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"abstract": "Clozapine is an atypical antipsychotic drug that is approved by the US Food and Drug Administration (FDA) for the treatment of psychotic disorders. Agranulocytosis is a well-established side effect of clozapine; clozapine has also been associated with other blood dyscrasias like leukocytosis, albeit rarely. In this paper, we aim to report a case of possible clozapine-associated leukocytosis in a 41-year-old woman.",
"affiliations": "Department of Psychiatry, Kocaeli University School of Medicine, Kocaeli, Turkey.;Department of Psychiatry, Abant İzzet Baysal University School of Medicine, Bolu, Turkey.;Department of Psychiatry, Kocaeli University School of Medicine, Kocaeli, Turkey.",
"authors": "Polat|Aslıhan|A|;Çakir|Uğur|U|;Gündüz|Nermin|N|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/npa.2015.9855",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-0667",
"issue": "53(1)",
"journal": "Noro psikiyatri arsivi",
"keywords": "Antipsychotics; clozapine; hematological; leukocytosis",
"medline_ta": "Noro Psikiyatr Ars",
"mesh_terms": null,
"nlm_unique_id": "9426194",
"other_id": null,
"pages": "87-88",
"pmc": null,
"pmid": "28360774",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "16044115;7593714;7211857;20643637;8515794;11114817;8105497;16160616;17388723;12640212;9541331",
"title": "Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia.",
"title_normalized": "leukocytosis after clozapine treatment in a patient with chronic schizophrenia"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-114145",
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"occurcountry": "TR",
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"activesubstancename": "CLOZAPINE"
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"abstract": "Agranulocytosis induced by thioamides is rare, occurring only in 0.2-0.5% of cases.\nWe present the case of a 45-year-old woman previously diagnosed with Graves' disease that discontinued the use of methimazole on her own. She attended the Emergency Department presenting fever (40.5¯C), agitation and diaphoresis. A thyroid storm diagnosis was initially thought, but after laboratory results showing neutrophil count near 0.06x109/L, sepsis due to neutropenia seemed the most logical hypothesis. Cephepime was promptly initiated. For thyrotoxicosis management, cholestyramine and atenolol were prescribed. In her second day of hospitalization, subcutaneous granulocyte colony-stimulating factor was started for an earlier medullar response. The patient was discharged after 7 days with atenolol 50mg/day and instructed to have a definite treatment for Graves disease as soon as possible.\nSuch case purpose is to remember clinicians that sepsis diagnosis can be challenged, especially when a thyroid storm is a possible diagnosis as well. In this particular case, both conditions should be treated, but life-threatening sepsis should have the focus for a quick therapeutic approach.",
"affiliations": "Ponta Grossa State University - Medicine, Ponta Grossa, Brazil.;Ponta Grossa State University - Medicine, Ponta Grossa, Brazil.;Ponta Grossa State University - Medicine, Ponta Grossa, Brazil.;Ponta Grossa State University - Medicine, Ponta Grossa, Brazil.;Ponta Grossa State University - Medicine, Ponta Grossa, Brazil.",
"authors": "Stumpf|M A M|MAM|;Schrut|G C A|GCA|;Ramthun|M|M|;Onuma|S|S|;Osternack|H E C G|HECG|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.4183/aeb.2019.522",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-0987",
"issue": "15(4)",
"journal": "Acta endocrinologica (Bucharest, Romania : 2005)",
"keywords": "Agranulocytosis; Graves’ disease; Methimazole; Sepsis; Thyroid Crisis",
"medline_ta": "Acta Endocrinol (Buchar)",
"mesh_terms": null,
"nlm_unique_id": "101269720",
"other_id": null,
"pages": "522-525",
"pmc": null,
"pmid": "32377252",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "28105610;26339512;29078933;29347874;23920160;28924483;22297058;25120607;23861276",
"title": "METHIMAZOLE-INDUCED AGRANULOCYTOSIS AND SEPSIS: WAS THYROID STORM PRESENT OR JUST BEING MIMICKED?",
"title_normalized": "methimazole induced agranulocytosis and sepsis was thyroid storm present or just being mimicked"
} | [
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"companynumb": "BR-AMGEN-BRASP2020138376",
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... |
{
"abstract": "BACKGROUND\nParaneoplastic neurological syndrome is an immune-mediated phenomenon where antibodies from tumor cells are produced against neuronal proteins. Amphiphysin antibody is an onconeural antibody linked to the diagnosis of breast cancer and small-cell lung cancer. It is uncommon and typically associated with stiff-person syndrome, of which 90% of patients are eventually diagnosed with breast cancer.\n\n\nMETHODS\nWe present a case of a 47-year-old Caucasian woman with metastatic hormone receptor-positive breast cancer who developed bilateral facial nerve palsy while on treatment with nab-paclitaxel. The patient was found to have anti-amphiphysin antibody in the serum and cerebrospinal fluid. She was treated with methylprednisolone and intravenous immunoglobulin, which resulted in partial improvement in her facial nerve palsy.\n\n\nCONCLUSIONS\nThis case highlights a rare presentation of bilateral facial nerve palsy that likely related to paraneoplastic syndrome associated with the presence of anti-amphiphysin antibody.",
"affiliations": "Medical Oncology Department, Alan Walker Cancer Centre, Royal Darwin Hospital, Northern Territory, Australia. v.kwatra@aoah.com.au.;Medical Oncology Department, Alan Walker Cancer Centre, Royal Darwin Hospital, Northern Territory, Australia.;Medical Oncology Department, Alan Walker Cancer Centre, Royal Darwin Hospital, Northern Territory, Australia.",
"authors": "Kwatra|Vineet|V|http://orcid.org/0000-0002-0912-4056;Charakidis|Michail|M|;Karanth|Narayan V|NV|",
"chemical_list": "D009419:Nerve Tissue Proteins; C075637:amphiphysin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02727-3",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2727\n10.1186/s13256-021-02727-3\nCase Report\nBilateral facial nerve palsy associated with amphiphysin antibody in metastatic breast cancer: a case report\nhttp://orcid.org/0000-0002-0912-4056\nKwatra Vineet v.kwatra@aoah.com.au\n\nCharakidis Michail Michail.Charakidis@nt.gov.au\n\nKaranth Narayan V. Narayan.Karanth@nt.gov.au\n\ngrid.240634.7 0000 0000 8966 2764 Medical Oncology Department, Alan Walker Cancer Centre, Royal Darwin Hospital, Northern Territory, Australia\n26 3 2021\n26 3 2021\n2021\n15 15828 6 2020\n10 2 2021\n© The Author(s) 2021\nOpen 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\nParaneoplastic neurological syndrome is an immune-mediated phenomenon where antibodies from tumor cells are produced against neuronal proteins. Amphiphysin antibody is an onconeural antibody linked to the diagnosis of breast cancer and small-cell lung cancer. It is uncommon and typically associated with stiff-person syndrome, of which 90% of patients are eventually diagnosed with breast cancer.\n\nCase presentation\n\nWe present a case of a 47-year-old Caucasian woman with metastatic hormone receptor-positive breast cancer who developed bilateral facial nerve palsy while on treatment with nab-paclitaxel. The patient was found to have anti-amphiphysin antibody in the serum and cerebrospinal fluid. She was treated with methylprednisolone and intravenous immunoglobulin, which resulted in partial improvement in her facial nerve palsy.\n\nConclusions\n\nThis case highlights a rare presentation of bilateral facial nerve palsy that likely related to paraneoplastic syndrome associated with the presence of anti-amphiphysin antibody.\n\nKeywords\n\nFacial nerve palsy\nBell’s palsy\nAmphiphysin antibody\nBreast cancer\nNab-paclitaxel\nParaneoplastic syndrome\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nParaneoplastic neurological syndrome (PNS) is an immune-mediated phenomenon in which antibodies respond against neuronal proteins produced by tumor cells (onconeural antibodies) [1]. The presence of onconeural antibodies is a useful diagnostic marker of PNS [2]. They are specific to a group of malignant diseases rather than identified as a neurological syndrome [3]. An amphiphysin antibody is an onconeural antibody that has been identified and linked to the diagnosis of breast cancer and small-cell lung cancer (SCLC) [4–6].\n\nWe describe the first case in the literature of bilateral facial nerve palsy with the presence of anti-amphiphysin antibodies in a patient diagnosed with metastatic hormone receptor-positive, estrogen receptor (ER)/progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.\n\nCase presentation\n\nA 47-year-old Caucasian woman with Eastern Cooperative Oncology Group (ECOG) grade 0 presented with a palpable mass in the left breast associated with an enlarging scalp lesion over 4 months. Biopsy confirmed a diagnosis of metastatic ER/PR positive, HER2-negative breast carcinoma (Fig. 1). Computerized tomography staging demonstrated a multifocal primary lesion fixed to the chest wall, axillary lymphadenopathy, and lung and liver lesions, as well as omental, scalp, and bony involvement. She had no other significant comorbidity. She was started on chemotherapy with nab-paclitaxel, a commonly used agent in the first-line treatment of metastatic breast cancer.Fig. 1 Photomicrograph of breast and scalp lesions shows staining for a AE1/AE3, b CK 7, c focal mucin droplets, and d mammaglobin\n\nFollowing three cycles of nab-paclitaxel (260 mg/m2 every 21 days each cycle), there was a partial response with shrinkage of tumor in all areas. Her cancer antigen 15-3 declined from 179 to 25 kU/L. She continued with a further three cycles of chemotherapy. Prior to proceeding with the sixth cycle of nab-paclitaxel, she presented with a left-sided lower motor neuron weakness of the face. It was classified as severe as she was unable to close her eyes. There was no evidence of an intracranial lesion or ischemic changes on CT or MRI of the brain. At this point, she was diagnosed with bilateral facial nerve palsy and was administered a trial of oral prednisolone for 5 days without any improvement in her symptoms.\n\nOne week later, she presented with a lower motor neuron weakness of the contralateral face, giving her bilateral facial nerve palsy. The remainder of the neurological examination did not reveal additional deficits. Subsequent MRI of the brain demonstrated evidence of bilateral facial nerve neuritis involving predominantly the terminal branches. Analysis of the cerebrospinal fluid (CSF) revealed no infective or malignant etiology. Interestingly, the paraneoplastic screening showed the presence of anti-amphiphysin antibodies in both serum and CSF. All other anti-neuronal antibodies, including anti-glutamic acid decarboxylase antibodies, were not detected. A repeat CT scan following the completion of six cycles of chemotherapy demonstrated a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to the visceral diseases, with a further reduction in cancer antigen 15-3 (Fig. 2).Fig. 2 Computerized tomography scans demonstrating reduction in tumor size of the liver (a–c) and lung (d–f) metastases after three and six cycles of nab-paclitaxel\n\nThe patient was started on 1 g IV pulse methylprednisolone for 3 days. This was followed up with intravenous immunoglobulins (IVIG) at a dose of 2 g/kg divided over 5 days. She completed four cycles of IVIG at the 2 g/kg dose, which resulted in a subtle improvement of the frontalis muscle; however, the loss of nasolabial folds and inability to close her eyes persisted. A repeat MRI revealed resolution of facial nerve neuritis. A repeat analysis of CSF showed a high level of anti-amphiphysin antibodies titer of 1:640. Nerve conduction study and electromyography suggested evidence of peripheral nerve reinnervation. She continued with monthly IVIG for the next 6 months. Her chemotherapy was stopped and switched to maintenance hormonal therapy with letrozole 2.5 mg daily to help control her malignant disease. A repeat CT scan 3 months later showed overall stable malignant disease.\n\nDiscussion\n\nPNS is a rare event that affects < 1% of patient with an underlying malignancy [3]. An international panel of neurologists categorize the diagnosis of PNS into two subgroups—“definite” and “possible.” A definite diagnosis can be made when there is a classical or nonclassical neurological syndrome with the presence of onconeural antibodies (that is, amphiphysin antibody), with or without evidence of malignancy. The classical neurological syndromes include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, and opsoclonus-myoclonus [7]. A small number of case reports have described the link between amphiphysin antibodies with these classical neurological syndromes in patients with breast cancer and SCLC [8, 9].\n\nAmphiphysin is a nerve-terminal protein that is found in high concentration in the nervous system and is presumed to have a role in synaptic vesicle endocytosis [10, 11]. The anti-amphiphysin autoantibody reacts with 128-kD protein in synaptic vesicles [8]. They are usually seen in both serum and CSF in a subset of patients with stiff-person syndrome (SPS), breast cancer, and SCLC [9]. Around 90% of SPS patients with amphiphysin antibody have been found to have breast cancer during their illness [12].\n\nThere has been no published report on the association between the presence of amphiphysin antibodies in breast cancer and bilateral facial nerve palsy. The diagnosis of bilateral facial nerve palsy is itself a rare entity. It is unlikely to be idiopathic in nature and usually reflects an underlying pathology. The potential causes include bilateral acoustic neuroma, Lyme disease, Guillain–Barre syndrome, syphilis, HIV, sarcoidosis, or a tumor, among others [13–15].\n\nOur case highlights an unusual presentation of bilateral facial nerve palsy and a diagnostic dilemma. The potential causes may be either PNS or drug-induced nerve palsy with nab-paclitaxel. The presence of amphiphysin antibody in her blood and CSF despite four cycles of IVIG and a modest response to treatment led us to believe the underlying process to be due to paraneoplastic syndrome. However, the indolent nature and stable state of her breast cancer does not support PNS, as it usually behaves aggressively.\n\nAlternatively, nab-paclitaxel can commonly cause sensory peripheral neuropathy and motor neuropathy [16]. One important risk factor for this is high dosing and frequency of treatment. A case report previously described a case of bilateral facial nerve palsy in metastatic breast cancer following one cycle of high-dose paclitaxel (825 mg/m2), which eventually resolved after 23 months [17]. Another case described a case of unilateral facial nerve palsy following nab-paclitaxel (260 mg/m2), which improved after 9 months [18]. Though drug-induced facial nerve palsy is a possible cause for our patient’s presentation, her facial nerve palsy has not significantly improved since cessation of nab-paclitaxel. Moreover, it does not explain the presence of amphiphysin antibody in our case.\n\nConclusions\n\nIdentifying the cause of PNS can sometimes be challenging. Our approach to the case was to stop nab-paclitaxel because of the possibility of its being a direct cause of bilateral facial nerve palsy and switch to endocrine therapy as well as treat the underlying PNS with IVIG and high-dose methyl prednisolone. Currently, there are no guidelines for the management of PNS; however, the principle of treatment suggests treating the underlying tumor with surgery, chemotherapy, or radiotherapy [3]. Other modalities of treatment include immunotherapy with high-dose methyl prednisolone or IVIG.\n\nAbbreviations\n\nCSF Cerebrospinal fluid\n\nCT Computerized tomography\n\nHIV Human immunodeficiency virus\n\nIVIG Intravenous immunoglobulins\n\nMRI Magnetic resonance imaging\n\nPNS Paraneoplastic neurological syndrome\n\nSCLC Small-cell lung cancer\n\nSPS Stiff-person syndrome\n\nAcknowledgements\n\nWe are grateful to our patient who consented to our writing this case report. Special thanks to Dr. Aijye Lim and the pathology department at Royal Darwin Hospital for sending us histology photos.\n\nAuthors’ contributions\n\nVK was involved in writing the manuscript. MC and NK supervised the case and helped with revision and final proofreading. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding\n\nAvailability of data and materials\n\nPlease contact author for data requests\n\nEthics approval and consent to participate\n\nEthics approval was provided by the Northern Territory Department of Health and the Menzies School of Health Research (HREC reference number 2016-2634).\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal\n\nCompeting interests\n\nThe authors declare that they have no competing interests\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Vedeler CA Antoine JC Giometto B Gilhus NE Barnes MP Brainin M Paraneoplastic neurological syndromes European Handbook of Neurological Management 2011 2 Blackwell Publishing Ltd Oxford 447 457\n2. Honnorat J Antoine JC Paraneoplastic neurological syndromes Orphanet J Rare Dis 2007 2 22 10.1186/1750-1172-2-22 17480225\n3. Kannoth S Paraneoplastic neurologic syndrome: a practical approach Ann Indian Acad Neurol. 2012 15 1 6 12 10.4103/0972-2327.93267 22412264\n4. De Camilli P Thomas A Cofiell R Folli F Lichte B Piccolo G Meinck H Austoni M Fassetta G Bottazzo G Bates D Cartlidge N Solimena M Kiliman MW The synaptic vesicle associated protein amphiphysin is the 128-kD autoan autoantigen of Stiff-Man syndrome with breast cancer J Exp Med 1993 178 2219 2223 10.1084/jem.178.6.2219 8245793\n5. Folli F Solimena M Cofiell R Austoni M Tallini G Fassetta G Bates D Cartlidge N Bottazzo GF Piccolo G Autoantibodies to a 128-kd synaptic protein in three women with the stiffman syndrome and breast cancer NEngl J Med 1993 328 546 551 10.1056/NEJM199302253280805\n6. Dropcho EJ Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis Ann Neurol 1996 39 659 667 10.1002/ana.410390516 8619552\n7. Graus F Delattre JY Antoine JC Dalmau J Giometto B Grisold W Honnorat J Smitt PS Vedeler Ch Verschuuren JJ Vincent A Voltz R Recommended diagnostic criteria for paraneoplastic neurological syndromes J Neurol Neurosurg Psychiatry 2004 75 1135 1140 10.1136/jnnp.2003.034447 15258215\n8. Antoine JC Absi L Honnorat J Boulesteix JM Brouker T Vial C Butler M De Camilli P Michel D Antiamphiphysin autoantibodies are associated with various paraneoplastic neurological syndromes and tumors Arch Neurol 1999 56 2 172 177 10.1001/archneur.56.2.172 10025422\n9. Saiz A Dalmau J Butler MH Chen Q Delattre JY De Camilli P Graus F Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma J Neurol Neurosurg Psychiatry 1999 66 214 217 10.1136/jnnp.66.2.214 10071102\n10. David C McPherson PS Mundigl O De Camilli P A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals Proc Natl Acad Sci U S A 1996 93 331 5 10.1073/pnas.93.1.331 8552632\n11. Lichte B Veh RW Meyer HE Kilimann MW Amphiphysin, a novel protein associated with synaptic vesicles EMBO J. 1992 11 2521 2530 10.1002/j.1460-2075.1992.tb05317.x 1628617\n12. Murinson BB Guarnaccia JB Stiff-person syndrome with amphiphysin antibodies Neurology 2008 71 1955 1958 10.1212/01.wnl.0000327342.58936.e0 18971449\n13. Jain V Deshmukh A Gollomp S Bilateral facial paralysis case presentation and discussion of differential diagnosis J Gen Intern Med. 2006 21 7 C7 C10 10.1111/j.1525-1497.2006.00466.x\n14. Gevers G Lemkens P Bilateral simultaneous facial paralysis—differential diagnosis and treatment options Acta Otorhinolaryngol Belg. 2003 57 139 146 12836471\n15. Burakgazi A Schmidley JW A rare cause of bilateral facial palsy Am J Med Case Rep 2016 4 2 62 64\n16. Freilich RJ Balmaceda C Seidman AD Rubin M DeAngelis LM Motor neuropathy due to docetaxel and paclitaxel Neurology. 1996 47 115 118 10.1212/WNL.47.1.115 8710063\n17. Lee RT Oster MW Balmaceda C Hesdorffer CS Vahdat LT Papadopoulos KP Bilateral facial nerve palsy secondary to administration of high-dose paclitaxel Ann Oncol. 1999 10 10 1245 1247 10.1023/A:1008380800394 10586344\n18. Minatani N Kosaka Y Sengoku N Kikuchi M Nishimiya H Waraya M Enomoto T Tanino H Watanabe M A case of facial nerve palsy induced by nab-paclitaxel. Abstract Gan To Kagaku Ryoho. 2013 40 12 2375 2377 24394117\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Amphiphysin antibody; Bell’s palsy; Breast cancer; Facial nerve palsy; Nab-paclitaxel; Paraneoplastic syndrome",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D001943:Breast Neoplasms; D005154:Facial Nerve; D005158:Facial Paralysis; D005260:Female; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D016750:Stiff-Person Syndrome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "158",
"pmc": null,
"pmid": "33766120",
"pubdate": "2021-03-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24394117;8381208;8552632;1628617;8619552;10071102;12836471;10025422;15258215;8710063;22412264;18971449;16808763;10586344;8245793;17480225",
"title": "Bilateral facial nerve palsy associated with amphiphysin antibody in metastatic breast cancer: a case report.",
"title_normalized": "bilateral facial nerve palsy associated with amphiphysin antibody in metastatic breast cancer a case report"
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"abstract": "Strongyloides stercoralis is an uncommon infection in Saudi Arabia. It can establish latency and cause an autoinfection in humans that lasts for years. The infection can get reactivated during immunosuppression and can result in a life-threatening Strongyloides hyperinfection syndrome. We present three cases of renal transplant recipients who developed Strongyloides infection following transplantation. A bronchoalveolar lavage specimen, a duodenal biopsy and/or a stool specimen from these patients revealed evidence of S. stercoralis larvae. The first two patients received kidneys from the same deceased donor, a native of Bangladesh, an area that is highly endemic for S. stercoralis. The data suggest that the first two cases might be donor derived. High-risk donors and recipients should be screened for Strongyloides infection to initiate treatment before transplantation thus reducing morbidity and mortality.",
"affiliations": "Department of Pathology and Laboratory Medicine, Multi-Organ Transplant Center, Department of Internal Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia.",
"authors": "Abdalhamid|Baha A|BA|;Al Abadi|Abdul Naser M|AN|;Al Saghier|Mohammed I|MI|;Joudeh|Amani A|AA|;Shorman|Mahmoud A|MA|;Amr|Samir S|SS|",
"chemical_list": "D000871:Anthelmintics; D015766:Albendazole",
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"issue": "26(1)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014184:Transplantation, Homologous",
"nlm_unique_id": "9436968",
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"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Strongyloides stercoralis infection in kidney transplant recipients.",
"title_normalized": "strongyloides stercoralis infection in kidney transplant recipients"
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"abstract": "Letrozole is a reversible aromatase inhibitor, used in the treatment of hormone-dependent woman cancer. No indication for medical use is available for men. In recent years, several cases of doping with letrozole have been observed, especially among high level athletes. Aromatase inhibitors reverse the harmful effects (feminizing) of the abuse of anabolic androgenic steroids. Letrozole is included on the list of products prohibited in- and out-competition by the World Anti-Doping Agency, under section S4.1. The aim of the present work was to develop a specific method to identify letrozole in human hair of a male amateur athlete by LC-MS/MS and confirmation by LC-HRMS, after incubation of 20 mg of matrix in 1 mL of methanol. The chromatographic separation was performed using a reverse phase column HSS C18 with a gradient elution of 15 min (from 87% to 5% of formate buffer adjusted to pH 3). Linearity was observed from 1 to 1000 pg/mg (r2 = 0.9999), after spiking blank hair with the corresponding amounts of letrozole. The limit of detection was estimated at 0.5 pg/mg and the lower limit of quantification was the first point of the calibration curve, i.e. 1 pg/mg. The precision was lower than 20% and there was no interference with the analytes by chemicals or any extractable endogenous materials present in hair. Letrozole was identified in the male amateur athlete hair at 310 pg/mg (segment 0-2 cm) and 245 pg/mg (segment 2-4 cm).",
"affiliations": "Institut de médecine légale, 11 rue Humann, 67000 Strasbourg, France. Electronic address: ameline.alice@gmail.com.;Institut de médecine légale, 11 rue Humann, 67000 Strasbourg, France.;Institut de médecine légale, 11 rue Humann, 67000 Strasbourg, France.;Institut de médecine légale, 11 rue Humann, 67000 Strasbourg, France; X-Pertise Consulting, 42 rue Principale, 67206 Mittelhausbergen, France.",
"authors": "Ameline|Alice|A|;Gheddar|Laurie|L|;Raul|Jean-Sébastien|JS|;Kintz|Pascal|P|",
"chemical_list": "D000077289:Letrozole",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jchromb.2020.122495",
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"issue": "1162()",
"journal": "Journal of chromatography. B, Analytical technologies in the biomedical and life sciences",
"keywords": "Doping; Hair; LC-HRMS; LC-MS/MS; Letrozole",
"medline_ta": "J Chromatogr B Analyt Technol Biomed Life Sci",
"mesh_terms": "D056352:Athletes; D002851:Chromatography, High Pressure Liquid; D004300:Doping in Sports; D006197:Hair; D006801:Humans; D000077289:Letrozole; D057230:Limit of Detection; D016014:Linear Models; D008297:Male; D015203:Reproducibility of Results; D015813:Substance Abuse Detection; D053719:Tandem Mass Spectrometry",
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"title": "Characterization of letrozole in human hair using LC-MS/MS and confirmation by LC-HRMS: Application to a doping case.",
"title_normalized": "characterization of letrozole in human hair using lc ms ms and confirmation by lc hrms application to a doping case"
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"abstract": "Cervical pregnancy can be complicated by perfuse vaginal bleeding. Mechanical compression directed at tamponing the cervical vessels can control hemostasis. There are several types of balloon catheters that have been described for cervical compression. However use of a double balloon catheter is a novel approach for cervical tamponade, as one balloon is positioned below the external cervical os and the second balloon is situated above in the internal cervical os. This compresses the cervix from internal os to external os between the two balloons, forming a \"cervical sandwich.\" We describe this method of cervical tamponade using a silicone double balloon cervical ripening catheter that rapidly controlled hemorrhage in a patient that failed conservative management with methotrexate.",
"affiliations": "Department of Obstetrics and Gynecology, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY 10310, USA.;Department of Obstetrics and Gynecology, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY 10310, USA.;Department of Obstetrics and Gynecology, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY 10310, USA.;Department of Obstetrics and Gynecology, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY 10310, USA; Department of Obstetrics and Gynecology, New York Medical College, 40 Sunshine Cottage Rd, Valhalla, NY 10595, USA.",
"authors": "Zambrano|Nabila|N|;Reilly|James|J|;Moretti|Michael|M|;Lakhi|Nisha|N|0000-0002-8413-4684",
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"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi Publishing Corporation 10.1155/2017/9396075Case ReportDouble Balloon Cervical Ripening Catheter for Control of Massive Hemorrhage in a Cervical Ectopic Pregnancy Zambrano Nabila \n1\nReilly James \n1\nMoretti Michael \n1\nhttp://orcid.org/0000-0002-8413-4684Lakhi Nisha \n1\n\n2\n\n*\n1Department of Obstetrics and Gynecology, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY 10310, USA2Department of Obstetrics and Gynecology, New York Medical College, 40 Sunshine Cottage Rd, Valhalla, NY 10595, USA*Nisha Lakhi: nlakhi@yahoo.comAcademic Editor: Loïc Sentilhes\n\n2017 2 2 2017 2017 939607512 11 2016 2 1 2017 9 1 2017 Copyright © 2017 Nabila Zambrano et al.2017This 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.Cervical pregnancy can be complicated by perfuse vaginal bleeding. Mechanical compression directed at tamponing the cervical vessels can control hemostasis. There are several types of balloon catheters that have been described for cervical compression. However use of a double balloon catheter is a novel approach for cervical tamponade, as one balloon is positioned below the external cervical os and the second balloon is situated above in the internal cervical os. This compresses the cervix from internal os to external os between the two balloons, forming a “cervical sandwich.” We describe this method of cervical tamponade using a silicone double balloon cervical ripening catheter that rapidly controlled hemorrhage in a patient that failed conservative management with methotrexate.\n==== Body\n1. Introduction\nCervical pregnancy (CP) is a rare type of ectopic pregnancy characterized by implantation of a fertilized ovum in the endocervical canal. CP accounts for less than 1% of all ectopic pregnancies [1–3]. Risk factors include endometrial damage after curettage or chronic endometritis, leiomyoma, intrauterine devices, and in vitro fertilization [2, 4, 5]. This type of ectopic pregnancy is highly dangerous because massive hemorrhage can ensue secondary to bleeding from the cervical vessels. Early detection has been improved by ultrasonography. However, even with advanced diagnostic modalities and treatment options, CP remains a life-threatening condition.\n\nDuring the last decade, in an effort to avoid hysterectomy and maintain fertility, a more conservative therapeutic approach has been advocated. This includes chemotherapy with methotrexate, intra-amniotic feticide, dilation and curettage, uterine tamponade, and uterine artery embolization [5, 6]. Usually more than one modality of treatment is necessary [2, 7]. We describe a novel method of cervical tamponade using a silicone double balloon cervical ripening catheter (Cook® Cervical Ripening Balloon, Cook Medical, Bloomington, Indiana) in a patient that presented with acute hemorrhage after conservative management with systemic chemotherapy.\n\n2. Case\nA 31-year-old gravida 2 para 0 at 7 weeks and 3 days presented to the emergency room with complaints of vaginal bleeding and abdominal cramping that began earlier that morning. On examination, her abdomen was nontender without rebound or guarding. No active bleeding was noted vaginally. Her serum beta human chorionic gonadotrophin (β-hCG) was 18,645 mIU/L.\n\nTransvaginal ultrasound revealed a 22 mm gestational sac implanted within the cervical canal with a fetal pole but no fetal cardiac activity. Decision was made to admit patient for systemic multidose methotrexate regimen for conservative management of a cervical pregnancy. Uterine artery embolization was considered but concern arose about long term effects on the patient's future fertility.\n\nMethotrexate 85 mg (1 mg/kg) was administered on days 1, 3, 5, and 7. Rescue leucovorin 8.5 mg (0.1 mg/kg) was administered on days 2, 4, 6, and 8. Her β-hCG levels on days 1, 3, 5, and 7 were 18,645 IU/mL, 15,527 IU/mL, 15,099 IU/mL, 12,718 IU/mL, and 10,222 IU/mL, respectively. On hospital day 7, repeat transvaginal ultrasonography showed a collapsing gestational sac with no visible yolk sac or fetal pole. The patient experienced no further vaginal bleeding during admission. The patient was discharged home with plan of having weekly β-hCG measured until levels declined to zero.\n\nThe patient returned to the emergency room two days after discharge with heavy vaginal bleeding. On examination, approximately 300 mL of blood was cleared from the vaginal vault. The vaginal vault was packed with gauze in an attempt to tamponade bleeding so that patient could be safely transported to the operating room for an examination under anesthesia. At the time of the patient's presentation to emergency room, interventional radiology was not readily available to perform uterine artery embolization. After removal of vaginal packing, approximately 500 mL of additional vaginal bleeding was noted. Dilation and suction curettage was performed in order to excise the remaining trophoblast tissue that was readily visualized at the cervical os. After curettage, the patient continued to actively hemorrhage. A silicone double balloon cervical ripening catheter (Cook Cervical Ripening Balloon) was introduced into the cervical canal (Figures 1 and 2). 80 mL of normal saline was inserted in the uterine valve and 60 mL of normal saline inserted in was introduced into the vaginal valve. Upon insufflation, the cervix was compressed between the two balloons of the catheter and hemostasis was rapidly achieved (Figures 3 and 4). Positioning of the Cook Balloon was ascertained by visual inspection and by gentle traction. Gentle traction insured that the uterine balloon of the Cook catheter was securely positioned above the internal os after insufflation. Once the uterine balloon was determined to be in the appropriate place, the vaginal valve was insufflated under direct visualization. Due to the acuity and urgency to stabilize the patient and to minimize bleeding, imaging to document placement could not be performed during the procedure.\n\nThe patient was observed overnight and reexamined the following morning. No further bleeding was noted and the patient remained hemodynamically stable. The compression balloon was removed without difficulty after 12 hours. The patient received two doses of tranexamic acid (1000 mg) approximately 18 hours apart after removal of Cook Balloon. The patient was discharged the following day in stable condition. β-hCG repeated 24 days after discharge from the hospital was 2 IU/mL.\n\n3. Discussion\nThe early diagnosis of cervical ectopic pregnancy in our patient was made by confirming the following ultrasound criteria: (1) an empty uterine cavity above the level of the internal cervical os (Figure 5), (2) barrel-shaped cervix (Figure 6), (3) gestational sac located below the level of the uterine arteries, and (4) vascularization around the gestational sac demonstrated by Doppler color flow ultrasonography (Figure 7) [7, 8]. Cervical pregnancy can be distinguished from an imminent aborting pregnancy within the cervix by the absence of the “sliding sign” (elicited when mechanical pressure from the ultrasound transducer causes the gestational sac to slide against the endocervical canal in case of imminent abortion but not in an implanted CP) [7].