-lived. With verapamil, side effects are rare, but may be serious if certain contraindications are not taken into account. Digitalis in the dose used in this trial rarely produced side effects. We conclude that ATP or verapamil is the drug of first choice for quick termination of PSVT in infancy.",
"affiliations": null,
"authors": "Greco|R|R|;Musto|B|B|;Arienzo|V|V|;Alborino|A|A|;Garofalo|S|S|;Marsico|F|F|",
"chemical_list": "D007799:Lanatosides; C018548:lanatoside C; D000255:Adenosine Triphosphate; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": "10.1161/01.cir.66.3.504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-7322",
"issue": "66(3)",
"journal": "Circulation",
"keywords": null,
"medline_ta": "Circulation",
"mesh_terms": "D000255:Adenosine Triphosphate; D002648:Child; D002675:Child, Preschool; D004070:Digitalis; D005260:Female; D006339:Heart Rate; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007799:Lanatosides; D008297:Male; D010946:Plants, Medicinal; D010947:Plants, Toxic; D013614:Tachycardia, Paroxysmal; D014700:Verapamil",
"nlm_unique_id": "0147763",
"other_id": null,
"pages": "504-8",
"pmc": null,
"pmid": "7201361",
"pubdate": "1982-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Treatment of paroxysmal supraventricular tachycardia in infancy with digitalis, adenosine-5'-triphosphate, and verapamil: a comparative study.",
"title_normalized": "treatment of paroxysmal supraventricular tachycardia in infancy with digitalis adenosine 5 triphosphate and verapamil a comparative study"
} | [
{
"companynumb": "IT-RECRO GAINESVILLE LLC-REPH-2019-000118",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"... |
{
"abstract": "Rosacea is a chronic inflammatory facial skin disease with psychosocial impact. Oral cyclines are recommended for moderate-to-severe papulopustular rosacea. Oral isotretinoin was found valuable for difficult-to-treat cases in several reports. This multicenter, double-blind, randomized-placebo-controlled trial compared oral isotretinoin (0.25 mg/kg/day) with placebo (2:1 ratio) for difficult-to-treat papulopustular rosacea. Included patients had at least eight papulopustular lesions. The primary endpoint after the 4-month treatment period was the response rate: at least 90% reduction of the number of papules/pustules compared with baseline. Secondary outcomes included measures on quality of life (Skindex score). Between February 2007 and August 2009, 156 patients were randomized to receive either isotretinoin (n = 108) or placebo (n = 48). In the intention-to-treat population, 57.4% of isotretinoin recipients reached the primary endpoint, compared with 10.4% of those taking the placebo (absolute difference, 47 percentage points; 95% confidence interval, 34.3-59.7; P < 0.0001). To consider therapy successful, 2.1 (95% confidence interval 1.7-2.9) patients had to be treated. Skindex scores had improved significantly more for isotretinoin- than placebo-treated patients. Rosacea relapsed in 27 (58.3%) of 51 patients who accepted 4 months of continued follow-up, with a median of 15 weeks to recurrence. The percentages of patients in each arm who stopped their treatment because of adverse event(s) did not differ. Low-dose isotretinoin was an effective therapeutic option for difficult-to-treat papulopustular rosacea. Further studies should investigate the value of a minimal effective isotretinoin dose to maintain these remissions.",
"affiliations": "Department of Dermatology, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Henri-Mondor, Université Paris-Est Créteil-Val de Marne, EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques) and INSERM, Centre d'Investigation Clinique (CIC), Créteil, France.;Unité de Recherche Clinique, APHP, Hôpital Fernand-Vidal, Université René-Diderot, Paris, France.;Laboratoire Bailleul, Paris, France.;Laboratoire Bailleul, Paris, France.;Department of Dermatology, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France.;Department of Dermato-oncology, Hôtel-Dieu, Université Nantes, Nantes, France.;Department of Dermatology, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Henri-Mondor, Université Paris-Est Créteil-Val de Marne, EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques) and INSERM, Centre d'Investigation Clinique (CIC), Créteil, France. Electronic address: olivier.chosidow@aphp.fr.",
"authors": "Sbidian|Emilie|E|;Vicaut|Éric|É|;Chidiack|Henri|H|;Anselin|Elie|E|;Cribier|Bernard|B|;Dréno|Brigitte|B|;Chosidow|Olivier|O|",
"chemical_list": "D007641:Keratolytic Agents; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jid.2016.01.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-202X",
"issue": "136(6)",
"journal": "The Journal of investigative dermatology",
"keywords": null,
"medline_ta": "J Invest Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D015474:Isotretinoin; D007641:Keratolytic Agents; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018579:Patient Selection; D018570:Risk Assessment; D012393:Rosacea; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0426720",
"other_id": null,
"pages": "1124-1129",
"pmc": null,
"pmid": "26854486",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Randomized-Controlled Trial of Oral Low-Dose Isotretinoin for Difficult-To-Treat Papulopustular Rosacea.",
"title_normalized": "a randomized controlled trial of oral low dose isotretinoin for difficult to treat papulopustular rosacea"
} | [
{
"companynumb": "FR-AKORN PHARMACEUTICALS-2016AKN00573",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
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{
"abstract": "OBJECTIVE\nCentral nervous system (CNS) infections after cervical spine surgery are a rare but serious complication and may be caused by uncommon pathogens. We report the case of a 57-year-old male who developed slowly progressive mental confusion with headaches, increased daytime sleepiness and mild gait disturbance within the last 3 weeks. Six weeks prior to admission to our department, he underwent an atlantoaxial fusion by C1-C2 transarticular screw fixation for rheumatoid arthritis related C1-C2 multidirectional instability.\n\n\nMETHODS\nWe analyzed clinical and neuroradiological findings.\n\n\nRESULTS\nThe findings were consistent with communicating hydrocephalus secondary to ventriculitis and the left C1-C2 screw was found to be misplaced with perforation of the dura. The situation was interpreted as implant related surgical site infection of the cerebrospinal fluid followed by ventriculitis and hydrocephalus. Bacterial broad range 16S rRNA gene PCR from the cerebrospinal fluid (CSF) followed by sequencing identified Aggregatibacter aphrophilus as the causative agent, while conventional cultures remained negative due to its fastidious growth. The patient was successfully treated with a lumbar drain and intravenous ceftriaxone.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of Aggregatibacter aphrophilus ventriculitis following C1-C2 transarticular screw fixation.",
"affiliations": "University Hospital Zurich, Department of Neurosurgery, University of Zurich, Zurich, Switzerland(1). Electronic address: sina.tok@kws.ch.;University Hospital Zurich, Department of Neurosurgery, University of Zurich, Zurich, Switzerland(1). Electronic address: marian.neidert@usz.ch.;Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland(2). Electronic address: bloemberg@imm.uzh.ch.;University Hospital Zurich, Department of Neurosurgery, University of Zurich, Zurich, Switzerland(1). Electronic address: oguzkan.sueruecue@usz.ch.",
"authors": "Tok|Sina|S|;Neidert|Marian Christoph|MC|;Bloemberg|Guido|G|;Sürücü|Oguzkan|O|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3843",
"issue": "50(1)",
"journal": "Neurologia i neurochirurgia polska",
"keywords": "Aggregatibacter aphrophilus; Atlantoaxial fusion; C1-C2 transarticular screw fixation; HACEK; Ventriculitis",
"medline_ta": "Neurol Neurochir Pol",
"mesh_terms": "D064207:Aggregatibacter aphrophilus; D001172:Arthritis, Rheumatoid; D001174:Arthrodesis; D001863:Bone Screws; D058565:Cerebral Ventriculitis; D002574:Cervical Vertebrae; D006801:Humans; D007593:Joint Instability; D008297:Male; D008875:Middle Aged; D016871:Pasteurellaceae Infections; D016459:Prosthesis-Related Infections",
"nlm_unique_id": "0101265",
"other_id": null,
"pages": "63-8",
"pmc": null,
"pmid": "26851694",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aggregatibacter aphrophilus ventriculitis following C1-C2 transarticular screw fixation.",
"title_normalized": "aggregatibacter aphrophilus ventriculitis following c1 c2 transarticular screw fixation"
} | [
{
"companynumb": "CH-MYLANLABS-2016M1031832",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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... |
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"abstract": "Objective: To evaluate the effects of application of vancomycin in the early stage of patients with extremely severe burn, in order to provide reference to drug for anti-infection treatment in the early stage of patients with extremely severe burn. Methods: Data of 15 patients of Kunshan explosion on August 2nd, 2014, admitted to the Department of Intensive Care in our hospital were retrospectively analyzed. The clinical efficacy of continuously intravenous dripping of vancomycin (combined with imipenem) in the early stage of burns (before and on post burn day 14) was analyzed. (1) The steady state plasma concentration of vancomycin was monitored respectively 30 min before the third, sixth, and tenth medication with direct chemiluminescent imaging method. (2) The distribution of Gram-positive bacteria of patients during hospitalization and their drug resistance to 14 antibiotics commonly used in clinic were analyzed. (3) Serum level of procalcitonin (PCT), white blood cell count, percentage of neutrophils before and after treatment, and efficacy grade of anti-infection treatment in the early stage of burns were analyzed. (4) Serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), creatinine before and after treatment, and the adverse effects during medication were analyzed. The WHONET 5.5 statistical software was used to analyze the distribution of Gram-positive bacteria in all the pathogens, and the status of drug resistance of Gram-positive bacteria to 14 antibiotics. Data were processed with Wilcoxon rank sum test. Results: (1) Twenty-nine times of steady state plasma concentration monitoring were performed in the patients in total, with the steady state plasma concentration of vancomycin from 4.3 to 42.1 μg/mL. In the monitoring before third, sixth, and tenth medication, the percentages of result reaching the standard were respectively 1, 3/14, and 2/7. (2) A total of 79 Gram-positive bacteria were isolated, including 49 (62.03%) strains of Staphylococcus aureus, 9 (11.39%) strains of Staphylococcus haemolyticus, 7 (8.86%) strains of Staphylococcus epidermidis, 12 (15.19%) strains of Enterococcus faecium, and 2 (2.53%) strains of Enterococcus faecalis. The above-mentioned Staphylococcus strains were with high drug resistance to antibiotics including penicillins, erythromycin, ciprofloxacin, and low drug resistance to linezolid, teicoplanin, and nitrofurantoin. The above-mentioned Enterococcus strains were with high drug resistance to antibiotics including erythromycin, ciprofloxacin, gentamicin, and low drug resistance to linezolid and teicoplanin. The above-mentioned Staphylococcus strains were all sensitive to vancomycin. Two strains of vancomycin-resistant Enterococcus were detected in the above-mentioned Enterococcus strains. (3) Serum level of PCT, white blood cell count, percentage of neutrophils of patients were (8.1±7.5) ng/mL, (24±10)×10(9)/L, and 0.898±0.029 before treatment, which were significantly higher than (3.0±2.8) ng/mL, (12±5)×10(9)/L, and 0.867±0.016 after treatment (with Z values respectively -2.103, -3.237, and -3.068, P<0.05 or P<0.01). After the early treatment, excellence, progess, and invalid results were achieved in 7, 5, and 3 patients, with the effective percentage of 4/5 in clinic. (4) There were no statistically significant differences in serum levels of AST, ALT, and creatinine of patients between before and after treatment (with Z values respectively-0.057, -1.508, and -1.363, P values above 0.05). Only one patient had liver and renal dysfunction during treatment. Conclusions: The positive and reasonable use of vancomycin can remove most of the Gram-positive bacteria, and control the development of sepsis combined with imipenem in the early stage of patients with extremely severe burn. However, the dose of vancomycin should be individualized and the steady state plasma concentration should be monitored to maintain the blood concentration within the safe and effective range, so as to improve the rational use of vancomycin.",
"affiliations": "Department of Pharmacy, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.",
"authors": "Zhu|Z|Z|;Cao|G W|GW|;Bao|J J|JJ|;Hu|Z H|ZH|;Shen|Z|Z|;Tao|H|H|;Cao|B|B|;Xu|F|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D015378:Imipenem; D002116:Calcitonin",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.1009-2587.2017.04.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2587",
"issue": "33(4)",
"journal": "Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns",
"keywords": "Blood concentration monitoring; Burns; Drug evaluation; Vancomycin",
"medline_ta": "Zhonghua Shao Shang Za Zhi",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002056:Burns; D002116:Calcitonin; D006801:Humans; D015378:Imipenem; D008826:Microbial Sensitivity Tests; D012189:Retrospective Studies; D018805:Sepsis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D014640:Vancomycin",
"nlm_unique_id": "100959418",
"other_id": null,
"pages": "206-210",
"pmc": null,
"pmid": "28427133",
"pubdate": "2017-04-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effects of application of vancomycin in the early stage of patients with extremely severe burn.",
"title_normalized": "effects of application of vancomycin in the early stage of patients with extremely severe burn"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1055846",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMIPENEM"
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"drugadditional": "1",
... |
{
"abstract": "A 54-year-old woman took an overdose of 1 800 mg piroxicam. She complained of nausea and abdominal pain. Endoscopy revealed multiple superficial ulcerations in the pyloric antrum and the first part of duodenum. There were no symptoms or signs from other organ system and recovery was uneventful. The highest serum concentration was 241.6 mg/l, which is about 30 times the usual therapeutic level of 5-10 mg/l.",
"affiliations": null,
"authors": "Mosvold|J|J|;Mellem|H|H|;Stave|R|R|;Osnes|M|M|;Laufen|H|H|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D013843:Thiazines; D010894:Piroxicam",
"country": "Sweden",
"delete": false,
"doi": "10.1111/j.0954-6820.1984.tb03814.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6101",
"issue": "216(3)",
"journal": "Acta medica Scandinavica",
"keywords": null,
"medline_ta": "Acta Med Scand",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D004381:Duodenal Ulcer; D005260:Female; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D010894:Piroxicam; D011708:Pylorus; D013276:Stomach Ulcer; D013843:Thiazines",
"nlm_unique_id": "0370330",
"other_id": null,
"pages": "335-6",
"pmc": null,
"pmid": "6496192",
"pubdate": "1984",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Overdosage of piroxicam.",
"title_normalized": "overdosage of piroxicam"
} | [
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"companynumb": "NO-PFIZER INC-2016263087",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIROXICAM"
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"drugadditional": "3",
... |
{
"abstract": "As an opportunistic phytopathogen, Sarocladium strictum has only been shown to cause neurological disease in immunocompromised patients, where antifungal therapy was not effective. We report a case of Sarocladium strictum meningoencephalitis in an apparently immunocompetent young woman who presented with severe headache and slight fever after undergoing transnasal endoscopic repair of cerebrospinal fluid rhinorrhea. Chronic sinusitis and suspicious intracranial fungal lesions were observed on enhanced magnetic resonance imaging (MRI). Both culture and metagenomic next-generation sequencing of her cerebrospinal fluid were positive for Sarocladium strictum. After local debridement, treatment with amphotericin B plus voriconazole and Ommaya reservoir implantation, the patient improved significantly. Unfortunately, her symptoms worsened again despite plenty of antifungal therapy for a month.",
"affiliations": "Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Scientific Affairs, Hugobiotech Co., Ltd., Beijing, China.;Department of Clinical Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.",
"authors": "Cui|Yue|Y|;Meng|Jiali|J|;Zhang|Jing|J|;Wang|Lin|L|;Yan|Haihan|H|;Xia|Han|H|;Cao|Jingrong|J|;Wu|Liyong|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.762763",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.762763\nMedicine\nCase Report\nCase Report: A Case of Sarocladium strictum Meningoencephalitis in an Immunocompetent Patient After Invasive Operation\nCui Yue 1\n\nMeng Jiali 1\nZhang Jing 1\n\nWang Lin 1\nYan Haihan 1\nXia Han 2\nCao Jingrong 3 * †\n\nWu Liyong 1 * †\n\n1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China\n2Department of Scientific Affairs, Hugobiotech Co., Ltd., Beijing, China\n3Department of Clinical Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China\nEdited by: Aleksandra Barac, University of Belgrade, Serbia\n\nReviewed by: Kacper Toczylowski, Medical University of Bialystok, Poland; Akihiko Morita, Nihon University, Japan; Yi-Wei Tang, Cepheid, United States\n\n*Correspondence: Jingrong Cao 13683581168@126.com\nLiyong Wu wmywly@hotmail.com\nThis article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n10 11 2021\n2021\n8 76276322 8 2021\n21 10 2021\nCopyright © 2021 Cui, Meng, Zhang, Wang, Yan, Xia, Cao and Wu.\n2021\nCui, Meng, Zhang, Wang, Yan, Xia, Cao and Wu\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nAs an opportunistic phytopathogen, Sarocladium strictum has only been shown to cause neurological disease in immunocompromised patients, where antifungal therapy was not effective. We report a case of Sarocladium strictum meningoencephalitis in an apparently immunocompetent young woman who presented with severe headache and slight fever after undergoing transnasal endoscopic repair of cerebrospinal fluid rhinorrhea. Chronic sinusitis and suspicious intracranial fungal lesions were observed on enhanced magnetic resonance imaging (MRI). Both culture and metagenomic next-generation sequencing of her cerebrospinal fluid were positive for Sarocladium strictum. After local debridement, treatment with amphotericin B plus voriconazole and Ommaya reservoir implantation, the patient improved significantly. Unfortunately, her symptoms worsened again despite plenty of antifungal therapy for a month.\n\nmeningoencephalitis\nSarocladium strictum\nmetagenomic next-generation sequencing\nfungal infection\ntreatment\nMinistry of Science and Technology of the People's Republic of China 10.13039/501100002855 National Key Research and Development Program of China 10.13039/501100012166\n==== Body\npmcIntroduction\n\nSarocladium, under the order Hypocreales, has traditionally been considered an opportunistic phytopathogen, and only a very few species of this pathogen can infect patients with predisposing conditions (1). Sarocladium strictum, initially isolated from Triticum aestivum, has increasingly been recognized as a clinically important species and was reallocated from Acremonium based on rDNA sequences in 2011 by Summerbell et al. (1, 2). Although there have been some reports of S. strictum infections in humans, most of them were derived from skin or blood, and the brain is considered one of the least susceptible organs (3). Until now, S. strictum meningoencephalitis has been reported only in three immunodeficient patients, all of whom died within a short time (4). Here, we report a case of an apparently immunocompetent young woman who presented with severe headache and slight fever after undergoing a transnasal endoscopic repair of cerebrospinal fluid (CSF) rhinorrhea. Both culture and metagenomic next-generation sequencing of her CSF were positive for S. strictum.\n\nCase Description\n\nOn March 8, 2021, a 51-year-old woman who worked as a peasant farmer in Inner Mongolia, China, sought treatment at Xuanwu Hospital, Beijing, for continuous fever and headache after undergoing a transnasal endoscopic repair for spontaneous rhinorrhea. The patient was devoted to the autumn harvest before the onset of symptoms and reported no travel history or animals contact. None of her family members or neighbors showed similar symptoms or other signs of infection at the same time. Her preexisting condition was a history of penicillin allergy.\n\nThree months before admission to Xuanwu Hospital, the patient experienced spontaneous cerebrospinal rhinorrhea and underwent a transnasal endoscopic repair surgery in a regional hospital, after which she began to develop night fever with intermittent headache. Meanwhile, multiple enhanced sinus magnetic resonance imaging (MRI) revealed increasingly severe bilateral nasosinusitis. In addition, her intracranial pressure was >300 mmH2O, and her CSF examination showed a high white blood cell (WBC) count with predominance of mononuclear cell (~70%) and high protein (95.40 g/L). The CSF-to-serum glucose ratio decreased to 0.53. Based on this evidence, she was diagnosed with meningoencephalitis and treated with a full course of intravenous meropenem (2.0 g per 8 h) and vancomycin (0.5 g per 6 h). However, her condition continued to deteriorate. Despite switching to anti-infective treatment with meropenem (as before), linezolid (1.0 mg/kg per 12 h intravenously), and fluconazole (400 mg per day orally), the patient's headaches persisted. Moreover, she began to present with blurred vision, epileptic seizures, and hallucination. In addition, her intracranial pressure rose higher than before (380 mmH2O).\n\nAt admission of Xuanwu Hospital, the main complaint of the patient was persistently severe headache, and physical examination revealed obvious meningeal irritation and eye movement disorders. Bilateral papilledema and abnormal signals at the right basal ganglia region were also found. She was also tested for HIV, syphilis, cancer, cellular and humoral immunity via flow cytometry, and immunoglobulins. All these tests were negative. Metagenomic next-generation sequencing (mNGS) and culture were done on collected CSF specimens 5 times during hospitalization. The infection of S. strictum was verified through culture and mNGS of CSF samples on March 24th and March 19th, respectively. Thereafter, the patient was treated with amphotericin B (1.0 mg per day originally and increased by 2 mg every other day for 7 days, then increased by 5 mg per week, intravenously) and 5-fluorocytosine (6.0 g per day orally in four divided doses), instead of antibacterial drugs. Moreover, she underwent sinus debridement, but the effect was not ideal. It was only after changing the antifungal therapy to amphotericin B plus voriconazole (4.0 mg/kg per 12 h intravenously) that her headache and epileptic seizures got relieved than before with normal body temperature. The WBC count in her CSF also reduced gradually (Figure 1). At the time of discharge, intravenous amphotericin B dosage had reached 25 mg per day and the total dose was 742 mg.\n\nFigure 1 The treatment procedures and corresponding leukocyte counts in the patient's cerebrospinal fluid. Monocytes were predominant among CSF white cells; they had a proportion of approximately between 60 and 90%. The CSF protein level was also elevated to 95.00–125.20 mg/dl. mNGS.P, metagenomic next-generation sequencing of cerebrospinal fluid detected Sarocladium strictum positive; Culture.P, Sarocladium strictum was positive in cerebrospinal fluid culture.\n\nSoon afterwards, the patient accepted Ommaya reservoir implantation to extract CSF and inject amphotericin B (0.2 mg per day) in a regional hospital, with intravenous amphotericin B (20.0 mg per day), which was extremely effective against intracranial hypertension. Her headache was relieved further, with no more epileptic seizures and hallucination, and her eyesight was partially restored. Unfortunately, although under a plenty of antifungal therapy, the patient's condition worsened again within a month. On June 29, 2021, the patient began to present with worsening headache and blurred vision, with unstable standing and poor coordination of fine movements. The WBC count in her CSF was also elevated again, and MRI revealed multiple new punctured abnormal signals in her bilateral cerebellum. After the addition of itraconazole orally, the WBC count in her CSF decreased, but her symptoms remained unrelieved. Eventually, the patient requested to take itraconazole orally (0.2 g per day orally in two divided doses) at home, and she still suffered from headache and blurred vision on September 29, 2021. The clinical case was approved by the Ethics Committee of the Xuanwu Hospital of Capital Medical University, China. Written informed consent was obtained from all the patients.\n\nIn our study, S. strictum was isolated and identified at the Clinical Laboratory of Xuanwu Hospital. BD BACTECTM FX (PEDS plus) was used for both blood and CSF cultures, but only CSF was positive on the third day (3d2h58m) of incubation. Floccus grew in a positive culture bottle of CSF, and fungal hyphae could be visualized on Gram staining (Figure 2A). Positive cultures were transferred onto sheep blood agar plates at 35°C and Sabouraud's glucose agar plates at 28°C. White tufted colonies with a pale salmon pink-colored base were observed (Figure 2B). Lactophenol cotton blue preparations from the colonies revealed abundant, small, cylindrical conidia that were produced from the phialide tips of long, slender, lateral hyphae (Figure 2C). These findings are in accordance with the morphological characteristics of S. strictum which could not be identified through Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS, Bruker) and was finally identified by ITS sequencing. It had 99% homology with known strains of S. strictum in GenBank.\n\nFigure 2 (A) The fungal hyphae by Gram stain (×100). (B) The colony on Sabouraud's agar plates after 2d at 28°C. (C) Micromorphology of a colony of Sarocladium strictum (lactophenol cotton blue preparation, ×100).\n\nCSF samples were transferred to dry ice for PACEseq mNGS detection (Hugobiotech, Beijing, China). DNA was extracted using the QIAamp DNA Micro Kit (Qiagen). QIAseq™ Ultralow Input Library Kit (Illumina) was used to construct the DNA libraries. After purification, the quality of the libraries was analyzed using a Qubit (Thermo Fisher) and Agilent 2100 Bioanalyzer (Agilent Technologies). The NextSeq 550 platform (Illumina) was used to sequence all the DNA reads in the libraries. After sequencing, short, low-quality, and low-complexity reads were removed from the raw data. Human DNA was also filtered out according to the human reference database. The clean reads were aligned to the microbial genome database (NCBI; ftp://ftp.ncbi.nlm.nih.gov/genomes) to identify all probable pathogens. Moreover, mNGS revealed S. strictum in the CSF samples on the second day after lumbar puncture, with coverage and abundance shown in Figure 3. Furthermore, detected reads are shown in Supplement File 1.\n\nFigure 3 The coverage and abundance of Sarocladium strictum detected by mNGS on March 19, 2021.\n\nDiscussion\n\nThe first case of S. strictum infection in the brain was reported in 1987 in a 9-year-old boy who received long-term corticosteroid treatment for Landry-Guillain-Barré syndrome with subacute S. strictum meningitis (5). In 1993, S. strictum was cultured from the brain abscess of a 60-year-old woman who was treated with antineoplastic chemotherapy for bronchoalveolar carcinoma before her death (6). Unfortunately, due to the age of the reports, their diagnostic accuracy was uncertain, and their therapeutic process was unavailable. The only detailed case reported in 2003 was that of a neonate born at 27 weeks of gestation who was diagnosed with S. strictum infection through blood and CSF cultures, as well as autopsy, with no response to therapy with amphotericin B plus fluconazole (7). In contrast to previous reports, S. strictum infection of the brain was only detected in critical patients with immunodeficiency. We reported an immunocompetent young woman diagnosed with S. strictum meningoencephalitis using both morphological and molecular methods.\n\nPseudomonas sp.QS1027 (255 specific reads) were also caught by mNGS of CSF. However, this microbe was previously discovered in Dictyostelium discoideum fruiting bodies and always found in the background of mNGS, including negative controls due to the use of multiple reagent buffers (8). This indicated that Pseudomonas sp.QS1027 was more likely a reagent engineering bacterium (9, 10). In addition, there is no clinical evidence of Pseudomonas sp.QS1027 to cause infections in human, and the patient's clinical characteristics did not match those of Pseudomonas infection (11). Thus, this bacterium was not considered as a potential causative agent in this case.\n\nBefore the onset of meningoencephalitis, the patient underwent transnasal endoscopic repair due to progressive nasosinusitis. Several blood cultures were negative during the entire disease course, which strongly excluded the possibility of hematogenous spread and supported that the intracranial infection was caused by the dissemination of local infection after invasive operation. This study suggested that in addition to patients with predisposing conditions, healthy humans who have undergone surgery or other invasive operations.\n\nAlthough there have been many reports on the susceptibility of S. strictum, with fluconazole and 5-fluorocytosine being considered ineffective in S. strictum infection, evidence regarding the effectiveness of amphotericin B has been greatly conflicting (4, 12). As an effective agent against most fungi, amphotericin B is often used as the first choice for S. strictum treatment and has shown promising results in cases of pulmonary infection (13). However, the patient had no response to amphotericin B plus 5-fluorocytosine in this case, and her CSF leukocyte count increased. Her symptoms did not improve until 5-fluorocytosine was switched to voriconazole. Previously, an in vitro study showed the high diversity and variable susceptibility of Sarocladium species. It was shown that S. strictum was susceptible to voriconazole and terbinafine but was resistant to amphotericin B (4). Although it could not be ruled out that amphotericin B might not be effective at initial doses, we believe that voriconazole also plays a critical role in the treatment of S. strictum meningoencephalitis. After discharged from Xuanwu hospital, the patient was treated with intravenous amphotericin B and Ommaya reservoir. The treatment was effective at first in relieving symptoms of cranial hypertension but turned ineffective before long, suggesting that Ommaya reservoir implantation may be a good strategy to control the symptoms of intracranial infection. However, appropriate drug selection remains a top priority in the treatment of intracranial fungal infections.\n\nThis case suggests the possibility of S. strictum meningoencephalitis in an immunocompetent patient and provides clinical evidence for its effective treatment. Since different species of Sarocladium have varying susceptibility to antifungal agents, mNGS, which identifies pathogens early and distinguishes species accurately prior to culture, is of great significance in guiding clinical medication.\n\nData Availability Statement\n\nThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: National Genomics Data Center, accession no: PRJCA006827.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Ethics Committees of the Xuanwu Hospital of Capital Medical University, China. Written informed consent was obtained from the patient.\n\nAuthor Contributions\n\nYC provided the initial and subsequent draft of the submission. JM, JZ, LWa, and HY provided patient details and time activity curves. HX and JC provided images and microbiological analysis. LWu helped to create subsequent drafts of the submissions and coordinated the editing process. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by grants from the Ministry of Science and Technology of China (No. 2019YFC0118600) to LWu, National Key Research and Development Program of China Research on the Precision Diagnosis, Treatment, and Integrated Prevention, Control for the Elderly with Common Infectious Disease (2020YFC2005403) to Professor Yan Zhang, and the Xuanwu Hospital Teaching Reform Foundation (2020XWJXGG-09) to JC.\n\nConflict of Interest\n\nHX was employed by the company Hugobiotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nWe would like to thank the patient for providing consent to publish this case, and thank Editage (www.editage.cn) for English language editing.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.762763/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Perdomo H Sutton DA García D Fothergill AW Cano J Gené J . Spectrum of clinically relevant Acremonium species in the United States. J Clin Microbiol. (2011) 49 :243–56. 10.1128/JCM.00793-10 21068274\n2. Giraldo A Gené J Sutton DA Madrid H De Hoog GS Cano J . Phylogeny of Sarocladium (Hypocreales). Persoonia. (2015) 34 :10–24. 10.3767/003158515X685364 26240442\n3. Pérez-Cantero A Guarro J . Sarocladium and Acremonium infections: new faces of an old opportunistic fungus. Mycoses. (2020) 63 :1203–14. 10.1111/myc.13169 33090564\n4. Yao L Wang H Wan Z Li R Yu J . The high diversity and variable susceptibility of clinically relevant Acremonium-like species in China. Mycopathologia. (2019) 184 :759–73. 10.1007/s11046-019-00399-8 31655952\n5. Medek S Nemes A Khoor A Széll A Dobolyi C Novák EK . [Acremonium strictum meningitis in prolonged steroid therapy]. Orv Hetil. (1987) 128 :2529–32.3320854\n6. Trupl J Májek M Mardiak J Jesenská Z Krcméry V Jr . Acremonium infection in two compromized patients. J Hosp Infect. (1993) 25 :299–301. 10.1016/0195-6701(93)90118-J 7907628\n7. Yalaz M Hilmioglu S Metin D Akisu M Nart D Cetin H . Fatal disseminated Acremonium strictum infection in a preterm newborn: a very rare cause of neonatal septicaemia. J Med Microbiol. (2003) 52 :835–7. 10.1099/jmm.0.05140-0 12909663\n8. Arp J Gotze S Mukherji R Mattern DJ Garcia-Altares M Klapper M . Synergistic activity of cosecreted natural products from amoebae-associated bacteria. Proc Natl Acad Sci USA. (2018) 115 :3758–63. 10.1073/pnas.1721790115 29592954\n9. Salter SJ Cox MJ Turek EM Calus ST Cookson WO Moffatt MF . Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. (2014) 12 :87. 10.1186/s12915-014-0087-z 25387460\n10. Meyer KJ Nodwell JR . Biology and applications of co-produced, synergistic antimicrobials from environmental bacteria. Nat Microbiol. (2021) 6 :1118–28. 10.1038/s41564-021-00952-6 34446927\n11. Girard L Hofte M De Mot R . Lipopeptide families at the interface between pathogenic and beneficial Pseudomonas-plant interactions. Crit Rev Microbiol. (2020) 46 :397–419. 10.1080/1040841X.2020.1794790 32885723\n12. Guarro J Gams W Pujol I Gené J . Acremonium species: new emerging fungal opportunists–in vitro antifungal susceptibilities and review. Clin Infect Dis. (1997) 25 :1222–9. 10.1086/516098 9402385\n13. Boltansky H Kwon-Chung KJ Macher AM Gallin JI . Acremonium strictum-related pulmonary infection in a patient with chronic granulomatous disease. J Infect Dis. (1984) 149 :653. 10.1093/infdis/149.4.653 6539355\n\n",
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"keywords": "Sarocladium strictum; fungal infection; meningoencephalitis; metagenomic next-generation sequencing; treatment",
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"title": "Case Report: A Case of Sarocladium strictum Meningoencephalitis in an Immunocompetent Patient After Invasive Operation.",
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"abstract": "BACKGROUND\nHydroxychloroquine (HCQ) retinopathy can accompany other retinal complications such as cystoid macular edema (CME), which leads to central visual loss. We report a case of CME with HCQ retinopathy that improved with the use of oral acetazolamide, and discussed the possible mechanisms of CME in HCQ retinopathy using multimodal imaging modalities.\n\n\nMETHODS\nA 62-year-old patient with systemic lupus erythematosus (SLE) and HCQ retinopathy developed bilateral CME with visual decline. Fluorescein angiography (FA) showed fluorescein leakage in the macular and midperipheral area. After treatment with oral acetazolamide (250 mg/day) for one month, CME was completely resolved, best corrected visual acuity (BCVA) improved from 20/50 to 20/25, and FA examination showed decreased dye leakage in the macular and midperipheral areas.\n\n\nCONCLUSIONS\nIn cases of vision loss in HCQ retinopathy, it is important to consider not only progression of maculopathy, but also development of CME, which can be effectively treated with oral acetazolamide.",
"affiliations": "Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, South Korea.;Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, South Korea.;Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, South Korea.;Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, South Korea. brlee@hanyang.ac.kr.",
"authors": "Hong|Eun Hee|EH|;Ahn|Seong Joon|SJ|;Lim|Han Woong|HW|;Lee|Byung Ro|BR|",
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"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 51710.1186/s12886-017-0517-0Case ReportThe effect of oral acetazolamide on cystoid macular edema in hydroxychloroquine retinopathy: a case report Hong Eun Hee prayseven@gmail.com Ahn Seong Joon ahnsj81@gmail.com Lim Han Woong limhw@nate.com Lee Byung Ro (82)-2-2290-8570brlee@hanyang.ac.kr Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-792 South Korea 12 7 2017 12 7 2017 2017 17 12426 10 2016 6 7 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHydroxychloroquine (HCQ) retinopathy can accompany other retinal complications such as cystoid macular edema (CME), which leads to central visual loss. We report a case of CME with HCQ retinopathy that improved with the use of oral acetazolamide, and discussed the possible mechanisms of CME in HCQ retinopathy using multimodal imaging modalities.\n\nCase presentation\nA 62-year-old patient with systemic lupus erythematosus (SLE) and HCQ retinopathy developed bilateral CME with visual decline. Fluorescein angiography (FA) showed fluorescein leakage in the macular and midperipheral area. After treatment with oral acetazolamide (250 mg/day) for one month, CME was completely resolved, best corrected visual acuity (BCVA) improved from 20/50 to 20/25, and FA examination showed decreased dye leakage in the macular and midperipheral areas.\n\nConclusions\nIn cases of vision loss in HCQ retinopathy, it is important to consider not only progression of maculopathy, but also development of CME, which can be effectively treated with oral acetazolamide.\n\nKeywords\nAcetazolamideCase reportCystoid macular edemaHydroxychloroquine retinopathyissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHydroxychloroquine (HCQ) retinopathy is a form of retinal toxicity caused by HCQ and is characterized classically as a bilateral bull’s-eye maculopathy, in which there is a ring of parafoveal retinal pigment epithelium (RPE) depigmentation with sparing of the fovea. HCQ retinopathy can accompany other retinal complications such as cystoid macular edema (CME) and epiretinal membrane [1]. Specifically, CME is the result of fluid accumulation in the outer plexiform layer in the macular area and leads to central visual loss.\n\nSeveral treatment modalities have been shown to be effective for CME combined with other retinal diseases. In eyes with combined CME and retinitis pigmentosa, treatment with oral or topical acetazolamide can produce successful resolution of CME and functional improvement according to previous studies [2–7]. Although the pathogenic mechanism of CME in HCQ retinopathy has not been elucidated, oral or topical acetazolamide may also be useful in the treatment of CME in HCQ retinopathy. Here, we report a case of CME in HCQ retinopathy that improved with the use of oral acetazolamide. Using multimodal imaging modalities, we explored the detailed retinal structural changes, and discussed the possible mechanisms of CME in HCQ retinopathy.\n\nCase presentation\nA 60-year-old woman visited our clinic complaining of blurred vision in both eyes. The patient had been diagnosed with systemic lupus erythematosus (SLE) and had taken HCQ for the past 20 years. Her daily dose of HCQ was 400 mg, and her total cumulative dose was estimated to be 2920 g. The patient had first come to our clinic 7 months prior, at which time her best corrected visual acuity (BCVA) was 20/30 in both eyes and fundus examination showed bilteral midperipheral retinal degeneration. Spectral-domain optical coherence tomography (SD-OCT) showed defects in the paracentral photoreceptor layers. Consistent with this finding, a visual field test revealed dense paracentral ring scotoma with decreased foveal sensitivity in both eyes (Fig. 1). The patient reported no family history of eye diseases and no visual symptoms before the initiation of HCQ therapy, and she had no auditory symptoms. At that time, the patient was diagnosed with HCQ-induced retinal toxicity, HCQ retinopathy, and HCQ treatment was discontinued. Four months later, BCVA was maintained as 20/30 in both eyes.Fig. 1 Diagnosis of hydroxychloroquine retinopathy based on visual field examination, optical coherence tomography, and fundus autofluorescence. a Humphrey 30-2 visual field test shows dense paracentral ring scotoma with decreased foveal sensitivity in both eyes. b Spectral-domain optical coherence tomography (SD-OCT) demonstrates defects in the paracentral photoreceptor layer. c Fundus autofluorescence reveals decreased paracentral and mid-peripheral fluorescence in both eyes\n\n\n\n\nDuring the patient’s visit of visual complaint, slit lamp examination showed no specific findings and there was no inflammation in the anterior chamber or vitreous cavity; however, her BCVA had declined to 20/50. SD-OCT examination showed the presence of a cystoid space within the inner retina and fluorescein angiography (FA) showed leakage in the macular area, a presentation typically associated with cystoid macular edema (CME), as well as diffuse leakage in the midperiphery (Figs. 2 and 3). Central macular thickness (CMT) was 245 μm and 335 μm in the right and left eyes, respectively. The patient was prescribed oral acetazolamide (250 mg) once a day.Fig. 2 \na Cystoid macular edema (CME) shown by spectral-domain optical coherence tomography (SD-OCT). b The patient’s CME completely resolved after treatment for one month with oral acetazolamide. Central macular thickness (CMT) decreased from 245 to 177 μm and from 335 to 146 μm in the right and left eyes, respectively\n\n\nFig. 3 Fluorescein angiography (FA) images in the patient before (a) and after (b) oral acetazolamide therapy obtained at 2 min after fluorescein injection. Dye leakage in both the macular and mid-peripheral areas is decreased by the treatment, as demonstrated by remarkably decreased leakage in the macula and more definite demarcation of hyperfluorescent lesion in the mid-peripheral retina\n\n\n\n\nAfter treatment with oral acetazolamide for one month, CME was resolved in both eyes on SD-OCT images (Fig. 2). CMT was decreased from 245 to 177 μm and from 335 to 146 μm in the right and left eyes, respectively. BCVA was improved to 20/25 in both eyes. Follow-up FA showed decreased dye leakage in both the macular and mid-peripheral areas (Fig. 3).\n\nDiscussion\nHCQ retinopathy presents with initial photoreceptor damage in a classic parafoveal distribution, known as a “bull’s eye” pattern, which corresponds to parafoveal scotomas upon visual field examination [8, 9] and parafoveal thinning of the outer nuclear layer with breakup of the ellipsoid zone and interdigitation zone lines on SD-OCT. [10] However, recent studies have shown that the initial pattern of damage in Asian eyes is more frequently in the more peripheral extramacular area near the arcades, as a pericentral pattern [11, 12]. In this pattern of retinopathy, CME may threaten relatively preserved central vision, leading to deterioration of visual function.\n\nCME can develop in various retinal disorders [13]. Macular edema associated with chloroquine (CQ) retinopathy is relatively rare, and it was reported in 5 of 78 patients during a study period from 1957 to 1979 [14]; however, its treatment has not been discussed extensively. Although some cellular and molecular factors have been elucidated, the precise mechanisms for the formation of CME are unknown, including for HCQ retinopathy. In retinitis pigmentosa, CME formation has been suggested to involve breakdown of the blood-retinal barrier (BRB) as a result of chronic, low-grade inflammation [15–21] and decreased fluid transport efficiency of the retinal pigment epithelium [3]. CME associated with HCQ retinopathy has been reported in both leaking [22] and non-leaking [23] forms. In this case, it can be assumed that the leaking form of CME occurred owing to a mechanism such as BRB breakdown due to HCQ damage and that CME developed because such damage was not recovered even after the drug was cut off; however, the precise mechanism should be revealed in future studies.\n\nIn the present case, the CME associated with HCQ retinopathy exhibited diffuse leakage on FA that resolved with oral acetazolamide as evidenced by decreased fluorescein leakage. Acetazolamide reduces macular edema and improves visual acuity in some patients with macular edema related to certain inflammatory and degenerative eye diseases, including chronic iridocyclitis and retinitis pigmentosa [4]. With respect to mechanism, acetazolamide has been suggested to stimulate outward active transport and passive permeability across the BRB [6, 24, 25]. More specifically, acetazolamide blocks the active transport of certain ions (HCO3-, Cl-) across the retinal pigment epithelium [26], and also hastens the rate of resorption of subretinal fluid [27]. In our patient, acetazolamide was thought to induce functional recovery of the BRB, leading to a reduction in diffuse leakage and also improvement of CME.\n\nUse of topical dorzolamide or oral acetazolamide (250 mg/day) in patients with CME in HCQ retinopathy has been described in only one recent study [1], which reported limited benefit. However, the patients in that study also had epiretinal membrane, which may have limited the beneficial effects of acetazolamide on reducing macular edema. Aside from carbonic anhydrase inhibitors, other treatment options for CME with HCQ retinopathy such as triamcinolone or anti-vascular endothelial growth factor antibodies have not been described in the literature. In our case, there were no accompanying structural alterations to the central macular area such as epiretinal membrane, which likely explains why acetazolamide was effective for anatomic and functional improvement of CME.\n\nRetinitis pigmentosa associated with various types of mutations shows similar features to advanced HCQ retinopathy; therefore, retinitis pigmentosa should be carefully assessed for the differential diagnosis in patients taking HCQ medication. In the present case, the patient reported no family history of eye diseases and no visual symptoms before the initiation of HCQ therapy and she had no auditory symptoms. Genetic analyses on the associated mutations might be helpful for ruling out the possibilities of retinitis pigmentosa; however, we believe that the baseline (at the time of HCQ initiation) full-field electroretinography (ERG) and/or multifocal ERG may be very suggestive for the differential diagnosis.\n\nConclusion\nIn conclusion, this case suggests that oral acetazolamide is an effective treatment for CME associated with HCQ retinopathy. Further prospective and comparative studies with a larger population are needed to assess the efficacy and safety of this treatment in patients with CME secondary to HCQ retinopathy.\n\nAbbreviations\nBCVABest corrected visual acuity\n\nBRBBlood-retinal barrier\n\nCMECystoid macular edema\n\nCMTCentral macular thickness\n\nCQChloroquine\n\nFAFluorescein angiography\n\nHCQHydroxychloroquine\n\nRPERetinal pigment epithelium\n\nSD-OCTSpectral-domain optical coherence tomography\n\nSLESystemic lupus erythematosus\n\nThis study received no specific grant from any funding agency.\n\nFunding\nNo funding was obtained for this study.\n\nAvailability of data and materials\nAll data supporting our findings are provided in the manuscript.\n\nAuthors’ contributions\nEHH, SJA, HWL and BRL contributed to conception and design, data acquisition, interpretation of data, and EHH and SJA drafted the article and all authors approved the final version.\n\nEthics approval and consent to participate\nThe local ethics committee ruled that no formal ethics approval was required in this case report.\n\nThe authors declare that they adhered to the CARE quidelines/methodology.\n\nConsent for publication\nWritten informed consent for publication of potentially identifying information and clinical images was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Kellner S Weinitz S Farmand G Kellner U Cystoid macular oedema and epiretinal membrane formation during progression of chloroquine retinopathy after drug cessation Br J Ophthalmol 2014 98 200 206 10.1136/bjophthalmol-2013-303897 24187053 \n2. Grover S Apushkin MA Fishman GA Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa Am J Ophthalmol 2006 141 850 858 10.1016/j.ajo.2005.12.030 16546110 \n3. Cox SN Hay E Bird AC Treatment of chronic macular edema with acetazolamide Arch Ophthalmol 1988 106 1190 1195 10.1001/archopht.1988.01060140350030 3415543 \n4. Fishman GA Gilbert LD Fiscella RG Kimura AE Jampol LM Acetazolamide for treatment of chronic macular edema in retinitis pigmentosa Arch Ophthalmol 1989 107 1445 1452 10.1001/archopht.1989.01070020519031 2803090 \n5. Fishman GA Gilbert LD Anderson RJ Marmor MF Weleber RG Viana MA Effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa Ophthalmology 1994 101 687 693 10.1016/S0161-6420(94)31277-2 8152764 \n6. Moldow B Sander B Larsen M Engler C Li B Rosenberg T Lund-Andersen H The effect of acetazolamide on passive and active transport of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular oedema Graefes Arch Clin Exp Ophthalmol 1998 236 881 889 10.1007/s004170050175 9865617 \n7. Wolfensberger TJ The role of carbonic anhydrase inhibitors in the management of macular edema Doc Ophthalmol 1999 97 387 397 10.1023/A:1002143802926 10896355 \n8. Marmor MF Efficient and effective screening for hydroxychloroquine toxicity Am J Ophthalmol 2013 155 413 414 10.1016/j.ajo.2012.10.020 23394729 \n9. Anderson C Blaha GR Marx JL Humphrey visual field findings in hydroxychloroquine toxicity Eye (Lond) 2011 25 1535 1545 10.1038/eye.2011.245 22094300 \n10. Brown DM s Benz M Wong TP Major JC Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign) Clin Ophthalmol 2010 4 1151 1158 21060664 \n11. Melles RB Marmor MF Pericentral retinopathy and racial differences in hydroxychloroquine toxicity Ophthalmology 2015 122 110 116 10.1016/j.ophtha.2014.07.018 25182842 \n12. Lee DH Melles RB Joe SG Lee JY Kim JG Lee CK Yoo B Koo BS Kim JT Marmor MF Pericentral hydroxychloroquine retinopathy in Korean patients Ophthalmology 2015 122 1252 1256 10.1016/j.ophtha.2015.01.014 25712474 \n13. Scholl S Augustin A Loewenstein A Rizzo S Kupperman B General pathophysiology of macular edema Eur J Ophthalmol 2011 21 Suppl 6 S10 S19 10.5301/EJO.2010.6050 23264324 \n14. Marks J Chloroquine retinopathy: is there a safe daily dose? Ann Rheum Dis 1982 41 52 58 10.1136/ard.41.1.52 7065730 \n15. Cunha-Vaz JG Travassos A Breakdown of the blood-retinal barriers and cystoid macular edema Surv Ophthalmol 1984 28 Suppl 485 492 10.1016/0039-6257(84)90230-3 6379947 \n16. Fishman GA Cunha-Vaz J Salzano T Vitreous fluorophotometry in patients with retinitis pigmentosa Arch Ophthalmol 1981 99 1202 1207 10.1001/archopht.1981.03930020076005 7259594 \n17. Kuchle M Nguyen NX Martus P Freissler K Schalnus R Aqueous flare in retinitis pigmentosa Graefes Arch Clin Exp Ophthalmol 1998 236 426 433 10.1007/s004170050101 9646087 \n18. Mallick KS Zeimer RC Fishman GA Blair NP Anderson RJ Transport of fluorescein in the ocular posterior segment in retinitis pigmentosa Arch Ophthalmol 1984 102 691 696 10.1001/archopht.1984.01040030547013 6721754 \n19. Vinores SA Kuchle M Derevjanik NL Henderer JD Mahlow J Green WR Campochiaro PA Blood-retinal barrier breakdown in retinitis pigmentosa: light and electron microscopic immunolocalization Histol Histopathol 1995 10 913 923 8574012 \n20. Yoshida N Ikeda Y Notomi S Ishikawa K Murakami Y Hisatomi T Enaida H Ishibashi T Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa Ophthalmology 2013 120 e5 12 10.1016/j.ophtha.2012.07.008 22986110 \n21. Yoshida N Ikeda Y Notomi S Ishikawa K Murakami Y Hisatomi T Enaida H Ishibashi T Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa Ophthalmology 2013 120 100 105 10.1016/j.ophtha.2012.07.006 22986109 \n22. Bhavsar KV Mukkamala LK Freund KB Multimodal imaging in a severe case of hydroxychloroquine toxicity Ophthalmic Surg Lasers Imaging Retina 2015 46 377 379 10.3928/23258160-20150323-14 25856825 \n23. Parikh VS Modi YS Au A Ehlers JP Srivastava SK Schachat AP Singh RP Nonleaking cystoid macular edema as a presentation of hydroxychloroquine retinal toxicity Ophthalmology 2016 123 664 666 10.1016/j.ophtha.2015.09.011 26459999 \n24. Takahashi J Mori F Hikichi T Yoshida A Effect of acetazolamide on outward permeability of blood-retina barrier using differential vitreous flyorophotometry Curr Eye Res 2001 23 166 170 10.1076/ceyr.23.3.166.5461 11803477 \n25. Moldow B Sander B Larsen M Lund–Andersen H Effects of acetazolamide on passive and active transport of fluorescein across the normal BRB Invest Ophthalmol Vis Sci 1999 40 1770 1775 10393047 \n26. Miller SS Steinberg RH Active transport of ions across frog retinal pigment epithelium Exp Eye Res 1977 25 235 248 10.1016/0014-4835(77)90090-2 304010 \n27. Marmor MF Maack T Enhancement of retinal adhesion and subretinal fluid resorption by acetazolamide Invest Ophthalmol Vis Sci 1982 23 121 124 7085214\n\n",
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"journal": "BMC ophthalmology",
"keywords": "Acetazolamide; Case report; Cystoid macular edema; Hydroxychloroquine retinopathy",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000086:Acetazolamide; D000284:Administration, Oral; D018501:Antirheumatic Agents; D002257:Carbonic Anhydrase Inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D006886:Hydroxychloroquine; D008180:Lupus Erythematosus, Systemic; D008269:Macular Edema; D008875:Middle Aged; D012160:Retina; D012164:Retinal Diseases; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
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"title": "The effect of oral acetazolamide on cystoid macular edema in hydroxychloroquine retinopathy: a case report.",
"title_normalized": "the effect of oral acetazolamide on cystoid macular edema in hydroxychloroquine retinopathy a case report"
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"abstract": "Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.\nA 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.\nSodium channel and N-methyl-D-aspartate receptor antagonists have evidence for neuropathic symptoms but can cause significant gastrointestinal side effects. Prescription cannabinoids such as nabiximol can be cost prohibitive to use in practice. Synthetic tetrahydrocannabinol products are dose limited by psychoactive side effects.\nA balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.\nThe patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.\nCannabinoids are possibly safe and effective in management of neuropathic pruritus.\nAdditional research is needed to establish efficacy and safety.",
"affiliations": "Palliative Medicine, The University of British Columbia, Vancouver, BC, Canada.;Palliative Medicine, The University of British Columbia, Vancouver, BC, Canada.;Palliative Medicine, The University of British Columbia, Vancouver, BC, Canada.",
"authors": "Lou|Kelvin|K|https://orcid.org/0000-0001-5922-0161;Murphy|Shane|S|;Talbot|Clair|C|",
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"fulltext": "\n==== Front\nPalliat Med\nPalliat Med\nPMJ\nsppmj\nPalliative Medicine\n0269-2163\n1477-030X\nSAGE Publications Sage UK: London, England\n\n34510973\n10.1177/02692163211045314\n10.1177_02692163211045314\nCase Report\nCannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report\nhttps://orcid.org/0000-0001-5922-0161\nLou Kelvin\nMurphy Shane\nTalbot Clair\nPalliative Medicine, The University of British Columbia, Vancouver, BC, Canada\nKelvin Lou, Palliative Medicine, The University of British Columbia, 6389 Stadium Road, Vancouver, BC V6T 1Z4, Canada. Email: klou@alumni.ubc.ca\n11 9 2021\n1 2022\n36 1 208211\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any 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).\nBackground:\n\nNeuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.\n\nCase presentation:\n\nA 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.\n\nPossible course of action:\n\nSodium channel and N-methyl-D-aspartate receptor antagonists have evidence for neuropathic symptoms but can cause significant gastrointestinal side effects. Prescription cannabinoids such as nabiximol can be cost prohibitive to use in practice. Synthetic tetrahydrocannabinol products are dose limited by psychoactive side effects.\n\nFormulation of a plan:\n\nA balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.\n\nOutcome:\n\nThe patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.\n\nLessons learned from case:\n\nCannabinoids are possibly safe and effective in management of neuropathic pruritus.\n\nView on research problems:\n\nAdditional research is needed to establish efficacy and safety.\n\nCannabis\ncannabinoids\nsmall fiber neuropathy\namyotrophic lateral sclerosis\ntypesetterts1\n==== Body\npmc What is already known about this topic?\n\n• Neuropathic pruritus is a chronic form of pruritus that causes significant symptom burden and can be difficult to treat. Cannabinoids have evidence to manage chronic neuropathic pain.\n\nWhat this paper adds?\n\n• This case demonstrates the safe and effective use of cannabinoids to manage neuropathic pruritus.\n\nImplications for practice, theory, or policy\n\n• This report show a potential role for cannabinoids for the management of neuropathic symptoms and highlights the need for further clinical trials.\n\nBackground\n\nThe clinical manifestations of neuropathic symptoms can range from pain, numbness, paraesthesia, or pruritus. 1 Neuropathic pruritus is a type of chronic pruritus caused by the dysfunction of itch-sensing neurons and damage to the C-fibers and A-delta fibers.1,2 Amyotrophic lateral sclerosis is a disorder characterized by the degeneration of upper and lower motor neurons leading to diffuse weakness and muscle wasting. There is growing evidence that amyotrophic lateral sclerosis is associated with small fiber neuron loss, which can be a cause of neuropathic pruritus.2,3 The presentation of neuropathic pruritus has a large overlap with other causes of pruritus, but can include sensations such as pain, burning, tingling, or numbness in a distal-to-proximal pattern. 1 Management of neuropathic pruritus begins with targeted investigations to look for reversible causes such as poorly controlled diabetes, thyroid disorders, or autoimmune conditions. The work up can also include nerve conduction studies and labs to rule out metabolic derangements such as uremia or hyperbilirubinemia. 2 Chronic pruritus can be difficult to control and these symptoms can lead to decreased quality of life. 1 The first-line treatments for non-cancer neuropathic symptoms include antidepressants and gabapentinoids. 4 Topical agents such as moisturizers, capsaicin and menthol also serve as useful adjuncts. 4 Given the lack of long-term efficacy of opioids in chronic non-cancer neuropathic pain, they are generally not recommended as first-line agents by international guidelines.4,5 As an alternative to standard therapies, there is emerging evidence for the use of cannabinoid within palliative care.4–6 The pharmacologically active components of cannabinoids include tetrahydrocannabinol (THC) and cannabidiol (CBD), which work as agonists on the endocannabinoid system. 7 The endocannabinoid system is a homeostatic regulator that is involved with many physiological function including neurotransmitter regulation, stress response, immune function, and nociceptive processing. 7 Tetrahydrocannabinol and cannabidiol work together synergistically and there is evidence that presence of cannabidiol may improve the tolerability of the psychoactive side effects of tetrahydrocannabinol. 7 Synthetic tetrahydrocannabinol products without cannabidiol such as nabilone are often limited by psychoactive side effects. 7 Balanced formulations such as nabiximol with both tetrahydrocannabinol and cannabidiol may be better tolerated as the CBD component helps mitigate the psychoactive side effects. 6\n\nThe evidence for cannabinoids is limited by small sample size, methodological design flaws, and lack of standardization of formulation and doses. 6 There are numerus examples in the literature where epidemiological and retrospective findings have not been borne out in trial conditions. 8 The strongest evidence comes from new trials with better trial design and stricter standardization of doses using pharmaceutical grade formulations. Based on international guidelines and multiple systematic reviews, cannabis has evidence for use in chemotherapy induced nausea and vomiting, multiple sclerosis spasticity, and intractable seizures in Dravet and Lennox-Gastaut syndromes.5,7–9 There is also growing evidence for the use of cannabinoids in a wide range of neuropathic pain conditions, such as diabetic, HIV, and multiple sclerosis.4–6 Although prescription cannabinoid products such as nabiximol are better studied, their use is limited by significant cost and lack of third-party drug coverage. With the legalization of medical cannabis in various parts of the world, patients are able to access medical cannabis products through avenues such as Licensed Producers. 10 Depending on the jurisdiction, Licensed Producers or their equivalents, are federally licensed distributors that undergo strict monitoring to ensure product quality and safety. 10\n\nCase presentation\n\nWe present the case of a 60-year old male with a history of amyotrophic lateral sclerosis and chronic neuropathic pruritus. The medical history is also significant for gastroparesis and constipation despite regular laxatives. He is followed by the outpatient Palliative Care Team in the community for symptom management. In regards to his amyotrophic lateral sclerosis, he is managed with 24-h nasal Bilevel Positive Airway Pressure and essentially has no use of his arms or hands. One of the persistent symptoms he has had over the years is chronic pruritus. Originally, the pruritus was intermittent and only involved the tips of the extremities. Over the years, it has become progressively worse where it is now a constant generalized pruritus involving the entire body. These symptoms persisted despite good adherence to topical moisturizers and menthol ointments. More recently in the last year the pruritus is now associated with paraesthesia, autonomic symptoms, and temperature changes along the skin of the chest. Given his minimal upper limb function, he is unable to scratch the affected areas and relies on his caretakers to provide relief. The constant nature of this symptom, especially at night when there is no one to provide scratching has caused significant distress and has interfered with his sleep and mood. Investigations revealed vitamin B12 256 pmol/L, Thyroid stimulating hormone (TSH) 1.01 ng/dL, and A1C 5.7%. Renal, liver enzymes, and protein electrophoresis were within normal range. The ANA and extractable nuclear antibody panel were both negative. Non-pharmacological strategies trialed include using an alternating pressure mattress and various topical moisturizers. Other topical therapies trialed include menthol and camphor ointment, steroid cream, antihistamine cream, and capsaicin cream. Systemic therapies trialed include hydroxyzine 25 mg three times daily, pregabalin 50 mg twice daily, venlafaxine 150 mg daily, nortriptyline 10 mg, and mirtazapine 15 mg. Each therapy was only helpful for a short time and the doses of systemic therapy were limited by significant sedation and anticholinergic side effects.\n\nPossible course of action: Medications with alternative mechanisms of action include sodium channel blockers and N-methyl-D-aspartate receptor such as mexiletine and methadone respectively. Both classes of medication have evidence for neuropathic pain, but the significant gastrointestinal symptoms the patient has at baseline precludes their use. 2 Psychostimulants have been used to manage medication related sedation but this would contribute to polypharmacy and the long-term safety is unclear. 11 The use of prescription cannabinoid products such as nabiximol is limited by the significant out of pocket costs. Synthetic tetrahydrocannabinol products such as nabilone are often dose-limited by psychoactive side effects.\n\nFormulation of a plan\n\nGiven the unresolving symptoms, a discussion was had regarding alternative treatment options, including antiepileptics, sodium channel blockers, or cannabis. After reviewing the risks and benefits of each, the patient decided to trial cannabinoid products from a federally licensed dispensary. The cannabinoid product chosen was a balanced oral capsule formulation (2.43 mg THC/CBD 2.75 mg). For pruritus intensity assessment, the numeric rating scale, which ranges from 0 (no pruritus) to 10 (worst possible pruritus) was used. At baseline evaluation, he was maintained on pregabalin 50 mg twice daily.\n\nOutcome\n\nPrior to the administration of the cannabinoid capsule, his pruritus score was 7/10 at baseline. He was started initially on one capsule daily, which improved his pruritus score to 5/10 after 2 days. During the first 2 days, he reported mild sedation up to a few hours after medication administration. By the third day, he had developed tolerance to the sedation and the dose was increased to one capsule twice daily. At the twice daily dose, his pruritus score decreased to 3/10 within a few days. Given the marked improvement to his pruritus, he was weaned off pregabalin over the course of 2 weeks with no change to his pruritus score and there was improvement to his level of sedation. During subsequent follow-up visits, the patient reported that the level of pruritus control is sufficient and that the improvement has been sustained. During the treatment course with cannabis, there was no change in the levels of anxiety experience by the patient but he did experience an overall improvement to his wellbeing given the improved symptom control.\n\nLessons learned from the case\n\nThis case report describes a sustained reduction of generalized pruritus of potential neuropathic origin by oral cannabinoids in a patient with ALS. Although there was mild sedation initially, tolerance developed quickly. The sustained efficacy is further supported by the weaning of pregabalin without worsening of pruritus control. Shared decision-making with the patient allows for additional treatment options when standard therapies are exhausted. With the increased availability and improved regulation of cannabinoid products, it may prove to be a useful tool to manage symptoms in the future.\n\nView on research problems, objectives or questions generated by the case: This case highlights the need for additional studies such as prospective-case series and placebo-controlled studies to establish efficacy and safety of cannabinoids.\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\nResearch ethics and patient consent: Written consent was obtained to publish this case report\n\nORCID iD: Kelvin Lou https://orcid.org/0000-0001-5922-0161\n==== Refs\nReferences\n\n1 Brenaut E Marcorelles P Genestet S , et al . Pruritus: an under recognized symptom of small-fiber neuropathies. J Am Acad Dermatol 2015; 72 (2 ): 328–332.25484269\n2 Oaklander AL. Neuropathic itch. In: Carstens E Akiyama T (eds) Itch: mechanisms and treatment. Frontiers in neuroscience. Boca Raton, FL: CRC Press/Taylor & Francis, 2014.\n3 Dalla Bella E Lombardi R Porretta-Serapiglia C , et al . Amyotrophic lateral sclerosis causes small fiber pathology. Eur J Neurol 2016; 23 (2 ): 416–420.26806218\n4 Attal N Cruccu G Baron R , et al . EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17 (9 ): 1113–e88.\n5 Sihota A Smith BK Ahmed S-A , et al . Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control. Int J Clin Pract 2021; 75 : e13871.33249713\n6 Wright P Walsh Z Margolese S , et al . Canadian clinical practice guidelines for the use of plant-based cannabis and cannabinoid-based products in the management of chronic non-cancer pain and co-occurring conditions: protocol for a systematic literature review. BMJ Open 2020; 10 (5 ): e036114.\n7 MacCallum CA Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med 2018; 49 : 12–19.29307505\n8 Allan GM Ramji J Perry D , et al . Simplified guideline for prescribing medical cannabinoids in primary care. Can Fam Physician 2018; 64 (2 ): 111–120.29449241\n9 Allan GM Finley CR Ton J , et al . Systematic review of systematic reviews for medical cannabinoids: pain, nausea and vomiting, spasticity, and harms. Can Fam Physician 2018; 64 (2 ): e78–e94.29449262\n10 Government of Canada. Licensed cultivators, processors and sellers of cannabis under the Cannabis Act. AEM. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/industry-licensees-applicants/licensed-cultivators-processors-sellers.html (2018, accessed 21 February 2021).\n11 Groenman AP Schweren LJ Dietrich A , et al . An update on the safety of psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Drug Saf 2017; 16 (4 ): 455–464.28277842\n\n",
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"abstract": "Rabbit syndrome is a rare side effect of chronic neuroleptic administration characterized by rapid, fine, rhythmic movements of the mouth along a vertical axis. It gains its name from an unusual resemblance to the chewing and puckering motions of the rabbit. It is generally thought to be an extra-pyramidal side effect, in part due to its rapid response to anti-cholinergic medication. This is the first case report of risperidone, an atypical antipsychotic, inducing the syndrome. The theoretical implications for the classification of the syndrome along the spectrum of neuroleptic-induced movement disorders are discussed.",
"affiliations": "Eitanim Mental Health Center, Tzfon Yehuda, Israel. levint@netvision.net.il",
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"abstract": "Rituximab represents a milestone in the treatment of mixed cryoglobulinemic vasculitis. Despite usually well-tolerated, rituximab may induce different types of adverse drug reactions, including exacerbation of vasculitis. Rituximab biosimilar have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of rituximab biosimilar in the treatment of mixed cryoglobulinemic vasculitis. We describe a severe skin vasculitis reactivation in a patient affected by rheumatoid arthritis and mixed cryoglobulinemic vasculitis treated with rituximab biosimilar. After 7 days from the first infusion, a severe purpuric rash at lower limbs appeared, that resolved in about 2 weeks with high dose-corticosteroid. Rituximab-induced vasculitis has also been described since 2001, but its pathophysiology is still controversial due to the anecdotical descriptions in literature and the variability of the time between the rituximab infusion and the onset of skin lesions. Up to date, this is the first report describing a vasculitic flare in a patient affected by mixed cryoglobulinemic vasculitis treated with rituximab biosimilar.",
"affiliations": "Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.;Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.;Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.;Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "Vacchi|Caterina|C|;Manfredi|Andreina|A|;Salvarani|Carlo|C|;Sebastiani|Marco|M|",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D058846:Antibodies, Monoclonal, Murine-Derived; D059451:Biosimilar Pharmaceuticals; D003449:Cryoglobulinemia; D006801:Humans; D000069283:Rituximab; D012867:Skin; D016896:Treatment Outcome; D014657:Vasculitis",
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"title": "Vasculitis in a patient with mixed cryoglobulinemia treated with rituximab biosimilar CT-P10: a case report.",
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"abstract": "BACKGROUND\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first line treatment for a subset of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Although transformation to small cell lung cancer (SCLC) is one of the known mechanisms of resistance to EGFR TKIs, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors.\n\n\nMETHODS\nWe identified six patients with primary lung adenocarcinoma that showed transformation to SCLC on second biopsy (n = 401) during a 6-year period. Clinicopathologic information was analyzed and EGFR mutation results were compared between initial and second biopsy samples.\n\n\nRESULTS\nSix patients showed transformation from adenocarcinoma to SCLC, of which four were pure SCLCs and two were combined adenocarcinoma and SCLCs. Clinically, four cases were EGFR-mutant tumors from non-smoking females who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The remaining two adenocarcinomas were EGFR wild-type, and one of these patients received EGFR TKI treatment.\n\n\nCONCLUSIONS\nNSCLC can acquire a neuroendocrine phenotype with or without EGFR TKI treatment.",
"affiliations": "Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Ahn|Soomin|S|;Hwang|Soo Hyun|SH|;Han|Joungho|J|;Choi|Yoon-La|YL|;Lee|Se-Hoon|SH|;Ahn|Jin Seok|JS|;Park|Keunchil|K|;Ahn|Myung-Ju|MJ|;Park|Woong-Yang|WY|",
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"fulltext": "\n==== Front\nJ Pathol Transl MedJ Pathol Transl MedJPTMJournal of Pathology and Translational Medicine2383-78372383-7845The Korean Society of Pathologists and the Korean Society for Cytopathology 2716068710.4132/jptm.2016.04.19jptm-2016-04-19Original ArticleTransformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases Ahn Soomin 1Hwang Soo Hyun 1Han Joungho 1Choi Yoon-La 1Lee Se-Hoon 2Ahn Jin Seok 2Park Keunchil 2Ahn Myung-Ju 2Park Woong-Yang 341 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea2 Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea3 Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea4 Samsung Genomic Institute, Samsung Medical Center, Seoul, KoreaCorresponding Author Joungho Han, MD Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-2765 Fax: +82-2-3410-0025 E-mail: hanjho@skku.edu7 2016 10 5 2016 50 4 258 263 24 2 2016 6 4 2016 18 4 2016 © 2016 The Korean Society of Pathologists/The Korean Society for Cytopathology2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first line treatment for a subset of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Although transformation to small cell lung cancer (SCLC) is one of the known mechanisms of resistance to EGFR TKIs, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors.\n\nMethods:\nWe identified six patients with primary lung adenocarcinoma that showed transformation to SCLC on second biopsy (n = 401) during a 6-year period. Clinicopathologic information was analyzed and EGFR mutation results were compared between initial and second biopsy samples.\n\nResults:\nSix patients showed transformation from adenocarcinoma to SCLC, of which four were pure SCLCs and two were combined adenocarcinoma and SCLCs. Clinically, four cases were EGFR-mutant tumors from non-smoking females who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The remaining two adenocarcinomas were EGFR wild-type, and one of these patients received EGFR TKI treatment.\n\nConclusions:\nNSCLC can acquire a neuroendocrine phenotype with or without EGFR TKI treatment.\n\nLung neoplasmsReceptor, epidermal growth factorTyrosine kinase inhibitorSmall cell lung carcinomaAdenocarcinoma\n==== Body\nCurrently, lung cancer is classified into two broad histological subgroups: non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The distinction between these two categories is important because the treatment options differ substantially. There are different chemotherapeutic regimens for SCLC and NSCLC, and the initial response to chemotherapy is much greater for patients with SCLC than for those with NSCLC [1,2]. Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for a subset of EGFR-mutated NSCLC patients [3]. In many cases, however, acquired resistance emerges within a year [4]. Although the secondary T790M mutation has been well-described and reported in up to 60% of resistant samples [5], there have been several studies proposing histological transformation from NSCLC to SCLC as another mechanism of EGFR TKI resistance [2,5-12]. The possible explanation of this phenomenon can be the transformation of NSCLC, mostly adenocarcinoma (ADC), to high-grade neuroendocrine phenotype [2]. The other possibility can be the presence of combined histology of NSCLC and SCLC in initial samples and acquisition of different histological areas in second biopsy samples [2]. The reports showed that every transformed SCLC tumor sample retained its original EGFR-activating mutation [6-11], supporting the idea that these were not independent second-primary cancers [2]. In addition, many patients with transformed SCLC tumors were female non-smokers [6-11], which is different from the typical SCLC patient demographic.\n\nThe recent reports of transformation from NSCLC to SCLC evoke questions regarding the origin of SCLC and clinical questions. The rate of transformation to SCLC in TKI resistant tumors varied according to the study [5,6,10]. Furthermore, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors. Practical questions include whether repeat biopsy is indicated after EGFR TKI resistance develops following treatment initiation, especially since a good response after switching to a SCLC chemotherapy regimen in transformed SCLC tumors has been reported [12].\n\nHere, we report six cases of SCLC transformed from pulmonary ADC in a single institute during a 6-year period.\n\nMATERIALS AND METHODS\nCases\nDuring a 6-year period (2010–2015), there were a total of 2,310 diagnoses of pulmonary ADC in our institute. Of 2,310 patients, 401 patients underwent a second biopsy or resection for recurrent or metastatic tumors. Out of 401 patients, a total of six patients (1.5%) with primary lung ADC showed transformed SCLC morphology in second biopsy. Two experienced pathologists reviewed the histological slides (S.A and J.H). All patients were treated in the Department of Oncology, Samsung Medical Center (Seoul, Korea). Clinical and follow-up data were obtained through a retrospective analysis of the medical records, including age, sex, smoking history, treatment, clinical course and follow-ups. All patients were followed until March 2016 with median follow-up period of 39.2 months. The study was approved by the Institutional Review Board at Samsung Medical Center (2014-14-08610).\n\nEGFR mutation test\nDNA was extracted from sections of formalin-fixed, paraffin-embedded (FFPE) tissue that was also used for histologic diagnosis. Manual microdissection was performed if tumor cell percentages were less than 70% in available samples. Genomic DNA was extracted using Qiagen DNA FFPE Tissue Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. In cases of lung ADC, routine testing for the EGFR mutation was performed in the pathology laboratory using peptide nucleic acid–mediated clamping polymerase chain reaction (PCR) mutation detection kit as previously described [13], and results were retrieved from electronic medical records. For one SCLC sample, the EGFR mutation was detected using targeted sequencing via Illumina HiSeq 2500 (Illumina Inc., San Diego, CA, USA), which was performed for clinical trial enrollment. For the rest of SCLC samples, the EGFR mutation was newly evaluated using Cobas test, a real-time PCR test as previously described [14]. EGFR mutation results were available for all samples except for one that had no residual tumor.\n\nImmunohistochemistry\nIn the current study, we used representative FFPE tissue sections for immunohistochemical staining (IHC). IHC for CD56 and thyroid transcription factor 1 (TTF-1) was performed for SCLC or combined tumors. Staining was performed on 3-μm-thick sections from each case using a biotin-avidin-peroxidase method on a BOND-MAX autostainer (Leica, Wetzlar, Germany) after retrieval with T/E buffer (CD56) or citrate buffer (TTF-1). We used primary antibodies to CD56 (1:200, Novocastra, Newcastle upon Tyne, UK) and TTF-1 (1:100, Dako, Glostrup, Denmark).\n\nRESULTS\nSample information and histologic features\nSix patients showed transformation from ADC to SCLC. Sample information and pathologic features are summarized in Table 1. Of the initial samples with diagnosis of ADC, four were obtained using needle biopsy and two were surgically resected specimens. All second biopsies were obtained using needle biopsy. The histology of the six ADCs was acinar (n=4), mixed acinar and papillary (n=1), and mixed acinar and solid (n=1). Of samples that showed transformation to SCLC upon second biopsy, four showed pure SCLC morphology and two showed combined ADC and SCLC morphology. In two cases, ADC components demonstrated acinar morphology (Fig. 1). For small cell components, TTF-1 was expressed in four of six cases and CD56 was expressed in all five available cases. CD56 was not expressed in ADC components.\n\nClinical information and EGFR status\nThe clinical information and EGFR mutation status of the six patients are summarized in Table 2. Initial treatments included complete resection and adjuvant chemotherapy for case 1 (cT2NO), palliative chemotherapy for case 2 (cT3N1M1) and case 4 (cT1N0M1), EGFR TKI for case 3 (cT2N3M1), incomplete resection and palliative chemotherapy for case 5 (cT1N0M1), and complete resection for case 6 (cT1NO). The sites of distant metastasis were as follows; brain (cases 2 and 4), pleura (case 3, 4, and 5), bone (case 4), and liver (case 4).\n\nOf the six patients with ADC in initial biopsy, four (cases 1–4) harbored an EGFR mutation (L858R mutation, n=1; exon 19 deletion, n=3). All four, along with case 5 who had wild-type EGFR but was enrolled in a clinical trial of gefetinib, were treated with EGFR TKIs. Cases 1 and 3 were treated with irressa, and afatinib was also added for case 1. Case 2 was treated with afatinib only, and cases 4 and 5 were treated with gefetinib only. All five patients who underwent TKI treatment were female non-smokers (Table 2). Despite TKI treatment, all five patients showed disease progression, upon which a second biopsy was performed. The interval between initial biopsy and second biopsy ranged from 5 to 50 months with mean of 25.3 months.\n\nAfter confirmation of transformation of SCLC on second biopsy, four patients received further treatment. The treatment option for two patients (cases 1 and 3) was switched to etoposide and cisplatin, and one of them (case 3) showed partial response. Case 5 died due to disease progression and the other patients were alive in the short-term follow-up period.\n\nEGFR mutation status was compared between initial and second samples, and all pairs showed the same EGFR status. The original EGFR mutation in cases 1–4 was retained in all transformed SCLC samples, while cases 5 and 6 showed no EGFR mutation in transformed SCLC samples.\n\nDISCUSSION\nTransformation of NSCLC to SCLC was recently proposed as a mechanism of resistance to TKI therapy [2,6]. Identification of histologic transformation may be an important factor in determining a patient’s treatment plan due to the differences between NSCLC and SCLC. While most reports of transformation of ADC to SCLC were identified in EGFR mutant patients related to TKI treatment, it is not certain whether transformation is exclusively related to EGFR mutation or EGFR TKI treatment [10]. Here, we report six cases of ADC which showed histologic transformation to SCLC over a 6-year period at a single institute. Similar to previous reports, four cases in our series were ADC with EGFR activating mutations that underwent TKI treatment and were subsequently found to have SCLC transformation on second biopsy. However, we also identified two additional cases of SCLC transformation that had no EGFR mutation, and one of these cases underwent initial TKI treatment.\n\nEGFR TKIs are now being used worldwide for first-line treatment in a subset of lung cancers bearing EGFR-activating mutations, and they have demonstrated dramatic therapeutic efficacy [15]. However, acquired resistance through multiple mechanisms has become a major problem [6]. One of mechanism of resistance to EGFR inhibitors is the histological transformation of ADC to SCLC [6]. Although the presence of combined ADC and SCLC histology at initial diagnosis is a possibility, genomic sequencing of EGFR mutations shows that both the original tumor and transformed SCLC at the time of resistance share the original EGFR-activating mutation, thus supporting the conclusion that these were not independent tumors [6-11]. However, the small biopsy size represents only a portion of tumors, and SCLC components may become dominant at the time of disease progression. Of the six patients with initially diagnosed with ADC in our report, two were diagnosed using surgically resected samples rather than needle biopsies. For these two cases, the possibility of combined histology at the initial biopsy can be excluded. In case 6, it was difficult to distinguish between SCLC transformation and second primary SCLC considering the early stage of initial ADC.\n\nIn our series, two of six cases were EGFR–wild-type ADC. This suggests that transformation to SCLC is not unique to tumors bearing EGFR mutations, nor does it exclusively result from TKI treatment. Transformation to SCLC is also reported as a mechanism of acquired resistance to crizotinib in ALK rearranged lung tumors [16]. In addition, transformation to large cell neuroendocrine carcinoma was identified as an acquired resistance mechanism to EGFR TKIs and crizotinib [17,18]. Recent studies suggest that alveolar type II cells can give rise to both ADC and SCLC [19], so EGFR-mutant lung cancers derived from alveolar type II cells may have the potential to transform into SCLC during the disease progression [2]. In sum, it seems that acquisition of neuroendocrine phenotype, which includes SCLC transformation, can occur in the progression of disease in both EGFR-mutant and EGFR–wild-type NSCLCs.\n\nSecond biopsies are not routinely performed for lung cancer patients when patients showed resistance to TKI treatment. Therefore, the incidence of transformation to SCLC in NSCLCs cannot be accurately calculated. An acquired TKI resistance arising from the histological transformation to SCLC has been reported to be as high as 3% [5]. In our institute, the incidence of transformation to SCLC identified in the second biopsy of total ADCs was 1.5%. Recently in our institute, there were two cases of SCLC transformation in EGFR mutant ADC during treatment with AZD9291, an oral irreversible EGFR TKI with selectivity for activating EGFR mutations and the T790M resistance mutation [20]. These cases were not included in this report. In clinical practice, identification of small cell component is important as the treatment option can be switched to etoposide and cisplatin against SCLC [12].\n\nIn conclusion, we report six cases of lung cancer demonstrating transformation from ADC to SCLC. Four cases were EGFR-mutant tumors from female non-smokers who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The other two ADCs were EGFR–wild-type, and one of these patients received EGFR TKI treatment. The neuroendocrine phenotype can thus be acquired during ADC disease progression independent of EGFR TKI treatment.\n\nConflicts of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1. Three cases showing transformation from non-small-cell lung cancer to small-cell lung cancer. (A) Initial biopsy of case 3 shows adenocarcinoma. Second biopsy after Iressa treatment, mediastinal lymph node specimen shows small cell carcinoma (B) and tumor cells are strongly positive for CD56 (C). (D) In case 4, second biopsy after gefetinib treatment reveals combined small-cell and adenocarcinoma histology. (E) Adenocarcinoma is identified in the brain tissue of case 2 at the time of initial diagnosis. (F) Second biopsy after afatinib treatment from this patient has combined small-cell and adenocarcinoma histology. (G) CD56 is expressed in the small cell component of the tumor sample.\n\nTable 1. Sample information and pathologic features of six patients showing transformation from non-small-cell lung cancer to small cell lung cancer\n\nCase No.\tInitial tumor\tSample type\tSample acquisition site\tSubtype\tInterval between biopsy (mo)\tTransformed tumor\tSample type\tSample acquisition site\tIHC TTF-1/CD56\t\n1\tADC\tBiopsy\tLung\tAcinar\t37\tSCLC\tBiopsy\tCeliac LN\t–/+\t\n2\tADC\tBiopsy\tLung, brain\tAcinar and papillary\t21\tCombined SCLC and ADC\tBiopsy\tLung\t–/+a\t\n3\tADC\tBiopsy\tLN 4\tAcinar\t8\tSCLC\tBiopsy\tLN 7\t+/+\t\n4\tADC\tBiopsy\tLung\tAcinar\t5\tCombined SCLC and ADC\tBiopsy\tLung (same site)\t+/NA\t\n5\tADC\tResection\tLung\tAcinar\t31\tSCLC\tBiopsy\tPleura\t+/+\t\n6\tADC\tResection\tLung\tAcinar and solid\t50\tSCLC\tBiopsy\tNeck LN\t+/+\t\nIHC, immunohistochemistry; TTF-1,thyroid transcription factor; ADC, adenocarcinoma; SCLC, small cell lung cancer; LN, lymph node; NA, not-applicable.\n\na CD56 was positive in only SCLC components.\n\nTable 2. Clinical information and EGFR status of six patients showing transformation from non-small-cell lung cancer to small cell lung cancer\n\nCase No.\tSex\tAge (yr)\tSmoking history (pack years)\tTumor histology in initial sample\tClinical tage\tInitial treatment\tEGFR mutation in initial sample\tTreatment related to TKI\tDuration of TKI treatment before transformation (mo)\tResponse to TKI\tTumor histology in second biopsy sample\tEGFR mutation in second biopsy ample\tTreatment after second biopsy\tProgression or recurrance\tDeath\t\n1\tF\t57\t0\tADC\tT2N0\tOperation, adjuvant CTx (paclitaxel/carboplatin)\tL858R\tIrressa, afatinib\t10\tPD\tSCLC\tL858R\tCTx (etoposide/cisplatin)\tF/U loss\tF/U loss\t\n2\tF\t54\t0\tADC\tT3N1M1\tCTx (Alimta/cisplatin)\tDel19\tAfatinib\t11\tPD\tCombined SCLC and ADC\tdel19\tCTx (gemcitabine/cisplatin)\tPR\tAlive\t\n3\tF\t55\t0\tADC\tT2N3M1\tIressa\tDel19\tIressa\t9\tPD\tSCLC\tdel19\tCTx (etoposide/cisplatin)\tPR\tAlive\t\n4\tF\t59\t0\tADC\tT1N0M1\tCTx (Alimta/cisplatin)\tDel19\tGefetinib\t11\tPD\tCombined SCLC and ADC\tdel19\tRociletinib\tPD\tAlive\t\n5\tF\t68\t0\tADC\tT1N0M1\tOperation, palliative CTx (Alimta/cisplatin)\tNo mutation\tGefetinib\t2\tPD\tSCLC\tNo mutation\tNo treatmenta\tPD\tDeadb\t\n6\tM\t67\t35\tADC\tT1NO\tOperation\tNo mutation\tNo TKI\tNA\tPD\tSCLC\tNo mutation\tNo treatmenta\tF/U loss\tF/U loss\t\nEGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; F, female; ADC, adenocarcinoma; CTx, chemotherapy; PD, progressive disease; SCLC, small cell lung cancer; F/U, follow-up; PR, partial response; M, male; NA, not-applicable.\n\na No further treatment due to poor condition;\n\nb Dead due to disease progression.\n==== Refs\nREFERENCES\n1 Goldstraw P Ball D Jett JR Non-small-cell lung cancer Lancet 2011 378 1727 40 21565398 \n2 Oser MG Niederst MJ Sequist LV Engelman JA Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin Lancet Oncol 2015 16 e165 72 25846096 \n3 Moiseenko VM Protsenko SA Semenov II Effectiveness of gefitinib (Iressa) as first-line therapy for inoperable non-small-cell lung cancer with mutated EGFR gene (phase II study) Vopr Onkol 2010 56 20 3 20361610 \n4 Engelman JA Jänne PA Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Clin Cancer Res 2008 14 2895 9 18483355 \n5 Yu HA Arcila ME Rekhtman N Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR -mutant lung cancers Clin Cancer Res 2013 19 2240 7 23470965 \n6 Sequist LV Waltman BA Dias-Santagata D Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Sci Transl Med 2011 3 75ra26 \n7 Zakowski MF Ladanyi M Kris MG Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group EGFR mutations in small-cell lung cancers in patients who have never smoked N Engl J Med 2006 355 213 5 16837691 \n8 van Riel S Thunnissen E Heideman D Smit EF Biesma B A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation Ann Oncol 2012 23 3188 9 23079729 \n9 Morinaga R Okamoto I Furuta K Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation Lung Cancer 2007 58 411 3 17601631 \n10 Norkowski E Ghigna MR Lacroix L Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology J Thorac Oncol 2013 8 1265 71 24457237 \n11 Watanabe S Sone T Matsui T Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma Lung Cancer 2013 82 370 2 24012411 \n12 Kim WJ Kim S Choi H Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor Thorac Cancer 2015 6 800 4 26557922 \n13 Lee B Han G Kwon MJ Han J Choi YL KRAS mutation detection in non-small cell lung cancer using a peptide nucleic acid-mediated polymerase chain reaction clamping method and comparative validation with next-generation sequencing Korean J Pathol 2014 48 100 7 24868222 \n14 Ahn S Lee J Sung JY Comparison of three BRAF mutation tests in formalin-fixed paraffin embedded clinical samples Korean J Pathol 2013 47 348 54 24009630 \n15 Pao W Miller VA Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions J Clin Oncol 2005 23 2556 68 15767641 \n16 Miyamoto S Ikushima S Ono R Transformation to small-cell lung cancer as a mechanism of acquired resistance to crizotinib and alectinib Jpn J Clin Oncol 2016 46 170 3 26613679 \n17 Kogo M Shimizu R Uehara K Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor Lung Cancer 2015 90 364 8 26384434 \n18 Caumont C Veillon R Gros A Laharanne E Bégueret H Merlio JP Neuroendocrine phenotype as an acquired resistance mechanism in ALK -rearranged lung adenocarcinoma Lung Cancer 2016 92 15 8 26775590 \n19 Sutherland KD Proost N Brouns I Adriaensen D Song JY Berns A Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung Cancer Cell 2011 19 754 64 21665149 \n20 Ham JS Kim S Kim HK Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment J Thorac Oncol 2016 11 e1 4 26762749\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2383-7837",
"issue": "50(4)",
"journal": "Journal of pathology and translational medicine",
"keywords": "Adenocarcinoma; Lung neoplasms; Receptor, epidermal growth factor; Small cell lung carcinoma; Tyrosine kinase inhibitor",
"medline_ta": "J Pathol Transl Med",
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"nlm_unique_id": "101650151",
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"pages": "258-63",
"pmc": null,
"pmid": "27160687",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "24457237;24868222;20361610;17601631;24012411;23470965;25846096;15767641;21565398;16837691;26384434;26762749;24009630;23079729;26557922;21430269;21665149;18483355;26775590;26613679",
"title": "Transformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases.",
"title_normalized": "transformation to small cell lung cancer of pulmonary adenocarcinoma clinicopathologic analysis of six cases"
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"abstract": "Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma (n = 19) or ES (n = 8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16-50 Gy in 1-10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity.",
"affiliations": "Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Mayo Medical School, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA ; Division of Orthopedic Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.",
"authors": "Brown|Lindsay C|LC|;Lester|Rachael A|RA|;Grams|Michael P|MP|;Haddock|Michael G|MG|;Olivier|Kenneth R|KR|;Arndt|Carola A S|CA|;Rose|Peter S|PS|;Laack|Nadia N|NN|",
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"doi": "10.1155/2014/418270",
"fulltext": "\n==== Front\nSarcomaSarcomaSARCOMASarcoma1357-714X1369-1643Hindawi Publishing Corporation 10.1155/2014/418270Clinical StudyStereotactic Body Radiotherapy for Metastatic and Recurrent Ewing Sarcoma and Osteosarcoma Brown Lindsay C. \n1\nLester Rachael A. \n2\nGrams Michael P. \n1\nHaddock Michael G. \n1\nOlivier Kenneth R. \n1\nArndt Carola A. S. \n3\n\n4\nRose Peter S. \n5\nLaack Nadia N. \n1\n\n*\n1Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA2Mayo Medical School, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA3Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA4Division of Orthopedic Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA5Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA*Nadia N. Laack: laack.nadia@mayo.eduAcademic Editor: Natia Esiashvili\n\n2014 9 12 2014 2014 4182706 6 2014 16 11 2014 17 11 2014 Copyright © 2014 Lindsay C. Brown et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma (n = 19) or ES (n = 8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16–50 Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity.\n==== Body\n1. Introduction\nOsteosarcoma and Ewing sarcoma (ES) are the most common pediatric primary bone malignancies, although combined they account for fewer than 10% of pediatric malignancies [1]. While typically classified as pediatric sarcomas, osteosarcoma and ES can arise in both children and adults.\n\nTreatment strategies are well defined for localized ES and osteosarcoma and significant improvement in outcomes has occurred over the past several decades [2]. However, the treatment of recurrent and metastatic disease remains a challenge. Distant metastases are common in patients with ES, with approximately 25% of patients presenting with distant disease [2] and an additional 20% of patients with initially localized disease developing distant metastases in the modern era [3]. Long-term event-free survival (EFS) on the order of 20–30% has been reported in metastatic ES, and aggressive local treatment of all sites of disease has been associated with significant improvement in outcomes [4].\n\nDistant metastases are similarly common in osteosarcoma. Distant disease is present at diagnosis in approximately 10–20% of patients [6] and develops in 30–50% of patients who initially present with localized disease [5]. Ten-year survival of 24% for patients with metastatic disease at presentation has been reported [6]. Localized osteosarcoma is typically treated with chemotherapy and surgical resection; radiotherapy is reserved for rare unresectable cases. However, chemotherapy and surgery often cannot adequately address metastatic disease, and it has been demonstrated that incomplete surgical resection of metastatic disease is associated with poorer outcomes [6]. For patients with unresectable disease or in those for whom surgery will entail significant morbidity, radiotherapy may be an effective alternative strategy.\n\nStereotactic body radiotherapy (SBRT) is one potential treatment option for patients with metastatic or recurrent ES and osteosarcoma. SBRT is noninvasive and has a convenient fractionation schedule, minimizing chemotherapy delays. Moreover, SBRT uses strict immobilization, advanced image guidance, and sophisticated treatment planning and delivery systems, resulting in highly conformal dose distributions that allow decreases in the size of treatment volumes relative to conventional radiotherapy. This, in turn, allows for delivery of large doses of radiation per fraction and increased biologically effective doses (BED) beyond those possible with conventional treatments. In addition to theoretical use in the curative/definitive treatment of metastatic or recurrent ES and osteosarcoma, SBRT may be of value in palliating symptoms associated with disease progression, for the reasons described above.\n\nThus, SBRT is, theoretically, an attractive alternative to surgical resection, conventional radiation, or other palliative measures for certain patients with metastatic or recurrent osteosarcoma or ES. In the current study, we report our early institutional experience with SBRT in patients with osteosarcoma and ES.\n\n2. Materials and Methods\n2.1. Patients\nWith the approval of our institutional review board, we retrospectively searched our patient database for the records of patients with recurrence of or metastases from osteosarcoma or ES who were treated with SBRT at our institution from 2008 through 2012. Both adults and children with ES and osteosarcoma were included in the analysis.\n\nThe American Society for Therapeutic Radiology and Oncology and American College of Radiology have published guidelines for the performance of SBRT, in which SBRT is defined as “an external beam radiation therapy method used to very precisely deliver a high dose of radiation to an extracranial target within the body, using either a single dose or a small number of fractions [7].” In the present study, we included patients treated with 10 or fewer fractions, high dose per fraction (≥5 Gy), strict immobilization, and daily stereotactic image guidance, generally with minimal planning target volume (PTV) margin, as described below. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, Version 4.0 [8]. We included patients treated with curative intent, definitive intent (i.e., with the intention of delivering an ablative dose of radiation such that subsequent treatment would not be required for the particular lesion being treated, while recognizing that progression will likely occur elsewhere), and palliative intent (i.e., with the intention of palliating pain or other symptomatologies or in order to delay symptom development). Intent of treatment was determined by the treating physician. For the purposes of description of technique, patients are considered based on intent of treatment, with patients treated with definitive and curative intent grouped together, as fractionation schemes were similar for the two groups.\n\nFollow-up imaging was dictated by the intent of treatment. In patients undergoing curative/definitive treatment, follow-up imaging was typically performed 3 months after treatment and every 3 to 6 months thereafter. Imaging modality varied with tumor location but always included cross-sectional imaging in the form of computed tomography (CT), positron-emission tomography/CT, or magnetic resonance imaging (MRI). In patients treated with palliative intent, imaging was performed based on the presence of symptoms. For patients treated palliatively, only known local failures are presented, with no information provided regarding local control, as patients did not have routine imaging.\n\n2.2. SBRT Technique\nCT-based simulation was performed for all patients. Patients were immobilized for simulation and treatment in a BodyFIX immobilization device (Elekta) or thermoplastic mask. Patients expected to have significant tumor motion with respiration underwent 4-dimensional CT-based planning. Use of contrast at the time of simulation was left to the discretion of the treating radiation oncologist.\n\nDelineation of tumor volumes and organs at risk was performed on either GE Advantage (GE Healthcare) or Eclipse (Varian Medical Systems, Inc.) workstations. Fusion with MRI and other diagnostic studies was performed at the discretion of the treating physician, when believed to aid in the definition of tumor and normal tissues. Expansions for clinical target volumes (CTV) and PTV were individualized on the basis of the clinical scenario, including tumor location and size, proximity of organs at risk, prior history of radiation, and intended dose and fractionation. For osseous lesions, CTV was typically determined by expanding the gross tumor volume by 1 cm within bone. If tumor extended into soft tissue, expansion into surrounding soft tissue by 5 mm was performed to account for possible microscopic disease. In the absence of soft tissue extension, no empiric extraosseous expansion was performed. Median expansion of CTV to PTV was 2 mm (range, 0–8 mm). For pulmonary tumors, patients underwent 4-dimensional CT simulation, allowing delineation of an internal tumor volume that accounts for tumor motion with respiration. PTV was an expansion from internal tumor volume, typically by 5 mm, with no defined CTV. TG-101 [12] dose constraints were generally used, with 10% reductions for pediatric patients (<18 years) or for patients receiving concurrent chemotherapy. PTV constraints required that 90% of the volume receive prescription dose, if critical normal tissue constraints could be met. If the normal tissue constraints could not be met, PTV coverage was sacrificed (with exceptions, as detailed in the Results section). Treatment planning was performed using Eclipse software.\n\nAll treatments were image-guided. For pulmonary lesions, daily cone-beam CT matching was performed. For osseous lesions, orthogonal kV imaging and ExacTrac (Brainlab) robotic table positioning were employed. A radiation oncologist was present at the treatment console and performed matching before treatment each day. Dose and fractionation pattern were determined by the treating physician.\n\n2.3. Statistical Analysis\nStatistics were performed using JMP software (SAS Institute, Inc.). Statistics were calculated from the first day of SBRT. Local failure was defined as tumor progression within the previously targeted volume.\n\n3. Results\n3.1. Treatment, Follow-Up, and Local Failure\nOur search identified 14 patients with 27 osseous (n = 21) or pulmonary (n = 6) metastases from osteosarcoma (n = 19) or ES (n = 8) who received SBRT during the study period. Fourteen lesions were treated with definitive or curative intent; 13 were treated in order to palliate or delay development of symptoms. Patient and tumor characteristics for the group are shown in Table 1. Median patient age was 24 years; 6 patients were less than 18 years of age at the time of treatment. Patients were treated on consecutive weekdays. Dose selection was influenced by intention of treatment, patient, tumor, and treatment characteristics, and provider preference.\n\nTables 2 and 3 detail tumor and treatment characteristics for lesions treated with curative/definitive and palliative intent, respectively. Two patients were initially treated with curative intent and later with palliative intent and thus appear in both tables. Footnotes denote patient and tumor characteristics that contributed to dose selection. As noted, four thoracic spine lesions in 2 patients were treated with additional radiation via SBRT after whole-lung irradiation (WLI) of 1500 cGy in 10 fractions. For lesions treated with curative/definitive intent, median dose delivered was 40 Gy (range, 30–60 Gy), delivered in a median of 5 fractions (range, 3–10) of a median of 7.5 Gy per fraction (range, 6–10 Gy). For lesions treated with palliative intent, median dose delivered was 40 Gy (range, 16–50 Gy), delivered in a median of 5 fractions (range, 1–10) of a median of 8 Gy per fraction (range, 5–21 Gy).\n\nRepresentative pretreatment and posttreatment MRIs and treatment isodose curves for a 5-year-old patient treated with 50 Gy in 5 fractions for a sacral metastasis from osteosarcoma are shown in Figures 1 and 2.\n\nFor surviving patients treated curatively or definitively, median follow-up was 2.0 years (range, 1.2–4.0 years). Median follow-up with imaging was 2.0 years (range, 0.7–4.0 years). Of patients treated with curative or definitive intent, one patient had failure in 2 sites after each was treated with 30 Gy in 3 fractions for osteosarcoma. Estimated local control at 2 years was 85%.\n\nFor patients treated with palliative intent, median follow-up was 0.2 years (range, 0.04–1.2). Three lesions treated with palliative intent progressed after SBRT. One patient had local progression in 2 locations, after treatment with 40 Gy in 5 fractions and 50 Gy in 10 fractions, respectively, for osteosarcoma. This was felt to be marginal failure/progression of disease that was too large to entirely encompass safely at the time of SBRT. Despite progression, the patient experienced pain improvement. A second patient had failure at a single site after treatment with 25 Gy in 5 fractions for ES. He also experienced pain improvement following treatment.\n\n3.2. Toxicity\nEarly and late toxicity are reported in Tables 2 and 3. No grade 3 or greater acute toxicity was reported. Significant symptomatic late toxicity was seen in 3 patients, although only 1 met criteria for classification as grade 3 toxicity. Grade 3 sacral plexopathy occurred in a patient reirradiated with curative intent, with 60 Gy in 10 fractions to the sacrum 1.75 years after receiving 59.4 Gy in 33 fractions for ES. Symptoms appeared approximately 5 months after SBRT administration. Given that portions of the sacral nerves and plexus were involved by tumor, they were not listed as organs at risk with constraints. During the initial treatment, much of the involved sacral plexus received 105% of the prescription dose. During reirradiation, the involved sacral nerve roots and plexus received 100% of prescription.\n\nMyonecrosis (grade 2 myositis) occurred in one patient 2 months after treatment with 50 Gy in 5 fractions to the right iliac wing with concurrent gemcitabine for osteosarcoma. Figure 3 shows isodose curves from her SBRT treatment and a posttreatment MRI, demonstrating clear correlation between treatment volumes and subsequent myonecrosis. The patient experienced significant pain and transient paraesthesia as a result. Two years after treatment, her paraesthesia has resolved and her pain is controlled with a narcotic-containing pain regimen.\n\nThe third significant late toxicity was in a patient treated with 60 Gy in 10 fractions to an osteosarcoma metastasis of the femoral head. The entirety of the femoral head and neck was involved by disease and received the prescription dose. Four and 8 months after SBRT, he developed grade 2 pathologic fracture and avascular necrosis of the femoral head, respectively. Both were managed conservatively and have not required surgical intervention.\n\n3.3. Long-Term Follow-Up\nSix patients treated with curative or definitive intent have been followed for more than 1 year after SBRT. One patient is 4 years from treatment for metastatic ES. He received an SBRT boost to T11, with 30 Gy in 5 fractions, after completing WLI. Eighteen months after SBRT, he had disease recurrence in the lung, underwent metastasectomy, and now has no evidence of recurrent ES. He developed myelodysplastic syndrome approximately 3 years after completing his initial ES therapy. A second patient was treated with SBRT for a hilar osteosarcoma metastasis with 50 Gy in 5 fractions and has been followed for 3.5 years with no evidence of recurrence in the treated site, although she had progression elsewhere 21 months after treatment. She had no toxicity from radiotherapy. The third patient is described above, in whom myositis developed after treatment for metastatic osteosarcoma of the iliac wing. At 2 years from treatment, she has no evidence of recurrent disease. The fourth patient with long-term follow-up underwent treatment of three thoracic spine metastases from ES, receiving a 35 Gy boost in 5 fractions after WLI. At last follow-up, 2 years after treatment, he had no evidence of disease and no toxicity. The patient with recurrent Ewing sarcoma of the sacrum, described above, has also been followed up for 2 years. Sacral plexopathy is his only reported toxicity. He developed lung metastases 1.5 years after SBRT. Lastly, the patient treated with 60 Gy in 10 fractions for a femoral head osteosarcoma metastasis has lived 1.6 years, with no evidence of recurrent disease. He experienced avascular necrosis and pathologic fracture due to SBRT, as described above.\n\nOne patient treated with palliative intent has survived more than one year. The patient was treated with SBRT to osseous metastases from osteosarcoma in T8 and the left ischium, receiving 4000 cGy in 5 fractions to each. At last follow-up, 14 months after treatment, he had progression elsewhere, but the treated lesions were stable and he had no evidence of toxicity.\n\n4. Discussion\nStereotactic body radiotherapy is a theoretically attractive local treatment modality in certain patients with recurrent or metastatic ES and osteosarcoma, as it is convenient, minimizes delays in chemotherapy administration, and offers the possibility of increased efficacy via biologically effective dose escalation. Careful consideration of potential toxicity is warranted, however, particularly in patients with limited life expectancy.\n\nThe importance of local therapy for patients with metastatic Ewing sarcoma and the possibility of durable cure in certain patients with metastatic disease have recently been described. Haeusler and colleagues [4] analyzed the effects of local therapy to the primary disease site and sites of metastatic disease for patients with primary, extrapulmonary, disseminated, multifocal ES. They demonstrated that event-free survival was superior in patients who received local therapy—in the form of conventionally fractionated radiotherapy, surgery, or a combination thereof—to all sites of disease involvement, in addition to systemic treatment. On the basis of these findings, patients with primary disseminated ES should be considered for local treatment to the primary lesion and all sites of metastasis, when deemed safe and appropriate in the patient's clinical context. In this series, 4 patients with ES were treated with definitive/curative SBRT, none of whom experienced local failure, three of whom are alive (at 1.6–4 years after treatment), and two of whom are alive with no evidence of disease at 2 and 4 years after SBRT.\n\nOsteosarcoma, unlike ES, has traditionally been considered a radioresistant tumor. In a study of conventional radiotherapy in the primary setting, DeLaney and colleagues [9] found that patients treated with radiotherapy after biopsy only, with doses equivalent to 68 Gy or higher in 2 Gy fractions, had only 40% local control at 5 years. Local control was slightly, although not significantly, better with higher radiation dose. Based on these and other similar data, radiotherapy has been reserved for tumors not amenable to surgical resection. In order to provide patients without feasible surgical options with a more effective alternative, recent interest has turned to the possible benefit of hypofractionation, which theoretically could overcome the reported radioresistance of osteosarcoma. Matsunobu and colleagues [10] studied patients with unresectable osteosarcoma of the trunk treated with carbon therapy. The median delivered dose was 70.4 Gy equivalents in 16 fractions over 4 weeks; the resulting 5-year local control rate was 62%. Patients with tumors smaller than 500 cm3 had an 88% local control rate.\n\nGiven historically poor local control with conventional radiotherapy for osteosarcoma and the suggestion of dose-response, the possibility of dose escalation in the treatment of osteosarcoma is appealing. Similarly, in light of the recent data of Matsunobu and colleagues [10] (recognizing inherent differences in physical properties of photons versus carbon ions), hypofractionation is increasingly thought to be beneficial in improving local control. Consequently, treatment modalities that allow for safe delivery of high-dose, hypofractionated radiotherapy offer promise in patients with osteosarcoma who are not surgical candidates. In this series, 5 of 6 patients (5 of 7 lesions) treated with SBRT with definitive/curative intent for osteosarcoma did not experience local failure. The patient who had local relapse of disease was treated with SBRT for two large sarcomatous lesions arising in a previously radiated field. It is possible that the large size of the tumors treated and inherent aggressiveness of a possible secondary malignancy contributed to failure of SBRT to control this disease. Three of the six patients treated definitively died within 1 year of SBRT receipt, all of whom had multiple sites of disease at the time of SBRT, underscoring the importance of proper patient selection and avoidance of toxicity for patients with limited lifespan. However, three of six patients, all of whom had a single site of disease at the time of SBRT, have had durable (1.6–3.5 years) local control of treated lesions, and two are without evidence of recurrent disease, suggesting that SBRT is a viable consideration for select patients.\n\nIn addition to potential use in the curative or definitive treatment of metastatic and recurrent ES and osteosarcoma, radiotherapy plays an important role in the palliation of symptoms related to these diseases. Even in osteosarcoma, radiation has long been used for palliation of symptoms in patients with metastatic disease, with good results in terms of pain reduction and mediocre durable control of disease at the treated site [11]. SBRT was effective in palliating symptoms in this series; however, most patients treated with palliative intent died of disease within 6 months of receiving SBRT. Cost, expected outcome, life expectancy, and benefit of SBRT versus conventional radiation should be considered before palliative SBRT is offered.\n\nThis observational series provides important instructive toxicity data that underscores the potential risks of SBRT. Three patients in this study experienced significant late toxicity. Two of these patients were treated with doses beyond those recommended by TG-101. Only 1 patient treated in a manner respecting TG-101 [12] constraints (with dose reduction as described above) experienced significant toxicity. This highlights the importance of respecting normal tissues when possible and proper patient counseling when constraints are knowingly exceeded. One patient developed grade 3 sacral plexopathy after high-dose reirradiation for localized, recurrent ES. For most pelvic SBRT treatments that pose risk to the sacral plexus, TG-101 [12] dose constraints for the nerve roots and plexus are respected, in order to reduce the risk of neuropathy. However, in this particular case, violation of constraints was allowed, for fear of treatment failure if volumes and doses were reduced, particularly given prior progression with conventionally fractionated radiotherapy. Thoughtful and candid consent was obtained from the patient, who felt that the risk of substantial neuropathy was preferable to hemipelvectomy, the surgical alternative to proceeding with reirradiation. Similarly, the patient with femoral head necrosis and fracture was counseled regarding the potential risk of toxicity and accepted the risk over surgical extirpation of disease.\n\nOne patient whose treatment met requested dose limits experienced myonecrosis after SBRT. This was likely due to concurrent administration of gemcitabine. Radiation recall after gemcitabine administration has been previously described [13]. Specific reactions reported in the literature vary widely but are universally of inflammatory etiology. Timing of the reaction is variable, with reports of symptomatic radiation recall several weeks to many months after administration of gemcitabine. Knowledge of this possible toxicity allows for appropriate counseling.\n\nThis study is, at the time of this writing, the first report of techniques and outcomes with SBRT for recurrent and metastatic ES and osteosarcoma. The study is limited by the small number of patients included and by short follow-up. Prior reports have demonstrated that longer follow-up is necessary to observe local recurrences following SBRT relative to conventional radiotherapy. Therefore, given the short follow-up in our report, it is not possible to draw meaningful conclusions regarding local control outcomes. Long-term follow-up is also critical to fully capture late toxicity associated with treatment. Although we report follow-up of greater than a year for 7 patients, toxicities can occur later than one year after SBRT, and thus no definitive conclusions regarding occurrence rates of long-term toxicities should be drawn.\n\nThe toxicities reported herein can help guide patient selection for SBRT going forward. This report underscores the importance of respecting SBRT dose constraints when feasible and careful patient counseling when constraints are exceeded. It also illustrates the importance of careful patient selection and counseling, bearing in mind expected duration of survival as well as collaboration with the multidisciplinary team to coordinate chemotherapy timing and agent choice.\n\nMost importantly, this small series demonstrates the need for systematic study of the use of SBRT in pediatric sarcomas such as ES and osteosarcoma. The Children's Oncology Group is proposing a protocol (DuBois S, written communication, June 2013) to assess the feasibility of administering SBRT to patients with metastatic ES in the context of a cooperative group trial. The protocol will use a dose of 40 Gy in 5 fractions and will provide very valuable information regarding toxicity and effectiveness of SBRT for ES. Such standardized trials are the cornerstone of evaluation of evolving treatment modalities.\n\n5. Conclusion\nIn conclusion, SBRT is a theoretically useful modality of radiation delivery for patients with recurrent or metastatic ES and osteosarcoma. More data is necessary before conclusions can be drawn regarding efficacy of treatment. Consideration of patient context and expected longevity is paramount. Significant toxicity may occur when established dose constraints are exceeded.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Magnetic resonance images of a sacral osteosarcoma metastasis in a 5-year-old boy. Axial (a and c) and sagittal (b and d) T1-weighted images acquired with gadolinium before treatment (a and b) and after treatment (c and d).\n\nFigure 2 Isodose curves. Axial (a) and sagittal (b) representative isodose curves from the treatment plan used for the osteosarcoma lesion depicted in Figure 1.\n\nFigure 3 Representative axial dose color wash (a) for a 17-year-old female treated with 50 Gy in 5 fractions for oligometastatic osteosarcoma of the iliac wing and (b) axial magnetic resonance imaging two months after treatment, demonstrating myonecrosis, with correlation between treatment volumes and subsequent soft tissue changes.\n\nTable 1 Patient and tumor characteristics.\n\nCharacteristic\tValuea\n\t\nPatients (n = 14)\t \t\n Age, y\t24 (4.9–66.4)\t\n Histology\t \t\n Osteosarcoma\t9\t\n Ewing sarcoma\t5\t\n Disease\t \t\n Metastatic\t13\t\n Recurrent, localized\t1\t\nLesions treated (n = 27)\t \t\n Histology\t \t\n Osteosarcoma\t19\t\n Ewing sarcoma\t8\t\n Location\t \t\n Osseous\t21\t\n Pulmonary/mediastinal\t6\t\n\naValues are median (range) or number of patients.\n\nTable 2 Description of definitive treatments*.\n\nHistology (solitary versus multiple lesions present)\tPatient age at time of SBRT (years)\tConcurrent chemotherapy\tLocation\tPTV size (cc)\tSBRT total dose (Gy)\tFractions (number)\tLocal failure (time to failure, years)\tOverall disease status (F/U, years)\tTime to F/U imaging1 (years)\tAcute toxicity (grade)\tLate toxicity (grade)\t\n\nMetastatic OGS (solitary)2\n\t\n17.7\n\t\nGemcitabine and docetaxel\n\t\nIliac wing\n\t\n13\n\t\n50\n\t\n5\n\t\nNo\n\t\nNED (2.0)\n\t\n2.0\n\t\nNone\n\t\nMyonecrosis (2), pain (2), neuropathy (2)\n\t\nMetastatic OGS (solitary)\t9.8\tIfosfamide and etoposide\tFemoral head\t43\t60\t10\tNo\tNED (1.6)\t1.6\tErythema (1)\tAVN (2), pathologic fracture (2)\t\n\nMetastatic OGS (solitary)\n\t\n23.8\n\t\nNone\n\t\nHilum\n\t\n24\n\t\n50\n\t\n5\n\t\nNo\n\t\nAWD (3.5)\n\t\n3.5\n\t\nNone\n\t\nNone\n\t\nMetastatic OGS (multiple)\t66.4\tNone\tS1\t175\t30\t3\tYes (0.4)\tDOD (0.8)\t0.4\tNone\tNone\t\nMetastatic OGS (multiple)2\n\t66.4\tNone\tL3\t99\t30\t3\tYes (0.1)\tDOD (0.8)\t0.1\tNone\tNone\t\n\nMetastatic OGS (multiple)\n\t\n17.3\n\t\nNone\n\t\nIliac crest\n\t\n11\n\t\n60\n\t\n10\n\t\nNo\n\t\nDOD (0.6)\n\t\nNone\n\t\nNone\n\t\nNone\n\t\nMetastatic OGS (multiple)\t4.9\tNone\tSacrum\t18\t50\t5\tNo\tDOD (0.3)\t0.2\tNone\tNone\t\n\nRecurrent ES (solitary)\n\n3\n\t\n23.1\n\t\nNone\n\t\nSacrum\n\t\n91\n\t\n60\n\t\n10\n\t\nNo\n\t\nAWD (2.0)\n\t\n2.0\n\t\nNone\n\t\nNeuropathy (3)\n\t\nMetastatic ES (multiple)4\n\t15.9\tNone\tT11\t5.6\t30\t5\tNo\tNED (4.0)\t4.0\tNone\tMyelodysplastic syndrome\t\n\nMetastatic ES (multiple)5\n\t\n19.7\n\t\nVincristine, topotecan, and cytoxan\n\t\nRUL\n\t\n1.5\n\t\n40\n\t\n5\n\t\nNo\n\t\nDOD (0.6)\n\t\n0.3\n\t\nNone\n\t\nNone\n\t\n\nMetastatic ES (multiple)5\n\t\n19.7\n\t\nVincristine, topotecan, and cytoxan\n\t\nRLL\n\t\n2.3\n\t\n40\n\t\n5\n\t\nNo\n\t\nDOD (0.6)\n\t\n0.3\n\t\nNone\n\t\nNone\n\t\nMetastatic ES (multiple)4\n\t30.2\tIfosfamide and etoposide\tT1-2\t0.7\t35\t5\tNo\tNED (2.0)\t2.0\tNone\tNone\t\nMetastatic ES (multiple)4\n\t30.2\tIfosfamide and etoposide\tT5\t0.7\t35\t5\tNo\tNED (2.0)\t2.0\tNone\tNone\t\nMetastatic ES (multiple)4\n\t30.2\tIfosfamide and etoposide\tT12-L2\t4.8\t35\t5\tNo\tNED (2.0)\t2.0\tNone\tNone\t\n\n*Continguous similarly bolded/non-bolded rows denote multiple lesions in an individual patient.\n\n\n1Time from SBRT to last follow-up imaging.\n\n\n\n2Treatment volume overlapped with field previously irradiated to 40 Gy in 20 fractions for plasmacytoma 6 years before.\n\n\n\n3Retreatment of recurrent disease, following 59.4 Gy in 33 fractions to the same region.\n\n\n\n4SBRT delivered immediately following whole-lung irradiation to 15 Gy in 10 fractions.\n\n\n\n5Status after contralateral pneumonectomy.\n\nPTV: planning target volume; SBRT: stereotactic body radiotherapy; OGS: osteosarcoma; NED: no evidence of disease; DOD: dead of disease; ES: Ewing sarcoma; RUL: right upper lobe of lung; RLL: right lower lobe of lung; AWD: alive with disease.\n\nTable 3 Description of palliative treatments*.\n\nHistology1\n\tPatient age at time of SBRT (years)\tConcurrent chemotherapy\tLocation\tPTV size (cc)\tSBRT total dose (Gy)\tFractions (number)\tPretreatment symptoms\tSymptom relief2\n\tOverall disease status (F/U, years)\tAcute toxicity (grade)\tLate toxicity (grade)\t\n\nOGS\n\t\n17.7\n\t\nNone\n\t\nScapula\n\t\n54\n\t\n21\n\t\n1\n\t\nPain\n\t\nComplete, durable\n\t\nDOD (0.2)\n\t\nNone\n\t\nN/A\n\t\n\nOGS\n\t\n17.7\n\t\nNone\n\t\nC7-T1\n\t\n34\n\t\n24\n\t\n3\n\t\nNone\n\t\nN/A\n\t\nDOD (0.2)\n\t\nNone\n\t\nN/A\n\t\n\nOGS\n\t\n17.7\n\t\nNone\n\t\nT4\n\t\n17\n\t\n24\n\t\n3\n\t\nPain\n\t\nUnclear3\n\t\nDOD (0.2)\n\t\nNone\n\t\nN/A\n\t\nOGS\t5.1\tNone\tT7–9\t8.5\t16\t1\tPain\tComplete, durable\tDOD (0.04)\tNone\tN/A\t\n\nOGS4\n\t\n24.2\n\t\nTopotecan and cyclophosphamide\n\t\nLeft lung\n\t\n432\n\t\n50\n\t\n10\n\t\nPain\n\t\nPartial, transient\n\t\nDOD (0.8)\n\t\nEsophagitis (2)\n\t\nNone\n\t\n\nOGS\n\t\n24.5\n\t\nNone\n\t\nMediastinum\n\t\n127\n\t\n50\n\t\n10\n\t\nHemoptysis\n\t\nDurable\n\t\nDOD (0.5)\n\t\nNone\n\t\nNone\n\t\n\nOGS5\n\t\n24.7\n\t\nNone\n\t\nLeft lung\n\t\n67\n\t\n40\n\t\n5\n\t\nPain\n\t\nPartial, transient\n\t\nDOD (0.3)\n\t\nPain flare (2)\n\t\nNone\n\t\n\nOGS\n\t\n24.9\n\t\nNone\n\t\nZygoma\n\t\n2.4\n\t\n16\n\t\n1\n\t\nPain\n\t\nComplete, durable\n\t\nDOD (0.1)\n\t\nNone\n\t\nN/A\n\t\nOGS\t33.4\tNone\tT8\t10\t40\t5\tNone\tN/A\tAWD (1.2)\tNone\tNone\t\nOGS\t33.4\tNone\tIschium\t9.6\t40\t5\tNone\tN/A\tAWD (1.2)\tNone\tNone\t\n\nES\n\t\n28.7\n\t\nNone\n\t\nSacrum and left ilium\n\t\n891\n\t\n50\n\t\n5\n\t\nPain\n\t\nComplete, durable\n\t\nDOD (0.1)\n\t\nNone\n\t\nN/A\n\t\n\nES\n\t\n28.7\n\t\nNone\n\t\nC2\n\t\n24\n\t\n50\n\t\n10\n\t\nPain\n\t\nComplete, durable\n\t\nDOD (0.1)\n\t\nNone\n\t\nN/A\n\t\nES6\n\t63.9\tNone\tL2\t3.9\t25\t5\tPain\tPartial, transient\tDOD (0.3)\tNone\tNone\t\n\n*Continguous similarly bolded/non-bolded rows denote multiple lesions in an individual patient.\n\n\n\n1All patients had metastatic disease.\n\n\n\n2Durable: until death or last follow-up.\n\n\n\n3Intrathecal pain pump placed immediately after SBRT; pain relief ensued.\n\n\n\n4Local failure noted at 0.6 years.\n\n\n\n5Local failure noted at 0.1 years.\n\n\n\n6Local failure noted at 0.2 years.\n\nPTV: planning target volume; SBRT: stereotactic body radiotherapy; OGS: osteosarcoma; DOD: dead of disease; ES: Ewing sarcoma; AWD: alive with disease.\n==== Refs\n1 Herzog C. E. Overview of sarcomas in the adolescent and young adult population Journal of Pediatric Hematology/Oncology 2005 27 4 215 218 10.1097/01.mph.0000161762.53175.e4 2-s2.0-18044364798 15838394 \n2 Esiashvili N. Goodman M. Marcus R. B. Jr. Changes in incidence and survival of ewing sarcoma patients over the past 3 decades: surveillance epidemiology and end results data Journal of Pediatric Hematology/Oncology 2008 30 6 425 430 2-s2.0-47549083691 10.1097/MPH.0b013e31816e22f3 18525458 \n3 Womer R. B. West D. C. Krailo M. D. Dickman P. S. Pawel B. R. Grier H. E. Marcus K. Sailer S. Healey J. H. Dormans J. P. Weiss A. R. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized ewing sarcoma: a report from the children's oncology group Journal of Clinical Oncology 2012 30 33 4148 4154 10.1200/JCO.2011.41.5703 2-s2.0-84869447819 23091096 \n4 Haeusler J. Ranft A. Boelling T. Gosheger G. Braun-Munzinger G. Vieth V. Burdach S. Van Den Berg H. Juergens H. 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E. Suit H. D. Radiotherapy for local control of osteosarcoma International Journal of Radiation Oncology Biology Physics 2005 61 2 492 498 10.1016/j.ijrobp.2004.05.051 2-s2.0-12844281977 \n10 Matsunobu A. Imai R. Kamada T. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk Cancer 2012 118 18 4555 4563 10.1002/cncr.27451 2-s2.0-84865959716 22359113 \n11 Mahajan A. Woo S. Y. Kornguth D. G. Hughes D. Huh W. Chang E. L. Herzog C. E. Pelloski C. E. Anderson P. Multimodality treatment of osteosarcoma: radiation in a high-risk cohort Pediatric Blood and Cancer 2008 50 5 976 982 10.1002/pbc.21451 2-s2.0-37349131216 18213710 \n12 Benedict S. H. Yenice K. M. Followill D. Galvin J. M. Hinson W. Kavanagh B. Keall P. Lovelock M. Meeks S. Papiez L. Purdie T. Sadagopan R. Schell M. C. Salter B. Schlesinger D. J. Shiu A. S. Solberg T. Song D. Y. Stieber V. Timmerman R. Tomé W. A. Verellen D. Wang L. Yin F.-F. Stereotactic body radiation therapy: the report of AAPM Task Group 101 Medical Physics 2010 37 8 4078 4101 2-s2.0-78149492263 10.1118/1.3438081 20879569 \n13 Jeter M. D. Jänne P. A. Brooks S. Burstein H. J. Wen P. Fuchs C. S. Loeffler J. S. Devlin P. M. Salgia R. Gemcitabine-induced radiation recall International Journal of Radiation Oncology Biology Physics 2002 53 2 394 400 10.1016/S0360-3016(02)02773-6 2-s2.0-0036603732\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1357-714X",
"issue": "2014()",
"journal": "Sarcoma",
"keywords": null,
"medline_ta": "Sarcoma",
"mesh_terms": null,
"nlm_unique_id": "9709257",
"other_id": null,
"pages": "418270",
"pmc": null,
"pmid": "25548538",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "22015453;15667972;18213710;20117285;12743156;22359113;23091096;19924786;15838394;18525458;12023144;20879569",
"title": "Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma.",
"title_normalized": "stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma"
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"abstract": "Tranylcypromine is an effective antidepressant from the class of monoamine oxidase inhibitors and is structurally related to amphetamine. However, reports differ regarding the potential metabolism of tranylcypromine to amphetamine and methamphetamine within the human body. We report a 25-year-old woman with severe depression who died due to a fatal tranylcypromine overdose in 2016. She had been prescribed tranylcypromine one day previously and had no history of previous suicide attempts or substance abuse. The body was transferred to a forensic medicine department in Tehran, Iran for the autopsy. A urine sample was positive for tranylcypromine, amphetamine and methamphetamine using gas chromatography/mass spectrometry after derivatisation with heptafluorobutyric acid. As amphetamines were present in the urine sample, it was assumed that the tranylcypromine had been converted to amphetamines metabolically. As such, it is possible that the legitimate use of certain prescription drugs may complicate the interpretation of test results for illegal drugs.",
"affiliations": "Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.;Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.;Department of Anaesthesiology & Critical Care, Tehran University of Medical Sciences, Tehran, Iran.;Department of Anaesthesiology & Critical Care, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Akhgari|Maryam|M|;Jokar|Farzaneh|F|;Etemadi-Aleagha|Afshar|A|;Ghasemi|Ali|A|",
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"doi": "10.18295/squmj.2016.17.02.013",
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"issue": "17(2)",
"journal": "Sultan Qaboos University medical journal",
"keywords": "Amphetamine; Case Report; Forensic Toxicology; Iran; Metabolism; Substance Abuse Detection; Tranylcypromine",
"medline_ta": "Sultan Qaboos Univ Med J",
"mesh_terms": "D000328:Adult; D000661:Amphetamine; D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants; D003863:Depression; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007492:Iran; D008694:Methamphetamine; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine",
"nlm_unique_id": "101519915",
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"title": "Discrimination Between Drug Abuse and Medical Therapy: Case report of a tranylcypromine overdose-related fatality.",
"title_normalized": "discrimination between drug abuse and medical therapy case report of a tranylcypromine overdose related fatality"
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"abstract": "We report a case of a 27-year old man with severe aplastic anemia who developed a Saprochaete clavata (Geotrichum clavatum) disseminated invasive infection shortly prior a scheduled allogeneic bone marrow transplantation. Treatment with a combination of voriconazole, liposomal amphotericin B and adjuvant granulocyte transfusions was successful before neutrophil recovery.",
"affiliations": "Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Laboratoire de Parasitologie Mycologie, CHU Pellegrin, Bordeaux, France.;Etablissement Français du Sang, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.;Laboratoire de Parasitologie Mycologie, CHU Pellegrin, Bordeaux, France.;Laboratoire de Parasitologie Mycologie, CHU Pellegrin, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.",
"authors": "Favre|Simon|S|;Rougeron|Amandine|A|;Levoir|Laure|L|;Pérard|Baptiste|B|;Milpied|Noël|N|;Accoceberry|Isabelle|I|;Gabriel|Frédéric|F|;Vigouroux|Stéphane|S|",