\n\nAlthough there are no definitive guidelines for the management of cervical pregnancies, a variety of modalities have been proposed [4]. Approaches include curettage combined with Foley balloon tamponade, methotrexate with/without potassium chloride injection, uterine artery embolization, and ligation of cervical branches of uterine arteries. The most commonly reported medical treatments are methotrexate, by either local injection (intra-amniotic or intrafetal) or systemic administration [6, 9, 10]. The outcome of conservative management with methotrexate has been reported to be relatively safe and effective, allowing for uterine preservation in more than 90% of cases treated before 12 weeks of gestation [6, 9, 10].\n\nIn the case presented, the patient desired to preserve fertility. Inpatient conservative therapy with multidose methotrexate was elected. Although her β-hCG levels declined appropriately over the course of her treatment, she re-presented with profuse bleeding per vagina. In the event of hemorrhage following failed medical therapy or postsuction curettage, mechanical compression or tamponade of the cervix can rapidly restore hemostasis [7, 11]. There are several types of balloon catheters that have been described for cervical compression in the literature [12]. These include the Bakri™ Balloon (Cook Medical, Bloomington, Indiana), Rusch hydrostatic catheter (Teleflex Medical Sdn Bhd, Kamuntung, Malaysia), condom catheters, and Foley catheters [12]. Fylstra describes treatment of cervical pregnancy being achieved successfully in 13 patients by curettage immediately followed by placement of 30 mL balloon Foley catheter for tamponade; tamponade was left in place for 24 hours [13]. The use of Foley balloon has also been cited to prophylactically control bleeding in cervical pregnancies [13, 14]. Similarly, Timor-Tritsch successfully treated cervical and cesarean scar ectopic pregnancies with double balloon catheter [15]. The double balloon catheter provided compression to terminate pregnancy and prevent bleeding. Our case report defers from both Fylstra and Timor-Tritsch in that use of double balloon catheter was to control hemorrhage with tamponade, not to prophylactically prevent hemorrhage nor to treat a live ectopic pregnancy.\n\nAs an alternative to the Foley catheter, in our patient, tamponade and further hemostasis were created with the Cook Balloon by the insufflation of the internal and external balloon, respectively. Although the Cook Balloon is normally used for cervical ripening for induction of labor, its use has been reported for the management of postabortal hemorrhage [12]. Unlike other compression devices such as the Foley balloon, the Cook catheter consists of a double balloon system. This allows for one balloon to be positioned below the internal-external cervical os and the second balloon to be situated above in the internal cervical os (Figure 1). Tamponade with a double balloon cervical ripening catheter has not been previously described to control hemorrhage in CP. The double balloon additionally adjusts to the length of the cervix prior to insufflation allowing for compression from internal to external os (Figure 2). A double balloon catheter, as used in our case, may be considered to control hemorrhage for CP as it was able to quickly create a tamponade by compressing the cervix from the internal to external os.\n\nTranexamic acid (TXA) in the case presented was used prophylactically to prevent any further event of hemorrhage. Tranexamic acid is a potent antifibrinolytic agent that exerts its effect by competitively blocking lysine binding sites on plasminogen molecules [16]. This prevents the binding of fibrin to plasminogen and therefore impairs fibrinolysis [16]. The use of TXA in cervical pregnancy has limited discussion in literature. However, the use of TXA in postpartum hemorrhage and trauma is a field of evolving study [17]. Clinically, TXA has been shown to decrease the need of blood transfusions, reoperation for bleeding, and mean of transfused units [17]. TXA's use for menorrhagia has shown to reduce mean blood loss, which may suggest a possible link in reducing uterine blood flow [18].\n\n4. Conclusion\nThe case presented delineates the use of conservative management and complications of cervical pregnancy. The use of methotrexate is well documented in literature for the treatment of cervical pregnancy. However, the use of a double balloon cervical ripening catheter (Cook Balloon) to achieve cervical tamponade during hemorrhage has limited citing in literature. In cases where future fertility is of greatest concern, the Cook Balloon may serve as an option for decreasing blood loss. Furthermore, the use of TXA to prevent future hemorrhage and decrease the need for reoperation is a possible consideration when patient's desire to maintain fertility is a major concern. The prophylactic use of TXA is not well established in cervical pregnancies and future studies are needed to demonstrate its effectiveness.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n\nFigure 1 Cook Balloon Inflated with 80 mL saline in the uterine balloon and 60 mL saline in vaginal balloon.\n\nFigure 2 Distance between the two balloons can be stretched approximately 5 cm.\n\nFigure 3 Placement of balloons in uterus and vagina (picture from package insert).\n\nFigure 4 Illustration of “sandwich effect” of the two inflated balloons. Note that space between the balloons is stretchable and can accommodate the entire cervix.\n\nFigure 5 Empty uterus with gestational sac (GS) in cervix.\n\nFigure 6 Gestational sac with yolk sac and fetal pole within the cervix.\n\nFigure 7 Vascularization around the gestational sac demonstrated by Doppler color flow.\n==== Refs\n1 Murji A. Garbedian K. Thomas J. Cruickshank B. Conservative management of cervical ectopic pregnancy Journal of Obstetrics and Gynaecology Canada 2015 37 11 1016 1020 10.1016/s1701-2163(16)30051-2 2-s2.0-84956947166 26629722 \n2 Stott D. Eissa A. Zaedi K. Cervical ectopics: less can be more BMJ Case Reports 2012 2012 10.1136/bcr-2012-006398 \n3 Monteagudo A. Tarricone N. J. Timor-Tritsch I. E. Lerner J. P. Successful transvaginal ultrasound-guided puncture and injection of a cervical pregnancy in a patient with simultaneous intrauterine pregnancy and a history of a previous cervical pregnancy Ultrasound in Obstetrics & Gynecology 1996 8 381 386 9014276 \n4 Surampudi K. A case of cervical ectopic pregnancy: successful therapy with methotrexate The Journal of Obstetrics and Gynecology of India 2012 62 supplement 1 S1 S3 10.1007/s13224-013-0351-0 2-s2.0-84874705061 \n5 Gun M. Mavrogiorgis M. Cervical ectopic pregnancy: a case report and literature review Ultrasound in Obstetrics and Gynecology 2002 19 3 297 301 10.1046/j.1469-0705.2002.00559.x 11896956 \n6 Hung T.-H. Shau W.-Y. Hsieh T.-T. Hsu J.-J. Soong Y.-K. Jeng C.-J. Prognostic factors for an unsatisfactory primary methotrexate treatment of cervical pregnancy: a quantitative review Human Reproduction 1998 13 9 2636 2642 10.1093/humrep/13.9.2636 2-s2.0-0031655773 9806299 \n7 Saeng-anan U. Sreshthaputra O. Sukpan K. Tongsong T. Cervical pregnancy with massive bleeding after treatment with methotrexate BMJ Case Reports 2013 2013 bcr2013200440 10.1136/bcr-2013-200440 \n8 Jurkovic D. Hacket E. Campbell S. Diagnosis and treatment of early cervical pregnancy: a review and a report of two cases treated conservatively Ultrasound in Obstetrics and Gynecology 1996 8 6 373 380 2-s2.0-0030340242 9014275 \n9 Kung F.-T. Chang S.-Y. Efficacy of methotrexate treatment in viable and nonviable cervical pregnancies American Journal of Obstetrics and Gynecology 1999 181 6 1438 1444 10.1016/S0002-9378(99)70389-3 2-s2.0-0033395960 10601926 \n10 Kirk E. Condous G. Haider Z. Syed A. Ojha K. Bourne T. The conservative management of cervical ectopic pregnancies Ultrasound in Obstetrics & Gynecology 2006 27 4 430 437 10.1002/uog.2693 2-s2.0-33646713476 16514619 \n11 Singh S. Diagnosis and management of cervical ectopic pregnancy Journal of Human Reproductive Sciences 2013 6 4 273 276 10.4103/0974-1208.126312 24672169 \n12 Tsui K.-H. Lin L.-T. Yu K.-J. Double-balloon cervical ripening catheter works well as an intrauterine balloon tamponade in post-abortion massive hemorrhage Taiwanese Journal of Obstetrics and Gynecology 2012 51 3 426 429 10.1016/j.tjog.2012.07.020 2-s2.0-84867143405 23040930 \n13 Fylstra D. L. Cervical pregnancy: 13 cases treated with suction curettage and balloon tamponade American Journal of Obstetrics & Gynecology 2014 210 6 581.e1 581.e5 10.1016/j.ajog.2014.03.057 2-s2.0-84901412719 24704060 \n14 Timor-Tritsch I. E. Cali G. Monteagudo A. Foley balloon catheter to prevent or manage bleeding during treatment for cervical and Cesarean scar pregnancy Ultrasound in Obstetrics and Gynecology 2015 46 1 118 123 10.1002/uog.14708 2-s2.0-84934842812 25346492 \n15 Timor-Tritsch I. E. Monteagudo A. Bennett T.-A. Foley C. Ramos J. Kaelin Agten A. A new minimally invasive treatment for cesarean scar pregnancy and cervical pregnancy American Journal of Obstetrics & Gynecology 2016 215 3 351.e1 351.e8 10.1016/j.ajog.2016.03.010 2-s2.0-84963717647 26979630 \n16 Hunt B. J. The current place of tranexamic acid in the management of bleeding Anaesthesia 2015 70 1 50 e18 10.1111/anae.12910 2-s2.0-84925224772 25440395 \n17 Sentilhes L. Daniel V. Darsonval A. Study protocol. TRAAP—TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter randomized, double-blind, placebo-controlled trial BMC Pregnancy and Childbirth 2015 15 1, article 135 10.1186/s12884-015-0573-5 2-s2.0-84931271008 \n18 Sentilhes L. Lasocki S. Ducloy-Bouthors A. S. Tranexamic acid for the prevention and treatment of postpartum haemorrhage British Journal of Anaesthesia 2015 114 4 576 587 10.1093/bja/aeu448 25571934\n\n",
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"title": "Double Balloon Cervical Ripening Catheter for Control of Massive Hemorrhage in a Cervical Ectopic Pregnancy.",
"title_normalized": "double balloon cervical ripening catheter for control of massive hemorrhage in a cervical ectopic pregnancy"
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"companynumb": "US-ACCORD-049401",
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"abstract": "BACKGROUND\nOn the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia.\n\n\nMETHODS\nTreatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918.\n\n\nRESULTS\n408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.\n\n\nCONCLUSIONS\nChemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia.\n\n\nBACKGROUND\nF Hoffmann-La Roche.",
"affiliations": "Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany. michael.hallek@uni-koeln.de",
"authors": "Hallek|M|M|;Fischer|K|K|;Fingerle-Rowson|G|G|;Fink|A M|AM|;Busch|R|R|;Mayer|J|J|;Hensel|M|M|;Hopfinger|G|G|;Hess|G|G|;von Grünhagen|U|U|;Bergmann|M|M|;Catalano|J|J|;Zinzani|P L|PL|;Caligaris-Cappio|F|F|;Seymour|J F|JF|;Berrebi|A|A|;Jäger|U|U|;Cazin|B|B|;Trneny|M|M|;Westermann|A|A|;Wendtner|C M|CM|;Eichhorst|B F|BF|;Staib|P|P|;Bühler|A|A|;Winkler|D|D|;Zenz|T|T|;Böttcher|S|S|;Ritgen|M|M|;Mendila|M|M|;Kneba|M|M|;Döhner|H|H|;Stilgenbauer|S|S|;|||;|||",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D015994:Incidence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014740:Vidarabine",
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"references": null,
"title": "Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.",
"title_normalized": "addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia a randomised open label phase 3 trial"
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{
"abstract": "BACKGROUND\nSuccessful late potential (LP) abolition and postprocedural ventricular tachycardia (VT) noninducibility constitute significant end points after catheter ablation for VT. We investigated the prognostic impact of a combined procedural end point of VT noninducibility and LP abolition in a large series of post-myocardial infarction patients with VT.\n\n\nRESULTS\nA total of 160 (154 men, 94% with implantable cardioverter defibrillators) consecutive post-myocardial infarction patients undergoing first-time ablation procedures from 2010 to 2012 were included. Of the 159 patients surviving the procedure, 137 (86%) were either inducible or in VT at baseline and 103 (65%) had baseline LP presence, of which 79 (77%) underwent successful LP abolition. The combined end point was assessable in 155 (97%) patients. There were 50 (32%) patients with VT recurrences and 17 (11%) cardiac deaths during follow-up. Patients who fulfilled the combined end point of VT noninducibility and LP abolition compared with inducible patients exhibited a significantly lower incidence of VT recurrence (16.4% versus 47.4%; log-rank P<0.001) and cardiac death (4.1% versus 42.1%; log-rank P<0.001). Among noninducible patients, those with additional LP abolition also had a lower incidence of VT recurrence (16.4% versus 46.0%; log-rank P<0.001). After multivariate analysis, the combined end point of VT noninducibility and LP abolition (hazard ratio, 0.205, P<0.001) was independently associated with VT recurrence and cardiac death (hazard ratio, 0.106; P=0.001).\n\n\nCONCLUSIONS\nAchieving a combined catheter ablation procedural end point of VT noninducibility and LP abolition reduces VT recurrence rates to low levels (16%). The overall strategy was associated with a significant impact on cardiac survival.",
"affiliations": "From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy.;From the Arrhythmia Unit and Electrophysiology Laboratories, Ospedale San Raffaele, Milan, Italy. dellabella.paolo@hsr.it.",
"authors": "Silberbauer|John|J|;Oloriz|Teresa|T|;Maccabelli|Giuseppe|G|;Tsiachris|Dimitris|D|;Baratto|Francesca|F|;Vergara|Pasquale|P|;Mizuno|Hiroya|H|;Bisceglia|Caterina|C|;Marzi|Alessandra|A|;Sora|Nicoleta|N|;Guarracini|Fabrizio|F|;Radinovic|Andrea|A|;Cireddu|Manuela|M|;Sala|Simone|S|;Gulletta|Simone|S|;Paglino|Gabriele|G|;Mazzone|Patrizio|P|;Trevisi|Nicola|N|;Della Bella|Paolo|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.113.001239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "7(3)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "cardiomyopathies; catheter ablation; myocardial infarction; tachycardia, ventricular",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000368:Aged; D000704:Analysis of Variance; D017115:Catheter Ablation; D002423:Cause of Death; D015331:Cohort Studies; D003131:Combined Modality Therapy; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "424-35",
"pmc": null,
"pmid": "24833642",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Noninducibility and late potential abolition: a novel combined prognostic procedural end point for catheter ablation of postinfarction ventricular tachycardia.",
"title_normalized": "noninducibility and late potential abolition a novel combined prognostic procedural end point for catheter ablation of postinfarction ventricular tachycardia"
} | [
{
"companynumb": "GR-VALIDUS PHARMACEUTICALS LLC-GR-2021VAL000942",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadd... |
{
"abstract": "Long-term clinical outcomes after hepatitis C virus (HCV) treatment of HIV/HCV patients are not well described. We aimed to compare the risk of all-cause and liver-related death (LRD) according to HCV treatment response in HIV/HCV patients in the multicohort study Collaboration of Observational HIV Epidemiological Research in Europe.\n\n\n\nAll patients who had started pegylated interferon + ribavirin (baseline) and followed for at least 72 weeks after baseline were included. Patients were categorized into three response groups depending on treatment duration and HCV-RNA measured in the window 24-72 weeks after baseline. Patients who received at least 24 weeks of therapy were defined as responders if their last HCV-RNA measured between 24 and 72 weeks after baseline was negative, and having 'unknown response' if HCV-RNA was unknown. Nonresponders were treated for less than 24 weeks or were HCV-RNA+ between 24 and 72 weeks after baseline. Mortality rates were compared using survival analysis, and Cox regression was used to compare hazard ratios of death between response groups.\n\n\n\nA total of 3755 patients were included: 1031 (27.5%) responders, 1639 (43.6%) nonresponders and 1085 (28.9%) with unknown response. Rates [per 1000 person-years of follow-up, 95% confidence interval (CI)] of all-cause death were 17.59 (14.88-20.78), 10.43 (7.62-14.28) and 11.00 (8.54-14.23) for nonresponders, responders and unknown responders, respectively. After adjustment, the relative hazard (nonresponders vs. responders) for all-cause death, LRD and nonliver-related death was 1.53 (95% CI 1.06-2.22), 3.39 (95% CI 1.32-8.75) and 1.22 (95% CI 0.80-1.84), respectively.\n\n\n\nHIV/HCV patients with a favourable virological response to pegylated interferon + ribavirin had reduced risk of all-cause and LRD, whereas there was no difference in risk of nonliver-related death when comparing responders and nonresponders.",
"affiliations": null,
"authors": "|||",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "31(5)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D015331:Cohort Studies; D060085:Coinfection; D005060:Europe; D005260:Female; D015658:HIV Infections; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D009026:Mortality; D011379:Prognosis; D012367:RNA, Viral; D012254:Ribavirin; D016019:Survival Analysis; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "661-668",
"pmc": null,
"pmid": "28005685",
"pubdate": "2017-03-13",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Is response to anti-hepatitis C virus treatment predictive of mortality in hepatitis C virus/HIV-positive patients?",
"title_normalized": "is response to anti hepatitis c virus treatment predictive of mortality in hepatitis c virus hiv positive patients"
} | [
{
"companynumb": "DK-009507513-1801DNK004437",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2B"
},
"drugadditional": ... |
{
"abstract": "Angiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC.\n\n\n\nWe did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual.\n\n\n\nBetween June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease.\n\n\n\nPazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials.\n\n\n\nGlaxoSmithKline and Novartis.",
"affiliations": "Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA. Electronic address: dadkins@wustl.edu.;Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA.;Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA.;Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA.;Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA.;Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA.;Metabolomics Facility, Washington University School of Medicine, St Louis, MO, USA.;Department of Pharmaceutical and Administrative Sciences, St Louis College of Pharmacy, St Louis, MO, USA; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.;Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA; Siteman Cancer Center, Biostatistics Shared Resource, Washington University School of Medicine, St Louis, MO, USA.;Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA.",
"authors": "Adkins|Douglas|D|;Mehan|Paul|P|;Ley|Jessica|J|;Siegel|Marilyn J|MJ|;Siegel|Barry A|BA|;Dehdashti|Farrokh|F|;Jiang|Xuntian|X|;Salama|Noha N|NN|;Trinkaus|Kathryn|K|;Oppelt|Peter|P|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30350-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "19(8)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011743:Pyrimidines; D000077195:Squamous Cell Carcinoma of Head and Neck; D013449:Sulfonamides",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1082-1093",
"pmc": null,
"pmid": "30001987",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10213212;11801954;12925349;15144956;16467544;16807070;17538161;17827454;18784101;19047292;19201650;19509175;19917865;20498388;21376230;21712450;21798893;21798897;21811833;22420963;22840785;22898037;23558953;23786770;24718888;25056374;25081631;25492084;25631445",
"title": "Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study.",
"title_normalized": "pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma an open label phase 1b and expansion study"
} | [
{
"companynumb": "PHHY2018US123004",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Children with altered mental status who present to the emergency department have a broad differential diagnosis. We report a case of a 19-month-old girl who presented in coma and who was later found to have a fentanyl patch adhered to her back. She was found to have changes on brain magnetic resonance imaging consistent with a toxic spongiform leukoencephalopathy but had a good neurologic outcome. This case report illustrates the importance of a thorough physical examination in children in coma and a rarely reported magnetic resonance imaging finding that has been seen in opioid intoxication and is usually associated with severe morbidity and mortality.",
"affiliations": "Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.",
"authors": "Foy|Lindsey|L|;Seeyave|Desiree M|DM|;Bradin|Stuart A|SA|",
"chemical_list": "D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0b013e31822c281f",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "27(9)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000061:Accidents, Home; D000279:Administration, Cutaneous; D001049:Apnea; D002675:Child, Preschool; D003128:Coma; D003655:Decerebrate State; D057210:Delayed Diagnosis; D004630:Emergencies; D005260:Female; D005283:Fentanyl; D006801:Humans; D006943:Hyperglycemia; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D015877:Miosis; D011041:Poisoning; D012021:Reflex, Abnormal; D019564:Unnecessary Procedures",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "854-6",
"pmc": null,
"pmid": "21926884",
"pubdate": "2011-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic leukoencephalopathy due to transdermal fentanyl overdose.",
"title_normalized": "toxic leukoencephalopathy due to transdermal fentanyl overdose"
} | [
{
"companynumb": "US-DEP_13194_2015",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 29-year-old healthy woman, 19 weeks pregnant, sustained a right posterolateral knee dislocation with multiligamentous injury and a complete occlusive injury to the right popliteal artery yet had adequate distal perfusion. She declined operative management for both the knee dislocation and the arterial injury, and successful collaboration between obstetrical, vascular, and orthopaedic surgical services resulted in limb preservation and restoration of function.\n\n\n\nThis is a unique case of traumatic complete popliteal artery occlusion with adequate collateral arterial perfusion after a reducible posterolateral knee dislocation in a pregnant patient that resulted in limb preservation with nonoperative management.",
"affiliations": "Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut.;Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut.;Yale School of Medicine, New Haven, Connecticut.;Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut.;Division of Vascular Surgery, Yale School of Medicine, New Haven, Connecticut.;Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut.",
"authors": "Schneble|Christopher A|CA|0000-0001-9893-8213;Kahan|Joseph B|JB|0000-0002-1088-954;Burroughs|Patrick J|PJ|0000-0003-4903-4060;Nasreddine|Adam Y|AY|;Sumpio|Bauer E|BE|0000-0002-8954-4295;Medvecky|Michael J|MJ|0000-0003-1481-3232",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.CC.20.00516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-3251",
"issue": "11(2)",
"journal": "JBJS case connector",
"keywords": null,
"medline_ta": "JBJS Case Connect",
"mesh_terms": null,
"nlm_unique_id": "101596828",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33835994",
"pubdate": "2021-04-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Popliteal Artery Occlusion with Collateral Blood Flow in a Reducible Knee Dislocation During Pregnancy: A Case Report.",
"title_normalized": "popliteal artery occlusion with collateral blood flow in a reducible knee dislocation during pregnancy a case report"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2022US092707",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": "4",
... |
{
"abstract": "The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.",
"affiliations": "a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;;a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;;a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;;a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;;c Department of Hematology , Hadassah University Hospital , Jerusalem , Israel.;a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;;a Department of Hematology , Tel Aviv Sourasky Medical Center , Tel Aviv , Israel ;",
"authors": "Sarid|Nadav|N|;Joffe|Erel|E|;Gibstein|Lili|L|;Avivi|Irit|I|;Polliack|Aaron|A|;Perry|Chava|C|;Herishanu|Yair|Y|",
"chemical_list": "D000069283:Rituximab; D005047:Etoposide; D016190:Carboplatin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2015.1106532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "57(7)",
"journal": "Leukemia & lymphoma",
"keywords": "ICE; diffuse large B-cell lymphoma; elderly; rituximab",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D003131:Combined Modality Therapy; D015897:Comorbidity; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009367:Neoplasm Staging; D012189:Retrospective Studies; D000069283:Rituximab; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1633-9",
"pmc": null,
"pmid": "26643787",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reduced-dose ICE chemotherapy ± rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma.",
"title_normalized": "reduced dose ice chemotherapy rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large b cell lymphoma"
} | [
{
"companynumb": "IL-ROCHE-1680724",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Psoriasis is one of the most common, chronic skin diseases of as yet unexplained etiopathogenesis. In the recent years it has been proven that an immunological factor plays an important role in the dermatosis onset. This has led to introduction of biological drugs to the disease treatment regimen, which include, inter alia, adalimumab and ustekinumab. New therapy has become an alternative for patients with psoriasis resistant to standard treatment methods as well as an alternative form of treatment in case of occurrence of severe adverse drug reactions after administration of standard treatment. Despite good treatment results the administration of these drugs is associated with the occurrence of adverse reactions. This article presents cases of 4 patients who have been administered biological treatment and in whom there have been observed, inter alia, the occurrence of hypersensitivity reactions in the form of acute urticaria as well as skin lesions of erythema multiforme nature or positive antinuclear antibodies titre. The symptoms experienced by the presented patients posed no direct threat to life and the benefits of the drugs' administration had a significant therapeutic importance.",
"affiliations": "Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland.;Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland.;Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland.;Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland.;Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland.",
"authors": "Hadas|Ewa|E|;Bozek|Andrzej|A|;Cudak|Anna|A|;Ciuk|Aleksandra|A|;Jarząb|Jerzy|J|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ada.2020.100482",
"fulltext": "\n==== Front\nPostepy Dermatol Alergol\nPostepy Dermatol Alergol\nPDIA\nAdvances in Dermatology and Allergology/Postȩpy Dermatologii i Alergologii\n1642-395X 2299-0046 Termedia Publishing House \n\n42292\n10.5114/ada.2020.100482\nOriginal Paper\nExamples of adverse effects after biological therapy\nHadas Ewa Bozek Andrzej Cudak Anna Ciuk Aleksandra Jarząb Jerzy Clinical Department of Internal Disease, Dermatology and Allergology in Zabrze, Medical University of Silesia in Katowice, Poland\nAddress for correspondence: Ewa Hadas MD, PhD, Clinical Department of Internal Disease, Dermatology and Allergology, Medical University of Silesia, 10 Skłodowskiej St, 41-800 Zabrze, Poland, phone: +48 32 271 31 65, e-mail: ewahadas@interia.pl\n07 11 2020 \n10 2020 \n37 5 712 718\n16 2 2018 06 3 2019 Copyright © 2020 Termedia2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)Psoriasis is one of the most common, chronic skin diseases of as yet unexplained etiopathogenesis. In the recent years it has been proven that an immunological factor plays an important role in the dermatosis onset. This has led to introduction of biological drugs to the disease treatment regimen, which include, inter alia, adalimumab and ustekinumab. New therapy has become an alternative for patients with psoriasis resistant to standard treatment methods as well as an alternative form of treatment in case of occurrence of severe adverse drug reactions after administration of standard treatment. Despite good treatment results the administration of these drugs is associated with the occurrence of adverse reactions. This article presents cases of 4 patients who have been administered biological treatment and in whom there have been observed, inter alia, the occurrence of hypersensitivity reactions in the form of acute urticaria as well as skin lesions of erythema multiforme nature or positive antinuclear antibodies titre. The symptoms experienced by the presented patients posed no direct threat to life and the benefits of the drugs’ administration had a significant therapeutic importance.\n\nbiological therapypsoriasisadalimumabustekinumabadverse effects\n==== Body\nIntroduction\nPsoriasis is one of the most frequent, chronic inflammatory skin diseases of complex pathogenesis. The course of the disease is influenced by genetic factors and environmental conditions. It is estimated that 2–4.8% of the population is affected by the disease and it has similar occurrence frequency in both males and females. Skin lesions are caused by interaction of genetic, immunologic and environmental factors [1].\n\nCurrently, it is believed that excessive epidermal proliferation in psoriasis is a result of immunological disorders associated with T-lymphocyte activity and the cytokines released by them: tumour necrosis factor α (TNF-α) and interleukins – IL-12, Il-17, IL-23. Both Th1 lymphocyte activation and cytokine production lead to excessive keratinocyte proliferation as well as induction and support of inflammatory condition [2, 3]. Additionally, patients with psoriasis are exposed to more frequent occurrence of ischemic heart disease, obesity, diabetes and depression [4]. In particular this occurs when the disease affects extensive body areas. In some cases psoriasis may affect family lives and lead to occurrence of other serious problems such as social exclusion [5]. Various types of questionnaires (e.g. SF-36, DLQI, PDI) are used in clinical practice to determine the patient’s quality of life. It has been demonstrated that the influence of psoriasis on patient’s general feeling is comparable to the state observed in severe chronic diseases such as neoplasms, arthritis or depression [6].\n\nMany patients with psoriasis require administration of general and complex treatment which is frequently associated with high costs and the risk of adverse reactions. For patients with moderate and severe psoriasis, who have not demonstrated any effects after traditional treatment, administration of biological drugs which positively affect immunological processes by blocking the activity of selected cytokines directly interfering with a cascade of the phenomena occurring in the inflammatory state is the effective treatment method. Introduction of biological drugs has revolutionized treatment of moderate and severe psoriasis and psoriatic arthritis. Biological drugs used in treatment of psoriasis and psoriatic arthritis include, inter alia:\n\n– TNF-α inhibitors – adalimumab, etanercept, infliximab,\n\n– IL-12 and IL-23 inhibitors – ustekinumab,\n\n– IL-17A inhibitors – secukinumab, ixekizumab,\n\n– medicinal agents inhibiting T lymphocyte proliferation,\n\n– alefacept,\n\n– LFA-1 subunit α adhesive particle blockers\n\n– efalizumab and other medicinal agents at various stages of clinical trials or the registration process.\n\n\n\nIn Poland, for 5 years there have been drug programs, within which patients are qualified to be administered free treatment with biological drugs. One of such drug programs includes plague-like psoriasis treatment and the other one, the treatment of arthropathic psoriasis. Patients who demonstrated no improvement after prior administration of at least two methods of classical general treatment are included in both drug programs. Due to an increasing number of patients being administered the above-mentioned drugs, an increasing number of adverse reactions after the drug administration have been recorded.\n\nAim\nThe paper aims to present the adverse reactions which occurred during administration of biological drugs, in particular during administration of adalimumab and ustekinumab, on the basis of my own observations. The described adverse reactions were observed in patients treated in the Clinical Department of Internal Diseases, Dermatology and Allergology Specialist Hospital in Zabrze in 2011–2016. The characteristics of the patients were presented in Table 1.\n\nTable 1 Characteristics of patients before therapy\n\nParameter\tResult\t\nAge, mean [years]\t61.6\t\nMen\t30\t\nWomen\t20\t\nDuration of disease before therapy – mean [years]\t17.6\t\nPASI score before therapy, mean\t22.9\t\nDLQI score before therapy, mean\t22\t\nPercentage of affected skin surface acc. BSA before therapy, mean\t45\t\nNumber of patients using:\t\t\n\tAdalimumab\t40\t\nNumber of patients using ustekinumab\t10\t\nPASI – Psoriasis Area and Severity Index, DLQI – Dermatology Life Quality Index, BSA – body surface area\n\nDescription of cases\nAmong the analysed cases of patients taking biological drugs the occurrence of various skin lesions as a treatment-related adverse reaction was observed. There were also observed hematologic disorders and deterioration of the general health condition.\n\nIn November 2013, adalimumab (Humira) therapy was started in a 46-year-old patient, who has been suffering from psoriasis vulgaris since 1989. A dissemination of maculopapular rash on the trunk and upper extremities with concurrent pruritus (Figures 1 A, B) was observed after 3 months of treatment. The patient was given antihistamines, including antazoline (Phenazolinum), and was given a clobetasol ointment (Novate) locally, i.e. on skin surface. Adalimumab administration was discontinued. After 2 weeks papular symptoms subsided, with pruritus symptoms still being persistent and producing numerous skin excoriations and erosions. In the performed laboratory tests, eosinophilia (21.4%) and elevated alanine aminotransferase levels (91 IU/l) were recorded. In the eosinophilia diagnostic procedure, parasitic diseases and hematologic causes were excluded. According to a haematologist’s recommendations, the adalimumab treatment was continued with simultaneous administration of triamcinolone in the initial dose of 8 mg/day for 7 days and then in the dose of 4 mg/day. Laboratory tests performed 10 days after administration of the drug demonstrated a decrease in the eosinophilic granulocyte level to 6.3% and after 2 weeks to 4.2%, achieving complete normalization after 2 months. Due to the drug program requirements, adalimumab administration was discontinued after 48 weeks of treatment. Triamcinolone 4 mg was administered until the therapy completion as prior attempts at the drug discontinuation led to pruritus recurrence.