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"doi": "10.1016/j.mmcr.2016.03.001",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30009-410.1016/j.mmcr.2016.03.001Case ReportSaprochaete clavata invasive infection in a patient with severe aplastic anemia: Efficacy of voriconazole and liposomal amphotericin B with adjuvant granulocyte transfusions before neutrophil recovery following allogeneic bone marrow transplantation Favre Simon aRougeron Amandine bLevoir Laure cPérard Baptiste aMilpied Noël adAccoceberry Isabelle bGabriel Frédéric bVigouroux Stéphane a⁎a Service d’Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, Franceb Laboratoire de Parasitologie Mycologie, CHU Pellegrin, Bordeaux, Francec Etablissement Français du Sang, Bordeaux, Franced Université Bordeaux Segalen, Bordeaux, France⁎ Corresponding author.08 3 2016 3 2016 08 3 2016 11 21 23 3 2 2016 2 3 2016 7 3 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of a 27-year old man with severe aplastic anemia who developed a Saprochaete clavata (Geotrichum clavatum) disseminated invasive infection shortly prior a scheduled allogeneic bone marrow transplantation. Treatment with a combination of voriconazole, liposomal amphotericin B and adjuvant granulocyte transfusions was successful before neutrophil recovery.\n\nKeywords\nSaprochaete clavataInvasive infectionHematological diseaseAplastic anemia\n==== Body\n1 Introduction\nSaprochaete clavata, formerly called Geotrichum clavatum, is an ascomycetous yeast genetically closely related to Magnusiomyces capitatus, formerly called Geotrichum capitatum\n[1]. S. clavata is a very rare, but emerging, causative agent of invasive human infections [1], [2], [3]. Between September 2011 and October 2012, a multicenter outbreak of 30 invasive infections caused by S. clavata was observed in France with a peak of 18 cases over 2 months in 2012. The majority (90%) of patients had acute leukemia and severe neutropenia. The clinical presentations included fever, diarrhea, and pulmonary symptoms. S. clavata was isolated from blood, stools, and respiratory samples in 86.7%, 57.9%, and 40% of patients, respectively. Most patients (60%) had multiple body sites infected. Prognosis was extremely poor with a crude mortality of 80% at day 60, with death occurring at a median time of 7 days after diagnosis [1]. Three concomitant cases were observed in patients hospitalized in the same hematological ward for induction chemotherapy in the context of acute myeloid leukemia. Patients died on days 14, 23 and 43, even if 2 of them were treated by a bi-antifungal therapy with liposomal amphotericin B and voriconazole [4]. A successfully treated case of invasive S. clavata infection in an acute myeloid leukemia patient with severe neutropenia was reported in which treatment with voriconazole and neutrophil recovery on day 8 after diagnosis had improved the outcome [5].\n\nOriginalities of the present case report of invasive S. clavata infection in a patient with severe aplastic anemia are rarity of specie, type of hematological disease and resolution with voriconazole, liposomal amphotericin B and adjuvant granulocyte transfusions before neutrophil recovery. In most reported cases, patients had severe neutropenia following chemotherapy for acute leukemia but no case had previously been reported in patients with aplastic anemia free of chemotherapy [1], [4], [5]. Furthermore, previous reports suggest that resolution of infection mostly relies on neutrophil recovery [4], [5]. As a consequence, a successful outcome before neutrophil recovery due to antifungal agents combined with granulocyte transfusions in this rare and severe invasive fungal infection is a valuable information.\n\n2 Case\nA 27-year old man was admitted on 4 September 2015 to an internal medicine unit of our hospital for pancytopenia (neutrophils: 0.8×109/L, hemoglobin: 9.4 gr/dl, platelets: 4×109/L) and muco-cutaneous hemorrhages. Day 1 was defined as the day of admission. Marrow aspiration and trephine biopsy established the diagnosis of idiopathic severe aplastic anemia. Empirical broad spectrum antibiotherapy with piperacillin–tazobactam (16 gr/day for 10 days) and amikacin (15 mg/kg/day for 4 days) was started on day 5 for febrile neutropenia. The fever rapidly resolved without bacterial identification. The following days, neutropenia worsened with 0.3×109/L. Then, despite the diagnosis of aplastic anemia, oral prednisone (40 mg/day) was started on day 12. The patient was admitted to the intensive care unit (ICU) for septic shock on day 19. Prednisone was stopped. Piperacillin-tazobactam was restarted with success and completed with levofloxacin when blood cultures returned positive for Streptococcus mitis and Klebsiella pneumoniae on day 20. The patient completely recovered and was admitted to our hematology unit on day 24 with the same antibiotics. A central venous catheter (CVC) was inserted on day 25.\n\nAs fever reappeared on day 29, piperacillin–tazobactam and levofloxacin were empirically replaced by meropenem (3 gr/day) and an antifungal treatment by caspofungin (loading dose 70 mg, then 50 mg/day) was initiated. Fever persisted with poor clinical condition, diarrhea, abdominal pain, dry cough and left thoracic pain. As peripheral and central venous blood cultures performed on day 29 returned positive for septate hyphae on day 31, caspofungin was replaced by liposomal amphotericin B (3 mg/kg/day) associated with intravenous (IV) voriconazole (6 mg/kg×2 on first day, then 4 mg/kg×2/day). This therapeutic strategy was also supported by a stool examination performed on day 22 in ICU that revealed rare colonies of S. clavata identified by the matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry BioTyper system (Bruker Daltonics). On day 31, a CT scan revealed a left pulmonary nodular lesion, diffuse bowel thickening, together with multiple nodular lesions of spleen, kidneys, and liver. The liver function tests were normal. The CVC was removed (culture was negative). The patient complained of a left blurred vision. Cerebral CT scan and magnetic resonance imaging were normal. The ophtalmological examination revealed a left retinal hemorrhage. An echocardiogram excluded the diagnosis of fungal endocarditis. The patient remained severely neutropenic (<0.1×109/L). On day 33, S. clavata was identified from the first blood culture (performed on day 29). The clinical condition rapidly improved during the first days of bi-antifungal therapy although daily blood cultures returned positive for S. clavata until day 34. After day 34, weekly stool examinations and daily blood cultures returned negative. The fever persisted until day 42 without any further documented infection. Weekly galactomannan antigenemia results were negative. Voriconazole blood levels were weekly checked to target 1–5 µg/ml and averaged 2.4 µg/mL [6]. Antifungal susceptibility testing was assessed by broth microdilution EUCAST method [7]. The minimal inhibitory concentrations (MICs) for echinocandins (caspofungin and micafungin) and fluconazole were high (≥4 µg/ml and 32 µg/ml, respectively) and much lower for amphotericin B (0.25 µg/ml), 5-fluorocytosine (0.25 µg/ml), voriconazole and posaconazole (0.5 µg/ml for both).\n\nThe patient underwent a sibling allogeneic bone marrow transplantation on day 42 after a conditioning regimen combining IV cyclophosphamide 300 mg/m2, IV fludarabine 30 mg/m2 both from day 35 to 38, and IV alemtuzumab 20 mg from day 36 to 39. Cyclosporine was started on day 41 for graft-versus-host disease prophylaxis. Because of severe prolonged neutropenia, immunosuppression by conditioning regimen and reported dismal prognosis in the literature, we decided to performed 5 granulocyte transfusions on days 39, 40, 41, 48 and 49 despite rapid clinical improvement with bi-antifungal therapy and negativity of blood cultures after day 34. The patient received 4.3, 3.8, 3, 3, and 2.9×1010 neutrophils/transfusion, respectively. No toxicity was observed. The neutrophil counts reached 0.5 to 1×109 /L the day after each transfusion and returned below 0.1×109/L the day after in the absence of transfusion. After day 42, the fever did not recur and the patient remained in good clinical condition. The neutrophil count reached 0.5×109/L on day 68 without granulocyte colony-stimulating factor. Voriconazole was given orally the same day but replaced by posaconazole (tablets, 300 mg/day once a day) on day 84 because of nausea and vomiting caused by voriconazole. Liposomal amphotericine B was discontinued on day 84. An abdominal ultrasound on day 84 showed only small splenic residual lesions. The patient left the unit on day 88 with posaconazole (tablets, 300 mg/day once a day) as secondary prophylaxis. Afterwards, fever did not recur and left vision progressively normalized. After a 4-month follow-up, the patient had no recurrence of infection or complication of transplantation.\n\n3 Discussion\nThe optimal therapy of invasive infection caused by S. clavata and M. capitatus has yet to be established and remains a challenge. Echinocandins are not recommended because of intrinsic resistance. Some breakthrough infections have indeed been reported in patients receiving echinocandins [1], [2], [4], [8], [9]. In contrast, voriconazole, posaconazole (but not fluconazole), amphotericin B and 5-fluorocytosine are suitable antifungal agents because of better in vitro and in vivo activities [1], [2]. There is no convincing data in the literature to recommend any combination of antifungal agents. In our case, we empirically chose to add liposomal amphotericin B to voriconazole because the clinical condition rapidly worsened and the in vitro antifungal susceptibility testing showed low MICs. We also decided to performed 5 adjuvant granulocyte transfusions because of expected poor prognosis, immunosuppression by conditioning regimen, and severe neutropenia, despite unproven benefit of this strategy in neutropenic patients with invasive fungal infections [10], [11]. The benefit of these transfusions is extremely difficult to assess since the clinical condition of our patient rapidly improved with bi-antifungal therapy before granulocyte transfusions. Moreover, negative blood cultures were obtained 5 days before the first transfusion. Whether or not early removal of CVC may have favored the outcome in our case despite stools colonization remains an open question as it has been reported as an important complementary treatment in some cases [2].\n\nOriginalities of our case are rarity of S. clavata, type of hematological disease, and resolution of infection before neutrophil recovery. In contrast to M. capitatus, S. clavata has only very infrequently been reported as human pathogen [1], [2], [3]. Nevertheless, we must acknowledge that frequency in the literature might be underestimated by difficult species identifications. In the rare reported cases of S. clavata invasive infections, most patients had acute leukemia and neutropenia caused by chemotherapy [1], [4], [5]. In these reports, gut colonization and translocation favored by chemotherapy-induced intestinal tract damages may have played an important role. In our case, the patient had S. clavata gut colonization but did not receive any chemotherapy before diagnosis of fungal infection. As a consequence, our case indicates that gut translocation should be considered even if the digestive tract is not damaged by chemotherapy. Interestingly, the resolution of infection in our case was obtained with bi-antifungal therapy several days before neutrophil recovery. The benefit of granulocyte transfusions cannot be excluded but is difficult to assess and remains hypothetical. Risks factors for infection in our patient were severe neutropenia, gut colonization, and possibly previous therapy with broad spectrum antibiotics and prednisone.\n\nIn conclusion, we report a case of an invasive infection to S. clavata in a patient with severe aplastic anemia, successfully treated by voriconazole and liposomal amphotericin B with adjuvant granulocyte transfusions before neutrophil recovery following allogeneic bone marrow transplantation. Our case clearly supports the possibility of successful treatment of disseminated S. clavata infection despite severe prolonged neutropenia and expected poor prognosis.\n\nConflict of interest\nThere are none.\n\nAcknowledgments\nThere is no acknowledgment.\n==== Refs\nReferences\n1 Vaux S. Criscuolo A. Desnos-Ollivier M. Diancourt L. Tarnaud C. Vandenbogaert M. Geotrichum investigation group. Multicenter outbreak of infections by Saprochaete clavata , an unrecognized opportunistic fungal pathogen MBio 5 6 2014 \n2 Arendrup M.C. Boekhout T. Akova M. Meis J.F. Cornely O.A. Lortholary O. European society of clinical microbiology and infectious diseases fungal infection study group; European confederation of medical mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of rare invasive yeast infections Clin. Microbiol. Infect. 20 Suppl. 3 2014 S76 S98 \n3 Girmenia C. Pagano L. Martino B. D’Antonio D. Fanci R. Specchia G. GIMEMA Infection Program. Invasive infections caused by Trichosporon species and Geotrichum capitatum in patients with hematological malignancies: a retrospective multicenter study from Italy and review of the literature J. Clin. Microbiol. 43 4 2005 1818 1828 15815003 \n4 Picard M. Cassaing S. Letocart P. Verdeil X. Protin C. Chauvin P. Concomitant cases of disseminated Geotrichum clavatum infections in patients with acute myeloid leukemia Leuk Lymphoma. 55 5 2014 1186 1188 23829307 \n5 Camus V. Thibault M.L. David M. Gargala G. Compagnon P. Lamoureux F. Invasive Geotrichum clavatum fungal infection in an acute myeloid leukaemia patient: a case report and review Mycopathologia 177 5–6 2014 319 324 24748454 \n6 Hulin A. Dailly E. Le Guellec C. [Level of evidence for therapeutic drug monitoring of voriconazole]. Groupe Suivi Therapeutique Pharmacologique de la Societe Francaise de Pharmacologie et de Therapeutique Therapie 66 2 2011 109 114 21635857 \n7 Subcommittee on antifungal susceptibility testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing, EUCAST Technical Note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia-forming moulds, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis, vol. 14, 2008, pp. 982–984.\n8 Chittick P. Palavecino E.L. Delashmitt B. Evans J. Peacock J.E. Case of fatal Blastoschizomyces capitatus infection occurring in a patient receiving empiric micafungin therapy Antimicrob. Agents Chemother. 53 2009 5306 5307 19738005 \n9 Schuermans C. van Bergen M. Coorevits L. Verhaegen J. Lagrou K. Surmont I. Breakthrough Saprochaete capitata infections in patients receiving echinocandins: case report and review of the literature Med. Mycol. 49 2011 414 418 21105848 \n10 Bhatia S. McCullough J. Perry E.H. Clay M. Ramsay N.K. Neglia J.P. Granulocyte transfusions: efficacy in treating fungal infections in neutropenic patients following bone marrow transplantation Transfusion 34 3 1994 226 232 8146895 \n11 Seidel M.G. Peters C. Wacker A. Northoff H. Moog R. Boehme A. Randomized phase III study of granulocyte transfusions in neutropenic patients Bone Marrow Transplant. 42 10 2008 679 684 18695660\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "11()",
"journal": "Medical mycology case reports",
"keywords": "Aplastic anemia; Hematological disease; Invasive infection; Saprochaete clavata",
"medline_ta": "Med Mycol Case Rep",
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"nlm_unique_id": "101598259",
"other_id": null,
"pages": "21-3",
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"references": "25516620;24102785;18695660;21105848;15815003;24748454;18828858;19738005;23829307;21635857;8146895",
"title": "Saprochaete clavata invasive infection in a patient with severe aplastic anemia: Efficacy of voriconazole and liposomal amphotericin B with adjuvant granulocyte transfusions before neutrophil recovery following allogeneic bone marrow transplantation.",
"title_normalized": "saprochaete clavata invasive infection in a patient with severe aplastic anemia efficacy of voriconazole and liposomal amphotericin b with adjuvant granulocyte transfusions before neutrophil recovery following allogeneic bone marrow transplantation"
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"abstract": "BACKGROUND\nAutoimmune hepatitis and autoimmune sclerosing cholangitis may lead to maternal and fetal complications in pregnant women diagnosed during childhood and treated long-term with immunosuppressive drugs. Immunosuppressive treatment with azathioprine is usually employed during pregnancy to maintain remission but his safety is still controversial. The aim of our study is to investigate pregnancy outcomes after maternal long-term immunosuppressive treatment for autoimmune hepatitis/sclerosing cholangitis.\n\n\nMETHODS\nWe conducted a retrospective cohort study including all pregnant women who received a diagnosis of autoimmune hepatitis or autoimmune sclerosing cholangitis during childhood and followed-up from 1989 to 2021.\n\n\nRESULTS\nFifteen pregnancies in 12 women were observed. The median follow-up from disease onset was 26.7 years. All patients had been treated with prednisone and azathioprine (AZA) as first line therapy. At the beginning of the pregnancy, 11/12 (91.6%) patients were in spontaneous or pharmacologically induced clinical and biochemical remission and one had received a liver transplant. During pregnancy, 8 patients continued azathioprine. No relapse during pregnancy occurred in any patient. One woman presented a flare five months after delivery and a second one, one year after delivery when AZA was discontinued. The 15 pregnancies resulted in 13 livebirths (86.6%) with 9 (69.2%) full-term healthy neonates. Two miscarriages (13.3%) were recorded and cesarean section was performed in 3 women (23%). No congenital malformations were observed.\n\n\nCONCLUSIONS\nPregnancy in women diagnosed during pediatric age with autoimmune hepatitis or autoimmune sclerosing cholangitis and treated long-term with immunosuppressants is possible with good maternal and neonatal outcomes. Azathioprine allows, in most cases, to maintain remission with a good safety profile. Careful monitoring of these patients during pregnancy is, however, mandatory.",
"affiliations": "Department of Medical, Surgery, and Health Sciences, University of Trieste, Trieste, Italy. Electronic address: lorenza.matarazzo@gmail.com.;Department of Pediatrics, Harvard Medical School, Boston's Children Hospital, MA, USA.;Pediatric Hepatology and Pediatric Liver Transplantation, ISMETT, University of Pittsburgh Medical Center Italy, Palermo, Italy.;Hepatogastroenterology, Nutrition and Liver Transplant Unit, IRCCS Pediatric Hospital Bambino Gesù, Rome, Italy.",
"authors": "Matarazzo|Lorenza|L|;Nastasio|Silvia|S|;Sciveres|Marco|M|;Maggiore|Giuseppe|G|",
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"journal": "European journal of obstetrics, gynecology, and reproductive biology",
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"title": "Pregnancy outcome in women with childhood onset autoimmune hepatitis and autoimmune sclerosing cholangitis on long-term immunosuppressive treatment.",
"title_normalized": "pregnancy outcome in women with childhood onset autoimmune hepatitis and autoimmune sclerosing cholangitis on long term immunosuppressive treatment"
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"abstract": "Extensive and significant technological advancements have enhanced the sensitivity and accuracy of the pathologic classification, diagnosis, and therapeutics of lymphoma. These advances have prompted a more comprehensive understanding of neoplastic behavior and have led to improvements in both treatment and prognosis. This paper presents a comprehensive review of lymphoma and features a case report of a unique presentation of peripheral T-cell lymphoma - not otherwise specified that presented with isolated hypoglossal nerve dysfunction.",
"affiliations": "Pennsylvania Hospital, University of Pennsylvania Health System, 800 Spruce Street, Philadelphia, PA, 19107, USA.;Pennsylvania Hospital, University of Pennsylvania Health System, 800 Spruce Street, Philadelphia, PA, 19107, USA.",
"authors": "Bryer|Emily|E|;Henry|David|D|",
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"fulltext": "\n==== Front\nInt J Hematol OncolInt J Hematol OncolIJHInternational Journal of Hematologic Oncology2045-13932045-1407Future Medicine Ltd London, UK 10.2217/ijh-2018-0002ReviewIsolated hypoglossal nerve palsy as a presenting symptom of metastatic peripheral T-cell lymphoma – not otherwise specified (PTCL–NOS): a unique case & a review of the literature Bryer & HenryIsolated hypoglossal nerve palsy as a presenting symptom of PTCL–NOS Bryer Emily *\n1\nHenry David \n1\n\n1 Pennsylvania Hospital, University of Pennsylvania Health System, 800 Spruce Street, Philadelphia, PA, 19107, USA*Author for correspondence: Tel.: +1 267 581 4166; Fax: +1 215 829 7129; Emily.Bryer@uphs.upenn.edu3 2018 28 6 2018 7 1 IJH0316 2 2018 08 5 2018 28 6 2018 © 2018 Emily Bryer2018This work is licensed under a Creative Commons Attribution-NonCommercial NonDerivative 4.0 Unported License\nExtensive and significant technological advancements have enhanced the sensitivity and accuracy of the pathologic classification, diagnosis, and therapeutics of lymphoma. These advances have prompted a more comprehensive understanding of neoplastic behavior and have led to improvements in both treatment and prognosis. This paper presents a comprehensive review of lymphoma and features a case report of a unique presentation of peripheral T-cell lymphoma – not otherwise specified that presented with isolated hypoglossal nerve dysfunction.\n\nKeywords: \nchemotherapyhypoglossal nerveimmunotherapylymphomanon-Hodgkin lymphomaperipheral T-cell lymphoma\n==== Body\nPractice points\nLymphomas are a diverse group of neoplasms with varying genotypes, presentation, behavior and treatment responsiveness.\n\nThe diagnosis of lymphoma requires biopsy and immunophenotype as defined by flow cytometry and/or immunohistochemistry.\n\nTissue histology differentiates Hodgkin lymphoma from non-Hodgkin lymphoma.\n\nLymphoma prognosis is evaluated by a variety of scoring systems, some of which incorporate age, lactate dehydrogenase, platelet count, Eastern Cooperative Oncology Group, extranodal and bone marrow involvement, and the Ki-67.\n\nLymphoma treatment is guided by prognosis and stage of disease.\n\nTreatment of Hodgkin lymphoma typically includes a variation of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) and radiation.\n\nTreatment of non-Hodgkin lymphoma traditionally involves cyclophosphamide, doxorubicin, prednisone, and vincristine (CHOP) or rituximab-CHOP (R-CHOP) and may be supplemented by radiation, surgery and/or stem cell therapy.\n\nThe development of immunotherapy in the form of monoclonal antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cell therapy allow for more tumor-specific therapeutics.\n\nPeripheral T-cell lymphoma-not otherwise specified (PTCL–NOS), also recognized as peripheral T-cell lymphoma of the unspecified variant (PTCL-U), is a highly aggressive subtype of T-cell non-Hodgkin lymphoma. The PTCL–NOS subtype of PTCL incorporates a heterogeneous group of T-cell lymphomas that do not meet inclusionary criteria for other subtypes and likely represent not yet identified subtypes of PTCL. Consequently, PTCL–NOS is a diagnosis of exclusion and lacks precise clinical, immunophenotypic and genetic inclusionary criteria. The featured case describes a young man who presented to the emergency department with symptoms suggestive for cranial nerve XII palsy. Further diagnostic investigation revealed a diagnosis of PTCL–NOS with meningeal involvement resulting in isolated cranial nerve disruption. This case report and accompanying review of lymphoma highlight a unique presentation and immunophenotype of PTCL–NOS not previously described in the literature.\n\nCase report\nA 25-year-old Hispanic male presented to the emergency room with a 2.5-week history of dysarthria, inability to protrude the tongue, and worsening right knee and back pain for 4–6 months duration. Patient additionally reported temporal headaches, fevers (Tmax 101°F), and chills for the past 2 weeks prior to presentation. Past medical history was unremarkable and family history significant only for hypertension. Medications at time of presentation included naproxen and prednisolone. Social history was notable for tobacco and alcohol use.\n\nVital signs on admission: temperature 98°F, blood pressure 130/76 mmHg, heart rate 94 bpm, respiratory rate 18, SpO2 98%, BMI 32.89 kg/m2. Physical examination was notable for inability to protrude the tongue, limited bilateral lateral tongue deviation, and decreased right palate elevation. Examination was otherwise unremarkable and there was no evidence of lymphadenopathy or other neurologic deficits. Laboratory tests revealed hemoglobin 9.4, leukocytes 19.4 thousand/μl, platelets 108, lactate 3.5 mmol/l, C-reactive protein > 160 mg/l, erythrocyte sedimentation rate 125 mm/h, ferritin 3389 ng/ml and lactate dehydrogenase (LDH) 963 U/l. Renal function parameters and liver enzymes were normal. Serology for cytomegalovirus IgG was positive at 1.5 mg/dl. Blood cultures were sterile, as well as serology for Lyme disease, Epstein-Barr virus (EBV), HIV, HSV, human T-lymphotropic virus type 1 (HTLV1) and HTLV2.\n\nMRI demonstrated diffuse dural thickening with enhancement and nonspecific diffuse marrow hypointensity without evidence of ischemic disease or mass effect (Figure 1). Lumbar puncture was performed to rule out infection. Cerebrospinal fluid (CSF) analysis displayed elevated protein (121 mg/dl), decreased glucose (31 mg/dl) and leukocytosis (317 per microliter), 90% of which were atypical cells suggestive of large cell lymphoma. MRI of the right femur demonstrated a dominant right anterior thigh soft tissue mass measuring up to 8.5 cm × 8.3 cm × 16.2 cm that encircled the femoral shaft and invaded the medullary cavity as well as anterior focal cortical destruction (impending pathologic fracture) and an enhancing soft tissue masses in the left obturator musculature, underlying acetabulum, right ischiopubic ramus and along the distal right femur. Biopsy of right femoral soft tissue mass yielded a diagnosis of lymphoma (Figure 2). Immunohistochemical stains showed neoplastic large cells positive for CD4, CD43 and CD30 (subset) and negative for CD3, CD5, CD20, CD138, BCL-2 and BCL-6. EBER (EBV-encoded RNA) was negative. The Ki-67 index was approximately 60%. Immunohistochemical stains confirmed a CD4+ T-cell lymphoma with abnormal phenotype (CD3-/CD5-), consistent with the diagnosis of PTCL–NOS. Further investigation revealed metastatic involvement of lung pleura and multiple cortically destructive lytic lesions within the spine consistent with malignant involvement. The patient's clinical presentation of dysarthria was thought to be secondary to meningeal thickening leading to compression of the hypoglossal nerve.\n\nFigure 1. \nMRI head: intracranial dural involvement – postcontrast T1-weighted images show asymmetric dural thickening in inferomedial left middle cranial fossa, adjacent to cavernous sinus and Meckel's cave.\n\nFigure 2. \nHematoxylin and eosin-stained tissue displaying diffuse sheets of lymphoid cells within fibrotic stroma (20×).\n\nFoci of large cells with neoplastic features (irregular, pleomorphic, hyperchromatic, vesicular nuclei, prominent nucleoli, frequent mitoses) are present (40×) morphologically consistent with lymphoma.\n\nChemotherapy was initiated and consisted of four cycles of intravenous EPOCH, consisting of etoposide, prednisone, doxorubicin, vincristine and cyclophosphamide followed by three cycles of gemcitabine and oxaliplatin. The patient also received intrathecal methotrexate and cytarabine for CNS involvement. With poor response to the above regimen and, in the setting of initial neoplastic overexpression of CD30, the patient was trialed on brentuximab vedotin without adequate response. The patient was evaluated for, but did not receive, stem cell transplant.\n\nFive months after initial presentation, the patient developed metastases to his thoracic vertebrae, ribs, femur, facial bones, and lymph nodes. Immunohistochemical stains obtained from a repeat bone marrow biopsy 7 months after presentation revealed neoplastic cells positive for CD45, CD4 (BCL-2 [subset] and c-MYC [subset]), while negative for CD3, CD5, CD79a, TdT and CD20. CD43 staining was suboptimal and equivocal. CD30 weakly stained a small subset of large cells. Overall, the second bone marrow biopsy displayed approximately 60% necrotic material.\n\nThe patient expired soon after 7 months following initial presentation.\n\nLiterature review\nThe 2008 WHO's designation of lymphoid neoplasms remains the current standard for lymphoma classification [1]. While the 2008 guidelines are currently in revision with update expected later this year, they are widely accepted by hematopathologists and clinicians to categorize lymphomas [2]. The WHO guidelines classify an incredibly diverse group of hematogenous malignancies by categorizing them into one of three main subsets – myeloid neoplasms, lymphoid neoplasms and histiocytic/dendritic neoplasms [1]. Lymphoid neoplasms, also referred to as lymphomas, represent a heterogeneous class of hematogenous malignancy that originates from lymphoid precursors, progenitor cells and mature lymphocytes. The WHO guidelines organize lymphomas according to the following: type of lymphocyte, microscopic pathology, chromosomal features of the lymphoma cells and the presence of specific proteins on the cell surface [4,5].\n\nLymphomas are diagnosed with tissue biopsy and classified by histologic morphology into one of two categories: Hodgkin and non-Hodgkin. The presence of Reed-Sternberg cells identifies a lymphoma as Hodgkin and, conversely, the absence of these specific cells distinguishes a lymphoma of the non-Hodgkin variety. While Hodgkin lymphomas are typically of B-lymphocyte origin, non-Hodgkin lymphomas can stem from B-lymphocytes, T-lymphocytes or natural killer (NK cells). Although both Hodgkin and non-Hodgkin lymphomas are hematogenous malignancies that stem from lymphocytes, in addition to having distinct pathologic diagnostic criteria, they can display unique progenitor cell types and immunophenotypes with corresponding treatment responsiveness.\n\nGenetic and molecular data contribute to the classification of neoplastic processes, improving the accuracy of lymphoma diagnoses. The immunophenotype of a cell is the combination of proteins/markers (such as CD20, CD3 and TdT) expressed by cells. Immunophenotype is evaluated by immunohistochemistry and/or flow cytometry, which help to determine the proportion of lymphoid cells that express a certain marker and their location and intensity within the cells [6]. Additionally, the immunophenotype can differentiate between lymphoid cells that are reactive versus those that are neoplastic in which growth and division are dependent on dysfunctional or abnormal cellular signaling.\n\nImmunophenotype analysis identifies the neoplastic cell of origin (B-, T- or NK) and, as a result, flow cytometry and fluorescence in situ hybridization studies have been incorporated into the diagnostic standard. Microscopic examination of specific cellular morphology including size, nuclear shape, chromatin configuration, nucleoli, and amount and hue of cytoplasm are also critical components of lymphoma diagnosis and classification [5]. The incorporation of morphologic, immunophenotypic and cytogenetic data, in addition to aiding in the diagnosis of the specific type of lymphoma, allows for more personalized and effective treatments that target specific culprit cells and receptors.\n\nHodgkin lymphoma\nHodgkin lymphoma represents about 10% of lymphomas and is much less common than non-Hodgkin lymphoma [7]. Within Hodgkin lymphoma, age distribution is bimodal (peaking at ages 20 and 65 years) with an incidence dependent largely on geographic location and relative to the degree of industrial development; the younger age group is associated with transitional economies [8–10].\n\nThe cells that compose Hodgkin lymphoma originate from the germinal center or postgerminal center in B cells. They feature pathognomonic Reed–Sternberg cells – large basophilic cells with bilobed/multilobed nuclei in the background of inflammatory cells [7]. Hodgkin lymphoma is further subdivided into both classical and nonclassical variants. Diagnosis of classical Hodgkin lymphoma by an excisional lymph node biopsy with immunophenotyping revealing minimal resemblance of their B-cell immunophenotype (as evidenced by dim expression of PAX5, but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 [6].\n\nClassical Hodgkin lymphoma typically presents as painless peripheral cervical lymphadenopathy and is further subdivided into nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted [7]. The mixed-cellularity and lymphocyte-depleted subtypes carry an association with EBV/human herpesvirus 4. EBV was the first virus identified to influence cancer pathogenesis and an infection with EBV in the setting of Hodgkin lymphoma is a poor prognostic factor [11]. The poor prognosis of an EBV+ neoplasm is due in part to the virus's ability to infect a cell and generate antiapoptotic effects. Some of the postulated mechanisms by which EBV contributes to a poor prognosis in patients with Hodgkin lymphoma include methylation of tumor-suppressor proteins and alteration of host chromosome structures (i.e., telomeres, chromatin) that are directly involved with cellular division and reproduction [12].\n\nTreatment of Hodgkin lymphoma is dependent on both prognosis and stage of disease. Favorable prognosis of Hodgkin lymphoma is defined by the European Organization for the Research and Treatment of Cancer as the following: age greater than 50; lack of mediastinal adenopathy and B-symptoms (or with an erythrocyte sedimentation rate of less than 30 with B-symptoms); or the absence of B symptoms in addition to disease limited to three or fewer anatomic regions [13]. B-symptoms are associated with both Hodgkin and non-Hodgkin lymphoma and include fever with temperature greater than 38°C, unexplained weight loss greater than 10% body weight over the past 6 months and the presence of drenching night sweats [3]. Stage of disease is classified by the Lugano classification – Stage I defined as involvement of a single lymph node, Stage II defined as involvement of two or more lymph nodes on the same side of the diaphragm, Stage III involvement of two or more lymph nodes on opposite sides of the diaphragm, Stage IV is diffuse and/or disseminated involvement with or without lymph node involvement [14].\n\nPatients with Stages I–II Hodgkin lymphoma are typically treated with radiation and ABVD therapy (doxorubicin, bleomycin, vinblastine and dacarbazine). Advanced Hodgkin lymphoma treatment involves either ABVD or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone). In patients with advanced disease receiving BEACOPP, the addition of radiation to chemotherapy has shown advantages in freedom from progression, but not overall survival [15]. A third treatment variation for advanced Hodgkin lymphoma, the Stanford V, includes radiation along with doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone [15].\n\nNon-Hodgkin lymphoma\nNon-Hodgkin lymphoma is exceedingly more common than Hodgkin lymphoma in the USA, accounting for about 90% of all new cases [1,15]. It is associated with a variety of factors including personal or family history of lymphoma, obesity, exposure to pesticides or other chemical agents in addition to autoimmune and immunodeficiency disorders [3]. Non-Hodgkin lymphoma is also associated with the following infections: HIV, HTLV-I, EBV, Borrelia burgdorferi (B. afzelii species), Chlamydia psittaci and Hepatitis B and C [17,18].\n\nNon-Hodgkin lymphomas are a diverse group of neoplasms with varying symptomatology, organ involvement, laboratory findings, virulence and prognosis. Aggressive non-Hodgkin lymphomas typically present acutely or subacutely with up to 40% reporting constitutional B-symptoms [19]. Tissue or lymph node biopsy provides data on classification of lymphoid neoplasms, with 85% of non-Hodgkin lymphomas classified as B-cell in origin and the remaining 15% of T-cell origin [4,5]. In addition to tissue or lymph node biopsy and appropriate imaging, patients with non-Hodgkin lymphoma classically have a bone marrow aspiration or biopsy to most accurately stage their disease before treatment is initiated [3]. Bone marrow involvement is estimated in 30–50% of patients with non-Hodgkin lymphoma and is more commonly observed in patients with indolent lymphomas [20,21]. If leptomeningeal metastases are suspected with likelihood of CNS involvement, lumbar punctures are performed with CSF analysis that typically reveals elevated protein and a lymphocyte-predominant pleocytosis [3].\n\nAn estimated 50% of patients with non-Hodgkin lymphoma develop extranodal disease and 10–35% have evidence of extranodal lymphoma on initial presentation [3,19]. When present, primary extranodal sites of non-Hodgkin lymphoma are most commonly gastrointestinal and cutaneous [3]. Non-Hodgkin lymphoma with bone involvement usually represents disseminated disease and presents as a painful solitary lesion with swelling or pathologic fracture [3].\n\nAggressive non-Hodgkin lymphoma subsets include diffuse large B-cell lymphoma, Burkitt lymphoma, adult T-cell leukemia-lymphoma and precursor B and T lymphoblastic leukemia/lymphoma [3]. The most common T-cell lymphomas are further subdivided into anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, and PTCL–NOS also referred to PTCL-U. Patients with highly aggressive and fast growing non-Hodgkin lymphoma may present with, or develop, an elevated LDH (suspected due to high tumor burden), hepatic infiltration, and concomitant immune hemolytic anemia [3]. An elevated LDH, especially if greater than two- to three-times the upper limit of normal, is a poor prognostic factor [3].\n\nWhile some non-Hodgkin lymphomas are quite aggressive, others are more indolent in nature and present more chronically as opposed to acutely. Indolent lymphomas may manifest as the gradual development of lymphadenopathy, hepatomegaly, splenomegaly or cytopenias [3]. Some common indolent non-Hodgkin lymphomas include follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and splenic marginal zone lymphoma [3].\n\nSimilar to Hodgkin lymphoma, treatment of non-Hodgkin lymphoma depends upon disease stage and corresponding prognosis. Treatment may involve chemotherapy, immunotherapy, radiation therapy, stem cell transplant or surgery. The most common chemotherapeutic regimen for the initial treatment of aggressive non-Hodgkin lymphoma is CHOP, a multidrug regimen consisting of cyclophosphamide, doxorubicin, prednisone and vincristine.\n\nPatients with non-Hodgkin lymphoma are treated with an alternate version of CHOP, R-CHOP. R-CHOP includes the addition of rituximab – a monoclonal antibody for the CD20 cell protein expressed by mature B cells. Rituximab can be used as monotherapy or as part of a multidrug regimen to treat lymphoma. Patients with diffuse large B-cell lymphoma treated with R-CHOP have a lower incidence of progression, relapse and death when compared with those treated with CHOP alone [22]. The addition of rituximab to the CHOP regimen in patients with diffuse large B-cell lymphoma was found to significantly affect outcomes independent of both disease severity (as determined by International Prognostic Index [IPI] score) and age [22]. The mechanisms of monoclonal antibody-mediated cellular destruction include activation of the complement pathway as well as direct antibody-dependent cellular toxicity. Rituximab was the first therapeutic monoclonal antibody used in cancer therapy. In addition to its role in induction therapy of B-cell malignancies, many patients continue to receive rituximab as maintenance therapy to further suppress malignant activity. The use of rituximab as maintenance therapy has been associated with significantly prolonged progression-free survival [23]. Other immunotherapeutic drugs used in non-Hodgkin lymphoma include two other CD20 monoclonal antibodies – obinutuzumab and ofatumumab – as well as a distinct class of drugs including monoclonal drug–antibody conjugates.\n\nBrentuximab vedotin\nBrentuximab vedotin is an antibody–drug conjugate that targets CD30+ cancer cells [24]. This antibody–drug conjugate is approved by the US FDA for patients with Hodgkin lymphoma following failure of autologous stem cell transplant or following failure of at least two multidrug chemotherapeutic regimens who are not candidates for autologous stem cell transplant. Brentuximab vedotin is also approved for patients with systemic anaplastic large-cell lymphoma after failure of at least one multidrug chemotherapeutic regimen.\n\nTreatment with the traditional CHOP regimen of PTCL has yielded an overall survival rate ranging from 12 to 49% [25]. In response to the bleak outcomes of CHOP in PTCL, and with prior demonstrated efficacy of brentuximab vedotin in Hodgkin and anaplastic large cell lymphoma, research has been directed to evaluate its efficacy in populations with PTCL [24]. An open-label Phase I international study published in 2014 involving 11 centers examined the efficacy of brentuximab vedotin in patients with PTCL that expressed CD30. The sample of 39 patients received brentuximab therapy either in sequence following CHOP therapy or in combination with cyclophosphamide, doxorubicin, prednisone (with the omission of vincristine from CHOP regimen) as initial treatment. 85% of the patients who received sequential therapy with brentuximab obtained a complete remission rate of 62% with an estimated 1-year progression-free survival rate of 71%. 88% of the combination group achieved complete remission with a 1-year progression-free survival rate of 71% [26]. While the total sample size for this study was 39, the rarity of PTCL makes it difficult to study, and only two of these patients had PTCL–NOS. Alternative therapeutic regimens that have been approved by the FDA for relapsed and refractory PTCL include pralatrexate, romidepsin and bleinostat [27].\n\nChimeric antigen receptor T-cell therapy\nDespite the encouraging role of monoclonal antibodies and drug–antibody conjugates in cancer treatment, some lymphomas remain either refractory to treatment or relapse following therapy; these limitations prompted the development of chimeric antigen receptor (CAR) therapy. CAR therapy is an emerging type of immunotherapy utilizing autologous or allogeneic T-cells that are genetically engineered to target malignant cells. CAR therapy involves modulating T-cells with artificial receptors to target specific tumor cell surface antigen, activate T-cells and thereby augment T-cell function. CD19, a cell-surface protein exclusively expressed by B-lymphocytes, is one target that has been investigated with CAR therapy. Patients with refractory B-cell lymphoma who received CD19 T-cells had improved clinical outcomes in comparison with those who received chemotherapy alone [28]. While CD19-redirected CAR targets a specific cellular protein on B-cells similar to the way rituximab targets CD20, this type of immunotherapy is unique in that it utilizes genetically modified T-cells to target receptors as opposed to the mechanism of a generic antibody. Unlike monoclonal antibody treatment, CAR therapy involves the manipulation of lymphocytes and requires immunosuppression in the form of lymphodepletion prior to receipt of genetically modified cells. Sources of variation with current investigations of CD19-redirected CAR therapy in non-Hodgkin lymphoma include the type and duration of immunosuppressant therapy as well as the time between immunosuppressive therapy and receipt of CAR T-cells.\n\nImmunophenotype\nMature T-cell lymphomas tend to display either a T-helper (CD4+) or cytotoxic (CD8+) immunophenotype and may show loss of markers expressed by most normal T-cells such as CD5 and CD7 [6]. Other cell markers implicated in lymphoma include c-MYC, a proto-oncogene present on chromosome 8, which regulates the expression of 15% of genes in the human genome [29]. In the setting of an aggressive lymphoma, c-MYC induces cell proliferation and promotes both genomic instability and apoptosis [30]. BCL-2, another cellular marker, is a potent inhibitor of apoptosis, therefore potentiating cell survival [31]. Genetic instability and DNA damage in MYC-induced lymphomas is due in part to the expression of proapoptotic proteins that, in the absence of BCL-2, bind to effector proteins such as BAX or BAK and initiate mitochondrial depolarization and subsequent cell death [32].\n\nThe coexpression of both c-MYC and BCL-2 prompts a synergistic and potentially hazardous genomic backdrop for catastrophic cellular signaling and division. The immunophenotypic expression of both BCL-2 and c-MYC is a phenomenon observed in B-cell lymphomas, specifically diffuse large B-cell lymphoma and referred to as ‘double-hit lymphoma’ [33]. Despite controlling for clinical and molecular prognostic factors such as germinal center genotype, patients with double-hit diffuse B-cell lymphoma have inferior overall survival [33].\n\nLymphoma prognostic data\nMultiple prognostic indicator scores have been developed that incorporate an expanding breadth of factors that help providers to estimate outcomes. Some of these lymphoma-specific prognostic scores include the International Prognostic Index, the International T-cell Lymphoma Project as well as well as other prognostic scores specific to PTCL–NOS, which is the focus of this case, such as the Prognostic Index for PTCL–NOS and the modified-Prognostic Index for PTCL–NOS (Table 1). These scores incorporate data regarding age, LDH, platelet count, Eastern Cooperative Oncology Group, the presence of extranodal and bone marrow involvement, and the Ki-67 to catalog the behavior of the lymphoma and estimate its virulence.\n\nTable 1. \nLymphoma prognostic indices.\n\nVariables\tPatient X\tIPI\tPIT\tm-PIT\tITCLP\t\nAge (>60)\t \tX\tX\tX\tX\t\n\t\nECOG (>1)\tX (3)\tX\tX\tX\tX\t\n\t\nElevated LDH\tX (963)\tX\tX\tX\t \t\n\t\nAnn Arbor stage (III–IV)\tX (IV)\tX\t \t \t \t\n\t\nExtranodal involvement (≥ two sites)\tX\tX\t \t \t \t\n\t\nBone marrow involvement\tX\t \tX\t \t \t\n\t\nPlatelet count (<150,000/mmc)\tX (108)\t \t \t \tX\t\n\t\nKi-67 (≥ 80%)\t \t \t \tX\t \t\nECOG: Eastern Cooperative Oncology Group; IPI: International prognostic index; ITCLP: International T-cell lymphoma project; LDH: Lactate dehydrogenase; m-PIT: Modified-prognostic index for PTCL–NOS; Patient X: Current patient under review; PIT: Prognostic index for PTCL–NOS; PTCL–NOS: Peripheral T-cell lymphoma–not otherwise specified.\n\nAdapted with permission from [27].\n\nPeripheral T-cell lymphoma-not otherwise specified\nMature T-cell neoplasms are known as PTCLs, a heterogeneous group of lymphoid disorders classified by morphology, immunophenotype, genetics, and clinical features. PTCL–NOS is a subtype of this category that encompasses all T-cell lymphomas that cannot be classified by specific features. It accounts for an estimated 25% of PTCL and makes up approximately 4% of all non-Hodgkin lymphomas [3,27]. PTCL–NOS occurs in older patients and usually presents in advanced stages with extremely variable symptomatology. While constitutional B-symptoms are the presenting symptom for 35% of patients with PTCL–NOS, presentation usually also includes generalized lymphadenopathy with or without extra-nodal involvement [34]. Only approximately 13% have extranodal involvement without evidence of nodal involvement [34]. The two most common sites for extranodal disease are cutaneous and gastrointestinal [3]. CNS involvement is only observed in approximately 4–6% of patients with PTCL. There are limited published studies that have specifically addressed the risk of CNS disease and relapse in PTCL.\n\nUnfavorable PTCL–NOS prognostic factors include those that compose the IPI (Table 1), B-symptoms, bulky disease as defined by tumor ≥10 cm, elevated serum C-reactive protein, circulating tumor cells, and platelet count less than 150 × 109. The aforementioned unfavorable prognostic factors are predictive of both overall survival and failure-free survival [34]. Notably, hypergammaglobulinemia was a favorable prognostic indicator of both overall survival and failure-free survival [34].\n\nHypoglossal nerve palsy\nCranial nerve XII, the hypoglossal nerve, is a purely motor nerve responsible for the innervation of the styloglossus, hyoglossus and genioglossus, muscles recruited for tongue protrusion. Isolated optic nerve, oculomotor nerve and trigeminal nerve involvement are the most common cranial nerve deficits observed with lymphoma [35]. Isolated palsy of the hypoglossal nerve is extremely atypical [36].\n\nIn both nuclear (medullary) and peripheral lesions, the clinical signs of hypoglossal nerve dysfunction are ipsilateral atrophy, fasciculation, dysarthria and tongue palsy with deviation toward the side of the lesion with tongue protrusion. Bilateral affection of the hypoglossal nerve manifests as a complete tongue palsy with consecutive oral dysphagia and dysarthria [37,27]. A 2016 review of 245 cases of hypoglossal nerve palsies revealed 14.2% to be primary neoplastic and 13% due to metastatic malignancy, with the remainder postoperative, inflammatory, and secondary to radiation and trauma [39]. Male gender and a personal history of malignancy are hypothesized to predict a neoplastic source of cranial nerve XII palsy [39].\n\nReported etiologies of hypoglossal nerve palsy without further neurologic manifestations include tumor, Chiari malformation, dural arteriovenous fistula of the transverse sinus, and idiopathic [36,40]. Other causes of isolated cranial nerve XII palsy include infectious sequelae from dengue fever, mononucleosis, and tuberculosis [41–43]. Autoimmune, vascular conditions, and mechanical compression secondary to osteophyte projection of the atlanto-occipital joint have also resulted in cranial nerve XII palsy [44].\n\nBeyond the scope of PTCL–NOS, a review of B-cell and T-cell lymphomas and the cranial nerves emphasizes the rarity of cranial and peripheral nerve involvement by lymphoma [35]. Although rare, when lymphoma does lead to isolated cranial nerve involvement, it is typically associated with a lymphoma of B-cell origin [35]. While leptomeningeal spread is possible if there is enlargement of cranial nerves within the leptomeningeal space, dural involvement is rare [35].\n\nA case published in Clinical Neurology in 2012 describes a patient with dysarthria, headaches and bilateral tongue atrophy found to have cranial nerve (CN) XII enlargement on MRI (Table 2). In contrast to the current T-cell lymphoma with isolated hypoglossal nerve palsy, this case is a B-cell lymphoma with hypoglossal nerve palsy along with both oculomotor nerve palsy and leg weakness [45].\n\nTable 2. \nPeripheral T-cell lymphoma-not otherwise specified, and the CNS involvement to date.\n\nCharacteristics\tPatient X\tFragou et al., 2009 [46]\tWeiss et al., 2012 [48]\tMatano et al., 2006 [49]\tWang et al., 2016 [47]\tGrau et al., 2010 [50]\t\nAge (gender) at dx\t25 (male)\t23 (female)\t56 (male)\t57 (male)\t23 (male)\t60 (female)\t\n\t\nRace\tHispanic\tCaucasian\tCaucasian\tJapanese\tNot reported\tNot reported\t\n\t\nPresenting symptom\tTwo-week history of fevers and temporal headaches; 2.5-week history of dysarthria, inability to protrude the tongue, 4–6 months of worsening right knee and back pain\tIschemic stroke (fever 39°C and hemiplegia)\tRight-sided facial weakness for 1 day (history of 2 months URI symptoms with frontal headache and postnasal drip), blurry vision, ipsilateral hearing loss\tSubcutaneous tumor on back. Complete remission after chemotherapy then relapsed. One year later developed diplopia, dysarthria, dysphagia\tOne-month history of intermittent high fever (Tmax 40°C) and low back pain, night sweats, progressive weight loss\tIntermittent diplopia for 1 day that then persisted the following day\t\n\t\nLymphadenopathy on presentation\tAbsent\tPresent (inguinal)\tAbsent\tPresent (axillary, inguinal)\tAbsent\tAbsent\t\n\t\nLDH\t963\t356\tNot reported\tCSF LDH 631, serum LDH not reported\tWNL\tNot reported\t\n\t\nAnn Arbor stage\tIV\tIV\tIV\tIV\t‘IE’\tI\t\n\t\nExtranodal involvement\tRight femur mass dural extension\tRetroperitoneal mass\tMass in left lower lung\tSubcutaneous back and leg tumors\tLumbar lesions\tExtra-axial mass at caudal clivus\t\n\t\nBone marrow involvement\tPresent\tAbsent\tAbsent\tPresent\tAbsent\tAbsent\t\n\t\nPlatelet count\t28\tNot reported\tNot reported\tNot reported\tNot reported\tNot reported\t\n\t\nKi-67\t60%\t8–10%\tNot reported\tNot reported\t60%\t40%\t\n\t\nFlow cytometry\tInitial: CD4, CD43, CD30 (subset); Repeat 7 months after diagnosis: CD45, CD4 (BCL-2 [subset] and c-MYC [subset])\tCD3, CD5\tCD45, CD8, CD2, CD7\tCD2, CD3, HLA-DR5, CD5, CD8, CD38, CD45RO, TCR-α\tCD45RO, CD3, CD2, CD45, CD43, Vim, CD38, Mum-1\tCD3, CD8, CD1a, CD20, focal signal for CD23\t\n\t\nNeurologic involvement\tCN XII\tSylvian infarction associated with cerebral edema\tCN III, IV, V, VI, VII, VIII\tCN III, V, VII, VIII, X, XI, XII\tPrimary spinal lymphoma with lesions in L3–L5 vertebrae\tCN VI\t\n\t\nCSF analysis\tProtein (121 mg/dl), glucose (31 mg/dl), white cell count (317 per microliter), 90% of which were atypical cells with oval nuclei and prominent nucleoli suggestive for large-cell lymphoma\tReported as ‘negative’\tGlucose 19 mg/dl, protein 272 mg/dl, RBCs 530/mm3 nucleated cells of 73/mm3, sterile cultures, cytology: blast cells with azurophilic cytoplasmic granules\t560 mononuclear cells/l; protein 540 mg/dl, glucose 8 mg/dl (plasma glucose, 84 mg/dl); and LDH, 631 IU/l, cytology: proliferation of atypical lymphocytes\t‘Free of lymphoma cells’\tSecondary meningiosis following removal of tumor\t\n\t\nViral serologies: EBV, CMV, HTLV1, and HTLV2 IgG\tSerum CMV+\tNegative\tSerum EBV+, HTLV not reported\tHTLV negative, EBV testing not reported\tNot reported\tNot reported\t\n\t\nNeurologic imaging\tMRI: diffuse dural thickening with enhancement and nonspecific diffuse marrow hypointensity CT: moderate partial opacification of bilateral mastoid air cells, moderate mucosal thickening of sphenoid sinuses\tCT: massive sylvian infarction associated with severe cerebral edema\tMRI: bilateral leptomeningeal asymmetric enhancement of III, IV, V, VI, VII and VIII, and right sphenoid polypoid lesion and polypoid lesions in right nasal cavity\tMRI: multiple cranial nerve thickenings with gadolinium enhancement without intraparenchymal lymphomatous lesions\tCT and MRI of lumbar spine with contrast: mass lesions at right of L3–L5 vertebra and in epidural space at L4 with resultant spinal stenosis\tCT: extra-axial mass mediolaterally on the caudal clivus without osseous infiltration\nMRI: homogeneously enhancing, well-circumscribed, extra-axial lesion with moderate displacement of the pontomedullary junction and close proximity to the jugular foramen\t\n\t\nTreatment\tFour cycles of EPOCH followed by three cycles of gemcitabine and oxaliplatin. He also received intrathecal methotrexate and cytarabine (Ommaya reservoir) for CNS involvement. Trial of brentuximab vedotin\tCHOP cyclophosphamide, doxorubicin, vincristine, prednisone\tOmmaya reservoir for intrathecal chemotherapy with methotrexate, cytarabine (Ara-C) and hydrocortisone. Two cycles of systemic treatment with etoposide, methylprednisolone, high-dose Ara-C and cisplatin (ESHAP)\tSix courses cyclophosphamide, doxorubicin, vincristine, prednisolone → complete remission → subcutaneous tumor relapsed 2002. 2003 neuro involvement intrathecal methotrexate, cytarabine and prednisolone\tSpinal surgery for tumor excision followed by local radiotherapy and chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone\tPreoperative dexamethasone followed by surgical excision of extra-axial mass at caudal clivus\t\n\t\nPrognosis\tDied 7 months after presentation\tDied 26 days after treatment initiation from multiple organ failure; autopsy revealed small periventricular and intraparenchymal mass infiltrations that caused multifocal occlusion of blood vessels\tDied 2 months after presentation\tDied 2 years after presentation\tDied 1 year after presentation\tSurgical removal of the lesion relieved the presenting symptoms but presumably also caused CSF dissemination of tumor cells resulting in secondary meningiosis with ‘possible poor prognosis’\t\nCHOP: Cyclophosphamide, doxorubicin, prednisone, and vincristine; CMV: Cytomegalovirus; CN: Cranial nerve; CSF: Cerebrospinal fluid; CT: Computed tomography; Dx: Diagnosis; EBV: Epstein-Barr virus; EPOCH: Etoposide, prednisone, doxorubicin, vincristine and cyclophosphamide; HTLV: Human T-lymphotropic virus type; IE: Single extranodal organ; LDH: Lactate dehydrogenase; Patient X: The current patient under review; RBC: Red blood cells; WNL: Within normal limits.\n\nCase discussion\nWhy this case is unique for PTCL–NOS\nPTCL–NOS metastatic on presentation with isolated CN XII involvement, extension into the dura, and an immunophenotype positive for BCL-2/c-MYC in a 25-year-old Hispanic male without EBV seropositivity or lymphadenopathy. Of the ten previously reported key prognostic factors of PTCL–NOS, the patient under review manifested seven with the exclusion of circulating tumor cells, bulky disease greater than 10 cm, and age more than 60 years [34].\n\nAge/BMI\nPTCL–NOS typically affects patients with a median age of 60 years and is twice as common in men than in women [34]. A review of the current case, in conjunction with the previously reported five other cases of PTCL–NOS with cranial nerve involvement, demonstrates a bimodal age distribution with peaks at ages 23–25 [46,47] and 56–60 years [48–50]. The patient in the current case study had a BMI of 32.89, which, per National Institute of Health standards, quantifies Class I obesity [51]. Per the Cancer Prevention Study II, the relative risk of mortality in patients with non-Hodgkin's lymphoma and a BMI between 29.9 and 39.9 is 1.50 [52].\n\nEthnicity\nThe patient under review is the only reported patient with PTCL–NOS and CNS involvement that is of Hispanic ethnicity. Two of the other five other documented cases of PTCL–NOS with CNS involvement did not report race, however, the patients in the remaining three studies were Caucasian [46,48] and Japanese [49]. According to data from the National Cancer Institute pooled from 2012 to 2014, Hispanic patients in their 20s have a 0.02% chance of being diagnosed with non-Hodgkin lymphoma in their 20s and an overall lifetime risk of 2.16% with an estimated death from cancer estimated at 0.77% [53]. Hispanics were reported to have the second to lowest risk of non-Hodgkin lymphoma diagnosis in their 20s, second to American Indians/Alaskan Natives, yet the second to the highest risk of death from non-Hodgkin lymphoma, following Caucasians [53].\n\nIsolated extranodal involvement\nThis presentation of PTCL–NOS is unique, representing the only reported case to date with isolated extranodal involvement lacking intrinsic nodal lymphadenopathy on initial presentation. Furthermore, while extranodal disease without intrinsic lymphadenopathy is a rarity in PTCL–NOS, when present it has been reported as primarily gastrointestinal and cutaneous [3]. Divergent from these previously reported sites of extranodal lymphadenopathy, the patient under review presented with lesions of the right femur, hypoglossal nerve, and dura.\n\nIsolated hypoglossal nerve involvement\nThe patient under review presented with a history of new-onset dysarthria with limited tongue protrusion, indicators of a bilateral hypoglossal nerve deficit, which retrospectively are presumed secondary to lymphoma. While there are five total reported cases of neurologic and cranial nerve involvement secondary to PTLC-NOS to our knowledge (Table 2), the present case characterizes the only presentation of isolated hypoglossal nerve involvement reported in the literature. The only other reported case of PTCL–NOS that affected the hypoglossal nerve was observed in a 57-year-old Japanese male and also simultaneously affected CN III, V, VII, VIII, X, XI [49]. Notably that case was the only other case, in addition to this current case of PTCL–NOS, with hypoglossal nerve dysfunction that displayed bone marrow involvement.\n\nThis case manifests an even more unusual presentation of the already rare lymphomatous cranial nerve involvement. In contrast to the B-cell lymphocyte usually responsible for cranial nerve involvement, a T- cell lymphocyte was the implicated cell. Aside from lymphocyte of origin, the localization of involvement to include the dura further differentiates this case from previously reported lymphomas. Although the patient in this case manifested cranial nerve involvement, it is notably differentiated from primary CNS lymphoma because the CNS was not the sole region of disease; disease burden appreciated initially in the right femur and over the course of disease progression unfortunately involved extensive metastatic bony spread with multiple resultant bony pathologic fractures.\n\nBone marrow involvement & immunophenotype\nAs previously referenced above, bone marrow involvement in non-Hodgkin lymphoma occurs in less than 50% of cases and, when present, most commonly is observed in indolent lymphomas. In contrast to the indolent nature of non-Hodgkin lymphoma with bone marrow involvement, this case of PTCL–NOS is a highly aggressive case, classified as one of the 20% of PTCL–NOS cases with bone marrow involvement. Per a review of 340 cases of PTCL–NOS, bone marrow involvement was not a strong predictor of overall survival [34].\n\nOf the five total reported cases of PTCL–NOS with CNS involvement, in addition to the current case, only one other displayed bone marrow involvement [49]. The current patient had two bone marrow biopsies over the course of his disease that, aside from the CD4 cell type present in both biopsies, featured the expression of different cellular markers. The first biopsy obtained during initial diagnosis revealed flow cytometry positive for CD3, CD4, CD5, CD8 and CD30. The second bone marrow biopsy obtained 1 month prior to death featured cells positive for CD4, CD45, BCL-2 and c-MYC.\n\nThe patient's initial bone marrow was positive for both CD4 and CD8 (markers of mature T-cell lymphomas) and CD30 (a cell surface receptor that is a member of the tumor necrosis factor family). Despite the fact that the second biopsy revealed lymphoma that did not express CD30, Brentuximab was trialed after the other treatment modalities failed to maintain remission, despite its FDA-approved use in Hodgkin lymphoma.\n\nThe second bone marrow biopsy, but not the initial biopsy, was positive for both c-MYC and BCL-2, indicating a virulent transformation. Literature review yields no other published case of human T-cell lymphoma without associated EBV infection that has an immunophenotype positive for both c-MYC and BCL-2. The only other reported case of T-cell lymphoma positive for c-MYC and BCL-2 is an extranodal NK/T-cell lymphoma nasal type associated with an EBV infection [54]. Extranodal NK/T-cell lymphoma nasal type involves the overexpression of latent membrane protein-1, which in turn stimulates expression of both MYC and BCL-2 [55]. While the immunotypic presence of both c-MYC and BCL-2 is observed in B-cell lymphomas and deemed a ‘double-hit lymphoma’, no such phenomenon has been reported to date of a non-EBV associated T-cell lymphoma.\n\nConclusion\nExtensive and significant technological advancements have enhanced the sensitivity and accuracy of the pathologic classification, diagnosis, and therapeutics of lymphomas. These advances have prompted a more comprehensive understanding of neoplastic behavior and have led to improvements in treatment and prognosis. The featured case report of PTCL–NOS is a unique presentation of a rare disease. The extranodal and metastatic presentation with initial femur involvement and interval development of diffuse dural enhancement with isolated hypoglossal nerve deficit and an immunophenotype remarkable for BCL-2 and c-MYC without associated EBV seropositivity or initial lymphadenopathy is unprecedented in the literature. Epidemiologically, PTCL–NOS with CNS involvement has not previously been reported in a young Hispanic male. The initial presentation with evidence of metastases and resistance to systemic chemotherapy, intrathecal chemotherapy, and novel immunotherapeutic techniques emphasize the aggressive nature of the disease.\n\nFuture perspective\nInnovations in biotechnology prompt the identification of cell surface receptors, cytokines, growth factors and associated genes, creating opportunities to intercept and modulate cell division. Optimistically, the aforementioned advancements and the development of immunotherapy will allow for treatment that selects solely for neoplastic tissue. Further specification and enhanced precision of immunotherapeutic targets will limit excessive cytotoxic effects on nontarget cells to achieve maximal tumor destruction with minimal effects on benign tissue growth. Prior investigations have utilized monoclonal antibodies as an adjunct to induction treatment (along with other regimens such as CHOP) as well as maintenance therapy. Further investigation is needed to deduce what effects preinduction treatment with monoclonal antibodies and/or CAR therapy would have on response to initial induction treatment, overall survival, and progression-free survival in patients with both Hodgkin and non-Hodgkin lymphoma. Clarification of optimal lymphodepletion duration and chronology for specific tumor types prior to induction of CAR therapy may improve responsiveness and lower the incidence of refractory disease.\n\n\nFinancial & competing interests disclosure\n\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nOpen access\n\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\nPapers of special note have been highlighted as: •• of considerable interest\n\n1 Swerdlow SH Campo E Harris NL WHO classification of tumours of haematopoietic and lymphoid tissues World Health Organization Classification of Tumours Bosman FT Jaffe ES Lakhani SR Ohgaki H IARC Lyon, France 2008 \n2 Swerdlow SH Campo E Pileri SA The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 20 2375 2390 2016 26980727 •• The current guidelines for the categorization of lymphomas.\n\n\n3 Freedman AS Friedberg JW Aster J Clinical presentation and diagnosis of non-Hodgkin lymphoma UpToDate, Inc. MA, USA 2017 https://pennmedaccess.uphs.upenn.edu/f5-w-68747470733a2f2f7777772e7570746f646174652e636f6d$$/contents/clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?search=non%20hodgkins%20lymphoma&source=search_result&selectedTitle=1∼150&usage_type=default&display_rank=1 \n4 Freedman AS Jacobson CA Mauch P Aster JC Chapter 103: non-Hodgkin's lymphoma DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology (10th Edition) DeVita VT Lawrence TS Rosenberg SA Lippincott Williams & Wilkins PA, USA 1552 1584 2015 \n5 Roschewski M Staudt LM Wilson WH Diffuse large B-cell lymphoma – treatment approaches in the molecular area Nat. Rev. Clin. Oncol. 11 12 23 2014 24217204 \n6 Caponetti G Bagg A Demystifying the diagnosis and classification of lymphoma: a hematologist/oncologist's guide to the hematopathologist's galaxy J. Community Support. 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"fulltext_license": "CC BY-NC-ND",
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"issue": "7(1)",
"journal": "International journal of hematologic oncology",
"keywords": "chemotherapy; hypoglossal nerve; immunotherapy; lymphoma; non-Hodgkin lymphoma; peripheral T-cell lymphoma",
"medline_ta": "Int J Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101600758",
"other_id": null,
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"pmid": "30302235",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Isolated hypoglossal nerve palsy as a presenting symptom of metastatic peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS): a unique case & a review of the literature.",
"title_normalized": "isolated hypoglossal nerve palsy as a presenting symptom of metastatic peripheral t cell lymphoma not otherwise specified ptcl nos a unique case a review of the literature"
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"abstract": "Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML.",
"affiliations": "Divisions of Infectious Diseases, Virginia Mason Medical Center, Seattle, WA, USA Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, WA, USA.;Divisions of Infectious Diseases, University of Washington, Seattle, WA, USA Hematology, University of Washington, Seattle, WA, USA hemdma@vmmc.org.",
"authors": "Malhotra|Uma|U|;Aboulafia|David M|DM|",
"chemical_list": "D006401:Hematologic Agents; D003520:Cyclophosphamide; D005169:Factor VIII",
"country": "United States",
"delete": false,
"doi": "10.1177/2325957415586259",
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"issn_linking": "2325-9574",
"issue": "15(2)",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "AIDS-associated progressive multifocal leukoencephalopathy",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D003520:Cyclophosphamide; D005169:Factor VIII; D006401:Hematologic Agents; D006467:Hemophilia A; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "109-13",
"pmc": null,
"pmid": "26013248",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy.",
"title_normalized": "cyclophosphamide treatment for acquired factor viii inhibitor in a patient with aids associated progressive multifocal leukoencephalopathy"
} | [
{
"companynumb": "US-GILEAD-2016-0209462",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "LORATADINE"
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{
"abstract": "A 77-year-old male was admitted to hospital after complaining of fever and a cough for three days. A diagnosis of multiple myeloma was confirmed following M protein identification and a bone marrow biopsy. The patient received chemotherapy regimens of bortezomib plus dexamethasone, cyclophosphamide, thalidomide and dexamethasone, and thalidomide and dexamethasone, and was prescribed thalidomide (100 mg/d) to be taken orally for maintenance therapy. After a further two years the patient was subsequently diagnosed with acute myeloid leukemia. Chemotherapy regimens of cytarabine, aclacinomycin and daunorubicin, homoharringtonine and etoposide, and mitoxantrone and cytarabine resulted in no remission. Partial remission was obtained with a course of ifosfamide, vindesine, cytarabine and prednisone chemotherapy. This therapy may be an alternative treatment for secondary leukemia, particularly in elderly patients.",
"affiliations": "Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China.;Department of Hematology, The Second Artillery General Hospital, Beijing 100088, P.R. China.;Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China.;Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China.;Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China.;Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China.",
"authors": "Shen|Man|M|;Sun|Wan-Jun|WJ|;Huang|Zhong-Xia|ZX|;Zhang|Jia-Jia|JJ|;An|Na|N|;Li|Xin|X|",
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"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2015.2867ol-09-03-1303ArticlesPartial remission of acute myeloid leukemia complicating multiple myeloma following COAP chemotherapy: A case report SHEN MAN 1*SUN WAN-JUN 2*HUANG ZHONG-XIA 1ZHANG JIA-JIA 1AN NA 1LI XIN 11 Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China2 Department of Hematology, The Second Artillery General Hospital, Beijing 100088, P.R. ChinaCorrespondence to: Dr Xin Li, Department of Hematology and Oncology, Beijing Chaoyang Hospital, Capital Medical University, 5 Jingyuan Road, Beijing 100043, P.R. China, E-mail: lixin0628@sohu.com* Contributed equally\n\n3 2015 12 1 2015 12 1 2015 9 3 1303 1306 27 2 2014 06 11 2014 Copyright © 2015, Spandidos Publications2015This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.A 77-year-old male was admitted to hospital after complaining of fever and a cough for three days. A diagnosis of multiple myeloma was confirmed following M protein identification and a bone marrow biopsy. The patient received chemotherapy regimens of bortezomib plus dexamethasone, cyclophosphamide, thalidomide and dexamethasone, and thalidomide and dexamethasone, and was prescribed thalidomide (100 mg/d) to be taken orally for maintenance therapy. After a further two years the patient was subsequently diagnosed with acute myeloid leukemia. Chemotherapy regimens of cytarabine, aclacinomycin and daunorubicin, homoharringtonine and etoposide, and mitoxantrone and cytarabine resulted in no remission. Partial remission was obtained with a course of ifosfamide, vindesine, cytarabine and prednisone chemotherapy. This therapy may be an alternative treatment for secondary leukemia, particularly in elderly patients.\n\nacute myeloid leukemiamultiple myelomapartial remissionCOAP\n==== Body\nIntroduction\nMultiple myeloma (MM) survival rates have improved significantly over the last 10 years (1–3). For example, in subsequent 10-year calendar periods, the median overall survival increased from 24.3 to 56.3 months (P=0.036) in patients ≤65 years old. With such improvements, a relatively new clinical challenge that has emerged is the risk of second malignancies. The association of acute leukemia [most frequently acute myeloid leukemia (AML)] and MM has often been reported, not only as a complication of chemotherapy, but also occurring in the absence of chemotherapy or simultaneously at the time of diagnosis (4). Prior studies have found that various therapies have made a contribution to secondary malignancies following multiple myeloma (5). The therapies included oral alkylating therapy (6–13), myeloablative therapy (used in conjunction with ASCT) (10–12), radiotherapy (14–16) and lenalidomide (17–19). There are several ongoing studies are attempting to understand the underlying mechanisms. Several studies have shown that the rate of hematological malignancy after multiple myeloma was 0.5%–12.2%. Reece and Goswami reported that the rate of MDS/AML after diagnosis of multiple myeloma of initiation of lenalidomide was 2.6%. Treatment of patients with two hematological cancers is difficult. The current study reports a case of MM complicated by AML. The patient received classic chemotherapy regimens including cytarabine, aclacinomycin, daunorubicin (CAG), mitoxantrone and cytarabine (NA) and homoharringtonine and etoposide (HE), however, did not respond to the treatment. A course of COAP chemotherapy was subsequently administered, which was selected as it is frequently used to treat AML and has been well-tolerated by patients, with few side effects. Guthrie reported that fifteen AML patients had received chemotherapy with a combination of high-dose, continuous-infusion COAP (20). The results showed that the rate of complete remission was 47% and the rate of partial remission was 40%. The main toxicity was primarily myelosuppression and there were no toxicities such as hemorrhagic cystitis or central nervous system, hepatic or pulmonary toxicity. Written informed consent was obtained from the patient’s family.\n\nCase report\nA 77-year-old male was admitted to the Department of Hematology, Peking Union Medical College Hospital (Beijing, China) on June 21st, 2011, after presenting with fever and a cough persisting for three days. Following hospitalization, laboratory tests revealed a white blood cell count of 3,900/mm3 (normal range, 4,000–10,000/mm3), a hemoglobin level of 128 g/l (normal range, 131–172 g/l), a platelet count of 54,000/mm3 (normal range, 100,000–300,000/mm3), and a serum creatinine level of 133 μmol/l (normal range, 53–115 μmol/l). Further analysis revealed a blood microglobulin level of 4.53 mg/l (normal range, 1.0–3.0 mg/l), a blood sedimentation rate of 21 mm/h (normal range, 0–20 mm/h), and M protein levels of 6.78 g/l for IgG (normal range, 7.51–15.6 g/l), 0.22 g/l for IgA (normal range, 0.82–4.53 g/l) and 0.26 g/l for IgM (normal range, 0.46–3.04 g/l). The serum free light chain (κ and λ) levels were measured as 6.52 g/l (κ) and 2.16 g/l (λ), and the total amount of κ measured in the urine was 7.5 g in 24 h. Myeloma cells accounted for 12.5% of bone marrow cytology. A bone marrow biopsy showed elevated numbers of plasma cells (12.5%). Immunohistochemistry revealed that the patient was positive for CD38, CD138, κ and epithelial membrane antigen. CD20, CD3, CD79a, Mum-1 were also positive, but scattered, and the positive rate of Ki-67 was 60%. A bone scan revealed uneven uptake of radioactive tracer in the thoracolumbar region. A diagnosis of multiple myeloma κ type light chain (Durie-Salmon stage II B, International Staging System stage III) was determined. The patient received a chemotherapeutic regimen of bortezomib (1.3 mg/m2, days 1, 4, 8 and 11) plus dexamethasone (20 mg, days 1, 4, 8 and 11) (PD) for three cycles, cyclophosphamide (500 mg, days 1–4), thalidomide (100 mg/day, every day) and dexamethasone (20 mg, days 1–4) (CTD) for one cycle, and thalidomide (100 mg/day, every day) and dexamethasone (20 mg, days 1–4) (TD) for one cycle, sequentially, where one cycle comprised 21 days. This was followed by a course of thalidomide (100 mg/d) for maintenance therapy. Blood analysis and tests of hepatorenal function and M protein levels were conducted every three months for two years, yielding normal results.\n\nIn April 2013, tests revealed a leukocyte count of 20,830/mm3 (normal range, 4,000–10,000/mm3) and a platelet count of 27,000/mm3 (normal range, 100,000–300,000/mm3), while the hemoglobin level was measured at 126 g/l (normal range, 131–172 g/l). Bone marrow examination showed clear signs of hyperplasia, with primitive granulocyte cells increasing from 1 to 74% and visible Auer’s bodies. The rate of positive peroxidase staining was 98%, which differentiated the patient’s diagnosis of AML from ALL. CD117, CD38, CD34, CD13, and HLA-DR were all positive in the immune peripheral blood classification. No FLT3/ITD, NPM1, c-kit/D816V and AML1-ETO mutations were identified in the bone marrow by immunohistochemistry. A diagnosis of AML-M2 was determined. On April 29th 2013, after receiving the CAG regimen (cytarabine, 10 mg/m2 every 12 h, days 1–14; aclarubicin, 10 mg, days 1–8; G-CSF, 200 μg/m2, days 1–14) for one cycle as induction chemotherapy, no remission (NR) was observed in the bone marrow biopsy. The patient subsequently received an additional regimen of HE (homoharringtonine, 3 mg, days 1–7; etoposide, 100 mg, days 1–7). During the entire treatment period, the patient had a respiratory infection and pleural effusion, which ultimately improved following aggressive anti-infection treatment.\n\nIn July 2013, the patient began attending the Department of Hematology and Oncology at Beijing Chaoyang Hospital (West Branch, Beijing 100043, China) for treatment. Tests revealed that myeloblasts accounted for 79% (normal range, <5%) of bone marrow cytology, while immature plasma cells accounted for 2% (normal range, <5%). This indicated that the patient now had leukemia, but that the multiple myeloma was well controlled at the same time. M protein identification and immunofixation electrophoresis (IFE) examination results indicated a polyclonal immunoglobulin, while M component was not detected. The patient’s previous medical history included tuberculosis and hemoptysis in 1956, hypertension in 2006 and a coronary computed tomography angiogram in 2010 which revealed 70% coronary stenosis. Coronary angiography and stent therapy was recommended, but the patient refused. In 2006, renal function was observed to be abnormal, with an elevated serum creatinine level of 110 μmol/l (normal range, 53–115 μmol/l). After two years, serum creatinine levels had increased to 140–150 μmol/l, while routine urine test results remained normal. In 2010, the patient was diagnosed with diabetes, cataracts and benign prostatic hyperplasia. Chemotherapy with NA (mitoxantrone, 4 mg, days 1–3; cytarabine, 100 mg, days 1–7) was accepted in July 2013 when bone marrow aspiration cytology results revealed that the high proportion of myeloblasts in the bone marrow (57%) had not yet returned to normal. On October 26th 2013, the patient began a chemotherapy cycle of ifosfamide, vindesine, cytarabine and prednisone (COAP) with ifosfamide, 0.5 g from d1 to d4 combined with vindesine, 4 mg, d1; cytarabine, 100 mg and prednisone, 50 mg every other day from d1 to d7. On November 28th 2013, a re-examination of the patient’s bone marrow indicated partial remission, with primitive cells accounting for 14.7% of all nucleated cells (>50% decrease). During this intermittent chemotherapy, the patient exhibited stable vital signs, with no fever, no cough, no sputum, and no evident abnormalities in routine blood test results. The periodic review of IFE was negative, which revealed that the patient had achieved complete remission of MM. Since November 28th, the patient continued COAP chemotherapy for three cycles. During this chemotherapy cycle, the patient exhibited fever, pancytopenia, agranulocytosis and severe anemia as a result of immunosupression induced by the chemotherapy treatment. A lung CT scan revealed pulmonary consolidation in the right upper lobe and possible lung abscess. This was treated with maxipime (2.0 g, twice a day), meropenem (0.5 g, three times a day) combined with vancomycin (1.0 g, twice a day) and teicoplanin (200 mg, twice a day). Candida albicans, detected in pathological examination of the sputum, was treated with caspofungin antifungal therapy (50 mg, once a day). Although the T spot result was negative, the lesions in the right upper lobe combined with a continuing low-grade fever led to a diagnosis of tuberculosis (TB). Isoniazid (0.3 g, once a day) and rifapentine (0.45 g, once a day) were administered orally to treat the TB. Thereafter, the patient’s fever persisted, peaking once per day. One week later, a further lung CT revealed serious pneumonia, airway obstructive pulmonary consolidation and occupying lesions. The hole-like lesions of the right upper lobe had increased markedly in size, with massive pleural effusion on the right side. Anti-inflammatory treatment was adjusted to sulperazon (3.0 g, twice a day) combined with tigecycline (50 mg, twice a day). The patient’s fever persisted throughout this period, and he subsequently succumbed to respiratory failure.\n\nDiscussion\nA number of studies have reported an increased risk of second primary malignancies (SPM) following MM diagnosis, which are proposed to be associated with novel anti-myeloma treatments (17–19). The introduction of agents such as thalidomide (5), bortezomib (21,22) and lenalidomide (17,23,24) has improved MM survival rates over the last decade. However, accurate estimates of incidence and pathogenesis of second malignancies following MM are lacking. Razavi et al (25) evaluated the risk of SPM among 36,491 MM cases reported to the surveillance, epidemiology and end results program between 1973 and 2008. The authors calculated overall and site-specific standardized incidence ratio (SIR) and 95% confidence intervals (CI) for 2,012 SPM cases diagnosed within the 35-year follow-up. No significant overall risk of SPM was identified (SIR=0.98; 95% CI=0.94–1.02).\n\nNumerous risk factors are associated with SPM, including MM disease-related factors, such as treatment and tumor microenvironment, in addition to host-related processes, such as genetic and environmental factors (26). Early observations indicated that treatment-related factors, such as from melphalan, may be the main cause of the increased incidence of myelodysplastic syndrome/acute leukemia in MM patients (13). Cyclophosphamide was found to be less leukemogenic than melphalan (27). In addition, maintenance therapy has been evaluated in relation to the risk of second malignancies in three recently reported multicenter randomized phase III trials (IFM 2005-02, CALGB 100104, and MM-015) (17–19). In the IFM 2005-02 and CALGB 100104 trials, 5.5 and 6.5% of lenalidomide-treated patients developed second malignancies, compared with 1 and 2.5% in the respective control groups.\n\nThe current study reports one case of a patient who developed AML two years after being diagnosed with MM. This patient had received velcade and ifosfamide treatment for three cycles, and continued to take thalidomide for two years thereafter. The cause of AML in this patient was unclear. Studies have reported that thalidomide may also potentiate solid SPMs (26,28). We therefore considered that thalidomide may be a cause of AML. Three clinical trials had shown that lenalidomide and thalidomide maintenance therapy could lead to a higher incidence of second primary malignancies, which is relevant to patients receiving melphalan (17–19). The patient in the present case had oral thalidomide as maintainance therapy for two years and, during this period, the patient was not adminstered any other drugs that could induce a tumor (28). The patient had taken thalidomide orally for two years prior to the diagnosis of AML and had received chemotherapy (PD, CTD, CAG and HE regimens) for seven cycles, however, complete remission was not achieved. After receiving the COAP chemotherapy regimen, the leukemia cells of the bone marrow decreased by >50% and the disease stabilized. A second cycle of COAP chemotherapy was predicted to produce CR, however, the patient subsequently acquired an obstructive pneumonia infection, which may have been associated with chemotherapy treatment. Although vigorous anti-infection treatments, including various antibiotics, antifungal agents and antituberculosis drugs, were administered, the patient succumbed to respiratory failure.\n\nThis study showed that the regimen of CA was an efficacious chemotherapy for MM combined with AML. However, the present study also indicated that the use of immunomodulatory drugs as a chemotherapy treatment may increase the risk of SPM development in older patients. Therefore, further studies are required to investigate the association between oral thalidomide and the development of AML.\n\nAcknowledgements\nThe authors would like to thank Dr Wan-jun Sun for helpful suggestions and for stimulating discussions.\n==== Refs\nReferences\n1 Turesson I Velez R Kristinsson SY Landgren O Patterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based study J Clin Oncol 28 830 834 2010 10.1200/JCO.2009.25.4177 20038719 \n2 Kumar SK Rajkumar SV Dispenzieri A Improved survival in multiple myeloma and the impact of novel therapies Blood 111 2516 2520 2008 10.1182/blood-2007-10-116129 17975015 \n3 Kristinsson SY Landgren O Dickman PW Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003 J Clin Oncol 25 1993 1999 2007 10.1200/JCO.2006.09.0100 17420512 \n4 Dunkley S Gibson J Iland H Li C Joshua D Acute promyelocytic leukaemia complicating multiple myeloma: evidence of different cell lineages Leuk Lymphoma 35 623 626 1999 10.1080/10428199909169629 10609802 \n5 Morgan GJ Davies FE Gregory WM Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment Clin Cancer Res 19 6030 6038 2013 10.1158/1078-0432.CCR-12-3211 23995858 \n6 Bergsagel DE Bailey AJ Langley GR The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia N Engl J Med 301 743 748 1979 10.1056/NEJM197910043011402 481481 \n7 [No Authors Listed] Acute leukaemia and other secondary neoplasms in patients treated with conventional chemotherapy for multiple myeloma Eur J Haematol 65 123 127 2000 10.1034/j.1600-0609.2000.90218.x 10966173 \n8 Dong C Hemminki K Second primary neoplasms among 53,159 haematolymphoproliferative malignancy patients in Sweden, 1958–1996: a search for common mechanisms Br J Cancer 85 997 1005 2001 10.1054/bjoc.2001.1998 11592772 \n9 Hasskarl J Ihorst G De Pasquale D Association of multiple myeloma with different neoplasms: systematic analysis in consecutive patients with myeloma Leuk Lymphoma 52 247 259 2011 10.3109/10428194.2010.529207 21054148 \n10 Barlogie B Tricot G Haessler J Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989 Blood 111 94 100 2008 10.1182/blood-2007-06-097444 17895401 \n11 Przepiorka D Buadi F McClune B Myelodysplastic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma Bone Marrow Transplant 40 759 764 2007 10.1038/sj.bmt.1705814 17680015 \n12 Govindarajan R Jagannath S Flick JT Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma Br J Haematol 95 349 353 1996 10.1046/j.1365-2141.1996.d01-1891.x 8904891 \n13 Cuzick J Erskine S Edelman D Galton DA A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis. A report to the Medical Research Council’s working party on leukaemia in adults Br J Cancer 55 523 529 1987 10.1038/bjc.1987.107 3300761 \n14 Featherstone C Delaney G Jacob S Barton M Estimating the optimal utilization rates of radiotherapy for hematologic malignancies from a review of the evidence: part II leukemia and myeloma Cancer 103 393 401 2005 10.1002/cncr.20755 15593373 \n15 Berrington de Gonzalez A Curtis RE Kry SF Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries Lancet Oncol 12 353 360 2011 10.1016/S1470-2045(11)70061-4 21454129 \n16 Berrington de Gonzalez A Curtis RE Gilbert E Second solid cancers after radiotherapy for breast cancer in SEER cancer registries Br J Cancer 102 220 226 2010 10.1038/sj.bjc.6605435 19935795 \n17 Attal M Cances-Lauwers V Maintenance treatment with lenalidomide after transplantation for myeloma: analysis of secondary malignancies within the IFM 2005-02 trial 13th International Myeloma Workshop 2011 Paris, France \n18 McCarthy P Anderson K Phase III Intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma CALGB ECOG BMT-CTN 100104 13th International Myeloma Workshop 2011 Paris, France \n19 Palumbo AP Catalano J Incidence of second primary malignancy in melphalan-prednisone-lenalidomide combination followed by lenalidomide maintenance in newly diagnosed multiple myeloma patients age 65 or older [abstract] J Clin Oncol 29 2011 \n20 Guthrie TH Jr High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia Cancer 59 1255 1257 1987 10.1002/1097-0142(19870401)59:7<1255::AID-CNCR2820590704>3.0.CO;2-S 3815301 \n21 Nooka AK Kaufman JL Behera M Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials Cancer 119 4119 4128 2013 10.1002/cncr.28325 24005889 \n22 Richardson PG Schlossman RL Alsina M PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma Blood 122 2331 2337 2013 10.1182/blood-2013-01-481325 23950178 \n23 Gay F Hayman SR Lacy MQ Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients Blood 115 1343 1350 2010 10.1182/blood-2009-08-239046 20008302 \n24 Dimopoulos MA Delforge M Hájek R Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial Haematologica 98 784 788 2013 10.3324/haematol.2012.074534 23242595 \n25 Razavi P Rand KA Cozen W Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics Blood Cancer J 28 e121 2013 10.1038/bcj.2013.19 23811785 \n26 Thomas A Mailankody S Korde N Second malignancies after multiple myeloma: from 1960s to 2010s Blood 119 2731 2737 2012 10.1182/blood-2011-12-381426 22310913 \n27 Greene MH Harris EL Gershenson DM Melphalan may be a more potent leukemogen than cyclophosphamide Ann Intern Med 105 360 367 1986 10.7326/0003-4819-105-3-360 3740675 \n28 Usmani SZ Sexton R Hoering A Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance Blood 20 1597 1600 2012 10.1182/blood-2012-04-421883 22674807\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1792-1074",
"issue": "9(3)",
"journal": "Oncology letters",
"keywords": "COAP; acute myeloid leukemia; multiple myeloma; partial remission",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1303-1306",
"pmc": null,
"pmid": "25663902",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "23950178;3815301;3300761;22674807;20008302;17895401;10609802;481481;22310913;23811785;21454129;24005889;20038719;15593373;11592772;17680015;23242595;17420512;10966173;23995858;21054148;8904891;3740675;17975015;19935795",
"title": "Partial remission of acute myeloid leukemia complicating multiple myeloma following COAP chemotherapy: A case report.",
"title_normalized": "partial remission of acute myeloid leukemia complicating multiple myeloma following coap chemotherapy a case report"
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"abstract": "Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy.\n\n\n\nRetrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy.\n\n\n\nClassical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes.\n\n\n\nMost patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.",
"affiliations": "From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.;From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands. m.titulaer@erasmusmc.nl.",
"authors": "Muñoz-Lopetegi|Amaia|A|;de Bruijn|Marienke A A M|MAAM|;Boukhrissi|Sanae|S|;Bastiaansen|Anna E M|AEM|;Nagtzaam|Mariska M P|MMP|;Hulsenboom|Esther S P|ESP|;Boon|Agnita J W|AJW|;Neuteboom|Rinze F|RF|0000-0001-6136-4981;de Vries|Juna M|JM|;Sillevis Smitt|Peter A E|PAE|;Schreurs|Marco W J|MWJ|;Titulaer|Maarten J|MJ|0000-0002-1033-3840",
"chemical_list": "D001323:Autoantibodies; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2",
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000696",
"fulltext": "\n==== Front\nNeurol Neuroimmunol Neuroinflamm\nNeurol Neuroimmunol Neuroinflamm\nnnn\nNEURIMMINFL\nNeurology® Neuroimmunology & Neuroinflammation\n2332-7812 Lippincott Williams & Wilkins Hagerstown, MD \n\n32123047\nNEURIMMINFL2019025817\n10.1212/NXI.0000000000000696\n132\n132\n132\n163\n303\nArticle\nNeurologic syndromes related to anti-GAD65\nClinical and serologic response to treatmentMuñoz-Lopetegi Amaia MD de Bruijn Marienke A.A.M. MD Boukhrissi Sanae BSc Bastiaansen Anna E.M. MD Nagtzaam Mariska M.P. BSc Hulsenboom Esther S.P. BSc Boon Agnita J.W. MD, PhD http://orcid.org/0000-0001-6136-4981Neuteboom Rinze F. MD, PhD de Vries Juna M. MD, PhD Sillevis Smitt Peter A.E. MD, PhD Schreurs Marco W.J. PhD http://orcid.org/0000-0002-1033-3840Titulaer Maarten J. MD, PhD From the Department of Neurology (A.M.-L., M.A.A.M.d.B., A.E.M.B., M.M.P.N., E.S.P.H., A.J.W.B., R.F.N., J.M.d.V., P.A.E.S.S., M.J.T.) and Department of Immunology (S.B., M.W.J.S.), Erasmus MC University Medical Center; Department of Neurology (A.M.-L.), IDIBAPS, Barcelona, Spain; and Health Care Provider of the European Reference Network on Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA) (M.J.T.), Rotterdam, the Netherlands.\nCorrespondence Dr. Titulaer m.titulaer@erasmusmc.nlGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\nThe Article Processing Charge was funded by Erasmus University.\n\n\n5 2020 \n02 3 2020 \n02 3 2020 \n7 3 e69625 11 2019 13 1 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.2020American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Objective\nAntibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy.\n\nMethods\nRetrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy.\n\nResults\nClassical anti–GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%–99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes.\n\nConclusion\nMost patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.\n\nOPEN-ACCESSTRUE\n==== Body\nAutoantibodies against glutamic acid decarboxylase (GAD) 65 have been linked to different types of syndromes. These antibodies are widely used as biomarkers for diabetes mellitus type 1 (DM1) diagnosis because they are present in 80% of patients at diagnosis.1,2 However, it is well known that anti-GAD65 can also be associated with specific neurologic disorders, including stiff-person syndrome (SPS), cerebellar ataxia (CA), epilepsy (Ep), and limbic encephalitis (LE).3–6\n\nThe pathophysiologic role of anti-GAD65 in neuroinflammation is still unclear. It is hard to understand whether there is a direct antibody-associated pathogenic effect because the target antigen is located intracellularly. Moreover, responses to immunotherapy seem to be poorer than in patients with neurologic disorders caused by most other antineuronal antibodies.7,8\n\nIn studies evaluating treatment effects in anti–GAD65-positive patients, methods used are variable, and patient cohorts are often restricted to one of the specific clinical phenotypes.9–11 In addition, some studies describing patients with neurologic symptoms and anti-GAD65 also include patients with low antibody concentrations. In these patients, clinical relevance of anti-GAD65 is questionable because low antibody concentrations are regularly found among patients with DM1 (without neurologic symptoms) and rarely in healthy individuals.1,2,12\n\nThe aim of this cohort study is to evaluate the clinical relevance of low and high anti-GAD65 concentrations in patients with neurologic symptoms, to establish clinically relevant cutoff values (in serum and CSF), and to evaluate clinical and serologic treatment responses.\n\nMethods\nPatients\nWe retrospectively included patients with neurologic symptoms and an increased anti-GAD65 concentration detected in serum and/or CSF, from January 2015 until June 2018. Anti-GAD65 was routinely detected at the Department of Immunology (Laboratory Medical Immunology) of the Erasmus University Medical Center by using ELISA and reported as negative or positive. Clinical information was obtained from medical files. Thirty of 56 patients (54%) were seen by one of the authors.\n\nStandard protocol approvals, registrations, and patient consents\nThe institutional review board of the Erasmus University Medical Center approved the study protocol. Written informed consent was obtained from all patients.\n\nLaboratory tests\nAnti-GAD65 was determined in serum and CSF when available, using 3 assays. Paired serum and CSF samples were used if possible. Otherwise, serum samples drawn closest to the CSF tap were used, provided they were preimmunotherapy samples. First, automated quantitative ELISA was performed according to the manufacturer's instructions (Medizym anti-GAD; Medipan, Berlin, Germany). Calibration curves based on 5 calibrators (5, 18, 35, 120, and 250 IU/mL) were used to infer antibody concentrations. Samples were considered positive with anti-GAD65 concentrations above 5 IU/mL. When concentrations were over 250 IU/mL, we tested serial dilutions (1:10; 1:100; 1:1,000; 1:10,000) and chose the most reliable result (i.e., optical density value in the linear part of the calibration curve) to determine the IU/mL end concentration. Second, immunohistochemistry (IHC) was used as a screening method to determine immunoreactivity of patients' serum (diluted 1:200) or CSF (diluted 1:2) against rat hippocampal brain tissue. A detailed description can be found elsewhere.13 GAD65 antibody binding causes a characteristic staining pattern.13 Finally, cell-based assay (CBA) (Euroimmun, Lübeck, Germany; REF: FA 1022-1005-50) was performed according to the manufacturer's instructions, using human embryonal kidney cells (HEK293) expressing recombinant GAD65. Serum was diluted 1:10, and CSF was used undiluted.\n\nELISA provided quantitative results. IHC and CBA were used as confirmatory qualitative techniques to determine clinically relevant cutoff values for serum and CSF. Samples positive by ELISA and confirmed with positive IHC and CBA were considered high-concentration samples.14 Samples showing a positive staining pattern on IHC, but no typical GAD pattern, were tested more extensively with commercial and in-house CBAs using fixed or live cells (Euroimmun kits and in-house CBAs).\n\nDefining clinical phenotypes and clinical relevance of anti-GAD65\nPatients were allocated into 6 groups based on the clinical phenotypes described in the literature: (1) SPS, (2) CA, (3) Ep, (4) LE, (5) overlap, and (6) other. The overlap category consisted of patients who had developed more than 1 anti–GAD65-associated neurologic syndrome over the disease course. Patients with LE, presenting with seizures or developing seizures following LE, were not considered as overlap syndromes and were all classified as LE.\n\nAfter determining cutoff values, patients were classified into a high-concentration or low-concentration group. Patients in the high-concentration group were studied more thoroughly to assess clinical and serologic response to immunotherapy. Immunotherapy responses were evaluated by one of the authors during follow-up or were retrospectively assessed from medical files. A seizure frequency reduction of at least 50% was considered as improvement in patients with Ep. For the other clinical phenotypes, the modified Rankin Scale (mRS) score and the Scale for the Assessment and Rating of Ataxia (SARA) score were used,15,16 when available. One-point improvement in the mRS score or 3 points at the SARA score was considered clinically relevant. In the absence of absolute scores, patients' and physicians' evaluations, as measured by the clinical global impression—improvement scale,17 were taken into account.\n\nSerologic response to treatment was measured comparing pre- and post-immunotherapy ELISA antibody concentrations. A reduction of at least 25% following immunotherapy was considered a relevant concentration reduction.\n\nPatients with isolated DM1\nTo explore the spectrum of concentrations of anti-GAD65 antibodies, we also assessed patients with DM1 without neurologic symptoms. At the Department of Immunology of the Erasmus University Medical Center, sera from 669 patients were tested for anti-GAD65 between January 2018 and December 2018. As the reason for testing was often unknown, filtering based on additional antibody testing for Islet Cell Cytoplasmic Autoantibodies (ICA) or tyrosine phosphatase antibodies (anti-IA2) was performed. This way, we selected samples from 198 patients that were sent specifically for a suspicion of insulin-dependent diabetes mellitus because neurologists would not request additional islet antigen antibodies. Seventy-three samples (37%) tested positive for anti-GAD65. Of these, 37 were analyzed more extensively with quantitative ELISA, IHC, and CBA. Patients with high concentrations and positive IHC and CBA (n = 3) were approached to identify associated neurologic disorders, of whom 2 could be traced.\n\nStatistics\nThe Fisher exact test was used to compare categorical variables between the high-concentration and low-concentration groups. Age, CSF cell count, and protein count were compared with the Mann-Whitney U test. To compare antibody tests, the McNemar test was used. p Values less than 0.05 were considered significant. We used SPSS 24.0 and Graph Path 7.0 for analysis and data visualization.\n\nData availability\nAny data not published within this article are available at the Erasmus University Medical Center. Patient-related data will be shared on request from any qualified investigator, maintaining anonymization of the individual patients.\n\nResults\nLaboratory tests\nWe identified 71 patients with neurologic symptoms and at least 1 positive serum or CSF anti-GAD65 test result, of whom 56 were included in our study. Eleven patients could not be reached to collect informed consent, and 4 patients refused to participate.\n\nThe median serum concentration measured with ELISA was 74,700 IU/mL (n = 54; interquartal range [IQR] 1,350–612,500 IU/mL; range 6–2,130,000 IU/mL), and the median CSF concentration was 2,430 IU/mL (n = 43; IQR 6–8,810 IU/mL; range 0–83,800 IU/mL). Serum and CSF samples were drawn a median of 25 months (IQR 6–69 months) and 19 months (IQR 1–69 months) after symptom onset, respectively.\n\nIHC and CBA showed a high concordance (figure 1). A cutoff of 100 IU/mL showed a 100% concordance among tests in CSF. For serum, with a cutoff value of 10,000 IU/mL, 100% of low-concentration samples had a negative IHC, and 97% of high-concentration samples had a positive IHC. Similarly, 100% of high-concentration samples were positive with CBA, and 96% of low-concentration samples were negative. All CBAs and IHCs corresponded, except 3 diabetes samples with positive CBA and negative IHC. In those 3 samples, ELISA concentrations were between 6,220 and 15,400 IU/mL. Samples with an unspecific neuropil staining on IHC were excluded for calculations. Other antibodies were found in 1 patient in the high anti-GAD65 concentration (anti-gamma-aminobutyric acid B receptor [GABAbR]) and 2 patients with low anti-GAD65 concentration (1 anti-GABAbR and 1 anti-GlyR).\n\nFigure 1 Comparison of laboratory techniques\nELISA concentrations of serum (A and B) and CSF (A and D) of patients with neurologic disorders in comparison to IHC and CBA. Patients identified with dark gray and yellow squares in A showed a neuropil staining on IHC, instead of the typical GAD pattern. Samples with a neuropil staining and high ELISA concentration had a positive GAD65-CBA result, whereas CBA was negative for low-concentration samples (A). In B and D, dark gray and yellow dots are used in both IHC and CBA columns to identify these samples. In the dark gray dotted patients, a different antibody was found. Serum or CSF of the yellow dotted patients showed a neuropil staining, but no known antibody was found. Serum results from patients with antibody testing for diabetes (DM-1) are shown (C). Logarithmic transformation was used for charts. Concordance rates for ELISA, IHC, and CBA are provided for serum and CSF (E). CBA = cell-based assay; GAD = glutamic acid decarboxylase; IHC = immunohistochemistry.\n\nIn the DM1 group without overt neurologic symptoms, the median serum concentration of 68 patients with DM1 (35% of 192 samples) was 86 IU/mL (IQR 51–3,670 IU/mL; range 15–145,400 IU/mL). Three samples (1.6%) showed an anti-GAD65 concentration >10,000 IU/mL and also tested positive by IHC and CBA. The 2 patients traceable had DM1.One also had multiple other autoimmunities (vitiligo, idiopathic thrombocytopenic purpura, and thyroiditis), but in both patients, no neurologic or psychiatric symptoms were present.\n\nPatients\nThirty-six patients were allocated into the high-concentration group (serum concentration >10,000 IU/mL or CSF concentration >100 IU/mL) and 20 patients into the low-concentration group. Clinical characteristics are shown in table 1.\n\nTable 1 Clinical and paraclinical characteristics of the high-concentration and low-concentration groups\n\nIn the high-concentration group, 34/36 (94%) patients had a typical anti–GAD-associated neurologic syndrome: SPS (n = 7), CA (n = 3), Ep (n = 9), LE (n = 9), or an overlap syndrome (n = 6). In the overlap group, 4 patients initially had drug-resistant focal Ep and developed CA, SPS, or a combination of both between 2 and 7 years after seizure onset (figure 2). One patient initially had CA and developed SPS 5 years later, and 1 SPS patient developed prominent cerebellar symptoms 7 years after onset. One patient with LE, no seizures and associated extralimbic involvement in MRI, had concomitant GABAbR antibodies, without a tumor. Of the remaining 2 patients, both with DM type 2, one had a pseudo-orthostatic tremor, and the other one had optic neuropathy.\n\nFigure 2 Patients treated with immunotherapy\nDisease courses and treatment regimens of the 27 patients that were treated with immunotherapy. In patients with overlapping syndromes, the specific syndromes are indicated below the gy bar with the corresponding color at the relative time when they were diagnosed. Symbols inside the color bars show specific treatments or the moment they were initiated. A line with the same color is used for chronic (continuous line) and periodic (discontinuous line) treatments to show their duration. Symbols on the left side correspond to those in Figure 5.\n\nIn the low-concentration group, 12/20 patients had an alternative diagnosis, including 1 LE with anti-GABAbR and a pancreatic adenocarcinoma and 1 progressive encephalomyelitis with rigidity and myoclonus with anti-GlyR without an associated tumor, different variants of subacute or chronic polyradiculoneuropathies, and other non–immune-mediated diseases (glioblastoma, hemispastic syndrome after brain surgery, multiple system atrophy, or functional disorder). The remaining 8 patients had chronic Ep, otherwise seronegative LE or nonspecific ataxia and gait disorder (see table e-1, links.lww.com/NXI/A209).\n\nFigure 3 shows patients distributed according to their clinical phenotype and antibody concentration in serum and CSF. The median concentrations of the different clinical phenotypes (in the high-concentration group) were comparable in serum (p = 0.210) and CSF (p = 0.067). No association was found between concentration levels and clinical severity between patients (data not shown).\n\nFigure 3 Antibody concentrations and clinical syndromes\nPatients were grouped according to their clinical phenotype into 1 of the 4 classical anti–GAD65-associated syndrome categories, in the overlap or other category. Serum (A) and CSF (B) ELISA concentrations are shown in a logarithmic scale. Small black dots represent patients with low antibody concentrations. The specific symptoms of these patients are listed in the supplementary material. Orange dots in the SPS column were patients with progressive encephalomyelitis with rigidity and myoclonus, which is considered an extended form of SPS. (C) Serum/CSF ratio of anti-GAD65 ELISA values within the different syndromes in the high-concentration group. The blue ribbon represents the ratio-frame where intrathecal antibody synthesis would be expected to start. CA = cerebellar ataxia; Ep = epilepsy; GAD = glutamic acid decarboxylase; LE = limbic encephalitis; SPS = stiff-person syndrome.\n\nWithin the high-concentration group, the median serum/CSF anti-GAD65 ratio was 53 (IQR 171; range 7–1,761, n = 28). After excluding overlaps, there were no significant ratio differences between the clinical syndromes (p = 0.29), although the median ratio of SPS was more than 2-fold that of the other phenotypes (figure 3C).\n\nTwenty-seven patients from the high-concentration group were treated with immunotherapy, of them 26 (96%) received IV immunoglobulins (IVIg) in different treatment regimes. Most used regime was 0.4 g/kg for 5 days, repeated monthly for at least 2 more times, to assess response. Eight patients (30%) were treated with IV methylprednisolone, and 3 patients received plasma exchange. Four patients were additionally treated with second-line immunotherapy, including rituximab (n = 3) and cyclophosphamide (n = 1). Chronic immunosuppression was given in 11 patients, consisting of combinations of azathioprine (n = 9), oral steroids (n = 8), mycophenolate mofetil (n = 5), and cyclosporine (n = 1). Figure 2 shows individual timelines of the high-concentration group patients treated with immunotherapy. Nineteen patients (70%) improved. Eight of 10 patients with SPS (including patients with overlap syndromes) improved according to themselves and their physicians, accompanied by the mRS score decrease in 7 of them (table 2). All patients with CA (including patients with overlap syndromes) except one felt better and obtained a reduction in the mRS score. SARA scores improved ≥3 points in the only 2 patients in whom scores were available. In patients with chronic Ep, >50% seizure frequency reduction was obtained in 4 of 7 patients. Immunotherapy was efficacious in 5 of 7 patients with LE, and 2 of them had relapses despite chronic treatment. Those 2 responded to more intensive therapies. Four typical patient examples are provided in figure 4.\n\nTable 2 Effects of immunotherapy in patients with high antiglutamic acid decarboxylase 65 concentrations\n\nFigure 4 Disease course and treatment response of 4 patients in the high-concentration group\nHorizontal bars containing treatment abbreviations represent the time periods of the corresponding treatments. Blue vertical lines represent seizure frequency over time. Green discontinuous line connected by green circles shows evolution of serum anti-GAD65 concentration. Thick dark-blue line connected by rhomboids represents functional status over time, according to the visual score at the right most part of the charts. AED = antiepileptic drug; AZA = azathioprine; GAD = glutamic acid decarboxylase; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; MMF = mycophenolate mofetil; PDN = prednisone; RTX rituximab.\n\nIn 17/36 high concentration patients, pre- and post-treatment samples were available for comparison. Antibody concentrations showed a median concentration reduction of 69% (range 27%–99%), and decrease was over 25% in 15 of the 17 serum samples after immunotherapy (figure 5). A clear clinical response was observed in 14 of these 15 treated patients. The 2 patients without consistent decrease in concentration showed no clinical improvement. Both had focal Ep for years.\n\nFigure 5 Antibody concentration response to immunotherapy\nConcentration responses to treatment of the 17 patients of whom pretreatment and posttreatment samples were available. Red lines represent the patients lacking clinical improvement. The blue dashed line in the right graph represent CSF samples obtained pretreatment and at clinical relapse. A reduction of at least 25% following immunotherapy was considered a relevant concentration reduction. GAD = glutamic acid decarboxylase.\n\nIn none of the patients, complete recovery was reached. Similarly, in none of the patients, antibodies disappeared in serum. In 6/17 patients with pre- and post-treatment samples, serum concentrations became lower than 10.000 IU/mL. Despite periodic or chronic immunotherapy, a stagnation, both clinically and serologically, was observed after initial improvement. However, after withdrawal or tapering of immunotherapy symptoms deteriorated, syndromes relapsed, or concentrations increased in 6 patients (figure 2 and figure 4). Four patients also had relapses or clinical worsening despite stable chronic or periodic immunotherapy.\n\nDiscussion\nThis study aimed to determine the clinical relevance of GAD65 antibodies in patients with neurologic syndromes and evaluate their responses to immunotherapy. We showed that patients with high anti-GAD65 concentrations presented with a limited number of specific neurologic syndromes, whereas the neurologic symptoms observed in patients with low concentrations were less specific, necessitating additional investigations. The laboratory tests used showed a high concordance and a clear cutoff value for the high and low antibody concentrations. Around two thirds of the patients responded to immunotherapy, although all incompletely. The clinical improvement was reflected in the reduction of anti-GAD65 concentrations in both serum and CSF.\n\nPatients with high antibody concentrations had well-defined clinical phenotypes that have been classically associated with GAD65 antibodies, such as stiff-person syndrome, CA, Ep, or LE. In addition, 1 of 5 patients had overlap syndromes. Remarkably, in these patients, the relapse tended to present with different phenotypes. Another interesting feature was a different, not previously described phenotype, including pseudo-orthostatic tremor and optic neuropathy in 2 patients in the high-concentration group. Unfortunately, these 2 patients were not seen by one of the authors, so diagnosis and absence of more typical symptoms should be taken with caution.\n\nFrom a different perspective, patients with low antibody concentrations presented with a diversity of neurologic syndromes. Some of them had a phenotype that is similar to the classically anti–GAD65-associated syndromes, which was probably the reason why anti-GAD65 was requested in these patients. However, frequently other diagnoses were identified in the workup or during the follow-up, like neurodegenerative diseases or tumors. In these cases, positive ELISA was not confirmed by IHC or CBA, and concentrations were low and comparable to those seen in samples tested for type 1 diabetes mellitus. In these patients, extensive workup to identify other diseases is warranted, including requesting other antibodies. Anti-GABAbR antibodies were identified in a few patients with high and low concentrations of GAD65 antibodies, in line with previous studies.18 Around 40% of the patients in both high- and low-concentration groups had been diagnosed with type 1 DM before the onset of neurologic symptoms, which is also in line with previous studies.19–22\n\nTo define which antibody concentration should be considered high and relevant, we compared 3 different laboratory techniques and found highly concordant results. ELISA concentrations above 10,000 IU/mL for serum and 100 IU/mL for CSF can be detected by IHC and CBA, with comparable results. CBA, as expected, is more specific, especially if a different antibody is concomitantly present in the tested sample (leading to an unspecific IHC staining pattern). Another cutoff value (of 2,000) has been suggested before,13,23 but these studies used a radioimmunoassay with different test calibration, currently not widely used anymore.\n\nThe role of GAD65 antibodies in neuroinflammation is debatable and still unknown. An obvious theory would be that antibodies block GAD65, interfering with GABA synthesis and impairing the inhibitory GABAergic circuits. This would result in a hyperexcitability state of the CNS. There are studies supporting this theory, demonstrating a reduced GABA concentration in the CSF and in the cerebral cortex of patients with SPS.24,25 However, GAD65 is located intracellularly and as such not accessible for extracellular antibodies. As an explanation, it has been hypothesized that GAD65 might transiently appear on the cell surface in the synaptic cleft during the process of neurotransmission and exocytosis.26 In rats, in vivo injection of GAD65 antibodies from patients with SPS induced electrophysiologic changes in myelinated neurons, whereas GAD65 antibodies from patients with DM1 did not.27 On the other hand, injection of GAD65-specific T cells in mice caused death even in mice without B cells.28 This suggests that the mechanism might be comparable to paraneoplastic syndromes, in which T cell–mediated responses primarily lead to symptoms.29 Similarly, despite several efforts, there are no convincing successful animal models to support the pathogenicity of GAD65 antibodies.\n\nMoreover, studies report poor responses to immunotherapy targeting different GAD syndromes,6,11,30 as compared to other neurologic disorders caused by antibodies targeted to extracellular neuronal structures, again questioning the direct pathogenic role of anti-GAD65. Although the mechanisms remain questionable, our results revealed that many patients show improvement after immunotherapy (mostly IVIg), coupled to a simultaneous concentration decrease. Many patients improve not immediately after initiating treatments but might need some months of treatment before improvement. This might explain some lack of treatment response from the literature. Repeated doses or combinations of different treatments might be considered before classifying a patient as a nonresponder. Nevertheless, some of the patients do not respond at all to immunotherapy. In addition, it is humbling that even in responders, improvement is generally incomplete, and often patients have stagnation in both the clinical and the serologic response after a few months with chronic immunotherapy. Unfortunately, no patient completely recovered. A possible explanation might be a combination of functional and structural neuronal damage, as different research groups have demonstrated in CA.9,30,31 Immunotherapy helps to restore cell function, but cell death is nonreversible.\n\nDespite clinical stabilization with immunotherapy, treatment intensity reductions or withdrawals frequently result in clinical progression (in CA) or relapses (in SPS, LE, and Ep). A few patients have relapses despite stable chronic immunotherapy. Fortunately, these patients usually respond to more intense treatments.\n\nThe limitations of this study are mainly linked to its retrospective design. In addition, not all patients were seen by one of the authors. Accordingly, it was sometimes difficult to assess outcome after treatment. Objective parameters such as mRS score, SARA score, and seizure frequency were used when applicable. As treatments were open label, a placebo effect or regression to the mean could explain part of the results. However, most patients had stable (or slowly progressive) disease for a longer period and showed a serious deviation from the time course before. Similarly, the association with concentrations also suggests some real effects. For future studies, it would be of additional value to study treatment outcome prospectively by using standardized questionnaires, examinations, serologic follow-up, and neuropsychological assessments.\n\nTo summarize, in patients with classical syndromes (stiff-person, CA, and encephalitis with seizures), detection of high concentrations of anti-GAD65 is practically diagnostic of an anti–GAD65-related syndrome. However, depending on the syndrome (e.g., LE), physicians should consider the possibility of concurrent antibodies, such as GABAbR. These classical syndromes should be treated with prolonged immunotherapy (as the current study suggests). On the other hand, the presence of atypical syndromes (or nonspecific encephalitic syndromes with seizures) or a typical syndrome but with low-concentration anti-GAD65 should raise concern for another underlying disease (anti-GAD65 as bystanders). In these patients, more extensive investigations for alternative diagnoses should be considered.\n\nAcknowledgment\nThe authors thank all patients for their participation. They thank all referring physicians. A. Muñoz-Lopetegi received a Research Experience Fellowship grant from the European Academy of Neurology (EAN) for this research project. Authors R.F. Neuteboom, J.M. de Vries, M.W.J. Schreurs, P.A.E. Sillevis Smitt, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases–Project ID No 739543.\n\nStudy funding\nA. Muñoz-Lopetegi was supported by the EAN Experience Fellowship from the European Academy of Neurology. M.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), from the Dutch Epilepsy Foundation (NEF, project 14-19), and from ZonMw (Memorabel program).\n\nDisclosure\nA. Muñoz-Lopetegi, M.A.A.M. de Bruijn, S. Boukhrissi, A.E.M. Bastiaansen, M.M.P. Nagtzaam, E.S.P. Hulsenboom, A.J.W. Boon, R.F. Neuteboom, J.M. de Vries, and M.W.J. Schreurs report no disclosures relevant to the manuscript. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. M.J. Titulaer received research funds for serving on a scientific advisory board of MedImmune LLC and a travel grant for lecturing in India from Sun Pharma, India. M.J. Titulaer has filed a patent for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, and an unrestricted research grant from Euroimmun AG. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\n\nGlossary\nCAcerebellar ataxia\n\nCBAcell-based assay\n\nEpepilepsy\n\nGADglutamic acid decarboxylase\n\nIHCimmunohistochemistry\n\nIVIgIV immunoglobulin\n\nLElimbic encephalitis\n\nmRSmodified Rankin Scale\n\nSARAScale for the Assessment and Rating of Ataxia\n\nSPSstiff-person syndrome\n==== Refs\nReferences\n1. Solimena M , de Camilli P , Blake R , et al \nAutoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus\n. Trends Neurosci \n1991 ;14 :452 –457\n.1722364 \n2. Sigurdsson E , Baekkeskov S \nThe 64-kDa beta cell membrane autoantigen and other target molecules of humoral autoimmunity in insulin-dependent diabetes mellitus\n. Curr Top Microbiol Immunol \n1990 ;164 :143 –168\n.2073783 \n3. Giometto B , Miotto D , Faresin F , Argentiero V , Scaravilli T , Tavolato B \nAnti-GABAergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia\n. J Neurol Sci \n1996 ;143 :57 –59\n.8981298 \n4. Peltola J , Kulmala P , Isojärvi J , et al \nAutoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy\n. Neurology \n2000 ;55 :46 –50\n.10891904 \n5. Honnorat J , Saiz A , Giometto B , et al \nCerebellar ataxia with anti–glutamic acid decarboxylase antibodies\n. Arch Neurol \n2001 ;58 :225 .11176960 \n6. Malter MP , Helmstaedter C , Urbach H , Vincent A , Bien CG \nAntibodies to glutamic acid decarboxylase define a form of limbic encephalitis\n. Ann Neurol \n2010 ;67 :470 –478\n.20437582 \n7. Mckeon A , Robinson MT , Mcevoy KM , et al \nStiff-man syndrome and variants clinical course, treatments, and outcomes\n. Arch Neurol \n2012 ;69 :230 –238\n.22332190 \n8. Martinez-Hernandez E , Ariño H , McKeon A , et al \nClinical and immunologic investigations in patients with stiff-person spectrum disorder\n. JAMA Neurol \n2016 ;73 :714 –720\n.27065452 \n9. Ariño H , Gresa-Arribas N , Blanco Y , et al \nCerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy\n. JAMA Neurol \n2014 ;71 :1009 –1016\n.24934144 \n10. Dalakas MC , Rakocevic G , Dambrosia JM , Alexopoulos H , McElroy B \nA double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome\n. Ann Neurol \n2017 ;82 :217 –277\n.\n11. Malter MP , Frisch C , Zeitler H , et al \nTreatment of immune-mediated temporal lobe epilepsy with GAD antibodies\n. Seizure \n2015 ;30 :57 –63\n.26216686 \n12. Baekkeskov S , Aanstoot H , Christgau S , et al \nIdentification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase\n. Nature \n1900 ;347 :151 –156\n.\n13. Saiz A , Arpa J , Sagasta A , et al \nAutoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity\n. Neurology \n1997 ;49 :1026 –1030\n.9339684 \n14. Saiz A , Blanco Y , Sabater L , et al \nSpectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association\n. Brain \n2008 ;131 :2553 –2563\n.18687732 \n15. Quinn TJ , Dawson J , Walters MR , Lees KR \nFunctional outcome measures in contemporary stroke trials\n. Int J Stroke \n2009 ;4 :200 –205\n.19659822 \n16. Weyer A , Abele M , Schmitz-Hübsch T , et al \nReliability and validity of the scale for the assessment and rating of ataxia: a study in 64 ataxia patients\n. Mov Disord \n2007 ;22 :1633 –1637\n.17516493 \n17. Guy W \nECDEU Assessment Manual for Psychopharmacology . Rockville : US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs ; 1976 .\n18. Höftberger R , Titulaer MJ , Sabater L , et al \nEncephalitis and GABA B receptor antibodies. Novel findings in a new case series of 20 patients\n. Neurology \n2013 ;81 :1500 –1506\n.24068784 \n19. Solimena M , Folli F , Aparisi R , Pozza G , De Camilli P \nAutoantibodies to GABA-ergic neurons and pancreatic beta cells in Stiff-Man syndrome\n. N Engl J Med \n1990 ;322 :1555 –1560\n.2135382 \n20. Dalakas MC , Fujii M , Li M , McElroy B \nThe clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome\n. Neurology \n2000 ;55 :1531 –1535\n.11094109 \n21. Meinck HM , Thompson PD \nStiff man syndrome and related conditions\n. Mov Disord \n2002 ;17 :853 –866\n.12360534 \n22. Rakocevic G , Raju R , Dalakas MC \nAnti–glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome\n. Arch Neurol \n2004 ;61 :902 .15210528 \n23. Pittock SJ , Yoshikawa H , Ahlskog JE , et al \nGlutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction\n. Mayo Clin Proc \n2006 ;81 :1207 –1214\n.16970217 \n24. Dalakas MC , Li M , Fujii M , Jacobowitz DM \nStiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies\n. Neurology \n2001 ;57 :780 –784\n.11552003 \n25. Levy LM , Levy-Reis I , Fujii M , Dalakas MC \nBrain γ-aminobutyric acid changes in stiff-person syndrome\n. Arch Neurol \n2005 ;62 :970 –974\n.15956168 \n26. Dalakas MC \nProgress and stiff challenges in understanding the role of GAD-antibodies in stiff-person syndrome\n. Exp Neurol \n2013 ;247 :303 –307\n.23485793 \n27. Manto M-U , Laute M-A , Aguera M , Rogemond V , Pandolfo M , Honnorat J \nEffects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases\n. Ann Neurol \n2007 ;61 :544 –551\n.17600364 \n28. Burton AR , Baquet Z , Eisenbarth GS , et al \nCentral nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells\n. J Immunol \n2010 ;184 :4863 –4870\n.20348424 \n29. Bien CG , Vincent A , Barnett MH , et al \nImmunopathology of autoantibody-associated encephalitides: clues for pathogenesis\n. Brain \n2012 ;135 :1622 –1638\n.22539258 \n30. Mitoma H , Hadjivassiliou M , Honnorat J \nGuidelines for treatment of immune-mediated cerebellar ataxias\n. Cerebellum Ataxias \n2015 ;2 :1 –10\n.26331044 \n31. Mitoma H , Manto M , Hampe CS \nImmune-mediated cerebellar ataxias: from bench to bedside\n. Cerebellum Ataxias \n2017 ;4 :2 –14\n.28074148\n\n",
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"issue": "7(3)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
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"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies; D020274:Autoimmune Diseases of the Nervous System; D002524:Cerebellar Ataxia; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D007167:Immunotherapy; D020363:Limbic Encephalitis; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D016750:Stiff-Person Syndrome; D055815:Young Adult",
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"references": "11552003;24934144;9339684;27065452;17516493;1722364;15210528;2073783;1697648;10891904;28749549;26216686;26561527;18687732;17600364;11176960;12360534;22539258;28944066;11094109;19659822;24068784;20437582;15956168;16970217;23485793;8981298;20348424;2135382;22332190",
"title": "Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment.",
"title_normalized": "neurologic syndromes related to anti gad65 clinical and serologic response to treatment"
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"abstract": "A 17-year-old male presented from an outside facility in acute respiratory failure and profound hypotension. He was found to have classic MRI brain findings of opiate-induced leukoencephalopathy which was corroborated with urine drug screen and history. This entity has been described in the adults but is not as well recognized in the pediatric population. As the opiate epidemic continues to evolve, this case brings heightened awareness of this disorder to pediatric radiologists.",
"affiliations": "Department of Medical Imaging, Phoenix Children's Hospital, Phoenix, AZ.;Department of Radiology, Maricopa Integrated Health System, Phoenix, AZ.;Department of Medical Imaging, Phoenix Children's Hospital, Phoenix, AZ.;Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.",
"authors": "Wong|Kevin|K|;Van Tassel|Dane C|DC|;Miller|Jeffrey H|JH|;Pfeifer|Cory M|CM|",
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"doi": "10.1016/j.radcr.2019.04.007",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(19)30126-810.1016/j.radcr.2019.04.007NeuroradiologyOpiate leukoencephalopathy in a pediatric patient Wong Kevin DOaVan Tassel Dane C MDbMiller Jeffrey H MDaPfeifer Cory M MD, MScory.pfeifer@UTSouthwestern.educ⁎a Department of Medical Imaging, Phoenix Children's Hospital, Phoenix, AZb Department of Radiology, Maricopa Integrated Health System, Phoenix, AZc Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390⁎ Corresponding author. cory.pfeifer@UTSouthwestern.edu25 4 2019 7 2019 25 4 2019 14 7 829 831 16 3 2019 7 4 2019 7 4 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 17-year-old male presented from an outside facility in acute respiratory failure and profound hypotension. He was found to have classic MRI brain findings of opiate-induced leukoencephalopathy which was corroborated with urine drug screen and history. This entity has been described in the adults but is not as well recognized in the pediatric population. As the opiate epidemic continues to evolve, this case brings heightened awareness of this disorder to pediatric radiologists.\n\nKeywords\nOpiate leukoencephalopathyPediatric opiate intoxication\n==== Body\nIntroduction\nToxic leukoencephalopathy is a rare neurologic impairment that occurs as a result of opiate exposure. The process may present as acute or chronic. This entity is particularly relevant in today's age of opioid epidemic but is not commonly seen in the pediatric population. Presented here is a rare case of leukoencephalopathy in an adolescent due to opiate intoxication.\n\nCase report\nA 17-year-old male was found unresponsive in his bed on the morning of presentation by his parents. He had last been reported to be acting normally the night before he left the home, and his parents heard him come home at approximately 1:00 AM, 7 hours prior to being discovered in distress. The patient was found to have white foam around his mouth and was breathing in an agonal fashion. Emergency services were called. Upon arrival, the paramedics administered naloxone without a clinical response. He was hypoxic at 49% and hypotensive in the 60/40 mm Hg during transport. He was brought to the nearest area hospital where he was intubated in the emergency department. He was also started on norepinephrine and dobutamine. A CT performed at the outside institution was interpreted as normal. An initial urine toxicology screen showed the patient to have tramadol, opiates, tetrahydrocannabinol, and benzodiazepines in his system. At this point, the patient was transferred to a children's hospital for further workup and management, though the CT images were not sent with the patient for review or additional opinion. He was found to be in cardiogenic shock with severe end-organ dysfunction and multisystem organ failure. Further history from his friends revealed that he had taken a combination of fentanyl, heroin, and alprazolam referred to as “white China” approximately 8 hours before he was found down. The patient did not remember how he took the drugs, but he thought it was only heroin without the additional substances. The patient's parents stated that he had used marijuana and benzodiazepines to manage stress but were not aware of any recent use. There had been no opiate use previously.\n\nAn MRI of the brain performed on day 3 of admission showed diffuse FLAIR hyperintensity and restricted diffusion in the white matter of the bilateral posterior centrum semiovale as well as the occipital lobes (Fig. 1, Fig. 2, Fig. 3). The occipital lobes also demonstrated associated T2 and FLAIR signal hyperintensity. The subcortical U fibers were relatively spared. The patient was diagnosed with opiate-induced leukoencephalopathy based on the characteristic imaging findings and positive urine drug screen.Fig. 1 Axial FLAIR of the brain demonstrates confluent T2 hyperintensity throughout the superior centrum semiovale bilaterally (arrows).\n\nFig 1Fig. 2 Axial diffusion weighted image of the brain exhibits hyperintensity in the region of white matter FLAIR signal abnormality (arrows).\n\nFig 2Fig. 3 Apparent diffusion coefficient correlation shows hypointense signal (arrows) confirming restriction of diffusion throughout the affected white matter.\n\nFig 3\n\nThe treatment for this disease is supportive while allowing the drug to clear, and the patient received this supportive care while in the hospital. He was then transferred to an inpatient rehabilitation facility and then later to a substance abuse program. Physical exam following discharge revealed residual right hemiparesis and neuropathic pain in the distal right lower extremity which was managed on gabapentin. As is the case with stroke and trauma, this patient's long-term outcome depends on the extent of the brain injury that the patient endured.\n\nDiscussion\nGiven the current opioid epidemic in this country, it is important that pediatric radiologists recognize the findings of toxic leukoencephalopathy, specifically opioid-induced toxic leukoencephalopathy. Differential considerations include stroke, metabolic disorder, infection, demyelinating process, and hypoxic ischemia. The confluence of signal abnormality and diffusion restriction in the central white matter seen in this patient are much more concordant with opiate leukoencephalopathy. Subsequent encephalomalacia is common and was observed in this patient as well.\n\nWhile most deaths due to opiate toxicity are in the adult population, there are a growing number of pediatric patients who are overdosing from opiates and ultimately dying. The mechanism of opioid-induced leukoencephalopathy has not been fully elucidated, but these findings are more common in heroin inhalation (“chasing the dragon”) [1], [2]. Pathologically, this produces spongiform degeneration of the involved white matter with vacuolization of the oligodendrocytes [3]. To date, a valid incidence of this disorder in the pediatric population has yet to be obtained, as pediatric opiate-induced leukoencephalopathy is described sparingly in case reports without specific epidemiologic investigation.\n\nCharacteristic MRI findings may prompt the diagnosis in an unresponsive child and provide information useful to guide therapy.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 Bartlett E. Mikulis D.J. Chasing “chasing the dragon” with MRI: leukoencephalopathy in drug abuse Br J Radiol 78 935 2005 997 1004 16249600 \n2 Keogh C.F. Andrews G.T. Spacey S.D. Forkheim K.E. Graeb D.A. Neuroimaging features of heroin inhalation toxicity: “Chasing the dragon AJR Am J Roentgenol 180 3 2003 847 850 12591709 \n3 Tamrazi B. Almast J. Your brain on drugs: imaging of drug-related changes in the central nervous system Radiographics 32 3 2012 701 719 22582355\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "14(7)",
"journal": "Radiology case reports",
"keywords": "Opiate leukoencephalopathy; Pediatric opiate intoxication",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
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"other_id": null,
"pages": "829-831",
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"pubdate": "2019-07",
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"title": "Opiate leukoencephalopathy in a pediatric patient.",
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"abstract": "This paper presents a case of systemic lupus erythematosus (SLE) with neuropsychiatric features, where the outcome was influenced by the development of hyperammonaemia, probably induced by sodium valproate. A case of severe SLE occurring in a 20-year-old Maori girl is described. Her disease had been characterised by neuropsychiatric features for several years, culminating in persistent seizure activity at the time of her final presentation. Her management with anticonvulsants was complicated by the development of intractable hyperammonaemia which contributed to irreversible clinical deterioration. We have reviewed the English literature for reports of valproate-related hyperammonaemia which has often been described in the setting of seizure and mood disorders. This is the first case where it has been reported, superimposed upon severe neuropsychiatric SLE (NP-SLE). The mechanism by which valproate induces hyperammonaemia remains incompletely understood but is likely to relate to the urea cycle. Under normal metabolic conditions, acyl-CoA is transported into the mitochondria via a carnitine transport system. It is then converted to acetyl-CoA via β-oxidation and eventually to N-acetyl glutamate. This pathway can be interrupted by the introduction of sodium valproate, leading to a reduction of free coenzyme A, acetyl-CoA and carnitine, and resulting in the decreased availability of cofactors necessary for the function of the urea cycle. As this is the primary means of ammonia metabolism, serious elevation in serum ammonia levels may occur in patients on this anticonvulsant medication. In this patient with active NP-SLE, the combined autoimmune and metabolic brain insult contributed to a fatal outcome.",
"affiliations": "Department of Rheumatology, Greenlane Clinical Centre, Auckland District Health Board, Private Bag 92024, Auckland Mail Centre, Auckland 1142, New Zealand. cheukyanestee@yahoo.co.nz",
"authors": "Chan|Estee|E|;McQueen|Fiona|F|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid; D000641:Ammonia",
"country": "Germany",
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"doi": "10.1007/s10067-012-2150-x",
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"issue": "32(3)",
"journal": "Clinical rheumatology",
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"mesh_terms": "D000641:Ammonia; D018692:Antimanic Agents; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D020945:Lupus Vasculitis, Central Nervous System; D016896:Treatment Outcome; D014635:Valproic Acid; D055815:Young Adult",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11689882;19742224;7625483;12906346;18480705;9247410;21873573;16908754;18375641;21978982;15349008;8941443;17823470;8192712;15316109;12199737;12095907;10211873;20920686;15602119;10485644;19382315;3928828;12151592;19724652;16288075;11581089;17412645;16787750;9598692;20337505;15935047;18212182;21353142;11903461;15016014;1613703;20184937;15380868;12734893;15079854;21349718;9779913;17606652;21700501;16150404;9674826;19304858",
"title": "Valproate-induced hyperammonaemia superimposed upon severe neuropsychiatric lupus: a case report and review of the literature.",
"title_normalized": "valproate induced hyperammonaemia superimposed upon severe neuropsychiatric lupus a case report and review of the literature"
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"abstract": "This case suggests a mechanistic rationale for the clinical efficacy of intravenous immunoglobulins (IVIG) in treating CD40 ligand (CD40L) deficiency associated neutropenia as it is the first reported instance of free and cell-bound antineutrophil antibodies in a case of CD40L deficiency, accompanied by a prolonged and clinically severe neutropenia.",
"affiliations": "Department of Clinical Immunology Odense University Hospital Odense Denmark.;Department of Clinical Immunology Aalborg University Hospital Aalborg Denmark.;Department of Clinical Immunology Odense University Hospital Odense Denmark.;Department of Clinical Immunology Odense University Hospital Odense Denmark.;Department of Clinical Immunology Odense University Hospital Odense Denmark.;Hans Christian Andersen's Children Hospital Odense University Hospital Odense Denmark.;Hans Christian Andersen's Children Hospital Odense University Hospital Odense Denmark.",
"authors": "Assing|Kristian|K|https://orcid.org/0000-0001-8744-1615;Nielsen|Kaspar René|KR|;Tenstad|Helene Broch|HB|;Jakobsen|Marianne Antonius|MA|;Nielsen|Christian|C|;Grosen|Dorthe|D|;Hartling|Ulla Birgitte|UB|",
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"doi": "10.1002/ccr3.2621",