\n\nFigure 1 A dissemination of maculopapular rash\n\nAfter 9 months from treatment completion, intensification of pathological lesions in the course of psoriasis allowed to re-include the patient’s to the drug program. The patient yet again was administered adalimumab, initially with good tolerance and clinical effect. However, after 3 months of treatment there occurred dissemination of erythema exudativum lesions resembling bull’s eye targets, localized in groins and ulnar flexions. A centrally localized vesicle appeared in some of the lesions. Additionally, the patient experienced a strong burning sensation and pruritus. Adalimumab treatment was discontinued and intensive dexamethasone 8 mg oral treatment was initiated, followed by oral administration of methylprednisolone 16 mg and antazoline in 2 × 1 ampoule. After 2 weeks there was observed a significant improvement of the patient’s clinical condition, pallor of skin lesions and their circumferential exfoliation. After 6 weeks the lesions subsided completely and it was decided to continue adalimumab treatment.\n\nIn July 2014, adalimumab 40 mg (Humira) treatment, with the drug being administered subcutaneously two times per month was started in another 23-year-old female patient suffering from psoriasis vulgaris and diagnosed with psoriatic arthritis. A reduction of skin lesions (PASI score 75%) and regression of articular complaints were achieved. After 4 months of treatment (December 2014), a few hours after adalimumab injection an inflammatory infiltration appeared in the drug injection site, i.e. on the surface of the abdominal skin (Figure 2). In palpable examination the lesion was non-painful, pink-red with increased consistency and warmth. After ca. 2 days a spontaneous regression of the infiltration was observed. The presented clinical symptoms were observed for a period of several to a few dozen minutes after each drug administration and persisted for a few hours, then they subsided completely for the next 3 months of Humira treatment, with no concurrent general symptoms. It was decided to simultaneously administer Humira, dexamethasone 4 mg IM and antazoline 100 mg/2 ml. In this management scheme a reaction, in the form of an infiltration, occurred 30 min after the injection, yet the lesion was significantly smaller in size and it was not accompanied by pruritus. The infiltration regressed significantly faster, being reduced to the period of merely 3 h. The drug management was similar in the period of the following 3 months of drug administration until finally the infiltration ceased to occur. The drug is still being administered to the patient and there has not been observed any local reaction in the drug injection site for 1.5 years.\n\nFigure 2 Inflammatory infiltration\n\nA 53-year-old male patient was diagnosed with psoriasis vulgaris in 2001. After 11 years the patient started to exhibit symptoms of psoriatic arthritis in the form of tendon sheath inflammation, complained of painful interphalangeal joints of hands and feet as well as complained of painful oedematous tarsal and knee joints. The patient was hospitalized for erythroderma with oedema and shank skin exudates as well as dactylitis within the joints of hands and feet, with concurrent dystrophy of all nail plates. The lesions were accompanied by pain of both knee joints and interphalangeal joints of the feet. Simultaneous administration of methotrexate 25 mg/week and cyclosporine in a dose of 3.5 mg/kg body weight was included in the treatment. A reduction of skin lesions was observed, yet no PASI score 50% improvement was recorded. Articular complaints subsided completely. Due to persistent skin lesions the patient was enrolled into the biological treatment program. After administration of the first dose of ustekinumab, the patient experienced strong pain of knee and feet joints which occurred on the second and third day after the drug injection. Additionally, there appeared rachialgia of the lumbar-sacral area, oedema of the shanks and intense general weakness forcing the patient to stay in bed and increased temperature within the limit of 38.5°C. The patient was unable to work. The above symptoms persisted for a period of 2 weeks after which the patient visited a doctor. The patient was hospitalized for observation and follow-up examinations. Laboratory examinations showed elevated ESR and symptoms of normocytic anaemia. After a period of another 2 weeks the symptoms subsided spontaneously so it was decided to administer the second dose of ustekinumab. The subsequent, pre-planned ustekinumab injections were administered with good drug tolerance, with no occurrence of similar symptoms. Due to prevailing articular complaints the patient has been administered Humira since 2014 with good clinical effect and good tolerance.\n\nThe last patient is a 36-year-old female with plaque-type psoriasis diagnosed 20 years ago and psoriatic arthritis diagnosed in 2007. The patient has been complaining of pain intensification in knee and elbow joints for 5 years which was accompanied by oedema and increased warmth. Moreover, interphalangeal joints of the hands and the left foot were affected with formation of the so-called sausage-shaped fingers (dactylitis). Periodically there co-occurred pain and stiffness of the neck region of the spine. The patient was treated with acitretin in a dose of 0.6 mg/kg body weight and methotrexate 15 mg/week, yet none of the administered treatment methods brought improvement in PASI 50% score. Articular complaints and intensification of psoriatic skin lesions (PASI 21.8, DLQI 27 pts, BSA 27.5%) induced enrolment of the patient into the biological therapy program. The program was started with etanercept (Enbrel) administration. After 2 weeks of treatment there occurred intensified erythema located in the area of the arms, accompanied by warmth of the affected areas, which did not cause any subjective complaints (lack of photographic documentation). The patient was administered antihistamines orally and glucocorticoid creams for external use which resulted in complete subsistence of skin lesions. After a 1-week gap in etanercept administration the treatment was resumed and continued for a period of 18 months.\n\nAfter Enbrel therapy completion, psoriatic skin symptoms were of the leading nature whereas joint complaints were reduced. Because of that the patient was enrolled into the severe plaque-type psoriasis adalimumab treatment program. Eleven days after the drug administration there occurred a dissemination of exudative-oedematous lesions located on the area of cleavage, arms, back and lower extremities (Figures 3 A, B), which tended to fuse over time. There appeared wheals on the patient’s thighs characterized by significant oedema and increased consistency. The patient also complained of severe pruritus. It was decided to admit the patient to the Clinical Department of Internal Diseases, Dermatology and Allergology, Specialist Hospital in Zabrze where she was intramuscularly administered antihistamines and dexamethasone 8 mg/day and hydrocortisone locally. Adalimumab treatment was also discontinued. After the administered treatment, a quick and complete remission of the skin lesions was achieved. Adalimumab treatment was resumed after 2 weeks, this time without occurrence of any adverse reactions.\n\nFigure 3 A dissemination of exudative-oedematosus lessions\n\nIn October of 2015, during Humira treatment in the same patient, there appeared erythematous lesions with stratified soft yellow crusts without any blisters in the chin skin area. Initially the patient was diagnosed with contagious impetigo and fusidic acid was externally administered. Following the treatment administered there was no remission of the lesions observed, instead the lesions gradually assumed the form of maroon-red infiltration with a small amount of squama (Figure 4). The lesions were accompanied by the sensation of skin tension and tightening.\n\nFigure 4 Erythematosus infiltration\n\nMetronidazole, mometasone and emollients were administered in the following months. This treatment produced no improvement in the patient’s condition. Instead, there was observed a constant small increase in the affected chin skin area and occurrence of lesions localized in the region of nasolabial grooves in the nasal alar area with evident exacerbation after exposure to UV radiation. In June and September 2016, diagnostic tests were performed for systemic lupus erythematosus and the presence of cytoplasmic homogeneous pattern ANA2 antinuclear antibodies at the titre of 1 : 160 was determined. The ANA3 profile demonstrated presence of native SS-A antibodies (+). After 6 months, ANA titre increased to 1 : 320. In the period between 2011 and 2014 several tests for ANA levels were performed with each test producing a negative result (the presence of granular ANA pattern at the titre of 1 : 100 and cytoplasmic ANA pattern). An unaffected segment of the skin exposed to UV radiation was also collected. IgM-class immunoglobulin deposits (LBT-Lupus Band Test ++) were detected in the examined material, at the dermis-epidermis border. The patient is being observed for systemic lupus erythematosus. The patient is currently not administered any biological treatment. Three months after adalimumab discontinuation a clear improvement of the local condition was observed: pallor of the lupus erythematosus and flattening of the infiltration localized on the chin skin and nasolabial grooves.\n\nDiscussion\nDespite achieving satisfactory results, biological drug therapy is not free of adverse reactions. Based on the drug safety analyses, the most frequent adverse reactions, occurring in 20% of the patients, included upper respiratory tract infections, elevated triglyceride levels and cardiovascular episodes [7, 8]. During adalimumab treatment the occurrence of skin complications was observed, such as infiltrative-inflammatory lesions [9], pruritus, abscess [7], as well as deterioration of psoriasis and pain intensification in affected joints [9, 10]. Similar adverse reactions after administering the first ustekinumab dose were reported by one of the observed patients: general weakness, excessive sweating, oedema of shanks, fever, intensification of skin and articular complaints. Such symptoms did not recur after administering successive drug doses and switching the drug to adalimumab. The cases described in this paper present patients who experienced the occurrence of inflammatory infiltration and pain sensation in the drug administration site as well as dissemination of wheals as the first adverse reaction. The lesions were frequently accompanied by pruritus. The inflammatory infiltration at the drug injection site was reported in long-term observations [9–13]. Similar comments were made by Leonardi et al. [12] who observed hypersensitivity reactions, predominantly urticaria, in patients who were administered adalimumab.\n\nTwo of the described patients experienced erythema multiforme type of skin lesions. Mounach et al. [14] described the occurrence of Stevens-Johnson syndrome in a 53-year-old female patient during adalimumab therapy due to rheumatoid arthritis. The symptoms occurred after administration of the fifth dose of the drug. The drug administration was discontinued due to occurrence of lesions localized on mucous membranes. Other authors reported cases of erythema nodosum, also of a recurrent nature [7].\n\nThe equally frequently reported adverse reactions occurring after biological drug administration include occurrence or intensification of contagious diseases and opportunistic infections [13]. Bergler-Czop et al. [15] describe occurrence of zoster during adalimumab therapy whereas Justice et al. [16] present disseminated cutaneous herpes simplex virus after infliximab treatment.\n\nA female patient, who simultaneously experienced several different adverse reactions, was of particular interest. She experienced a hypersensitivity reaction in the form of acute urticaria as well as symptoms of erythema multiforme. During adalimumab therapy, as in the case described by Sobjanek et al. [17], the patient demonstrated positive ANA titre and positive Lupus Band Test (++). There also appeared symptoms suggesting the occurrence of drug-induced lupus. Facial skin lesions and hypersensitivity to UV radiation, as well as positive negative immunological test results are related to the received drug, with no prior history of lupus occurrence, indicate a drug-induced lupus diagnosis. One cannot completely exclude the occurrence of idiopathic lupus, yet improvement of the local condition after drug discontinuation indicates drug-induced symptoms. Also Burmester et al. [13] describe the occurrence of a lupus-like syndrome during biological drug therapy. Furthermore, there can be found numerous reports in the literature on the subject concerning cases of lupus erythematosus being induced by anti-TNF-α drugs, including reports of 130 such cases [17–20] that can be found in articles in the English language. Mattozzi et al. [21] present another example of an induced autoimmune disease. The case concerned the occurrence of circumscribed scleroderma during adalimumab treatment. Similar observations are presented by Posada et al. [22] who, while using adalimumab in treatment of a female patient with a Crohn’s disease, observed vitiligo foci.\n\nIn medical literature there can also be found cases of psoriasis dissemination and psoriasis-like lesions in the course of biological treatment for indications other than psoriasis [1, 2]. Iborra et al. [23] describe such complications after administration of infliximab and adalimumab in the treatment of Crohn’s disease. The authors of another interesting article describe 5 patients who experienced the occurrence of plaque psoriasis for the first time during biological therapy [24]. Rallis et al. [25] describe the case of disseminated pustular psoriasis. The mechanism of this phenomenon is probably associated with possible cutaneous interferon α (IFN-α) induction which predisposes to development of lesions [15]. Within TNF-α inhibitors, infliximab is the drug which most frequently induces psoriatic eruptions and psoriasis-like ones [26].\n\nSeveral authors describe patients with alopecia induced by biological drugs. Le Bidre et al. [27] describe patients treated with adalimumab, diagnosed with alopecia areata. Other authors describe diffuse alopecia as a result of TNF-α action [28]. In patients described by Doyle et al. [29] apart from alopecia areata and diffuse alopecia there also occurred psoriasis-like skin lesions. Literature on the subject also describes dermatologic diseases as biological treatment complications, inter alia lichen planus and lichen-like exanthema [30], skin and mucus membrane neoplasms [3] including malignant melanoma [31].\n\nFurthermore, the authors of numerous publications have observed the occurrence of other extra-cutaneous complications which followed administration of biological drugs, such as inflammation of nasal and pharyngeal mucous membrane [31], subacute thyroiditis [11], demyelinating diseases [32], congestive heart failure [13], severe dilated cardiomyopathy [33], purpura of Henoch-Schönlein [34] or pulmonary lymph node tuberculosis [20].\n\nConclusions\nDespite spectacular, relatively quickly-achieved treatment effects and treatment safety, the action of biological drugs is not free of adverse reactions. Biological drugs used in dermatology do not fulfil all hopes placed in them, yet they are a strong alternative to the hitherto used systemic treatment. There have been observed treatment-related adverse reactions in each of the presented cases. However, they have not posed a considerable threat to patients’ lives and the health benefits achieved by the patients have been much more significant.\n\nConflict of interest\nThe authors declare no conflict of interest.\n==== Refs\n1 Grochowiec M , Pakla-Misiur A , Narbutt J \n“Adherence” and “compliance” in the treatment of psoriasis–literature review\n. Dermatol Rev \n2016 ; 103 : 153 -61\n.\n2 Tyc-Zdrojewska E , Kaszuba A , Michalak I \nPreparaty biologiczne w terapii łuszczycy–doœwiadczenia własne\n. Forum Med Rodz \n2009 ; 3 : 468 -79\n.\n3 Adamski Z \nQuo vadis leczenie biologiczne w łuszczycy?\n\nDermatol Rev \n2016 ; 103 : 447 .\n4 Komorowska O , Szczerkowska-Dobosz A , Purzycka-Bohdan D , et al \n£uszczyca jako czynnik ryzyka rozwoju chorób serca i naczyń\n. Dermatol Rev \n2014 ; 101 : 500 -6\n.\n5 Miêkoœ-Zydek B , Ryglewska-Cho A , Lassota-Falczewska M , et al \nJakoœæ ¿ycia pacjentów z łuszczyc¹\n. Adv Dermatol Allergol \n2006 ; 23 : 273 -7\n.\n6 Neneman A , Adamski Z \nAspekty kliniczne i epidemiologiczne zaburzeń ogólnoustrojowych u chorych na łuszczycê\n. Forum Med Rodz \n2009 ; 3 : 447 -53\n .\n7 Parcheta P , Kłujszo E \nNawrotowy rumień guzowaty i gruźlica wêzłów chłonnych płuc u pacjentki leczonej inhibitorami TNF\n. Dermatol Rev \n2014 ; 101 : 390 -6\n.\n8 Asahina A , Ohtsuki M , Etoh T , et al \nAdalimumab treatment optimization for psoriasis: Results of a long-term phase 2/3 Japanese study\n. J Dermatol \n2015 ; 42 : 1042 -53\n.26118825 \n9 Menter A , Thaci D , Papp KA , et al \nFive-year analysis from the ESPRIT 10-years postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriaris\n. J Am Acad Dermatol \n2015 ; 73 : 410 -9\n.e6.26190240 \n10 Nowa B , Sokolik R \nOcena skutecznoœci i bezpieczeństwa stosowania adalimumabu w leczeniu chorych reumatoidalne zapalenie stawów\n. Prz Reumatol \n2007 ; 45 : 241 -7\n.\n11 Chiriac A , Foia L , Chiriac AE , et al \nA case of subcute thyroiditis in a patient on adalimumab for treatment of refractory palmo-plantar psoraris\n. Muller J Sci Res \n2014 : 5: 70 -3\n.\n12 Leonardi C , Papp K , Strober B , et al \nThe long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials\n. Am J Clin Dermatol \n2011 ; 12 : 321 -37\n.21834597 \n13 Burmester GR , Panaccione R , Gordon KB , et al \nAdalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease\n. Ann Rheum Dis \n2013 ; 72 : 517 -24\n.22562972 \n14 Mounach A , Rezqi A , Nouijai A , et al \nStevens-Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease\n. Rheumatol Int \n2013 ; 33 : 1351 -3\n.22187054 \n15 Bergler-Czop B , Wcisło-Dziadecka D , Wodok K , Brzezińska-Wcisło L \n£ojotokowe zapalenie skóry oraz infekcja Herpes zoster w trakcie terapii adalimumabem ze wskazań gastroenterologicznych–opis przypadku\n. £uszczyca News \n2013 ; 3 .\n16 Justice EA , Khan SY , Logan S , Jobanputra P \nDisseminated cutaneous Herpes Simplex Virus-1 in a woman with rheumatoid arthritis receiving infliximab: a case report\n. J Med Case Rep \n2008 ; 2 : 282 .18727822 \n17 Sobjanek M , Wilkowska A \nAnti TNF-alfa induced lupus erythematosus in a patient with psoriasis – diagnostic controversy\n. Dermatol Rev \n2012 , 99, 605 -10\n.\n18 Katz U , Zandman-Goddard G \nDrug-induced lupus: update\n. Autoimm Rev \n2010 ; 10 : 46 -50\n.\n19 Vedove CD , Del Giglio M , Schena D , Girolomoni G \nDrug-induced lupus erythematosus\n. Arch Dermatol Res \n2009 ; 301 : 99 -105\n.18797892 \n20 Levine D , Switlyk S , Gottlieb A \nCutaneous lupus erythematosus and anti-TNF-alpha therapy: a case report with review of the literature\n. J Drugs Dermatol \n2010 ; 9 : 83 -87\n.\n21 Mattozzi C , Richetta AG , Cantisani C , et al \nMorphea, an unusual side effect of anti-TNF-alpha treatment\n. Eur J Dermatol \n2010 ; 20 : 400 -1\n.20299314 \n22 Posada C , Florez A , Batalla A , et al \nVitiligo during treatment of Crohn’s disease with adalimumab, adverse effect of co-occurrence\n. Case Rep Dermatol \n2011 ; 3 : 28 -31\n.21931575 \n23 Iborra M , Beltrán B , Bastida G , et al \nInfliximab and adalimumab-induced psoriasis in Crohn’s disease: a paradoxical side effect\n. J Crohns Colitis \n2011 ; 5 : 157 -61\n.21453886 \n24 Sfikakis PP , Iliopoulos A , Elezoglou A \nPsoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction,\n. Arthritis Rheum \n2005 ; 52 : 2513 -8\n.16052599 \n25 Rallis E , Korfitis C , Stavropoulou E , et al \nOnset of palmoplantar pustular psoriasis while on adalimumab for psoriatic arthritis: a ‘class effect’ of TNF-alpha antagonists or simply an anti-psoriatic treatment adverse reaction?\n\nJ Dermatolog Treat \n2010 ; 21 : 3 -5\n.19701844 \n26 Ko JM , Gottlieb AB , Kerbleski JF , et al \nInduction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases\n. J Dermatolog Treat \n2009 ; 20 : 100 -8\n.18923992 \n27 Le Bidre E , Chaby G , Martin L , et al \nAlopecia areata during anti-TNF alpha therapy: nine cases\n. Ann Dermatol Venereol \n2011 ; 138 : 285 -93\n.21497255 \n28 El Shabrawi-Caelen L , La Placa M , Vincenzi C , et al \nAdalimumab-induced psoriasis of the scalp with diffuse alopecia: a severe potentially irreversible cutaneous side effect of TNF-alpha blockers\n. Inflamm Bowel Dis \n2010 ; 16 : 182 -3\n.19462433 \n29 Doyle LA , Sperling LC , Baksh S , et al \nPsoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor-alpha therapy: a novel cause of noncicatricial alopecia\n. Am J Dermatopathol \n2011 ; 33 : 161 -6\n.21317611 \n30 Asarch A , Gottlieb AB , Lee J , et al \nLichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists\n. J Am Acad Dermatol \n2009 ; 61 : 104 -11\n.19539844 \n31 Manganoni AM , Zane C , Pavoni L , et al \nCutaneous melanoma in patients in treatment with biological therapy: review of the literature and case report\n. Dermatol Online J \n2011 ; 17 : 12 .\n32 Asahina A , Ohtsuki M , Etoh T , et al \nAdalimumab treatment optimization for psoriasis: results of a long-term phase 2/3 Japanese study\n. J Dermatol \n2015 ; 42 : 1042 -52\n.26118825 \n33 Burmester G , Mease P , Dijkmans B , et al \nAdalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases\n. Ann Rheum Dis \n2009 ; 68 : 1863 -9\n.19147611 \n34 Marques I , Lagos A , Reis J , et al \nReversible Henoch-Schönlein purpura complicating adalimumab therapy\n. J Crohns Colitis \n2012 ; 6 : 796 -9\n.22445079\n\n",
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"keywords": "adalimumab; adverse effects; biological therapy; psoriasis; ustekinumab",
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"title": "Examples of adverse effects after biological therapy.",
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"abstract": "OBJECTIVE\nThe aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.\n\n\nMETHODS\nWe performed a retrospective review (2005-2010) of a large prospectively collected administrative database.\n\n\nRESULTS\nMedications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.\n\n\nCONCLUSIONS\nMedication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants.",
"affiliations": "Duke-National University of Singapore Graduate Medical School, Singapore.;Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.;Pediatrix-Obstetrix Center for Research and Education, Sunrise, Florida.;Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina.;Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.;Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.",
"authors": "Hsieh|Emily M|EM|;Hornik|Christoph P|CP|;Clark|Reese H|RH|;Laughon|Matthew M|MM|;Benjamin|Daniel K|DK|;Smith|P Brian|PB|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0033-1361933",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "31(9)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D004358:Drug Therapy; D004363:Drug Utilization; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D015931:Intensive Care, Neonatal; D008297:Male; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "811-21",
"pmc": null,
"pmid": "24347262",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "12492616;20363447;16388164;12415059;16882832;22128226;17568029;16907660;16126045;16396864;15912383;22300711;10974130;20813274;19772996;16390920;15701577;11938479;16740839;18809946",
"title": "Medication use in the neonatal intensive care unit.",
"title_normalized": "medication use in the neonatal intensive care unit"
} | [
{
"companynumb": "SG-JNJFOC-20170821713",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.",
"affiliations": "Hematology, \"Cardarelli\" Hospital, Naples, Italy. salvatore.palmieri@aocardarelli.it.;Hematology, \"Cardarelli\" Hospital, Naples, Italy.;Hematology, \"Cardarelli\" Hospital, Naples, Italy.;Hematology, AUOP \"Federico II\", Naples, Italy.;Hematology, AUOP \"Federico II\", Naples, Italy.;Hematology Unit, \"Bianchi-Melacrino-Morelli\" Hospital, Reggio Calabria, Italy.;Hematology Unit, \"Bianchi-Melacrino-Morelli\" Hospital, Reggio Calabria, Italy.;Onco-Hematology, Hematology Unit, AO of Cosenza, Italy.;Onco-Hematology, \"S. Anna e S. Sebastiano\" Hospital, Caserta, Italy.;Onco-Hematology, \"Tortora\" Hospital, Pagani, SA, Italy.;Hematology, \"Santa Maria di Loreto Nuovo\" Hospital, Naples, Italy.;Hematology, \"San Giuseppe Moscati\" Hospital, Aversa, CE, Italy.;Hematology/Oncology and SCT Unit, National Cancer Institute, Fondazione \"Pascale\", Naples, Italy.;Hematology, \"Rummo\" Hospital, Benevento, Italy.;Hematology, AOU \"Ruggi d'Aragona\", Salerno, Italy.;Hematology and SCT Unit, \"San Giuseppe Moscati\" Hospital, Avellino, Italy.;Onco-Hematology, AOU \"Vanvitelli\", Naples, Italy.;Hematology, \"San Giuliano\" Hospital, Giugliano in Campania, Naples, Italy.;Hematology, AUOP \"Federico II\", Naples, Italy.;Hematology, \"Cardarelli\" Hospital, Naples, Italy.",
"authors": "Palmieri|Salvatore|S|https://orcid.org/0000-0001-9634-4147;Rocco|S|S|;Vitagliano|O|O|;Catalano|L|L|;Cerchione|C|C|;Vincelli|I D|ID|;Scopelliti|A|A|;Gentile|M|M|;Farina|G|G|;Barone|M|M|;Gagliardi|A|A|;Esposito|D|D|;Arcamone|M|M|;Amico|V|V|;Fontana|R|R|;Sementa|A|A|;Sica|A|A|;Svanera|G|G|;Pane|F|F|;Ferrara|F|F|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D007155:Immunologic Factors; D009842:Oligopeptides; C524865:carfilzomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04158-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(12)",
"journal": "Annals of hematology",
"keywords": "Carfilzomib; Lenalidomide; Real-life; Relapsed refractory multiple myeloma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007558:Italy; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2903-2909",
"pmc": null,
"pmid": "32583088",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "30030033;30537552;29615082",
"title": "KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.",
"title_normalized": "krd carfilzomib and lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma in the real life a retrospective survey in 123 patients"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1049040",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Our aim was to investigate the reason for relatively low detection rates for opioids and fentanyl in particular in post-mortem cases in the State of Hamburg. We re-analysed 822 blood samples from two different time periods, 2011/12 and 2016. These samples had been previously analysed in accordance with post-mortem routine by a case selected strategy. All samples were re-analysed with an LC-MS/MS method specific for prescription opioids. The main point in the evaluation was to determine whether the previous analysis strategy had led to underreporting of drug-related deaths (DRD), especially with regard to fentanyl. Another aim was to evaluate changes in prescribing prevalence of opiates and opioids. We compared pharmacy claims data in Hamburg with Germany. The analyses showed that the number of DRD remained unaffected by the new analytical strategy. Detection rates in DRD, however, increased for fentanyl 3.4-fold from 1.2% to 4.1%, buprenorphine from 5.9% to 7.6%, oxycodone from 0% to 1.8%, tilidine from 1.8% to 2.4%. The most frequently detected opioids in DRD cases were methadone (39.4%) and heroin (20%). Prescription rates between 2011-2017 decreased in Hamburg for nearly all opioids, morphine by - 43.5%, buprenorphine - 43%, codeine - 57%, fentanyl - 25%, tilidine -17%, tramadol - 31%, and hydromorphone -6%. Oxycodone, tapentadol, and piritramide prescription rates increased. For Germany, a decrease in the prescription rates for fentanyl was also found during this period (-12.9 %), although not as pronounced as in Hamburg. Prescription rates for methadone were three to greater than five times higher in Hamburg as compared to the German average due to the higher number of substituted persons per inhabitant. Conclusion: Despite the global problem of opioid abuse, there are significant regional differences in the nature and extent of opioid abuse. It is necessary to collect data at the national level to develop appropriate prevention strategies.",
"affiliations": "Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Germany.;Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Germany.;German Institute for Drug Use Evaluation (DAPI), Berlin, Germany; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, freie Universität Berlin, Germany.;German Institute for Drug Use Evaluation (DAPI), Berlin, Germany.;Institute of Legal Medicine, University Hospital of Cologne, Germany.;Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Germany.;Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: s.iwersen-bergmann@uke.de.",
"authors": "Schönfeld|T|T|;Heinemann|A|A|;Schulz|M|M|;Gradl|G|G|;Andresen-Streichert|H|H|;Müller|A|A|;Iwersen-Bergmann|S|S|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2019.109970",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "305()",
"journal": "Forensic science international",
"keywords": "Drug abuse; Fatal poisoning; Fentanyl; Opioid; Post-mortem concentration; Prevalence",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D002853:Chromatography, Liquid; D011307:Drug Prescriptions; D005260:Female; D005283:Fentanyl; D053593:Forensic Toxicology; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D011180:Postmortem Changes; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "109970",
"pmc": null,
"pmid": "31629200",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Post-mortem analysis of prescription opioids-A follow-up examination by LC-MS/MS with focus on fentanyl.",
"title_normalized": "post mortem analysis of prescription opioids a follow up examination by lc ms ms with focus on fentanyl"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1022316",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "The outcome of romiplostim for secondary failure of platelet recovery (SFPR) was investigated in children who had undergone hematopoietic stem cell transplantation (HSCT). Seven transfusion-dependent pediatric patients (median age 11 years), with platelet counts below 10 × 10(9)/L, received four weekly doses of subcutaneous romiplostim to treat SFPR developed after HSCT. All patients, except one (patient 4), became platelet transfusion-independent in the second week from the beginning of treatment and no patient needed to discontinue drug treatment because of adverse events. Romiplostim could represent a beneficial first-line treatment, but further studies are required.",
"affiliations": "Bone Marrow Transplantation Unit, Pediatric Hemato Oncology Department, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Via dell'Istria 65, 34134, Trieste, Italy. natalia.maximova@burlo.trieste.it.;Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Pharmacy and Clinical Pharmacology, Trieste, Italy.;Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Pharmacy and Clinical Pharmacology, Trieste, Italy.;Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Pharmacy and Clinical Pharmacology, Trieste, Italy.;Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Pharmacy and Clinical Pharmacology, Trieste, Italy.;Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Pharmacy and Clinical Pharmacology, Trieste, Italy.",
"authors": "Maximova|Natalia|N|;Zanon|D|D|;Rovere|F|F|;Maestro|A|A|;Schillani|G|G|;Paparazzo|R|R|",
"chemical_list": "D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1821-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "102(5)",
"journal": "International journal of hematology",
"keywords": "Pediatric patients; Romiplostim; Secondary failure of platelet recovery; Virus infection",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D002648:Child; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D010976:Platelet Count; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013921:Thrombocytopenia; D013926:Thrombopoietin",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "626-32",
"pmc": null,
"pmid": "26084627",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3881142;25118016;23832091;23913253;11535499;23997988;14688814;11302549;22775392;7581076;17219966;19932428;21864167;19908296;21927039;11167808",
"title": "Romiplostim for secondary thrombocytopenia following allogeneic stem cell transplantation in children.",
"title_normalized": "romiplostim for secondary thrombocytopenia following allogeneic stem cell transplantation in children"
} | [
{
"companynumb": "IT-AMGEN-ITASP2016150923",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drug... |
{
"abstract": "A 47-year-old man who had been using finasteride for male pattern alopecia for 4 years complained of progressive bilateral blurring of vision. His general health had been good, and he was not on any other long-term medication. Examination showed bilateral anterior subcapsular cataracts. Phacoemulsification and insertion of intraocular lenses were performed, and both eyes showed features of intraoperative floppy-iris syndrome (IFIS), including undulation and billowing of the iris, iris prolapse, and pupil constriction. We believe the use of finasteride can be associated with cataract formation and IFIS. Ophthalmologists and physicians prescribing finasteride should be aware of this possible association.\n\n\nBACKGROUND\nNeither author has a financial or proprietary interest in any material or method mentioned.",
"affiliations": "Department of Ophthalmology, Union Hospital, Hong Kong, China. dralbertcmw@gmail.com",
"authors": "Wong|Albert Chak-Ming|AC|;Mak|Shiu Ting|ST|",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D018120:Finasteride",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrs.2011.04.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "37(7)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000505:Alopecia; D002386:Cataract; D018120:Finasteride; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D007431:Intraoperative Complications; D007499:Iris Diseases; D019654:Lens Implantation, Intraocular; D007908:Lens, Crystalline; D008297:Male; D008875:Middle Aged; D009123:Muscle Hypotonia; D018918:Phacoemulsification; D011391:Prolapse",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "1351-4",
"pmc": null,
"pmid": "21555201",
"pubdate": "2011-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Finasteride-associated cataract and intraoperative floppy-iris syndrome.",
"title_normalized": "finasteride associated cataract and intraoperative floppy iris syndrome"
} | [
{
"companynumb": "HK-ALKEM LABORATORIES LIMITED-HK-ALKEM-2020-01331",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FINASTERIDE"
},
"drug... |
{
"abstract": "A pediatric patient requiring venovenous (VV) extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation developed heparin-induced thrombocytopenia. Unfractionated heparin was discontinued, and a bivalirudin infusion was started. During the lung transplant evaluation, he was found to have allosensitization, requiring treatment with plasma exchange along with pulse methylprednisolone, rituximab, bortezomib, and pooled immunoglobulin infusion. We describe our experience with successful plasma exchange for allosensitization during bivalirudin anticoagulation on VV ECMO in a pediatric patient.",
"affiliations": "Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA Heart Center, Nationwide Children's Hospital, Columbus, OH, USA Department of Cardiovascular Perfusion and ECMO, Nationwide Children's Hospital, Columbus, OH, USA thomas.preston@nationwidechildrens.org.;Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix Children's Hospital, Phoenix, AZ, USA.;Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA Department of Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Heart Center, Nationwide Children's Hospital, Columbus, OH, USA.;Clinical Pharmacy, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA Section of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Preston|Thomas J|TJ|;Dalton|Heidi J|HJ|;Nicol|Kathleen K|KK|;Ferrall|Brit R|BR|;Miller|Julie C|JC|;Hayes|Don|D|",
"chemical_list": "D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006493:Heparin; C074619:bivalirudin",
"country": "United States",
"delete": false,
"doi": "10.1177/2150135114553476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": "6(1)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": "bivalirudin; extracorporeal membrane oxygenation; plasma exchange; venovenous",
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D000991:Antithrombins; D015199:Extracorporeal Membrane Oxygenation; D017809:Fatal Outcome; D006493:Heparin; D006629:Hirudins; D006801:Humans; D007223:Infant; D016040:Lung Transplantation; D008297:Male; D010446:Peptide Fragments; D010951:Plasma Exchange; D011300:Preoperative Care; D011994:Recombinant Proteins; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "119-22",
"pmc": null,
"pmid": "25548358",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plasma exchange on venovenous extracorporeal membrane oxygenation with bivalirudin anticoagulation.",
"title_normalized": "plasma exchange on venovenous extracorporeal membrane oxygenation with bivalirudin anticoagulation"
} | [
{
"companynumb": "PHHY2015US067543",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Excellent efficacy and safety profile of second-generation DAA combinations improved treatment of chronic hepatitis C (HCV) as well as in HCV recurrence after orthotopic liver transplantation (OLT). The need of ribavirin addition is under debate as anaemia and decreased renal function are prevalent in transplant cohorts. The aim of this study was thus to assess safety and long-term efficacy of RBV-free DAA combinations in HCV-recurrent patients after OLT.\n\n\n\nA total of 62 OLT recipients (male: 50%/81%; age: 60.7 ± 8.5 years [mean ± SD]; GT - 1: 48, GT - 3: 9, GT - 4: 5; cirrhosis: 34%/55% [7%/21% decompensated], fibrosing cholestatic hepatitis: 1%/2%) received RBV-free treatment with second-generation DAA combinations: sofosbuvir (SOF)/daclatasvir (DCV): 42%/68%, SOF/simeprevir (SMV): 10%/16%, SOF/ledipasvir (LDV): 6%/10% and PrOD: 4%/7%.\n\n\n\nData of at least 96 weeks of FUP after treatment cessation (mean: 120; up to 167 weeks) were analysed. All patients showed on-treatment response. By intention-to-treat (ITT) analysis, SVR12 was 97% (60/62, GT-1a: 11/11 [100%]; 1b: 33/34 [97%]; 1g: 1/1 [100%]; subtype not specified: 2/2 [100%]; GT3a: 9/9 [100%]; GT4: 4/5 [80%]) compared to SVR96 of 89% (55/62). No late relapses occurred. In total, 16 severe adverse events occurred, including two newly diagnosed carcinoma (lung cancer, hepatocellular carcinoma). Six patients died; one at treatment week 24 (HCV-RNA undetectable) and five during treatment-free FUP and after achieving SVR (SVR4: N = 1, SVR12: N = 3, after SVR96: N = 1 respectively). Reasons for death were: multi-organ failure (N = 4), impaired graft function (N = 1) and unknown (N = 1).\n\n\n\nRBV-free DAA combinations for the treatment of HCV recurrence after OLT are highly efficacious and well tolerated. Our long-term data show that viral eradication is durable but not necessarily translated into beneficial long-term clinical outcome.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Department of Internal Medicine 2, Division of Gastroenterology and Hepatology, Universitätsklinikum, St. Pölten, Austria.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.;Department of Gastroenterology and Hepatology, Paracelsus Medical University Salzburg, Salzburg, Austria.;Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Internal Medicine, Landeskrankenhaus Hall, Hall/Tirol, Austria.;Department of Transplant Surgery, Medical University of Vienna, Vienna, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.",
"authors": "Beinhardt|Sandra|S|0000-0002-0785-9710;Al-Zoairy|Ramona|R|;Kozbial|Karin|K|0000-0002-5012-7662;Stättermayer|Albert F|AF|;Maieron|Andreas|A|;Stauber|Rudolf|R|;Strasser|Michael|M|;Zoller|Heinz|H|;Graziadei|Ivo|I|;Rasoul-Rockenschaub|Susanne|S|;Trauner|Michael|M|;Ferenci|Peter|P|;Hofer|Harald|H|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D005449:Fluorenes; D007093:Imidazoles; D011759:Pyrrolidines; C586541:ledipasvir; D012254:Ribavirin; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "38(7)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "HCV recurrence; direct acting antiviral(s); hepatocellular carcinoma; long-term follow-up; orthotopic liver transplantation",
"medline_ta": "Liver Int",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001317:Austria; D001562:Benzimidazoles; D002219:Carbamates; D006528:Carcinoma, Hepatocellular; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D005500:Follow-Up Studies; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012008:Recurrence; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D014633:Valine",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1188-1197",
"pmc": null,
"pmid": "29197145",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term follow-up of ribavirin-free DAA-based treatment in HCV recurrence after orthotopic liver transplantation.",
"title_normalized": "long term follow up of ribavirin free daa based treatment in hcv recurrence after orthotopic liver transplantation"
} | [
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"companynumb": "AT-MYLANLABS-2019M1031359",
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"abstract": "OBJECTIVE\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are medical emergencies. Mainstays of treatment include removal of the offending agent, supportive care, and wound care. The use of immunosuppressive agents such as corticosteroids and intravenous immunoglobulin (IVIg) is controversial. Some case reports and small studies report the successful use of cyclosporin A (CsA) for SJS/TEN in halting disease progression, fostering reepithelialization, and reducing mortality.\n\n\nOBJECTIVE\nTo report on the efficacy of cyclosporine A in the treatment of SJS/TEN in three pediatric patients.\n\n\nMETHODS\nWe describe three pediatric patients seen at a tertiary care hospital in Boston, Massachusetts, diagnosed with SJS/TEN confirmed by skin biopsy who were successfully treated with CsA with improvements seen in time to cessation of disease progression or new lesion formation, reepithelialization, and duration of hospital stay.\n\n\nRESULTS\nThe average time cessation of disease progression or new lesion formation after CsA administration was 2.2 days (range 1.5-3 days) and average time to remission or reepithelialization was 13 days (range 10-15 days). The average length of hospital stay was 11.7 days (range 4-19 days).\n\n\nCONCLUSIONS\nWe describe three pediatric patients treated successfully with CsA and provide evidence for the use of cyclosporine in children with SJS/TEN. These results further support previous observations that CsA use for SJS/TEN produces consistently favorable outcomes. The results in this case series are limited by their observational nature. Additional trials are needed to evaluate the safety and efficacy of CsA use in children.",
"affiliations": "Department of Dermatology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts.;Department of Dermatology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts.;Department of Dermatology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts.",
"authors": "St John|Jessica|J|http://orcid.org/0000-0002-2916-0118;Ratushny|Vladimir|V|;Liu|Kristina J|KJ|;Bach|Daniel Q|DQ|;Badri|Omar|O|;Gracey|Lia E|LE|;Ho|Allen W|AW|;Raff|Adam B|AB|;Sugai|Daniel Y|DY|;Schalock|Peter|P|;Kroshinsky|Daniela|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "34(5)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D001900:Boston; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007902:Length of Stay; D008297:Male; D012867:Skin; D013262:Stevens-Johnson Syndrome; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "540-546",
"pmc": null,
"pmid": "28884910",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Use of Cyclosporin A for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Three Children.",
"title_normalized": "successful use of cyclosporin a for stevens johnson syndrome and toxic epidermal necrolysis in three children"
} | [
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"companynumb": "US-FRESENIUS KABI-FK201708519",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"abstract": "OBJECTIVE\nTo study the incidences of and risk factors for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy in Thai rheumatologic patients.\n\n\nMETHODS\nA retrospective cohort study of 234 rheumatologic patients receiving either CQ or HCQ was conducted. Patients were divided based on whether or not they developed retinopathy as retinopathy-positive or negative groups. Medical records giving details regarding age, gender, body weight, underlying diseases, daily doses, and cumulative doses of CQ or HCQ were reviewed. CQ and HCQ retinopathy were diagnosed by indirect ophthalmoscopy, Humphrey visual field test, and optical coherence tomography. The main outcome measures were incidences and risk factors of CQ and HCQ retinopathy.\n\n\nRESULTS\nThe CQ retinopathy was detected in 14 of 173 patients (8.09%) who received CQ for 139-2,033 days, cumulative doses from 14.3 to 325.1 g, and daily doses from 0.8 to 18.5 mg/kg/d. Their ages ranged from 27 to 65 years. When compared to the CQ retinopathy-negative group, only age, body weight, and cumulative dose showed statistically significant differences. The HCQ retinopathy-positive group was comprised of 2 of 61 patients (3.28%) who received HCQ for 660-828 days, cumulative doses from 80 to 130 g, and daily dose from 1.9 to 4.4 mg/kg/d. Their ages were 36 and 39 years. Compared to the HCQ retinopathy-negative group, there were no statistically significant differences in studied risk factors.\n\n\nCONCLUSIONS\nIncidences of and risk factors for CQ and HCQ retinopathy were reported. Since most patients developed retinopathy earlier than 5 years, it is suggested that patients taking long-term CQ or HCQ should undergo ophthalmologic screening annually after the baseline examination.",
"affiliations": "KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.",
"authors": "Tangtavorn|Nuanpan|N|;Yospaiboon|Yosanan|Y|;Ratanapakorn|Tanapat|T|;Sinawat|Suthasinee|S|;Sanguansak|Thuss|T|;Bhoomibunchoo|Chavakij|C|;Laovirojjanakul|Wipada|W|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S119872",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S119872opth-10-2179Original ResearchIncidence of and risk factors for chloroquine and hydroxychloroquine retinopathy in Thai rheumatologic patients Tangtavorn Nuanpan Yospaiboon Yosanan Ratanapakorn Tanapat Sinawat Suthasinee Sanguansak Thuss Bhoomibunchoo Chavakij Laovirojjanakul Wipada KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, ThailandCorrespondence: Yosanan Yospaiboon, KKU Eye Center, Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Highway, Khon Kaen 40002, Thailand, Tel +66 43 348 383, Email yosanan@kku.ac.th2016 02 11 2016 10 2179 2185 © 2016 Tangtavorn et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nTo study the incidences of and risk factors for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy in Thai rheumatologic patients.\n\nMethods\nA retrospective cohort study of 234 rheumatologic patients receiving either CQ or HCQ was conducted. Patients were divided based on whether or not they developed retinopathy as retinopathy-positive or negative groups. Medical records giving details regarding age, gender, body weight, underlying diseases, daily doses, and cumulative doses of CQ or HCQ were reviewed. CQ and HCQ retinopathy were diagnosed by indirect ophthalmoscopy, Humphrey visual field test, and optical coherence tomography. The main outcome measures were incidences and risk factors of CQ and HCQ retinopathy.\n\nResults\nThe CQ retinopathy was detected in 14 of 173 patients (8.09%) who received CQ for 139–2,033 days, cumulative doses from 14.3 to 325.1 g, and daily doses from 0.8 to 18.5 mg/kg/d. Their ages ranged from 27 to 65 years. When compared to the CQ retinopathy-negative group, only age, body weight, and cumulative dose showed statistically significant differences. The HCQ retinopathy-positive group was comprised of 2 of 61 patients (3.28%) who received HCQ for 660–828 days, cumulative doses from 80 to 130 g, and daily dose from 1.9 to 4.4 mg/kg/d. Their ages were 36 and 39 years. Compared to the HCQ retinopathy-negative group, there were no statistically significant differences in studied risk factors.\n\nConclusion\nIncidences of and risk factors for CQ and HCQ retinopathy were reported. Since most patients developed retinopathy earlier than 5 years, it is suggested that patients taking long-term CQ or HCQ should undergo ophthalmologic screening annually after the baseline examination.\n\nKeywords\nchloroquinehydroxychloroquineretinopathyincidencerisk factors\n==== Body\nIntroduction\nChloroquine (CQ) and hydroxychloroquine (HCQ) are widely used to control effects of various rheumatologic diseases, for example, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SS), or other connective tissue diseases. They are found to inhibit CD4 T-cell stimulation while also promoting CD8 T-cell stimulation, and hence they are a popular choice for controlling the progression of autoimmune diseases without increasing the rate of opportunistic infections.1 HCQ is more molecularly polar than CQ making it less lipophilic, leading to poorer diffusion through biological membranes and resulting in less toxicity.1 One of the most severe complications of these drugs is retinopathy, which leads to visual field defects and visual loss as a result of damaged photoreceptors. This damage is incurable and may progress even after the drugs are discontinued.2 An ophthalmologic screening examination, therefore, has to be regularly performed to early detect and prevent this destructive morbidity.2\n\nThe American Academy of Ophthalmology (AAO) established guidelines for CQ and HCQ retinopathy screening examinations, which was revised in 2011 and 2016.3,4 Patients were classified as high risk when they have at least one of the following risk factors: an average daily dose exceeding 2.3 mg/kg real weight for CQ and 5 mg/kg real weight for HCQ,4 cumulative doses exceeding 460 g for CQ and 1,000 g for HCQ,3 a duration of treatment exceeding 5 years, being elderly, having concomitant renal disease, or using Tamoxifen.4 Routinely, one baseline examination within the first year and annual screening beginning 5 years after the first dose are recommended.3,4\n\nSince most of studies reported are performed in Caucasian populations,5–8 application of the findings of these studies and recommendations may not be appropriate for Asian populations. For the Thai patients, there have been some studies on prevalence and risk factors of CQ retinopathy, but the results seemed to be paradoxical to the AAO recommendations, and the obvious risk factors are still not well defined.9–11 Hence, this study was intended to produce a more inclusive report on incidence of and risk factors for CQ and HCQ retinopathy in Thai rheumatologic patients.\n\nSubjects and methods\nThis study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Khon Kaen University Ethics Committee for Human Research (HE571052). The Khon Kaen University Ethics Committee for Human Research waived the requirement for patient consent due to the retrospective nature of the study. A retrospective cohort study of rheumatologic patients at Srinagarind Hospital, Khon Kaen University, Thailand, was conducted. The patients, aged not less than 18 years old, started receiving either CQ or HCQ from 2004 to 2014 and regularly underwent eye screening examinations for CQ or HCQ retinopathy at the KKU Eye Center. Patients whose medical records were incomplete or those who had undeterminable records of the CQ or HCQ dosages were excluded. Also, patients who started the drugs before being referred to the hospital or were switched from CQ to HCQ or vice versa were excluded. Moreover, patients with retinal or macular diseases or optic neuropathy, which could possibly interfere with the visual field test, were excluded as well.\n\nData collections\nThe medical records of all the patients who fulfilled the criteria mentioned in the “Subjects and methods” section were reviewed and recorded in prepared case report forms. The record form for each patient was labeled with a new number to conceal the real identity of patients. The information collected were:\nAge: the age at the latest eye examination.\n\nGender: male or female.\n\nBody weight: the real body weight at the latest follow-up at the rheumatologic clinics.\n\nUnderlying disease: diabetes mellitus, dyslipidemia, hypertension, or other diseases.\n\nHistory of rheumatologic diseases.\n\nDuration of drug use:\n○ If the patients had no retinopathy and still continued the drug, it was counted from the day of the first dose to the day of the last eye examination.\n\n○ If the patients had no retinopathy and stopped the medication, it was counted from the day of the first dose to the day of the last dose.\n\n○ If the patients had retinopathy, it was counted from the day of the first dose to the day that retinopathy was diagnosed despite whether patients had stopped the medication or not.\n\n\n\nCumulative dosage (g): For each patient, the dosage, the duration of each dosage, and dose changes throughout treatment were recorded. The summation of products of dosage and duration were recorded as the cumulative dosage.\n\nAverage dosage per real body weight per day (mg/kg/d): Cumulative dose divided by real body weight and duration in days each patient received the medication.\n\nPresence of signs of CQ or HCQ retinopathy from the eye screening examinations.\n\n\n\nDetermination of CQ and HCQ retinopathy\nAccording to AAO recommendations, retinal toxicity was defined in 2 levels: “possible” toxicity and “probable” toxicity.3 Possible toxicity indicates an early sign of toxicity. Patients who repeatedly demonstrated these conditions in both eyes for at least 2 consecutive tests were recommended to stop the medications until the cause, other than CQ or HCQ retinopathy, was identified. These conditions were:\nParafoveal depigmentation of retinal pigment epithelium (RPE) as observed by indirect ophthalmoscopic examination after patients’ pupils were fully dilated.\n\nDecreased parafoveal visual field sensitivities at the same area for at least 2 consecutive visits as tested by Humphrey visual fields (HVF) 10-2 using Humphrey Field Analyzer II (Zeiss Meditech Inc., Dublin, CA, USA). All the tests must show reliable test-fixation loss of less than 20% and have false-negative and false-positive response rates of less than 33%.\n\nLoss of parafoveal inner segment–outer segment junction from spectral domain optical coherence tomography (OCT) using Spectralis (Heidelberg Engineering, Heidelberg, Germany).\n\nIncreased autofluorescence at parafoveal area using Spectralis (Heidelberg Engineering).\n\n\n\nFor probable toxicity, the same findings as in possible toxicity were included, but those defects were shown in the bull’s eye pattern and in both eyes.\n\nThe screening tests were routinely performed and interpreted by retinal specialists at the KKU Eye Center.\n\nSample size calculation\nEstimated sample size was calculated with 95% confidence level, 5% absolute precision, and 13.5% estimated prevalence, resulting in a sample size of 171.9\n\nStatistical analysis\nAs these data did not match that of normal distribution, continuous data were reported as the median with minimal and maximal values, and comparisons between data of each group were performed using Mann–Whitney tests. Categorical data were compared via Fisher exact tests. The risk factors were analyzed as hazard ratios using univariate Cox regression analysis. The incidence of retinopathy and the duration of the medication use were demonstrated with Kaplan–Meier survival analysis. The risk factors that had a value of P<0.2 were further analyzed with multivariate Cox regression analysis. All statistics were performed using SPSS for Windows version 20.0 (IBM Corporation, Armonk, NY, USA). The statistical significance was defined at P<0.05.\n\nResults\nTwo hundred and thirty-four patients were enrolled in the study according to the criteria established. There were 173 patients who received only CQ (CQ group) and 61 patients who received only HCQ (HCQ group). In the CQ group, there were 63 RA patients, 63 SLE patients, 23 SS patients, and 24 patients with other connective tissue diseases. In the HCQ group, there were 11 RA patients, 31 SLE patients, 4 SS patients, and 15 patients with other connective tissue diseases.\n\nIn the CQ positive group, retinopathy had developed in 14 of 173 patients, all of which were categorized “possible” toxicity as evidenced by indirect ophthalmoscopic examination, HVF test, and OCT findings. The specific details of these patients are shown in Table 1. The incidence of CQ retinopathy was 8.09% of the patients who used CQ over the 10 years considered. The risk factors are shown in Table 2. It was noted that only age, real body weight, and cumulative dose showed statistical significance at P<0.05. Moreover, other coexisting diseases, thyroid disease, heart disease, and anemia, in both the retinopathy-positive and the retinopathy-negative groups were recorded. Also, hepatitis B virus infection, nasopharyngeal carcinoma, pulmonary tuberculosis, Parkinson’s disease, and renal disease in the retinopathy-negative group were recorded. Unfortunately, the numbers of these diseases were too small to statistically compare the data.\n\nIn the HCQ group, 2 of 61 patients developed retinopathy; therefore, the incidence of HCQ retinopathy was 3.28% over the 10 years of the study. Both patients were also categorized as having “possible” toxicity as evidenced by indirect ophthalmoscopic examination, HVF test, and OCT findings. The specific details of these patients are shown in Table 3. The risk factors are shown in Table 4. Other underlying diseases such as thyroid disease, bulimia nervosa, anemia, hepatitis, rheumatic heart disease, and ischemic stroke were also noted in patients in the retinopathy-negative group. In contrast to CQ, no statistically significant hazard ratios of any items studied in the HCQ group were found. The incidence of CQ and HCQ retinopathy versus duration of medication use were analyzed via Kaplan–Meier survival analysis and are illustrated in Figures 1 and 2. It is noted that CQ retinopathy can occur as early as 4 months after drug use. Moreover, both CQ and HCQ retinopathy can develop within the first 3 years.\n\nDiscussion\nAccording to results of this study, the incidence of CQ retinopathy was 8.09% over 10 years. Back in the 19th century, CQ retinopathy was diagnosed by the appearance of bull’s eye maculopathy in patients taking CQ. This presentation indicated disease in the full-blown stage. As a result, the studies conducted on the disease yielded quite a very low prevalence of disease, 1 in 270.12 Currently, physicians tend to detect CQ retinopathy at an earlier stage on the basis of the revised AAO recommendations; therefore, most of recent studies showed higher prevalence rates ranging from 7.3% to 26.6%.9–12 The incidence from this study could not be compared directly with previous studies that reported the prevalence. According to the report of life expectancy in rheumatologic patients by Mok et al13 and understanding that the normal Thai population has an average life expectancy of 74.72 years,14 the prevalence of retinopathy in this study can be calculated from the incidence as being 14.9%, which was in agreement with the previous studies.9–12\n\nThe revised CQ and HCQ retinopathy screening recommendations of AAO stated that high-risk patients were those who used CQ longer than 5 years, or those who had a cumulative dose >460 g or a daily dose >250 mg/d or 2.3 mg/kg real weight/d, or those who were elderly or had concurrent liver or renal dysfunction.3,4 This current study seemed to agree with the recommendations that the elderly are at higher risk than younger patients, but the median age was less than 60 years. Chiowchanwisawakit et al, also demonstrated that the elderly (>60 years) had a significant association with CQ retinopathy.9 This was because their studied populations were only RA patients who were basically older than patients with other connective tissue diseases such as SLE or SS. However, Puavilai et al and Leecharoen et al reported no relationship between old age and CQ retinopathy.10,11 This might be because they included pediatric patients in their studies.\n\nTable 2 also shows that real body weight was one of the statistically significant risk factors for CQ retinopathy. However, the size of the difference was too small to indicate clinical significance. Regardless of the effect of dose per unit of body weight, no previous studies mentioned the relationship between body weight and occurrence of CQ retinopathy.\n\nThis study found no relationship between duration of CQ use and CQ retinopathy, whereas the revised recommendations of AAO concluded the opposite and recommended screening tests starting not earlier than 5 years of CQ use. Moreover, those patients in the CQ retinopathy-positive group developed the disease at a median time of 724 days (1.98 years), ranging from 139 to 2,033 days (0.38–5.57 years), and only one of them had used CQ for more than 5 years. Similar results were reported by Chiowchanwisawakit et al, Leecharoen et al, and Puavilai et al.9–11 The latter recommended screening tests to be done every 6 months after the baseline test. Surprisingly, the Kaplan–Meier analysis of CQ presented in Figure 1 revealed that CQ retinopathy mostly developed within the first 3 years after the patients started the medication and that no retinopathy was detected after 6 years. These results were in contrast to the AAO recommendations.\n\nDespite the fact that the present study showed a statistically significant relationship between the occurrence of CQ retinopathy and cumulative dose, the results were too small to be clinically significant. In addition, the cumulative dose these patients with CQ retinopathy received, 101.3 g (ranging from 14.3 to 325.1 g), was far less than 460 g recommendation of the AAO for the high-risk group. The daily dose of CQ retinopathy group in this study was 250 mg/d (averaged >4 mg/kg/d). Since the available CQ was manufactured as 250 mg tablets, the rheumatologist had to prescribe CQ at multiplicands of 250 mg doses, and therefore the dose was usually 250 mg/d. This is the reason no significant differences of daily doses in retinopathy in the retinopathy-negative group were found. Unfortunately, with a daily dose of 250 mg/d, most of the patients received CQ doses exceeding 2.3 mg/kg/d, which is the safe dose according to the AAO recommendations. This could be the reason CQ retinopathy in the Thai patients developed earlier and with a less cumulative dose than the previous studies conducted in Caucasian populations. Also, CQ binds to the melanin pigment of the RPE, which, perhaps, leads to toxicity and damage to RPE. Since Thai populations have more melanin pigment than Caucasians, CQ might accumulate more in the RPE than it would in the Caucasian eyes. There is currently no conclusive mechanism known for CQ retinopathy. The role of RPE and CQ binding to melanin pigment is still unclear and should be further investigated.\n\nAccording to the results of the present study, the incidence of HCQ retinopathy was 3.28% over 10 years, which was consistent with the results of a meta-analysis conducted in 2006, which concluded that the incidence of HCQ retinopathy ranged from 0% to 4%.15 A recent prospective study reported an incidence of only 0.65%.16\n\nNone of the risk factors showed statistical significance in the present study, as opposed to the revised AAO recommendations. A large prospective study, however, has shown consistent results with the current study of no significant risk factors.16 Aging showed no relation to the HCQ retinopathy in the patients. The participants diagnosed with HCQ retinopathy were 36 and 39 years old (median 37.5 years). As compared to the revised AAO recommendations, retinopathy developed at a younger age. Wolfe and Marmor,16 in a recent, large prospective study, showed no relation between aging and HCQ retinopathy.\n\nHCQ retinopathy developed in 2 patients who received HCQ for 660–828 days (1.81–2.27 years), a median of 744 days (2.04 years); not nearly reaching 5 years. It was mainly noted that there was no retinopathy found after 3 years. These 2 patients received the drug cumulatively from 80 to 130 g (median 105.1 g), which was far less than the 1,000 g of cumulative dose recommended by AAO. It can actually be seen that the there is a possible difference between the duration and daily dose of HCQ retinopathy and the retinopathy-negative patients, but the statistics fail to show the significance because of the small number of participants. Similar to the results of CQ, the patients seemed not to tolerate as high a HCQ dose as the AAO recommendations.\n\nPatients who developed HCQ retinopathy used HCQ at an average dose of 129.4–200 mg/d (median 164.7 mg/d). For the same reasons as with the CQ group, the daily dosages of not only patients who were retinopathy positive, but also those who were retinopathy negative tended to be approximately equal to the available dose of the HCQ tablet – 200 mg. Nevertheless, unlike the CQ group, the daily dose per real body weight of the patients who were HCQ retinopathy positive was only 1.9–4.4 mg/kg/d (median: 3.2 mg/kg/d), which was less than the daily dose recommended by the AAO. In this case, the lower body weight would not be a reasonable explanation for the patients developing retinopathy with less treatment duration and less cumulative dosages compared to Caucasians. The theory of correlation between HCQ binding to melanin pigment in RPE and its toxicity could be a possible explanation; hence, further studies on pathophysiology of the disease should be done in the future in order to understand these findings.\n\nStrength and limitations\nOne of the important aims of this study was to assess incidence of and risk factors for CQ and HCQ in Thai people. Surprisingly, many results that diverged from the AAO recommendations were found, highlighting the risk factors. These results could lead to further investigation and renewed guidelines for Asian people in the future. An obvious limitation of the study was that we used possible toxicity for diagnosis of CQ and HCQ retinopathy. These early findings may be nonspecific and misinterpreted. Since bull’s-eye retinopathy in patients with definite toxicity is a late irreversible finding, we had to report early toxicity and suggest all patients with possible toxicity to stop the medication before they reached the full-blown disease state. However, we improved the accuracy of diagnosis by using a combination of 3 diagnostic procedures and demonstrated both functional (HVF) and structural (OCT) changes. Another limitation was that this study was a retrospective study; also, the number of patients was too small in the HCQ group. It is recommended that further prospective studies on the same issue with larger sample sizes be pursued.\n\nConclusion\nThe incidence of CQ retinopathy was 8.09% over 10 years. There was a statistically significant relationship between age, real body weight, and cumulative dose in patients with retinopathy. It was found that the retinopathy could develop before 5 years and with a lower cumulative dose than 460 g. The daily dose exceeding 2.3 mg/kg/d could be the reason.\n\nThe incidence of HCQ retinopathy was 3.24% over 10 years. The study found no statistically significant relation between age, real body weight, duration of HCQ use, cumulative dose, and daily dose. A lack of sufficient patients in the study may have failed to prove the significance of risk factors.\n\nSince CQ and HCQ are essential drugs to control the effects of connective tissue diseases and the patients sometime need higher doses to control the diseases, it is suggested that patients taking long-term CQ or HCQ should undergo one baseline ophthalmologic screening examination at the first visit and annual screening thereafter. Moreover, the routine 250 mg CQ and 200 mg HCQ tablets should be used cautiously, or divided, especially in patients with low body weight.\n\nAcknowledgments\nThe authors thank Dr Kaewjai Thepsuthammarat, Clinical Epidemiology Unit, Faculty of Medicine, Khon Kaen University for statistical analysis and Professor James A Will, University of Wisconsin for assistance with the English-language presentation of the manuscript. This study was supported by invitation research grant (I 57215) from the Faculty of Medicine, Khon Kaen University.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Kaplan–Meier survival analysis of patients with CQ retinopathy.\n\nNote:\nY-axis represents patients who had not developed retinopathy and X-axis represents duration of CQ use.\n\nAbbreviation: CQ, chloroquine.\n\nFigure 2 Kaplan–Meier survival analysis of patients with HCQ retinopathy.\n\nNote:\nY-axis represents patients who had not developed retinopathy and X-axis represents duration of HCQ use.\n\nAbbreviation: HCQ, hydroxychloroquine.