"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/ccr3.2621\nCCR32621\nCase Report\nCase Reports\nAssociation between neutropenia and IgG antineutrophil antibodies in a case of CD40LG deficiency due to two novel mutations\nASSING et al.Assing Kristian https://orcid.org/0000-0001-8744-1615\n1\nKristian.assing@rsyd.dk Nielsen Kaspar René \n2\n Tenstad Helene Broch \n1\n Jakobsen Marianne Antonius \n1\n Nielsen Christian \n1\n Grosen Dorthe \n3\n Hartling Ulla Birgitte \n3\n\n4\n \n1 \nDepartment of Clinical Immunology\nOdense University Hospital\nOdense\nDenmark\n\n\n2 \nDepartment of Clinical Immunology\nAalborg University Hospital\nAalborg\nDenmark\n\n\n3 \nHans Christian Andersen’s Children Hospital\nOdense University Hospital\nOdense\nDenmark\n\n4 Present address:\nDepartment of Pediatrics\nAarhus University Hospital\nAarhus\nDenmark\n\n* Correspondence\n\nKristian Assing, Department of Clinical Immunology, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark.\n\nEmail: Kristian.assing@rsyd.dk\n\n25 12 2019 \n2 2020 \n8 2 10.1002/ccr3.v8.2313 316\n20 8 2019 21 11 2019 23 11 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nThis case suggests a mechanistic rationale for the clinical efficacy of intravenous immunoglobulins (IVIG) in treating CD40 ligand (CD40L) deficiency associated neutropenia as it is the first reported instance of free and cell‐bound antineutrophil antibodies in a case of CD40L deficiency, accompanied by a prolonged and clinically severe neutropenia.\n\nThis case suggests a mechanistic rationale for the clinical efficacy of intravenous immunoglobulins (IVIG) in treating CD40 ligand (CD40L) deficiency associated neutropenia as it is the first reported instance of free and cell‐bound antineutrophil antibodies in a case of CD40L deficiency, accompanied by a prolonged and clinically severe neutropenia.\n\n\nCD40 ligand deficiencyhyper‐IgM syndromeneutropenianeutrophil IgG auto‐antibodies source-schema-version-number2.0cover-dateFebruary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:26.02.2020\n\n\nAssing \nK \n, \nNielsen \nKR \n, \nTenstad \nHB \n, et al. Association between neutropenia and IgG antineutrophil antibodies in a case of CD40LG deficiency due to two novel mutations\n. Clin Case Rep . 2020 ;8 :313 –316\n. 10.1002/ccr3.2621\n==== Body\n1 INTRODUCTION\nThe CD40 ligand (CD40L) expressed by CD40LG fulfills diverse functions. T cell‐expressed CD40L is involved in the stimulation of germinal center B cells, antibody isotype switching and the generation of high‐affinity antibodies through the process called somatic hypermutation (SHM). Functional mutations in CD40LG result in a hyper‐IgM syndrome characterized by normal to elevated IgM levels and low to absent IgG and IgA levels.\n\n2 CASE PRESENTATION\nA 12 months old male patient was referred to our university hospital due to a respiratory infection. Neutropenia, which subsequently lasted for 15 months (with neutrophil concentrations often <0.05 × 109/L (neutropenia grade 4), Figure 1), was diagnosed. The patient was not thrombocytopenic and his erythrocytes were direct antiglobulin test (DAT) negative. Antinuclear antibodies (ANA) were not detected. He received subcutaneous granulocyte‐colony stimulating factor (G‐CSF), according to recommended dosage1 (5 μg/kg/day = 50 μg Neupogen®/day), for seven consecutive days, without effect on his neutrophil levels but for a marked increase in his eosinophil counts: 2.2 × 109/L (age‐adjusted range: <0.05 × 109/L). A bone marrow biopsy showed lively erythropoiesis, normal thrombocytopoiesis, inhibited neutropoiesis, normal eosinophilopoiesis, and no signs of neoplastic hematologic disease. A possible cellulitis, located to his left instep, responded to amoxicillin and clavulanic acid. After discharge from the hospital, he was given preventive amoxicillin. In the following 10 months, his main complaints were gingivitis, oral ulcers, and mucocutaneous candidiasis, the latter amenable to oral antifungals. Next‐generation sequencing, using a custom made in‐house panel (Thermo Fischer Scientific) found no mutations in genes associated with severe congenital neutropenia: ELANE, HAX1, GFI1, WAS, or G6PC3 but revealed that the patient was hemizygous for two new genetic variants in CD40LG: LRG_141, c.[517G > C; 521delA] p.(Ala173Pro; Gln174fs). The patient's two CD40LG variants were confirmed by Sanger sequencing. None of the patient's CD40LG variants were described in the dbSNP database at NCBI, nor in HGMD, nor in Exome Aggregation Consortium nor in 1000 Genomes Data. Three (SIFT, PolyPhen‐2, and mutationassessor.org) out of six prediction tools rated the missense variant c. 517G > C as probably damaging. The other deletion variant c. 521delA, which caused a frameshift at amino acid position 174 (Gln174fs) and introduced a stop codon at amino acid position 190, was clearly damaging. According to the sequence variant nomenclature: varnomen.hgvs.org, the two CD40LG variants are to be described as separate mutations.\n\nFigure 1 The patient's neutrophil concentrations during 28 mo (with 15 mo of neutropenia) divided upon 38 measurements. The blue line depicts the age‐adjusted neutrophil concentration (lower normal range). G‐CSF (50 μg/d) was administered daily for 7 d. Ten grams of intravenous Privigen® were administered every fourth week\n\nThe same CD40LG variants (in cis) were detected by Sanger sequencing in the patient's mother. The patient had undetectable IgG (<0.4 g/L), IgA (<0.05 g/L) but elevated IgM (8.45 g/L) levels consistent with the hyper‐IgM syndrome. A lymphocyte marker study, performed at the age of 27 months, showed normal CD4+, CD8+ T, and CD19+ B‐cell concentrations but total absence (0%) of isotype switched (CD27+IgD−) memory B cells (age adjusted 5‐95 percentile range: 4.7%‐21.2% of CD19+ B cells). Patient B cells exhibited reduced SHM (determined by a restriction enzyme‐based hot spot mutation assay [REHMA]) of kappa light chain genes: 2% (age‐adjusted normal range: >10%, Tissue Typing laboratory, National University Hospital, Copenhagen). Clostridium tetani antibody levels (following three tetanus toxoid vaccinations) were nonprotective (<0.01 IU/mL, Statens Serum Institut). Ex vivo stimulation of his CD3+ T cells, with phorbol 12‐myristate 13‐acetate (PMA: 20 ng/mL) and ionomycin (300 ng/mL), failed to upregulate surface CD40L, although his CD3+ T cells were activated as evidenced by upregulation of surface CD69. Repeated testing of patient sera by the Luminex‐based LABScreen multi‐assay (prior to institution of antibody replacement therapy) revealed no antibody specificities toward a wide range of human leukocyte antigen (HLA)‐class I, HLA‐class II determinants as well as toward human neutrophil antigens (HNAs). Patient sera (prior to and after institution of antibody replacement therapy) and patient neutrophils were tested for granulocyte‐reactive antibodies using flow direct‐granulocyte immunofluorescence test (D‐GIFT), flow indirect‐granulocyte immunofluorescence test (I‐GIFT), granulocyte agglutinations tests (GAT), and monoclonal‐antibody‐specific immobilization of granulocyte antigens (MAIGA) as earlier described.2 Results were confirmed by another ISBT granulocyte immunology reference laboratory (Karolinska University Hospital). Patient neutrophils were repeatedly (moderately to heavily) covered with IgG (Figure 1) and the corresponding patient sera contained free neutrophil reactive (IgG) antibodies (Figure1). Possibly reflecting the aftermath of reactive leukocytosis (concomitant leukocyte: 20.5 × 109/L (normal range <14.0 × 109/L) and lymphocyte concentration: 13.8 × 109/L (normal range <7.9 × 109/L), but with normal CRP (<1 mg/L), we recorded a single instance where the patient's neutrophil concentration was normalized (≥1.6 × 109/L), (Figure 1) despite the presence of neutrophil auto‐antibodies. The more prolonged normalization of our patient's neutrophil counts coincided with the disappearance of free and cell‐bound neutrophil antibodies (measured on three different occasions, Figure1). While on IVIG (10 g Privigen®/4th week was initiated at the age of 27 months, Figure 1) and prophylactic sulfamethoxazole with trimethoprim, our patient, aged three years and 6 months, underwent successful allogeneic bone marrow transplantation. Written consent by the patient's parents and permission from the chairman of the Regional Committee on Health Research Ethics for Southern Denmark (case S‐20192000‐48) was obtained.\n\n3 DISCUSSION\nNeutropenia affects approximately two‐thirds of patients with CD40L deficiency, leading to significant comorbidity due to mucocutaneous inflammation.3 The pathogenesis underlying CD40L deficiency associated neutropenia has not yet been clearly delineated. As bone marrow stromal cells express CD40,4 stimulation by CD40L can induce them to produce G‐CSF.5 Hence, CD40L deficiency could compromise the ability of bone marrow stromal cells to secrete G‐CSF, thereby causing neutropenia. Supporting that hypothesis, treatment with G‐CSF has been reported to increase or normalize the neutrophil counts in CD40L deficiency.6 However, seven days of treatment with a standard dosage of G‐CSF did not affect our patient's neutropenia but instead markedly increased his peripheral eosinophil concentration, indicating that the G‐CSF levels were sufficient to induce myelopoietic lineage differentiation. Still, we cannot exclude that the standard G‐CSF dosage was insufficient, since the patient, despite the presence of antineutrophil antibodies, experienced a pronounced, possibly reactive, neutrophil increase, consistent with G‐CSF responsiveness. Infection‐induced G‐CSF secretion results in massive bone marrow neutrophil release7 which may override the effects of neutrophil antibodies. Hence, pronounced bone marrow release of neutrophils, secondary to infection, may have effected our patient's transiently normalized neutrophil count in the presence of neutrophil auto‐antibodies. Theoretically, our patient could have experienced additional unrecorded instances of normalized neutrophil concentrations, however, his prolonged clinical complaints, involving gingivitis, oral ulcers, and mucocutaneous candidiasis, indicated sustained neutropenia.\n\nThe clinical efficacy of IVIG, in treating CD40L deficiency associated neutropenia,8 suggests that autoimmune mechanisms might also be involved, although autoimmune neutropenia has never been confirmed in this disorder8 and some authors even mention it as unlikely.9 We hereby represent the first case of CD40L deficiency, accompanied by undetectable plasma IgG and IgA concentrations, but where free and cell‐bound antineutrophil IgG antibodies coincided with a protracted, clinically significant neutropenia. We were not able to determine the subclass specificity of these IgG antibodies, but to varying degrees all IgG subclasses may engage Fc‐receptors and thereby contribute to splenic opsonization of antibody‐coated neutrophils. The mechanism (s) underlying our patient's sparse production of IgG is uncertain. However, CD40L independent production of IgG toward viral glycoproteins has been documented10 and neutrophils express several surface glycoproteins, such as CD11b11 and CD47,12 which could constitute targets for CD40L independent IgG production. Interestingly, Litinskiy et al13 have demonstrated that human dendritic cells can induce CD40L independent IgG class shift through expression of the B‐cell stimulator proteins: B‐cell activating factor of the tumor‐necrosis‐factor family (BAFF) and a proliferation‐inducing ligand (APRIL). We were not able to confirm the antigen specificity of the IgG antibodies, however, we cannot preclude that the antibodies were “neutrophil specific” as other autoantigen specificities were not detected (no thrombocytopenia, the patient was DAT negative and we observed no ANA reactivity). However, the lack of any known neutrophil antigen specificity of these antibodies concurred with our patient's severely reduced SHM, as CD40L is crucial for SHM. Auto‐reactivity is often a feature of compromised SHM, since inherently auto‐reactive B‐cell clones are prevented from rescuing themselves, through the process of SHM, from auto‐reactivity, a process called “clonal redemption”.14\n\n\n4 CONCLUSION\nWe present a case of CD40L deficiency where the presence of neutrophil reactive IgG coincided with a clinically severe neutropenia. Due to its diverse immunomodulatory capabilities, IVIG therapy is widely used for treating autoimmune disorders. Our case suggests a mechanistic rationale for the clinical efficacy of IVIG in attenuating CD40L deficiency associated neutropenia and substantiates models showing that the requirement for CD40L, in mediating B‐cell IgG isotype switching, can be circumvented.\n\nCONFLICT OF INTEREST\nThe authors have no conflicts of interest relevant to this article to disclose.\n\nAUTHOR CONTRIBUTIONS\nKristian Assing conceptualized the case, collected blood samples and wrote the final paper. Kaspar René Nielsen performed the neutrophil specific auto‐antibody assays and critically read the final paper. Helene Broch Tenstad collected blood samples, wrote parts of the initial paper and critically read the final paper. Marianne Antonius Jakobsen performed genetic work‐up and critically read the final paper. Christian Nielsen performed flow‐cytometric analyses and critically read the final paper. Dorthe Grosen organized blood sampling, attended the patient and critically read the final paper. Ulla Birgitte Hartling attended the patient, collected blood samples, wrote parts of the initial paper and critically read the final paper. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nACKNOWLEDGMENTS\nWe are grateful for the technical assistance provided by Anne‐Louise Fjordside Bilde and for the critical comments provided by Niels Fisker, MD., PhD.\n==== Refs\nREFERENCES\n1 \n\nPaul \nM \n, \nRam \nR \n, \nKugler \nE \n, et al. Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato‐oncological patients: randomized controlled trial\n. Am J Hematol . 2014 ;89 (3 ):243 ‐248\n.24178750 \n2 \n\nBux \nJ \n, \nKober \nB \n, \nKiefel \nV \n, \nMueller‐Eckhardt \nC \n. Analysis of granulocyte‐reactive antibodies using an immunoassay based upon monoclonal‐antibody‐specific immobilization of granulocyte antigens\n. Transfus Med . 1993 ;3 (2 ):157 ‐162\n.8374701 \n3 \n\nSeyama \nK \n, \nNonoyama \nS \n, \nGangsaas \nI \n, et al. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X‐linked hyper IgM syndrome\n. Blood . 1998 ;92 (7 ):2421 ‐2434\n.9746782 \n4 \n\nFranco \nG \n, \nGuarnotta \nC \n, \nFrossi \nB \n, et al. Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma\n. Blood . 2014 ;123 (12 ):1836 ‐1849\n.24452203 \n5 \n\nMavroudi \nI \n, \nPapadaki \nV \n, \nPyrovolaki \nK \n, \nKatonis \nP \n, \nEliopoulos \nAG \n, \nPapadaki \nHA \n. The CD40/CD40 ligand interactions exert pleiotropic effects on bone marrow granulopoiesis\n. J Leukoc Biol . 2011 ;89 (5 ):771 ‐783\n.21367977 \n6 \n\nLeven \nEA \n, \nMaffucci \nP \n, \nOchs \nHD \n, et al. Hyper IgM syndrome: a report from the USIDNET registry\n. J Clin Immunol . 2016 ;36 (5 ):490 ‐501\n.27189378 \n7 \n\nChristopher \nMJ \n, \nLink \nDC \n. Regulation of neutrophil homeostasis\n. Curr Opin Hematol . 2007 ;14 (1 ):3 ‐8\n.17133093 \n8 \n\nLevy \nJ \n, \nEspanol‐Boren \nT \n, \nThomas \nC \n, et al. Clinical spectrum of X‐linked hyper‐IgM syndrome\n. J Pediatr . 1997 ;131 (1 Pt 1 ):47 ‐54\n.9255191 \n9 \n\nEtzioni \nA \n, \nOchs \nHD \n. The hyper IgM syndrome–an evolving story\n. Pediatr Res . 2004 ;56 (4 ):519 ‐525\n.15319456 \n10 \n\nSzomolanyi‐Tsuda \nE \n, \nWelsh \nRM \n. T‐cell‐independent antiviral antibody responses\n. Curr Opin Immunol . 1998 ;10 (4 ):431 ‐435\n.9722919 \n11 \n\nHill \nGE \n, \nAlonso \nA \n, \nThiele \nGM \n, \nRobbins \nRA \n. Glucocorticoids blunt neutrophil CD11b surface glycoprotein upregulation during cardiopulmonary bypass in humans\n. Anesth Analg . 1994 ;79 (1 ):23 ‐27\n.7912043 \n12 \n\nOldenborg \nPA \n. CD47: a cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease\n. ISRN Hematol . 2013 ;2013 :614619 .23401787 \n13 \n\nLitinskiy \nMB \n, \nNardelli \nB \n, \nHilbert \nDM \n, et al. DCs induce CD40‐independent immunoglobulin class switching through BLyS and APRIL\n. Nat Immunol . 2002 ;3 (9 ):822 ‐829\n.12154359 \n14 \n\nReed \nJH \n, \nJackson \nJ \n, \nChrist \nD \n, \nGoodnow \nCC \n. Clonal redemption of autoantibodies by somatic hypermutation away from self‐reactivity during human immunization\n. J Exp Med . 2016 ;213 (7 ):1255 ‐1265\n.27298445\n\n",
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"title": "Association between neutropenia and IgG antineutrophil antibodies in a case of CD40LG deficiency due to two novel mutations.",
"title_normalized": "association between neutropenia and igg antineutrophil antibodies in a case of cd40lg deficiency due to two novel mutations"
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"abstract": "A 31-year-old woman with treatment-resistant pregnancy-induced hypertension during her first pregnancy delivered a small-for-gestational-age infant (weight: 1,070 g). After delivery, she was diagnosed with primary aldosteronism (PA) associated with a left adrenal adenoma. Following a thorough examination, she underwent laparoscopic left adrenalectomy, and the diagnosis of an aldosterone-producing adenoma was confirmed based on a pathological examination. Thereafter, the patient's hypertension and hypokalemia completely disappeared. She became pregnant again and successfully delivered her second infant at the 37th week of gestation (weight: 2,720 g) without developing treatment-resistant hypertension. Secondary causes of hypertension should not be overlooked, even in young pregnant women.",
"affiliations": "Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Japan.",
"authors": "Eguchi|Kazuo|K|;Hoshide|Satoshi|S|;Nagashima|Shuichi|S|;Maekawa|Takashi|T|;Sasano|Hironobu|H|;Kario|Kazuomi|K|",
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"issue": "53(21)",
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"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D000315:Adrenalectomy; D018246:Adrenocortical Adenoma; D000328:Adult; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism; D046110:Hypertension, Pregnancy-Induced; D007008:Hypokalemia; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic",
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"references": null,
"title": "An adverse pregnancy-associated outcome due to overlooked primary aldosteronism.",
"title_normalized": "an adverse pregnancy associated outcome due to overlooked primary aldosteronism"
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"abstract": "BACKGROUND\nAcinetobacter baumannii is a leading agent of healthcare-associated infection. The objective of this study was to evaluate cases of colonization or infection with polymyxin-resistant A. baumannii (PRAB) in liver transplant recipients and to identify the risk factors for the acquisition of PRAB.\n\n\nMETHODS\nWe evaluated all patients undergoing liver transplantation (LT) between January and November of 2011. The exclusion criterion was death within the first 72 h after transplant. Patients were screened for PRAB through weekly rectal and inguinal swabs during their stay in the intensive care unit (ICU) and at ICU discharge. Patients who came from other hospitals or had been treated in the emergency room for >72 h were screened at ICU admission. The minimum inhibitory concentrations (MICs) for polymyxins were determined by broth microdilution, and clonality was determined by pulsed-field gel electrophoresis. The stepwise logistic regression was used to identify risk factors related to acquisition of PRAB, and Cox forward regression used to identify risk factors for 60-day mortality.\n\n\nRESULTS\nWe evaluated 65 patients submitted to LT, among whom PRAB was isolated in 7, 4 of whom developed infection. The MICs for polymyxin E ranged from 16 to 128 mg/mL. All patients with PRAB required dialysis. The median time of polymyxin use before PRAB isolation was 21 days. These 4 included 1 case of primary bloodstream infection (BSI), which was treated with the carbapenem-polymyxin combination; 1 case of surgical site infection, which was treated with gentamicin, polymyxin, ampicillin-sulbactam, and tigecycline; and 2 cases of pneumonia, treated with the combination of carbapenem-polymyxin. In the case of BSI and in 1 of the cases of pneumonia, the treatment was considered successful. Mortality was 71% among the cases, compared with 33% among the non-cases.\n\n\nCONCLUSIONS\nIn the final model of the survival analysis, PRAB colonization or infection after LT was independently associated with mortality. One predominant clone was identified. The only risk factor identified in the multivariate analysis was polymyxin use. PRAB was an agent with high mortality, and the most important risk factor associated with colonization or infection for such bacterium was polymyxin use.",
"affiliations": "Infection Control Service, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil.",
"authors": "Freire|M P|MP|;Van Der Heijden|I M|IM|;do Prado|G V B|GV|;Cavalcante|L S|LS|;Boszczowski|I|I|;Bonazzi|P R|PR|;Rossi|F|F|;Guimarães|T|T|;D'Albuquerque|L A C|LA|;Costa|S F|SF|;Abdala|E|E|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011113:Polymyxins",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12210",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "16(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Acinetobacter baumannii; CRAB; PRAB; early infection; liver transplantation; multidrug resistance; polymyxin",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000900:Anti-Bacterial Agents; D002353:Carrier State; D016022:Case-Control Studies; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011113:Polymyxins",
"nlm_unique_id": "100883688",
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"pmc": null,
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"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Polymyxin use as a risk factor for colonization or infection with polymyxin-resistant Acinetobacter baumannii after liver transplantation.",
"title_normalized": "polymyxin use as a risk factor for colonization or infection with polymyxin resistant acinetobacter baumannii after liver transplantation"
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"abstract": "Tigecycline has been approved by the US (United States) Food and Drug Administration in a variety of complicated infections due to its broad-spectrum antibiotic activity. Following phase III trials, the product label was revised and acute pancreatitis was listed as an adverse effect. Its safety profile in special groups such as renal transplant patients is not exactly known. We report the first case of unintentional rechallenge of tigecycline induced pancreatitis in a renal transplant patient. Ten days following the renal transplantation, a 35-year-old patient presented to the clinic with acute rejection. He received anti-thymocyte globulin (ATG) and pulse steroid treatments for rejection. Following the treatment, he developed perianal cellulitis and tigecycline was started. Nine days following initiation of tigecycline he received thrombectomy for his incidental cardiac thrombus. One day after thrombectomy, he developed acute pancreatitis (AP). Thrombectomy was suspected to be the cause of AP. During hospitalization for transplant rejection, tigecycline was re-started for a newly developed complicated abdominal infection. On the third day of the tigecycline re-treatment, he developed a second episode of AP. Following tigecycline withdrawal, his symptoms resolved and serum pancreatic enzymes returned to normal, thus AP was ultimately attributed to tigecycline. This lethal side effect should be kept in mind while treating severe infections in renal transplant recipients.",
"affiliations": "Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Clinical Pharmacy, Hacettepe University Faculty of Pharmacy, Ankara, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Nephrology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Gastroenterology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Nephrology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Nephrology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.",
"authors": "Yazirli|Bercemhan|B|https://orcid.org/0000-0003-0895-8865;Kara|Emre|E|;Inkaya|Ahmet Cagkan|AC|;Maden|Sarpcan|S|;Ozberk|Ugur|U|;Yildirim|Tolga|T|;Parlak|Erkan|E|;Uzun|Omrum|O|;Yilmaz|Seref Rahmi|SR|;Arici|Mustafa|M|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000078304:Tigecycline",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13593",
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"issn_linking": "1398-2273",
"issue": "23(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "acute pancreatitis; calcineurin inhibitors; kidney transplantation; tigecycline",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D065095:Calcineurin Inhibitors; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D010195:Pancreatitis; D000078304:Tigecycline",
"nlm_unique_id": "100883688",
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"pages": "e13593",
"pmc": null,
"pmid": "33655683",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case report of tigecycline induced acute pancreatitis in a renal transplant patient and review of the literature: Should we avoid tigecycline in patients on calcineurin inhibitors?",
"title_normalized": "a case report of tigecycline induced acute pancreatitis in a renal transplant patient and review of the literature should we avoid tigecycline in patients on calcineurin inhibitors"
} | [
{
"companynumb": "TR-STRIDES ARCOLAB LIMITED-2021SP028649",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo report a case of tubulointerstitial nephritis and uveitis syndrome with a primary presentation of acute posterior multifocal placoid pigment epitheliopathy after use of lamotrigine.\n\n\nMETHODS\nRetrospective case report with ultra-widefield fundus imaging, optical coherence tomography, and fluorescein angiography.\n\n\nRESULTS\nA 19-year-old woman presented with decreased visual acuity and acute renal failure after starting lamotrigine. Her examination demonstrated 1+ anterior chamber cell and numerous white deep retinal plaque-like lesions predominantly in the macula in both eyes. After extensive ophthalmic and systemic evaluation, the patient was diagnosed with tubulointerstitial nephritis and uveitis syndrome with a primary presentation of acute posterior multifocal placoid pigment epitheliopathy. She had excellent visual recovery with topical and systemic steroids.\n\n\nCONCLUSIONS\nAcute posterior multifocal placoid pigment epitheliopathy is a rare but important clinical presentation of tubulointerstitial nephritis and uveitis syndrome. Oral corticosteroid treatment can be considered for tubulointerstitial nephritis but is generally not necessary for acute posterior multifocal placoid pigment epitheliopathy.",
"affiliations": "Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.",
"authors": "Lee|Andrew R|AR|;Sharma|Sumit|S|;Mahmoud|Tamer H|TH|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000299",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "11(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D009395:Nephritis, Interstitial; D012164:Retinal Diseases; D055213:Retinal Pigment Epithelium; D012189:Retrospective Studies; D014227:Triazines; D014605:Uveitis; D055815:Young Adult",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "100-103",
"pmc": null,
"pmid": "26967965",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME WITH A PRIMARY PRESENTATION OF ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY.",
"title_normalized": "tubulointerstitial nephritis and uveitis syndrome with a primary presentation of acute posterior multifocal placoid pigment epitheliopathy"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2017068910",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
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"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nMethadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins.\n\n\nOBJECTIVE\nTo investigate the metabolic derangement of the white matter (WM) and blood-brain barrier (BBB) after DAL caused by methadone overdose.\n\n\nMETHODS\nCase report of 2 patients with DAL after a single dose of \"diverted\" methadone used for pain control.\n\n\nRESULTS\nIn both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging ((1) H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired.\n\n\nCONCLUSIONS\nMethadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods.",
"affiliations": "Department of Neurology, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA. bhuisa@unm.edu",
"authors": "Huisa|Branko N|BN|;Gasparovic|Charles|C|;Taheri|Saeid|S|;Prestopnik|Jillian L|JL|;Rosenberg|Gary A|GA|",
"chemical_list": "D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1552-6569.2011.00669.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-2284",
"issue": "23(3)",
"journal": "Journal of neuroimaging : official journal of the American Society of Neuroimaging",
"keywords": "Hypoxic ischemic injury; MR spectroscopy; coma; dynamic contrast enhanced MRI; perfusion MRI",
"medline_ta": "J Neuroimaging",
"mesh_terms": "D000328:Adult; D001812:Blood-Brain Barrier; D002561:Cerebrovascular Disorders; D062787:Drug Overdose; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008691:Methadone; D055815:Young Adult",
"nlm_unique_id": "9102705",
"other_id": null,
"pages": "441-4",
"pmc": null,
"pmid": "22211853",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "9371929;19252780;19196933;16971632;19450568;10448796;15832538;4685708;18195154;21413067;16627790;17021399;15717005;9756602;14487254",
"title": "Imaging of subacute blood-brain barrier disruption after methadone overdose.",
"title_normalized": "imaging of subacute blood brain barrier disruption after methadone overdose"
} | [
{
"companynumb": "US-MALLINCKRODT-T201503698",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "The combination chemotherapy regimen of eribulin (ERI) and trastuzumab (TRA)-the ERI-TRA regimen-has been shown to be highly tolerable for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no sufficient clinical evidence is available for the long-term safety profile of the regimen. We report on three patients in the Phase I combination study of the regimen, for whom the regimen could be conducted over the long term. Patient #1 was a 68-year-old woman and underwent the regimen until cycle 23. Patient #2 was a 61-year-old woman and underwent the regimen until cycle 27. Patient #3 was a 59-year-old woman and underwent the regimen until cycle 22. All these patients had undergone TRA-based combination therapy before the onset of the regimen. Any new categories of adverse events did not occur in association with the long-term combination chemotherapy. Neutropenia experienced by these patients was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Neither increase in the risk of cardiomyopathy nor the worsening of peripheral neuropathy greater than grade 1 was found. The present regimen was suggested to be a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer. The fact that the long-term ERI-TRA regimen was successfully conducted for these patients can be supplementary clinical information that is beneficial for clinical oncologists.",
"affiliations": "1Department of Breast Oncology, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka, Saitama, 350-1298 Japan.;2Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo, 135-0141 Japan.;3Division of Medical Oncology, Department of Medicine, Showa University Koto Toyosu Hospital, 5-1-38, Toyosu, Koto-Ku, Tokyo, 135-8577 Japan.;1Department of Breast Oncology, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka, Saitama, 350-1298 Japan.;4Division of Medical Oncology, Department of Medicine, Showa University Fujigaoka Hospital, 1-30, Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501 Japan.;5Department of Medical Oncology, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka, Saitama, 350-1298 Japan.;6Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577 Japan.",
"authors": "Saeki|Toshiaki|T|;Araki|Kazuhiro|K|;Shimada|Ken|K|;Shigekawa|Takashi|T|;Nakayama|Hirofumi|H|;Segawa|Yoshihiko|Y|;Mukai|Hirofumi|H|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-016-0253-y",
"fulltext": "\n==== Front\nInt Cancer Conf JInt Cancer Conf JInternational cancer conference journal2192-3183Springer Japan Tokyo 25310.1007/s13691-016-0253-yCase ReportLong-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer Saeki Toshiaki tsaeki@saitama-med.ac.jp 1Araki Kazuhiro 2Shimada Ken 3Shigekawa Takashi 1Nakayama Hirofumi 4Segawa Yoshihiko 5Mukai Hirofumi 61 grid.410802.f0000000122162631Department of Breast Oncology, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka, Saitama, 350-1298 Japan 2 grid.410807.a0000000100374131Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo, 135-0141 Japan 3 grid.410714.70000000088643422Division of Medical Oncology, Department of Medicine, Showa University Koto Toyosu Hospital, 5-1-38, Toyosu, Koto-Ku, Tokyo, 135-8577 Japan 4 grid.412808.70000000417649041Division of Medical Oncology, Department of Medicine, Showa University Fujigaoka Hospital, 1-30, Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501 Japan 5 grid.410802.f0000000122162631Department of Medical Oncology, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka, Saitama, 350-1298 Japan 6 grid.272242.30000000121685385Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 21 6 2016 21 6 2016 10 2016 5 4 178 182 14 2 2016 24 5 2016 © The Author(s) 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 combination chemotherapy regimen of eribulin (ERI) and trastuzumab (TRA)—the ERI-TRA regimen—has been shown to be highly tolerable for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no sufficient clinical evidence is available for the long-term safety profile of the regimen. We report on three patients in the Phase I combination study of the regimen, for whom the regimen could be conducted over the long term. Patient #1 was a 68-year-old woman and underwent the regimen until cycle 23. Patient #2 was a 61-year-old woman and underwent the regimen until cycle 27. Patient #3 was a 59-year-old woman and underwent the regimen until cycle 22. All these patients had undergone TRA-based combination therapy before the onset of the regimen. Any new categories of adverse events did not occur in association with the long-term combination chemotherapy. Neutropenia experienced by these patients was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Neither increase in the risk of cardiomyopathy nor the worsening of peripheral neuropathy greater than grade 1 was found. The present regimen was suggested to be a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer. The fact that the long-term ERI-TRA regimen was successfully conducted for these patients can be supplementary clinical information that is beneficial for clinical oncologists.\n\nKeywords\nBreast cancerEribulinTrastuzumabAnticancer drugCombination chemotherapyhttp://dx.doi.org/10.13039/501100003769Eisaiissue-copyright-statement© The Japan Society of Clinical Oncology 2016\n==== Body\nIntroduction\nWe conducted a Phase I combination study of eribulin (ERI) mesylate and trastuzumab (TRA) in 12 Japanese female patients with HER2-positive metastatic breast cancer [1]. The design of the study consisted of Part 1 (weekly administration of TRA) and Part 2 (triweekly administration of TRA). In both Part 1 and 2, ERI mesylate 1.4 mg/m2 [equivalent to ERI 1.23 mg/m2 (expressed as free base)] was administered intravenously for 2–5 min on days 1 and 8 of each cycle. In Part 1, TRA 4 mg/kg was given by ≥90-minute infusion as the loading dose, followed by ≥30-minute infusion at 2 mg/kg on days 1, 8, and 15 of the 21-day cycle. In Part 2, TRA 8 mg/kg was administered as the loading dose, followed by infusion at 6 mg/kg on day 1 of the second and subsequent 21-day cycles [1]. Consequently, the combination chemotherapy regimen of ERI mesylate 1.4 mg/m2 on days 1 and 8 of the 21-day cycle with weekly or triweekly TRA was shown to be highly tolerable. Results from the Phase I combination study [1] and the Phase II study [2] suggest the reasonableness of further examining the long-term safety profile of the regimen.\n\nWe hereby report on three Japanese patients with HER2-positive metastatic breast cancer for whom this regiment was continued after the cutoff date (August 2, 2013) in the Phase I combination study and in whom subsequent 9-month follow-up revealed that the total number of the chemotherapy cycles had exceeded 20.\n\nCase reports\nPatient #1: A 68-year-old woman in Part 1. The patient had undergone mastectomy for right breast cancer at our hospital and was enrolled in this study because of progressive disease (PD). Immunohistochemistry (IHC) staining revealed HER2 positivity (3+), as well as estrogen receptor (ER) and progesterone receptor (PgR) negativity. The patient had been treated with a combination of tegafur and tamoxifen as anticancer drugs for adjuvant chemotherapy, followed by a combination of TRA and paclitaxel (PTX) for the treatment of breast cancer that recurred. At baseline, the patient had grade 1 peripheral neuropathy but did not present cardiac dysfunction. After enrollment, dose-limiting toxicity (DLT) did not develop. The unequivocal progression of nontarget lesions in the right femur led to treatment discontinuation in cycle 23. Grade 2 or greater adverse events (AEs) in this study included grade 4 neutropenia, grade 3 leukopenia, grade 2 mucositis, grade 2 phlebitis, grade 2 anorexia, grade 2 dysgeusia, and grade 2 alopecia. Reduced left ventricular ejection fraction (LVEF) was not found.\n\nPatient #2: A 61-year-old woman in Part 1. The patient had undergone conservation surgery of the left breast at our hospital and was enrolled in this study because of PD. IHC staining revealed ER and PgR negativity, as well as HER2 positivity (2+) that was subsequently verified by gene amplification by fluorescence in situ hybridization (FISH). The patient had been treated by combination chemotherapy with doxorubicin (DXR) and cyclophosphamide, followed by PTX alone, radiotherapy, and TRA alone. Furthermore, the patient underwent combination chemotherapy with TRA and docetaxel (DTX) for the treatment of breast cancer that recurred. At baseline, the patient had grade 1 peripheral neuropathy but did not present cardiac dysfunction. After enrollment, DLT did not develop. The unequivocal progression of nontarget lesions in the right kidney led to treatment discontinuation in cycle 27. Grade 2 or greater AEs in this study included grade 4 neutropenia, grade 2 leukopenia, grade 2 extravascular leakage at injection site, grade 2 LVEF, grade 2 alopecia, and grade 2 hyperlipidemia. Grade 2 LVEF developed in cycle 19.\n\nPatient #3: A 59-year-old woman in Part 2. The patient could not be treated surgically because of stage IIIc breast cancer and was referred to our hospital for enrollment in this study. IHC staining revealed ER and PgR positivity, as well as HER2 positivity (3+) that was subsequently verified by FISH. The patient had been treated by combination chemotherapy with TRA and PTX, followed by TRA alone. At baseline, the patient had grade 1 peripheral neuropathy but did not present cardiac dysfunction. After enrollment, DLT did not develop. Grade 2 or greater AEs in this study included grade 4 neutropenia, grade 3 febrile neutropenia, grade 3 hypertriglyceridemia, grade 2 leukopenia, grade 2 lymphopenia, grade 2 anemia, grade 2 pyrexia, grade 2 spondylolisthesis, grade 2 stomatitis, and grade 2 urticaria. Treatment was discontinued due to interstitial pneumonia in cycle 22. Reduced LVEF was not found. Patient characteristics at baseline are shown in Table 1.Table 1 Patient characteristics at baseline\n\nVariables\tPatients\t\n\nN = 3*\t\nN = 9†\n\tTotal = 12\t\nER and/or PgR plus disease, n (%)\t1 (33.3)\t4 (44.4)\t5 (41.7)\t\nECOG performance status, n (%)\t\n 0\t0\t5 (41.7)\t5 (41.7)\t\n 1\t3 (100)\t4 (44.4)\t7 (58.3)\t\nNumber of prior chemotherapy regimens, n (%)‡\n\t\n 1\t1 (33.3)\t0\t1 (8.3)\t\n 2\t0\t1 (11.1)\t1 (8.3)\t\n 3\t2 (66.7)\t0\t2 (16.7)\t\n 4\t0\t2 (22.2)\t2 (16.7)\t\n ≥5\t0\t6 (66.7)\t6 (50.0)\t\nMedian (range)\t3.0 (1–3)\t5.0 (2–14)\t4.5 (1–14)\t\nNumber of prior trastuzumab treatment, n (%)‡\n\t\n 1\t2 (66.7)\t1 (11.1)\t3 (25.0)\t\n 2\t1 (33.3)\t3 (33.3)\t4 (33.3)\t\n ≥3\t0\t5 (55.6)\t5 (41.7)\t\nMedian (range)\t1.0 (1–2)\t3.0 (1–5)\t2.0 (1–5)\t\nPrior taxane treatment, n (%)‡\n\t\n 1\t2 (66.7)\t5 (55.6)\t7 (58.3)\t\n 2\t1 (33.3)\t3 (33.3)\t4 (33.3)\t\n 3\t0\t1 (11.1)\t1 (8.3)\t\nPrior anthracycline treatment, n (%)\t1 (33.3)\t5 (55.6)\t6 (50.0)\t\n\nECOG Eastern Cooperative Oncology Group, ER estrogen receptor, PgR progesterone receptor\n\n* Patients who received more than 20 cycles of the treatment\n\n\n†Patients who received less than 20 cycles of the treatment\n\n\n‡Including the neoadjuvant, adjuvant, and therapeutic regimens\n\n\n\n\nThe Phase I combination study described two patients with grade 2 reduced LVEF and indicated no clearly increased risk of severe cardiac dysfunction resulting from the present combination chemotherapy regimen because they recovered within 1 week without requiring treatment. The follow-up subsequent to the cutoff date for the Phase I combination study did not disclose any new case of reduced LVEF (Table 2).Table 2 Adverse events (all grades in ≥10 % of patients and grade 3/4 in total)\n\nPreferred terms in CTCAE, n (%)\tPatients\t\n\nN = 3*\t\nN = 9†\n\tTotal\t\nAll grades\tGrade 3/4\tAll grades\tGrade 3/4\tAll grades\tGrade 3/4\t\nLeukopenia\t3 (100.0)\t2 (66.7)\t9 (100.0)\t8 (88.9)\t12 (100.0)\t10 (83.3)\t\nNeutropenia\t3 (100.0)\t3 (100.0)\t9 (100.0)\t9 (100.0)\t12 (100.0)\t12 (100.0)\t\nAnemia\t2 (66.7)\t0\t6 (66.7)\t0\t8 (66.7)\t0\t\nLymphopenia\t1 (33.3)\t1 (33.3)\t2 (22.2)\t2 (22.2)\t3 (25.0)\t3 (25.0)\t\nFebrile neutropenia\t1 (33.3)\t1 (33.3)\t1 (11.1)\t1 (11.1)\t2 (16.7)\t2 (16.7)\t\nPalpitations\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nNausea\t0\t0\t3 (33.3)\t0\t3 (25.0)\t0\t\nVomiting\t1 (33.3)\t0\t2 (22.2)\t0\t3 (25.0)\t0\t\nConstipation\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nStomatitis\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nPyrexia\t2 (66.7)\t0\t3 (33.3)\t0\t5 (41.7)\t0\t\nMalaise\t2 (66.7)\t0\t1 (11.1)\t0\t3 (25.0)\t0\t\nChest discomfort\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nInjection site reaction\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nLung infection\t0\t0\t2 (22.2)\t0\t2 (16.7)\t0\t\nTonsillitis\t2 (66.7)\t0\t0\t0\t2 (16.7)\t0\t\nALAT increased\t1 (33.3)\t0\t2 (22.2)\t0\t3 (25.0)\t0\t\nASAT increased\t1 (33.3)\t0\t2 (22.2)\t0\t3 (25.0)\t0\t\nBlood CPK increased\t1 (33.3)\t0\t2 (22.2)\t0\t3 (25.0)\t0\t\nEjection fraction decreased§\n\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nDecreased appetite\t3 (100.0)\t0\t3 (33.3)\t0\t6 (50.0)\t0\t\nHypertriglyceridemia\t1 (33.3)\t1 (33.3)\t2 (22.2)\t2 (22.2)\t3 (25.0)\t3 (25.0)\t\nHypophosphatemia\t0\t0\t1 (11.1)\t1 (11.1)\t1 (8.3)\t1 (8.3)\t\nMyalgia\t2 (66.7)\t0\t2 (22.2)\t0\t4 (33.3)\t0\t\nMuscle spasms\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nDysgeusia\t2 (66.7)\t0\t2 (22.2)\t0\t4 (33.3)\t0\t\nPeripheral neuropathy‡\n\t2 (66.7)\t0\t3 (33.3)\t1 (11.1)\t5 (41.7)\t1 (8.3)\t\nHeadache\t1 (33.3)\t0\t1 (11.1)\t0\t2 (16.7)\t0\t\nAlopecia\t3 (100.0)\tNA\t5 (55.6)\tNA\t8 (66.7)\tNA\t\nRash\t2 (66.7)\t0\t3 (33.3)\t0\t5 (41.7)\t0\t\n\nALAT alanine aminotransferase, ASAT aspartate aminotransferase, CPK creatinine phosphokinase, NA not applicable, CTCAE Common terminology criteria for adverse events, Japanese version 4.0\n\n* Patients who received more than 20 cycles of the treatment\n\n\n†Patients who received 20 or less cycles of the treatment\n\n\n‡Including neuropathy peripheral and peripheral sensory neuropathy in preferred terms\n\n\n§Patient #2 developed this change in cycle 19\n\n\n\n\nDiscussion\nAt the onset of the Phase I combination study in 2011, the preferred first-line chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN) [3]—which combined TRA with one and/or two anticancer drugs, e.g., PTX [4, 5], DTX [6–10], capecitabine [CAPE] [7, 11, 12], and vinorelbine [VNR] [10, 13, 14]—were conducted for patients with HER2-positive recurrent or metastatic breast cancer. The package inserts of these anticancer drugs describe the following as major AEs: (1) TRA: cardiomyopathy and anaphylactoid symptoms; (2) PTX: myelosuppression, hypersensitive reaction, and peripheral neuropathy; (3) DTX: myelosuppression, anaphylaxis, and nail disorders; (4) CAPE: dehydration, hand-foot syndrome, and hepatopathy; and (5) VNR: myelosuppression, interstitial pneumonia, pulmonary congestion, and phlebitis. Furthermore, myelosuppression, infections, peripheral neuropathy, and hepatic dysfunction have been reported regarding ERI.\n\nNeutropenia experienced by all 12 patients in the Phase I combination study was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Three of 12 patients, in whom the long-term ERI-TRA regimen could be conducted, showed no increased risk of cardiomyopathy in association with the present regimen; nevertheless, reduced LVEF was observed with two patients prior to the cutoff date. Therefore, cardiac function should be routinely assessed in patients undergoing the ERI-TRA regimen, which is consistent with the recommendation for patients receiving trastuzumab in other combination therapies. Nonhematologic AEs, e.g., nausea, vomiting, pyrexia, and rash, were mild in intensity. Especially, it is of note that this regimen provoked little AEs that considerably affect the quality of life of patients during the chemotherapy cycles, e.g., hypersensitive reaction, nail disorders, phlebitis, as well as hand-foot syndrome observed with PTX, DTX, VNR, and CAPE, respectively. Prior studies of PTX and DTX have reported the incidences of grade 3/4 peripheral neuropathy ranging between 5–35 % [15–17] and 3–14 % [18, 19]. Peripheral neuropathy was grade 1/2 in all 12 patients, except one who had grade 3 peripheral neuropathy. Furthermore, any peripheral neuropathy that worsened to greater than grade 1 was not found in these three patients. At baseline, on the other hand, the patients presented the less number of prior chemotherapy regimens and less exposure to TRA as compared with the remaining nine patients; these facts probably favored the long-term management of the pathology. Examination of the safety profile revealed no emergence of any new categories of AEs associated with long-term combination chemotherapy subsequent to the cutoff date of Phase I combination study, which leads us to consider that the present regimen is safe for a long term. Taken together, we believe that information on the long-term safety of eribulin described above is of clinical relevance for clinical oncologists.\n\nThe objectives of treatment for patients with recurrent or metastatic breast cancer, about whom cure is hopeless, are the extension of their survival and the sustainment of or improvement in their quality of life. Therefore, it is essential to conduct anticancer combination chemotherapy for a longer period of time to fulfill these objectives. In many clinical settings, however, we frequently find treatment difficult to continue because of disease progression, sorts of AEs, loss of efficacy, and others. In fact, the ERI-TRA regimen was discontinued not later than cycle 12 in nine of our 12 patients [1]. The 2015 NCCN Clinical Practice Guidelines in Oncology: Breast Cancer mention two preferred first-line regimens for chemotherapy combinations: pertuzumab (PER), TRA, and DTX; and PER, TRA, and PTX, in addition to other first-line regimens combining TRA with PTX ± carboplatin, DTX, CAPE, or VNR [20]. The results from our analysis indicated no deterioration of hematologic or nonhematologic AEs in three patients of interest, suggesting the potential of the present regimen as a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer.\n\nThe fact that long-term chemotherapy using ERI mesylate in combination with TRA was successfully conducted for patients with recurrent or metastatic HER2-positive breast cancer can be supplementary clinical information that is beneficial for clinical oncologists.\n\n\nFunding to support this study was provided by Eisai Co., Ltd. The authors thank Satoshi Sakima, MD, for his gracious review of the manuscript.\n\nConflict of interest statement\nToshiaki Saeki received lecture fees and research funding from Eisai Co., Ltd. Kazuhiro Araki received research funding from Eisai Co., Ltd. for another study. Yoshihiko Segawa received lecture fees from Eisai Co., Ltd. and Chugai Pharmaceutical Co., Ltd., and received research funding from Chugai Pharmaceutical Co., Ltd. Hirofumi Mukai received lecture fees and research funding from Eisai Co., Ltd. Other authors have no conflict of interest to disclose.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\n1. Mukai H Saeki T Shimada K Phase 1 combination study of Eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 33 119 127 10.1007/s10637-014-0161-y 25242374 \n2. Wilks S Puhalla S O’Shaughnessy J Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer Clin Breast Cancer 2014 14 405 412 10.1016/j.clbc.2014.04.004 25024001 \n3. Carlson RW Allred DC Anderson BO Invasive breast cancer J Natl Compr Canc Netw 2011 9 136 222 21310842 \n4. Slamon DJ Leyland-Jones B Shak S Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 783 792 10.1056/NEJM200103153441101 11248153 \n5. Gori S Colozza M Mosconi AM Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer Br J Cancer 2004 90 36 40 10.1038/sj.bjc.6601485 14710203 \n6. Swain SM Kim SB Cortés J Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study Lancet Oncol 2013 14 461 471 10.1016/S1470-2045(13)70130-X 23602601 \n7. Wardley AM Pivot X Morales-Vasquez F Randomized phase II trial of first-line trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer J Clin Oncol 2010 28 976 983 10.1200/JCO.2008.21.6531 20038734 \n8. Marty M Cognetti F Maraninchi D Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment J Clin Oncol 2005 23 4265 4274 10.1200/JCO.2005.04.173 15911866 \n9. Valero V Forbes J Pegram MD Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens J Clin Oncol 2011 29 149 156 10.1200/JCO.2010.28.6450 21115860 \n10. Livingston RB Barlow WE Kash JJ SWOG S0215: a phase II study of docetaxel and vinorelbine plus filgrastim with weekly trastuzumab for HER2-positive, stage IV breast cancer Breast Cancer Res Treat 2011 130 123 131 10.1007/s10549-011-1698-5 21826527 \n11. Schaller G Fuchs I Gonsch T Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes J Clin Oncol 2007 25 3246 3250 10.1200/JCO.2006.09.6826 17577021 \n12. Chan A Conte PF Petruzelka L Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer Anticancer Res 2013 33 2657 2664 23749924 \n13. Andersson M Lidbrink E Bjerre K Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA Study J Clin Oncol 2011 29 264 271 10.1200/JCO.2010.30.8213 21149659 \n14. Esfahani K Ferrario C Le P Panasci L The trastuzumab and vinorelbine combination: an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer Curr Oncol 2014 21 e723 e727 10.3747/co.21.2069 25301539 \n15. Lee JJ Swain SM Peripheral neuropathy induced by microtubule-stabilizing agents J Clin Oncol 2006 24 1633 1642 10.1200/JCO.2005.04.0543 16575015 \n16. Seidman AD Berry D Cirrincione C Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia J Clin Oncol 2008 26 1642 1649 10.1200/JCO.2007.11.6699 18375893 \n17. Winer EP Berry DA Woolf S Duggan D Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342 J Clin Oncol 2004 22 2061 2068 10.1200/JCO.2004.08.048 15169793 \n18. Stubblefield MD Burstein HJ Burton AW NCCN task force report: management of neuropathy in cancer J Natl Compr Canc Netw Suppl 2009 5 S1 S26 \n19. Jones SE Erban J Overmoyer B Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer J Clin Oncol 2005 23 5542 5551 10.1200/JCO.2005.02.027 16110015 \n20. NCCN Clinical Practice Guidelines in Oncology. Breast cancer. Version 2. 2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed April 2015\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2192-3183",
"issue": "5(4)",
"journal": "International cancer conference journal",
"keywords": "Anticancer drug; Breast cancer; Combination chemotherapy; Eribulin; Trastuzumab",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "178-182",
"pmc": null,
"pmid": "31149450",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "11248153;14710203;15169793;15911866;16110015;16575015;17577021;18375893;19755042;20038734;21115860;21149659;21310842;21826527;23602601;23749924;25024001;25242374;25301539",
"title": "Long-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.",
"title_normalized": "long term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2 positive metastatic breast cancer"
} | [
{
"companynumb": "JP-ACCORD-045879",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Ceftriaxone-induced immune hemolytic anemia (CIHA) is the second most common cause of drug-induced hemolytic anemia. Prompt recognition of this drug reaction is essential because brisk hemolysis can be deadly. The extent to which ceftriaxone antibodies persist after CIHA is unknown; rechallenging patients who have experienced CIHA is not recommended. We report a case of CIHA in a neurooncology patient, which is the first to show anticeftriaxone antibodies with Rh specificity and persisted for 8 months after the drug reaction. These findings have implications for understanding the mechanism of CIHA.",
"affiliations": "Children's National Health System, Washington, District of Columbia.;Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia.;Diagnostic Laboratories, Blood Center of Wisconsin, Wisconsin.;Children's National Health System, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia.",
"authors": "Pecker|L H|LH|;Timsar|A|A|;Pary|P P|PP|;Denomme|G A|GA|;Criss|V R|VR|;Luban|N L C|NL|;Hwang|E I|EI|;Wong|E C C|EC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000906:Antibodies; D002443:Ceftriaxone",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(10)",
"journal": "Pediatric blood & cancer",
"keywords": "anemias; blood bank; immune cytopenias; transfusion medicine",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D000900:Anti-Bacterial Agents; D000906:Antibodies; D001932:Brain Neoplasms; D002443:Ceftriaxone; D002675:Child, Preschool; D005260:Female; D005910:Glioma; D006801:Humans",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1852-5",
"pmc": null,
"pmid": "27304608",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Unusual serological findings associated with ceftriaxone-induced immune hemolytic anemia in a child with disseminated low-grade glioma.",
"title_normalized": "unusual serological findings associated with ceftriaxone induced immune hemolytic anemia in a child with disseminated low grade glioma"
} | [
{
"companynumb": "US-ROCHE-1660291",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 35-year-old woman intentionally took 40,000 mg of lithium carbonate, and she was transferred to our hospital with nausea, vomiting, and diarrhea. She was diagnosed as having bipolar disorder 10 years ago and was receiving oral lithium therapy. Blood test results on arrival were remarkable for a negative anion gap of -2.1 and later, the serum lithium level turned out to be as high as 15.4 mEq/L. Intubation was required because of disrupted consciousness, and continuous hemodiafiltration (CHDF) was immediately started in the intensive care unit to obtain constant removal of lithium. After adding intermittent hemodialysis (IHD) twice during the daytime to accelerate the lithium clearance, CHDF became unnecessary on day 4, and she was extubated on day 6 with complete recovery of consciousness. Close monitoring of the patient data showed recovery of the decreased anion gap as indicator of the serum lithium level reduction. On day 36, she was discharged without any complication and sequela. The current case highlighted the effective use of CHDF between IHD sessions to prevent the rebound elevation of lithium and the role of the anion gap as a surrogate marker of serum lithium concentration during the treatment.",
"affiliations": "Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Emergency and General Medicine, JR Tokyo General Hospital, Tokyo, Japan.;Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, Tokyo, Japan.;Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, Tokyo, Japan.",
"authors": "Komaru|Yohei|Y|;Inokuchi|Ryota|R|;Ueda|Yoshihiro|Y|;Nangaku|Masaomi|M|;Doi|Kent|K|",
"chemical_list": "D008094:Lithium",
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12583",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "22(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Lithium; acute-on-chronic; intoxication; renal replacement therapy",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000136:Acid-Base Equilibrium; D000328:Adult; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D008094:Lithium; D006435:Renal Dialysis",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "E15-E18",
"pmc": null,
"pmid": "28796408",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in extremely high dose acute-on-chronic lithium poisoning: A case report.",
"title_normalized": "use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in extremely high dose acute on chronic lithium poisoning a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-148564",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nThe authors report a case of retinal pigment epithelial (RPE) tear following pars plana vitrectomy (PPV), subretinal recombinant tissue plasminogen activator (rt-PA), and intravitreal gas administration for the displacement of large submacular hemorrhage.\n\n\nMETHODS\nA patient with a large submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) received a subretinal rt-PA injection and intravitreal air installation after PPV. Ophthalmic examination included standardized visual acuity testing and fluorescein angiography.\n\n\nMETHODS\nOne patient from the authors' outpatient clinic.\n\n\nRESULTS\nBaseline visual acuity of the eye was 20/160. Ophthalmoscopy showed a predominantly hemorrhagic lesion in the macula. Ophthalmoscopy and fluorescein angiography 2 weeks after the surgery revealed a RPE tear. Postoperative visual acuity was 20/1000.\n\n\nCONCLUSIONS\nThis case demonstrates that a RPE tear is a possible complication of the procedure of subretinal rt-PA and intravitreal air tamponade after PPV for the displacement of a large submacular hemorrhage secondary to neovascular AMD. The surgeon has to be aware about this complication and should inform the patient before surgery.",
"affiliations": "From the Center for Ophthalmology, University of Tuebingen, Germany.",
"authors": "Biester|Sabine|S|;Bartz-Schmidt|Karl U|KU|;Gelisken|Faik|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e318159e813",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "3(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "62-3",
"pmc": null,
"pmid": "25390842",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retinal pigment epithelial tear after subretinal rtpa and intravitreal air for the displacement of a large submacular hemorrhage.",
"title_normalized": "retinal pigment epithelial tear after subretinal rtpa and intravitreal air for the displacement of a large submacular hemorrhage"
} | [
{
"companynumb": "DE-ROCHE-1530806",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "The objective of this study is to evaluate clinical picture, radiological findings and response to treatment in patients with antibiotic associated status epilepticus (SE). In a retrospective review, 12 out of 117 (10%) patients with SE had temporal association with antibiotic administration. Their medical history, clinical findings, and duration and type of SE were recorded. Serum chemistry, blood counts, cranial MRI, EEG and CSF examination were carried out. The offending antibiotics were withdrawn and the patients were treated with phenytoin, lorazepam, sodium valproate or midazolam. The response to treatment was recorded and death during hospital stay noted. The median age of the patients was 36 (18 and 74) years and 5 were females. Eight patients had convulsive and four nonconvulsive SE. The median duration of status was 12 h. The antibiotics related to SE included intravenous cephalosporin (ceftazidime 5, amoxyclavulenic acid 2, piperacillin 2, cefepime 1) and quinolones (levofloxacin 3, ofloxacin 1, ciprofloxacin 2) in isolation or in combinations. Five patients had hepatic (41.7%) and 6 (50%) renal failure; the later received higher than the recommended dose of antibiotics. Cranial MRI was abnormal in 7 out of 9 (77.8%) patients that include cortical lesion in one, corticosubcortical in three and subcortical in three. SE responded to first antiepileptic drug in four and to second in five patients. Three patients (25%) had refractory SE. Eight (66.7%) patients died and death was related to SE in 2 patients. 10% SE patients may be related to antibiotics. Hence the antibiotic should be carefully chosen in patients with hepatic and renal failure, and the dose should be modified.",
"affiliations": "Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226014, India. drukmisra@rediffmail.com",
"authors": "Misra|Usha K|UK|;Kalita|Jayantee|J|;Chandra|Satish|S|;Nair|Pradeep P|PP|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-012-1001-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "34(3)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013226:Status Epilepticus; D055815:Young Adult",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "327-31",
"pmc": null,
"pmid": "22395944",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article",
"references": "11675843;3110537;17784538;8351027;5945968;9330839;9738086;1541177;8122952;14986079;8059139;8884160;10394645;6504330;7910370;16796600;11498064;16278098",
"title": "Association of antibiotics with status epilepticus.",
"title_normalized": "association of antibiotics with status epilepticus"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-00531",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is rare but potentially fatal in children. Fever and rash, which are salient features of DRESS, may mimic other commonly encountered pediatric conditions. We profiled the DRESS cases in a tertiary children's hospital in Singapore.\n\n\nMETHODS\nThe medical records of all pediatric DRESS patients diagnosed from 2006 to 2016. Data on epidemiology, inciting drugs, clinical, pathologic manifestations, and treatment were assessed.\n\n\nRESULTS\nTen patients aged 4-16 years old were diagnosed with DRESS within the 10-year period. Drugs implicated were antibiotics, such as trimethoprim-sulfamethoxazole, and anticonvulsants, such as carbamazepine, phenobarbitone, and levetiracetam. All patients had fever and pruritic exanthems. Desquamation, purpura, and oral mucositis were also observed. Lymphadenopathy, hepatomegaly, and facial edema occurred frequently. There was liver involvement in all cases, but none progressed to liver failure. Seven patients had eosinophilia, and nine had atypical lymphocytosis. Other laboratory abnormalities included low hemoglobin, thrombocytosis, and prolonged coagulation times. All patients received systemic corticosteroids of varying durations and dosages. Systemic steroids were weaned after 19 days to 4 months. Disease resolution, with liver enzyme levels returning to normal, occurred within 28-90 days. One patient developed TSH-receptor-antibody-positive hyperthyroidism 6 months after the onset of DRESS, while another patient developed chronic urticaria 4 months after resolution of DRESS.\n\n\nCONCLUSIONS\nEarly recognition of DRESS is important to ensure that the inciting drug is discontinued, and supportive treatment started expediently. Liver involvement was very common but responded well to systemic steroids.",
"affiliations": "Dermatology Service, KK Women's and Children's Hospital, Singapore, Singapore.;Dermatology Service, KK Women's and Children's Hospital, Singapore, Singapore.;Dermatology Service, KK Women's and Children's Hospital, Singapore, Singapore.",
"authors": "Han|Xiuhui D|XD|https://orcid.org/0000-0002-7778-4558;Koh|Mark J-A|MJ|;Wong|Sharon M Y|SMY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13812",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "36(3)",
"journal": "Pediatric dermatology",
"keywords": "DRESS (drug reaction with eosinophilia and systemic symptoms); drug reaction; eosinophilia; pediatric drug reaction; systemic symptoms",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D044466:Asians; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D008297:Male; D011379:Prognosis; D012307:Risk Factors; D012846:Singapore",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "324-329",
"pmc": null,
"pmid": "30920020",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug reaction with eosinophilia and systemic symptoms in a cohort of Asian children.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms in a cohort of asian children"
} | [
{
"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213420",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
... |
{
"abstract": "In recent years, denosumab has been used to treat giant cell tumour of bone (GCTB) not only in cases where surgery is complicated but also preoperatively to decrease the preoperative grade or to facilitate surgery for Campanacci grade II and III cases. However, there are no clear protocols regarding the preoperative use of denosumab before en bloc resection. There are a few reports of recurrent cases after en bloc resection; however, the association with the use of denosumab is unknown. We present the clinical, radiological and histopathological findings of a case of Campanacci grade III GCTB at the distal end of the ulna, which resulted in soft tissue recurrence after en bloc resection with the preoperative use of denosumab.",
"affiliations": "Orthopaedic, Aichi Cancer Center, Nagoya, Aichi, Japan nfujihara@aichi-cc.jp.;Orthopaedic, Aichi Cancer Center, Nagoya, Aichi, Japan.;Orthopaedic, Aichi Cancer Center, Nagoya, Aichi, Japan.;Orthopaedic, Aichi Cancer Center, Nagoya, Aichi, Japan.",
"authors": "Fujihara|Nasa|N|http://orcid.org/0000-0002-4197-0586;Hamada|Shunsuke|S|;Yoshida|Masahiro|M|;Tsukushi|Satoshi|S|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-245022",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbcr-2021-245022\n10.1136/bcr-2021-245022\nCase Report\n1506\n1560\n1316\n334\n1349\n622\nRecurrent giant cell tumour of the distal ulna after en bloc resection with preoperative denosumab use\nhttp://orcid.org/0000-0002-4197-0586\nFujihara Nasa\nHamada Shunsuke\nYoshida Masahiro\nTsukushi Satoshi\nOrthopaedic, Aichi Cancer Center, Nagoya, Aichi, Japan\nCorrespondence to Dr Nasa Fujihara; nfujihara@aichi-cc.jp\n2021\n11 11 2021\n11 11 2021\n14 11 e24502212 10 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nIn recent years, denosumab has been used to treat giant cell tumour of bone (GCTB) not only in cases where surgery is complicated but also preoperatively to decrease the preoperative grade or to facilitate surgery for Campanacci grade II and III cases. However, there are no clear protocols regarding the preoperative use of denosumab before en bloc resection. There are a few reports of recurrent cases after en bloc resection; however, the association with the use of denosumab is unknown. We present the clinical, radiological and histopathological findings of a case of Campanacci grade III GCTB at the distal end of the ulna, which resulted in soft tissue recurrence after en bloc resection with the preoperative use of denosumab.\n\nmusculoskeletal and joint disorders\northopaedics\northopaedic and trauma surgery\nprosthesis failure\nspecial-featureunlocked\n==== Body\npmcBackground\n\nGiant cell tumour of bone (GCTB) accounts for 20% of benign bone tumours and is slightly more common in women aged 20–40 years. Tumours often occur in the epiphysis and metaphysis of long bones, half of which are located around the knee.1\n\nIn the distal forearm, the distal radius is the most affected site, accounting for 10% of all GCTB cases, followed by GCTB of the ulna accounting for 3%–6%; however, GCTB of the hand is relatively rare, accounting for 2%–3% of cases.2 3\n\nTraditionally, the only treatment option for GCTB was surgery; however, after the approval by the Food and Drug Administration in 2013, denosumab has been more actively used as a medication for GCTB. Denosumab binds to and inhibits the receptor activator of nuclear factor-kappa B ligand; its ability to reduce the formation and activation of osteoclasts has been effectively used for unresectable GCTB or preoperative downstaging of cases with extraskeletal extension. However, some of the recent evidence suggests that the preoperative use of denosumab is associated with higher postoperative recurrence in cases involving bone curettage; therefore, it should be used with caution.4 5 While there is no consensus on how to use denosumab when performing en bloc resection, a few case reports have suggested that it is suitable for clarifying the resection margin, thereby facilitating surgery.\n\nIn this study, we report a rare case of GCTB at the distal end of the ulna that developed soft tissue recurrence despite en bloc resection. Furthermore, we review the outcomes of distal ulna GCTB over the past 10 years during the denosumab era. The patient referenced in this case report provided written consent after being informed that all clinical data from the case would be submitted for publication. This study was approved by our institutional review board.\n\nCase presentation\n\nA 26-year-old woman presented at our institution after experiencing progressive swelling and pain in the left wrist of her non-dominant hand over the previous 7 months. She had no history of trauma; however, the primary doctor diagnosed it as a postfracture condition. At a local clinic, the patient underwent observation for 3 months and was prescribed painkillers without any rehabilitation or X-ray examination. During our initial examination, we observed that the patient exhibited a limited range of motion (ROM) in the wrist, with 45°, 50°, 90° and 20° of extension, flexion, pronation and supination of the forearm, respectively. She had severe pain on the ulnar side of her wrist joint; however, there was no numbness in her fingers. The blood test findings were normal, and the possibility of metabolic diseases, infection or osteomyelitis was considered to be low.\n\nInvestigations\n\nRadiography (figure 1A) and MRI revealed an expansive Campanacci grade III osteolytic lesion. T1-weighted images showed low-signal to iso signal intensity, and T2-weighted images revealed heterogeneous high-signal and mixed low-signal areas due to haemosiderin and fibrosis. In addition, gadolinium-based MRI scans showed prominent contrast effect, which is typical of GCTB. Incisional biopsy was performed using local anaesthesia, and a pathological diagnosis of GCTB was made.\n\nFigure 1 (A) Subarticular lytic expansile lesion of the distal ulna in the epiphysis and metaphysis showing a ‘soap bubble appearance’. (B) After five injections of the oncology dose of denosumab, there is surrounding osteosclerosis and clarification of internal septations.\n\nTreatment\n\nThe patient was started on an oncology dose (120 mg) of denosumab to reduce the tumour volume. Denosumab was administered with a 2-week interval between the first and second doses and every 4 weeks thereafter for a total of five doses. After five injections of denosumab, the patient’s wrist pain resolved and the ROM improved to 60° of supination, 60° of dorsal flexion and 70° of volar flexion. X-ray imaging revealed tumour shrinkage and osteosclerosis of the margins (figure 1B).\n\nSurgical resection was performed under general anaesthesia 5 months after the first presentation. En bloc bone resection and ulnar stabilisation were performed using the extensor carpi ulnaris (ECU) tendon because the original tumour was Campanacci grade III, which has a high reported rate of local recurrence, particularly in areas where it is difficult to perform curettage treatment, such as the distal forearm or finger bones. A portion of the ulna, measuring 7 cm, was resected. The ECU tendon was cut into half at the distal end, passed through a hole at the end of the ulna and fixed to the flexor carpi ulnaris tendon. Subsequently, the extensor retinaculum was partially inverted and sutured to the ECU tendon to stabilise the ulnar bone (figure 2).\n\nFigure 2 (A) Postoperative radiograph of the wrist after the first operation during which a 7 cm resection of the distal end of the ulna was performed. (B) The ECU tendon was cut into half and sutured to the flexor carpi ulnaris tendon through the bony hole of the ulnar end. The extensor retinaculum was partially inverted and sutured to the ECU tendon. This illustration was drawn by Nasa Fujihara. ECU, extensor carpi ulnaris; FCU, flexor carpi ulnaris.\n\nIn the final pathological evaluation, no variable cells were detected in the resection specimen, suggesting that denosumab had been fully effective (figure 3). However, 22 months after the initial surgery, the patient again experienced swelling on the ulnar side of the left wrist joint, which was left untreated because of her work schedule.\n\nFigure 3 (A) Excised specimen. (B) Destruction of the osteoid and replacement with relatively loose fibrous tissues. There is increased fibrotic cell growth; variable giant cell tumour cells are absent (stain, H&E; original magnification, ×40).\n\nShe presented at the hospital with an obvious mass-like lesion at 27 months after the first surgery. The X-ray imaging revealed scattered calcification at the margins, indicating soft tissue recurrence. MRI revealed the recurrence of an oval-shaped tumour measuring 6 cm in the soft tissues of the distal ulna, with an internal signal similar to that of a GCTB—low T1 and iso signal to high T2 signal. In addition, the tumour displayed a contrast effect, similar to that of a GCTB (figure 4). CT was also performed to check for lung metastases, which revealed no distant metastases.\n\nFigure 4 (A) Scattered calcifications and osteogenesis along the periosteum of the ulnar stamp. (B) T2-weighted MRI image shows high and low heterogeneous signal areas. (C) Recurrent soft tissue tumours display a prominent contrast effect.\n\nAfter five additional denosumab injections, marginal resection was performed. The surrounding soft tissues of the ECU tendon were scarred and sclerotic, whereas the remaining ulnar fragment was stable after resection; therefore, a simple resection was adequate. Postoperative pathological evaluation revealed a consistent recurrence of GCTB and variable tumour cells (figure 5), suggesting that the second set of denosumab injections might not have been as effective as the first.\n\nFigure 5 (A) Resected specimen during the second operation. (B) Mononuclear short spindle-shaped cells proliferated with multinucleated giant cells; osteogenesis is observed. There is no osteoid, and the patient is positive for H3.3G34W mutation-specific antibodies, consistent with the recurrence of giant cell tumour of bone. Vascular invasion is also present. Most tumours are viable giant cell tumour tissues (stain, H&E; original magnification, ×40).\n\nOutcome and follow-up\n\nThere was no evidence of tumour recurrence or worsening of the ROM of the wrist at a year after the second surgery.\n\nDiscussion\n\nThere is no established treatment for Campanacci grade II and III distal ulnar GCTB; nevertheless, en bloc resection has been the empirical choice to prevent tumour recurrence unless the patient specifically asks to preserve his or her joints. A review of the literature of the past 10 years since denosumab was first clinically used revealed that there were 19 reports describing 44 cases of Campanacci grade II and III distal ulnar GCTB (table 1).\n\nTable 1 Case reports of Campanacci grade II and III distal ulna giant cell tumour of bone in the previous 10 years\n\nAuthor\tYear\tJournal\tAge/Sex\tCampanacci\tTreatment\tReconstruction\tRecurrence\tWrist function\tDenosumab\tFollow-up (months)\t\nArchik et al28\t2017\tJ Cancer Res Ther\t24 /M\tII\tR\t \tNo\tFull ROM\t \t1.5\t\nAycan et al6\t2019\tActa Orthop Traumatol Turc\t27 /F\t \tC\t \tYes—after 14 years\tMSTS 9/30\t \t172\t\n \t\t \t24 /M\t \tC\t \tNo\tMSTS 24/30\t \t12\t\nFerguson et al13\t2015\tJHS E\t48 /F\tII\tR\tStabilisation with ECU\tNo\tFull ROM\t \t24\t\n \t\t \t22 /F\tIII\tR\tStabilisation with ECU\tNo\tFull ROM\t \t24\t\nGracia et al14\t2011\tStrategies Trauma Limb Reconstr\t56 /M\tIII\tR\tProsthesis\tNo\tFull ROM\t \t24\t\nJamshidi et al7\t2018\tMed J Islam Repub Iran\t29 /M\tII\tC\t \tNo\tMSTS 93.3%\t121\t\n \t\t \t19 /F\tII\tC\t \tNo\tMSTS 96.6%\t99\t\n \t\t \t65 /F\tII\tC\t \tNo\tMSTS 93.3%\t54\t\n \t\t \t36 /F\tII\tC\t \tNo\tMSTS 90%\t \t43\t\n \t\t \t27 /F\tIII\tR\t \tNo\tMSTS 83.3%\t67\t\n \t\t \t28 /M\tIII\tR\t \t(Yes—after the initial curettage)\tMSTS 90%\t \t56\t\n \t\t \t29 /M\tIII\tR\t \t(Yes—after the initial curettage)\tMSTS 93.9%\t \t72\t\n \t\t \t27 /F\tIII\tR\t \tNo\tMSTS 83.3%\t \t79\t\n \t\t \t29 /M\tIII\tR\t \tNo\tMSTS 93.3%\t25\t\nJeejesh et al8\t2020\tInt J Surg Case Rep\t19 /F\tII\tC\t \tNo\tFull ROM\t \t24\t\nJones et al15\t2020\tHAND(NY)\t29 /M\tIII\tR\tProsthesis\tNo\tFull ROM\t \t24\t\nKotrych et al16\t2011\tJHS E\t35 /M\tIII\tR\tProsthesis\tNo\tDASH 42\t \t24\t\nMcCarthy et al21\t2017\tClin Sarcoma Res\t39 /F\tII\tR\t \tNo\t \tPreop\t54\t\nJones and Graham7\t2020\tInt J Surg Case Rep\t43 /M\tIII\tR\tStabilisation with ECU\tNo\tMSTS 25/30\t \t10\t\n \t\t \t31 /F\tIII\tR\tstabilisation with ECU\tNo\tMSTS 24/30\t \t10\t\nKotrych et al18\t2013\tIndian J Orthop\t43 /M\tIII\tR\tS-K with bone graft\tNo\tFull ROM\t \t36\t\nPapanastassiou et al9\t2019\tHAND(NY)\t44 /F\t \tR\t \tNo\tMSTS 30/30\t \t30\t\n \t\t \t25 /F\t \tR\tStabilisation with ECU\tNo\tMSTS 29/30\t \t108\t\n \t\t \t65 /M\t \tR\t \tNo\tMSTS 30/30\t \t60\t\n \t\t \t40 /F\tIII\tR\t \tNo\tMSTS 29/30\t \t30\t\n \t\t \t37 /F\tIII\tR\tStabilisation with ECU\tNo\tMSTS 28/30\t \t30\t\n \t\t \t24 /M\t \tR\t \t(Yes—after the initial curettage)\tMSTS 23/30\t \t30\t\n \t\t \t24 /F\t \tR\t \tNo\tMSTS 29/30\t \t60\t\n \t\t \t28 /M\t \tR\tStabilisation with ECU\t(Yes-after the initial curettage)\tMSTS 21/30\t \t24\t\n \t\t \t44 /F\tIII\tR\tStabilisation with ECU\tNo\tMSTS 29/30\t \t24\t\nPark et al12\t2014\tSkeletal Radiol\t35 /F\tIII\tR\t \tYes—after 21 months\t \t \t\t\nSanchez-Pareja et al22\t2016\tInt J Surg Pathol\t35 /M\tIII\tR\t \tNo\t \tPreop\t\t\nThiounn et al19\t2017\tHand Surg Rehabil\t60 /F\tIII\tR\tProsthesis and stabilisation with BR\tNo\tDASH 40.9\t \t18\t\n \t\t \t52 /M\tIII\tR\tProsthesis and stabilisation with BR\tNo\tDASH 42.5\t \t18\t\nTsai et al20\t2019\tJBJS Case Connect\t33 /M\tII\tR\tS-K with bone graft\tNo\t DASH 4.5\t \t12\t\nVanni et al10\t2012\tJ Med Case Rep\t17 /M\tII\tC\t \tNo\tFull ROM\t \t36\t\nvon Borstel et al11\t2017\tSkeletal Radiol\t29 /M\tIII\tC\t \tYes—after 5 months\t \tPreop\t\t\nZhan et al29\t2016\tMol Clin Oncol\t\tII to III, 6 cases\tR\t \tNo\t \t \t\t\nBR, brachioradialis; C, curettage; DASH Score, The Disabilities of the Arm, Shoulder and Hand Score; ECU, extensor carpi ulnaris; MSTS, Musculoskeletal Tumor Society scoring system; R, resection; S-K, Sauvé-Kapandji.\n\nIn 13 cases, bone curettage was performed in the initial surgery,6–11 in which at least three were grade III cases. However, there was local recurrence in all grade III cases,7 11 suggesting that en bloc resection is necessary in such conditions. Among the patients who underwent en bloc resection in the first surgery, only one exhibited local recurrence; this was a soft tissue recurrence, as noted in the present case.12 Tendons or implants were used for reconstruction in 15 cases (15/35, 42.9%),9 13–20 and all these cases exhibited favourable postoperative results. The most common method for stabilisation of the ulnar stump is using the ECU tendon.9 13 17 In three studies, prosthetic reconstruction with implant arthroplasty of the distal radioulnar joint was reported,14–16 while reconstruction of the distal radioulnar joint using an iliac bone block and screws—a modification of the Sauvé-Kapandji procedure—was reported in two studies.18–20 Ferguson et al13 and Papanastassiou et al9 reported that reconstruction was not essential based on case comparisons of their own studies. In fact, in more than half of the reviewed cases, no reconstruction was performed, and almost all obtained favourable results (average Musculoskeletal Tumor Society scoring system score: 88.7%, range 30%–100%). Although the indication remains controversial, unlike in cases of trauma, reconstruction of the distal ulnar portion may not be mandatory in cases of slow-growing tumours if the tumour size is relatively small. However, considering that in most cases there was no long-term follow-up, we believe that it is better to consider reconstruction, particularly in younger patients when the disadvantages of reconstruction are not significant. In the present case, we obtained favourable results by resecting 7 cm (distal one-third portion) of the ulna and reconstructing it using the ECU tendon, which is the most common reconstruction method.\n\nDenosumab was used as a preoperative adjuvant in three cases (3/45, 6.7%).11 21 22 In all cases, denosumab was used in the same dosage and manner (120 mg every 4 weeks with additional loading doses of 120 mg on days 8 and 15 of the first month) for 3–6 months. In addition, denosumab was used only preoperatively in all three cases. There were no reports of decreased efficacy when used at the time of recurrence, as in this case. McCarthy et al21 described the effects of a short preoperative course of denosumab on distal forearm GCTB, and all patients experienced some pain relief after initiating denosumab. They suggested that the origin of pain may be multifactorial, including mechanical stress from tumour-related pressure, expansion of the periosteum, loss of structurally significant bone and mechanical failure. In addition, the production of prostaglandins, endothelin and other noxious factors by the tumour itself is known to cause pain. Similar to that report, in our case, short-term preoperative denosumab use resulted in pain alleviation and improvement in ROM of the wrist. Sanchez-Pareja et al22 reported that a slight tumour enlargement was observed immediately after denosumab use. Although there was some concern regarding sarcomatous changes, they ultimately concluded that the changes were a reactive phenomenon. In our case, osteosclerosis was observed, as reported in other studies,21 22 which might have facilitated the removal of the tumour but did not reduce its size.\n\nA recent review of the preoperative use of denosumab in treating GCTB5 suggests that it should be avoided owing to the risk of tumour cells getting trapped in the sclerotic bone cortex and that bone curettage is the treatment of choice. However, there is no definitive indication regarding its use when en bloc resection is performed.4 5 23 In our case, the sclerosis of the mass edges and the degree of swelling that reduced the patient’s pain and ROM restriction proved advantageous and facilitated surgical resection; however, soft tissue recurrence was a disadvantage. It is possible that dormant tumour cells that remained in the soft tissues could have been activated when denosumab was discontinued after the surgery.24\n\nGiven the effect of denosumab on the tumour, it may be necessary to continue its use as adjuvant therapy even after surgery; however, evidence on the safety of long-term denosumab use in young patients has not been established.24 25 Furthermore, a previous report discussed a rare case wherein sarcomatous changes were observed after denosumab use.26 Therefore, the effects of long-term use of denosumab in young patients with GCTB require further investigation, and more case studies are necessary. Furthermore, there is no report that denosumab use could contribute to soft tissue recurrence. Tumour recurrence in the soft tissues after en bloc resection itself is rare (1.5%–3.1%).27 It is also possible that there are consequences to denosumab discontinuation; nevertheless, details of the pharmacological effects are unknown.\n\nIn summary, we report a rare case of distal ulnar GCTB where soft tissue recurrence occurred despite performing en bloc resection. A review of the literature revealed that patients with grade III distal ulnar GCTB require at least en bloc resection; however, reconstruction may not be mandatory in some cases. Preoperative denosumab use alone may be insufficient to achieve acceptable oncological outcomes. It is also possible that denosumab may be less effective at the time of tumour recurrence. The duration and appropriate dose of denosumab should be investigated in future research.\n\nLearning points\n\nThis is a rare case of giant cell tumour of bone wherein the patient developed soft tissue recurrence despite undergoing en bloc resection.\n\nIt is unclear whether the use of denosumab affected the soft tissue recurrence.\n\nThe therapeutic effect of denosumab at the time of recurrence was possibly poor.\n\nEthics statements\n\nPatient consent for publication\n\nConsent obtained directly from patient(s)\n\nTwitter: @fujinasa\n\nContributors: ST provided supervision. The patient was under the care of ST and NF. The report was written by NF, SH and MY. Figure 2B was created by NF.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Hakim DN, Pelly T, Kulendran M, et al . Benign tumours of the bone: a review. J Bone Oncol 2015;4 :37–41. 10.1016/j.jbo.2015.02.001 26579486\n2 Verschoor AJ, Bovée JVMG, Mastboom MJL, et al . Incidence and demographics of giant cell tumor of bone in the Netherlands: first nationwide pathology registry study. Acta Orthop 2018;89 :570–4. 10.1080/17453674.2018.1490987 29987945\n3 Biscaglia R, Bacchini P, Bertoni F. Giant cell tumor of the bones of the hand and foot. Cancer 2000;88 :2022–32. 10.1002/(SICI)1097-0142(20000501)88:9<2022::AID-CNCR6>3.0.CO;2-Y 10813712\n4 Urakawa H, Yonemoto T, Matsumoto S, et al . Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study. World J Surg Oncol 2018;16 :160. 10.1186/s12957-018-1459-6 30089488\n5 Yayan J. Denosumab for effective tumor size reduction in patients with giant cell tumors of the bone: a systematic review and meta-analysis. Cancer Control 2020;27 :107327482093482. 10.1177/1073274820934822\n6 Aycan OE, Sökücü S, Özer D, et al . Primary bone tumors and tumor like lesions of the ulna. Acta Orthop Traumatol Turc 2019;53 :30–4. 10.1016/j.aott.2018.04.005 29773449\n7 Jamshidi K, Bahrabadi M, Bagherifard A, et al . Surgical treatment outcome of giant cell tumor of distal ulna: en bloc resection vs. curettage and bone graft. Med J Islam Repub Iran 2018;32 :249–53. 10.14196/mjiri.32.44\n8 T K JK, Pai PK, Rajasubramanya P. Two rare cases of giant cell tumor of distal ulna. Int J Surg Case Rep 2020;76 :474–9. 10.1016/j.ijscr.2020.10.010 33207413\n9 Papanastassiou ID, Savvidou OD, Chloros GD, et al . Extensor carpi ulnaris tenodesis versus no stabilization after wide resection of distal ulna giant cell tumors. Hand 2019;14 :242–8. 10.1177/1558944717743598 29182026\n10 Vanni D, Pantalone A, Andreoli E, et al . Giant cell tumor of the distal ulna: a case report. J Med Case Rep 2012;6 :143. 10.1186/1752-1947-6-143 22657940\n11 von Borstel D, A. Taguibao R, A. Strle N, et al . Giant cell tumor of the bone: aggressive case initially treated with denosumab and intralesional surgery. Skeletal Radiol 2017;46 :571–8. 10.1007/s00256-017-2588-7 28188337\n12 Park S-Y, Lee MH, Lee JS, et al . Ossified soft tissue recurrence of giant cell tumor of the bone: four case reports with follow-up radiographs, CT, ultrasound, and MR images. Skeletal Radiol 2014;43 :1457–63. 10.1007/s00256-014-1898-2 24816907\n13 Ferguson KB, Jane M, Mahendra A. Giant cell tumour of the distal ulna: is reconstruction required after excision of the distal third of the ulna? J Hand Surg Eur Vol 2016;41 :771–2. 10.1177/1753193415568912 25646142\n14 Gracia I, Proubasta IR, Trullols L, et al . Distal radioulnar joint prosthesis for the treatment of giant cell tumor of the distal ulna: a case report and literature review. Strategies Trauma Limb Reconstr 2011;6 :103–6. 10.1007/s11751-011-0113-4 21773775\n15 Jones NF, Graham DJ. Radical resection of a recurrent giant cell tumor of the distal ulna and immediate reconstruction with a distal radio-ulnar joint implant arthroplasty. HAND 2020;15 :NP68–72. 10.1177/1558944719895779\n16 Kotrych D, Żyluk A, Walaszek I. Reconstruction of the distal radioulnar joint with a prosthesis after excision of a recurrent giant-cell tumour of the distal ulna. J Hand Surg Eur Vol 2011;36 :428–30. 10.1177/1753193411404348 21490030\n17 Jones NF, Graham DJ. Radical resection of a recurrent giant cell tumor of the distal ulna and immediate reconstruction with a distal radio-ulnar joint implant arthroplasty. Hand 2020;15 :NP68–72. 10.1177/1558944719895779\n18 Kotrych D, Zyluk A, Walaszek I. Reconstruction of the distal radioulnar joint with a prosthesis after excision of a recurrent giant-cell tumour of the distal ulna. J Hand Surg Eur Vol 2011;36 :428–30. 10.1177/1753193411404348 21490030\n19 Thiounn A, Guerre E, Szymanski C, et al . Two cases of distal ulna giant cell tumors treated by extensive resection, prosthetic reconstruction and stabilization using the brachioradialis tendon. Hand Surg Rehabil 2017;36 :419–22. 10.1016/j.hansur.2017.09.002 29054719\n20 Tsai T-C, Chen C-C, Huang H-K, et al . Modified Sauve-Kapandji procedure using iliac bone graft for giant cell tumor of the distal ulna: stabilizing with two-screw fixation: a case report. JBJS Case Connect 2019;9 :e0299. 10.2106/JBJS.CC.18.00299 31211751\n21 McCarthy CL, Gibbons CLMH, Bradley KM, et al . Giant cell tumour of the distal radius/ulna: response to pre-operative treatment with short-term denosumab. Clin Sarcoma Res 2017;7 :19. 10.1186/s13569-017-0085-3 29214010\n22 Sanchez-Pareja A, Larousserie F, Boudabbous S, et al . Giant cell tumor of bone with pseudosarcomatous changes leading to premature denosumab therapy interruption: a case report with review of the literature. Int J Surg Pathol 2016;24 :366–72. 10.1177/1066896916629546 26842345\n23 Li H, Gao J, Gao Y, et al . Denosumab in giant cell tumor of bone: current status and pitfalls. Front Oncol 2020;10 :580605. 10.3389/fonc.2020.580605 33123484\n24 Tsourdi E, Langdahl B, Cohen-Solal M, et al . Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 2017;105 :11–17. 10.1016/j.bone.2017.08.003 28789921\n25 Dempster DW, Brown JP, Fahrleitner-Pammer A, et al . Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 2018;103 :2498–509. 10.1210/jc.2017-02669 29672714\n26 Aponte-Tinao LA, Piuzzi NS, Roitman P, et al . A high-grade sarcoma arising in a patient with recurrent benign giant cell tumor of the proximal tibia while receiving treatment with denosumab. Clin Orthop Relat Res 2015;473 :3050–5. 10.1007/s11999-015-4249-2 25758379\n27 Xu L, Jin J, Hu A, et al . Soft tissue recurrence of giant cell tumor of the bone: prevalence and radiographic features. J Bone Oncol 2017;9 :10–14. 10.1016/j.jbo.2017.09.002 29018768\n28 Archik S, Tripathi SK, Nanda SN, et al . Giant cell tumour of distal ulna. J Cancer Res Ther 2017;13 :586–8. 10.4103/0973-1482.174190 28862232\n29 Zhang J, Li Y, Li D, et al . 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"journal": "BMJ case reports",
"keywords": "musculoskeletal and joint disorders; orthopaedic and trauma surgery; orthopaedics; prosthesis failure",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D000069448:Denosumab; D018212:Giant Cell Tumor of Bone; D006801:Humans; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D014457:Ulna",
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"pubdate": "2021-11-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29214010;21490030;28789921;33123484;31965863;29018768;33207413;29182026;10813712;25646142;28862232;25758379;29987945;31211751;29054719;27900098;24816907;26842345;29672714;26579486;32869648;28188337;22657940;21773775;30159295;29773449;30089488",
"title": "Recurrent giant cell tumour of the distal ulna after en bloc resection with preoperative denosumab use.",
"title_normalized": "recurrent giant cell tumour of the distal ulna after en bloc resection with preoperative denosumab use"
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... |
{
"abstract": "BACKGROUND\nContraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels.\n\n\nMETHODS\nA 28-year-old Caucasian active-duty male with a history of autosomal dominant polycystic kidney disease and diarrhea-predominant Irritable Bowel Syndrome (D-IBS) presented to his primary care provider (PCP) with elevated blood pressure (136/96 mmHg), was diagnosed with stage-2 hypertension, and started oral HCTZ (25 mg/day). His medications included dicyclomine (10 mg oral three times daily). Subsequently, (Visit 1), his blood pressure was 130/91 mmHg and he was started on telmisartan (20 mg/day). At Visit 2, 4 weeks later, his blood pressure improved (121/73 mmHg); however, blood chemistry revealed elevated serum CO2 (32 mEq/L) and chloride (94 mmol/L). Four days later, the patient presented to the Emergency Department with dyspnea and swallowing difficulty. The patient returned to his PCP 3 days later complaining of cough, congestion, vomiting, and mild dyspnea, blood pressure of 124/84 mmHg. Two months later, sudden onset of projectile vomiting and abdominal pain while running was reported, resolved by rehydration and a single oral dose of prochlorperazine 25 mg. Three months later, (Visit 3), he complained of lightheadedness and cloudy judgment, suggesting contraction alkalosis. HCTZ was discontinued and telmisartan was increased to 20 mg twice daily. A follow-up blood chemistry panel 2 weeks later revealed serum chloride and CO2 levels within normal limits and blood pressure under 130/80 mmHg.\n\n\nCONCLUSIONS\nThis is the first known report of contraction alkalosis driven by drug-drug interaction between dicyclomine and HCTZ.",
"affiliations": "Department of Clinical and Administrative Sciences, 212874California Northstate University College of Pharmacy, Elk Grove, CA, USA.;Department of Clinical and Administrative Sciences, 212874California Northstate University College of Pharmacy, Elk Grove, CA, USA.;Department of Family Medicine, 9th Medical Group Beale Air Force Base, Beale, CA, USA.;212874California Northstate University College of Pharmacy, Elk Grove, CA, USA.;212874California Northstate University College of Pharmacy, Elk Grove, CA, USA.;Department of Pharmaceutical and Biomedical Sciences, 212874California Northstate University College of Pharmacy, Elk Grove, CA, USA.",
"authors": "Eid|Tony J|TJ|https://orcid.org/0000-0002-8117-949X;Horton|Matthew|M|https://orcid.org/0000-0002-9297-4747;Hendrix|Claire|C|;Yu|Janie M|JM|https://orcid.org/0000-0002-1220-0777;Browning|Elizabeth A|EA|https://orcid.org/0000-0001-9494-996X;Malhotra|Ashim|A|https://orcid.org/0000-0003-0676-9614",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08971900211052829",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "HCTZ; blood pH; contraction alkalosis; dicyclomine; thiazide diuretics",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "8971900211052829",
"pmc": null,
"pmid": "34670427",
"pubdate": "2021-10-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A First Report of HCTZ and Dicyclomine Induced Uncharacteristic Contraction Alkalosis.",
"title_normalized": "a first report of hctz and dicyclomine induced uncharacteristic contraction alkalosis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-318980",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICYCLOMINE HYDROCHLORIDE"
},
... |
{
"abstract": "Supplement use is prevalent, and its use is increasing among older adults. Dermatologists need to be aware of the adverse cutaneous effects that can result from herbal supplement use. A 55-year-old man presented with an eruption in a sebotropic distribution after consuming kava kava for 3 weeks, which resolved after discontinuation of the supplement. This case highlights the need for clinicians to consider kava kava in the differential of sebotropic eruptions. The biology, mechanism of action, and potential systemic and cutaneous effects of kava kava are reviewed.",
"affiliations": "Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.",
"authors": "Huynh|J C|JC|;Asgari|M M|MM|;Moore|M M|MM|",
"chemical_list": "D028321:Plant Preparations",
"country": "England",
"delete": false,
"doi": "10.1111/ced.12439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "39(7)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D019587:Dietary Supplements; D003875:Drug Eruptions; D004890:Erythema; D005076:Exanthema; D006801:Humans; D020901:Kava; D008297:Male; D008875:Middle Aged; D008517:Phytotherapy; D028321:Plant Preparations; D012627:Sebaceous Glands",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "816-8",
"pmc": null,
"pmid": "25214405",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sebotropic eruption associated with use of oral kava kava supplement.",
"title_normalized": "sebotropic eruption associated with use of oral kava kava supplement"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0048121",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nEfforts to achieve balance between effective pain management and opioid-related adverse events (ORAEs) have led to multimodal analgesia regimens. This study compared opioids delivered via patient-controlled analgesia (PCA) plus liposomal bupivacaine, a long-acting local anesthetic with potential to be an effective component of such regimens, to opioids delivered through PCA alone or PCA plus subcutaneous bupivacaine infusion (ONQ), following laparotomy.\n\n\nMETHODS\nProspective, randomized controlled trial.\n\n\nMETHODS\nSingle, tertiary-care institution.\n\n\nMETHODS\nOne hundred patients undergoing nonemergent laparotomy.\n\n\nMETHODS\nPatients were randomly assigned to one of three study treatments: PCA only (PCAO), PCA with ONQ, or PCA with injectable liposomal bupivacaine suspension (EXP).\n\n\nMETHODS\nCumulative opioid use, daily mean patient-reported pain scores, and ORAEs through 72 hours postoperatively.\n\n\nRESULTS\nOn average, the EXP (n = 31) group exhibited less than 50 percent of the total opioid consumption of the PCAO (n = 36) group, and less than 60 percent of that for the ONQ (n = 33) group. Postoperative days 1 and 3 pain scores were significantly lower for the EXP group as compared to the ONQ and PCAO groups (p ≤ 0.005). Fewer patients in the EXP group (19.4 percent) experienced ORAEs compared to the PCAO (41.1 percent) and ONQ (45.5 percent) groups (p = 0.002).\n\n\nCONCLUSIONS\nLaparotomy patients treated with liposomal bupivacaine as part of a multimodal regimen consumed less opioids, had lower pain scores, and had fewer ORAEs. The role of liposomal bupivacaine in the postoperative care of laparotomy patients merits further study.",
"affiliations": "Resident, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Resident, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Attending, Program Director (Surgery), Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Resident, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Resident, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Resident, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Attending, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Attending, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Research Nurse, Department of Research Affairs, Mount Carmel Health System, Columbus, Ohio.;Senior Statistical Analyst, Department of Research Affairs, Mount Carmel Health System, Columbus, Ohio.;Biostatistician, Exponent, Inc., Menlo Park, California.;Attending, Former Program Director (Surgery), Department of Surgery, Mount Carmel Health System, Columbus, Ohio.;Attending, Department of Surgery, Mount Carmel Health System, Columbus, Ohio.",
"authors": "Yalmanchili|Harish M|HM|;Buchanan|Stephanie N|SN|;Chambers|Lowell W|LW|;Thorns|Jantzen D|JD|;McKenzie|Nicholas A|NA|;Reiss|Alisha D|AD|;Page|Maurice P|MP|;Dizon|Victor V|VV|;Brooks|Sheila E|SE|;Shaffer|Lynn E|LE|;Lovald|Scott T|ST|;Hartranft|Thomas H|TH|;Price|Phillip D|PD|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D008081:Liposomes; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.5055/jom.2019.0498",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-7489",
"issue": "15(2)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D006801:Humans; D007267:Injections; D007813:Laparotomy; D008081:Liposomes; D010147:Pain Measurement; D010149:Pain, Postoperative; D011446:Prospective Studies",
"nlm_unique_id": "101234523",
"other_id": null,
"pages": "169-175",
"pmc": null,
"pmid": "31343718",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postlaparotomy pain management: Comparison of patient-controlled analgesia pump alone, with subcutaneous bupivacaine infusion, or with injection of liposomal bupivacaine suspension.",
"title_normalized": "postlaparotomy pain management comparison of patient controlled analgesia pump alone with subcutaneous bupivacaine infusion or with injection of liposomal bupivacaine suspension"
} | [
{
"companynumb": "US-PACIRA-201900262",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROMORPHONE"
},
"drugadditional": null,
... |
{
"abstract": "Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that is potentially life-threatening when presenting with Kasabach-Merritt phenomenon (KMP). KMP is clinically characterized as severe thrombocytopenia and hypofibrinogenemia and therefore is associated with a high mortality rate. There is no standard of cure for KHE currently. Potential medications, including corticosteroids, propranolol, and chemotherapy drugs such as sirolimus, are often used for alleviating KHE symptoms. Although some case reports of sirolimus treatment have shown promising results with recovered coagulant parameters, the off-target effects may cause severe problems. Here we describe 2 cases of infant patients with KHE and KMP who were scheduled to receive sirolimus on a long-term basis. However, both patients developed paroxysmal cough and tachypnea shortly after the onset of sirolimus treatment and succumbed to infection thereafter. This report reveals a potential risk of infection in sirolimus-treated infant patients. The fatal complication highlights the importance of antibiotic prophylaxis and serum sirolimus level monitoring to ensure the safe use of sirolimus in the treatment of infant patients with KHE.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital and School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital and School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital and School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital and School of Medicine, Shanghai Jiao Tong University, Shanghai, China linxiaoxi@126.com.",
"authors": "Ying|Hanru|H|;Qiao|Congzhen|C|;Yang|Xi|X|;Lin|Xiaoxi|X|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2016-2919",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "141(Suppl 5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D001996:Bronchopneumonia; D017809:Fatal Outcome; D005260:Female; D006390:Hemangioendothelioma; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D059885:Kasabach-Merritt Syndrome; D008297:Male; D045803:Mycoplasma pulmonis; D011019:Pneumonia, Mycoplasma; D012514:Sarcoma, Kaposi; D020123:Sirolimus",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "S425-S429",
"pmc": null,
"pmid": "29610165",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Case Report of 2 Sirolimus-Related Deaths Among Infants With Kaposiform Hemangioendotheliomas.",
"title_normalized": "a case report of 2 sirolimus related deaths among infants with kaposiform hemangioendotheliomas"
} | [
{
"companynumb": "CN-PFIZER INC-2018147460",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nIsolated abdominal epilepsia partialis continua (EPC) without the involvement of other body parts is rarely seen. Abdominal EPC usually occurs either as a part of hemibody EPC or as an evolution of refractory EPC after initial treatment. As the isolated abdominal EPC was rarely reported up to date, the data regarding its pathophysiology and management are limited. Herein, we aimed to describe the clinical, neuroimaging, and electroencephalographic findings of a patient with abdominal EPC.\n\n\nMETHODS\nA 48-year-old woman with a history of surgical resection for right posterior frontal astrocytoma was admitted with left abdominal EPC. Magnetic resonance imaging of the brain showed a residual mass lesion and encephalomalacia in the right frontoparietal region.\n\n\nRESULTS\nAlthough the initial electroencephalography (EEG) was normal, independent spikes were detected in the right frontal and parietal derivations in the second EEG. Although her EPC was refractory to levetiracetam, lamotrigine, phenytoin, and gabapentin, oral lacosamide treatment ceased the seizures.\n\n\nCONCLUSIONS\nThe history of this patient emphasizes the necessity of repetitive recordings in case of a normal initial EEG. The independent spikes in her frontal and parietal regions suggested the presence of a large epileptogenic zone generating independent epileptiform activities in the pre-central motor cortex and the post-central sensory cortex as the pathophysiologic phenomena in persistent abdominal EPC. To the best of our knowledge, this is the first report presenting a patient experiencing an abdominal EPC due to a cerebral mass resolved with lacosamide suggesting this drug is a promising treatment option in resistant EPC.",
"affiliations": "Department of Neurology, Sakarya University, Faculty of Medicine, Sakarya, Turkey. dr.alemdar@gmail.com.",
"authors": "Alemdar|M|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.26355/eurrev_202110_26997",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "25(20)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": null,
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "6277-6282",
"pmc": null,
"pmid": "34730207",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Abdominal epilepsia partialis continua in a patient with astrocytoma treated with Lacosamide - value of repetitive EEG recordings.",
"title_normalized": "abdominal epilepsia partialis continua in a patient with astrocytoma treated with lacosamide value of repetitive eeg recordings"
} | [
{
"companynumb": "TR-MLMSERVICE-20211124-3235349-1",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "4... |
{
"abstract": "Percutaneous driveline infections (DI) are leading factors for morbidity and mortality in ventricular assist device (VAD) patients. In recent years, cold atmospheric plasma (CAP) has been safely and effectively used in clinical settings to treat topical infections. We describe the first use of CAP to treat a superficial DI. CAP was applied with the kinPen® MED plasma jet device (neoplas tools GmbH, Greifswald, Germany), in the treatment of a DI in a 66-year-old VAD patient in Klinikum Karlsburg, Germany. The patient received a daily application of CAP of 1 min for 12 days. One CAP application was administered each week for 4 weeks in our outpatient clinic after patient discharge. Laboratory tests were conducted and photographs of the driveline exit site were taken. After CAP treatment, the local infection was completely regressed without any signs of exudation or recurrence of the infection. There were no adverse side effects observed, and the HVAD logfile data did not show any abnormalities during treatment. Here, we demonstrate a successful resolution of a VAD DI with the kinPen plasma jet device. We believe that CAP has the potential to be a simple and effective tool in the treatment of superficial DIs.",
"affiliations": "Clinic for Cardiothoracic Surgery, Klinikum Karlsburg, Karlsburg, Germany hilker@drguth.de ludovici@gmx.de.;Leibniz Institute for Plasma Science and Technology, Greifswald, Germany.;Leibniz Institute for Plasma Science and Technology, Greifswald, Germany.;Clinic for Cardiothoracic Surgery, Klinikum Karlsburg, Karlsburg, Germany.",
"authors": "Hilker|Lutz|L|;von Woedtke|Thomas|T|;Weltmann|Klaus Dieter|KD|;Wollert|Hans-Georg|HG|",
"chemical_list": "D000900:Anti-Bacterial Agents; D058626:Plasma Gases; D002444:Cefuroxime",
"country": "Germany",
"delete": false,
"doi": "10.1093/ejcts/ezw212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-7940",
"issue": "51(1)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Cold atmospheric plasma; Driveline infection; Left ventricle assist device",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D004203:Disinfection; D024881:Drug Resistance, Bacterial; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D058626:Plasma Gases; D016459:Prosthesis-Related Infections",
"nlm_unique_id": "8804069",
"other_id": null,
"pages": "186-187",
"pmc": null,
"pmid": "27354253",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cold atmospheric plasma: a new tool for the treatment of superficial driveline infections.",
"title_normalized": "cold atmospheric plasma a new tool for the treatment of superficial driveline infections"
} | [
{
"companynumb": "PHHY2017DE142639",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient's symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis.\nHCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.",
"affiliations": "Departments of Diabetes and Endocrinology.;Departments of Diabetes and Endocrinology.;Departments of Diabetes and Endocrinology.;Departments of Diabetes and Endocrinology.;Gastroenterology.;Neurology.;Orthopedic Surgery , Tamana Central Hospital, Tamana , Japan.;Department of General and Community Medicine , Kumamoto University Hospital, Kumamoto , Japan.;Orthopedic Surgery , Tamana Central Hospital, Tamana , Japan.",
"authors": "Miyamura|Nobuhiro|N|;Nishida|Shuhei|S|;Itasaka|Mina|M|;Matsuda|Hirofumi|H|;Ohtou|Takeshi|T|;Yamaguchi|Yasuhiro|Y|;Inaba|Daisuke|D|;Tamiya|Sadahiro|S|;Nakano|Tetsuo|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-16-0097EDM160097Unique/Unexpected Symptoms or Presentations of a DiseaseA case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy N Miyamura and othersHCAO controlled by pulse steroid therapyMiyamura Nobuhiro 1Nishida Shuhei 1Itasaka Mina 1Matsuda Hirofumi 1Ohtou Takeshi 2Yamaguchi Yasuhiro 3Inaba Daisuke 4Tamiya Sadahiro 5Nakano Tetsuo 41 Departments of Diabetes and Endocrinology2 Gastroenterology3 Neurology4 Orthopedic Surgery, Tamana Central Hospital, Tamana, Japan\n5 Department of General and Community Medicine, Kumamoto University Hospital, Kumamoto, Japan\nCorrespondence should be addressed to N Miyamura; Email: miyamura@tamana-chp.jp12 11 2016 2016 2016 16-00973 10 2016 26 10 2016 This is an Open Access article distributed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.2016The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nHepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient’s symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis.\n\nLearning points:\nHCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.\n\nPathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.\n\nSteroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.\n\nThe speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.\n==== Body\nBackground\nHepatitis C-associated osteosclerosis (HCAO) is a very rare disorder in which an extremely rapid bone turnover occurs, resulting in generalized osteosclerosis. Affected patients suffer from excruciating deep bone pain in appendicular skeleton. This condition occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 despite the high prevalence of hepatitis C worldwide, and its etiopathogenesis still remains unclear (1). Here we report a new case, with diagnosis confirmed by bone biopsy and treated initially with a bisphosphonate, next with steroid therapy including intravenous pulse administration, and finally with direct acting antivirals (DAA) aiming at sustained virological response (SVR). We also describe detailed data including patient’s symptoms, biochemical values and bone markers through the clinical course.\n\nCase presentation\nA 50-year-old Japanese man was admitted to our hospital because of long-standing pains mainly in his lower extremities. His body mass index was 19.5 kg/m2 and blood pressure was 153/88. He had been well until approximately 2.5 years before this admission, when he experienced a sudden onset of pain in both legs. Initially, thermalgia occurred along his tibias, and it gradually extended to thigh bones, hip joints and lumbar area in 2 years. Skeletal radiographs showed a diffuse osteosclerosis of thickening diaphyseal cortices, pelvic bones and spinal vertebrae. A radiologic appearance in which the endplates are densely sclerotic (sandwich vertebral body), which is distinctive for osteopetrosis, was absent. Paget’s disease of bone was ruled out because no focal bone deformation or sign of bone fracture was observed. An abdominal ultrasound examination revealed several gallstones sized up to 8 mm within the gallbladder.\n\nThere was no family history of bone disease. History of exposure to fluoride or specific heavy metals was also absent. He was first told that he had been infected with HCV in his age 20, however, he had been asymptomatic and never been treated until this episode. Although he had no history of drug abuse, blood transfusion, acupuncture or tattoo, he had once pierced his ear using a non-sterilized needle.\n\nInvestigation\nLaboratory data revealed low-normal serum calcium level with remarkable hypocalciuria, high levels of both intact-PTH and 1,25-dihydroxy vitamin D with low-normal level of 25-hydroxy vitamin D. Very high levels of both bone formation markers and bone resorption markers were present (data at the initial evaluations are summarized in Table 1, 1st column, hospital day −20 to +30).\nTable 1 Clinical data summary of serum and urine, bone histomorphometry and HCV viral parameters.\n\n\tReference\tHospital day\t\n\tRange\t−20~30\t~130\t~190\t~280\t\nTreatment\t\tNone (before treatment)\tAfter mPSL infusion\tPSL (per os Continued\tAfter DAA therapy\t\nSerum\t\n Calcium (mg/dL)\t8.3–10.4\t8.2\t8.6*\t9.2*\t9.3\t\n Phosphate (mg/dL)\t2.5–4.5\t3\t3.5*\t4.0*\t4.4\t\n Albumin (mg/dL)\t4.1–5.1\t4.1\t4\t4\t4.3\t\n Creatinine (mg/dL)\t0.6–1.2\t0.72\t0.88\t1.06\t1.11\t\n AST (IU/L)\t13–34\t42\t68\t102\t21\t\n ALT (IU/L)\t7–37\t37\t171\t332\t32\t\n Alkaline phosphatase (IU/L)\t106–350\t1529\t1571\t697\t280\t\n TSH (IU/mL)\t0.35–4.94\t0.74\t–\t–\t–\t\n GH (ng/mL)\t<2.47\t0.37\t–\t–\t–\t\n IGF-1 (ng/mL)\t87–245\t82\t–\t–\t–\t\n PTH (pg/mL)\t10–65\t219\t167*\t42*\t69\t\n Osteocalcin (ng/mL)\t2.5–13\t40\t21\t11\t5.7\t\n BAP (mg/mL)\t3.7–20.9\t184\t197\t68.6\t28.8\t\n Total-PINP\t18–74\t1200<\t1080\t97.1\t49.4\t\n TRACP-5b (U/dL)\t170–590\t1220\t1180\t1150\t738\t\n 25-Hydroxyvitamine D (ng/mL)\t7–41\t11\t13*\t10*\t13\t\n 1,25-Dihydroxyvitamine D (pg/mL)\t20–60\t95\t119*\t57.9*\t47.7\t\nUrinary\t\n NTX (nmolBCE/mmol Cr)\t13–66\t900\t286\t142\t154\t\n DPD (nmol/mmol Cr)\t2.1–5.4\t34.2\t14.8\t6.7\t8.8\t\n Calcium/creatinine ratio (%)\t5–15\t0.29\t3.6*\t1.38*\t1.11\t\nBone histomorphometry (iliac crest)\t\n Bone volume BV/TV (%)\t25.7 ± 6.9\t44.1 (+2.7 s.d.)\t–\t–\t–\t\n Trabecular thickness (μm)\t138 ± 6.2\t256 (+19 s.d.)\t–\t–\t–\t\n Osteoid volume OV/BV (%)\t4.5 ± 0.8\t8.36 (+4.8 s.d.)\t–\t–\t–\t\n Osteoid surface OS/BS (%)\t27 ± 2.8\t75.9 (+17 s.d.)\t–\t–\t–\t\n Osteoid thickness (μm)\t11.1 ± 0.7\t13.6 (+3.6 s.d.)\t–\t–\t–\t\n Eroded surface ES/BS (%)\t3.7 ± 0.5\t6.2 (+5.0 s.d.)\t–\t–\t–\t\n Mineral apposition rate (μm/day)\t1.02 ± 0.5\t0.37 (−1.3 s.d.)\t–\t–\t–\t\n Mineralizing surface MS/BS (%)\t7.4 ± 3.8\t38.4 (+8.2 s.d.)\t–\t–\t–\t\n Bone formation rate (mm3/mm2/year)\t0.016 ± 0.008\t0.052 (+4.5 s.d.)\t–\t–\t–\t\nHCV viral parameters\t\n HCV antibody\t\tReactive\t–\t–\t–\t\n Serotype group\t\tType 2\t–\t–\t–\t\n RNA quantification (log IU/mL)\t\t–\t5.7\t5.6\tNot detected\t\n* Data were sampled under supplementation with alfacalcidol and calcium. – not measured.\n\nBAP, bone-specific alkaline phosphatase; BS, bone surface; BV, bone volume; DAA, direct acting antivirals; DPD, deoxypiridinoline; ES, eroded surface; mPSL, methylprednisolone; MS, mineralizing surface; NTX, N-terminal telopeptide; OS, osteoid surface; OV, osteoid volume; PINP, N-terminal propeptides of procollagen type I; TRACP, tartrate-resistant acid phosphatase; TV, total volume.\n\n\n\n\nBone scintigraphy using 99m-Tc-HMDP showed an enhanced radionuclide uptake without any focal abnormality (Fig. 1). Neither parathyroid gland swelling nor abnormal 99m-Tc-MIBI uptake was detected by ultrasound imaging or parathyroid scintigraphy. Dual-energy X-ray absorptiometry (DEX) revealed remarkably elevated levels of generalized bone mineral density (BMD) (Table 2, 1st column).\nFigure 1 Bone scintigraphy using 99m-Tc-HMDP. Left panel, anterior view. Right panel, posterior view.\n\n\nTable 2 Initial values and changes in bone mineral density and bone mineral content.\n\nMeasured date\tday 0\tday 155\tday 216\tday 249\tday 302\tday 422\t\nBMD total (g/cm2) (T-score)\t1.446 (3.8)\t1.509 (4.6)\t1.531 (4.8)\t1.557 (5.2)\t1.569 (5.3)\t1.594 (5.6)\t\nLeft femoral neck hip\t1.417 (4.4)\t1.436 (4.5)\t1.496 (5.0)\t1.492 (5.0)\t1.522 (5.2)\t1.544 (5.4)\t\nLumbar spine (L2–L4)\t1.513 (3.9)\t1.730 (5.7)\t1.759 (6.0)\t1.788 (6.2)\t1.709 (5.6)\t1.687 (5.4)\t\nTotal BMC (g)\t3184\t3442\t3529\t3607\t3653\t3689\t\nIncrease rate of total BMC (g/day)\t–\t1.66\t1.43\t2.36\t0.87\t0.3\t\nBMC, bone mineral content; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry.\n\n\n\n\nBone biopsy specimen taken from iliac crest after double tetracycline labeling was analyzed (Fig. 2). Parametric values of bone volume, trabecular thickness, osteoid volume, osteoid thickness, osteoid surface and eroded surface were enormously elevated (Table 1, 1st column). A number of osteoclasts were also present. Immature bone mineralization occurred in many trabecula suggesting exceedingly rapid bone formation (Fig. 3). These observations suggested that the bone turnover rate was highly increased, in which, bone formation exceeded resorption leading to a positive balance and were consistent with the results of biochemical markers of bone metabolism. Other disorders causing osteosclerosis were inconsistent with the case. HCAO, a quite rare disorder for which there are no established diagnostic criteria, seemed the most appropriate diagnosis. To evaluate the severity of pain, universal pain assessment tool was used with arbitrary pain scale unit of 0 (no pain) to 10 (worst possible pain), and the patient recorded the score every one hour or two during daytime of the hospitalization period. The pain score at the initial evaluation was located at around 7–8.\nFigure 2 Bone biopsy specimen taken from iliac crest. Cortical bone zones are evidently thickened and cancellous bone zone is thinned.\n\n\nFigure 3 Bone histomorphometry of high magnification field (×200). Arrows indicate immaturely mineralized area, which suggests highly increased bone formation rate.\n\n\n\n\nTreatment\nAfter obtaining informed consent of the patient and approval of Institutional Ethics Committee, treatment was initiated with risedronate, 17.5 mg/day. Supplementation with calcium l-aspartate hydrate (2400 mg/day) and alphacalcidol (1.0 μg/day) was required to maintain normocalcemia soon after the regimen was started. We stopped risedronate on regimen day 38 because a preferable effect was not observed in bone pain or biochemical markers of bone (Fig. 4A and B), and hypocalciuria was remarkable despite supplementation. Calcium carbonate (3000 mg/day) was added to the supplementation aiming at increasing urinary calcium excretion by phosphorus absorption, which did not seem effective (Fig. 4A and B).\nFigure 4 Clinical course of the patient during the hospitalization. Two-way arrows show the periods of treatments, red vertical arrows indicate pulse steroid therapy. (A) Pain score (arbitrary unit: 0 none −10 most severe), ALP and BAP (% of initial value) are shown as line graphs of black, blue and red respectively. (B) OC, DPD (% of initial value) and ALT (IU/L) are shown as line graphs of black, blue and red respectively. BAP, bone-specific alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; DPD, deoxypyridinoline; DXA, dual-energy X-ray absorptiometry; mPSL, methylprednisolone; PSL, prednisolone; OC, osteocalcin.\n\n\n\n\nSteroid administration was initiated on 100th hospital day. First, a regimen consisting of intravenous infusion of methylprednisolone (mPSL), 500 mg/day for three days, and subsequent withdrawal for four days was repeated four times (pulse steroid therapy). Subsequent to the regimen, oral administration of prednisolone (PSL) was started, and the dose was soon increased up to 50 mg. The dose was gradually decreased down to 10 mg/day. DAA therapy (sofosbuvir, 400 mg/day and ribavirin, 800 mg/day) was initiated on 195th day and continued for 84 days. Supplementation was gradually withdrawn by 240th day because the hypocalcemic tendency of the patient seemed to disappear.\n\nOutcome and follow-up\nSteroid administration revealed its impact on the symptoms and biochemical data of the patient. Pulse steroid therapy led to a notable improvement of pains of his lower extremities and decrease of ALP and a bone formation marker of BAP during infusion periods (Fig. 4A). The pain-relieving effect was weakened during each withdrawal period. Oral administration of PSL was started, and the dose was increased up to 50 mg because his pain worsened again. Values of ALP and BAP, once decreased by mPSL therapy, became higher levels than those before. They, however, reached peak levels on around 150th hospital day, and then began to decrease linearly down to the levels around the upper limit of normal range in about 50 days (Fig. 4A). Meanwhile, pain score, which had been 6–8 before mPSL infusion, was decreased by the treatment to the level of 3–5, but was sustained at the same level thereafter (Fig. 4A). DAA therapy successfully achieved SVR (Table 1, hospital day 280) but showed no additional effect on his symptoms or bone markers (Fig. 4A and B).\n\nThe representative markers of bone resorption and formation, urine deoxypyridinoline and serum osteocalcin respectively, were also observed through the course (Fig. 4B and Table 1). Risedronate decreased the elevated values of both markers during the initial 2 or 3 weeks but thereafter the effect seemed to disappear, so did the phosphorus absorption therapy with calcium carbonate. Pulse steroid therapy and subsequent oral administration successfully decreased the levels of both markers, which reached around the upper limit of normal range in about 10 weeks. Of note, steroid therapy seemed to aggravate hepatitis, leading to elevated levels of transaminases, which were promptly normalized with the use of DAA (Fig. 4B and Table 1, 4th column, hospital day 280).\n\nDXA evaluations revealed sustained increase of BMD and bone mineral content (BMC) despite decreasing levels of bone markers. Total BMC was increased by the rate of 1.43–2.36 g/day since the initial evaluation until day 249 (Table 2). These values were compatible with those estimated by calcium balance, suggesting that most of the orally ingested calcium was incorporated into bone without being excreted in urine. The rate, however, slowed down thereafter to 0.87 g/day, and the most recent data showed further slowdown to 0.30 g/day in the subsequent 120 days.\n\nThe patient was gaining 870 mg of bone mineral content daily (absolute value estimated by whole body dual-energy X-ray absorptiometry). Bone mineral content seems to consist of hydroxyapatite (Ca10(PO4)6(OH)2), of which the weight percentage of calcium is ~40%. The value was consistent with calcium balance (oral ingestion and urinary excretion).\n\nDiscussion\nThe first several cases of HCAO were reported in 1992 (2). This is a very uncommon condition and can be defined as an acquired painful skeletal disorder characterized by a remarkable increase of bone mass. Osteosclerosis is characterized by nonspecific, often diffuse bony pain and tenderness over involved bones due to periosteal stretching, in the absence of joint swelling. Radiographic examination shows thickening of the long bone cortices, mainly diaphyseal cortical bone. Deterioration of bone strength has not been reported except for an elderly woman who suffered from multiple fractures after several falls 10 years after the diagnosis of HCAO (1). The pathogenesis of this rare condition still remains unclear. It has been suggested that HCV alone or in combination with other unknown factor(s) may infect and alter bone cells or their precursors in predisposed individuals. Abnormalities have been demonstrated by previous studies in the insulin-like growth factor (IGF) system (3), the receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) system imbalance (4, 5), and the transforming growth factor (TGF)–β-Smad signaling (6). With regards to therapeutic approaches to the disease, the hallmarks are the changes in deep, torturing bony pain, bone markers, thickening of the long bone cortices and BMD. Attempts to treat with anti-resorptive agents in at least five patients were ineffective, whereas symptomatic treatments may provide some benefit (1). In some cases, a partial or complete spontaneous remission of symptoms and/or osteosclerosis was observed during follow-up. Cholecystectomy in a case having xanthogranulomatous cholecystitis with multiple gallstones might have led to the declining of her elevated BMD, although characteristic bone pain was absent in the case (7). The antiviral therapy in a case using ribavirin and interferon was followed by a recovery of skeletal sclerosis (8).\n\nThe 19th case of HCAO was herein described with the detailed clinical course of the patient for almost one year. We focused on the therapeutic effect of several treatments on his bone pain, biochemical data and bone markers (Fig. 4). Bony pain was measured every one hour by a pain scale during daytime, and serum and urine were sampled almost every week. A bisphosphonate (risedronate; used in a high-dose regimen) showed only a transient partial remission. This unusual regimen of an anti-resorptive agent is recommended only for the patients with Paget’s disease of bone in Japan. Our result suggested that the mechanisms that lead to accelerated bone turnover in HCAO (diffuse sclerosis) and Paget’s disease (focal) differ with each other. DAA has never been challenged for HCAO treatment before this case, and ineffectiveness of DAA therapy using sofosbuvir was observed on the abnormal bone turnover and bony pain despite an achieved SVR (Fig. 4B). An argument would be that it was used after a remission achieved by steroid treatment and some positive effect of SVR might be veiled. In addition, skeletal recovery by the antiviral treatment reported previously was recognized when 7 years passed after the treatment (8).\n\nWe found an impact of intravenous pulse therapy followed by high-dose oral administration of glucocorticoids on the patient’s pain and laboratory data. Among 20 cases of HCAO in the literature, steroid treatment was described only in a case, with 5 mg/day of PSL for 2.5 months, without subjective improvement (9). Our results strongly suggested that some underlying immunological alteration is the crucial key to clarify the pathogenesis. DEX revealed increased lumbar BMD (1.513 g/cm2 in L2–L4 average), which further reached 1.73 g/cm2 in the subsequent 130 days since initial evaluation (Table 2). Elevated levels of both PTH and 1,25-OH vitamin D and strongly suppressed urinary calcium excretion despite low-normal 25-OH vitamin D and a large amount of calcium supplementation suggested that they worked in accordance to increase BMD (Table 1) and that some unknown factor(s) might regulate all of these actions. It might be that promoted bone resorption is the reaction to protect skeletal from osteosclerosis, and treatment by anti-resorptive agent could be with adverse effect. One of the most remarkable therapeutic effects for osteoporosis, reported in a clinical study using intermittent subcutaneous injections of PTH in postmenopausal women with severe osteoporosis, was an increase by 8% per year in lumbar BMD, the rate far smaller than that observed in this case (14% per 130 days). Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis.\n\nIn conclusion, HCAO is a very rare disorder, and no definitive treatment has hitherto been found. We reported the first case of HCAO in which a therapy using high dose of steroid was evidently effective, proposing not only a key to solve the question for its pathogenesis but also an entrance to a new treatment strategy for bone loss syndromes in future.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent was obtained from the patient.\n\nAuthor contribution statement\nAll the authors have read the manuscript and have approved this article. N Miyamura is the author and the corresponding author of this article. S Nishida, M Itasaka, H Matsuda, T Ohtou, Y Yamaguchi, D Inaba, S Tamiya and T Nakano are clinicians who contributed to the management of this case.\n==== Refs\nReferences\n1 Serraino C Melchio R Silvestri A Borretta V Pomero F Fenoglio L \n2015 \nHepatitis C-associated osteosclerosis: a new case with long-term follow-up and a review of the literature . Internal Medicine \n54 \n777 –783 . (10.2169/internalmedicine.54.3448 )25832941 \n2 Villareal DT Murphy WA Teitelbaum SL Arens MQ Whyte MP \n1992 \nPainful diffuse osteosclerosis after intravenous drug abuse . American Journal of Medicine \n93 \n371 –381 . (10.1016/0002-9343(92)90165-8 )1329508 \n3 Khosla S Hassoun AAK Baker BK Liu F Zein NN Whyte MP Reasner CA Nippoldt TB Tiegs RD Hintz RL \n1998 \nInsulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults . Journal of Clinical Investigation \n101 \n2165 –2173 . (10.1172/JCI1111 )9593772 \n4 Manganelli P Giuliani N Fietta P Mancini C Lazzaretti M Pollini A Quaini F Pedrazzoni M \n2005 \nOPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key? \nClinical Rheumatology \n24 \n296 –300 . (10.1007/s10067-004-1031-3 )15583970 \n5 Enjuanes A Ruiz-Gaspà S Peris P Ozalla D Álvarez L Combalia A Martínez De Osaba MJ Monega A Pares A Guañabens N \n2010 \nThe effect of the alendronate on OPG/RANKL system in differentiated primary human osteoblasts . Endocrine \n37 \n322 –328 . (10.1007/s12020-009-9306-8 )20960270 \n6 Kaji H Naito J Sowa H Sugimoto T Chihara K \n2006 \nSerum soluble factors induce the proliferation, alkaline phosphatase activity and transforming growth factor-β signal in osteoblastic cells in the patient with hepatitis C-associated osteosclerosis . Experimental Clinical Endocrinology and Diabetes \n114 \n599 –604 . (10.1055/s-2006-924399 )\n7 Hataya Y Komatsu Y Chusho H Kirishima T Shintani H Morimoto T \n2011 \nA case of hepatitis C-associated osteosclerosis with xanthogranulomatous cholecystitis . Internal Medicine \n50 \n1703 –1708 . (10.2169/internalmedicine.50.4675 )21841329 \n8 Javier RM Vernejoul MC Afif N Kunts JL Sibilia J \n2011 \nSkeletal recovery from hepatitis C-associated osteosclerosis (HCAO) following antiviral treatment . Joint Bone Spine \n78 \n409 –411 . (10.1016/j.jbspin.2011.02.016 )21498104 \n9 Schwartz KM Skinner JA \n2008 \nHepatitis C-associated osteosclerosis: a case report . Skeletal Radiology \n37 \n679 –681 . (10.1007/s00256-008-0471-2 )18414851\n\n",
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"pages": null,
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"pmid": "27933174",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "25832941;21841329;17177144;20960270;15583970;18414851;1329508;21498104;9593772",
"title": "A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy.",
"title_normalized": "a case of hepatitis c associated osteosclerosis accelerated bone turnover controlled by pulse steroid therapy"
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"abstract": "The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.",
"affiliations": "Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan. Electronic address: i-kuki@med.osakacity-hp.or.jp.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Electrophysiology, Osaka City General Hospital, Osaka, Japan.;Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.;Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.;Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.;Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.;Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Biochemistry, Hamamatsu University School of Medicine, Shizuoka, Japan.;Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.",
"authors": "Fukuoka|Masataka|M|;Kuki|Ichiro|I|;Kawawaki|Hisashi|H|;Okazaki|Shin|S|;Kim|Kiyohiro|K|;Hattori|Yuka|Y|;Tsuji|Hitomi|H|;Nukui|Megumi|M|;Inoue|Takeshi|T|;Yoshida|Yoko|Y|;Uda|Takehiro|T|;Kimura|Sadami|S|;Mogami|Yukiko|Y|;Suzuki|Yasuhiro|Y|;Okamoto|Nobuhiko|N|;Saitsu|Hirotomo|H|;Matsumoto|Naomichi|N|",
"chemical_list": "D000927:Anticonvulsants; C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2016.08.002",
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"issn_linking": "0387-7604",
"issue": "39(1)",
"journal": "Brain & development",
"keywords": "Children; Epileptic encephalopathy; Epileptic spasms; Potassium channel; Treatment",
"medline_ta": "Brain Dev",
"mesh_terms": "D000927:Anticonvulsants; D001921:Brain; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine; D013036:Spasms, Infantile",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "80-83",
"pmc": null,
"pmid": "27578169",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Quinidine therapy for West syndrome with KCNTI mutation: A case report.",
"title_normalized": "quinidine therapy for west syndrome with kcnti mutation a case report"
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-123983",
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"abstract": "NCs occur commonly after solid organ transplantation and affect 15%-30% of liver transplant recipients. The aim of this retrospective study was to evaluate the type and incidence of neurologic events in pediatric patients following LT. Between May 2006 and June 2015, 242 patients (118 females, 124 males) requiring LT for different etiologies at the İnönü University Liver Transplantation Institute were included. The incidence, types, and risk factors of NCs that occurred following LT were evaluated retrospectively. Neurologic events occurred in 57 (23.5%) of the patients. Early NCs were encephalopathy (12.4%), seizures (11.5%), and PRES (7%). Of 57 patients, five (8.7%) experienced NCs at least 1 month after LT; these late NCs included tremor, headaches, encephalopathy, ataxia, and neuropathy. The psychiatric symptoms after LT were noted in 42 patients (17.4%). The mortality rate after LT in those with or without neurological events was not significantly different (P=.73). There was a high incidence of serious neurologic events after LT. The major neurologic manifestation in our patients was encephalopathy followed by seizures.",
"affiliations": "Department of Pediatric Neurology, Faculty of Medicine, İnönü University, Malatya, Turkey.;Department of Pediatric Neurology, Faculty of Medicine, İnönü University, Malatya, Turkey.;Department of Pediatric Neurology, Faculty of Medicine, İnönü University, Malatya, Turkey.;Department of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, İnönü University, Malatya, Turkey.;Department of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, İnönü University, Malatya, Turkey.;Department of Surgery, Faculty of Medicine, İnönü University, Malatya, Turkey.",
"authors": "Gungor|Serdal|S|;Kilic|Betul|B|;Arslan|Mujgan|M|;Selimoglu|M Ayse|MA|;Karabiber|Hamza|H|;Yilmaz|Sezai|S|",
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"doi": "10.1111/petr.12872",
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"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(3)",
"journal": "Pediatric transplantation",
"keywords": "childhood; liver transplantation; neurological complication",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D001927:Brain Diseases; D002648:Child; D002675:Child, Preschool; D058625:End Stage Liver Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D009422:Nervous System Diseases; D012189:Retrospective Studies; D012307:Risk Factors; D012640:Seizures",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28042689",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Early and late neurological complications of liver transplantation in pediatric patients.",
"title_normalized": "early and late neurological complications of liver transplantation in pediatric patients"
} | [
{
"companynumb": "PHHY2017TR000881",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nHigh-dose methotrexate (hdmtx) is a common therapeutic agent in the treatment of osteosarcoma. However, hdmtx is highly toxic and requires complex pharmacokinetic monitoring and leucovorin rescue. Thus, alternative therapeutic strategies are necessary. Here, we analyzed the clinical efficacy of a dia regimen (cisplatin-ifosfamide-doxorubicin) to evaluate its potential as an alternative to hdmtx-based therapy.\n\n\nMETHODS\nPatients received 12 cycles of chemotherapy administered over 2 years (2 preoperative cycles and 10 postoperative cycles). Cumulative dose was the same in all cycles: cisplatin 120 mg/m(2) on day 1 of week 1, followed by ifosfamide 2.0 g/m(2) days 1-5 of week 2, and doxorubicin 20 mg/m(2) days 1-3 of week 2.\n\n\nRESULTS\nBetween January 2004 and October 2008, 39 eligible patients (median age: 16 years) were enrolled, with 36 being evaluable for the study. Of those 36 patients, 20 (55.6%) had a good histologic response to preoperative chemotherapy (>90% tumour necrosis). The estimated 5-year rates of event-free survival (efs) and overall survival were 54.8% and 61.5% respectively.\n\n\nCONCLUSIONS\nThe results of our study suggest that, in osteosarcoma patients, the dia regimen produces an efs rate and survival outcomes comparable to those attained with hdmtx-containing regimens, with fewer adverse reactions. The dia regimen is well tolerated, and we observed a high level of patient compliance. Our results demonstrate that hdmtx-free osteosarcoma treatment regimens can be effective, warranting further investigation.",
"affiliations": "Orthopedic Department, General Hospital of Jinan Military Region, Jinan, PR China.;Orthopedic Department, General Hospital of Jinan Military Region, Jinan, PR China.;Orthopedic Department, General Hospital of Jinan Military Region, Jinan, PR China.",
"authors": "Xu|M|M|;Xu|S F|SF|;Yu|X C|XC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.21.1973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "21(5)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Osteosarcoma; chemotherapy; methotrexate-free regimens; survival",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e678-84",
"pmc": null,
"pmid": "25302038",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": "16246977;19097774;11118463;16766682;21656756;21151406;1403038;19889609;22502948;21434784;20842228;20555083;11821461;9789613;20347613;18802144;17460416;8021736;12751380;15073863;3520317;12393991;9314869;21707700;12017378",
"title": "Clinical analysis of osteosarcoma patients treated with high-dose methotrexate-free neoadjuvant chemotherapy.",
"title_normalized": "clinical analysis of osteosarcoma patients treated with high dose methotrexate free neoadjuvant chemotherapy"
} | [
{