\n\nTable 1 Specific details of the patients with CQ retinopathy\n\nNumber\tAge (years)\tGender\tWeight (kg)\tUnderlying diseases\tRheumatologic diseases\tDuration (days)\tCumulative dose (g)\tCumulative dose/kg (g/kg)\tDaily dose/d (mg/d)\tDaily dose/kg/d (mg/kg/d)\t\n1\t63\tF\t48\tNo\tSS\t279\t32\t0.67\t114.69\t2.39\t\n2\t49\tM\t65\tNo\tRA\t140\t35\t0.54\t250\t3.85\t\n3\t54\tM\t54\tNo\tRA\t791\t191\t3.54\t241.47\t4.47\t\n4\t27\tF\t58\tNo\tRA\t897\t201\t3.47\t224.08\t3.86\t\n5\t59\tF\t55\tNo\tRA\t139\t14\t0.26\t100.72\t1.83\t\n6\t50\tF\t56\tThyroid\tSLE\t1,023\t263\t4.69\t257.09\t4.59\t\n7\t56\tM\t59\tNo\tSLE\t194\t41\t0.69\t211.34\t3.58\t\n8\t65\tM\t60\tDM, HT\tRA\t1,159\t302\t5.03\t260.57\t4.34\t\n9\t45\tF\t51\tNo\tSLE\t1,189\t139\t2.72\t116.91\t2.29\t\n10\t53\tF\t98\tDM, DL, CHF\tUCTD\t2,033\t325\t3.32\t159.86\t1.63\t\n11\t45\tF\t56\tNo\tSLE\t1,154\t64\t1.14\t55.46\t0.99\t\n12\t44\tM\t60\tNo\tCPA\t269\t63\t1.05\t234.2\t3.90\t\n13\t36\tF\t73\tNo\tSLE\t300\t75\t1.03\t250\t3.42\t\n14\t64\tM\t68\tNo\tRA\t657\t194\t2.85\t295.28\t4.34\t\nAbbreviations: CQ, chloroquine; F, female; M, male; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic scleroderma; CPA, chronic polyarthritis; UCTD, unspecified connective disease; DM, diabetes mellitus; HT, hypertension; DL, dyslipidemia; CHF, congestive heart failure.\n\nTable 2 Risk factors of CQ retinopathy\n\nRisk factors\tRetinopathy (N=14) median (min–max)\tNo retinopathy (N=159) median (min–max)\tHazard ratio\tP-value\t\nAge (years)\t53 (27–65)\t44 (15–78)\t1.06 (1.00–1.12)\t0.04\t\nAge >60 yearsa\t3\t16\t2.98 (0.82–10.73)\t0.10\t\nGender (male)a\t6\t37\t1.68 (0.55–5.14)\t0.36\t\nReal weight (kg)\t57 (48–98)\t53 (36–80)\t1.05 (1.00–1.10)\t0.04\t\nHypertensiona\t1\t6\t1.07 (0.14–8.24)\t0.95\t\nDiabetes mellitusa\t2\t8\t1.83 (0.24–13.89)\t0.56\t\nDyslipidemiaa\t1\t3\t2.22 (0.29–17.45)\t0.44\t\nDuration (days)\t724 (139–2,033)\t397 (17–3,307)\t–\t0.60\t\nDuration >5 years\t1\t25\t–\t0.39\t\nCumulative dose (g)\t101.3 (14.3–325.1)\t91.5 (6–1,111.1)\t0.99 (0.98–1.00)\t0.03\t\nCumulative dose >460 g\t0\t6\t–\t–\t\nDaily dose (mg/d)\t250 (46.8–250)\t234 (54.3–500)\t1.00 (0.99–1.01)\t0.50\t\nDaily dose >250 mg/d\t0\t3\t–\t–\t\nDaily dose/RW (mg/kg/d)\t4.2 (0.8–18.5)\t4.2 (0.83–25.64)\t1.03 (0.92–1.16)\t0.58\t\nDaily dose/RW >2.3 mg/kg/d\t9\t126\t1.27 (0.42–3.81)\t0.67\t\nNote:\n\na Data are shown in numbers.\n\nAbbreviations: CQ, chloroquine; RW, real weight; min, minimum; max, maximum.\n\nTable 3 Specific details of the patients with HCQ retinopathy\n\nNumber\tAge (years)\tGender\tWeight (kg)\tUnderlying diseases\tRheumatologic diseases\tDuration (days)\tCumulative dose (g)\tCumulative dose/kg (g/kg)\tDaily dose/d (mg/d)\tDaily dose/kg/d (mg/kg/d)\t\n1\t36\tF\t45\tRHD\tSLE\t828\t130.2\t2.89\t157.25\t3.49\t\n2\t39\tF\t68\tAIHA\tSLE\t660\t80\t1.18\t121.21\t1.78\t\nAbbreviations: HCQ, hydroxychloroquine; F, female; SLE, systemic lupus erythematosus; RHD, rheumatic heart disease; AIHA, autoimmune hemolytic anemia.\n\nTable 4 Risk factors of HCQ retinopathy\n\nRisk factors\tRetinopathy (N=2) median (min–max)\tNo retinopathy (N=59) median (min–max)\tHazard ratio\tP-value\t\nAge (years)\t37.5 (36–39)\t43 (18–72)\t0.99 (0.89–1.09)\t0.80\t\nAge >60 years\t0\t6\t–\t–\t\nGender (male)a\t0\t8\t–\t–\t\nReal weight (kg)\t56.5 (45–68)\t54 (33–73)\t1.04 (0.90–1.20)\t0.62\t\nHypertensiona\t0\t2\t–\t–\t\nDiabetes mellitusa\t0\t2\t–\t–\t\nDyslipidemiaa\t0\t1\t–\t–\t\nDuration (days)\t744 (660–828)\t331 (18–3,052)\t1.48 (0.72–3.07)\t0.53\t\nDuration >5 years\t0\t1\t–\t–\t\nCumulative dose (g)\t105.1 (80–130)\t77.6 (8.4–375.6)\t1.00 (0.98–1.01)\t0.62\t\nCumulative dose >1,000 g\t0\t0\t–\t–\t\nDaily dose (mg/d)\t164.7 (129.4–200)\t200 (40.22–500)\t1.00 (0.98–1.02)\t0.86\t\nDaily dose >400 mg/d\t0\t1\t–\t–\t\nDaily dose/RW (mg/kg/d)\t3.2 (1.9–4.4)\t3.8 (0.7–9.8)\t0.93 (0.35–2.53)\t0.89\t\nDaily dose/RW >5 mg/kg/d\t0\t6\t–\t–\t\nNote:\n\na Data are shown in numbers.\n\nAbbreviations: HCQ, hydroxychloroquine; RW, real weight; min, minimum; max, maximum.\n==== Refs\nReferences\n1 Browning DJ Pharmacology of chloroquine and hydroxychloroquine Browning DJ Hydroxychloroquine and Chloroquine Retinopathy New York, NY Springer Science+Business Media 2014 35 63 \n2 American Academy of Ophthalmology Basic Science and Clinical Course 2013–2014 Retina and Vitreous San Francisco, CA FSC 2013 266 267 \n3 Marmor MF Kellner U Lai TY Lyons JS Mieler WF American Academy of Ophthalmology Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy Ophthalmology 2011 118 2 415 422 21292109 \n4 Marmor MF Kellner U Lai TY Melles RB Mieler WF American Academy of Ophthalmology Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision) Ophthalmology 2016 123 1386 1394 26992838 \n5 Elman A Gullberg R Nilsson E Chloroquine retinopathy in patients with rheumatoid arthritis Scand J Rheumatol 1976 5 161 166 981992 \n6 Easterbrook M Long term case of antimalarial toxicity after cessation of treatment Can J Ophthalmol 1992 27 237 239 1393809 \n7 Levy GD Munz SJ Paschal J Incidence of hydroxychloroquine retinopathy in a large multicenter outpatient practice Arthritis Rheum 1997 40 1482 1486 9259429 \n8 Wolfe F Marmor MF Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus Arthritis Care Res (Hoboken) 2010 62 775 784 20535788 \n9 Chiowchanwisawakit P Nilganuwong S Srinonprasert V Prevalence and risk factors for chloroquine maculopathy and role of plasma chloroquine and desethylchloroquine concentrations in predicting chloroquine maculopathy Int J Rheum Dis 2013 16 1 47 55 23441772 \n10 Puavilai S Kunavisarut S Vatanasuk M Ocular toxicity of chloroquine among Thai patients Int J Dermatol 1999 38 12 934 937 10632778 \n11 Leecharoen S Wangkaew S Louthrenoo W Ocular side effects of chloroquine in patients with rheumatoid arthritis, systemic lupus erythematosus and scleroderma J Med Assoc Thai 2007 90 1 52 58 17621733 \n12 Elman A Gullberg R Nilsson E Rendahl I Wachtmeister L Chloroquine retinopathy in patients with rheumatoid arthritis Scand J Rheumatol 1976 5 3 161 166 981992 \n13 Mok CC Kwok CL Ho LY Chan PT Yip SF Life expectancy, standardized mortality ratios, and cause of death in six rheumatic disease in Hong Kong, China Arthritis Rheum 2011 63 5 1182 1189 21391198 \n14 The World: Life expectancy 2016 – [cited 2016 Mar 10] Available from: http://www.geoba.se/ \n15 Yam JC Kwok AK Ocular toxicity of hydroxychloroquine Hong Kong Med J 2006 12 4 294 304 16912357 \n16 Wolfe F Marmor MF Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus Arthritis Care Res (Hoboken) 2010 62 6 775 784 20535788\n\n",
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"title": "Incidence of and risk factors for chloroquine and hydroxychloroquine retinopathy in Thai rheumatologic patients.",
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"abstract": "The tragic case of Mayra Cabrera who died as a result of wrong route drug administration is notable as it was the first time a verdict of unlawful killing was recorded against an NHS Trust. Error within medicine is a significant cause of patient morbidity and mortality. We explore the costs of error, the dynamics of error causation, the role of both the individual and institution in accountability for error, as well as transferrable lessons from other industries to reduce error.",
"affiliations": "Frimley Health NHS Foundation Trust, Wexham Park Hospital, Slough, UK.;Frimley Health NHS Foundation Trust, Wexham Park Hospital, Slough, UK.",
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"title": "Classic cases revisited - Death of a nurse and the anatomy of error.",
"title_normalized": "classic cases revisited death of a nurse and the anatomy of error"
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"abstract": "The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late-stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first-line treatment in CLL) is not effective in removing the 2p+ clone - even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow-up is now required to evaluate bendamustine-rituximab, ibrutinib, and idelalisib-rituximab treatments.",
"affiliations": "Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Gustave Roussy, INSERM U1170, Université Paris-Saclay, Villejuif, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie Cellulaire, Université Clermont Auvergne, Clermont-Ferrand, France.;Gustave Roussy, INSERM U1170, Université Paris-Saclay, Villejuif, France.;INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Paris, France.;Service d'Hématologie Clinique et de Thérapie Cellulaire, Université Clermont Auvergne, Clermont-Ferrand, France.;Service d'Hématologie Biologique, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.",
"authors": "Kostopoulou|Fotini|F|;Gabillaud|Clementine|C|;Chapiro|Elise|E|0000-0003-3427-7596;Grange|Beatrice|B|0000-0001-6613-9302;Tran|Julie|J|;Bouzy|Simon|S|;Degaud|Michael|M|;Ghamlouch|Hussein|H|0000-0002-2932-1081;Le Garff-Tavernier|Magali|M|;Maloum|Karim|K|;Choquet|Sylvain|S|;Leblond|Veronique|V|;Gabarre|Jean|J|;Lavaud|Anne|A|;Morel|Veronique|V|;Roos-Weil|Damien|D|0000-0002-7767-755X;Uzunov|Madalina|M|;Guieze|Romain|R|;Bernard|Olivier A|OA|;Susin|Santos A|SA|;Tournilhac|Olivier|O|;Nguyen-Khac|Florence|F|0000-0003-3107-6668;|||",
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"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 3106621410.1002/cam4.2123CAM42123Original ResearchCancer BiologyOriginal ResearchGain of the short arm of chromosome 2 (2p gain) has a significant role in drug‐resistant chronic lymphocytic leukemia KOSTOPOULOU et al.Kostopoulou Fotini \n1\n\n2\nGabillaud Clementine \n1\nChapiro Elise http://orcid.org/0000-0003-3427-7596\n1\n\n3\nGrange Beatrice http://orcid.org/0000-0001-6613-9302\n1\nTran Julie \n1\nBouzy Simon \n1\nDegaud Michael \n1\nGhamlouch Hussein http://orcid.org/0000-0002-2932-1081\n4\nLe Garff‐Tavernier Magali \n1\n\n3\nMaloum Karim \n1\nChoquet Sylvain \n5\nLeblond Veronique \n5\nGabarre Jean \n5\nLavaud Anne \n5\nMorel Veronique \n5\nRoos‐Weil Damien http://orcid.org/0000-0002-7767-755X\n5\nUzunov Madalina \n5\nGuieze Romain \n6\nBernard Olivier A. \n4\nSusin Santos A. \n3\nTournilhac Olivier \n6\nNguyen‐Khac Florence http://orcid.org/0000-0003-3107-6668florence.nguyen-khac@psl.aphp.fr \n1\n\n3\nthe French Innovative Leukemia Organization (FILO) group \n1 \nService d‘Hématologie Biologique\nSorbonne Université\nHôpital Pitié‐Salpêtrière\nAPHP\nParis\nFrance\n\n2 \nMolecular Diagnostics Laboratory\nKARYO Ltd\nThessaloniki\nGreece\n\n3 \nINSERM U1138\nCentre de Recherche des Cordeliers\nSorbonne Université\nParis\nFrance\n\n4 \nGustave Roussy\nINSERM U1170\nUniversité Paris‐Saclay\nVillejuif\nFrance\n\n5 \nService d'Hématologie Clinique\nSorbonne Université\nHôpital Pitié‐Salpêtrière\nAPHP\nParis\nFrance\n\n6 \nService d'Hématologie Clinique et de Thérapie Cellulaire\nUniversité Clermont Auvergne\nClermont‐Ferrand\nFrance\n* Correspondence\n\nFlorence Nguyen‐Khac, Hôpital Pitié‐Salpêtrière, 83 Boulevard de l'Hôpital, F‐75013 Paris, France.\n\nEmail: florence.nguyen-khac@psl.aphp.fr\n07 5 2019 6 2019 8 6 10.1002/cam4.2019.8.issue-63131 3141 14 12 2018 07 2 2019 12 3 2019 © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nThe different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy‐chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late‐stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first‐line treatment in CLL) is not effective in removing the 2p+ clone ‐ even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow‐up is now required to evaluate bendamustine‐rituximab, ibrutinib, and idelalisib‐rituximab treatments.\n\n2p gainchronic lymphocytic leukemiadrug resistanceGEFLUC2017CURAMUSINCA‐DGOS‐Inserm_12560Association Laurette FugainALF 14/08Fondation ARC pour la Recherche sur le CancerSFI20111203530Roche Diagnostics2017 source-schema-version-number2.0component-idcam42123cover-dateJune 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:10.07.2019\n\n\nKostopoulou \nF \n, \nGabillaud \nC \n, \nChapiro \nE \n, et al.; on behalf of the French Innovative Leukemia Organization (FILO) group \n. Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug‐resistant chronic lymphocytic leukemia . Cancer Med . 2019 ;8 :3131 –3141 . 10.1002/cam4.2123 \n31066214 \n\n\nFK and CG contributed equally to this work\n==== Body\n1 INTRODUCTION\nChronic lymphocytic leukemia (CLL, the most common lymphoproliferative disorder among elderly adults in Western countries) is characterized by the progressive accumulation of mature CD5+ B lymphocytes in the bone marrow, peripheral blood, and secondary lymphoid organs. The prevalence of CLL increases with age, and its clinical profile ranges from CLLs that may not require treatment to others that progress aggressively.1 In addition to conventional immunochemotherapies (such as fludarabine‐cyclophosphamide‐rituximab [FCR] and bendamustine‐rituximab [BR]), a number of novel drugs have significantly modified the treatment strategies in this disease; they include kinase inhibitors (ibrutinib and idelalisib, targeting Bruton's tyrosine kinase and phosphatidyl‐inositol 3‐kinase, respectively), and an antagonist of the antiapoptotic Bcl‐2 protein (venetoclax).2\n\n\nGenetic alterations (such as gains and losses of chromosomal regions) have prognostic value in CLL, due to their significant impact on the drug response and overall survival (OS).1, 3 Hence, these alterations should be taken into account when defining personalized treatments.1 The most frequent genetic abnormalities in CLL (deletions [del] of 11q, 13q, and 17p, and trisomy [tri] 12) have been extensively studied; del(17p) (which is tightly linked to TP53 mutation) is associated with the worst prognosis.3, 4 Although del(17p) and/or a TP53 mutations are found in up to 40% or 50% of patients with relapsing or refractory CLL, other genetic abnormalities may also be associated with drug resistances.5, 6 Several recurrent mutations have been described in CLL (in around 20% of patients) but cannot account for all the observed resistance.7 Lastly, a complex karyotype (CK) (observed in fewer than 20% of patients with CLL) might be associated with poor prognosis.8 It is therefore essential to understand the role of each recurrent genomic abnormality in the development and outcome of CLL, in order to assess individual risk factors. Furthermore, each genomic abnormality may create abnormal and potentially druggable activities.\n\nWe and others have previously reported that the gain of the short arm of chromosome 2 (2p+) is recurrent and frequent in late‐stage CLL (corresponding to about 15% of patients).9, 10, 11, 12 However, this abnormality is rarely analyzed specifically in clinical trials or in routine clinical practice. The 2p+ is associated with markers of a poor prognosis, such as 11q deletion and unmutated immunoglobulin heavy‐chain variable region gene (IGHV) status. Moreover, we have shown that the gene coding for exportin 1 (XPO1, located in 2p) has a central role in drug resistance in 2p+ CLL.12, 13 However, as the whole short arm of chromosome 2 is often gained in patients with 2p+ CLL, other known proto‐oncogenes located in the same region (such as REL and MYCN) might also be associated with CLL drug resistance.9, 10, 11, 12, 13\n\n\nWith a view to gaining a better understanding of prognostic and drug resistance factors in CLL, we have evaluated the role of 2p+ in disease progression and its response to treatment.\n\n2 METHODS\n2.1 Cases of CLL\nWe retrospectively collected data on 47 patients with 2p+ CLL, all of whom were diagnosed and/or treated at Pitié‐Salpêtrière Hospital (Paris, France) between 1990 and 2018. We also included 17 patients with 2p+ CLL who had been included and prospectively assessed by other centers as part of the ICLL1 BOMP trial (ClinicalTrials.gov identifier: NCT01612988).5 The diagnosis of CLL was based on lymphocytosis and immunophenotyping, according to the International Workshop on Chronic Lymphocytic Leukemia criteria.1 Patients with CLL were routinely examined for their IGHV status. Longitudinal cytogenetic analyses (ie at least two samples over time) were available for 26 of the 64 patients included in the study. In line with the ethical tenets of the Declaration of Helsinki, all the patients provided their informed consent to participation in the study. The study protocol was approved by the local investigational review board (CPP Ile de France VI, Paris, France) on 21 May 2014.\n\n2.2 Karyotyping and fluorescence in situ hybridization\nTo obtain R‐banded chromosomes, cells from peripheral blood samples were stimulated with CpG‐oligonucleotides and interleukin‐2 (IL‐2) in culture for 72 hours, using standard techniques.14 All Ks were described according to the International System for Human Cytogenetic Nomenclature (ISCN) 2016. Complex Ks were defined as the presence of three or more numerical or structural chromosomal abnormalities, and highly complex Ks (HCKs) were defined as the presence of five or more abnormalities.15\n\n\nFluorescence in situ hybridization (FISH) was performed on metaphase and interphase nuclei, using the following panel of probes: MYCN (Abbott, Rungis, France), TP53/ATM (Cytocell Ltd, UK), LSI D13S319/12cen (Metasystems, Altlusshein, Germany), and “home‐grown” bacterial artificial chromosome probes for the XPO1 (RP11‐240F4+RP11‐477N2), REL (RP11‐373L24) and BIRC3 (RP11‐177O8) genes were selected using the University of California Santa Cruz Genome Bioinformatic database (NCBI37/hg19 build) and obtained from Genoscope (Evry, France). Results were recorded using a fluorescent microscope (Olympus) with appropriate filters, and Isis imaging software (Metasystems, Heidelberg, Germany). All FISH preparations were scored by two independent assessors, with at least two independent counts of 100 nuclei/probe/assessor.\n\n2.3 Single nucleotide polymorphism array analysis\nSingle nucleotide polymorphism (SNP) array analyses were performed as described previously.13\n\n\n2.4 Mutations in TP53\n\nFor patients with more than one sample, TP53 mutations were analyzed using: (a) Sanger sequencing of exons 4‐10 (n = 2); (b) next‐generation sequencing on a MiSeq® system (Illumina, San Diego, CA) using the CLL MASTR PLUS kit (Agilent, Santa Clara, CA) (n = 6); or (c) as previously described in the report on BOMP trial (n = 11).5\n\n\n2.5 Statistical analysis\nThe time to first treatment (TTFT) was defined as the time interval between diagnosis and first‐line treatment. The OS time was defined as the time interval between diagnosis and death or (in the absence of death) last follow‐up. OS was analyzed using the Kaplan‐Meier method. The log‐rank test was used for intergroup comparisons of TTFT or OS curve. The variables analyzed were CK, HCK, del(13q), del(11q), IGHV mutation status, XPO1/REL/MYCN gain (homogeneous gain vs heterogeneous gain). Quantitative variables were reported as the median (range) or the median [95% confidence interval (CI)], and categorical variables were reported as the number (percentage).\n\n3 RESULTS\n3.1 Characteristics of the study population\nA total of 64 patients with 2p+ CLL were included in the study. Most of the patients were male (51 out of 64, 80%), and the median (range) age at diagnosis was 60 (42‐78) (Table S1). Of the 63 patients with available data, 41 (65%) had not been treated before karyotyping; the median (range) time between diagnosis and karyotyping was 5 months (0‐88). The Binet stage was known for 36 of these 41 untreated patients, with four (11%) stage A cases, 27 (75%) stage B cases, and five (14%) stage C cases. The IGHV status was unmutated in 50 of the 56 tested patients (89%).\n\nThe median (range) number of lines of treatment was two (0‐8). Twenty‐eight of the 64 patients (44%) died during the study period, with a median follow‐up from diagnosis of 79 months (0‐317). At last follow‐up, 61 of the 62 patients with available data (98%) had been treated (Table S1).\n\nAll 64 patients had a 2p+ (as evidenced by FISH and/or SNP array analysis), and 53 of them had been successfully karyotyped. Seven of these 53 patients (13%) had a normal karyotype (K), and 28 (53%) had a CK, including 14 (26%) HCKs. The results were similar when we considered only the 35 patients who had not been treated before karyotyping (Figure 1A, Table S1, and Figure S1).\n\nFigure 1 A, Distribution of chromosomal abnormalities in 64 patients with 2p+ CLL. Each column represents a patient, and each row represents a parameter. Color code: gray, absence; black or other colors, presence; white, not available. CK: complex karyotype, defined as three or more chromosomal abnormalities; HCK: highly complex karyotype, defined as five or more chromosomal abnormalities; Un‐IGHV: unmutated IGHV. B, Description of longitudinal samples for 26 patients with 2p+ CLL. FCR: fludarabine/cyclophosphamide/rituximab; BR: bendamustine‐rituximab; BOMP: bendamustine/ofatumumab and methylprednisolone\n\nThe 2p+ could be clearly identified by R‐banding in 17 of the 53 (32%) Ks (Table S2); it was never the sole abnormality, and was present in the main clone in ten of the 17 cases (59%), in a subclone in four cases (24%), and in an independent clone in three cases (18%). It is noteworthy than when the 2p+ was subclonal, it occurred after 11q deletion. The gain of 2p material was due to a duplication in the short arm of chromosome 2 in four of the 17 cases (24%), while an isochromosome 2p was present in one case. In the remaining cases, 2p was attached to different chromosomes (chromosomes 8, 11, 18, 20, and 22). The most frequent partner chromosome was chromosome 18 (five out of 17, 29%) (Tables S1 and S2).\n\nUsing FISH and/or an SNP array, del(13q) was identified in 39 of the 64 patients (61%), del(11q) in 34 (53%), del(17p) in 16 (25%), and tri12 in two (3%). When considering only the patients who had not been treated before analysis, the results were quite similar (Figure 1A, and Tables S1 and S2).\n\nTo investigate the three main genes located on the short arm of chromosome 2 (MYCN [2p24], REL [2p16] and XPO1 [2p15]), we performed a locus‐specific FISH analysis of the 48 patients with available material (Table S2). The median (range) percentage of cells with 2p+ was 40% (8%‐96%). In 42 of the 47 cases (89%), there were three copies of the gained genes. In five cases, we observed a mixture of cells with three, four, or five copies. Interestingly, we found discrepancies between the three gene loci. To rule out variations due to the technical limitations of FISH, we considered that a difference of more than 20% in the 2p+ cell count was a marked change—unless a gain was not detected for one gene or if the same differences were observed in the longitudinal analysis (Figure S2A). Most cases (38 out of 48, 79%) had a homogeneous gain of the three genes, whereas the two regions (2p15‐16 and 2p24) were not gained in the same manner in the remaining ten patients (21%). In the latter cases, the percentages of cells with XPO1 and REL gains were always correlated, whereas the percentage of cells with an MYCN gain differed. More specifically, chromosomal region 2p15‐16 (XPO1/REL) was gained in a higher proportion of tumor cells than the 2p24 region (MYCN) in eight of the 48 patients (17%). In five of these eight patients, a gain of the MYCN gene was not detected at all. Only two (4%) patients had a higher percentage of cells having gained the 2p24 region (including MYCN gene) than cells having gained the region 2p15‐16 (including the XPO1 and REL genes).\n\nGiven that BIRC3 was recently reported to be involved in the 11q deletion, we performed FISH using two specific probes (encompassing either ATM or BIRC3) for 50 patients.16 We found that 24 of the 50 cases (48%) had an ATM deletion, and 20 of these 24 cases (83%) had a BIRC3 deletion. In four of the 24 cases (25%), we observed the deletion of ATM alone, while none of the patients had a BIRC3 deletion alone. The percentages of cells with a deletion were similar for both genes in all cases. The median (range) percentage of cells with a deletion was 71% (11%‐99%) (Figure S2B).\n\n3.2 Time to first treatment and overall survival\nThe median TTFT was 16 months; the median OS time was 124 months (Table S1). In a univariate analysis, the only parameter associated with significantly shorter TTFT was the del(17p) (2.5 vs 22 months in 2p+ CLL with or without del(17p), respectively; P = .04). There were no statistically significant differences in the impact on OS for all the analyzed parameters (Table S3).\n\n3.3 Patients with more than one cytogenetic analysis (n = 26)\nWe were able to perform a longitudinal cytogenetic analysis for 26 patients with 2p+ CLL (Figure 1B). All 26 had received treatment, with a median (range) follow‐up time of 90 months (25‐317). The median [95% CI] TTFT was 23.5 months [12‐43]. Ten of the 26 CLL (38%) patients with 2p+ died during the study period; the median [95% CI] OS time was 164 months [114‐not reached]. For the 17 patients with available data, the 2p+ was observed before treatment in 13 (77%) cases and after treatment in four cases (23%). It is noteworthy that none of the 15 patients lacking a 17p deletion had a TP53 mutation.\n\nWe next analyzed the change in the 2p+ clone and recurrent chromosomal abnormalities in patients treated with a panel of drugs (Table 1). To exclude variations related to the technical limitations of FISH, we considered that a difference of more than 20% in the number of 2p+ cells was a marked change between pretreatment and relapse, except when a clone was no longer detected or when we were able to perform a valid comparison with other clones. The proportion of cells with MYCN/REL/XPO1 gains remained stable in all but one patient (CLL_58), in whom a MYCN gain was detected at relapse (XPO1 and REL had been gained before treatment). The median (range) number of lines of treatment was two (1‐8), and the patients were assessed in detail as a function of the drugs included in each treatment regimen.\n\nTable 1 Change over time in the 2p+ clone after various treatments\n\nTreatment\tPrior lines of treatment\t2p+ before treatment\tCK (>3) before treatment\tdel(17p) before treatment\t\nTP53 mutd before treatment\tdel(11q) before treatment\tUn‐IGHV\n\tTime to next 2p+ evaluation\tDisease status when the second sample was collected\tDecrease in 2p+\tStable 2p+\tIncrease in 2p+\t\n\nPatients not treated when 2p+ was first detected\n\t\nFCR n = 5\t0\t5/5\t1/3\t0/5\t0/3\t3/5\t4/4\tMedian (range): 45 m (32 m‐59 m)\trelapse\t0\t3\t2\t\nBR n = 1\t0\t1/1\t1/1\t0/1\t0/1\t1/1\tna\t26 m\trelapse\t0\t1\t0\t\n\nPatients already treated when 2p+ was first detected\n\t\nFCR n = 2\t0‐1\t1/2\t0/1\t0/2\t0/1\t1/2\t0/1\t26 m‐29 m\trelapse\t0\t1\t1a\n\t\nBR n = 2\t1\t2/2\t1/2\t0/2\t0/2\t2/2\t1/1\t3 m‐7 m\tremission\t2\t0\t0\t\nBOMP n = 11\t1‐3\t10/11\t4/10\t5/11\t5/11\t8/11\t11/11\tMedian (range): 14 m (5 m‐62 m)\trelapse\t4b\n\t4\t3c\n\t\nIbrutinib n = 5\t1‐6\t5/5\t3/5\t3/5\t2/3\t1/5\t3/4\tMedian (range): 11 m (5 m‐20 m)\tnormal/decreased lymphocytosis (n = 4)/relapse (n = 1)\t2\t3\t0\t\nIdelalisib + R n = 2\t2\t2/2\t2/2\t2/2\tna\t0/2\t2/2\t13‐16 m\tpartial remission (n = 1)/relapse (n = 1)\t0\t2\t0\t\nCK: complex karyotype > 3 chromosomal abnormalities; na: not available; Un, unmutated.\n\na The 2p gain appeared after FCR treatment (CLL_1).\n\nb In one case (CLL_43), the 2p gain was no longer detected.\n\nc In one case (CLL_5), the 2p gain appeared after BOMP treatment.\n\nd No cases with a TP53 mutation (mut) but no del(17p).\n\nJohn Wiley & Sons, Ltd3.4 Longitudinal analysis after first‐line immunochemotherapy\n3.4.1 Fludarabine/cyclophosphamide/rituximab\nSixteen of the 19 patients treated with FCR in the longitudinal subgroup relapsed, after a median (range) time interval between the end of treatment and relapse of 24 months (5.4‐78); the other three patients have not finished their course of treatment. Cytogenetic data before front line FCR and at relapse (evaluation pre‐next treatment) were available for six patients (Table 1).\n\nIn two patients (CLL_37 and CLL_40), the percentage of 2p+ cells was stable at relapse. Furthermore, the clone del(13q) remained large and stable in one patient (CLL_40) but could no longer be detected in the other (CLL_37). The clone del(11q) also remained large and stable in both patients; the deletion encompassed ATM and BIRC3 in one patient (CLL_37), and ATM only in the other (CLL_40). In patient CLL_40, del(17p) was detected after FCR treatment, along with a HCK (Figure 2A).\n\nFigure 2 Treatment of 2p+ CLL with FCR (n = 7) (A, B) or BR (n = 3) (C, D). A and B, Samples before treatment and at relapse (ie, the evaluation before the next treatment). Before relapse, all the patients achieved complete remission after FCR. With the exception of one patient (CLL_53), FCR was the first‐line treatment. The time interval between the first day of treatment and the cytogenetic analysis at relapse is indicated below each graph. A, The 2p+ clone remained stable at relapse after FCR therapy. Patient CLL_53 underwent a splenectomy and received chlorambucil before FCR. B, After FCR therapy, the 2p+ clone increased at relapse. In CLL_1, the 2p+ clone appeared after FCR treatment. After FCR treatment, none of the patients displayed a reduction of the size of the 2p+ clone at relapse. C, After first‐line treatment with BR, the 2p+ was stable at relapse. D, After second‐line treatment with BR. In patient CLL_37, the abnormal clones were transiently negative for 2p+. The frequency of the 2p+ clone decreased but was still detected in the two patients in complete remission. Abs: abnormalities; CK: complex karyotype\n\nIn four patients, the number of 2p+ cells had increased (by a factor of 1.5‐2) at relapse. The del(13q) remained stable in one of these patients (CLL_32) but disappeared in a second (CLL_42) (Figure 2B). Two patients (CLL_12, CLL_1) had a clone with del(11q), including both ATM and BIRC3. In patient CLL_12, the frequency of 2p+ and del(11q) had doubled after FCR treatment. Interestingly, del(11q) was detected at diagnosis in patient CLL_1; the 2p+ appeared after treatment (along with del(17p) and CK) but the del(11q) disappeared (Figure 2B).\n\n3.4.2 Bendamustine‐rituximab\nOne patient received first‐line treatment with BR. After clinical remission, he relapsed at 26 months; the clones 2p+ and del(11q) were stable but a del(13q) clone appeared (Table 1 and Figure 2C).\n\n3.5 Longitudinal analysis after post‐relapse immunochemotherapy\n3.5.1 Fludarabine/cyclophosphamide/rituximab\nOne patient (CLL_53) underwent splenectomy, and received chlorambucil and then FCR. The percentage of cells with 2p+ and del(13q) remained stable at the time of relapse (Table 1 and Figure 2A). Overall, after FCR treatment, none of the patients displayed a reduction in the 2p+ clone at relapse (Table 1 and Figure 2A,B).\n\n3.5.2 Bendamustine‐rituximab\nTwo patients with available cytogenetic data were treated with BR after one course of FCR (Table 1 and Figure 2D). They were both in clinical remission after 3 and 7 months, although persistent clonal abnormalities were still present in peripheral blood cells including 2p+ (even though the abnormal clones were transiently negative in patient CLL_37).\n\n3.5.3 Bendamustine/ofatumumab and methylprednisolone (BOMP)\nA total of 17 of the 64 patients were included in the BOMP trial, including one patient with a detectable 2p+ clone at relapse. All of them relapsed, with a median (range) time from inclusion to relapse of 13 months (5.4‐38.2). Cytogenetic data before BOMP treatment and at relapse (at an evaluation prior to selection of the following treatment) were available for 11 patients (Table 1). At relapse after the course of BOMP, the 2p+ decreased or disappeared in four patients (Figure 3A). It is noteworthy that the percentage of 2p+ cells was below 5% in two patients. The percentage remained stable in four other patients (Figure 3B). In three cases, BOMP therapy resulted in an increase in the 2p+. One of the three (CLL_5) did not display the clone before BOMP treatment (Figure 3C). Most FISH abnormalities were stable at relapse (four out of four del[13q], four out of five del[17p], and six out of eight del[11q]). Five of the eight cases with del(11q) included ATM and BIRC3. Of the two cases (CLL_59, CLL_58) with an elevated del(11q) clone at relapse, the deletion involved ATM alone in CLL_59 only. The number of karyotype abnormalities increased in five of the seven patients with available data.\n\nFigure 3 Treatment of patients with 2p+ CLL (n = 11) with BOMP. Only two patients (CLL_59 and CLL_29) were in complete remission after the BOMP therapy. A, At relapse, the size of the 2p+ clone had decreased in four patients, including one patient with no detectable 2p+ cells (CLL_43). The percentage of 2p+ cells was below 5% in two patients (CLL_59, CLL_34). B, The 2p+ clone was stable in four patients. C, The size of the 2p+ clone increased in three patients, including one patient with a detectable clone at relapse only (CLL_5). Abs: abnormalities; CK: complex karyotype\n\n3.6 Longitudinal analysis after post‐relapse treatment with a kinase inhibitor\n3.6.1 Ibrutinib\nFive patients with available cytogenetic data received ibrutinib, after 1‐6 other lines of treatment (Table 1). After 11 and 10 months, CLL_42 and CLL_1 were in clinical remission, and showed a reduction (according to FISH) in the percentage of cells with 2p+ (Figure 4A). The percentage of cells with 2p+ remained stable in the other patients (as evidenced by karyotyping and FISH) after five (CLL_53), 20 (CLL_20), and 15 (CLL_40) months (Figure 4B). The patient CLL_40 relapsed at 15 months, and the patient CLL_53 died 6 months after the last cytogenetic analysis. The clone del(17p) fell by 50% in one patient (CLL_1) and remained stable in the other cases (CLL_20, CLL_40). The del(11q) involving ATM only persisted in CLL_40, as was also the case during the other treatments (FCR and BOMP). It is noteworthy that even though three patients were in clinical remission (CLL_42, CLL_1, and CLL_20), the abnormalities were still present in karyotyping and FISH analysis.\n\nFigure 4 2p+ CLL treated with ibrutinib (n = 5) (A, B) and idelalisib‐rituximab (n = 2) (C). A, The size of the 2p+ clone decreased but was still detectable in patients in complete remission (CLL_42, CLL_1) after ibrutinib treatment. B, With ibrutinib, the size of the 2p+ clone was stable during follow‐up, even for a patient in complete remission (CLL_20). C, With idelalisib + R, the size of the 2p+ clone was stable at relapse for both patients. Abs: abnormalities; CK: complex karyotype\n\n3.6.2 Idelalisib‐rituximab (idelalisib‐R)\nTwo patients with available cytogenetic data were treated with idelalisib‐R after two other lines of treatment (Table 1). In patient CLL_3, lymphocytosis increased (up to 62 G/l) after a partial remission, and the patient died 4 months after the last cytogenetic analysis (9 years after diagnosis). Patient CLL_20 relapsed after 16 months. For both patients, the 2p+ clone was stable at relapse (Figure 4C).\n\nLastly, regarding the clonal outcome of the del(11q), the different treatment groups did not differ in terms of whether del(11q) encompassed ATM alone or both ATM and BIRC3 (Table S4). The size of the deletion (whether encompassing one or two genes) remained stable during the course of the disease.