"companynumb": "CN-JNJFOC-20141013357",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "To evaluate the efficacy and adverse effects of using low-dose intravitreal triamcinolone acetonide (IVTA) to preserve vision in polypoidal choroidal vasculopathy (PCV) eyes.\n\n\n\nThis retrospective chart review study examined 8 eyes of 7 PCV patients, for whom verteporfin photodynamic therapy (vPDT) or antivascular endothelial growth factor (VEGF) therapy was not affordable/available and also with intolerable risk because of underlying cardiovascular and/or cerebrovascular ischemia. Low-dose IVTA (1 mg/0.025 mL) monotherapy was administered and repeated every 4 weeks if intraretinal edema or subretinal fluid persisted.\n\n\n\nThe median follow-up time was 26.4 months. Three eyes (3/8) maintained their initial best-corrected visual acuity and 4 eyes (4/8) exhibited improvement, whereas 1 eye (1/8) sustained some loss. The mean injection number per month was 0.7 for the first 6 months, after which it decreased to 0.4. In regard to adverse effects, intraocular pressure (IOP) of more than 21 mmHg was noted as persisting for a few weeks in 4 eyes and that of more than 30 mmHg was noted once in 1 eye. The increased IOP was adequately controlled by using IOP-lowering agents. Two initially phakic eyes each underwent cataract surgery in the 12th and 14th months after treatment.\n\n\n\nLow-dose IVTA therapy may be valuable for preserving the vision of PCV patients, while vPDT or anti-VEGF is not affordable/available or of those with underlying diseases for whom anti-VEGF therapy is with intolerable risk.",
"affiliations": "1 Cathay General Hospital , Taipei, Taiwan .;1 Cathay General Hospital , Taipei, Taiwan .;1 Cathay General Hospital , Taipei, Taiwan .;1 Cathay General Hospital , Taipei, Taiwan .",
"authors": "Liang|I-Chia|IC|;Lin|Yi-Ru|YR|;Chien|Hsiang-Wen|HW|;Liu|Kwan-Rong|KR|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D014222:Triamcinolone Acetonide",
"country": "United States",
"delete": false,
"doi": "10.1089/jop.2015.0150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-7683",
"issue": "33(1)",
"journal": "Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics",
"keywords": "adjunctive therapy; polypoidal choroidal vasculopathy; triamcinolone acetonide",
"medline_ta": "J Ocul Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D020256:Choroidal Neovascularization; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014222:Triamcinolone Acetonide; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "9511091",
"other_id": null,
"pages": "42-49",
"pmc": null,
"pmid": "27991837",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vision Preservation in Eyes of Polypoidal Choroidal Vasculopathy with Low-Dose Intravitreal Triamcinolone Acetonide.",
"title_normalized": "vision preservation in eyes of polypoidal choroidal vasculopathy with low dose intravitreal triamcinolone acetonide"
} | [
{
"companynumb": "TW-MYLANLABS-2017M1015082",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is an uncommon but potentially life-threatening adverse effect associated with conventional antipsychotic agents. The syndrome is characterized by muscular rigidity, hyperpyrexia, altered consciousness, and autonomic dysfunction. Few cases of quetiapine-induced NMS have been reported. A 54-year-old man was unsuccessfully challenged with quetiapine after conventional antipsychotic-induced NMS.",
"affiliations": "Clinical and Administrative Division, College of Pharmacy, University of Iowa, Iowa City 52242-1112, USA.",
"authors": "Hatch|C D|CD|;Lund|B C|BC|;Perry|P J|PJ|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D006220:Haloperidol; D008140:Lorazepam; D002746:Chlorpromazine",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.21.11.1003.34528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "21(8)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000544:Alzheimer Disease; D014150:Antipsychotic Agents; D002746:Chlorpromazine; D003987:Dibenzothiazepines; D006220:Haloperidol; D006801:Humans; D006980:Hyperthyroidism; D008140:Lorazepam; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D011595:Psychomotor Agitation; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1003-6",
"pmc": null,
"pmid": "11718487",
"pubdate": "2001-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics.",
"title_normalized": "failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-07254",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"druga... |
{
"abstract": "In 2017, concerns regarding adverse events (AEs) associated with the Mirena levonorgestrel intrauterine device were largely echoed in the media in France. This resulted in a tremendous reporting of AEs to pharmacovigilance centres. The aim of this study was to describe the reporting of AEs regarding Mirena in France and to study the impact of media coverage on this reporting.\n\n\n\nAll cases reports involving Mirena recorded in the French national pharmacovigilance database from marketing (21 July 1995) until 04 August 2017 were extracted. To allow studying the influence of mediatisation, reports were described separately for the periods preceding and following the observed media coverage peak (15 May 2017).\n\n\n\nOverall, 3224 reports were considered, 510 (15.8%) recorded before the media coverage peak, and 2714 (84.2%) after. Before the peak, 76.5% of reports originated from health professionals; median time-to-report was of 5.5 months (interquartile range: 1.7-18.6), and median number of AEs per report was 1 (range: 1-17). After the peak, 98.6% originated from patients; median time-to-report was 21 months (interquartile range: 8.1-45.5), and median number of AEs per report was 6 (range: 1-37). After the peak, most reports mentioned anxio-depressive disorders (38.8 vs 10.6% before) or sexual disorders (47.3 vs 6.9%). Other emphasised AEs were weight increase (42.3 vs 10.2%) and pain (gastrointestinal, 19.1 vs 3.5%; musculoskeletal, 22.2 vs 4.5%).\n\n\n\nThis study highlighted the importance of mediatisation impact on spontaneous reporting with changes concerning amounts of reports, type of reporter, and type of reported AEs. For Mirena, this led to generate signals regarding anxio-depressive and sexual disorders.",
"affiliations": "Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team PHARMACOEPIDEMIOLOGY, UMR 1219, Bordeaux, France.;Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team PHARMACOEPIDEMIOLOGY, UMR 1219, Bordeaux, France.;Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team PHARMACOEPIDEMIOLOGY, UMR 1219, Bordeaux, France.;Service Hospitalo-Universitaire de Pharmacotoxicologie, CHU de Lyon, Lyon, France.;Pharmacologie clinique et vigilances, LNEC, INSERM U1084, CHU de Poitiers, Poitiers, France.;Centre de pharmacovigilance du Nord Pas de Calais, 1 place de Verdun, Lille, France.;Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team PHARMACOEPIDEMIOLOGY, UMR 1219, Bordeaux, France.;Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team PHARMACOEPIDEMIOLOGY, UMR 1219, Bordeaux, France.",
"authors": "Langlade|Claire|C|;Gouverneur|Amandine|A|0000-0001-6253-1833;Bosco-Lévy|Pauline|P|;Gouraud|Aurore|A|;Pérault-Pochat|Marie-Christine|MC|;Béné|Johana|J|;Miremont-Salamé|Ghada|G|;Pariente|Antoine|A|;|||",
"chemical_list": "D016912:Levonorgestrel",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "85(9)",
"journal": "British journal of clinical pharmacology",
"keywords": "drug safety; gynaecology/obstetrics; pharmacovigilance",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D001007:Anxiety; D003863:Depression; D005260:Female; D005602:France; D006760:Hospitalization; D006801:Humans; D033181:Information Dissemination; D007434:Intrauterine Devices; D016912:Levonorgestrel; D008297:Male; D008402:Mass Media; D060735:Pharmacovigilance; D012735:Sexual Dysfunction, Physiological",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2126-2133",
"pmc": null,
"pmid": "31218710",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": "29785475;19707273;25934164;17867726;19552751;10082069;12039121;30569481;28696796;29669717;30871933;11072960;2865527;27558545;19920976;21477680;8137626;22621627;29149325;21668037;8745956;30379373;31218710",
"title": "Adverse events reported for Mirena levonorgestrel-releasing intrauterine device in France and impact of media coverage.",
"title_normalized": "adverse events reported for mirena levonorgestrel releasing intrauterine device in france and impact of media coverage"
} | [
{
"companynumb": "FR-BAYER-2019-158895",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "Liver chemistry abnormalities are a frequent manifestation of coronavirus disease 2019 (COVID-19) but are usually transient and resolve with disease resolution.\n\n\n\nWe describe the clinical course and histologic features of 3 adults who developed prolonged and severe cholestasis during recovery from critical cardiopulmonary COVID-19.\n\n\n\nThese patients had clinical and histologic features similar to secondary sclerosing cholangitis of the critically ill patient, but with unique histologic features including severe cholangiocyte injury and intrahepatic microangiopathy suggestive of direct hepatic injury from COVID-19.\n\n\n\nWe believe that these cases constitute a novel severe post-COVID-19 cholangiopathy with potential for long-term hepatic morbidity.",
"affiliations": "Division of Hepatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Division of Infectious Diseases, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Division of Infectious Diseases, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Division of Hepatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.;Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.",
"authors": "Roth|Nitzan C|NC|;Kim|Angela|A|;Vitkovski|Taisia|T|;Xia|Jianxiang|J|;Ramirez|Guillermo|G|;Bernstein|David|D|;Crawford|James M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/ajg.0000000000001154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "116(5)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D000086382:COVID-19; D002760:Cholangiopancreatography, Endoscopic Retrograde; D049448:Cholangiopancreatography, Magnetic Resonance; D002761:Cholangitis; D003422:Critical Care; D016638:Critical Illness; D003937:Diagnosis, Differential; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D000086402:SARS-CoV-2; D012720:Severity of Illness Index",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1077-1082",
"pmc": null,
"pmid": "33464757",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-COVID-19 Cholangiopathy: A Novel Entity.",
"title_normalized": "post covid 19 cholangiopathy a novel entity"
} | [
{
"companynumb": "US-009507513-2206USA002314",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IVERMECTIN"
},
"drugadditional": "4",
... |
{
"abstract": "Factitious disorder is a rare psychiatric illness characterized by the willful and deceptive induction of illness for the purpose of assuming the sick role. It presents a substantial diagnostic challenge, as patients often go to great lengths to conceal their deception. Accordingly, its presence in the full spectrum of gastrointestinal diseases is likely underappreciated. While factitious gastrointestinal bleeding, abdominal pain and diarrhea are relatively common, factitious non-gastrointestinal symptoms in the setting of gastrointestinal illness have been infrequently reported. We present the case of a patient with Crohn's disease with recurrent pancytopenia attributed to the surreptitious ingestion of 6-mercaptopurine. In patients with possible access to immunomodulatory drugs, a high suspicion for and early identification of factitious disorder may improve patient outcomes and avoid invasive and costly diagnostic evaluations.",
"affiliations": "Department of Medicine, Mayo Clinic, Phoenix, Ariz., USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Ariz., USA.;Department of Psychiatry, Mayo Clinic, Phoenix, Ariz., USA.;Division of Hematology and Oncology, Mayo Clinic, Phoenix, Ariz., USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Ariz., USA.",
"authors": "Kahn|Allon|A|;Boroff|Erika S|ES|;Martin|Kari A|KA|;Northfelt|Donald W|DW|;Heigh|Russell I|RI|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000382073",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000382073crg-0009-0137Published online: May, 2015Factitious Disorder in Crohn's Disease: Recurrent Pancytopenia Caused by Surreptitious Ingestion of 6-Mercaptopurine Kahn Allon aBoroff Erika S. bMartin Kari A. cNorthfelt Donald W. dHeigh Russell I. b*aDepartment of Medicine, Mayo Clinic, Phoenix, Ariz., USAbDivision of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Ariz., USAcDepartment of Psychiatry, Mayo Clinic, Phoenix, Ariz., USAdDivision of Hematology and Oncology, Mayo Clinic, Phoenix, Ariz., USA*Russell Heigh, MD, Division of Gastroenterology and Hepatology, 13400 E. Shea Blvd., Scottsdale, AZ 85259 (USA), E-Mail rheigh@mayo.eduMay-Aug 2015 7 5 2015 7 5 2015 9 2 137 141 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Factitious disorder is a rare psychiatric illness characterized by the willful and deceptive induction of illness for the purpose of assuming the sick role. It presents a substantial diagnostic challenge, as patients often go to great lengths to conceal their deception. Accordingly, its presence in the full spectrum of gastrointestinal diseases is likely underappreciated. While factitious gastrointestinal bleeding, abdominal pain and diarrhea are relatively common, factitious non-gastrointestinal symptoms in the setting of gastrointestinal illness have been infrequently reported. We present the case of a patient with Crohn's disease with recurrent pancytopenia attributed to the surreptitious ingestion of 6-mercaptopurine. In patients with possible access to immunomodulatory drugs, a high suspicion for and early identification of factitious disorder may improve patient outcomes and avoid invasive and costly diagnostic evaluations.\n\nKey Words\nFactitious disorderMedicationComplicationInflammatory bowel diseaseIntentionalDyserythropoiesisAnemiaThrombocytopeniaLeukopenia\n==== Body\nIntroduction\nFactitious disorder (FD) is defined in the 5th edition of the Diagnostic and Statistical Manual for Mental Disorders as the falsification of physical or psychological signs or symptoms, or induction of injury or disease, associated with identified deception [1]. In the spectrum of feigned illness, FD is distinguished by the absence of an overt external reward. In contrast, malingering is the intentional induction or falsification of illness for the acquisition of secondary gain [2]. Clinical manifestations of FD are variable and categorized as either predominantly psychiatric or physical. Existing reports in the gastroenterology literature have been characteristically limited to factitious abdominal pain, diarrhea and gastrointestinal bleeding (GIB) [3, 4, 5]. Conversely, non-gastrointestinal presenting manifestations of FD in the setting of gastrointestinal disorders, such as inflammatory bowel disease (IBD), have been infrequently reported. We report a case of recurrent pancytopenia in a patient with Crohn's disease surreptitiously ingesting 6-mercaptopurine (6-MP).\n\nCase Presentation\nA 50-year-old female with an 8-year history of fistulizing Crohn's disease and active recurrent perirectal abscesses presented to the outpatient clinic for initial consultation. She had undergone a diverting colostomy elsewhere 2 years prior to consultation and reported a history of greater than 30 perianal surgical procedures. Her medical history also consisted of vitamin D deficiency, peripheral neuropathy, osteopenia and obstructive lung disease related to ongoing tobacco use. She reported unsuccessful treatment with 5-aminosalicylic acid agents, methotrexate, infliximab, adalimumab and certolizumab pegol.\n\nThe patient was started on 75 mg of 6-MP daily, however severe abdominal pain and active perianal disease persisted. Thiopurine metabolite testing for thioguanine nucleotide (TGN) and methyl mercaptopurine nucleotide (MMPN) revealed low levels and the dose was increased to 100 mg daily. Six weeks later she presented with worsening abdominal pain. Laboratory testing demonstrated elevated lipase levels (4 times upper limit of normal) and the patient was told to discontinue 6-MP indefinitely, both by telephone and at a face-to-face follow-up visit, because of probable drug-induced pancreatitis\n\nTwo months later, the patient presented to the emergency department with a 3-day history of progressive headache, fatigue and a spreading erythematous rash. Laboratory studies demonstrated pancytopenia, with hemoglobin of 8.3, mean corpuscular volume of 112, leukocyte count of 1.7, absolute neutrophil count of 0.42 and platelet count of 90. A hematology consultation was obtained and her prior use of 6-MP dosing, followed by cessation, was specifically noted. The pancytopenia was attributed to residual effect of long-term 6-MP use and she was closely monitored, with counts progressively recovering throughout the remainder of her hospitalization.\n\nInfliximab was reintroduced, and laboratory tests showed normalization of blood counts through the 4-month follow-up visit. However, she subsequently returned to the emergency department 8 days later with abdominal pain and increased ostomy output. Pancytopenia was again present with hemoglobin, leukocyte count and platelet count of 7.2, 2.1 and 42, respectively. Long-term immune-suppressive therapy was suspected as the etiology of the pancytopenia. Bone marrow biopsy showed hypocellularity, panhypoplasia and mild dyserythropoiesis. Further analysis demonstrated diploid XX cytogenetics and normal flow cytometric analysis, with no clonal or aberrant leukocyte population identified and no blast proliferation. She underwent transfusion of numerous blood products and ultimately was started on filgrastim. Her counts improved and she was discharged.\n\nThe patient was readmitted twice over the next 5 months with recurrent pancytopenia. A repeat bone marrow biopsy remained non-diagnostic. Again, she was transfused and given colony-stimulating factors as well as a prednisone taper and her counts improved. Several months later, she was readmitted for pancytopenia, oral ulcers and increased ostomy output. Out of concern for her repeated admissions with no identified cause, thiopurine metabolite testing was repeated and demonstrated TGN and MMPN levels of 385 (therapeutic window 230–400 pmol) and 12,417 (target <5,700 pmol to minimize toxicity), respectively, consistent with drug being present in the body and with MMPN levels predisposing toward toxicity. In the course of her evaluation, her community pharmacist contacted her outpatient providers and indicated that a refill of 6-MP had been dispensed 1 month prior to admission. The patient denied refilling the old prescription and indicated she did not take the 6-MP. The difficult situation was directly discussed with the patient and she again denied taking the 6-MP. She was specifically advised to not use this medication as it was likely responsible for prior pancreatitis and recurrent pancytopenia. Budesonide was initiated and all hematologic abnormalities resolved by 3 months. The patient subsequently canceled appointments at our institution and has been out of contact for 6 months.\n\nAfter the pancreatitis attributed to 6-MP in January 2013, the patient was hospitalized 8 times during the time of this report extending to June 2014. Four of these admissions were related to pancytopenia. She had multiple consultations with gastroenterology, hematology, colorectal surgery and single consultations with infectious disease, rheumatology, dermatology, endocrinology and pulmonary medicine. At each hospital discharge, a written list of prescriptions was specifically reviewed with and provided to the patient. Medication reconciliation was performed at each outpatient visit, and her list, from which 6-MP was absent, was confirmed on every occasion.\n\nDiscussion\nFD was first described in the second century by Claudius Galen, a Roman physician who reported feigned medical illness, including factitious GIB. The British physician Hector Gavin coined the term ‘factitious disorder’ in 1843 when he published a systematic account of feigned illness in soldiers and seamen [5]. It was not until 1951 that Dr. Richard Asher coined the widely recognized term ‘Munchausen syndrome’ for the most severe variety, in which the deceptive induction of illness becomes the central preoccupation of the patient [6]. A large retrospective cohort study of FD patients spanning 21 years showed a Caucasian female preponderance, with an average age of 30.7 years [7]. Modern estimates suggest that FD is present in approximately 1.3% of all hospitalized patients [8]. However, given the central role of deception in the classification of the disorder, it is likely grossly underdiagnosed and therefore underestimated.\n\nTo our knowledge, this is the first reported case of FD presenting without gastrointestinal manifestations in a patient with IBD. Outside of the gastroenterology literature, pancytopenia is a relatively common presenting manifestation of FD. In contrast, the existing gastroenterology literature regarding FD has been limited to several case reports of factitious GIB, diarrhea and abdominal pain. The mode of disease induction in cases of GIB varied greatly and included autophlebotomy and oral ingestion of blood [9], administration of blood enemas and injection of blood into the abdomen to simulate extravasation [10], swallowing razor blades [11], and disconnection and infusion of radioisotope-tagged red blood cells directly into the rectum during a scintigraphy study [12]. All reported patients had undergone extensive diagnostic testing without identified cause, including conventional radiography, endoscopy and scintigraphy.\n\nFactitious diarrhea is also well described and often occurs in the setting of surreptitious laxative ingestion, whether for obtaining medical care or other secondary purposes, such as weight loss [5]. In some instances of gastrointestinal FD, patients attributed their symptoms to exacerbations of IBD, either diagnosed by themselves or by other physicians whose identities could not be verified [4, 12]. A high prevalence of chronic abdominal pain amongst patients with gastrointestinal disorders, including IBD, has led to anecdotal reports of factitious pain leading to hospitalization. Narcotic drug dependence is also noted to be highly prevalent in IBD, however feigned illness for obtaining medication would be classified as malingering for secondary gain.\n\nWhile no systematic analysis of FD in IBD has been undertaken, there is growing recognition that patients with IBD face unique psychosocial challenges. Studies of pediatric IBD patients have demonstrated marked difficulty with social assimilation and resulting isolation, leading to increased absenteeism and refusal to participate in extracurricular activities [13]. Examinations of the connection between psychiatric illness and IBD have been fraught with controversy due to methodological heterogeneity. However, they have consistently demonstrated high rates of concurrent depression and anxiety at all ages, beyond what is seen in healthy controls and demographically matched patients with other chronic diseases [14]. Concomitant psychiatric illness may also place patients at risk of poor outcomes, as they experience more frequent disease relapse [15]. Examinations of the connection between self-perceived stress, irrespective of psychiatric illness, and IBD disease activity have yielded contradictory findings.\n\nThe diagnosis of FD is notoriously difficult and requires both a high index of suspicion and a systematic approach to exclusion of medical etiology. While not diagnostic, there are several characteristics that suggest the presence of feigned illness when medical causes have been sufficiently evaluated. These include treatment at multiple hospitals and/or clinics, an inordinate number of diagnostic tests without disease identification, eager agreement for invasive testing, unwillingness to provide prior medical records, history of employment or studies within health-related fields, symptom magnitude inconsistent with objective findings, opposition to psychiatric assessment and atypical disease course [3]. Of these, the atypical intermittent nature of our patient's disease course and the similarity to thioguanine toxicity was the aspect which drew suspicion and led to her diagnosis.\n\nThis case illustrates several clinical points. Patients with IBD often have comorbidities that include psychiatric illness, and frequently possess an in-depth knowledge of the medical system by virtue of their life experiences. For an inappropriately motivated patient, access to potent immunomodulatory agents provides an opportunity to experience problems unexpected by a treating team. Clinical suspicion of factitious illness is critical to management, as significant morbidity and even mortality may ensue. Early identification may ultimately improve patient outcomes. In spite of examination by multiple providers with elaborate processes to ensure reconciliation of medications prescribed and medications being actually taken, a determined patient may be taking substances unknown to the treating medical team. Unfortunately, as was seen in this case, patients confronted with evidence of their deception may disconnect entirely from their providers and seek a new health care system.\n==== Refs\nReferences\n1 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2013 Fifth Edition Arlington American Psychiatric Association \n2 Sutherland AJ Rodin GM Factitious disorders in a general hospital setting: clinical features and a review of the literature Psychosomatics 1990 31 392 399 2247566 \n3 Bass C Halligan P Factitious disorders and malingering: challenges for clinical assessment and management Lancet 2014 383 1422 1432 24612861 \n4 Huffman JC Stern TA The diagnosis and treatment of Munchausen's syndrome Gen Hosp Psychiatry 2003 25 358 363 12972228 \n5 Savino AC Fordtran JS Factitious disease: clinical lessons from case studies at Baylor University Medical Center Proc (Bayl Univ Med Cent) 2006 19 195 208 17252033 \n6 Asher R Munchausen's syndrome Lancet 1951 1 339 341 14805062 \n7 Krahn LE Li H O'Connor MK Patients who strive to be ill: factitious disorder with physical symptoms Am J Psychiatry 2003 160 1163 1168 12777276 \n8 Fliege H Grimm A Eckhardt-Henn A Gieler U Martin K Klapp BF Frequency of ICD-10 factitious disorder: survey of senior hospital consultants and physicians in private practice Psychosomatics 2007 48 60 64 17209151 \n9 McIntyre AS Kamm MA A case of factitious colonic bleeding J R Soc Med 1990 83 465 466 2168489 \n10 Bakkers JT Crobach LF Pauwels EK Factitious gastrointestinal bleeding J Nucl Med 1985 26 666 667 3873527 \n11 Barkin JA Biagini TM Barkin JS Factitious disorder as a cause of gastrointestinal bleeding: use of a gastroenterologist's ‘secondary survey’ Am J Gastroenterol 2013 108 456 458 23459058 \n12 Foga MM Leslie WD Gastrointestinal bleeding, Munchausen style Clin Nucl Med 2003 28 330 331 12642719 \n13 Desir B Seidman EG Transitioning the paediatric IBD patient to adult care Best Pract Res Clin Gastroenterol 2003 17 197 212 12676115 \n14 Engstrom I Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: a comparison with children having other chronic illnesses and with healthy children J Child Psychol Psychiatry 1992 33 563 582 1577899 \n15 Mittermaier C Dejaco C Waldhoer T Oefferlbauer-Ernst A Miehsler W Beier M Tillinger W Gangl A Moser G Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study Psychosom Med 2004 66 79 84 14747641\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "9(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Anemia; Complication; Dyserythropoiesis; Factitious disorder; Inflammatory bowel disease; Intentional; Leukopenia; Medication; Thrombocytopenia",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "137-41",
"pmc": null,
"pmid": "26078732",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "12777276;17209151;2247566;24612861;14747641;12972228;2168489;17252033;14805062;12642719;1577899;23459058;12676115;3873527",
"title": "Factitious Disorder in Crohn's Disease: Recurrent Pancytopenia Caused by Surreptitious Ingestion of 6-Mercaptopurine.",
"title_normalized": "factitious disorder in crohn s disease recurrent pancytopenia caused by surreptitious ingestion of 6 mercaptopurine"
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"companynumb": "US-ROXANE LABORATORIES, INC.-2015-RO-02043RO",
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"activesubstancename": "MERCAPTOPURINE"
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"abstract": "OBJECTIVE\nLittle information is available regarding the safety of ultrasound contrast agents in children. The purpose of this article was to assess the safety profile of the i.v. administration of ultrasound contrast agents in the pediatric oncology population.\n\n\nMETHODS\nPatients with pediatric solid malignancies who were enrolled on institutional clinical trials conducted between June 2003 and January 2013 and who met our institutional screening criteria for contrast-enhanced ultrasound (CEUS) were eligible. After providing informed consent or assent for CEUS, subjects received i.v. bolus injections of one of two contrast agents for imaging of the primary tumor or a metastatic target lesion. Hemodynamic parameters, including heart rate, cardiac rhythm, and oxygen saturation, were monitored immediately before and for 30 minutes after the administration of the contrast agent. Interviews with the subject or a guardian were conducted by the principal investigator or a radiologist coinvestigator before and after the examination to assess for any adverse effects.\n\n\nRESULTS\nThirty-four subjects (21 male and 13 female) ranging in age from 8 months to 20.7 years (median, 8.7 years) underwent 134 CEUS. No detrimental change in hemodynamic status occurred in any subject. Three subjects (3/134, 2.2%) reported mild transient side effects on one occasion each, two (2/134, 1.5%) had taste alteration, and one (1/134, 0.8%) reported mild transient tinnitus and lightheadedness. These reactions did not recur in these subjects on subsequent CEUS examinations.\n\n\nCONCLUSIONS\nThe i.v. administration of ultrasound contrast agents is safe and well tolerated in the pediatric oncology population. Further studies in children are needed to confirm our findings.",
"affiliations": "1 Department of Radiological Sciences, MS 220, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105.",
"authors": "Coleman|Jamie L|JL|;Navid|Fariba|F|;Furman|Wayne L|WL|;McCarville|M Beth|MB|",
"chemical_list": "D003287:Contrast Media",
"country": "United States",
"delete": false,
"doi": "10.2214/AJR.13.12010",
"fulltext": null,
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"issn_linking": "0361-803X",
"issue": "202(5)",
"journal": "AJR. American journal of roentgenology",
"keywords": null,
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003287:Contrast Media; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms; D061214:Patient Safety; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "966-70",
"pmc": null,
"pmid": "24758648",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12127209;20851938;16641788;23816393;18287440;15448949;16374692;17606728;16965977;17709836;22249601;18046031;11373197;21796439;12541132;15081132;12733472;11884252;12030347;17526609;20308500;23052725;21938505;15173954;2183463;12928758;19236217;9741522;19790253;20980447;10980221;23143218;12861961;20350680;17766543;11793136;18094294;22516936;18992671;14652701;11801205",
"title": "Safety of ultrasound contrast agents in the pediatric oncologic population: a single-institution experience.",
"title_normalized": "safety of ultrasound contrast agents in the pediatric oncologic population a single institution experience"
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"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OPTN-PR-1612L-0012",
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"abstract": "OBJECTIVE\nTo determine whether two adults with stress fractures receiving low weekly doses of methotrexate had methotrexate osteopathy.\n\n\nMETHODS\nTwo adult patients developed features consistent with methotrexate osteopathy while receiving low weekly doses of methotrexate.\n\n\nMETHODS\nIliac crest biopsy samples were taken and bone histomorphometry carried out.\n\n\nRESULTS\nSymptoms resolved when the methotrexate was discontinued. Bone histology showed changes consistent with osteoblast inhibition by methotrexate.\n\n\nCONCLUSIONS\nWhen given in low doses for prolonged periods, methotrexate may have adverse effects on bone, particularly in post-menopausal women.",
"affiliations": "Department of Rheumatology, Royal North Shore Hospital, St Leonards, Australia.",
"authors": "Preston|S J|SJ|;Diamond|T|T|;Scott|A|A|;Laurent|M R|MR|",
"chemical_list": "D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1136/ard.52.8.582",
"fulltext": null,
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"issn_linking": "0003-4967",
"issue": "52(8)",
"journal": "Annals of the rheumatic diseases",
"keywords": null,
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D001847:Bone Diseases; D001842:Bone and Bones; D005260:Female; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D010006:Osteoblasts; D011859:Radiography; D012216:Rheumatic Diseases",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "582-5",
"pmc": null,
"pmid": "8215620",
"pubdate": "1993-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1062231;880755;6707039;6424236;4522143;3220728;2919850;2672136;5264439;6334586",
"title": "Methotrexate osteopathy in rheumatic disease.",
"title_normalized": "methotrexate osteopathy in rheumatic disease"
} | [
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"companynumb": "AU-ORION CORPORATION ORION PHARMA-20_00011680",
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"activesubstancename": "METHOTREXATE"
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"abstract": "BACKGROUND\nSpinal epidural abscess is an uncommon complication in clinical practice. If the abscess is large enough, the patient will rapidly develop neurologic signs of spinal injury, and urgent neurosurgical intervention may be required.\nRapid and correct diagnosis and treatment is important for spinal epidural abscess complication.\nThis report describes a cervical epidural abscess (CEA) caused by epidural analgesia, wherein the patient was punctured twice. A CEA was suspected based on the patient's significant neck pain and elevated white blood cell and neutrophil counts. A CEA from C6 to T8 was confirmed by magnetic resonance imaging scan.\n\n\nMETHODS\nThe patient was treated with a combination of intravenous vancomycin and imipenem/cilastatin for more than 4 weeks.\n\n\nRESULTS\nAfter more than 2 weeks of intensive antibiotic treatment, the epidural abscess gradually diminished in size, the white blood cell count, neutrophil count, hyperallergic C-reactive protein (CRP), and general CRP decreased, and the patient's neck and back pain resolved. After more than 4 weeks of anti-inflammation therapy, the epidural abscess was completely absorbed, and there was no relapse during the 3-month follow-up period.\n\n\nCONCLUSIONS\nAlthough an effective combination of intravenous antibiotics can cure an epidural abscess, caution is warranted when performing epidural steroid injections in immunocompromised patients.",
"affiliations": "903 Hospital, Jiangyou City, Sichuan Province The Second Affiliated Hospital, State Key Clinical Specialty in Pain Medicine, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.",
"authors": "Zhang|Jun-Hui|JH|;Wang|Zhi-Li|ZL|;Wan|Li|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000007789",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28984753MD-D-17-0105310.1097/MD.0000000000007789077895300Research ArticleClinical Case ReportCervical epidural analgesia complicated by epidural abscess A case report and literature reviewZhang Jun-Hui BSabWang Zhi-Li BSaWan Li MD, PhDb∗Amornyotin. Somchai a 903 Hospital, Jiangyou City, Sichuan Provinceb The Second Affiliated Hospital, State Key Clinical Specialty in Pain Medicine, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.∗ Correspondence: Li Wan, Department of Pain Management, The Second Affiliated Hospital, State Key Clinical Specialty in Pain Medicine, Guangzhou Medical University, Guangzhou, Guangdong P.R. China (e-mail: wanli5000cn@163.com).10 2017 27 10 2017 96 40 e77897 3 2017 11 7 2017 26 7 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0Abstract\nRationale:\nSpinal epidural abscess is an uncommon complication in clinical practice. If the abscess is large enough, the patient will rapidly develop neurologic signs of spinal injury, and urgent neurosurgical intervention may be required.\n\nPatient concerns:\nRapid and correct diagnosis and treatment is important for spinal epidural abscess complication.\n\nDiagnoses:\nThis report describes a cervical epidural abscess (CEA) caused by epidural analgesia, wherein the patient was punctured twice. A CEA was suspected based on the patient's significant neck pain and elevated white blood cell and neutrophil counts. A CEA from C6 to T8 was confirmed by magnetic resonance imaging scan.\n\nInterventions:\nThe patient was treated with a combination of intravenous vancomycin and imipenem/cilastatin for more than 4 weeks.\n\nOutcomes:\nAfter more than 2 weeks of intensive antibiotic treatment, the epidural abscess gradually diminished in size, the white blood cell count, neutrophil count, hyperallergic C-reactive protein (CRP), and general CRP decreased, and the patient's neck and back pain resolved. After more than 4 weeks of anti-inflammation therapy, the epidural abscess was completely absorbed, and there was no relapse during the 3-month follow-up period.\n\nLessons:\nAlthough an effective combination of intravenous antibiotics can cure an epidural abscess, caution is warranted when performing epidural steroid injections in immunocompromised patients.\n\nKeywords\nantibioticscervical epidural abscessepidural analgesiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA cervical epidural abscess (CEA) is a rare complication after epidural puncture and injection. Immunocompromised hosts, diabetes mellitus, and epidural catheter placement, are risk factors for epidural abscess.[1–6] The classical triad of a spinal epidural abscess (SEA) is pain, fever, and neurologic deficits.[7] Specifically, CEA seems to initially present with neck pain, neck stiffness, and/or fever.[8] The combination of neck pain or stiffness along with fever should raise the suspicion for CEA. Magnetic resonance imaging (MRI) is a useful diagnostic method to identify an epidural abscess and has contributed to the recent increase in SEA diagnoses. After diagnosis, urgent treatment, including early, effective, and adequate antibiotics as well as surgical decompression may be necessary to facilitate neurologic recovery.[8] In this article, we present a unique case of a patient who developed an epidural abscess after a cervical epidural puncture and injection. Once the diagnosis of CEA was made, antibiotics were promptly started, the patient was closely monitored, and the abscess was cured without surgical intervention.\n\n2 Case presentation\nA 65-year-old woman with 4 days of neck and shoulder pain that affected her sleep in addition to left arm numbness was seen in our Pain Management Department. Prior to her arrival, the patient had taken some medications (specific details were not clear), but the pain did not improve and became intolerable. The patient had a history of hypertension that had not been treated regularly, and her highest blood pressure was 180/100 mm Hg. All of the patient's examinations and treatments were approved by the ethics committee of 903 Hospital.\n\nUpon arrival, the patient's vital signs showed hypertension with a blood pressure of 170/92 mm Hg; her other vital signs were normal. Physical examination showed a normal spine and extremities. There was slight tenderness over the cervical and the corresponding paravertebral area. The Spurling test, Jackson test, and left Eaton test were all positive. Sensation to pain and muscular tension of the extremities were normal bilaterally, and motor strength was grade 4/5 in the upper and lower extremities bilaterally. The biceps and triceps reflexes were normal bilaterally, and the Hoffmann sign was negative.\n\nWhen she arrived, the patient underwent an MRI scan that showed multiple disc herniation at cervical 3/4, 4/5, and 5/6, and the epidural sac was compressed by the disc herniation (Fig. 1).\n\nFigure 1 Magnetic resonance imaging shows multiple disc herniation of cervical 3/4, 4/5, and 5/6. The epidural sac is compressed by disc herniation (yellow arrow head). Epidural inflammation is seen with increased signal intensity (red arrow).\n\nThe initial diagnosis was cervical spondylosis and primary hypertension. It was decided to treat the patient conservatively with loxoprofen 60 mg twice a day, nifedipine sustained release tablets 10 mg daily, and an intravenous drip of 250 mL of 20% mannitol daily.\n\nTwo days later, the patient manifested clusters of tiny blisters along the C4 and C5 dermatome; the vesicular fluid was clear and there was no tenderness, suggesting the patient might have a concurrent acute herpes zoster infection. The antiviral drug famciclovir 0.25 g was started 3 times a day. The next day, the patient under went a nerve block procedure with an epidural puncture at the C7 to T1 space, and a catheter was inserted. The patient received an injection of 3 mL of the following mixture through the epidural catheter: 5 mL of 2% lidocaine, dexamethasone 10 mg, vitamin B1 100 mg, vitamin B6 100 mg, mecobalamine 1 mg, and 2 mL 0.9% saline, total volume 12 mL). The patient was observed for 10 minutes after the injection, and there were no signs of spinal anesthesia; the remaining volume of the mixture was subsequently injected and the catheter was removed.\n\nThe following day, the patient's pain had decreased and the clusters of blisters were somewhat reduced in size. A second epidural puncture and injection were performed, and the patient received the same nerve block mixture as before. The patient then showered and began to complain of body soreness, slight weakness, and a headache. Bilateral lung wheezing was heard on physical examination, and the patient was given 1 capsule of amoxicillin. However, the patient experienced severe pain of the shoulder, neck, and head accompanied by a low-grade fever (37.8°C), fatigue, and nighttime muscle aches. The patient also fell 1 time on the ward. Blood was tested due to these aggravated symptoms, and the white blood cell count was 24.27 × 109/L, neutrophil percentage was 92.41%, erythrocyte sedimentation rate (ESR) was 66 mm/h, hyperallergic C-reactive protein (CRP) was over 10 mg/L, and general CRP was 193.8 mg/L, suggesting an acute inflammation. The patient underwent a chest x-ray and cervical/thoracic MRI scan and was started on intravenous cefperazone/sulbactam 2 g twice a day and fosfomycin sodium. One day later the patient still complained of severe shoulder pain and headache; physical examination revealed C4 to T8 tenderness and neck stiffness; however, limb strength was normal. The MRI scan indicated epidural inflammation from C6 to T8 and an abscess formation (Fig. 2).\n\nFigure 2 Magnetic resonance imaging shows cervical and thoracic epidural inflammation accompanying the abscess in the axial T2-weighted image. The epidural space in the C6 to T8 segment shows high signal gathering, and the right spinal cord has been compressed (red arrow).\n\nThe patient was moved to the intensive care unit to receive more intensive antibiotic treatment with vancomycin 1 g every 12 hours combined with imipenem/cilastatin sodium 1 g every 8 hours for anti-inflammation. Famciclovir was also changed to gentinovir 0.15 g twice a day for antiviral treatment. The patient's neck and back pain significantly improved after 4 days of anti-inflammation therapy, and the MRI scan showed significant absorption of the abscess (Fig. 3). This therapeutic regimen was continued for 17 days, during which the white blood cell count decreased to 5.11 × 109/L, the neutrophil percentage decreased to 57.3%, the ESR decreased to 76 mm/h, the hyperallergic CRP decreased to 4.71 mg/L, and the general CRP was less than 10 mg/L. The patient's neck and back pain disappeared, and the clusters of blisters scabbed over. On physical examination, there was slight tenderness to percussion but no pressing pain or neck stiffness. After 3 weeks of anti-inflammation therapy, the antibiotics were gradually weaned. After over a month of anti-inflammation therapy, the epidural abscess was completely absorbed and the patient was discharged from the hospital (Fig. 4).\n\nFigure 3 Magnetic resonance imaging shows partial resolution of the abscess. On axial T2-weighted imaging, the gathering signal intensity is reduced, and the area of inflammation has decreased compared to Fig. 2.\n\nFigure 4 Magnetic resonance imaging shows that the epidural abscess is almost completely absorbed, and the epidural space now shows normal signal intensity (red arrow).\n\n3 Discussion\nAn epidural abscess is a life-threatening infection with a high risk of disability and mortality. If the patient in this case had not been diagnosed and treated promptly, the patient may have developed permanent complications such as paraplegia or even death.[9] Therefore, rapid identification and treatment of an epidural abscess will yield the best outcomes.[10]\n\nThe most common symptoms and signs reported with an SEA are neck and back pain, fever, and neurologic deficits.[7,8,11] In this case, the patient showed some of the signs and symptoms, such as neck pain, neck stiffness, and a low-grade fever, which raised the suspicion for an epidural abscess. The inflammatory markers, such as the ESR, CRP, and white blood cell count, supported the diagnosis of an epidural abscess.[8] An MRI scan can provide a definitive diagnosis once an SEA is suspected, and MRI enhancement has a sensitivity over 90%.[7,12] In this case, the MRI scan provided direct evidence of an epidural abscess between C6 and T8, which guided the treatment strategy.\n\nAn MRI is able to differentiate between SEAs and other spinal lesions such as subdural abscesses and tumors. The classical description of an SEA on MRI is an iso- or hyperintense collection in the epidural space on a T1-weighted image that enhances with gadolinium contrast and a non-homogeneous and hyperintense signal on a T2-weighted image.[8,11,13] These classical imaging signs of an epidural abscess were present in this case (Fig. 2).\n\nAnti-inflammation by antibiotics is an important non-surgical treatment for an epidural abscess, especially in the early stages before any neurologic deficit occurs. Chan and Oh[11] reported that there is no guarantee that medical treatment will succeed. If antibiotic therapy alone is considered for aneurologically intact patient, frequent neurologic examinations, blood testing (such as ESR, CRP, and white blood cell count), and MRI examinations are required to monitor the development of the disease. Once the patient shows any neurologic deficit, surgical decompression should be considered.[8] Although the period of antibiotic therapy for epidural abscess is still being debated, it is preferable to continue treatment for at least 4 weeks, because studies have shown a 25% rate of relapse in patients who were treated for less than 4 weeks.[11,14,15] In the present case, the patient received antibiotic therapy for more than 1 month and showed no evidence of relapse during the 3-month follow-up period.\n\nThe patient in this case had a prodrome of herpes zoster infection of the shoulder and posterior neck pain with numbness followed by clusters of tiny blisters along the C4 to C5 dermatome; this suggests that the patient may have been immunocompromised, which could explain the development of an epidural abscess. There were other iatrogenic mechanisms that could significantly increase the risk of an epidural abscess that we cannot exclude, including repeated punctures, epidural catheter placement, and injection of drugs,[16] which can disturb the local microenvironment and result in the spread of pathogens into the epidural space. Based on the events in this case, it is suggested that repeated epidural punctures should be avoided in immunocompromised patients to decrease the risk of an epidural abscess.\n\n4 Conclusions\nIn conclusion, an epidural abscess is a rare complication that requires rapid diagnosis and treatment. An MRI scan has a high sensitivity and specificity when an epidural abscess is suspected, and prompt diagnosis and treatment are key to curing this disease.\n\nAbbreviations: CEA = cervical epidural abscess, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, MRI = magnetic resonance imaging, SEA = spinal epidural abscess.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Tang HJ Lin HJ Liu YC \nSpinal epidural abscess—experience with 46 patients and evaluation of prognostic factors . J Infect \n2002 ;45 :76 –81 .12217707 \n[2] Huang RC Shapiro GS Lim M \nCervical epidural abscess after epidural steroid injection . Spine \n2004 ;29 :E7 –9 .14699291 \n[3] Alcock E Regaard A Browne J \nFacet joint injection: a rare form cause of epidural abscess formation . Pain \n2003 ;103 :209 –10 .12749975 \n[4] Philipneri M Al-Aly Z Amin K \nRoutine replacement of tunneled, cuffed, hemodialysis catheters eliminates paraspinal/vertebral infections in patients with catheter-associated bacteremia . Am J Nephrol \n2003 ;23 :202 –7 .12771502 \n[5] Bang MS Lim SH \nParaplegia caused by spinal infection after acupuncture . Spinal Cord \n2006 ;44 :258 –9 .16151454 \n[6] Sillevis Smitt P Tsafka A van den Bent M \nSpinal epidural abscess complicating chronic epidural analgesia in 11 cancer patients: clinical findings and magnetic resonance imaging . J Neurol \n1999 ;246 :815 –20 .10525980 \n[7] Sendi P Bregenzer T Zimmerli W \nSpinal epidural abscess in clinical practice . QJM \n2008 ;101 :1 –2 .17982180 \n[8] Al-Hourani K Al-Aref R Mesfin A \nUpper cervical epidural abscess in clinical practice: diagnosis and management . Global Spine J \n2016 ;6 :383 –93 .27190742 \n[9] Murata M Yoshikawa K Hiratsuka M \nA case of extensive sacral decubitus ulcer complicated by an epidural abscess . Plast Reconstr Surg Glob Open \n2016 ;4 :e790 .27536469 \n[10] Ramos AD Rolston JD Gauger GE \nSpinal subdural abscess following laminectomy for symptomatic stenosis: a report of 2 cases and review of the literature . Am J Case Rep \n2016 ;17 :476 –83 .27402228 \n[11] Chan JJ Oh JJ \nA rare case of multiple spinal epidural abscesses and cauda equina syndrome presenting to the emergency department following acupuncture . Int J Emerg Med \n2016 ;9 :22 .27456667 \n[12] An HS Seldomridge JA \nSpinal infections: diagnostic tests and imaging studies . Clin Orthop Relat Res \n2006 ;444 :27 –33 .16523124 \n[13] Jarvik JG Deyo RA \nDiagnostic evaluation of low back pain with emphasis on imaging . Ann Intern Med \n2002 ;137 :586 –97 .12353946 \n[14] Shweikeh F Saeed K Bukavina L \nAn institutional series and contemporary review of bacterial spinal epidural abscess: current status and future directions . Neurosurg Focus \n2014 ;37 :1 –1 .\n[15] Suppiah S Meng Y Fehlings MG \nHow best to manage the spinal epidural abscess? A current systematic review . World Neurosurg \n2016 ;93 :20 –8 .27262655 \n[16] Philipneri M Al-Aly Z Amin K \nRoutine replacement of tunneled, cuffed, hemodialysis catheters eliminates paraspinal/vertebral infections in patients with catheter-associated bacteremia . Am J Nephrol \n2003 ;23 :202 –7 .12771502\n\n",
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"mesh_terms": "D000368:Aged; D015360:Analgesia, Epidural; D002574:Cervical Vertebrae; D020802:Epidural Abscess; D005260:Female; D006801:Humans; D006973:Hypertension; D007405:Intervertebral Disc Displacement; D019547:Neck Pain; D013129:Spinal Puncture",
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"title": "Cervical epidural analgesia complicated by epidural abscess: A case report and literature review.",
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"abstract": "Cytarabine, a pyramidine analog, is used for treating various hematological malignancies such as acute leukemias and lymphomas. Side effects of cytarabine are dose dependent and include bone marrow suppression, fever, cerebellar toxicity, cardiomyopathy, hepato-renal insufficiency, necrotizing enterocolitis, pancreatitis, acute respiratory distress, corneal toxicity and dermatological side effects. The dermatological side effects can be immediate or due to delayed hypersensitivity reactions. They have been attributed largely to release of cytokines. We present three such cases of delayed hypersensitivity to cytarabine affecting the ears bilaterally.",
"affiliations": "Department of Hematooncology and BMT, BLK Superspeciality Hospital, New Delhi, India.;Department of Hematooncology and BMT, BLK Superspeciality Hospital, New Delhi, India.;Department of Hematooncology and BMT, BLK Superspeciality Hospital, New Delhi, India.;Department of Hematooncology and BMT, BLK Superspeciality Hospital, New Delhi, India.;Department of Hematooncology and BMT, BLK Superspeciality Hospital, New Delhi, India.",
"authors": "Doval|Divya|D|https://orcid.org/0000-0002-3511-0977;Kumar Sharma|Sanjeev|S|;Kumar|Meet|M|;Khandelwal|Vipin|V|;Choudhary|Dharma|D|",
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"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Acute myeloid leukemia; cytarabine; drug rash; ears",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D064420:Drug-Related Side Effects and Adverse Reactions; D004423:Ear; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged",
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"title": "Cytarabine ears - A side effect of cytarabine therapy.",
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"abstract": "Placental Site Trophoblastic Tumor (PSTT) is a rare malignancy that often presents with extensive disease and can be resistant to traditional treatments. We present the case of a woman with stage IV PSTT who was initially managed with neoadjuvant chemotherapy followed by tumor debulking. Adjuvant therapy was guided by further pathologic analysis that revealed high levels of staining for PD-L1 as well as the presence of tumor infiltrating lymphocytes (TILs). Subsequently, the patient was treated with traditional chemotherapy with the EP/EMA regimen with the addition of pembrolizumab. The patient's treatment course was complicated by the development of pulmonary arteriovenous malformations, autoimmune thyroiditis thought to be secondary to immunotherapy, and significant tinnitus secondary to platinum agents. Currently the patient is in follow up and remains in a complete remission.",
"affiliations": "University of California Los Angeles, Division of Hematology Oncology, Los Angeles, CA, USA.;University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA.;University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA.;University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA.;University of California Los Angeles, Division of Interventional Radiology, Los Angeles, CA, USA.;California Los Angeles, Department of Pathology, Los Angeles, CA, USA.;California Los Angeles, Department of Pathology, Los Angeles, CA, USA.;Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, United Kingdom.;Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, United Kingdom.;Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, United Kingdom.;Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, United Kingdom.;University of California Los Angeles, Division of Hematology Oncology, Los Angeles, CA, USA.;University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA.",
"authors": "Porter|A|A|;Barcelon|J M|JM|;Budker|R L|RL|;Marsh|L|L|;Moriarty|J M|JM|;Aguiar|X|X|;Rao|J|J|;Ghorani|E|E|;Kaur|B|B|;Maher|G|G|;Seckl|M J|MJ|;Konecny|G E|GE|;Cohen|J G|JG|",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789\nElsevier\n\nS2352-5789(21)00086-2\n10.1016/j.gore.2021.100782\n100782\nCase Report\nTreatment of metastatic placental site trophoblastic tumor with surgery, chemotherapy, immunotherapy and coil embolization of multiple pulmonary arteriovenous fistulate\nPorter A. a\nBarcelon J.M. b\nBudker R.L. b\nMarsh L. b\nMoriarty J.M. c\nAguiar X. d\nRao J. d\nGhorani E. e\nKaur B. e\nMaher G. e\nSeckl M.J. e\nKonecny G.E. gkonecny@mednet.ucla.edu\na⁎\nCohen J.G. b\na University of California Los Angeles, Division of Hematology Oncology, Los Angeles, CA, USA\nb University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA\nc University of California Los Angeles, Division of Interventional Radiology, Los Angeles, CA, USA\nd California Los Angeles, Department of Pathology, Los Angeles, CA, USA\ne Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, United Kingdom\n⁎ Corresponding author.at: 100 Medical Plaza, Suite 550, University of California Los Angeles, Los Angeles, CA 90095. gkonecny@mednet.ucla.edu\n07 5 2021\n5 2021\n07 5 2021\n36 1007826 3 2021\n25 4 2021\n30 4 2021\n© 2021 The Authors. Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nHighlights\n\n• Placental site trophoblastic tumor can be resistant to chemotherapy.\n\n• Multidisciplinary care is required for management of advanced disease.\n\n• Increased PD-L1 expression can help guide use of immunotherapies.\n\n• Complete responses are possible with aggressive multidisciplinary management.\n\nPlacental Site Trophoblastic Tumor (PSTT) is a rare malignancy that often presents with extensive disease and can be resistant to traditional treatments. We present the case of a woman with stage IV PSTT who was initially managed with neoadjuvant chemotherapy followed by tumor debulking. Adjuvant therapy was guided by further pathologic analysis that revealed high levels of staining for PD-L1 as well as the presence of tumor infiltrating lymphocytes (TILs). Subsequently, the patient was treated with traditional chemotherapy with the EP/EMA regimen with the addition of pembrolizumab. The patient’s treatment course was complicated by the development of pulmonary arteriovenous malformations, autoimmune thyroiditis thought to be secondary to immunotherapy, and significant tinnitus secondary to platinum agents. Currently the patient is in follow up and remains in a complete remission.\n\nKeywords\n\nPlacental site trophoblastic tumor\nImmunotherapy\nPembrolizumab\n==== Body\n1 Introduction\n\nPSTT is a rare form of gestational trophoblastic neoplasia (GTN) and accounts for just 0.2% of all gestational trophoblastic disease. PSTT differs from other forms of GTN as they are slower growing, produce less hCG for the volume of disease present, metastasize later and involve lymph nodes more frequently (Schmid et al., 2009). As the disease is less chemosensitive, the use of single-agent chemotherapy is not appropriate and the International Federation of Gynecology and Obstetrics (FIGO) scoring system is not used. Surgery has an important role in the management of localized disease. Patients with disease localized to the uterus or with minimal metastatic disease should be counseled regarding hysterectomy because of the relative resistance of PSTT to chemotherapy. Stage-adapted treatment is determined by two independent poor prognostic factors: an interval of >48 months from the causative pregnancy and stage IV disease (Schmid et al., 2009, Froeling et al., 2019). Those with stage IV versus stage I disease irrespective of interval have an overall survival (OS) of 42% and 89%, respectively (Froeling et al., 2019).\n\nTo enable appropriately selected risk-adjusted treatment it is essential to have both a histological diagnosis providing material for genetic analysis to determine the causative pregnancy and whole-body imaging to assess spread of disease. Stage II-IV patients should be offered aggressive platinum-based chemotherapy including the option for experimental treatments such as high dose chemotherapy. More recently, immunotherapy may represent a promising treatment option for metastatic disease. Although PSTTs may not express program death-ligand 1 (PD-L1) as strongly as choriocarcinomas (Veras et al., 2017), success with metastatic PSTT has been reported with anti-PD1 treatment (Ghorani et al., 2017) and this is already playing an increasing role in the management of relapsed chemo-resistant tumors. Here we describe a clinical case of a patient with stage IV PSTT metastatic to the adrenal gland and lungs successfully treated with multimodal therapy: surgical debulking, combination chemotherapy and immunotherapy, and embolization of post treatment arteriovenous fistulae (pAVF). Immunotherapy was employed after discovery of elevated PD-L1 expression and significant involvement of tumor infiltrating lymphocytes (TILs).\n\n2 Case report\n\nA 34-year-old female, gravida 2, para 1, presented with a protruding vaginal mass 8 months following a preterm cesarean delivery at 27 weeks gestational age for preeclampsia and HELLP syndrome. A transvaginal ultrasound demonstrated an enlarged uterus, dilated varicose vessels throughout the myometrium with vascular structures extending to the vagina. MRI and CT scans confirmed vaginal involvement as well as enhancing left renal and right adrenal lesions, and multiple nodules in the lung bases were identified. The lung lesions measured up to 14 mm and some were in close proximity to the pulmonary veins concerning for vascular invasion. A brain MRI was unremarkable and a fluoroscopy-guided lumbar puncture was negative for malignant cells. The hCG levels of the spinal fluid were within the normal range; 3 IU/L (CSF/Serum ratio < 1:60). A PET/CT confirmed the aforementioned lesions albeit without significant FDG activity. A biopsy of the vaginal tumor was consistent with PSTT.\n\nIn an attempt to reduce the risk of pulmonary hemorrhage from high burden of disease the patient initially received treatment with low dose etoposide (E) 100 mg/m2 and cisplatin (P) 20 mg/m2 on days 1 and 2, repeated every week for 3 weeks. Five weeks after initiation of low dose EP the hCG level stabilized at 1138 from 1114 mIU/mL. Given the significant tumor burden in the uterus, the decision was made to proceed with cytoreductive surgery with hysterectomy. Preoperative imaging confirmed there was significant collateral vascularity involving the primary tumor. The patient underwent bilateral uterine artery embolization in order to reduce risk of hemorrhage prior to the planned surgery which included an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingectomy, and excision of the vaginal tumor. Postoperatively the hCG level decreased to 472 mIU/mL.\n\nGross surgical pathology revealed tumor infiltrating the entire uterine wall to the serosal surface with parametrial margin involvement, anterior vaginal wall involvement and lymphovascular space involvement (Fig. 1). Immunohistochemical (IHC) analysis (Fig. 2A) shows tumor cells with large pleomorphic nuclei and abundant eosinophilic cytoplasm. There was scattered expression of HCG (Fig. 2B) and diffuse positive staining for GATA3 (Fig. 2C). Ki67 staining (Fig. 2D) revealed a mildly increased proliferation index of 15–20%. There was no expression of p63 (Fig. 2E). PD-L1 was found to be highly expressed (90% (in house mAB) and 100% using the Tumor Proportion Score (TPS; Dako 22C3 pharmDx™) (Fig. 2F).Fig. 1 Image of uterus demonstrating vascularity involving the lower uterine segment.\n\nFig. 2 IHC stains A. H&E (40×) B. HCG (40×) C. GATA3 (40×) D. Ki67 (40×) E. P63 (40×) F. PDL1 (20×).\n\nPost operatively the EP/EMA (etoposide, cisplatin/etoposide, methotrexate, actinomycin D) regimen was initiated intravenously: day 1 cisplatin 75 mg/m2 and etoposide 150 mg/m2, day 8 actinomycin D 0.5 mg, day 10 etoposide 100 mg/m2 and methotrexate 300 mg/m2. With completion of 5 cycles of EP/EMA, the hCG had decreased from 472 to 55 mIU/mL.\n\nAfter cycle 5, the patient developed left sided upper abdominal pain and a follow up PET/CT demonstrated bilateral pulmonary nodules, some increased and some decreased since the prior exam. In addition, a splenic vein thrombosis with splenic infarct involving the middle and lower pole of the spleen was noticed for which she was started on anticoagulation with apixaban. Two weeks after completion of cycle 5 she developed chills and fever (38.5 °C). Blood cultures revealed methicillin-sensitive staphylococcus (MSSA) bacteremia thought to be secondary to port-a-cath infection. A transthoracic echocardiogram revealed a 2.5 cm right atrial mass (thrombus versus vegetation) as well as a patent foramen ovale. An MRI of the brain revealed multiple embolic infarcts. On additional review of the imaging by interventional radiology (IR), it was determined the patient had multiple pulmonary arterial pseudo-aneurysms with arteriovenous shunting. These correlated with the sites of previous lung nodules and were thought to be the result of vascular trauma due to regression of prior PSTT metastases.\n\nIn order to mitigate the risk of paradoxical embolus as well as pulmonary hemorrhage, she underwent transarterial embolization of these pulmonary shunts. A large arterial aneurysm within the right lower lobe of the lung as well as a large right lower lobe arteriovenous fistula with associated aneurysm were successfully treated with coil embolization (Fig. 3). The patient was bridged from intravenous heparin to apixaban on discharge and completed a four-week course of intravenous oxacillin. An interval MRI performed 1 month later revealed resolution of right atrial thrombus, and improvement in cystic lung disease, with a newly identified small pseudoaneurysm in the left lower lobe. The patient again underwent successful IR coil embolization of this lesion with subsequent resolution.Fig. 3 (a) Digital subtraction angiogram of the right pulmonary arteries demonstrates two large pseudoaneurysms with fistulous communication to the pulmonary vein. (b) Following coil embolization there is no residual shunting and no further right sided pulmonary arterial aneurysms or pseudoaneurysms.\n\nGiven the high PD-L1 expression of the tumor as well as the presence of TILs (40% and 10% positive CD4 and CD8 cells, respectively) the decision was made to add pembrolizumab 200 mg every three weeks starting with cycle 6. At the time of the third pembrolizumab infusion, the patient’s hCG level became undetectable. Chemotherapy with EP/EMA in addition to pembrolizumab was continued for an additional 2 months thereafter as consolidative therapy before transitioning to maintenance pembrolizumab (Fig. 4). The patient experienced several toxicities secondary to chemotherapy including thrombocytopenia as well as ototoxicity and tinnitus that was confirmed with formal audiological evaluation. This prompted the substitution of carboplatin for cisplatin with cycle 10 in the hopes of minimizing further adverse events.Fig. 4 Chemotherapy and immunotherapy treatment cycles with correlating HCG levels. Surgery took place five weeks after initiation of EP with a total of 3 weeks of treatment given prior to hysterectomy.\n\nSeveral days after the patient’s second infusion of pembrolizumab the patient developed symptomatic palpitations with heart rates elevated to the 130–140 range. Thyroid function tests (TFTs) were significantly elevated with a free T4 of 1.3 ng/dL, TSH of 8.2 mIU/mL, free T3 of 122 pg/dL, and total T3 of 36 ng/dL most consistent with inflammatory thyroiditis secondary to pembrolizumab. The patient required administration of methimazole and beta blockade followed by thyroid supplementation with resolution of TFT abnormalities as well as symptoms. The patient completed a total of 10 cycles of adjuvant chemotherapy with an end of treatment PET/CT demonstrating continued treatment response with an undetectable HCG level. The patient remains on pembrolizumab and disease free 7 months since completion of chemotherapy.\n\nTo enable appropriate counseling on the future prognosis, genetic analysis was performed to determine the causative pregnancy. DNA from tumor specimens, maternal and paternal tissue (blood), as well as child (saliva) was evaluated for 24 short tandem repeat loci as previously described at the Gestational Trophoblastic Disease Service at the Imperial College Hospital in London, UK (Zhao et al., 2016). Because all of the informative paternal alleles present in the tumor were also present in the female child born 8 months prior to the PSTT diagnosis, the antecedent pregnancy was found to be the source of the tumor.\n\n3 Discussion\n\nHere we describe the case of a patient with diffusely metastatic PSTT successfully treated with multimodal therapy including surgical debulking, combination chemotherapy and immunotherapy, and IR embolization of post treatment arteriovenous fistulae. Generally, definitive surgical management is reserved for those with early-stage disease, however given this patient’s largest volume of tumor was involving the uterus, the decision was made to proceed with surgery in order to achieve local control after EP had been given to minimize risk of bleeding from lung metastases. Review of the literature demonstrates improvement in long term disease control with combination of surgery and systemic treatment with advanced stage disease (Gadducci et al., 2019).\n\nThe use of immunotherapy was exquisitely effective in the management of this patient. GTN (invasive mole and choriocarcinoma) strongly expresses PD-L1 (Veras et al., 2017) and therefore the successful use of checkpoint inhibitors has increased. Pembrolizumab (anti-PD-1) has induced complete responses in 75–80% of unresectable, chemo-resistant GTN including cases that had failed high dose chemotherarpy (Ghorani et al., 2017, Clair et al., 2020, Huang et al., 2017). Currently, it is unclear how to select responding cases as all are PD-L1 positive and mutational burden may be absent or extremely low in GTN. Detection of TILs and HLA-G expression may be important but much more work is required. The PD-L1 inhibitor avelumab has also shown efficacy in GTN, inducing complete serological response in approximately 53% of patients who had previously been treated with single agent chemotherapy (You et al., 2020).\n\nIt is well known that GTN can have the propensity to form uterine AVMs, however the development of AVMs in the lung following treatment effect in pulmonary metastasis is rare. Patients can experience significant complications as a result of these AVMs if not promptly managed including hemorrhage and paradoxical brain emboli (Yamanari et al., 2017). Thankfully, these shunts or post-treatment fistulae are able to be definitively managed either with coiling via interventional radiology, as in our case, or with surgery. A multidisciplinary approach to the management of patients with metastatic PSTT is imperative. In this case, gynecologic oncology, medical oncology, interventional radiology, pathology, and cardiology experts were imperative to maximize this young woman’s cancer care. A combination of surgery and systemic treatment with the growing potential of immunotherapy should be considered in the setting of metastatic PSTT.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\nClair K.H. Gallegos N. Bristow R.E. Successful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab: a case for immune checkpoint salvage therapy in trophoblastic tumors Gynecol. Oncol. Rep. 34 2020 100625 10.1016/j.gore.2020.100625\nFroeling F.E.M. Ramaswami R. Papanastasopoulos P. Kaur B. Sebire N.J. Short D. Seckl M.J. Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours Br. J. Cancer 120 6 2019 587 594 10.1038/s41416-019-0402-0 30792530\nGadducci A. Carinelli S. Guerrieri M.E. Aletti G.D. Placental site trophoblastic tumor and epithelioid trophoblastic tumor: clinical and pathological features, prognostic variables and treatment strategy Gynecol. Oncol. 153 3 2019 684 693 10.1016/j.ygyno.2019.03.011 31047719\nGhorani E. Kaur B. Fisher R.A. Short D. Joneborg U. Carlson J.W. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia Lancet 390 10110 2017 2343 2345 10.1016/S0140-6736(17)32894-5 29185430\nHuang M. Pinto A. Castillo R.P. Slomovitz B.M. Complete serologic response to pembrolizumab in a woman with chemoresistant metastatic choriocarcinoma J. Clin. Oncol. 35 27 2017 3172 3174 10.1200/JCO.2017.74.40523172-3174 28742453\nSchmid P. Nagai Y. Agarwal R. Hancock B. Savage P.M. Sebire N.J. Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study Lancet 374 9683 2009 48 55 10.1016/S0140-6736(09)60618-8 19552948\nVeras E. Kurman R.J. Wang T.L. Shih I.M. PD-L1 expression in human placentas and gestational trophoblastic diseases Int. J. Gynecol. Pathol. 36 2 2017 146 153 10.1097/PGP.0000000000000305 27362903\nYamanari T. Sawamura M. Lee H.J. Kai Chi C. Katz A. Acquired pulmonary arteriovenous fistula within metastasis from choriocarcinoma: a case report Case Rep. Oncol. 10 2 2017 671 6775 10.1159/000478088 28878648\nYou B. Bolze P.A. Lotz J.P. Massardier J. Gladieff L. Joly F. Avelumab in patients with gestational trophoblastic tumors with resistance to single-agent chemotherapy: cohort a of the TROPHIMMUN phase II trial J. Clin. Oncol. 38 27 2020 3129 3137 10.1200/JCO.20.00803 32716740\nZhao S. Sebire N.J. Kaur B. Seckl M.J. Fisher R.A. Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance Gynecol. Oncol. 142 3 2016 501 507 10.1016/j.ygyno.2016.05.033 27246306\n\n",