\n\n4 DISCUSSION\nHere, we presented a detailed cytogenetic analysis of what is (to the best of our knowledge) the largest yet cohort of patients with 2p+ CLL (n = 64). A longitudinal analysis was possible in 26 cases (ie patients with more than one sample collected over the course of the disease). Our first key observation was that the male‐to‐female ratio (3.9:1) is higher than the one reported for CLL in general (1.5‐2:1).17 We therefore confirmed Jarosova et al.'s report of male predominance in 2p+ CLL.18 We also corroborated our previous report whereby 2p gain is frequent in untreated, late‐stage CLL (32 of the 36 cases [89%] of Binet stage B/C CLL in the present cohort) and in relapsed/refractory CLL (22% of the BOMP trial, unpublished data).12, 13 The 2p gain was associated with a CK in 53% of cases and a HCK in 26%; these percentages are higher than the literature values for CLL in general (15%‐18% and 4%, respectively).8, 19 In line with literature reports, we further confirmed that 2p gain is closely associated with del(11q) (53% of untreated patients in our series), unmutated IGHV status (in 89%) and—to a lesser extent—del(17p) (in 19%).7, 12, 13, 20 Conversely, tri12 was very rare in our patients with 2p+ CLL (3% here, vs 15% in CLL in general).3, 8 Interestingly, in contrast to CLL in general, we did not observe—in our cohort of 2p+ CLL—a significant association between the OS and the common poor prognostic factors, that is, del(17p), unmutated IGHV and HCK.1, 15 Lastly, 2p gain was overlooked by karyotyping in 68% of our cases; we therefore strongly recommend systematic FISH screening for this abnormality.\n\nRossi et al.16 reported the involvement of ATM and BIRC3 in 11q deletion. As the del(11q) was present in more than a half of our cohort of 2p+ CLL cases, we investigated the two genes. We found that del(11q) involves both genes in the majority of cases, and that BIRC3 is never deleted alone (as also shown by another group21). Moreover, whether del(11q) encompassed one or two genes did not seem to influence the treatment response in our cohort.\n\nAs 2p gain often involves the whole short arm of chromosome 2, we decided to study two previously described minimal regions of gain: 2p24 and 2p15‐16.10, 12, 13, 18, 20, 22 The 2p24 region encompasses MYCN, and the 2p15‐16 encompasses XPO1 and REL, all of which are overexpressed in 2p+ CLL.13\nMYCN and REL are already known oncogenes involved in lymphoid malignancies. MYCN (a member of the MYC family) is associated with a variety of tumors, including neuroblastoma.23\nREL encodes a member of the NF‐Κb family of transcription factors involved in cell growth and differentiation, and is overexpressed in Hodgkin's lymphoma.24 Lastly, we recently highlighted the role of XPO1 (coding for exportin 1) in the drug resistance associated with 2p+.13 In the majority of cases in our series, the three oncogenes had been gained together in the same proportions—thus confirming their relevance in CLL drug resistance. Nevertheless, we found that the two regions can also be gained differently; in some cases, MYCN is not gained. We therefore recommend investigating these two regions using FISH. As MYCN is never gained alone, at least one probe encompassing REL or XPO1 should be used.\n\nTo evaluate clonal changes in patients with 2p+ CLL, we assessed the consequences of different drug treatments on 2p gain and other abnormalities. Nineteen patients were treated with FCR; this remains a major first‐line option for many patients with CLL, and is considered to be effective in cases with favorable features (including mutated IGHV status).2 We found that FCR is not able to eliminate the 2p clone. The majority of the FCR‐treated patients with 2p+ CLL relapsed within 3 years. Indeed, in our series, 2p gain increased or remained stable at relapse after FCR treatment. It even appears that FCR induced 2p gain in one patient. It is noteworthy that FCR was able to eliminate two clones with del(13q) and one with del(11q). Taken as a whole, our data suggest that the first‐line use of FCR is not a good choice for 2p+ CLL—even for patients lacking factors for a poor prognosis (IGHV‐U, del(17p), del(11q), and CK).\n\nThree patients received first‐ or second‐line treatment with BR. Even a short period without a 2p+ clone was observed for one patient, the clone was still detected in all the patients in clinical remission. One patient (with first‐line BR) relapsed at 26 months but more follow‐up is required for the other two patients. Hence, we are not yet able to draw conclusions about BR and 2p+ CLL.\n\nEleven patients received BOMP therapy. This regimen included the fully humanized anti‐CD‐20 antibody ofatumumab, which is considered to be feasible and effective in patients with relapsed/refractory CLL ‐ including those with high‐risk clinical and laboratory features.5 All 11 patients had already received other treatments, and had factors linked to a poor prognosis. However, when looking specifically at the 2p clone, the frequency decreased in three patients or was even no longer detected in a fourth patient at relapse. In contrast, no other FISH abnormalities were eliminated, and the two del(11q) clones and the del(17p) clone increased. Our results suggest that BOMP is a good treatment option for some patients with 2p+CLL.\n\nA number of new treatment options have recently emerged for patients with CLL, including inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidyl‐inositol 3‐kinase (idelalisib).2 In our study, five patients had been treated with ibrutinib. We found that the 2p gain clone either remained stable or decreased but was still detectable—even when the lymphocyte count had normalized. After treatment with idelalisib, the 2p gain was still detected in patients in clinical remission. It is noteworthy that all the other abnormalities were still present. Hence, longer follow‐up is required to evaluate these drugs’ long‐term impact on 2p+ CLL. Nevertheless, our initial data appear to indicate that ibrutinib or idelalisib do not eliminate the 2p+ clone. Three patients had started treatment with venetoclax.\n\nIn conclusion, the results of our large study indicate that 2p gain is frequent in relapsed/refractory CLL. The 2p gain is also associated with male gender, a HCK, del(11q), del(17p), and unmutated IGHV status. The gain can appear during natural disease progression or after treatment. The commonly used first‐line treatment FCR is not effective with regard to the 2p+ clone, even when a CK or del(17p) is absent. Treatment with BOMP appears to have an effect on the 2p+ clone in some patients. We need more follow‐up data for ibrutinib, idelalisib‐R, and bendamustine‐R. Overall, our results strongly suggest that it is essential to systematically screen for 2p gain (using karyotyping and FISH) to better characterize CLL.\n\nSupporting information\n \n\nClick here for additional data file.\n\n \n\nClick here for additional data file.\n\n \n\nClick here for additional data file.\n\n \n\nClick here for additional data file.\n\n \n\nClick here for additional data file.\n\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nWe thank N Bougacha for unpublished assessments. This work was funded by Roche Diagnostics, Association Laurette Fugain (ALF 14/08), Fondation ARC (SFI20111203530), and GEFLUC. This work was supported by the Cancer United Research Associating Medicine, University and Society (CURAMUS) « INCA‐DGOS‐Inserm_12560 ».\n==== Refs\nREFERENCES\n1 \n\nHallek \nM \n, \nCheson \nBD \n, \nCatovsky \nD \n, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL . Blood . 2018 ;131 (25 ):2745 ‐2760 .29540348 \n2 \n\nBurger \nJA \n, \nO'Brien \nS \n. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy . Nat Rev Clin Oncol . 2018 ;15 (8 ):510 ‐527 .29777163 \n3 \n\nDohner \nH \n, \nStilgenbauer \nS \n, \nBenner \nA \n, et al. Genomic aberrations and survival in chronic lymphocytic leukemia . N Engl J Med . 2000 ;343 (26 ):1910 ‐1916 .11136261 \n4 \n\nZenz \nT \n, \nKrober \nA \n, \nScherer \nK \n, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long‐term follow‐up . Blood . 2008 ;112 (8 ):3322 ‐3329 .18689542 \n5 \n\nGuieze \nR \n, \nRobbe \nP \n, \nClifford \nR \n, et al. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL . Blood . 2015 ;126 (18 ):2110 ‐2117 .26316624 \n6 \n\nZenz \nT \n, \nHabe \nS \n, \nDenzel \nT \n, et al. Detailed analysis of p53 pathway defects in fludarabine‐refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53‐p21 dysfunction, and miR34a in a prospective clinical trial . Blood . 2009 ;114 (13 ):2589 ‐2597 .19643983 \n7 \n\nLandau \nDA \n, \nTausch \nE \n, \nTaylor‐Weiner \nAN \n, et al. Mutations driving CLL and their evolution in progression and relapse . Nature . 2015 ;526 (7574 ):525 ‐530 .26466571 \n8 \n\nBaliakas \nP \n, \nIskas \nM \n, \nGardiner \nA \n, et al. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data . Am J Hematol . 2014 ;89 (3 ):249 ‐255 .24166834 \n9 \n\nBea \nS \n, \nLopez‐Guillermo \nA \n, \nRibas \nM \n, et al. Genetic imbalances in progressed B‐cell chronic lymphocytic leukemia and transformed large‐cell lymphoma (Richter's syndrome) . Am J Pathol . 2002 ;161 (3 ):957 ‐968 .12213724 \n10 \n\nSchwaenen \nC \n, \nNessling \nM \n, \nWessendorf \nS \n, et al. Automated array‐based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations . Proc Natl Acad Sci U S A . 2004 ;101 (4 ):1039 ‐1044 .14730057 \n11 \n\nPfeifer \nD \n, \nPantic \nM \n, \nSkatulla \nI \n, et al. Genome‐wide analysis of DNA copy number changes and LOH in CLL using high‐density SNP arrays . Blood . 2007 ;109 (3 ):1202 ‐1210 .17053054 \n12 \n\nChapiro \nE \n, \nLeporrier \nN \n, \nRadford‐Weiss \nI \n, et al. Gain of the short arm of chromosome 2 (2p) is a frequent recurring chromosome aberration in untreated chronic lymphocytic leukemia (CLL) at advanced stages . Leuk Res . 2010 ;34 (1 ):63 ‐68 .19406473 \n13 \n\nCosson \nA \n, \nChapiro \nE \n, \nBougacha \nN \n, et al. Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1 . Leukemia . 2017 ;31 (7 ):1625 ‐1629 .28344316 \n14 \n\nDicker \nF \n, \nSchnittger \nS \n, \nHaferlach \nT \n, \nKern \nW \n, \nSchoch \nC \n. Immunostimulatory oligonucleotide‐induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression . Blood . 2006 ;108 (9 ):3152 ‐3160 .16840733 \n15 \n\nBaliakas \nP \n, \nJeromin \nS \n, \nIskas \nM \n, et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations and clinical impact . Blood . 2019 ;133 (11 ):1205 ‐1216 .30602617 \n16 \n\nRossi \nD \n, \nFangazio \nM \n, \nRasi \nS \n, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild‐type chronic lymphocytic leukemia . Blood . 2012 ;119 (12 ):2854 ‐2862 .22308293 \n17 \n\nSwerdlow \nSH \n, \nCampo \nE \n, \nPileri \nSA \n, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms . Blood . 2016 ;127 (20 ):2375 ‐2390 .26980727 \n18 \n\nJarosova \nM \n, \nUrbankova \nH \n, \nPlachy \nR \n, et al. Gain of chromosome 2p in chronic lymphocytic leukemia: significant heterogeneity and a new recurrent dicentric rearrangement . Leuk Lymphoma . 2010 ;51 (2 ):304 ‐313 .20078324 \n19 \n\nSutton \nL \n, \nChevret \nS \n, \nTournilhac \nO \n, et al. Autologous stem cell transplantation as a first‐line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM‐TC and GFLLC . Blood . 2011 ;117 (23 ):6109 ‐6119 .21406717 \n20 \n\nForconi \nF \n, \nRinaldi \nA \n, \nKwee \nI \n, et al. Genome‐wide DNA analysis identifies recurrent imbalances predicting outcome in chronic lymphocytic leukaemia with 17p deletion . Br J Haematol . 2008 ;143 (4 ):532 ‐536 .18752589 \n21 \n\nRose‐Zerilli \nMJ \n, \nForster \nJ \n, \nParker \nH \n, et al. ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q‐deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial . Haematologica . 2014 ;99 (4 ):736 ‐742 .24584352 \n22 \n\nEdelmann \nJ \n, \nHolzmann \nK \n, \nMiller \nF \n, et al. High‐resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations . Blood . 2012 ;120 (24 ):4783 ‐4794 .23047824 \n23 \n\nHuang \nM \n, \nWeiss \nWA \n. Neuroblastoma and MYCN . Cold Spring Harb Perspect Med . 2013 ;3 (10 ):a014415 .24086065 \n24 \n\nEnciso‐Mora \nV \n, \nBroderick \nP \n, \nMa \nY \n, et al. A genome‐wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3) . Nat Genet . 2010 ;42 (12 ):1126 ‐1130 .21037568\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "8(6)",
"journal": "Cancer medicine",
"keywords": "2p gain; chronic lymphocytic leukemia; drug resistance",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002869:Chromosome Aberrations; D058674:Chromosome Duplication; D002889:Chromosomes, Human, Pair 2; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D012008:Recurrence; D061665:Time-to-Treatment; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "3131-3141",
"pmc": null,
"pmid": "31066214",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24584352;24086065;23047824;21406717;30602617;29777163;22308293;31066214;24166834;20078324;21037568;17053054;18689542;14730057;16840733;11136261;28344316;19406473;18752589;29540348;19643983;26466571;12213724;26980727;26316624",
"title": "Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug-resistant chronic lymphocytic leukemia.",
"title_normalized": "gain of the short arm of chromosome 2 2p gain has a significant role in drug resistant chronic lymphocytic leukemia"
} | [
{
"companynumb": "FR-GILEAD-2019-0408332",
"fulfillexpeditecriteria": "1",
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{
"abstract": "Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival.From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival.In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.",
"affiliations": "Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Hematology and Laboratory Medicine Department and Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Central University Hospital of Asturias, Oviedo, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.;Hematology Service, Miguel Servet Hospital, Zaragoza, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.;Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.;Hematology Service, Río Hortega Hospital, Valladolid, Spain.;Hematology Service, University Hospital of Getafe, Madrid, Spain.;Hematology Service, University Hospital of Getafe, Madrid, Spain.;Hematology Service, University Hospital, Valladolid, Spain.;Hematology Service, University Hospital, Valladolid, Spain.;Hematology Service, Juan Ramón Jiménez Hospital, Huelva, Spain.;Hematology Service, Segovia General Hospital, Segovia, Spain.;Hematology Service, Nuestra Señora de Sonsoles Hospital, Avila, Spain.;Hematology Service, León Hospital, León, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.;Cytometry Service (NUCLEUS), Department of Medicine, IBSAL and CIBERONC, Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain. orfao@usal.es.",
"authors": "Matarraz|Sergio|S|;Leoz|Pilar|P|;Fernández|Carlos|C|;Colado|Enrique|E|;Chillón|María Carmen|MC|;Vidriales|María Belén|MB|;González|Marcos|M|;Rivera|Daniel|D|;Osuna|Carlos Salvador|CS|;Caballero-Velázquez|Teresa|T|;Van Der Velden|Vincent|V|;Jongen-Lavrencic|Mojca|M|;Gutiérrez|Oliver|O|;Bermejo|Ana Yeguas|AY|;Alonso|Luis García|LG|;García|Monique Bourgeois|MB|;De Ramón Sánchez|Cristina|C|;García-Donas|Gloria|G|;Mateo|Aránzazu García|AG|;Recio|Isabel|I|;Sánchez-Real|Javier|J|;Mayado|Andrea|A|;Gutiérrez|María Laura|ML|;Bárcena|Paloma|P|;Barrena|Susana|S|;López|Antonio|A|;Van Dongen|Jacques|J|;Orfao|Alberto|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41379-018-0038-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-3952",
"issue": "31(8)",
"journal": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc",
"keywords": null,
"medline_ta": "Mod Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001491:Basophils; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult",
"nlm_unique_id": "8806605",
"other_id": null,
"pages": "1318-1331",
"pmc": null,
"pmid": "29572500",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy.",
"title_normalized": "basophil lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1051743",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.",
"affiliations": "Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States.;Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University Health System, Durham, NC, United States.;Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University Health System, Durham, NC, United States.;Division of Biologics Review and Research 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, US FDA, Bethesda, MD, United States.;Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States.",
"authors": "Desai|Ankit K|AK|;Baloh|Carolyn H|CH|;Sleasman|John W|JW|;Rosenberg|Amy S|AS|;Kishnani|Priya S|PS|",
"chemical_list": "D000906:Antibodies; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069283:Rituximab; C509951:GAA protein, human; D000520:alpha-Glucosidases; D008727:Methotrexate",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.01727",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.01727\nImmunology\nOriginal Research\nBenefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort\nDesai Ankit K. 1 Baloh Carolyn H. 2 Sleasman John W. 2 Rosenberg Amy S. 3 Kishnani Priya S. 1* 1Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States\n2Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University Health System, Durham, NC, United States\n3Division of Biologics Review and Research 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, US FDA, Bethesda, MD, United States\nEdited by: Christoph T. Berger, University of Basel, Switzerland\n\nReviewed by: Pim Pijnappel, Erasmus Medical Center, Netherlands; Roland W. Herzog, Indiana University, United States\n\n*Correspondence: Priya S. Kishnani Priya.kishnani@duke.eduThis article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology\n\n\n06 8 2020 \n2020 \n11 172727 1 2020 29 6 2020 Copyright © 2020 Desai, Baloh, Sleasman, Rosenberg and Kishnani.2020Desai, Baloh, Sleasman, Rosenberg and KishnaniThis 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.Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26–39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1–11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11–55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.\n\nanti-drug antibodiesenzyme replacement therapyimmune tolerance inductionanti-rhGAA IgG antibodyalglucosidase alfaimmunogenicity\n==== Body\nIntroduction\nLysosomal storage disorders (LSDs) are a group of inherited metabolic disorders caused by disease-associated variants in genes encoding catabolic enzymes active in the lysosome. The deficiency or complete absence of endogenous enzyme leads to a build-up of undegraded macromolecules in lysosomes affecting various target tissues depending on the specific enzyme deficiency (1–3). Although there is no cure for LSDs, the development of enzyme replacement therapy (ERT) aimed at replacing the deficient lysosomal enzymes and reducing the toxic substrate accumulation has greatly improved the course for several LSDs including Gaucher disease, Fabry disease, Pompe disease, Mucopolysaccharidoses (MPS) I, II, IVA, VI, and VII, and Wolman disease, with additional therapeutic proteins in development (4, 5). Despite the success of ERTs in improving outcomes for patients with LSDs, the development of anti-drug antibodies (ADA) against the therapeutic protein remains a challenge that impacts both the safety and efficacy of the treatment (6).\n\nIn 2006, the FDA approved alglucosidase alfa (recombinant human acid alfa-glucosidase, rhGAA) for treatment of Pompe disease, an autosomal recessive LSD caused by disease-associated variants in the GAA gene resulting in deficiency of acid-alpha glucosidase (GAA), predominantly affecting skeletal, smooth, and cardiac muscle (7, 8). Pompe disease has a phenotypic spectrum ranging from classic infantile Pompe disease (IPD) to late-onset Pompe disease. Classic IPD is the most severe end of the disease spectrum, with patients presenting with severe cardiomyopathy in the first few days to weeks of life and rarely surviving beyond 2 years of age without treatment (9). The availability of ERT with alglucosidase alfa has changed the natural course of Pompe disease, significantly prolonging survival and improving long-term clinical outcomes. Despite the considerable benefits of ERT, the overall response is heterogeneous and impacted by multiple factors including age at ERT, the extent of underlying pathology, the dose of ERT, and development of anti-drug antibodies. Additionally, there are other limitations of ERT including clearance by non-muscle tissue, limited cellular uptake in muscles, inability to cross blood-brain barrier, and variability of skeletal muscle response (10, 11). Published literature has demonstrated that long-term IPD survivors often have residual physical impairments including muscle weakness, hypernasal speech, dysphagia with a risk of aspiration, ptosis, and risk of arrhythmias (12).\n\nThe negative impact of IgG ADA to alglucosidase alfa in patients with IPD has been well established since the first clinical trial (13–15). In two alglucosidase alfa clinical trials, 89% (35/39) of patients (NCT00125879, n = 16/18 and NCT00053573, n = 19/21) with IPD developed ADA to alglucosidase alfa and a subset developed high and sustained IgG antibody titers (HSAT) causing suboptimal treatment response resulting in clinical deterioration and death despite treatment with ERT (9, 14). Of critical importance, the development of ADA to ERT is strongly influenced by the patient's genetic variants which determine whether any GAA protein is generated, even if non-functional, as the production of a non-functional enzyme may still tolerize the immune system to some extent. Patients with two null variants, produce no GAA, resulting in the immune system recognizing rhGAA as foreign (16). IPD patients with two null GAA variants are considered cross-reactive immunologic material (CRIM)-negative and are at the highest risk of developing significant ADA to ERT (16, 17). A previous study assessing the impact of CRIM status on treatment outcomes in Pompe disease showed that CRIM-negative patients who received ERT monotherapy were either deceased or ventilator-dependent by age of 27.1 months due to the development of ADA (16). Immune tolerance induction (ITI) in the ERT-naïve setting has been established as a strategy to diminish the development and minimize the impact of ADA on treatment response to ERT and has become the standard of care for CRIM-negative IPD patients (18–23). Although endogenous GAA detected in CRIM-positive IPD patients can tolerize them to ERT, up to 32% of CRIM-positive IPD patients also develop deleterious ADA to ERT and the clinical course is indistinguishable from that of CRIM-negative IPD patients (24). Some CRIM-positive IPD patients at high risk of developing deleterious ADA can be identified based on previously reported GAA variants in IPD patients who developed HSAT or based on development of HSAT by an older sibling. We thus have instituted an immunomodulation approach at ERT initiation based on an algorithm of early immune response data in this subset of CRIM-positive IPD patients considered as high risk (22–24).\n\nDifferent approaches to overcoming the challenges of ADA to ERT have been tried in patients with Pompe disease with varying degrees of success (25). These immunomodulation approaches, initiated with ERT, are intended to target B and T cells to induce long-term immune tolerance and improve treatment response to ERT (21, 23, 26, 27). While approaches have differed in terms of drug combinations, all approaches included rituximab, an anti-CD20 monoclonal antibody, which targets antibody-producing B cells. We previously reported success in inducing immune tolerance with a short-course of rituximab, low-dose of methotrexate, with/without IVIG in an international cohort of 19 CRIM-negative IPD patients (23). Combination therapy targeting different cells of the immune system (B and T cells) to prevent the cascade for antibody development was the rationale for using rituximab and methotrexate. Rituximab is a chimeric monoclonal antibody that has been approved for multiple types of malignancy and autoimmune diseases. Methotrexate, an inhibitor of dihydrofolate reductase, impacts rapidly dividing T and B cells (28, 29). Experience from rheumatologic disorders has shown that the addition of methotrexate with other biological therapy has prevented the development of ADA against therapeutic proteins (30). We added IVIG at a dose of 500 mg/kg to provide passive immunity until B cell reconstitution would assure production of antibodies to pathogens. The duration of B cell depletion varied based upon patient age, treatment indication, additional immunosuppressive medication administration, and duration of treatment. An example of this is that children typically achieve B cell reconstitution within 1 year of rituximab discontinuation, while adults can take up to 2 years (31). Long-term follow-up studies show that there is skewing of B cell populations to naïve phenotypes resulting in prolonged low immunoglobulin levels and impaired responses to vaccines (32–37). Published literature of rituximab use in autoimmunity and malignancy has shown that though rare, infections can occur when B cells are undetectable (36, 38, 39).\n\nThe short 5-week course of ITI was able to tolerize IPD patients to ERT, as evidenced by negative/low anti-rhGAA IgG antibody titers even after B cell reconstitution and ability to receive age-appropriate routine vaccination. The data suggested that combination therapy was safely tolerated and was successful in inducing immune tolerance in most IPD patients. However, the long-term safety of this approach was not evaluated and published data on the safety of immunomodulation with rituximab, especially in pediatric populations, is limited. At this time, there are limited data in the literature on the long-term safety of rituximab, especially in patients younger than a year of age. Considering that the majority of patients with infantile Pompe disease are initiated on treatment within weeks of birth, it is important to understand the long-term safety of treatment in such a young and medically fragile population. The purpose of this study was to determine if patients with IPD who received rituximab experienced long-term impairment of the immune system, as described in the literature for its use in diverse disease settings. In the current study, we present the long-term safety and efficacy of short-course immune tolerance induction (ITI) in a relatively large cohort of CRIM-negative and CRIM-positive IPD patients by evaluating anti-rhGAA IgG antibody titers, absolute neutrophil count (ANC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), B cell and T cell quantitation, vaccination history and titers against vaccines, left ventricular mass index (LVMI), and overall and ventilator-free survival.\n\nMaterials and Methods\nPatients and Inclusion Criteria\nInclusion criteria for the present study were based on the following; (1) a confirmed diagnosis of IPD with two disease-associated GAA variants and low GAA enzyme activity (8), (2) a history of ITI with rituximab, methotrexate, with or without IVIG in ERT-naïve setting, and (3) at least 6 months of follow-up data since initiation of ITI. A retrospective chart review of qualifying patients with IPD was conducted. Data on patients included in the previous publication were reviewed and further longitudinal data since the last publication on patients who met the inclusion criteria were included for the analysis (23).\n\nEthics Approval\nAll patients were enrolled in a Duke institutional review board (IRB)-approved study protocol (Pro00001562; Determination of Cross-Reactive Immunological Material [CRIM] Status and Longitudinal Follow-up of Individuals with Pompe disease; LDN6709 Site 206; ClinicalTrials.gov NCT01665326). One CRIM-negative IPD patient included in this study had IRB/ethics committee approval from a local institution. All other patients were enrolled in the Duke IRB-approved study through written informed consent from a parent or legal guardian (15, 22, 40–42).\n\nImmune Tolerance Induction (ITI)\nThe 5-week short-course immune tolerance induction approach included four doses of weekly rituximab (375 mg/m2, intravenously), and three cycles of low-dose methotrexate (0.4 mg/kg; three doses per cycle with first three ERT infusions, subcutaneously or orally), as described previously (Supplementary Figure 1) (22). To provide passive immunity during B cell suppression, monthly IVIG at 500 mg/kg was added to the combination therapy during the time of B cell suppression. To avoid any significant interference of IVIG with antibody-dependent cellular cytotoxicity mediated B cell depletion, the first dose of IVIG was administered 24–48 h after the first dose of rituximab. There was no recommended supplier for rituximab, methotrexate, and IVIG in ITI protocol that was shared with treating physicians. To assess the safety of ITI, patients were monitored for incidence of infection around the time of ITI, decrease in ANC, and increase in AST, and/or ALT levels. An ANC of <750 cells/mm3 or AST and/or ALT >3 times their respective baseline values were considered as adverse events. Routine vaccinations, except for the flu shot were withheld while patients were B cell suppressed. Vaccinations were resumed following evidence of B cell reconstitution, defined as normalization of CD19% (40).\n\nPatients were classified into three groups based on anti-rhGAA IgG antibody titers; (1) HSAT, defined as titers of ≥51,200 on two or more occasions at or beyond 6 months on ERT (15), (2) sustained intermediate titer (SIT), defined as titers of ≥12,800 and <51,200 on ERT (LumizymeTM prescribing information) (15, 41), and (3) low titer (LT), defined as titers of ≤6,400. The cutoffs of 51,200 and 12,800 were utilized based on the findings from previous publications and LumizymeTM prescribing information (15, 41). Previous studies have demonstrated that CRIM-positive and CRIM-negative IPD patients who developed anti-rhGAA IgG titers of ≥12,800 had poor clinical outcomes (15, 17, 42). Additionally, the Lumizyme prescribing information states that patients developing sustained anti-alglucosidase alfa antibody titers of ≥12,800 may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Patients with antibody titers ≥12,800 at Week 12 of treatment had an average increase in alglucosidase alfa clearance of 50% from Week 1 to 12. In our study with ITI, patients were considered immune tolerant if they met the following criteria: (1) were seronegative (did not develop anti-rhGAA IgG antibodies) or maintained anti-rhGAA IgG titers of ≤6,400 throughout ERT, and (2) were able to receive age-appropriate routine vaccines.\n\nData Collection\nClinical data including GAA variants, CRIM status, age at diagnosis, age at ERT initiation, dose of ERT, longitudinal anti-rhGAA IgG antibody titers, LVMI, motor status, feeding status, and pulmonary status were extracted from medical records provided by the principal care provider of the patient. CRIM status was determined by western blot analysis in skin or blood at Duke GSD/LSD Enzymology Laboratory and confirmed by GAA variants or was predicted based on GAA variants as previously described (43). Anti-rhGAA IgG antibody titers were determined by Sanofi Genzyme (Framingham, MA, USA) by enzyme-linked immunosorbent assay and confirmed using radioimmunoprecipitation as previously described (8). Since the decrease in ANC and elevations in AST and ALT have been noted with treatment with rituximab and methotrexate, we evaluated these values in patients on the ITI protocol. ANC, ALT, and AST levels were monitored bi-weekly during ITI followed by monthly monitoring until return to baseline levels. Flow cytometry was performed in CLIA certified laboratories to define the following cell populations: CD19, CD3, CD3CD4, CD3CD8. Lymphocyte quantitation including CD19% was evaluated to monitor B cell suppression and B cell reconstitution. Lymphocyte quantitation was performed every 4 weeks until B cell recovery, then every 3–6 months. B cell depletion was defined as detection of CD19% below 1%. B cell reconstitution was measured in terms of normalization of CD19% to the normal range for the age as previously described (40). Additionally, CD3, CD4, and CD8% were evaluated to monitor T cell response. Titers against Diphtheria, Tetanus, Pneumoccoal, Measles, Mumps, and Rubella (MMR) were assessed after vaccination and humoral response to vaccines were categorized as adequate (immune) or inadequate (not immune). Humoral response to Tetanus, Diphtheria, and MMR were determined to be adequate based on the respective CLIA certified laboratory reference ranges. The response to the Pneumoccocal vaccine was determined to be adequate if >50% of serotypes had an antibody concentration of >1.3 micrograms per milliliter, as all patients were <6 years old (44). B cell reconstitution, vaccination status at baseline and after ITI, and titers against routine vaccines were collected to assess if administration of rituximab resulted in long-term immunodeficiency. Data collection continued until October 2019 or until at least 6 months had passed since the initiation of ERT and ITI, at which time the database was locked for analysis.\n\nStatistics\nOverall survival and ventilator-free survival for patients who received ITI were analyzed using the Kaplan-Meier method with two-tailed P-values generated using the log-rank test and compared to a historical cohort of CRIM-negative IPD patients who received ERT monotherapy (15). Age at ERT, age at diagnosis, longitudinal anti-rhGAA IgG antibody titers, and LVMI were compared using Wilcoxon/Kruskal-Wallis rank-sum test. Analyses were performed with JMP Pro 14.0. Descriptive data are presented as medians.\n\nResults\nPatients and Treatment Details\nFrom our international cohort of infantile Pompe disease patients (IPD), 34 patients (25 CRIM-negative and 9 CRIM-positive) who met all inclusion criteria and had received a short-course of ITI with rituximab, methotrexate, and/or IVIG in ERT-naïve setting were identified. ADDIN EN.CITE (23) Of the 25 CRIM-negative patients, 17 patients (CN1 to CN17) were included in our previous publication and met the inclusion criteria for the current study. Three CRIM-negative IPD patients (CN1, CN2, and CN6) received ITI with rituximab and methotrexate and did not receive IVIG, as per the local treating physician's decision.\n\nPatient demographics, age at diagnosis, age at ERT initiation, GAA variants, dose of ERT, current age, age at death, and CRIM status are shown in Table 1. The median age at diagnosis was 2.4 months (range, 0.0–5.9 months) and 4.2 months (range, 0.0–10.9 months) for CRIM-negative and CRIM-positive IPD groups, respectively (Table 2). The median age at ERT and ITI initiation was 3.1 months (range, 0.1–6.7 months) and 4.8 months (range, 0.1–11.0 months) for CRIM-negative and CRIM-positive groups, respectively (Table 2). There were no statistically significant differences in age at diagnosis (p = 0.3189) or age at ERT initiation (p = 0.2828) between CRIM-negative and CRIM-positive IPD patients. At the time of database lock, 27 IPD patients were alive (18 CRIM-negative and 9 CRIM-positive) and 7 CRIM-negative IPD patients were deceased (Table 1). No statistically significant differences were observed in age at diagnosis (p = 0.2584) or age at ERT initiation (p = 0.2246) between living and deceased IPD patients.\n\nTable 1 Demographics and treatment history.