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"title": "Treatment of metastatic placental site trophoblastic tumor with surgery, chemotherapy, immunotherapy and coil embolization of multiple pulmonary arteriovenous fistulate.",
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"abstract": "To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy.\n\n\n\nWe evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported.\n\n\n\nAt week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308).\n\n\n\nThe EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.",
"affiliations": "CNR Institute of Clinical Physiology, Pisa, Italy.;Global Medical CVRM, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, Maryland, United States.;Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.;Late CVRM, BioPharmaceuticals R&D, Gaithersburg, Maryland, United States.;Pharmapace Inc., San Diego, California, United States.;Division of Endocrinology, Diabetes and Metabolic Diseases, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;CNR Institute of Clinical Physiology, Pisa, Italy.",
"authors": "Gastaldelli|Amalia|A|0000-0003-2594-1651;Repetto|Enrico|E|;Guja|Cristian|C|0000-0002-8703-0522;Hardy|Elise|E|;Han|Jenny|J|;Jabbour|Serge A|SA|0000-0002-4080-0470;Ferrannini|Ele|E|0000-0002-1384-1584",
"chemical_list": "D001559:Benzhydryl Compounds; D015415:Biomarkers; D005960:Glucosides; D007004:Hypoglycemic Agents; C529054:dapagliflozin; D000077270:Exenatide",
"country": "England",
"delete": false,
"doi": "10.1111/dom.13907",
"fulltext": "\n==== Front\nDiabetes Obes Metab\nDiabetes Obes Metab\n10.1111/(ISSN)1463-1326\nDOM\nDiabetes, Obesity & Metabolism\n1462-8902 1463-1326 Blackwell Publishing Ltd Oxford, UK \n\n10.1111/dom.13907\nDOM13907\nOriginal Article\nOriginal Articles\nExenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes\nGastaldelli et al.Gastaldelli Amalia PhDhttps://orcid.org/0000-0003-2594-1651\n1\namalia@ifc.cnr.it Repetto Enrico MD\n2\n Guja Cristian MDhttps://orcid.org/0000-0002-8703-0522\n3\n Hardy Elise MD\n4\n Han Jenny MS\n5\n Jabbour Serge A. MDhttps://orcid.org/0000-0002-4080-0470\n6\n Ferrannini Ele MDhttps://orcid.org/0000-0002-1384-1584\n1\n \n1 \nCNR Institute of Clinical Physiology\nPisa\nItaly\n\n\n2 \nGlobal Medical CVRM, BioPharmaceuticals Medical, AstraZeneca\nGaithersburg\nMaryland\nUnited States\n\n\n3 \nDepartment of Diabetes, Nutrition and Metabolic Diseases\nCarol Davila University of Medicine and Pharmacy\nBucharest\nRomania\n\n\n4 \nLate CVRM, BioPharmaceuticals R&D\nGaithersburg\nMaryland\nUnited States\n\n\n5 \nPharmapace Inc., San Diego\nCalifornia\nUnited States\n\n\n6 \nDivision of Endocrinology, Diabetes and Metabolic Diseases\nSidney Kimmel Medical College of Thomas Jefferson University\nPhiladelphia\nPennsylvania\nUnited States\n\n* Correspondence\n\nAmalia Gastaldelli, Cardiometabolic Risk Laboratory, Institute of Clinical Physiology, CNR, Via Moruzzi 1, 56124 Pisa, Italy.\n\nEmail: amalia@ifc.cnr.it\n\n14 12 2019 \n3 2020 \n22 3 10.1111/dom.v22.3393 403\n08 8 2019 18 10 2019 31 10 2019 © 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nAim\nTo assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION‐8, a 104‐week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy.\n\nMaterials and methods\nWe evaluated the impact of the study treatments on non‐invasive markers of hepatic steatosis (fatty liver index [FLI] and non‐alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis‐4 index [FIB‐4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported.\n\nResults\nAt week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; −2.92, 95% confidence interval [CI] −5.11, −0.73; P = 0.0092) or DAPA+PLB (−2.77 [95% CI −4.93, −0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (−3.23 [95% CI −5.79, −0.68]; P = 0.0134). FIB‐4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (−0.06 [95% CI −0.11, −0.01]; P = 0.0135) and week 52 (−0.05 [95% CI −0.09, −0.004]; P = 0.0308).\n\nConclusions\nThe EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.\n\ndapagliflozinexenatidelivertype 2 diabetesAstraZeneca 10.13039/100004325GPP3 source-schema-version-number2.0cover-dateMarch 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.7 mode:remove_FC converted:11.03.2020\n\n\nGastaldelli \nA \n, \nRepetto \nE \n, \nGuja \nC \n, et al. Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes\n. Diabetes Obes Metab . 2020 ;22 :393 –403\n. 10.1111/dom.13907 \n31692226 \n\n\n\nPeer Review The peer review history for this article is available at https://publons.com/publon/10.1111/dom.13907.\n\n\nFunding information AstraZeneca, Grant/Award Number: GPP3\n==== Body\n1 INTRODUCTION\nType 2 diabetes is associated with an increased risk of non‐alcoholic fatty liver disease (NAFLD) as a result of factors including obesity and insulin resistance.1, 2 It has been estimated that 50% of people with type 2 diabetes have NAFLD despite exhibiting liver enzymes within normal ranges.1 People with type 2 diabetes and NAFLD are at an increased risk of disease progression to non‐alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma.2 Moreover, NAFLD is independently associated with both prevalent and incident cardiovascular disease,2, 3 and mortality risk increases exponentially with the severity of NAFLD.4 The most recent American Diabetes Association guidelines recommend that people with type 2 diabetes or prediabetes with elevated liver enzymes or fatty liver should be evaluated for the presence of NASH and fibrosis, with non‐invasive biomarkers used to assess the risk of fibrosis.5 Despite this, less than 5% of diabetes specialists correctly assess the prevalence and severity of advanced fibrotic NAFLD in patients with type 1 or type 2 diabetes.6\n\n\nFor the screening/diagnosis of NAFLD, imaging techniques are expensive and are recommended only after an initial diagnosis of NAFLD is made using non‐invasive biomarkers.2, 7 Non‐invasive, clinically validated biomarkers that combine metabolic and hepatic parameters routinely measured in clinical practice have been developed and approved by the European Association for the Study of the Liver, the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity.2 These include the fatty liver index (FLI)8 and the NAFLD liver fat score (NLFS)9 for the diagnosis of NAFLD, and the NAFLD fibrosis score (NFS)10 and the fibrosis‐4 index (FIB‐4)11 for the diagnosis of liver fibrosis.\n\nEarly diagnosis, assessment and intervention are important to stop the progression of NAFLD, because no pharmacotherapies are currently approved by the US Food and Drug Administration for the treatment of the more advanced stage NASH.2 Glucose‐lowering agents have been shown to improve NAFLD, but their direct, long‐term impact remains to be fully explored.12 Pioglitazone has demonstrated reductions in fatty liver content and has provided some resolution of NASH in patients with type 2 diabetes, but with the side effect of significant weight gain.2, 13 Evidence indicates that glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have some benefits in patients with type 2 diabetes and NAFLD/NASH.14, 15, 16, 17, 18, 19 For example, in a phase 2 study, 48 weeks of liraglutide treatment led to biopsy‐confirmed resolution of NASH in 39% of overweight patients with or without type 2 diabetes.14 Furthermore, semaglutide treatment reduced markers of NAFLD (ie, alanine aminotransferase [ALT] and high‐sensitivity C‐reactive protein) in patients with obesity and/or type 2 diabetes.15 With regard to SGLT2 inhibitors, a 24‐week, open‐label, randomized trial of dapagliflozin (DAPA) monotherapy in patients with type 2 diabetes and NAFLD reported overall improvements in hepatic steatosis, along with attenuation of fibrosis in a subset of patients with significant fibrosis.16 Additionally, 24 weeks of canagliflozin treatment demonstrated improvements in the individual histological components of NASH (eg, steatosis, lobular inflammation and ballooning) in patients with type 2 diabetes and NAFLD.17 Building on these results, the GLP‐1RA and SGLT2 inhibitor combination could have a synergistic effect on improving steatosis, steatohepatitis and/or fibrosis in patients with type 2 diabetes and NAFLD; however, this remains to be examined in a randomized controlled trial.\n\nDURATION‐8 (NCT02229396) was a multicentre, double‐blind, randomized, active‐controlled, phase 3 trial that evaluated the effects of exenatide (EXE) once weekly plus DAPA once daily (EXE once weekly + DAPA) compared with EXE once weekly plus placebo (PLB; EXE once weekly + PLB) and DAPA + PLB in people with type 2 diabetes (n = 695) and poor glycaemic control despite metformin monotherapy.20, 21, 22 At 28 weeks, treatment with EXE once weekly + DAPA, compared with each drug alone, significantly reduced glycated haemoglobin (HbA1c) from baseline, along with body weight and systolic blood pressure,20 with improvements maintained at 52 and 104 weeks.21, 22 In the present study, we conducted a post hoc analysis to evaluate the change from baseline to weeks 28 and 52 in non‐invasive biomarkers of fatty liver/steatosis and fibrosis in the three treatment groups.\n\n2 MATERIALS AND METHODS\nThe study design of DURATION‐8 has been previously described.20, 21 In brief, the multicentre study (118 sites) enrolled adults aged ≥18 years with type 2 diabetes and poor glycaemic control (HbA1c 64–108 mmol/mol [8.0%–12.0%]) despite stable metformin monotherapy at ≥1500 mg/d for at least 2 months before screening. Participants (n = 695) were randomized (1:1:1) to receive EXE once weekly 2 mg plus oral DAPA 10 mg once daily, EXE once weekly 2 mg plus DAPA‐matched oral PLB or DAPA 10 mg once daily plus EXE once weekly‐matched PLB injections for 104 weeks (28‐week initial treatment period followed by a 24‐week, double‐blind first extension period and a 52‐week, second double‐blind extension period; Figure S1).20, 21, 22 Baseline characteristics of patients have been previously reported20, 21 and were broadly similar across treatment groups (Table 1).\n\nTable 1 Key demographics and baseline characteristics (intention‐to‐treat population)\n\nCharacteristics\tEXE once weekly + DAPA (n = 228)\tEXE once weekly + PLB (n = 227)\tDAPA + PLB (n = 230)\t\nAge, years\t53.8 ± 9.8\t54.2 ± 9.6\t54.5 ± 9.2\t\nWomen, n (%)\t126 (55)\t111 (49)\t120 (52)\t\nWeight, kg\t91.8 ± 22.2\t89.8 ± 20.2\t91.1 ± 19.7\t\nBMI, kg/m2\n\t33.2 ± 6.8\t32.0 ± 5.9\t33.0 ± 6.1\t\nWaist circumference, cm\t108.7 ± 16.6\t107.1 ± 16.2\t109.0 ± 15.6\t\nDiabetes duration, years\t7.6 ± 6.0\t7.4 ± 5.5\t7.1 ± 5.5\t\nFasting plasma insulin, pmol/L\t81.5 ± 66.6\t82.6 ± 114.8\t83.8 ± 82.8\t\nHbA1c, %\t9.3 ± 1.1\t9.3 ± 1.1\t9.3 ± 1.0\t\nTriglycerides, mmol/L\t2.1 ± 1.2\t2.2 ± 1.3\t2.1 ± 1.3\t\nALT, U/L\t26.4 ± 16.8\t30.2 ± 19.7\t28.1 ± 17.3\t\nAST, U/L\t21.3 ± 11.6\t23.3 ± 13.2\t22.7 ± 11.4\t\nAST:ALT ratio\t0.9 ± 0.3\t0.9 ± 0.3\t0.9 ± 0.2\t\nGGT, U/L\t40.0 ± 36.4\t41.5 ± 38.0\t38.0 ± 27.2\t\nAlbumin, g/L\t44.0 ± 2.6\t44.7 ± 2.8\t44.0 ± 2.8\t\nPlatelet count, ×103/μL\t256.3 ± 70.5\t254.0 ± 65.4\t260.9 ± 72.3\t\nHOMA‐IR\t2.0 ± 1.8\t1.6 ± 0.9\t1.9 ± 1.2\t\nAdipo‐IR\t44.6 ± 31.7\t47.4 ± 57.4\t40.3 ± 36.1\t\nFFA, mmol/L\t0.6 ± 0.2\t0.6 ± 0.2\t0.5 ± 0.2\t\n\nNAFLD biomarkers, mean ± SD (n [%])\n\t\nFLI overall\t78.1 ± 22.8 (190 [100])\t76.2 ± 24.3 (180 [100])\t78.5 ± 22.2 (190 [100])\t\nFLI ≥60\t87.4 ± 11.8 (153 [81])\t86.4 ± 11.1 (145 [81])\t87.2 ± 11.2 (156 [82])\t\nNLFS overall\t1.0 ± 1.7 (179 [100])\t1.0 ± 2.0 (167 [100])\t1.1 ± 2.1 (180 [100])\t\nNLFS > −0.64\t1.2 ± 1.6 (168 [94])\t1.2 ± 2.0 (153 [92])\t1.2 ± 2.1 (168 [93])\t\nNFS overall\t−0.8 ± 1.2 (224 [100])\t−0.9 ± 1.1 (225 [100])\t−0.9 ± 1.2 (227 [100])\t\nNFS >0.676\t1.3 ± 0.5 (25 [11])\t1.3 ± 0.7 (16 [7])\t1.2 ± 0.5 (21 [9])\t\nFIB‐4 overall\t1.0 ± 0.6 (224 [100])\t1.0 ± 0.9 (225 [100])\t1.0 ± 0.5 (227 [100])\t\nFIB‐4 ≥ 1.3\t1.8 ± 0.9 (39 [17])\t1.9 ± 1.5 (46 [20])\t1.7 ± 0.4 (50 [22])\t\nAbbreviations: Adipo‐IR, adipose tissue insulin resistance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DAPA, dapagliflozin; EXE, exenatide; FFA, free fatty acids; FIB‐4, fibrosis‐4 index; FLI, fatty liver index; GGT, gamma‐glutamyltransferase; HbA1c, glycated haemoglobin; HOMA‐IR, homeostatic model assessment of insulin resistance; n, number of patients; NAFLD, non‐alcoholic fatty liver disease; NFS, NAFLD fibrosis score; NLFS, NAFLD liver fat score; PLB, placebo; SD, standard deviation; SE, standard error. Data are mean ± SD or geometric mean ± SE, unless specified otherwise.\n\nThe primary endpoint of DURATION‐8 was change in HbA1c from baseline to week 28.20 The main objective of the present post hoc analysis was to assess the effects of EXE once weekly + DAPA, EXE once weekly + PLB and DAPA + PLB treatments on change from baseline to weeks 28 and 52 in guideline‐approved2 biomarkers of fatty liver/steatosis (FLI and NLFS)8, 9 and fibrosis (NFS and FIB‐410, 11; Table S1). In brief, the FLI comprises body mass index (BMI), waist circumference and serum levels of triglycerides and gamma‐glutamyltransferase (GGT); a cut‐off score of ≥60 rules‐in hepatic steatosis as detected by ultrasonography.8 The NLFS includes presence of metabolic syndrome and type 2 diabetes, fasting serum insulin concentration, aspartate aminotransferase (AST) and AST:ALT ratio; a cut‐off score of > − 0.640 has good sensitivity to predict increased liver fat.9 The NFS is based on age, BMI, the presence of type 2 diabetes or impaired fasting glucose, platelet count, albumin and AST:ALT ratio.10 The FIB‐4 comprises age, AST, ALT and platelet count.11 A FIB‐4 ≥ 1.3 cut‐off score has high sensitivity and specificity for the diagnosis of fibrosis, whilst the NFS cut‐off score of >0.676 is used for the diagnosis of severe fibrosis (stages F3 and F4).10, 11 Additional details of the constituent elements of the biomarkers used in the present study, including their scoring criteria and cut‐offs, can be found in Table S1.\n\nChanges from baseline to weeks 28 and 52 in ALT, AST, AST:ALT ratio and GGT were assessed, along with the proportion of participants with positive biomarker scores at weeks 28 and 52 versus baseline. Additional metabolic variables evaluated were changes from baseline to weeks 28 and 52 in homeostatic model assessment of insulin resistance (HOMA‐IR), adipose tissue insulin resistance (Adipo‐IR), HbA1c, body weight, triglycerides and fasting plasma insulin (FPI). HOMA‐IR was calculated with the HOMA2 Calculator, based on fasting plasma glucose and FPI.23 Adipo‐IR was calculated as the product of fasting plasma non‐esterified fatty acids (NEFA) and FPI (Adipo‐IR = NEFA × FPI). As increased Adipo‐IR is a characteristic of patients with NAFLD,24, 25, 26, 27 we assessed the correlations between change in Adipo‐IR and changes in biomarkers of fatty liver/steatosis and fibrosis at week 28.\n\nA path analysis hypothesizing a direct treatment effect on weight change, changes in triglycerides, AST:ALT ratio and Adipo‐IR, and an indirect treatment effect mediated by weight loss on changes in triglycerides, AST:ALT ratio and Adipo‐IR, was built to provide estimates of the magnitude and significance of these potentially causal connections.28\n\n\n2.1 Statistical analyses\nAnalyses were conducted on the intention‐to‐treat population, which included all randomized participants who received ≥1 dose of study medication and had ≥1 post‐baseline HbA1c assessment. Changes in HbA1c and body weight from baseline to weeks 28 and 52 were analysed using a mixed‐effects model with repeated measures.20, 21 Clinical indices of fatty liver/steatosis and fibrosis were calculated and scored in accordance with published methodologies (Table S1).8, 9, 10, 11 Changes from baseline in least squares mean, or geometric mean ratio (HOMA‐IR), to weeks 28 and 52 were analysed using analysis of covariance (ANCOVA) with the last observation carried forward (LOCF) method. The ANCOVA model included the following factors: treatment, region, baseline HbA1c stratum and baseline value of the dependent variable as a covariate. In the LOCF method, the last post‐baseline measurement was carried forward to impute the missing value at weeks 28 and 52. HOMA‐IR values were log‐transformed and the log (endpoint/baseline) was analysed (eg, log[y2]–log[y1] = log[y2/y1]). All outcomes except HbA1c and body weight change at week 28 were exploratory and therefore nominal P values were reported for these variables. Data were first checked for normality of distribution and, as the calculated NAFLD biomarkers either did not follow a log‐normal distribution or had negative values that were invalid for log‐transformation, additional P values based on non‐parametric Wilcoxon rank‐sum tests for the between‐treatment group comparisons were reported as supportive evidence. Pearson's correlation coefficients were used to assess the association between change in Adipo‐IR and biomarkers of fatty liver/steatosis and fibrosis at week 28. Path analysis was conducted to examine correlations among variables for interpretation of direct and indirect effects; standardized path coefficients were calculated for the path diagram to quantify the contribution (effect) from different paths. All statistical analyses were conducted using SAS version 9.2 or higher (SAS Institute Inc., Cary, North Carolina).\n\n3 RESULTS\n3.1 Baseline characteristics\nThe intention‐to‐treat population comprised 685 participants: EXE once weekly + DAPA, n = 228; EXE once weekly + PLB, n = 227; and DAPA + PLB, n = 230 (Table 1). The mean BMI was 32.7 kg/m2, the mean HbA1c was 78 mmol/mol (9.3%) and the mean duration of type 2 diabetes was 7.4 years.20, 21 At baseline, liver enzymes and biomarker scores were similar across the three groups (Table 1). In participants with available data at baseline, 81.3% and 93.0% had altered biomarker scores indicating the presence of fatty liver/steatosis (FLI ≥60 and NLFS > − 0.640 cut‐offs, respectively) and 19.9% and 9.0% had biomarker scores suggestive of fibrosis and severe fibrosis (ie, stages F3 and F4; FIB‐4 ≥ 1.3 and NFS >0.676 cut‐offs [Table 1]).\n\n3.2 Effects of treatment at weeks 28 and 52\nAt week 28, indices of fatty liver/steatosis (FLI overall, FLI in participants with baseline cut‐off of ≥60, NLFS overall and NLFS in participants with baseline cut‐off of > − 0.640) decreased from baseline in all three treatment groups (Table 2). At week 28, the proportions of participants with biomarker scores suggestive of fatty liver/steatosis (ie, FLI ≥60 and NLFS > − 0.640) were reduced by 10.5% and 6.1%, respectively, with EXE once weekly + DAPA. At weeks 28 and 52, changes in FLI and NLFS in the EXE once weekly + DAPA group were larger than the corresponding changes in the EXE once weekly + PLB group; change in FLI was also larger with EXE once weekly + DAPA versus DAPA + PLB at week 28 (Figure 1). Regarding the indices of fibrosis and severe fibrosis at weeks 28 and 52, FIB‐4 showed a reduction versus baseline in the EXE once weekly + DAPA group only and NFS was reduced in all treatment groups versus baseline (Table 2). Changes in NFS and FIB‐4 were similar in all treatment groups (Figure 1). At week 28, the proportions of participants with biomarker scores suggestive of fibrosis and severe fibrosis (ie, FIB‐4 ≥ 1.3 and NFS >0.676) were reduced by 2.8% and 4.1%, respectively, with EXE once weekly + DAPA.\n\nTable 2 Changes from baseline in biomarkers of fatty liver/steatosis and fibrosis at weeks 28 and 52\n\n\tEXE once weekly + DAPA\tEXE once weekly + PLB\tDAPA + PLB\tEXE once weekly + DAPA vs. EXE once weekly + PLB\tEXE once weekly + DAPA vs. DAPA + PLB\t\n\nFLI\n\t\nN\t190\t180\t190\t‐\t\nChange from baseline at week 28\t−6.81 (−8.52, −5.10); P < 0.0001\t−3.90 (−5.70, −2.09); P < 0.0001\t−4.04 (−5.77, −2.32); P < 0.0001\t−2.92 (−5.11, −0.73); P = 0.0092 [P = 0.0080]\t−2.77 (−4.93, −0.62); P = 0.0119 [P = 0.0162]\t\nN\t190\t180\t190\t\t\nChange from baseline at week 52\t−6.23 (−8.23, −4.24); P < 0.0001\t−3.00 (−5.11, −0.88); P = 0.0055\t−4.58 (−6.60, −2.56); P < 0.0001\t−3.23 (−5.79, −0.68); P = 0.0134 [P = 0.0036]\t−1.65 (−4.17, 0.87); P = 0.1981 [P = 0.1012]\t\n\nFLI ≥ 60\n\t\nN\t153\t145\t156\t\t\nChange from baseline at week 28\t−7.06 (−8.93, −5.19); P < 0.0001\t−5.13 (−7.11, −3.16); P < 0.0001\t−4.67 (−6.54, −2.79); P < 0.0001\t−1.93 (−4.32, 0.47); P = 0.1149 [P = 0.1353]\t−2.39 (−4.74, −0.05); P = 0.0458 [P = 0.0401]\t\nN\t153\t145\t156\t\t\nChange from baseline at week 52\t−6.29 (−8.45, −4.12); P < 0.0001\t−4.46 (−6.75, −2.18); P = 0.0001\t−5.79 (−7.96, −3.62); P < 0.0001\t−1.82 (−4.60, 0.95); P = 0.1969 [P = 0.0982]\t−0.49 (−3.21, 2.22); P = 0.7209 [P = 0.4663]\t\n\nNLFS\n\t\nN\t179\t167\t180\t\t\nChange from baseline at week 28\t−0.32 (−0.53, −0.120); P = 0.0017\t−0.03 (−0.25, 0.18); P = 0.7740\t−0.36 (−0.57, −0.16); P = 0.0005\t−0.29 (−0.55, −0.03); P = 0.0271 [P = 0.0006]\t0.04 (−0.21, 0.29); P = 0.7557 [P = 0.6825]\t\nN\t179\t167\t180\t\t\nChange from baseline at week 52\t−0.31 (−0.52, −0.11); P = 0.0026\t0.01 (−0.20, 0.23); P = 0.8926\t−0.41 (−0.62, −0.21); P < 0.0001\t−0.33 (−0.59, −0.07); P = 0.0141 [P = 0.0002]\t0.10 (−0.16, 0.36); P = 0.4447 [P = 0.8473]\t\n\nNLFS > −0.640\n\t\nN\t168\t153\t168\t\t\nChange from baseline at week 28\t−0.40 (−0.64, −0.16); P = 0.0012\t−0.16 (−0.41, 0.10); P = 0.2201\t−0.40 (−0.64, −0.16); P = 0.0011\t−0.24 (−0.54, 0.06); P = 0.1167 [P = 0.0023]\t0.00 (−0.29, 0.30); P = 0.9788 [P = 0.6403]\t\nN\t168\t153\t168\t\t\nChange from baseline at week 52\t−0.41 (−0.65, −0.17); P = 0.0008\t−0.10 (−0.35, 0.16); P = 0.4547\t−0.45 (−0.69, −0.21); P = 0.0002\t−0.31 (−0.61, −0.02); P = 0.0389 [P = 0.0004]\t0.04 (−0.25, 0.33); P = 0.7824 [P = 0.9355]\t\n\nNFS\n\t\nN\t224\t225\t227\t\t\nChange from baseline at week 28\t−0.17 (−0.27, −0.07); P = 0.0008\t−0.20 (−0.31, −0.01); P = 0.0001\t−0.13 (−0.23, −0.03); P = 0.0113\t0.03 (−0.1, 0.16); P = 0.6544 [P = 0.7861]\t−0.04 (−0.17, 0.08); P = 0.4956 [P = 0.3641]\t\nN\t224\t225\t227\t\t\nChange from baseline at week 52\t−0.17 (−0.27, −0.07); P = 0.0007\t−0.12 (−0.22, −0.02); P = 0.0201\t−0.11 (−0.21, −0.02); P = 0.0217\t−0.05 (−0.17, 0.07); P = 0.4160 [P = 0.1009]\t−0.06 (−0.18, 0.07); P = 0.3718 [P = 0.1436]\t\n\nNFS > 0.676\n\t\nN\t25\t16\t21\t\t\nChange from baseline at week 28\t−0.11 (−0.56, 0.35); P = 0.6451\t−0.37 (−0.79, 0.05); P = 0.0851\t−0.20 (−0.67, 0.27); P = 0.3912\t0.26 (−0.21, 0.73); P = 0.2691 [P = 1.0000]\t0.10 (−0.32, 0.51); P = 0.6503 [P = 0.9912]\t\nN\t25\t16\t21\t\t\nChange from baseline at week 52\t−0.32 (−0.74, 0.10); P = 0.1336\t−0.44 (−0.83, −0.05); P = 0.0271\t−0.58 (−1.02, −0.15); P = 0.0089\t0.12 (−0.32, 0.56); P = 0.5842 [P = 0.9574]\t0.26 (−0.13, 0.65); P = 0.1798 [P = 0.2654]\t\n\nFIB‐4\n\t\nN\t224\t225\t227\t\t\nChange from baseline at week 28\t−0.06 (−0.11, −0.01); P = 0.0135\t−0.03 (−0.08, 0.02); P = 0.2264\t−0.04 (−0.09, 0.003); P = 0.0697\t−0.03 (−0.09, 0.03); P = 0.3184 [P = 0.9038]\t−0.02 (−0.08, 0.04); P = 0.5848 [P = 0.5447]\t\nN\t224\t225\t227\t\t\t\nChange from baseline at week 52\t−0.05 (−0.09, −0.004); P = 0.0308\t−0.02 (−0.07, 0.02); P = 0.3214\t−0.04 (−0.08, 0.003); P = 0.0669\t−0.03 (−0.08, 0.03); P = 0.3551 [P = 0.4564]\t−0.01 (−0.06, 0.05); P = 0.7792 [P = 0.5979]\t\n\nFIB‐4 ≥ 1.3\n\t\nN\t39\t46\t50\t\t\nChange from baseline at week 28\t−0.03 (−0.45, 0.39); P = 0.8902\t−0.15 (−0.54, 0.25); P = 0.4613\t−0.15 (−0.58, 0.27); P = 0.4746\t0.12 (−0.26, 0.50); P = 0.5428 [P = 0.3364]\t0.12 (−0.25, 0.50); P = 0.5124 [P = 0.4225]\t\nN\t39\t46\t50\t\t\nChange from baseline at week 52\t0.11 (−0.55, 0.78); P = 0.7424\t−0.43 (−1.05, 0.19); P = 0.1739\t−0.27 (−0.94, 0.40); P = 0.4203\t0.54 (−0.06, 1.14); P = 0.0778 [P = 0.2137]\t0.38 (−0.21, 0.97); P = 0.2001 [P = 0.2899]\t\nAbbreviations: CI, confidence interval; DAPA, dapagliflozin; EXE, exenatide; FIB‐4, fibrosis‐4 index; FLI, fatty liver index; LS, least squares; NAFLD, non‐alcoholic fatty liver disease; NFS, NAFLD fibrosis score; NLFS, NAFLD liver fat score; PLB, placebo. Change from baseline in biomarker score data are LS mean (95% CI). Between group comparison P values in parentheses are derived from the Wilcoxon rank‐sum test.\n\nFigure 1 Least squares (LS) mean change in A, fatty liver index (FLI), B, non‐alcoholic fatty liver disease (NAFLD) liver fat score (NLFS), C, NAFLD fibrosis score (NFS) and D, fibrosis‐4 index (FIB‐4) from baseline to weeks 28 and 52. DAPA, dapagliflozin; EXE, exenatide; PLB, placebo\n\nLevels of ALT decreased from baseline to weeks 28 and 52 in the EXE once weekly + DAPA (P = 0.0026 vs. EXE once weekly + PLB) and the DAPA + PLB group. AST decreased from baseline to week 28 in the EXE once weekly + DAPA group (P = 0.0052 vs. EXE once weekly + PLB) and the DAPA + PLB group, and at week 52 in the EXE once weekly + DAPA group (Table 3).Triglyceride concentration decreased in the EXE once weekly + DAPA group at weeks 28 and 52 (P < 0.0500 vs. DAPA + PLB), and in the EXE once weekly + PLB group at week 28 (Table 2). GGT levels decreased at weeks 28 and 52 in the EXE once weekly + DAPA group, and at week 28 in the DAPA + PLB group (data not shown).\n\nTable 3 Change from baseline in metabolic and liver biomarkers at weeks 28 and 52\n\n\tEXE once weekly + DAPA (n = 228)\tEXE once weekly + PLB (n = 227)\tDAPA + PLB (n = 230)\tEXE once weekly + DAPA vs. EXE once weekly + PLB\tEXE once weekly + DAPA vs. DAPA + PLB\t\n\nBody weight, kg\n\t\nChange from baseline at week 28\t−3.55 (−4.12, −2.99); P < 0.05\t−1.56 (−2.13, −0.98); P < 0.05\t−2.22 (−2.78, −1.66); P < 0.05\t−2.00 (−2.79, −1.20); P < 0.001\t−1.33 (−2.12, −0.55); P < 0.001\t\nChange from baseline at week 52\t−3.31 (−4.05, −2.57); P < 0.05\t−1.51 (−2.28, −0.73); P < 0.05\t−2.28 (−3.05, −1.52); P < 0.05\t−1.80 (−2.87, −0.73); P < 0.001\t−1.02 (−2.08, 0.03); P = 0.057\t\n\nFasting plasma insulin, pmol/L\n\t\nChange from baseline at week 28\t−5.46 (−20.4, 9.49); P = 0.4736\t12.03 (−3.67, 27.73); P = 0.1329\t−11.6 (−26.4, 3.25); P = 0.1257\t−17.5 (−36.5, 1.52); P = 0.0713\t6.10 (−12.4, 24.64); P = 0.5185\t\nChange from baseline at week 52\t−8.58 (−18.7, 1.53); P = 0.0959\t4.76 (−5.82, 15.34); P = 0.3771\t−14.4 (−24.4, −4.39); P = 0.0049\t−13.3 (−26.2, −0.45); P = 0.0426\t5.82 (−6.74, 18.39); P = 0.3631\t\n\nHbA1c, %\n\t\nChange from baseline at week 28\t−1.98 (−2.16, −1.79); P < 0.05\t−1.60 (−1.79, −1.41); P < 0.05\t−1.39 (−1.57, −1.21); P < 0.05\t−0.38 (−0.63, −0.13); P = 0.003\t−0.59 (−0.84, −0.34); P < 0.001\t\nChange from baseline at week 52\t−1.75 (−1.94, −1.56); P < 0.05\t−1.38 (−1.57, −1.18); P < 0.05\t−1.23 (−1.42, −1.04); P < 0.05\t−0.37 (−0.64, −0.11); P = 0.006\t−0.52 (−0.79, −0.26); P < 0.001\t\n\nTriglycerides, mmol/L\n\t\nChange from baseline at week 28\t−0.31 (−0.47, −0.16); P < 0.0001\t−0.18 (−0.34, −0.02); P = 0.0237\t−0.11 (−0.26, 0.04); P = 0.1448\t−0.13 (−0.32, 0.06); P = 0.1813\t−0.20 (−0.39, −0.01); P = 0.0364\t\nChange from baseline at week 52\t−0.24 (−0.43, −0.05); P = 0.0143\t−0.07 (−0.27, 0.13); P = 0.4748\t0.00 (−0.19, 0.19); P = 0.9695\t−0.16 (−0.41, 0.08); P = 0.1804\t−0.27 (−0.48, 0.00); P = 0.0463\t\n\nALT, U/L\n\t\nChange from baseline at week 28\t−5.68 (−7.74, −3.62); P < 0.0001\t−1.72 (−3.81, 0.37); P = 0.1072\t−4.56 (−6.61, −2.52); P < 0.0001\t−3.96 (−6.54, −1.39); P = 0.0026\t−1.12 (−3.68, 1.44); P = 0.3915\t\nChange from baseline at week 52\t−4.44 (−6.75, −2.14); P = 0.0002\t−0.02 (−2.36, 2.32); P = 0.9865\t−3.13 (−5.42, −0.85); P = 0.0072\t−4.42 (−7.30, −1.55); P = 0.0026\t−1.31 (−4.17, 1.55); P = 0.3688\t\n\nAST, U/L\n\t\nChange from baseline at week 28\t−3.44 (−5.00, −1.87); P < 0.0001\t−0.65 (−2.24, 0.93); P = 0.4186\t−2.75 (−4.30, −1.20); P = 0.0005\t−2.78 (−4.73, −0.83); P = 0.0052\t−0.69 (−2.63, 1.26); P = 0.4875\t\nChange from baseline at week 52\t−2.31 (−4.06, −0.56); P = 0.0096\t−0.18 (−1.95, 1.60); P = 0.8441\t−1.48 (−3.22, 0.25); P = 0.0934\t−2.13 (−4.31, 0.05); P = 0.0551\t−0.83 (−3.00, 1.34); P = 0.4541\t\n\nAST:ALT ratio\n\t\nChange from baseline at week 28\t0.07 (0.04, 0.10); P < 0.001\t0.04 (0.00, 0.07); P = 0.027\t0.03 (0.00, 0.06); P = 0.038\t0.03 (−0.01, 0.07); P = 0.087\t0.04 (−0.00, 0.08); P = 0.061\t\nChange from baseline at week 52\t0.06 (0.03, 0.09); P = 0.001\t0.02 (−0.02, 0.05); P = 0.311\t0.03 (−0.00, 0.06); P = 0.058\t0.04 (0.00, 0.08); P = 0.048\t0.03 (−0.01, 0.07); P = 0.195\t\n\nHOMA‐IR\n\t\nChange from baseline at week 28\t0.81 (0.75, 0.88); P < 0.0001\t1.00 (0.92, 1.08); P = 0.9344\t0.75 (0.70, 0.81); P < 0.0001\t0.81 (0.74, 0.90); P < 0.0001\t1.08 (0.98, 1.18); P = 0.1116\t\nChange from baseline at week 52\t0.80 (0.74, 0.87); P < 0.0001\t1.00 (0.93, 1.09); P = 0.9672\t0.77 (0.71, 0.83); P < 0.0001\t0.80 (0.73, 0.88); P < 0.0001\t1.04 (0.95, 1.15); P = 0.3972\t\n\nAdipo‐IR\n\t\nChange from baseline at week 28\t−4.32 (−12.4, 3.72); P = 0.2919\t5.36 (−2.95, 13.67); P = 0.2054\t−4.68 (−12.4, 3.07); P = 0.2360\t−9.68 (−19.9, 0.54); P = 0.0632\t0.36 (−9.49, 10.21); P = 0.9425\t\nChange from baseline at week 52\t−6.92 (−12.5, −1.36); P = 0.0148\t−2.33 (−8.23, 3.58); P = 0.4386\t−7.35 (−12.7, −1.99); P = 0.0073\t−4.59 (−11.8, 2.66); P = 0.2142\t0.44 (−6.53, 7.40); P = 0.9022\t\nAbbreviations: Adipo‐IR, adipose tissue insulin resistance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; DAPA, dapagliflozin; EXE, exenatide; HbA1c, glycated haemoglobin; HOMA‐IR, homeostatic model assessment‐insulin resistance; LS, least squares; n, number of patients; PLB, placebo. Change data are LS mean (95% CI) apart from change in HOMA‐IR, which is reported as the geometric LS mean ratio (95% CI); HOMA‐IR values <1 relate to a decrease, values >1 relate to an increase.\n\nRegarding the indices of insulin resistance, HOMA‐IR improved similarly in the EXE once weekly + DAPA and DAPA + PLB groups at weeks 28 and 52, with the effect observed in the EXE once weekly + DAPA group being larger than that in the EXE once weekly + PLB group (Table 3). Adipo‐IR improved in the EXE once weekly + DAPA and the DAPA + PLB groups at week 52, with the change in the EXE once weekly + DAPA group being no different from those in the individual drug groups (Table 3). In the EXE once weekly + DAPA group, changes in Adipo‐IR were mainly associated with improvements in biomarkers of fatty liver/steatosis (FLI and NLFS) compared with biomarkers of fibrosis (NFS and FIB‐4; Figure 2).\n\nFigure 2 Pearson's correlations between changes in Adipo‐IR and A, fatty liver index (FLI), B, non‐alcoholic fatty liver disease (NAFLD) liver fat score (NLFS), C, NAFLD fibrosis score (NFS) and D, fibrosis‐4 index (FIB‐4) at week 28 in the exenatide (EXE) once weekly + dapagliflozin (DAPA) group. Adipo‐IR, adipose tissue insulin resistance; r, Pearson's correlation coefficient\n\nBy path analysis, weight loss had a significant (P < 0.05) direct effect on AST:ALT ratio (β = −0.12) and Adipo‐IR (β = 0.16), but not on triglycerides (β = 0.06; Figure S2). There were significant (P < 0.05) indirect treatment effects on AST:ALT ratio and Adipo‐IR with EXE once weekly + DAPA (ie, mediated by weight loss) versus EXE once weekly + PLB (β = 0.29) and DAPA + PLB (β = 0.19; Figure S2).\n\n4 DISCUSSION\nDURATION‐8 investigated the efficacy and safety of EXE once weekly + DAPA combination therapy compared with each individual drug plus PLB in people with type 2 diabetes inadequately controlled on metformin.20, 22 In the present post hoc analysis, we evaluated the effect of these treatments on liver enzymes and serum non‐invasive biomarkers of fatty liver/steatosis and fibrosis.8, 9, 10, 11 EXE once weekly + DAPA showed improvements in liver enzymes and all biomarkers of fatty liver/steatosis and fibrosis versus baseline, with superior improvements observed for biomarkers of fatty liver/steatosis (the FLI and NLFS at week 28 and the FLI at week 52) compared with EXE once weekly + PLB and/or DAPA + PLB. All treatments reduced the NFS, a marker of severe fibrosis, from baseline; FIB‐4 was reduced in the EXE once weekly + DAPA group only, but no difference was observed between the treatment groups. However, the number of participants with fibrosis or severe fibrosis was small, which affects the interpretability of these results. Extending recent data demonstrating the individual effects of GLP‐1RAs or SGLT2 inhibitors on NAFLD,14, 15, 16, 17, 18, 19 the present results are the first to demonstrate the effect of this combination in reducing NAFLD biomarkers in people with type 2 diabetes, and indicate that combining these two agents may exert stronger beneficial effects on NAFLD than each drug alone. Moreover, as NAFLD is independently associated with cardiovascular disease,2, 3 and the cardiovascular benefits of GLP‐1RAs and SGLT2 inhibitors are now well established,5, 29 the EXE once weekly + DAPA combination may confer a reduction in cardiovascular risk in patients with type 2 diabetes and NAFLD. However, this needs to be evaluated in a specific, prospective trial.\n\nWith regard to the potential mechanisms underlying the beneficial effects of EXE once weekly + DAPA treatment, weight loss and/or an improvement in hyperglycaemia, hyperinsulinaemia and resultant glucotoxicity may explain the present results. Weight loss was greater with EXE once weekly + DAPA versus the individual drugs at 28 and 52 weeks,20, 21 and the path analysis suggested that weight loss mediated the treatment effect of EXE once weekly + DAPA, versus the individual drugs, on AST:ALT ratio and Adipo‐IR. Weight loss is the mainstay of NAFLD treatment,2 and it has been previously demonstrated that the extent of weight loss achieved by patients is directly proportional to reduced NAFLD activity score, NASH resolution and fibrosis regression.30 Moreover, the Diabetes Remission Clinical Trial (DiRECT) reported that a weight loss of ~15% in patients with type 2 diabetes was associated with a substantial decrease in liver fat content and recovery of β‐cell function, suggesting that the normalization of liver fat may help put type 2 diabetes into remission.31 However, in overweight, insulin‐resistant patients without type 2 diabetes, it has been reported that 12 weeks of DAPA treatment had no impact on hepatic steatosis despite a mean weight loss of 4.4 kg.32 Recent evidence suggests that DAPA reduces specific hepatocyte injury biomarkers, such as cytokeratin 18‐M30 and plasma fibroblast growth factor 21, suggesting an intrinsic disease‐modifying effect in NAFLD.18 Regarding hyperglycaemia, excess dietary sugars can induce liver glucotoxicity by increasing hepatic steatosis, via de novo lipogenesis, and exacerbating insulin resistance and cellular demise, through mechanisms including the activation of oxidative and endoplasmic reticulum stress responses.33 Recently, amelioration of hepatic dysfunction following at least 6 months of SGLT2 inhibitor treatment in patients with type 2 diabetes was mediated partly through an alleviation of hyperglycaemia, independent of weight loss.34\n\n\nIn the present study, we observed that EXE once weekly + DAPA combination therapy led to an improvement in insulin resistance, as measured by Adipo‐IR and HOMA‐IR. Adipo‐IR (ie, the impaired suppression of lipolysis in the presence of high insulin levels) plays a key role in the pathogenesis of NAFLD.24, 25, 26, 27 Adipose tissue dysfunction affects both glucose and lipid metabolism by releasing proinflammatory adipokines and NEFA.24, 26 These have an impact on all tissues, including skeletal muscle, β cells and the liver, and modify inflammatory responses as well as glucose and lipid metabolism, thus contributing to metabolic abnormalities.24, 26, 33 In patients with NAFLD, increased Adipo‐IR is linked with deterioration of metabolic variables, in conjunction with increased liver insulin resistance and fibrosis.25 Accordingly, improvement in Adipo‐IR has been associated with a reduction in liver fat and associated necroinflammation following pioglitazone treatment in patients with NASH.27 In the present study, we observed that correlations were stronger between improvement in Adipo‐IR and reduction in biomarkers of fatty liver/steatosis versus biomarkers of fibrosis. However, as the proportion of participants with biomarker scores suggestive of fibrosis was considerably lower than fatty liver/steatosis, with less pronounced changes from baseline than the FLI and NLFS, the absence of a strong association between improvement in Adipo‐IR and fibrosis is perhaps not surprising.\n\nAlthough DURATION‐8 was not primarily designed to investigate the beneficial effects of EXE once weekly + DAPA on NAFLD, the present results suggest that the combination could be effective in reducing liver steatosis, and may potentially improve NASH and fibrosis in patients with type 2 diabetes. Strengths of the study include the large number of participants enrolled, its double‐blind, placebo‐controlled design, and being the first to evaluate the effects of a GLP‐1RA and SGLT2 inhibitor combination on biomarkers of fatty liver/steatosis and fibrosis in people with type 2 diabetes. There are also several limitations. For instance, DURATION‐8 was not primarily powered to assess the effect of the EXE once weekly + DAPA combination on markers of fatty liver/steatosis and fibrosis, and these were exploratory outcomes. Further, the biomarkers that include type 2 diabetes in their formulae (ie, NLFS and NFS) may not be fully reliable in a solely diabetic population. Also, there was an imbalance between treatment groups in the number of participants with high FPI values, mainly in the EXE once weekly + PLB group. Further, the histological features of NASH were not assessed, and imaging tools were not available. However, when imaging tools are not available or feasible, clinical guidelines recommend the use of serum biomarkers as an acceptable alternative for the assessment of steatosis and fibrosis, particularly in large populations.2 Indeed, the use of biomarkers can be particularly helpful in clinical practice to identify those individuals at risk of severe fibrosis who require an early management approach,5 and improvement in NAFLD biomarkers has been shown to independently predict biopsy‐confirmed improvement in fibrosis after 1 year of lifestyle intervention in people with NASH.35\n\n\nIn conclusion, the present analysis is the first to describe improvements in biomarkers of fatty liver/steatosis and fibrosis in a large trial of GLP‐1RAs plus SGLT2 inhibitor combination therapy in people with type 2 diabetes. This nascent evidence may inform future, specifically designed prospective clinical trials that will investigate the efficacy and long‐term safety of the GLP‐1RA and SGLT2 inhibitor combination for the treatment of NASH in people with or without type 2 diabetes.\n\nPRIOR ABSTRACT PUBLICATION\nParts of this study were presented at the 54th Annual Meeting of the EASD, Berlin, Germany, October 1–5, 2018; and at the 55th Annual Meeting of the EASD, Barcelona, Spain, September 16–20, 2019.\n\nAUTHOR CONTRIBUTIONS\nJ.H. conducted the data analyses. All authors contributed to the conception and design of the study, interpretation of the data and made critical revisions to the manuscript. All authors read and approved the final version. All authors are the guarantors of this work and take responsibility for the integrity of the data and the accuracy of the data analysis.\n\nCONFLICTS OF INTEREST\nE.F. has participated in scientific advisory boards for Boehringer Ingelheim, Eli Lilly and Sanofi, has been an ad hoc consultant for Janssen, AstraZeneca and Mitsubishi Tanabe, has participated in occasional speaking engagements for AstraZeneca, Novo Nordisk, Sanofi, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim and Merck Sharp & Dohme (MSD), and has received research grant support from Boehringer Ingelheim and AstraZeneca. A.G. is a consultant for Eli Lilly, Genentech, Menarini, Inventiva and Gilead. C.G. has participated in scientific advisory boards and received consulting fees from AstraZeneca, Egis Pharmaceuticals, Eli Lilly, MSD, Novo Nordisk, Sanofi and Zentiva. E.R. and E.H. are employees of AstraZeneca. J.H. is a consultant with AstraZeneca. S.A.J. is a consultant with AstraZeneca, Eli Lilly and Janssen.\n\nDATA SHARING AND ACCESSIBILITY\nData underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.\n\nSupporting information\n\nAppendix S1: Supporting information\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThis work was funded by AstraZeneca. The sponsor was involved in the study design; collection, analysis and interpretation of data; report writing; and the decision to submit. The authors thank the patients and investigators who participated in the study. Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Liam Gillies, PhD, of Cactus Communications (London, UK), and was funded by AstraZeneca.\n==== Refs\nREFERENCES\n1 \n\nPortillo‐Sanchez \nP \n, \nBril \nF \n, \nMaximos \nM \n, et al. 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DURATION‐8 randomised controlled trial 104‐week results—once‐weekly exenatide (ExQW) plus once‐daily dapagliflozin (DAPA) vs. ExQW or DAPA alone [ADA abstract 104‐LB]\n. Diabetes . 2018 ;67 (suppl 1 ):LB29 ‐LB30\n.\n23 HOMA2 Calculator, a copyright material used under licence from Oxford University. https://www.dtu.ox.ac.uk/homacalculator/.\n24 \n\nSaponaro \nC \n, \nGaggini \nM \n, \nCarli \nF \n, \nGastaldelli \nA \n. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis\n. Nutrients . 2015 ;7 :9453 ‐9474\n.26580649 \n25 \n\nLomonaco \nR \n, \nOrtiz‐Lopez \nC \n, \nOrsak \nB \n, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease\n. Hepatology . 2012 ;55 :1389 ‐1397\n.22183689 \n26 \n\nMarchesini \nG \n, \nPetta \nS \n, \nDalle Grave \nR \n. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice\n. Hepatology . 2016 ;63 :2032 ‐2043\n.26663351 \n27 \n\nGastaldelli \nA \n, \nHarrison \nSA \n, \nBelfort‐Aguilar \nR \n, et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis\n. Hepatology . 2009 ;50 :1087 ‐1093\n.19670459 \n28 \n\nKlem \nL \n. Path analysis In: Grimm LG , Yarnold PR , eds. Reading and understanding multivariate statistics . Washington, DC, US : American Psychological Association ; 1995 :65 ‐97\n.\n29 \n\nGiugliano \nD \n, \nMaiorino \nMI \n, \nBellastella \nG \n, et al. Preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta‐analysis of cardiovascular outcome trials and intensive glucose control trials\n. J Am Heart Assoc . 2019 ;18:8 (12 ):e012356.\n30 \n\nVilar‐Gomez \nE \n, \nMartinez‐Perez \nY \n, \nCalzadilla‐Bertot \nL \n, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis\n. Gastroenterology \n2015 ;149 :367 –378\n, 378.e5.25865049 \n31 \n\nTaylor \nR \n, \nAl‐Mrabeh \nA \n, \nZhyzhneuskaya \nS \n, et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery\n. Cell Metab . 2018 ;28 :547 ‐556\n.30078554 \n32 \n\nMarjot \nT \n, \nGreen \nC \n, \nMcNeil \nC \n, et al. SGLT2 inhibition does not reduce hepatic steatosis in overweight, insulin resistant patients without type 2 diabetes [International Liver Congress abstract PS‐107]\n. J Hepatol . 2019 ;70 (suppl 1 ):e68.\n33 \n\nMota \nM \n, \nBanini \nBA \n, \nCazanave \nSC \n, \nSanyal \nAJ \n. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease\n. Metabolism . 2016 ;65 :1049 ‐1061\n.26997538 \n34 \n\nLee \nPCH \n, \nGu \nY \n, \nYeung \nMY \n, et al. Dapagliflozin and empagliflozin ameliorate hepatic dysfunction among Chinese subjects with diabetes in part through glycemic improvement: a single‐center, retrospective, observational study\n. Diabetes Ther . 2018 ;9 :285 ‐295\n.29322486 \n35 \n\nVilar‐Gomez \nE \n, \nCalzadilla‐Bertot \nL \n, \nFriedman \nSL \n, et al. Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy‐proven NASH\n. Liver Int . 2017 ;37 :1887 ‐1896\n.28544769\n\n",
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"issue": "22(3)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "dapagliflozin; exenatide; liver; type 2 diabetes",
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"mesh_terms": "D001559:Benzhydryl Compounds; D015415:Biomarkers; D003924:Diabetes Mellitus, Type 2; D000077270:Exenatide; D005355:Fibrosis; D005960:Glucosides; D006801:Humans; D007004:Hypoglycemic Agents; D065626:Non-alcoholic Fatty Liver Disease; D011446:Prospective Studies",
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"references": "28241279;30174213;25865049;26580649;19670459;30178600;30660725;30559230;22183689;17393509;29322486;26663351;31692226;31246368;27651331;30082326;29094442;28130788;19524579;27062661;19523535;28544769;29971527;30078554;30577089;26608256;28314735;29859912;17081293;26997538;31166153;25885947",
"title": "Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes.",
"title_normalized": "exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes"
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"abstract": "Background: Imunoglobulin A (IgA) deficiency (IgAD) is the most common form of primary immunodeficiency in Western countries. There have been several reports on IgAD complicated by glomerulonephritis in adults, but only very few cases of IgAD with nephropathy have been reported in children. We present two cases of IgAD with relapsing nephrotic syndrome in pediatric age. Case presentation: A 4-year-old boy and a 2-year-old boy presented with bilateral periorbital oedema and weight gain. The results of laboratory tests revealed IgAD (IgA < 7 mg/dL), normal creatinine, hypoprotidaemia, hypoalbuminaemia, and nephrotic proteinuria. A diagnosis of IgAD and idiopathic nephrotic syndrome was made, and steroid treatment (prednisone 60 mg/mq/day) was started. During steroid tapering, the children experienced several relapses and to obtain a positive outcome they required therapy with human monoclonal anti-CD20 antibodies (rituximab in the first child, ofatumumab in the second one). Conclusions: Our cases highlight that IgAD can be observed in nephrotic syndrome and nephropathy in children with IgAD appears to be complicated and difficult to treat with corticosteroids alone. Further research is needed to better describe the clinical manifestations and pathological pictures among subjects with IgAD and nephrotic syndrome to understand whether IgAD has a prognostic value in children with nephrotic syndrome and to let clinical physicians define a more personalized and appropriate approach for the management of these patients.",
"affiliations": "Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy. lory.digenova@gmail.com.;Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy. stefipg22@yahoo.it.;Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy. maurizio.stefanelli@ospedale.perugia.it.;Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy. susanna.esposito@unimi.it.",
"authors": "Di Genova|Lorenza|L|;Ceppi|Stefania|S|;Stefanelli|Maurizio|M|;Esposito|Susanna|S|0000-0003-4103-2837",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D000069283:Rituximab; C527517:ofatumumab",
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"fulltext": "\n==== Front\nInt J Environ Res Public HealthInt J Environ Res Public HealthijerphInternational Journal of Environmental Research and Public Health1661-78271660-4601MDPI 10.3390/ijerph15081702ijerph-15-01702Case ReportIgA Deficiency and Nephrotic Syndrome in Children Di Genova Lorenza Ceppi Stefania Stefanelli Maurizio https://orcid.org/0000-0003-4103-2837Esposito Susanna *Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy; lory.digenova@gmail.com (L.D.G.); stefipg22@yahoo.it (S.C.); maurizio.stefanelli@ospedale.perugia.it (M.S.)* Correspondence: susanna.esposito@unimi.it; Tel.: +39-075-578-4417; Fax: +39-075-578-4415409 8 2018 8 2018 15 8 170230 7 2018 06 8 2018 © 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Imunoglobulin A (IgA) deficiency (IgAD) is the most common form of primary immunodeficiency in Western countries. There have been several reports on IgAD complicated by glomerulonephritis in adults, but only very few cases of IgAD with nephropathy have been reported in children. We present two cases of IgAD with relapsing nephrotic syndrome in pediatric age. Case presentation: A 4-year-old boy and a 2-year-old boy presented with bilateral periorbital oedema and weight gain. The results of laboratory tests revealed IgAD (IgA < 7 mg/dL), normal creatinine, hypoprotidaemia, hypoalbuminaemia, and nephrotic proteinuria. A diagnosis of IgAD and idiopathic nephrotic syndrome was made, and steroid treatment (prednisone 60 mg/mq/day) was started. During steroid tapering, the children experienced several relapses and to obtain a positive outcome they required therapy with human monoclonal anti-CD20 antibodies (rituximab in the first child, ofatumumab in the second one). Conclusions: Our cases highlight that IgAD can be observed in nephrotic syndrome and nephropathy in children with IgAD appears to be complicated and difficult to treat with corticosteroids alone. Further research is needed to better describe the clinical manifestations and pathological pictures among subjects with IgAD and nephrotic syndrome to understand whether IgAD has a prognostic value in children with nephrotic syndrome and to let clinical physicians define a more personalized and appropriate approach for the management of these patients.\n\nIgA deficiencymonoclonal antibodynephropathynephrotic syndromepediatric nephrology\n==== Body\n1. Background\nImmunoglobulin A (IgA) deficiency (IgAD) is defined as a serum IgA level below or equal to 7 mg/dL in subjects older than 4 years and in whom other causes of hypogammaglobulinaemia have been excluded [1]. IgAD is a life-long disorder in most cases, and reports have shown that low IgA levels remain stable in IgAD patients over more than 20 years of observation [2,3]. Although IgAD is the most common form of primary immunodeficiency in Western countries, there is a marked variability in its prevalence in different ethnic groups, suggesting a genetic basis for the disorder [4,5].\n\nIgAD can be acquired as a result of certain medications (e.g., phenytoin, carbamazepine, valproic acid, zonisamide, sulfasalazine, gold, penicillamine, hydroxychloroquine, and nonsteroidal anti-inflammatory drugs) or infections (e.g., Epstein-Barr virus infection, congenital cytomegalovirus infection, congenital toxoplasmosis, congenital rubella, HIV infection) [6]. Moreover, it can be a feature of genetic disorders such as chromosomopathies (e.g., chromosome 18q deletion syndrome, monosomy 22 disease, trisomy 22 or trisomy 8) and monogenic diseases (e.g., ataxia-telangiectasia syndrome, Wiskott–Aldrich syndrome) [6]. IgAD can be sporadic or associated with common variable immunodeficiency (CVID) in approximately 20% of cases [7]. Differences in population prevalence in various ethnic groups, strong familial clustering of both disorders, a predominant inheritance pattern in multiple-case families compatible with autosomal dominant transmission and a high relative risk for siblings suggest the involvement of genetic factors that regulate lymphocyte survival and activation in the pathogenesis of IgAD/CVID [8].\n\nMost affected subjects with IgAD are asymptomatic and are diagnosed during routine tests for other conditions or following screening of a related proband with IgAD/CVID, but some do have problems over time [6,9]. Clinical manifestations can include respiratory and gastrointestinal tract infections, atopy, autoimmune diseases, celiac disease and malignancy. Long-term vigilance is recommended [9]. Up to one-third of symptomatic patients experience recurrent infections, such as viral infections, otitis media and sinopulmonary infections, as well as gastrointestinal infections. In addition to infections, IgAD may also play a role in the development of autoimmune disorders, including lupus-like illnesses, arthritis thyroiditis and type 1 diabetes mellitus; haematologic disorders, including neutropenia and thrombocytopenia; and gastrointestinal illnesses, including Crohn’s disease, ulcerative colitis, and celiac disease [10,11,12]. Patients with IgAD are also at higher risk for gastrointestinal and lymphoid malignancies later in life [1]. There have been several reports on SIgAD complicated by glomerulonephritis in adults, but only very few cases of IgAD with nephropathy have been reported in children. We present two cases of IgAD with relapsing nephrotic syndrome in pediatric age.\n\n2. Case Presentation\nCase 1\nA 4-year-old boy presented with bilateral periorbital oedema dating back a month and was admitted to our hospital. He had a good general condition and normal pressure values. The results of laboratory tests revealed normal creatinine, hypoprotidaemia (3.8 g/day), hypoalbuminaemia (1.8 g/dL), hypercholesterolaemia (283 mg/dL), hypertriglyceridaemia (242 mg/dL) and nephrotic proteinuria (2.7 g/day < 40 mg/mq/h). Immunological studies showed normal C3 and C4, increased antinuclear antibody titre with mild positivity at IFA Hep-2 (titre of 1:160, speckled pattern), anti-dsDNA antibody negativity, phospholipase A2 receptor (PLA2R) antibodies negativity, IgG 450 mg/dL (less than 2 standard deviations below the normal age-adjusted mean), IgA 3 mg/dL (less than 2 standard deviations below the normal age-adjusted mean) and IgM 94 mg/dL (normal). HBsAg and hepatitis B and C virus serology results were negative, while Epstein-Barr virus, cytomegalovirus and varicella-zoster virus serology results were positive for IgG. Renal ultrasound was normal.\n\nWithout performing renal needle biopsy due to ethical issues, a diagnosis of idiopathic nephrotic syndrome associated with IgAD was made, and steroid treatment (prednisone 60 mg/mq/day) was started. Proteinuria became negative after 12 days of treatment; after 4 weeks, the prednisone dose was tapered to 40 mg/mq/day given every other day for 4 weeks, and then this alternate-day dose was slowly tapered over the next 2 months. The subsequent measurement of serum immunoglobulins showed normal IgG and IgM values, but IgA remained very low.\n\nThree months after diagnosis of nephrotic syndrome, during steroid tapering, the child experienced a relapse that was treated with high dose of prednisone (60 mg/mq/day) until remission, then changed to an alternate-day dose for 4 weeks that gradually tapered over three months. During decalage of steroid therapy for the first relapse, the child experienced a second relapse that required a high dose of steroid treatment as before. Subsequently, the child had two additional relapses, becoming frequent and steroid dependent. Therefore, he required rituximab (a chimeric monoclonal anti-CD20 antibody) infusion. Currently, after 2 years his nephrotic syndrome is in remission. His IgA is always very low, with normal values of other immunoglobulins and IgG subclasses.\n\nCase 2\nA 2-year-old boy was admitted to our hospital for bilateral periorbital oedema, scrotal oedema and weight gain. He had a good general condition and normal pressure values. Investigations showed normal creatinine, hypoprotidaemia (3.9 g/day), hypoalbuminemia (2 g/dL), hypercholesterolaemia (417 mg/dL), hypertriglyceridemia (444 mg/dL), nephrotic proteinuria (spot proteinuria/creatininuria 15.5; nephrotic range > 2) and transient microscopic haematuria (5–10 erythrocytes per high-power field). Immunological studies revealed normal C3 and C4, increased antinuclear antibody titre (30.2 U/mL) with mild positivity at IFA Hep-2 (titre of 1:80, speckled pattern), anti-dsDNA antibody negativity, PLA2R antibodies negativity, IgG 42 mg/dL (less than 2 standard deviations below the normal age-adjusted mean), IgA 5 mg/dL (less than 2 standard deviations below the normal age-adjusted mean) and IgM 87 mg/dL (normal). Virus serology was negative, and renal ultrasound was normal.\n\nWithout performing renal needle biopsy due to ethical issues, a diagnosis of idiopathic nephrotic syndrome associated with IgAD and partial deficiency of IgG was made, and steroid treatment (prednisone 60 mg/mq/day) was started. The proteinuria decreased, but after 6 weeks of steroid therapy, it did not become negative. Therefore, he was treated with 3 high-pulse doses of methylprednisolone followed by steroid therapy, which achieved remission. As late responder, he started cyclosporin, and then steroid was gradually tapered over one month. While he was on cyclosporin therapy, he relapsed six months later and was treated with steroid therapy, with transitory remission. Therefore, cyclosporin was shifted to tacrolimus after one year. In the next three years, while he was on tacrolimus therapy, he had three relapses that required steroid treatment, and then he was treated with ofatumumab (a fully human monoclonal anti-CD20 antibody) infusion. As he had a relapse nine months later, a second ofatumumab infusion was made.\n\nAfter 2 years, he is still in remission. During follow-up, the measurement of serum immunoglobulins showed IgAD associated with partial deficiency of IgG and normal values of IgM; coeliac disease antibody tests were negative, but he is HLA-DQ2 positive.\n\n3. Discussion\nNephropathy has been previously observed in few children with IgAD (Table 1). Liu et al. described a 6-year-old boy with nephrotic syndrome and a medical history of asthma, chronic otitis media and IgA deficiency (IgA levels less than 3 mg/dL) [13]. A percutaneous renal needle biopsy was performed, and a diagnosis of diffuse and generalized mesangiopathic glomerulonephritis was rendered. Direct IFA showed moderate granular and clumped staining in mesangial areas for IgG, IgM, C3, and Clq. The authors underlined the importance to detect IgAD in patients with renal diseases because they frequently require blood transfusion and may experience anaphylactic reactions. Kawasaki et al. presented a 5-year-old boy with a primary nephrotic syndrome and IgAD (IgA less than 5 mg/dL) [14]. Oral prednisolone (2 mg kg/day) was started, and the proteinuria became negative at after 14 days of treatment. However, the subject experienced a relapse of nephrotic syndrome caused by influenza virus infection after 9 months. Methylprednisolone pulse therapy was then started and resulted in complete remission for 6 months. The patient subsequently experienced one relapse associated with the viral infection. A percutaneous renal needle biopsy was performed at 6 years old. IFA staining showed diffuse granular deposits of IgG, IgG4, and C3 in the glomerular capillary wall. The final pathological diagnosis was diffuse membranous glomerulonephritis stage 1. The authors did not find direct evidence of a pathogenic association between IgAD and membranous glomerulonephritis and supposed that the mechanism of onset of glomerulonephritis in their patient with IgAD could be the association with circulating immune complexes. Ichikawa et al. described a 9-year-old boy with Rasmussen syndrome, IgAD (IgA less than 5 mg/dL) and juvenile alopecia who developed a nephrotic syndrome [15]. The boy died at the age of 14 years, and a kidney specimen indicated progressive membranous nephropathy. The authors considered that the patient suffered from a multimodal autoimmune disorder producing juvenile alopecia, autoimmune encephalitis and a membranous nephropathy, based on the IgAD. In our cases, although renal biopsy was not performed, the diagnosis of idiopathic nephrotic syndrome was clear and made on the basis of clinical and laboratory findings. Both children presented IgAD (the first patient with an IgA level of 3 mg/dL, the second patient with an IgA level of 5 mg/dL) and showed a complicated, relapsing nephrotic syndrome. We do not have an explanation on persistence of partial IgG deficiency in the second patient. Moreover, both children showed the presence of antinuclear antibody titre with mild positivity at IFA Hep-2, but anti-dsDNA antibody were negative. Interestingly, both children needed a personalized therapeutic approach with monoclonal antibodies directed against CD20 in order to obtain a favourable outcome. Due to PLAR2 antibodies negativity, membranous nephropathy can be excluded and positive outcome with anti-CD20 monoclonal antibodies suggest a diagnosis of focal segmental glomerulosclerosis (FSGS). It is difficult to understand whether IgAD is causally linked or of prognostic value in minimal change-FSGS disease. Our speculation is that if IgAD is of prognostic value in these patients, it indicates steroid-dependence or -resistance warranting treatment with anti-CD20 monoclonal antibodies.\n\n4. Conclusions\nOur cases highlight that IgAD can be observed in nephrotic syndrome and nephropathy in children with IgAD appears to be complicated and difficult to treat with corticosteroids alone. Further research is needed to better describe the clinical manifestations and pathological pictures among subjects with IgAD and nephrotic syndrome (including the meaning of antinuclear antibody positivity) to understand whether IgAD has a prognostic value in children with nephrotic syndrome and to let clinical physicians define a more personalized and appropriate approach for the management of these children.\n\nAuthor Contributions\nL.D.G. wrote the first draft of the manuscript; S.C. and M.S. performed the diagnosis and the patients’ follow-up; S.E. critically revised the text and made substantial scientific contributions. All the authors approved the final version of the manuscript.\n\nFunding\nThis research was partially funded by the [World Association of Infectious Diseases and Immunologcal Disorders] grant number [WAidid2018_01].\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nijerph-15-01702-t001_Table 1Table 1 Renal pathology in children with IgA deficiency.\n\nCase No.\tAge\tSex\tIgG\tIgM\tIgA\tUnderlying Disease\tKidney Histology\tImmunofluorescence\tReference\t\n1\t6\tM\tN\tNA\t3 mg/dL\tAsthma\tDiffuse and generalized mesangiopathic glomerulonephritis\tIgG, IgM, C3 and C1q\tLiu et al., 1995\n[13]\t\n2\t5\tM\tN\tN\t<5 mg/dL\tNone\tDiffuse membranous glomerulonephritis stage I\tIgG, IgG4, and C3\tKawasaki et al., 2004\n[14]\t\n3\t9\tM\tN\tN\t<5 mg/dL\tRasmussen syndrome\tStages III-IV of membranous nephropathy\tNA\tIchikawa et al., 2009\n[15]\t\n4 *\t4\tM\tN\tN\t3 mg/dL\tNone\tNA\tNA\t\n\t\n5 *\t2\tM\t45 mg/dL\tN\t5 mg/dL\tNone\tNA\tNA\t\n\t\nM: male; NA: not available; N: normal value; *: case described in the present study.\n==== Refs\nReferences\n1. Bonilla F.A. Khan D.A. Ballas Z.K. Chinen J. Frank M.M. Hsu J.T. Keller M. Kobrynski L.J. Komarow H.D. Mazer B. Practice parameter for the diagnosis and management of primary immunodeficiency J. Allergy Clin. Immunol. 2015 136 1186 1205 10.1016/j.jaci.2015.04.049 26371839 \n2. Hammarstrom L. Vorechovsky I. Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID) Clin. Experim. Immunol. 2000 120 225 231 10.1046/j.1365-2249.2000.01131.x \n3. Koskinen S. Tolo H. Hirvonen M. Koistinen J. Long-term persistence of selective IgA deficiency in healthy adults J. Clin. Immunol. 1994 14 116 119 10.1007/BF01541344 8195313 \n4. Shkalim V. Monselize Y. Segal N. Zan-Bar I. Hoffer V. Garty B.Z. Selective IgA deficiency in children in Israel J. Clin. Immunol. 2010 30 761 765 10.1007/s10875-010-9438-x 20571893 \n5. Hammarstrom L. Genetic approach to common variable immunodeficiency and IgA deficiency Primary Immunodeficiency Disease, A Molecular and Genetic Approach 1st ed. Ochs H.D. Edvard Smith C.I. Puck J.M. Oxford University Press Oxford, UK 1999 250 262 \n6. Wang N. Hammarstrom L. IgA deficiency: What is new? Curr. Opin. Allergy Clin. Immunol. 2012 12 602 608 10.1097/ACI.0b013e3283594219 23026772 \n7. Espanol T. Catala M. Hernandez M. Caragol I. Bertran J.M. Development of a common variable immunodeficiency in IgA-deficient patients Clin. Immunol. Immunopathol. 1996 80 333 335 10.1006/clin.1996.0132 8811056 \n8. Aghamohammadi A. Mohammadi J. Parvaneh N. Rezaei N. Moin M. Espanol T. Progression of Selective IgA Deficiency to Common Variable Immunodeficiency Intern. Arch. Allergy Immunol. 2008 147 87 92 10.1159/000135694 18520152 \n9. Aytekin C. Tuygun N. Gokce S. Dogu F. Ikinciogullari A. Selective IgA deficiency: Clinical and laboratory features of 118 children in Turkey J. Clin. Immunol. 2012 32 961 966 10.1007/s10875-012-9702-3 22547079 \n10. Jorgensen G.H. Gardulf A. Sigurdsson M.I. Sigurdardottir S.T. Thorsteinsdottir I. Gudmundsson S. Hammarström L. Ludviksson B.R. Clinical symptoms in adults with selective IgA deficiency: A case-control study J. Clin. Immunol. 2013 33 742 747 10.1007/s10875-012-9858-x 23389234 \n11. Wang N. Shen N. Vyse T.J. Anand V. Gunnarson I. Sturfelt G. Rantapää-Dahlqvist S. Elvin K. Truedsson L. Andersson B.A. Selective IgA deficiency in autoimmune diseases Mol. Med. Rep. 2011 17 1383 1396 \n12. Bashar A. Patrick B. The association of celiac disease, diabetes mellitus type 1, hypothyroidism, chronic liver disease, and selective IgA deficiency Clin. Pediatr. 2000 39 229 231 \n13. Liu K. Wigfall D.R. Harland R.C. Sanfilippo F.P. Howell D.N. Identification of selective immunoglobulin a deficiency by renal biopsy Am. J. Kidney Dis. 1995 26 520 526 10.1016/0272-6386(95)90501-4 7645563 \n14. Kawasaki Y. Suzuki J. Onishi N. Takahashi A. Isome M. Suzuki H. IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome Pediatr. Nephrol. 2005 20 662 664 10.1007/s00467-004-1720-9 15711951 \n15. Ichikawa K. Takeshita S. Ito S. Nezu A. Rasmussen syndrome combined with IgA deficiency and membranous nephropathy Pediatr. Neurol. 2009 40 468 470 10.1016/j.pediatrneurol.2008.12.008 19433284\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "15(8)",
"journal": "International journal of environmental research and public health",
"keywords": "IgA deficiency; monoclonal antibody; nephropathy; nephrotic syndrome; pediatric nephrology",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002675:Child, Preschool; D006801:Humans; D017098:IgA Deficiency; D007166:Immunosuppressive Agents; D008297:Male; D009404:Nephrotic Syndrome; D011507:Proteinuria; D012008:Recurrence; D000069283:Rituximab",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30096909",
"pubdate": "2018-08-09",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "20571893;18520152;10792368;19433284;21826374;8195313;23389234;15711951;26371839;10791135;8811056;22547079;7645563;23026772",
"title": "IgA Deficiency and Nephrotic Syndrome in Children.",
"title_normalized": "iga deficiency and nephrotic syndrome in children"
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"activesubstancename": "PREDNISONE"
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