\n\nPatient/Gender\tGAA disease-associated variants\tCRIM status\tAge at diagnosis (months)\tAge at ERT initiation (months)\tCurrent age (months)\tERT dose at the time of initiation\t\n\tAllele 1\tAllele 2\t\t\t\t\t\t\nALIVE PATIENTS\t\nCN1/F\tc.341insT\tc.341insT\tNegative\t1.9\t3.8\t148.8\t20 mg/kg EOW*\t\nCN3/F\tc.2608C>T\tc.2608C>T\tNegative\t2.5\t3.0\t112.0\t20 mg/kg EOW*\t\nCN4/M\tc.546+2T>C\tc.546+2T>C\tNegative\t3.5\t4.6\t111.2\t20 mg/kg EOW\t\nCN5/F\tc.236_246del\tc.236_246del\tNegative\t2.0\t2.5\t108.4\t20 mg/kg EOW*\t\nCN10/M\tc.2560C>T\tc.1292_1295dupTGCA\tNegative\t2.4\t2.6\t92.3\t20 mg/kg Weekly*\t\nCN11/F\tc.2560C>T\tc.2560C>T\tNegative\t0.3\t1.3\t88.8\t20 mg/kg EOW*\t\nCN12/F\tc.258dupC\tc.2227C>T\tNegative\t2.6\t3.1\t71.1\t20 mg/kg EOW*\t\nCN13/M\tc.1754+2T>A\tc.1822C>T\tNegative\t0.9\t1.8\t87.5\t20 mg/kg EOW*\t\nCN14/F\tc.2237G>A\tc.437delT\tNegative\t5.9\t6.6\t71.5\t20 mg/kg EOW\t\nCN16/F\tc.2560C>T\tc.2560C>T\tNegative\tPrenatal\t0.1\t50.5\t20 mg/kg EOW*\t\nCN17/M\tc.2560C>T\tc.525delT\tNegative\t3.3\t3.6\t43.1\t20 mg/kg Weekly*\t\nCN18/F\tc.1195-18_2190-20del\tc.1195-18_2190-20del\tNegative\t3.9\t4.4\t53.7\t20 mg/kg EOW*\t\nCN19/M\tc.1827C>G\tc.2662G>T\tNegative\t0.3\t0.8\t41.5\t20 mg/kg EOW*\t\nCN20/M\tc.525delT\tc.1694_1697delTCTC\tNegative\t0.9\t1.0\t20.2\t20 mg/kg EOW*\t\nCN22/M\tc1548G>A\tc2560C>T\tNegative\t4.9\t5.4\t41.8\t20 mg/kg EOW\t\nCN23/M\tc.525delT\tc.2560C>T\tNegative\t0.7\t1.4\t39.0\t20 mg/kg EOW*\t\nCN24/M\tc.1051delG\tc.1579delA\tNegative\t0.4\t0.5\t27.0\t20 mg/kg EOW*\t\nCN25/M\tc.525delT\tc.2560C>T\tNegative\tPrenatal\t0.1\t8.1\t40 mg/kg EOW\t\nCP1/M\tc.1912G>T\tc.2481+102_2646+31del\tPositive\t4.5\t4.8\t70.6\t20 mg/kg EOW*\t\nCP2/M\tc.2457_246delCTG\tc.2560C>T\tPositive\t3.8\t4.0\t70.9\t20 mg/kg EOW*\t\nCP3/F\tc.1844G>A\tc.1844G>A\tPositive\t10.9\t11.0\t109.5\t20 mg/kg EOW\t\nCP4/M\tc.2105G>T\tc.2512C>T\tPositive\tPrenatal\t0.7\t73.1\t20 mg/kg EOW\t\nCP5/F\tc.525delT\tc.2481+110_2646+39del\tPositive\t6.0\t7.3\t87.8\t20 mg/kg EOW\t\nCP6/F\tc.1841C>A\tc2481+102_2646+31del\tPositive\t4.2\t5.1\t46.5\t40 mg/kg EOW*\t\nCP7/M\tc.1118T>G\tc.1118T>G\tPositive\tPrenatal\t0.1\t21.2\t20 mg/kg Weekly*\t\nCP8/M\tc.716delT\tc.871C>T\tPositive\t6.0\t6.4\t42.9\t20 mg/kg EOW*\t\nCP9/F\tc.1843G>A\tc.1933G>C\tPositive\t0.1\t0.9\t36.9\t20 mg/kg EOW\t\nDECEASED PATIENTS\t\nCN2/M\tc.1548G>A\tc.525delT\tNegative\t2.4\t3.6\t56.9\t20 mg/kg EOW\t\nCN6/F\tc.525delT\tc.2560C>T\tNegative\t0.3\t0.4\t63.2\t20 mg/kg Weekly\t\nCN7/F\tc.2560C>T\tc.2560C>T\tNegative\t3.0\t3.4\t25.4\t20 mg/kg EOW\t\nCN8/F\tc.525_526delTG\tc.525_526delTG\tNegative\t5.5\t6.7\t30.0\t20 mg/kg EOW\t\nCN9/F\tc.2560C>T\tc.2560C>T\tNegative\t3.2\t3.9\t15.0\t20 mg/kg EOW\t\nCN15/F\tc.2560C>T\tc.2560C>T\tNegative\t5.1\t6.6\t15.5\t20 mg/kg EOW*\t\nCN21/F\tc.2238G>A\tc.2560C>T\tNegative\t5.9\t6.3\t25.1\t40 mg/kg EOW*\t\nGAA, gene encoding acid α-glucosidase; CRIM, Cross-reactive immunologic material; ERT, enzyme replacement therapy; EOW, every other week.\n\n* Patient was initiated on or subsequently received ERT at a higher dose than the recommended dose of 20 mg/kg EOW.\n\nTable 2 Summary of age at diagnosis, age at ERT initiation, anti-rhGAA IgG antibody titer, B cell, and LVMI.\n\n\tN\tMedian\tRange\t\nAge at diagnosis\t\nCRIM-negative\t25\t2.4 months\t0.0–5.9 months\t\n • Alive CRIM-negative\t18\t2.0 months\t0.0–5.9 months\t\n • Deceased CRIM-negative\t7\t3.2 months\t0.3–5.9 months\t\nCRIM-positive (all alive)\t9\t4.2 months\t0.0–10.9 months\t\nAlive (CRIM-negative and CRIM-positive)\t27\t2.4 months\t0.0–10.9 months\t\nAge at ERT initiation\t\nCRIM-negative\t25\t3.1 months\t0.1–6.7 months\t\n • Alive CRIM-negative\t18\t2.5 months\t0.1–6.6 months\t\n • Deceased CRIM-negative\t7\t3.9 months\t0.4–6.7 months\t\nCRIM-positive\t9\t4.8 months\t0.1–11.0 months\t\nAlive (CRIM-negative and CRIM-positive)\t27\t3.0 months\t0.1–11.0 months\t\nPeak anti-rhGAA IgG antibody titer\t\nCRIM-negative\t25\t200\t0–51,200\t\n • CRIM-negative tolerized\t21\t0\t0–6,400\t\n • CRIM-negative nontolerized\t4\t38,400\t25,600–51,200\t\nCRIM-positive (all tolerized)\t9\t0\t0–200\t\nAnti-rhGAA IgG antibody titer at last assessment (time since ERT initiation)\t\nCRIM-negative\t25\t100\n (108 weeks)\t0–51,200\n (19–351 weeks)\t\n • CRIM-negative tolerized\t21\t0\n (103 weeks)\t0–6,400\n (19–351 weeks)\t\n • CRIM-negative nontolerized\t4\t19,200\n (228 weeks)\t3,200–51,200\n (72–343 weeks)\t\nCRIM-positive (all tolerized)\t9\t0\n (104 weeks)\t0–100\n (35–272 weeks)\t\nB cell response\t\nTime to B cell depletion\t31\t3 weeks\t1–5 weeks\t\nTime to B cell reconstitution\t33\t17 weeks\t11–54 weeks\t\nLVMI at baseline\t\nCRIM-negative\t20\t178.2 g/m2\t55.5–448.9 g/m2\t\nCRIM-positive\t8\t221.0 g/m2\t93.98–628.6 g/m2\t\nLVMI at most recent follow-up (time since ERT initiation)\t\nCRIM-negative\t24\t62.9 g/m2\n (84 weeks)\t46.0–257.0 g/m2 (9–437 weeks)\t\nCRIM-positive\t8\t69.7 g/m2\n (73 weeks)\t61.0–174.6 g/m2 (23–102 weeks)\t\nN, number; CRIM, cross-reactive immunologic material; ERT, enzyme replacement therapy; LVMI, left ventricular mass index.\n\nAnti-rhGAA IgG Antibody Titers (Table 3)\nOf the 34 IPD patients, 30 patients [88%; 21 CRIM-negative (84%) and 9 CRIM-positive (100%)] were immune tolerant with the longest follow-up of 348 weeks following ITI. Of these 30 IPD patients, sixteen (47%; 11 CRIM-negative and 5 CRIM-positive) remained seronegative (did not develop detectable anti-rhGAA IgG antibodies) and 14 (41%; 10 CRIM-negative and 4 CRIM-positive) developed low antibody titers (defined as titers of ≤6,400) throughout the course of ERT. Of the four CRIM-negative IPD patients who failed to tolerize, two (6%) (CN10 and CN12) developed sustained intermediate titers (titers of ≥12,800 and <51,200) and two (6%) (CN13 and CN21) developed high and sustained antibody titers (titers of ≥51,200 on two or more occasions). None of the CRIM-positive IPD patients who received immunomodulation developed SIT or HSAT. There was no recognizable difference in baseline characteristics between CRIM-negative IPD patients who developed HSAT/SIT and those who maintained low/negative anti-rhGAA IgG antibody titers (Table 1). The median peak anti-rhGAA IgG antibody titers were 200 (range, 0–51,200) and 0 (range, 0–200) for ITI treated CRIM-negative and CRIM-positive IPD groups, respectively (Table 2). The median peak anti-rhGAA IgG antibody titers were 0 (range, 0–6,400) for tolerized (n = 21) and 38,400 (range, 25,600–51,200) for nontolerized CRIM-negative IPD patients (n = 4). The median anti-rhGAA IgG antibody titers at the final assessment were 100 (range, 0–51,200) for ITI treated CRIM-negative IPD and 0 (range, 0–100) for ITI treated CRIM-positive IPD at the median timepoint following ERT initiation of 108 weeks (range, 19–351 weeks) and 104 weeks (range, 35–272 weeks) for ITI treated CRIM-negative and CRIM-positive groups, respectively (Figure 1). The median anti-rhGAA IgG antibody titers at the final assessment were 0 (n = 21; range, 0–6,400) and 19,200 (n = 4; range, 3,200–51,200) for tolerized and nontolerized CRIM-negative IPD patients, respectively. Overall, 88% of IPD patients who received immunomodulation in the ERT-naïve setting either remained seronegative or maintained low anti-rhGAA IgG antibody titers (Table 3).\n\nTable 3 B cell reconstitution, infections, vaccination, anti-rhGAA IgG antibody titers, and ITI protocol deviations in IPD patients treated with immunomodulation.\n\nID\tRounds of ITI\tB Cell recovery (weeks post-RTX)\tWeeks post-RTX at last CD19% follow-up\tInfections\tVaccination prior to ERT\tVaccination up to date for age\tAnti-rhGAA IgG antibody titers\tITI protocol deviations\t\n\t\t\t\t\t\t\tPeak titers (weeks on ERT)\tLast titers (weeks on ERT)\tImmune tolerant (Yes/No)\t\t\nALIVE PATIENTS\t\nCN1\t1\tYes (17)\t17\tNo\tNA\tYes\t1,600 (38)\t200 (103)\tYes\tDid not receive IVIG\t\nCN3\t1\tYes (19)\t43\tEnterococcus faecalis, Pseudomonas fluorescens/putida, Enterococcus raffinosus\tNA\tYes\t0\t0 (281)\tYes\tIVIG: 1 dose during ITI + 2 doses after ITI\t\nCN4\t1\tYes (17)\t21\tRSV infection\tNA\tYes\t0\t0 (284)\tYes\tIVIG started at Week 4 on ERT\t\nCN5\t1\tYes (11)\t73\tNo\tNA\tYes\t0\t0 (269)\tYes\tNone\t\nCN10\t2\tYes (19)\t195\tNo\tNA\tYes\t25,600 (198)\t25,600 (198)\tNo\tMaintenance rituximab every 2 to 3 months following ERT+ITI for 32 months\t\nCN11\t1\tYes (32)\t156\tNo\tNA\tYes\t200 (69)\t0 (351)\tYes\t3rd cycle of MTX was administered with 4th ERT infusion instead of 3rd ERT infusion\t\nCN12\t1\tYes (25)\t33\tKlebsiella pneumoniae\tNA\tYes\t25,600 (94)\t3,200 (258)\tNo\tNone\t\nCN13\t>2\tYes (17)\t208\tNo\tYes\tYes\t51,200 (71)\t12,800 (343)\tNo\tMultiple cycle of ITI\t\nCN14\t1\tYes (25)\t82\tAspiration pneumonia, enterovirus/rhinovirus\tYes\tYes\t200 (81)\t200 (81)\tYes\tNone\t\nCN16\t1\tYes (27)\t91\tNo\tNo\tYes\t0\t0 (174)\tYes\tNone\t\nCN17\t1\tYes (13)\t29\tNo\tNA\tYes\t6,400 (54)\t3,200 (135)\tYes\tNone\t\nCN18\t1\tYes (13)\t45\tURI rhinorrhea; UTI E. Coli; Ear infection\tYes\tYes\t200 (34)\t100 (161)\tYes\tNone\t\nCN19\t1\tYes (17)\t159\tNA\tYes\tYes\t0\t0 (112)\tYes\tNone\t\nCN20\t1\tYes (13)\t13\tNA\tYes\tNo\t0\t0 (19)\tYes\tNone\t\nCN22\t1\tYes (16)\t29\tNo\tNo\tNo\t200 (108)\t200 (108)\tYes\tNone\t\nCN23\t1\tYes (20)\t102\tNo\tYes\tYes\t0\t0 (144)\tYes\tNone\t\nCN24\t1\tYes (12)\t36\tNo\tNA\tNA\t0\t0 (31)\tYes\tNone\t\nCN25\t1\tYes (19)\t19\tNo\tNo\tNo\t0\t0 (31)\tYes\tNone\t\nCP1\t1\tYes (18)\t21\tNA\tYes\tNA\t0\t0 (35)\tYes\tNone\t\nCP2\t1\tYes (13)\t248\tNA\tYes\tYes\t0\t0 (171)\tYes\tNone\t\nCP3\t1\tYes (43)\t75\tNA\tNA\tNA\t100 (4)\t100 (78)\tYes\tNone\t\nCP4\t1\tYes (19)\t19\tNA\tNo\tYes\t200 (22)\t0 (272)\tYes\tNone\t\nCP5\t1\tYes (13)\t53\tNA\tYes\tYes\t0\t0 (39)\tYes\tNone\t\nCP6\t1\tYes (14)\t164\tNA\tNA\tYes\t0\t0 (117)\tYes\t2nd cycle of MTX was withheld. Three cycles of MTX administered with 1st, 3rd, and 4th ERT infusions.\t\nCP7\t1\tYes (15)\t37\tNo\tNo\tYes\t100 (66)\t100 (66)\tYes\tNone\t\nCP8\t1\tYes (17)\t141\tNA\tNA\tYes\t0\t0 (105)\tYes\tNone\t\nCP9\t1\tYes (12)\t28\tNA\tYes\tYes\t200 (26)\t100 (104)\tYes\tNone\t\nDECEASED PATIENTS\t\nCN2\t1\tYes (23)\t51\tNo\tNA\tYes\t0\t0 (67)\tYes\tTwo doses of MTX with 3rd ERT infusion and additional cycles of MTX administered with 4th, 5th, and 6th ERT infusions. Did not receive IVIG.\t\nCN6\t1\tNA\tNA\tNo\tNo\tYes\t0\t0 (70)\tYes\t14 cycles of MTX administered with first 14 ERT infusions (Total 42 doses). Did not receive IVIG.\t\nCN7\t2\tYes (55)\t59\tNo\tYes\tYes\t6,400 (31)\t3,200 (91)\tYes\tReceived a second cycle of ITI\t\nCN8\t2\tYes (43)\t43\tNo\tNA\tYes\t6,400 (29)\t6,400 (46)\tYes\tReceived a second cycle of ITI\t\nCN9\t1\tYes (22)\t35\tNo\tNA\tYes\t1,600 (38)\t800 (45)\tYes\tIVIG initiated at Week 4 on ERT\t\nCN15\t1\tYes (22)\t31\tNo\tYes\tNo\t200 (3)\t200 (32)\tYes\tNone\t\nCN21\t1\tYes (13)\t17\tNA\tYes\tYes\t51,200 (65)\t51,200 (72)\tNo\tNone\t\nRTX, rituximab; ERT, enzyme replacement therapy; NA, not available; wks, weeks; ITI, immune tolerance induction; MTX, methotrexate; IVIG, intravenous immunoglobulin.\n\nFigure 1 Longitudinal anti-rhGAA IgG antibody titers in IPD patients treated with immune tolerance induction. CRIM, cross-reactive immunologic material. CN, CRIM-negative; CP, CRIM-positive; ERT, enzyme replacement therapy; ITI, immune tolerance induction; SIT, sustained intermediate titer; HSAT, high and sustained antibody titer; rhGAA, recombinant human acid alpha-glucosidase.\n\nSafety Measures\nANC, ALT, and AST Data\nIn the first 10 weeks on ERT and ITI, AST and ALT data were available for 28 IPD patients. Only one IPD patient (CN14) had an increase in AST >3 times baseline value and subsequently decreased to baseline levels 6 weeks following the last dose of rituximab. None of the other IPD patients exhibited such an increase in AST or ALT during immunomodulation. AST decreased to baseline levels 6 weeks following the last dose of rituximab. Moreover, since methotrexate and rituximab can induce neutropenia, ANC data for the first 10 weeks on ITI were analyzed and were available in 21 IPD patients. Eight patients (6 CRIM-negative and two CRIM-positive; patients: CN10, CN11, CN12, CN13, CN16, CN24, CP6, and CP7) developed ANCs of <750 cells/mm3 following immunomodulation. Neutropenia was transient and ANC level returned to normal in all patients within 23 weeks following cessation of immunomodulation.\n\nInfections During Immunomodulation\nDetailed information on the presence or absence of infections during ITI was available for 23 IPD patients (Table 3): five patients (CN3, CN4, CN12, CN14, and CN18) experienced infections while immune suppressed (23). Of these five IPD patients, details on four IPD patients have been reported previously (23). Central line infections and bacteremia were observed in Patient CN3 (Enterococcus faecalis, Pseudomonas fluorescens/putida, and Enterococcus raffinosus) and Patient CN12 (Klebsiella pneumoniae) requiring central line removal and antibiotic treatment. Patient CN4 had a respiratory syncytial virus infection and Patient CN14 suffered an episode of aspiration pneumonia and enterovirus/rhinovirus infection during immunomodulation. Patient CN18 experienced rhinorrhea, ear infection, and Escherichia coli urinary tract infection 4 weeks following completion of rituximab administration. Infections were managed with antibiotics without interrupting ERT infusions or ITI therapy. Overall, ITI was safely tolerated without any life-threatening infections.\n\nB Cell Reconstitution\nLongitudinal follow-up of CD19% was available for 33 IPD patients (except patient CN6), with the longest follow-up of 248 weeks following the last dose of rituximab (Table 3). T cell percentages (CD3+, CD4+, CD8+) were within normal ranges for age making CD19% an appropriate measure for B cell reconstitution (Supplementary Figure 2). Complete B cell reconstitution, defined as normalization of CD19% for age, was seen in all 33 IPD patients. The median time to B cell depletion was 3 weeks (n = 31; range, 1–5 weeks) following initiation of ERT + ITI and the median time to complete B cell reconstitution was 17 weeks (n = 33; range, 11–54 weeks) following the last dose of rituximab. Following B cell reconstitution, all patients continued to maintain normal B cell counts, as measured by CD19%, with a median follow-up of 43 weeks (n = 33; range, 11–248 week). B cell reconstitution within 3 months following the last dose of rituximab was observed in three IPD patients (CN5, CN24, and CP9) and three patients (CN7, CN8, and CP3) experienced B cell recovery later than 9 months following the last dose of rituximab.\n\nVaccination and Titers Against Vaccines\nData on routine vaccination prior to initiation of ITI were available on 19 IPD patients (13 CRIM-negative and 6 CRIM-positive) (Table 3). Of these 19 patients, 13 patients received age-appropriate vaccination prior to immunomodulation. Vaccination details post immunomodulation were available on 31 IPD patients (24 CRIM-negative and 7 CRIM-positive) and all except four CRIM-negative patients (CN15, CN20, CN22, and CN25) were up to date on their routine vaccination. Patient CN22 did not receive any vaccinations as per the decision of the parents/legal guardians. Patient CN15 was deceased, due to disease progression, prior to completion of routine immunization. Immunization was not yet resumed in Patients CN20 and CN25 at the time of database lock. After B cell reconstitution, titers against routine vaccines were performed in 12 patients (8 CRIM-negative and 4 CRIM-positive) and were categorized as adequate or inadequate based on the reference antibody values (Table 4). Two CRIM-positive IPD patients (CP2 and CP8) demonstrated an inadequate response to certain serotypes of the Pneumococcal vaccine. These two CRIM-positive IPD patients (CP2 and CP8) had an adequate humoral response to other vaccines where titers against the vaccine were performed. Four IPD patients (CN18, CN19, CN21, and CP2) had received age-appropriate vaccination prior to ITI and had titers against vaccines available (Tables 3, 4). All four IPD patients showed adequate humoral responses, although, it was not possible to determine if the response to the pre-ITI vaccine was maintained or lost, as all four patients received revaccination following complete B cell reconstitution after cessation of immunomodulation.\n\nTable 4 Humoral response to routine vaccinations.\n\nPatient\tTetanus\tDiphtheria\tMeasles\tMump\tRubella\tPneumoccocal\t\nCN3\tAdequate\tND\tAdequate\tAdequate\tAdequate\tAdequate\t\nCN11\tAdequate\tAdequate\tAdequate\tAdequate\tAdequate\tND\t\nCN12\tAdequate\tAdequate\tAdequate\tAdequate\tAdequate\tAdequate\t\nCN16\tAdequate\tAdequate\tND\tND\tND\tND\t\nCN17\tAdequate\tAdequate\tAdequate\tAdequate\tAdequate\tAdequate\t\nCN18\tAdequate\tAdequate\tAdequate\tAdequate\tND\tND\t\nCN19\tAdequate\tAdequate\tND\tAdequate\tAdequate\tND\t\nCN21\tAdequate\tAdequate\tND\tND\tND\tND\t\nCP2\tAdequate\tND\tAdequate\tAdequate\tAdequate\tInadequate\t\nCP6\tAdequate\tAdequate\tND\tND\tAdequate\tND\t\nCP8\tAdequate\tAdequate\tND\tND\tAdequate\tInadequate\t\nCP9\tND\tND\tND\tND\tND\tAdequate\t\nND, Not done.\n\nLeft Ventricular Mass Index (LVMI)\nLVMI at baseline was available for 28 IPD patients (20 CRIM-negative and 8 CRIM-positive) and at follow-up for 32 IPD patients (24 CRIM-negative and 8 CRIM-positive) (Table 5). Median LVMI at baseline was 178.2 g/m2 (n = 20; range, 55.5–448.9 g/m2) and 221.0 g/m2 (n = 8; range, 93.98–628.6 g/m2) for CRIM-negative and CRIM-positive IPD groups, respectively, with the upper limit of normal LVMI at 64 g/m2. Median LVMI at the most recent follow-up of CRIM-negative IPD patients was 62.9 g/m2 (n = 24; range, 46.0–257.0 g/m2) at a median time since ERT initiation of 84 weeks (range, 9–437 weeks). Median LVMI at the most recent follow-up of CRIM-positive IPD patients was 69.7 g/m2 (n = 8; range, 61.0–174.6 g/m2) at a median time since ERT initiation of 73 weeks (range, 23–102 weeks). It is important to note that all patients experienced decreases in their LVMI with 17 IPD patients (13 CRIM-negative and 4 CRIM-positive) having LVMIs within the normal range (below 64 g/m2) at the most recent follow-up. In contrast, CRIM-negative IPD patients from the original alglucosidase alfa clinical trials, who were not tolerized, but treated with ERT monotherapy, had progressive increases in their LVMI beyond the first 6 months on ERT (8, 9, 45, 46).\n\nTable 5 Efficacy of ERT + ITI.\n\nID\tLVMI\tMotor Status\tVentilation Status\tFeeding Status\t\n\tBaseline\tFinal assessment (weeks on ERT)\tBaseline\tFinal assessment (weeks on ERT)\tBaseline\tFinal assessment (weeks on ERT)\tBaseline\tFinal assessment (weeks on ERT)\t\nALIVE PATIENTS\t\nCN1\tNA\tNA\tHypotonia\tAmbulatory (378)\tNo support\tNo support (378)\tOral\tOral (378)\t\nCN3\t160.3\t57.8 (437)\tHead lag, severe hypotonia, and motor delay\tAmbulatory; wheelchair as needed, mostly for transportation (450)\tOxygen\tNo support (450)\tNG tube\tOral (450)\t\nCN4\t445.8\t68 (274)\tHead lag, and antigravity movements (arms> legs)\tCan move arms against gravity (286)\tOxygen and BiPAP at night\tInvasively ventilated (271)\tNG tube\tG Tube (271)\t\nCN5\t277\t80 (334)\tSevere hypotonia, floppy baby, and no head or neck control\tAmbulatory (76)\tOxygen\tNo support (76)\tNG tube\tOral (76)\t\nCN10\tNA\t58.4 (227)\tHypotonia\tAmbulatory (199)\tInvasively ventilated\tNo support (199)\tTP\tOral (199)\t\nCN11\t140.6\t53.7 (252)\tMotor status and milestones appropriate for the age\tAmbulatory (182)\tNo support\tNo support (213)\tOral\tCPAP with nasal mask (199)\t\nCN12\t156.7\t53.82 (208)\tHypotonia\tAmbulatory (273)\tNo support\tVest/cough assist (273)\tOral\tOral (273)\t\nCN13\tNA\t53.5 (217)\tHypotonia\tSeverely hypotonic, unable to hold head up, rollover, or sit unassisted. Can move both arms weakly (350)\tNo support\tInvasively ventilated (350)\tOral\tG Tube (350)\t\nCN14\t176\t48 (105)\tHypotonia\tNA\tBiPAP\tBiPAP (92)\tG tube\tG tube (92)\t\nCN16\t65.4\t58.8 (48)\tHead lag, and hypotonia\tNormal developmental milestones (58)\tCPAP for a week\tNo support (37)\tOral\tOral (37)\t\nCN17\t433.1\t49.9 (124)\tNormal symmetric bulk and appeared to have normal tone\tStands with support and braces, sitsunassisted rollsside to side, and can lift head up. Crawls and pushes to quadruped and creeps on hands and knees. (130)\tNo support\tNo support (130)\tOral\tG Tube, eating puree orally (130)\t\nCN18\t448.9\t62.7 (185)\tDelayed motor milestones\tAmbulatory (195)\tNasal O2\tRecommended CPAP at night (195)\tOral and NG tube\tOral (195)\t\nCN19\tNA\t63.02 (163)\tNA\tAmbulatory (162)\tNA\tNo support (162)\tNA\tOral (162)\t\nCN20\t180.4\t80.4 (23)\tHypotonia\tGeneralized hypotonia (50)\tNo support\tOvernight BiPAP (59)\tNG tube\tG tube (59)\t\nCN22\t211.9\t192.5 (26)\tMild hypotonia and delayed head control at 3 months but rolling\tAmbulatory. Walks, runs, jumps, feeds self, plays with siblings, dresses self, and walks upstairs (136)\tNo support\tNo support (136)\tNG tube\tNG tube and oral (136)\t\nCN23\t156.2\t60.2 (141)\tMild hypotonia\tAmbulatory; meeting developmental milestones (101)\tNo support\tNo support (101)\tOral\tOral (101)\t\nCN24\t158\t46 (47)\tDelayed milestones\tAmbulatory. Walking, running, and jumping (88)\tNo support\tNo support (156)\tOral\tOral (156)\t\nCN25\t55.5\t62.3 (9)\tAge appropriate gross motor skill development\tMeeting developmental milestones (27)\tNo support\tNo support (27)\tOral\tOral (27)\t\nCP1\t423.6\t75.1 (31)\tMild axial hypotonia with head lag\tAmbulatory with moderate hypotonia. Severe delay in gross motor development (196)\tNo support\tNo support (220)\tOral, NG Tube at night\tOral (220)\t\nCP2\t186\t61 (81)\tGood muscle strength and tone. Minimal head lag, lifts head up\tNot ambulatory. Does not move legs in supine, requires assistance for head control in supported sitting (274)\tNo support\tInvasively ventilated (274)\tNG Tube\tG Tube (274)\t\nCP3\t628.6\t174.6 (76)\tHead lag.\tAmbulatory. Mild proximal weakness (100)\tNo support\tNo support (411)\tOral\tOral (411)\t\nCP4\t251.7\t75.6 (23)\tNA\tAmbulatory. Uses a wheelchair for transportation (297)\tNo support\tOxygen at night (268)\tOral\tOral (297)\t\nCP5\t248\t105.3 (98)\tNA\tNA\tNA\tNA\tNA\tNA\t\nCP6\tNA\tNA\tGeneral hypotonia\tAmbulatory. Low muscle tone, global muscle weakness, and delayed motor skills (167)\tHigh flow nasal cannula\tNo support (167)\tNG Tube\tOral (167)\t\nCP7\t93.98\t64.2 (37)\tNormal muscle tone\tAmbulatory; Low tone (72)\tNo support\tNo support (72)\tOral\tOral (72)\t\nCP8\t194\t62 (70)\tRolling supine to left and right, and side lying\tAmbulatory (137)\tNo support\tNo support (137)\tOral\tOral (137)\t\nCP9\t122\t63 (102)\tSlightly decreased tone. Able to control head without support\tAmbulatory. Able to get up and down from the floor and steps with assistance (130)\tNo support\tNo support (135)\tOral\tOral (135)\t\nDECEASED PATIENTS\t\nCN2\tNA\t257 (63)\tHypotonia\tProp-sits unassisted, rolls from supine to side lying, and bears weight through lower extremities in supported standing (80)\tTransient ventilation for 3 days\tNo support (67)\tOral\tOral (80)\t\nCN6\t409.6\t92.3 (53)\tAxial hypotonia, withdraws extremities to stimulation, weak grasp\tSits with support and minimal capacity for weight-bearing on lower extremities (53)\tInvasively ventilated\tInvasively ventilated (off ventilator 10–12 hours a day) (58)\tG tube\tG tube (58)\t\nCN7\t317.2\t144.9 (54)\tHead lag and unable to sit or rollover\tStanding with support (46)\tInvasively ventilated\tOxygen and BiPAP at night (46)\tNJ Tube\tG Tube (46)\t\nCN8\t347.1\t107.9 (36)\tSevere hypotonia\tAble to move arms against gravity but near-complete lower extremity immobility (50)\tInvasively ventilated\tBiPAP at night (50)\tNG Tube\tG Tube (50)\t\nCN9\t220\t83 (39)\tUnable to independently hold head or sit unsupported\tNot able to hold head or sit unsupported (46)\tNo support\tInvasively ventilated (46)\tNG Tube\tGJ Tube (46)\t\nCN15\t127.5\t118.3 (28)\tHypotonia\tNot ambulatory (38)\tInvasively ventilated\tInvasively ventilated (38)\tNG tube\tG tube (38)\t\nCN21\t160.1\t76 (15)\tNA\tNot ambulatory, severely limited motor skills (56)\tInvasively ventilated\tInvasively ventilated (56)\tNG Tube\tG Tube (56)\t\nLVMI, left ventricular mass index; ERT, enzyme replacement therapy; ITI, immune tolerance induction; NA, not available; NG, nasogastric tube; TP, transpyloric.\n\nTwo CRIM-positive IPD patients had inadequate humoral response to Pneumoccocal vaccine while demonstrating adequate response to other age-appropriate vaccines. It is not clear if the lack of response to Pneumoccocal vaccine in these two patients was due to immunosuppression or normal variability in the efficacy of vaccine. As per the CDC, the efficacy of PCV13 is 45.6–75.0% and PPSV23 is 60–70%.\n\nOverall and Invasive Ventilator-Free Survival (Figure 2)\nOf the 34 IPD patients, 27 (18 CRIM-negative and all 9 CRIM-positive) were alive and seven were deceased (all CRIM-negative; CN2, CN6, CN7, CN8, CN9, CN15, and CN21) at the time of database lock. Among the living IPD patients, the median current age is 70.6 months (range, 8.1–148.8 months). Of the seven deceased CRIM-negative patients, the median age of death was 25.4 months (range, 15.0–63.2 months). The cause of death for all seven was cardiorespiratory failure due to disease progression and was unrelated to ITI. However, there were no statistically significant differences in either age at diagnosis (p = 0.0896) or age at ERT initiation (p = 0.0693) between living and deceased CRIM-negative IPD patients (Table 1). Mortality in this population better reflects the extent of pathology prior to treatment initiation.\n\nFigure 2 Kaplan-Meler survival analysis: overall and invasive ventilator-free survival. CN, CRIM-negative; CP, CRIM-positive; ERT, enzyme replacement therapy; ITI, immune tolerance induction.\n\nMedian age at ERT initiation was 3.0 months (range, 0.1–11.0 months) and 3.9 months (range, 0.4–6.7 months) and median age at diagnosis was 2.4 months (range, 0.0–10.9 months) and 3.2 months (range, 0.3–5.9 months) for living and deceased groups, respectively. Among living CRIM-negative IPD patients (n = 18) median age at diagnosis (2.0 months; range, 0.0–5.9 months) and median age at ERT initiation (2.5 months; range, 0.1–6.6 months) were earlier compared to the median age at diagnosis (3.2 months; range, 0.3–5.9 months) and median age at ERT initiation (3.9 months; range 0.4–6.7 months) in deceased CRIM-negative IPD patients (n = 7). Although lacking statistical significance, even a relatively short delay in ERT may impact extent of clinical benifits and lead to permanent muscle loss.\n\nAs previously reported, all CRIM-negative IPD patients from original clinical trials, who received ERT monotherapy, were either deceased or invasive ventilator-dependent by 27.1 months of age (17). In the current cohort of CRIM-negative IPD patients, 16 CRIM-negative IPD patients (64%) were living without the need for invasive ventilation with the age of the oldest survivor being 148.8 months (range, 8.1–148.8 months) (Figure 2). Invasive ventilator-free survival was significantly (p = 0.0010) improved in CRIM-negative IPD patients who received ERT with ITI compared to ERT monotherapy.\n\nIn the current analysis, at baseline, eleven CRIM-negative (CN1, CN9, CN11, CN12, CN13, CN17, CN20, CN22, CN23, CN24, and CN25) and seven CRIM-positive (CP1, CP2, CP3, CP4, CP7, CP8, and CP9) IPD patients did not require any respiratory support whereas six CRIM-negative IPD patients (CN2, CN6, CN7, CN8, CN15, and CN21) were invasively ventilated (Table 5). Of these six invasively ventilated IPD patients, three (CN7, CN8, and CN10) were able to come off invasive ventilation with patient CN10 requiring no respiratory support at the most recent follow-up. At the most recent follow-up, 13 CRIM-negative (CN1, CN2, CN3, CN5, CN10, CN11, CN16, CN17, CN19, CN22, CN23, CN24, and CN25) and 6 CRIM-positive (CP1, CP3, CP6, CP7, CP8, and CP9) IPD patients did not require respiratory assistance whereas six CRIM-negative (CN4, CN6, CN9, CN13, CN15, CN21) and one CRIM-positive (CP2) IPD patients were invasively ventilated.\n\nDiscussion\nThe negative impact of high and sustained anti-rhGAA IgG antibody titers to treatment response has been evident since the first clinical trial of alglucosidase alfa (46). Although the published literature has supported that abrogation of the immune response to ERT improves the efficacy of ERT in patients with Pompe disease (22, 23, 47), the long-term safety with the use of rituximab in such a young and medically fragile population has been an outstanding concern, thus prompting this study. This is the largest cohort of CRIM-negative and CRIM-positive IPD patients, to our knowledge, treated with ITI in the ERT-naïve setting with the longest follow-up of 148 months on ERT. It is also the youngest cohort of patients that have received rituximab for any indication; 16 patients were initiated on rituximab ages ≤3 months. In the published literature, the experience on safety of rituximab has been reported on patinets aged 4 months to 18 years (33–35, 38, 48–53).\n\nWe found important clinical improvements from the initiation of a short course of ITI with rituximab, methotrexate, and IVIG concomitant with ERT. These improvements included reduced need for mechanical ventilation, LVMI, improved motor ability and longer overall survival. Importantly, three CRIM-negative IPD patients, who were invasively ventilated at baseline, no longer required invasive ventilation at the most recent follow-up, demonstrating a significant reversal in the disease course. This was an important finding as IPD patients are rarely able to come off ventilatory support once invasively ventilated. This further demonstrates the benefits of initiation of a short course of ITI with rituximab, methotrexate, and IVIG concomitant with ERT.\n\nImmunomodulation was largely successful in reducing the development of anti-rhGAA IgG antibody titers. Thirty patients with IPD (88%), who received prophylactic ITI, either did not develop (n = 16) or maintained low anti-rhGAA IgG antibody titers (n = 14). Four CRIM-negative IPD patients developed anti-rhGAA IgG antibody titers in the SIT or HSAT ranges; one of the SIT patient's rhGAA IgG antibody titers subsequently decreased to 3,200 at the final assessment. There were no recognizable differences in baseline characteristics between IPD patients who maintained low antibody titers and IPD patients who developed SIT or HSAT. There is no apparent explanation as to why these four IPD patients did not respond to ITI similarly to other patients in the current cohort. One hypothesis for the lack of response is resistance to rituximab. Rituximab resistance is known to be a common occurrence in naïve patients; however, its mechanism is incompletely understood. The potential mechanism of rituximab resistance is Fc receptor genetic variants affecting the affinity of effector cells for rituximab, complement depletion, and loss or decreased expression of CD20 on target antigen (54). Another possible reason for the development of high sustained anti-rhGAA IgG antibody titers in a few cases (CN10, CN12, CN13, and CN21) is incomplete B cell depletion. Rituximab has important limitations in that it doesn't deplete plasma cells, as they do not express CD20. Additionally, murine models have shown that 5% of B cells in lymph nodes survive CD20 depletion strategies (55). Although another recognized challenge with the use of rituximab is infusion-related reactions; with an incidence of infusion-related reactions of 25% of NHL patients and 25% of CLL patients interestingly, we did not observe any infusion-related reactions to rituximab in the current cohort of IPD patients.\n\nMajor concerns with the use of rituximab in patients with neoplastic and autoimmune disorders consist of significant delays in B cell recovery, skewing of B cell subpopulation to immature phenotype, and inability to mount a protective humoral response to vaccines (32). The addition of methotrexate to rituximab in the immunosuppressive regimen IPD patients receive only heightens the potential concerns. Much of the published data on rituximab originated from the treatment of adult populations where the extent of symptomatic hypogammaglobulinemia with an average of 4–6% of patients on rituximab requiring IVIG for symptomatic hypogammaglobulinemia. Persistent hypogammaglobulinemia was seen in up to 40% of patients on rituximab (usually those on long courses of rituximab to treat lymphoma), vaccine response was sometimes altered, and B cell reconstitution could take up to 24 months (36, 37). Small studies in pediatric populations have been more optimistic showing normalization of B cells by 1 year in nearly all patients, regardless of indication or duration of rituximab, and hypogammaglobulinemia rates at a maximum of 22% (33, 34, 38, 52). Our cohort of IPD patients is the largest group of patients under 1 year of age evaluated for rituximab impact. Most notably, all of the IPD patients experienced complete B cell reconstitution after discontinuation of rituximab with a relatively fast median time to reconstitution (median = 17 weeks) supporting the contention that the younger the patient the more rapid the reconstitution after immunomodulation with rituximab.\n\nMethotrexate is an inhibitor of dihydrofolate reductase, an enzyme necessary for the synthesis of purine nucleotides and thymidylate. It predominantly affects rapidly dividing cells, such as lymphocytes, by interfering with DNA synthesis and repair. In addition to impacting B and T cells, methotrexate can help to prevent the development of ADA to rituximab.Methotrexate's ability to prevent ADA development stems from different lines of evidence- A murine study showed that methotrexate's interaction with BAFF (B cell activating factor of the TNF family), a driver of B cell activation, is important in the prevention of ADA development (28, 29). In rheumatic disease, concomitant therapy with a biologic and methotrexate prevented the development of antibodies against the biologic (30). Available data on methotrexate's impact on B cells indicate that it does not impact the overall CD19% but rather impacts B cell subsets and immunoglobulin levels (56–58). Our tracking of B cell depletion is limited by inconsistent collection of absolute counts with consistent reporting of CD19%. Future analysis will be necessary to assess B cell subsets and immunoglobulin levels during immunomodulation and immune reconstitution.\n\nAlthough data were available for a small number of patients (titers available for 12 patients), patients generally had protective vaccine titers to polysaccharide (T cell-independent) antigen and conjugated (T cell-dependent) antigen. All IPD patients demonstrated an adequate humoral response against tetanus and diphtheria vaccines, and all except two CRIM-positive IPD patients (CP2 and CP8) had adequate pneumococcal titers. It is not clear if the lack of response to polysaccharide vaccines in these two patients was due to immunosuppression or normal variability in response to pneumococcal vaccines.\n\nThe short course of prophylactic ITI was safely tolerated without any major adverse events. Although infections were reported in five CRIM-negative patients which required treatment with antibiotics and central line removal in two patients, no interruption in ERT or immunomodulation was required in any of the patients. At the most recent follow-up, seven IPD patients were deceased at a median age of 25.4 months (range, 15.0–63.2 months). The cause of death was cardiorespiratory failure due to disease progression and was unrelated to immunomodulation but likely pertained to the extent of disease progression prior to treatment. Overall survival was significantly (p = 0.0001) improved in CRIM-negative IPD patients who received ITI with ERT compared to CRIM-negative IPD patients on ERT monotherapy.\n\nVarious immunomodulation strategies using rituximab in patients with Pompe disease have been reported in the literature. The combination of rituximab, methotrexate, with or without IVIG initiated along with the first ERT infusion, as shown in the current study, has proven to be the most successful strategy in inducing immune tolerance in patients with IPD (25). The immunomodulation strategy reported by Elder et al. used a combination of rituximab, mycophenolate/sirolimus, and IVIG in five IPD patients (four CRIM-negative and one CRIM-positive) (27). This protocol required long-term immune suppression and more significantly delayed ERT initiation by at least 3 weeks which can be very detrimental in a rapidly progressive irreversible muscle disease (59). Poelman et al. utilized a combination of rituximab, methotrexate, and IVIG similar to our ITI protocol, however, with a different dosing schedule of methotrexate, in three IPD patients (one CRIM-negative and two CRIM-positive) (26). All three patients developed anti-rhGAA IgG antibodies with two developing HSAT. Although B cell reconstitution was observed in all three patients, B cell reconstitution also resulted in an increase in rhGAA IgG antibody titers. In contrast, our immunomodulation approach was able to tolerize 84% of CRIM-negative and 100% of CRIM-positive IPD patients as evidenced by the maintenance of low or complete absence of anti-rhGAA IgG antibody titers even well after B cell recovery (22, 23).\n\nTo our knowledge, this the largest cohort of patients with IPD treated with ITI in ERT-naïve settings and the largest cohort of pediatric patients under a year of age evaluated for the safety of rituximab. Overall, this short course of immune modulation in the ERT-naïve setting significantly increased the likelihood of achieving long-term immune tolerance to ERT and did not lead to any long-term sequelae. Patients who received ITI were able to receive routine vaccinations and demonstrated adequate humoral immune responses. The data suggest that short-course prophylactic immunomodulation with rituximab, methotrexate, and IVIG initiated in the ERT-naïve setting is safe and efficacious in achieving long-term immune tolerance to ERT. The addition of this ITI regimen to ERT is life-saving and our data show that the benefits of adding immune modulation (ITI regimen) outweigh the risks in this setting.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/Supplementary Material.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Duke Health Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\nConception and study design and development of methodology were performed by AD and PK. Analysis and interpretation of data were performed by AD, CB, JS, and PK. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nAD has received research support from Sanofi Genzyme and Lysosomal Disease Network (LDN). CB has received research support from the National Institute of Health (NIH) T32 training grant (Award number AI007062-38). PK has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics, consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Vertex Pharmaceuticals and Asklepios Biopharmaceutical, Inc. (AskBio), is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies, and has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease. 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\nThe authors thank the patients who participated in this study and their families. We thank Cindy Li, BS of Duke University Medical Center for her help with data acquisition. The authors acknowledge the editorial assistance of Heidi Cope, MS, CGC of Duke University Medical Center.\n\nFunding. This research was supported by a grant from Sanofi Genzyme (Cambridge, Massachusetts, USA), and supported in part by the Lysosomal Disease Network (LDN). The Lysosomal Disease Network (2U54NS065768-06) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS, funded through a collaboration between the NCATS, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.01727/full#supplementary-material\n\nSupplementary Figure 1 In patients with Pompe disease receiving ERT at dose of 20 or 40 mg/kg every other week, ITI with rituximab (4 weekly doses), methotrexate (3 cycles with first 3 ERT infusions; total 9 doses), and IVIG (every 4 weeks) is admintered as described in the figure. *For patients receiving ERT at dose of 20 mg/kg or 40 mg/kg weekly, three cycle of methotrexate is administered with first three ERT infusion at weeks 0–2. The dosing of rituximab and IVIG remains the same.\n\nClick here for additional data file.\n\n Supplementary Figure 2 CD3 10th Percentile, CD4 10th Percentile, CD8 10th Percentile, and CD19 10th Percentile represent the lower limit of age-appropriate normal range for respective lymphocye subset.\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Boustany RM . Lysosomal storage diseases–the horizon expands\n. Nat Rev Neurol. (2013 ) 9 :583 –98\n. 10.1038/nrneurol.2013.163 23938739 \n2. Platt FM d'Azzo A Davidson BL Neufeld EF Tifft CJ \nLysosomal storage diseases\n. Nat Rev Dis Primers. (2018 ) 4 :27 \n10.1038/s41572-018-0037-0 30275469 \n3. Sun A . Lysosomal storage disease overview\n. Ann Transl Med . (2018 ). 6 :476 . 10.21037/atm.2018.11.39 30740407 \n4. Parenti G Andria G Valenzano KJ . Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders\n. Mol Ther. 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "alglucosidase alfa; anti-drug antibodies; anti-rhGAA IgG antibody; enzyme replacement therapy; immune tolerance induction; immunogenicity",
"medline_ta": "Front Immunol",
"mesh_terms": "D000906:Antibodies; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D056947:Enzyme Replacement Therapy; D005260:Female; D006009:Glycogen Storage Disease Type II; D006801:Humans; D007108:Immune Tolerance; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D008727:Methotrexate; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D000520:alpha-Glucosidases",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "1727",
"pmc": null,
"pmid": "32849613",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29162675;25987172;24909567;23938739;22935624;21889385;22538254;11286229;12138068;12531800;29936438;22970722;29569510;23825616;30076384;23601496;26685070;14610491;16737883;19816575;19129538;26597321;29428273;19542901;19775921;19421786;22237443;28814660;25881001;20238230;25643241;18808404;31392203;19287243;17151339;16352811;7506951;17570702;26277594;21637107;24920861;27027812;11705566;30214072;26827664;26567244;30740407;22252923;21658619;25741864;31193175;28230306;25117653;31392197;16860134;30275469;25213054",
"title": "Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort.",
"title_normalized": "benefits of prophylactic short course immune tolerance induction in patients with infantile pompe disease demonstration of long term safety and efficacy in an expanded cohort"
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"abstract": "This case series demonstrates the potential of molecular profiling to improve selection of antitumor therapies in the treatment of patients with neuroendocrine and carcinoid tumors. Carcinoid tumors resected at one institution over a 3-year period were sent for molecular profiling to guide choice of treatment. Potentially beneficial therapies were identified based on the measured expression of 20 proteins and oncogenes and a comprehensive review of the chemotherapy response literature. The clinical charts of 41 patients were reviewed retrospectively, and 12 were selected as representatives of the range of effects molecular profiling has on carcinoid treatment. Their presentation, molecular profile results, treatment, and disease progression is reviewed in the following case series. A total of nine patients were treated with drugs identified as potentially beneficial by molecular profile reports. These include capecitabine, 5-fluorouracil, temozolomide, oxaliplatin, and gemcitabine. Based on clinical symptoms, serum markers of disease, and radiographic evidence five of nine patients responded to treatment, two had mixed responses, and two did not respond to treatment. At this early juncture, our critique of molecular profiling for neuroendocrine tumors is favorable, as a significant number of our patients responded to drugs identified by molecular profiling as potentially beneficial.",
"affiliations": "Icahn School of Medicine at Mount Sinai, New York, New York, USA.",
"authors": "Cutler|Holt S|HS|;Ogando|Paul|P|;Uhr|Joshua H|JH|;Gonzalez|Dani O|DO|;Warner|Richard R P|RR|;Divino|Celia M|CM|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-1348",
"issue": "82(4)",
"journal": "The American surgeon",
"keywords": null,
"medline_ta": "Am Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D002276:Carcinoid Tumor; D017024:Chemotherapy, Adjuvant; D000066491:Clinical Decision-Making; D004067:Digestive System Neoplasms; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0370522",
"other_id": null,
"pages": "369-75",
"pmc": null,
"pmid": "27097632",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of Molecular Profiling to Guide Treatment Decisions in Patients with Neuroendocrine Tumors: Preliminary Results.",
"title_normalized": "use of molecular profiling to guide treatment decisions in patients with neuroendocrine tumors preliminary results"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-021276",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
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"drugadditional": null,
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{
"abstract": "Late growth of infantile hemangiomas is an uncommon complication. We report three patients with segmental facial hemangiomas who experienced late growth and recurrent ulceration predominantly of the lower lip. These patients shared common clinical features including involvement of the S3 facial segment, oral and airway hemangiomas, and vascular anomalies associated with PHACE syndrome. This report highlights a clinical presentation at-risk for late growth and recurrent ulceration.",
"affiliations": "Division of Dermatology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio, USA.;Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA.",
"authors": "Fernandez Faith|Esteban|E|https://orcid.org/0000-0002-8641-6730;Cordisco|Maria|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14253",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "37(5)",
"journal": "Pediatric dermatology",
"keywords": "PHACE syndrome; hemangioma; propranolol; segmental hemangioma; ulceration",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D005145:Face; D006391:Hemangioma; D006801:Humans; D007223:Infant; D013577:Syndrome; D054079:Vascular Malformations",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "884-889",
"pmc": null,
"pmid": "32639025",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Unrelenting facial segmental hemangiomas: A case series of late growth and recurrent ulcerations.",
"title_normalized": "unrelenting facial segmental hemangiomas a case series of late growth and recurrent ulcerations"
} | [
{
"companynumb": "US-PFM-2021-05667",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": "4",
... |
{
"abstract": "Ceftaroline is increasingly prescribed for \"off-label\" indications involving longer durations and higher doses. There have been postmarketing case reports of neutropenia among patients who have received extended durations of ceftaroline, but limited published data currently exist on its incidence and risk factors. We review a total of 37 published cases of ceftaroline-associated neutropenia including cases (n = 4) identified in our health care system. The median time from ceftaroline initiation to development of neutropenia (range) was 25 (8-125) days, with a median duration of neutropenia (range) of 4 (1-16) days. Agranulocytosis (absolute neutrophil count [ANC] nadir < 100 cells/mm3) developed in 49% of cases (n = 18), and there was an ANC nadir of 0 in 27% (n = 10). The overall incidence of neutropenia among cases receiving ceftaroline for ≥7-14 days (range) was 12% (7%-18% per individual study), higher than for comparator antibiotics in the literature. Risk factors for ceftaroline-associated neutropenia varied among studies and remain poorly defined.",
"affiliations": "Pharmacy Department, Scripps Mercy Hospital, San Diego, California.;School of Pharmacy, Pacific University, Hillsboro, Oregon.;Pulmonary & Critical Care Medicine, Louisiana State University Health/Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana.;Internal Medicine Department, Scripps Mercy Hospital, San Diego, California.",
"authors": "Sullivan|Eva L|EL|;Turner|R Brigg|RB|;O'Neal|Hollis R|HR|;Crum-Cianflone|Nancy F|NF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz168",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n31123688\n10.1093/ofid/ofz168\nofz168\nReview Article\nCeftaroline-Associated Neutropenia: Case Series and Literature Review of Incidence, Risk Factors, and Outcomes\nSullivan Eva L 1 Turner R Brigg 2 O’Neal Hollis R Jr3 Crum-Cianflone Nancy F 45 1 \nPharmacy Department, Scripps Mercy Hospital, San Diego, California\n2 \nSchool of Pharmacy, Pacific University, Hillsboro, Oregon\n3 \nPulmonary & Critical Care Medicine, Louisiana State University Health/Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana\n4 \nInternal Medicine Department, Scripps Mercy Hospital, San Diego, California\n5 \nInfectious Disease Division, Scripps Mercy Hospital, San Diego, California\nCorrespondence: E. L. Sullivan, PharmD, Scripps Mercy Hospital, 4077 Fifth Ave, San Diego, CA 92103 (sullivan.eva@scrippshealth.org).\n5 2019 \n28 3 2019 \n28 3 2019 \n6 5 ofz16807 2 2019 27 3 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nCeftaroline is increasingly prescribed for “off-label” indications involving longer durations and higher doses. There have been postmarketing case reports of neutropenia among patients who have received extended durations of ceftaroline, but limited published data currently exist on its incidence and risk factors. We review a total of 37 published cases of ceftaroline-associated neutropenia including cases (n = 4) identified in our health care system. The median time from ceftaroline initiation to development of neutropenia (range) was 25 (8–125) days, with a median duration of neutropenia (range) of 4 (1–16) days. Agranulocytosis (absolute neutrophil count [ANC] nadir < 100 cells/mm3) developed in 49% of cases (n = 18), and there was an ANC nadir of 0 in 27% (n = 10). The overall incidence of neutropenia among cases receiving ceftaroline for ≥7–14 days (range) was 12% (7%–18% per individual study), higher than for comparator antibiotics in the literature. Risk factors for ceftaroline-associated neutropenia varied among studies and remain poorly defined.\n\nceftarolineincidenceneutropeniareviewside effects\n==== Body\nThe development of novel antibiotics is important in addressing the growing rates of antibiotic resistance. For instance, Staphylococcus aureus remains a leading cause of bacteremia and endocarditis, with an increasing preponderance due to methicillin-resistant S. aureus (MRSA) strains [1, 2]. Given the limitations of the currently available antibiotics (eg, vancomycin) for treating MRSA infections, including drug intolerance, adverse events, and/or clinical failure [3, 4], new antibiotics with anti-MRSA activity have been recently developed.\n\nCeftaroline (Teflaro®) gained Food and Drug Administration (FDA) approval in 2010 and is the first licensed cephalosporin that includes coverage against MRSA. Studies leading to its approval include 2 clinical trials on community-acquired bacterial pneumonia (CABP; FOCUS 1 and FOCUS 2) [5, 6] and 2 additional studies on acute bacterial skin and skin structure infections (ABSSSIs; CANVAS 1 and CANVAS 2) [7, 8]. These 4 studies evaluated a total of 1307 subjects, with the most common adverse events among those receiving ceftaroline being diarrhea, nausea, and rash; no patient developed neutropenia. All studies utilized a ceftaroline dosage of 600 mg intravenously (IV) every 12 hours for durations of 5–14 days [5–8]. More recently, approval for bacteremia in the setting of ABSSSI has been added as an indication for ceftaroline use [9].\n\nPostmarketing data are important for detecting unexpected adverse events associated with newly marketed drugs, especially when they are utilized for “off-label” use, an increasingly common practice for multidrug-resistant organism (MDRO) infections with limited treatment options. As such, ceftaroline has been utilized to treat MRSA bacteremia, endocarditis, and orthopedic infections [3, 10]. For these indications, ceftaroline has often been utilized for longer treatment durations (up to ≥6 weeks). Further, higher doses of ceftaroline have often been prescribed (600 mg IV every 8 hours vs 12 hours). This higher dosing frequency is based on pharmacokinetic studies suggesting that every-8-hour dosing may optimize time-dependent killing in severe infections involving high bacterial inoculums [11, 12], although clinical data to support this approach are currently lacking.\n\nData on potential adverse events associated with ceftaroline use, especially when utilized for longer durations or at higher doses, are needed. Hematologic effects are of particular interest, as long durations of β-lactam antibiotics may cause leukopenia [13]. To date, postmarketing case reports of neutropenia among patients receiving extended durations of ceftaroline have been published [14, 15]; however, data remain limited.\n\nHence, we conducted a case series of patients in our health care system who received ceftaroline for ≥7 days and subsequently developed incident neutropenia. In addition, given the limited data on the incidence as well as the timing and risk factors of ceftaroline-associated neutropenia, we conducted a review of the published literature to provide a comprehensive summary of this emerging adverse event.\n\nMETHODS\nCase Series: Study Setting and Patients\nOur health care system is comprised of 4 large urban hospitals with a total of 1400 available beds located in Southern California. Ceftaroline is restricted to the infectious diseases service and is typically reserved for complicated MRSA infections that have failed or are intolerant to firstline therapies. Adult patients who received consecutive ceftaroline therapy for ≥7 days during January 2010 to December 2017 were screened for study inclusion. This 7-day cutoff was selected based on the phase III studies having a mean/median ceftaroline duration of approximately 7 days with no subjects developing neutropenia [5–8] and previous noncomparative retrospective studies [16–18] identifying a higher neutropenia risk in patients receiving >7 days of therapy. We excluded patients who had neutropenia immediately before ceftaroline initiation or in whom an alternate cause of neutropenia was likely based on assessment by an infectious diseases physician, along with subsequent retrospective review by 2 authors (E.S., N.C.). In addition, the Naranjo Adverse Drug Reaction Probability Scale was applied to identified cases; a score of 3 or 4 indicated that the drug was a possible cause of neutropenia, and a score of 5 to 7 indicated that the drug was a probable cause of neutropenia [19].\n\nStudy Outcome\nThe primary outcome was the incidence of neutropenia during ceftaroline therapy. Neutropenia was defined as an absolute neutrophil count (ANC) of <1500 cells/mm3.\n\nReview of Literature\nA search of the published English medical literature (PubMed, Embase, Ovid Medline) from 2010 (the year of ceftaroline approval) to December 2017 was conducted. Keywords included “ceftaroline” or “cephalosporin” and “neutropenia,” “leukopenia,” or “agranulocytosis.” References from identified papers were reviewed for additional publications.\n\nTo be included in this review, cases had to be adults (≥18 years) who received ≥7 days of ceftaroline and subsequently developed new-onset neutropenia (ANC < 1500 cells/mm3). The Naranjo Adverse Drug Reaction Probability Scale was applied as above [19]. Cases in duplicative publications (eg, Blumenthal et al. and Furtek et al.) were counted once [16, 20]. Cases with preexisting neutropenia before ceftaroline use or cases receiving other agents expected to cause neutropenia (eg, chemotherapy) were excluded, as reported within the respective papers. For publications without individualized data in the original published manuscript, authors were contacted electronically and individualized data were requested; cases in which no or very limited individualized data could be obtained were excluded from this review.\n\nFor each identified case, data collected included demographics, underlying medical conditions, weight/body mass index, creatinine clearance, microbiology and location of infection, and initial antibiotic therapy. Data collected regarding ceftaroline use included indication, duration and dosage, and concurrent antibiotics. In addition, we evaluated if the recommended dosage adjustments were made based on creatinine clearance (CrCl; ≤50 mL/min) [21]. Baseline (at ceftaroline initiation) and nadir counts for the white blood cell count (WBC), neutrophil percentage, ANC, hemoglobin, and platelets were collected. Symptoms and signs at the time of neutropenia (eg, fever, rash) and any complications from the neutropenia were collected. The use of alternate antibiotics (after ceftaroline discontinuation) and G-CSF (for the management of neutropenia) was noted. Finally, the outcome of the patient and infection was collected. Missing data were accounted for within the denominator for each variable when calculating percentages.\n\nRESULTS\nCase Series\nA total of 61 patients received ceftaroline for ≥7 days in our health care system. Five of these patients were excluded: 4 patients for preexisting neutropenia and 1 patient who received a concurrent antimicrobial IV vancomycin, thought to be the cause of neutropenia based on evaluation by an infectious diseases physician.\n\nOverall, 4 (7%) of the 56 patients developed incident neutropenia without another identifiable cause. The duration of ceftaroline use among these 4 cases was 8, 20, 21, and 23 days, respectively. The duration among those without neutropenia was a median (range) of 14 (7–103) days. The score on the Naranjo Adverse Drug Reaction Probability Scale was 7 for each case. Concurrent medications that may be associated with neutropenia were reviewed, and it is important to note that neutropenia resolved despite continuation of these agents. These cases are summarized below and in Table 1.\n\nTable 1. Summary of Current Cases of Ceftaroline-Associated Neutropenia\n\nAge Sex\tMedical History\tBMI, kg/m2\tCeftaroline Indication and Duration, d\tDose/CrCl, mL/min\tInitial ANC and Nadir ANC, cells/mm3\tDays of Neutropenia\tG-CSF Use\tEosinophilia\tConcurrent Drugsa/ Antibioticsb at Time of Neutropenia\tAntibiotics Post-ceftaroline\tOutcome\t\n66 M\tAlcoholic/hepatitis C cirrhosis, polysubstance abuse, chronic kidney disease, diabetes mellitus\t26.5\tProsthetic knee infection × 8 d\t300 mg IV q8h/22\t2976/1172\t2\tNo\tYes (8.6%)\tQuetiapine/none\tDaptomycin\tFavorable\t\n59 F\tDiabetes mellitus, drug use\t28.1\tBacteremia, endocarditis, diskitis/osteomyelitis × 20 d\t400 mg IV q8h/47 \t4284/20\t10\tYes (2 doses)\tYes (36%)\tNone/daptomycin \tTelavancin\tFavorable\t\n26 F\tIV drug use\t26.5\tBacteremia, endocarditis × 21 d\t600 mg & 400 mg IV 8 h/100 & 45\t17 484/5\t7\tYes (7 doses)\tNo\tFamotidine/daptomycin \tDaptomycin + doxycycline\tFavorable\t\n44 M\tDiabetes mellitus, alcoholic cirrhosis\t25.1\tOsteomyelitis, endocarditis, endophthalmitis, and septic arthritis × 23 d\t600 mg IV q12 h/85\t1886/1472\t2\tNo\tYes (12%)\tFamotidine/daptomycin\tDaptomycin\tFavorable\t\nAbbreviations: ANC, absolute neutrophil count; BMI, body mass index; CrCl, creatinine clearance; G-CSF, granulocyte colony-stimulating factor; IV, intravenous.\n\n\naDrugs associated with neutropenia [33, 34].\n\n\nbAntibiotics not associated with neutropenia.\n\nCase 1\nA 66-year-old male was initiated on vancomycin IV for a MRSA prosthetic knee infection. Due to an increase in serum creatinine, vancomycin was switched to ceftaroline 300 mg IV every 8 hours (creatinine clearance of 22 mL/min) on hospital day 2. By day 9, the patient became neutropenic with an ANC of 1172 cells/mm3. On day 11, he continued to be neutropenic with an ANC of 1205 cells/mm3 (Figure 1A) and also developed eosinophilia (8.6%), at which time ceftaroline was switched to daptomycin. Follow-up WBC on day 14 was 2900 cells/mm3 (61.4% neutrophils).\n\nFigure 1. Absolute neutrophil count (ANC) trajectories for current cases.\n\nCase 2\nA 59-year-old female was treated with multiple antibiotic courses that included vancomycin and daptomycin for MRSA bacteremia with endocarditis. On day 24, antibiotics were changed to ceftaroline (renally adjusted at 400 mg IV every 12 hours × 3 days, then 400 mg IV every 8 hours for a CrCl of 47 mL/min) and daptomycin due to a newly discovered spinal infection including osteomyelitis and epidural abscess noted on imaging. On day 44 of hospitalization, she developed neutropenia with an ANC nadir of 20 cells/mm3, and ceftaroline was discontinued (Figure 1B). The patient’s neutropenia resolved after 10 days, with a follow-up ANC of 2223 cells/mm3, and the patient required broad-spectrum antibiotics and G-CSF due to neutropenic fevers. This case has been previously reported [22].\n\nCase 3\nA 26-year-old female was started on vancomycin IV for MRSA bacteremia complicated by endocarditis. On hospital day 3, ceftaroline 600 mg IV every 8 hours was added to vancomycin due to blood cultures remaining positive. Vancomycin was discontinued on day 14 because the patient developed acute renal failure. Daptomycin was then added to ceftaroline for additional coverage for MRSA endocarditis on day 20. After 21 days of ceftaroline therapy, the ANC had decreased to 4.5 cells/mm3, resulting in its discontinuation (Figure 1C). Neutropenia was present for 7 days, and G-CSF was administered daily for 7 days.\n\nCase 4\nA 44-year-old male with extensively disseminated MRSA infection including endocarditis, endophthalmitis, septic arthritis, and spinal osteomyelitis with abscesses was treated with vancomycin IV. On day 6, ceftaroline 600 mg IV every 8 hours was added due to persistent bacteremia. By day 8, vancomycin IV was changed to daptomycin due to continued positive blood cultures. Due to concern for eosinophilia (12%), ceftaroline was discontinued on day 54. On day 85, daptomycin was changed to combination therapy with linezolid and vancomycin IV due to worsening endophthalmitis. Vancomycin IV was subsequently changed to ceftaroline 600 mg IV every 12 hours on day 89. By day 90, the linezolid was changed to daptomycin due to cytopenias. Ceftaroline was discontinued at day 112 due to pancytopenia (WBC of 3100 cells/mm3, 48% neutrophils, ANC of 1472 cells/mm3) and eosinophilia (10%) (Figure 1D). By day 116, the pancytopenia and eosinophilia had improved, with a WBC at 4100 cells/mm3 with 52% neutrophils.\n\nReview of the Literature\nIn total, 37 cases were identified, including 5 single case reports [23–27]; 2 case series (3 and 4 cases, respectively) [14, 15] and 4 retrospective studies (with 4, 5, 7, and 9 cases, respectively) current study [16, 17, 28]. An additional 6 cases were found in the literature; however, individualized data could not be obtained [18, 29]. Detailed information for each case is provided in Supplementary Table 1.\n\nDemographics among the 37 cases of ceftaroline-associated neutropenia included in this review are in shown in Table 2. All cases with reported information on medical history had an underlying condition; the types of conditions varied widely, with the most common being illicit drug use, reported in 5 cases.\n\nTable 2. Summary Characteristics of Patients in the Systematic Review Receiving Ceftaroline who Developed Neutropenia, 2010–2017 (n = 37)\n\nDemographics\t\t\n Median age (range), y\t44 (20–90)\t\n Sex, female, No. (%)\t22 (59)\t\nInfection characteristics, No. (%)\t\t\nOrganism treated\t\t\n S. aureus (most commonly MRSA)\t31 (83)\t\n Streptococcus\t1 (3)\t\n Coagulase-negative Staphylococcus\t1 (3)\t\n Unknown\t4 (11)\t\nType of infection,a No. (%)\t\t\n Bacteremia\t8 (22)\t\n Heart/endocarditis\t10 (27)\t\n Orthopedic\t18 (49)\t\n Spinal/CNS\t5 (14)\t\n SSTI/wound\t4 (11)\t\n Endovascular NOS\t5 (14)\t\n Pneumonia\t5 (14)\t\nCeftaroline dosage, No. (%)\t\t\n CrCl > 50 mL/min\t\t\n 600 mg every 12 h\t15/22 (68)\t\n 600 mg every 8 h\t7/22 (32)\t\nCrCl 31–50 mL/min\t\t\n 600 mg every 12 h\t1/3 (33)\t\n 400 mg every 8 h\t2/3 (67)\t\nCrCl 15–30 mL/min\t\t\n 400 mg every 12 h\t1/2 (50)\t\n 300 mg every 8 h\t1/2 (50)\t\nCrCl NR\t\t\n 600 mg every 12 h\t5/7 (71)\t\n 600 mg every 8 h\t2/7 (29)\t\nDose NR\t3/3 (100)\t\nNeutropenia\t\t\n Median time to development (range), d\t25 (8–125)\t\n Nadir ANC < 100 cells/mm3, No. (%)\t18 (49)\t\n Mean duration of neutropenia (range), d\t4 (1–16)\t\n Concurrent antibiotic, yes, No. (%)\t12/30 (40)\t\n Concurrent renal insufficiency (CrCl < 60 mL/min), No. (%)\t7/27 (26)\t\nConcurrent hematologic effects, No. (%)\t\t\n New-onset anemia (drop of ≥2 mg/dL)\t6/25 (24)\t\n New-onset thrombocytopenia (drop of > 100 cells/ mm3)\t8/26 (31)\t\n Eosinophilia\t9/26 (35) \t\nNeutropenic complications, No. (%)\t\t\n Fever\t6 (16)\t\n Bacteremia\t1 (3)\t\nReceipt of G-CSF for neutropenia, No. (%)\t11 (30)\t\nOutcome, No. (%)\t\t\n Favorable\t37 (100)\t\nDenominator is n = 37, unless otherwise noted.\n\nAbbreviations: ANC, absolute neutrophil count; CNS, central nervous system; CrCl, creatinine clearance; G-CSF, granulocyte colony-stimulating factor; MRSA, methicillin-resistant Staphylococcus aureus; NOS, not otherwise specified; NR, not reported.\n\n\naSome patients had multiple sites of infection.\n\nThe organism most frequently being treated with ceftaroline was S. aureus, most commonly MRSA. Only 10 cases provided information on the rationale for ceftaroline use: clinical failure of prior antibiotic therapy in 6 cases, renal failure or concern for worsening renal function in 2 cases, decreasing WBC and platelet counts in 1 case, and a minimal inhibitory concentration of 2 µg/mL for vancomycin in 1 case. Two (7%) of 27 patients received higher-than-FDA-approved recommended doses based on their creatinine clearance among those with available data.\n\nThe median time from ceftaroline initiation to the development of neutropenia (range) was 25 (8–125) days. Only 2 cases had a ceftaroline duration of ≤14 days, 6 had a duration of 15–20 days, and 28 cases had been receiving ceftaroline for ≥21 days (1 case did not report the duration). Of note, many of the reviewed studies did not include patients who received ceftaroline for less than 7 or 14 days. The median duration of neutropenia (range) was 4 (1–16) days. Agranulocytosis (ANC nadir < 100 cells/mm3) developed in 49% of cases (n = 18), and there was an ANC nadir of 0 in 27% (n = 10).\n\nAt the time of neutropenia, 40% (12/30) were receiving concurrent antibiotics (4 daptomycin, 3 rifampin, 2 clindamycin, 1 rifampin plus trimethoprim-sulfamethoxazole, 1 rifampin and linezolid, and 1 both oral metronidazole and vancomycin). Concurrent renal insufficiency (CrCl < 60 mL/min) was noted among 26% (7/27) who developed neutropenia while receiving ceftaroline.\n\nAdditional symptoms at the time of neutropenia were reported: 6 (16%) had fevers, 3 (8%) abdominal pain, 2 (5%) rash, 1 (3%) nausea/vomiting, and 1 (3%) bleeding. Complications of neutropenia included a single case of Enterobacter bacteremia. Eleven (30%) cases received G-CSF (range of 2–8 doses) for management of neutropenia. All cases survived and had a favorable outcome.\n\nFour studies (including the current study) included both cases developing neutropenia associated with ceftaroline use and those without neutropenia. From these studies, incidence and identified associated factors (excluding the current study) are summarized below.\n\nThe first study [17] was conducted at a medical center in Baton Rouge, Louisiana (2012–2014), and reported 39 patients who received ≥7 days of ceftaroline, of whom 7 (18%) developed neutropenia after a median duration of therapy (range) of 27 (9–125) days. The authors did not find an association in univariate analyses between ceftaroline duration or dosage and the development of neutropenia. In their analyses, female sex and lower body mass index (BMI) were associated with neutropenia.\n\nA second study was conducted at 2 hospitals in Boston examining ≥7 days of ceftaroline use (2010–2015), in which a total of 67 patients were studied and 5 (7%) developed neutropenia [16]. Of note, 2 cases included in their original report were excluded in our analyses as the ANC nadir was not <1500 cells/mm3. Those who developed neutropenia had a longer median (range) duration of therapy (25 [13–68] days) compared with those not developing neutropenia (15 [ 7–64] days); however, no associations with other factors including demographics, underlying conditions, BMI, or concurrent antibiotic use were demonstrated.\n\nA third study examined patients receiving ≥14 days of ceftaroline compared with those receiving other antibiotics for S. aureus infections (eg, cefazolin, daptomycin, linezolid, nafcillin, or vancomycin) [28]. This study found that 17% (9/53) of the ceftaroline group developed neutropenia (ie, ANC < 1500 cells/mm3), an incidence 4-fold higher than the comparator group. Younger age and bone or joint infections were risk factors for neutropenia. Duration of ceftaroline use was not significantly different between those with and without neutropenia, and although females were more likely to develop neutropenia, this did not reach significance (personal communication with R. Brigg Turner, PharmD, School of Pharmacy, Pacific University, May 14, 2018).\n\nThe combined incidence of neutropenia in these 4 studies that evaluated ceftaroline use for ≥7–14 days was 11.6% (25/215 total patients; range, 7%–18%). An important consideration when interpreting these results is that these studies occurred at separate institutions with different patient populations and study designs; thus there is a notable limitation to combining these data. Overall, factors associated with the development of neutropenia were inconsistent among the evaluable studies.\n\nDISCUSSION\nNeutropenia is an increasingly recognized complication associated with the long-term use of ceftaroline. Ceftaroline utilized for short durations (5–14 days) for its FDA-approved indications of ABSSSI and CABP is associated with minimal risk of neutropenia. However, as ceftaroline is increasingly utilized for durations and doses greater than those studied in the initial clinical trials [10], safety data in these settings are needed. Our case series and review of the literature suggest that extended-duration ceftaroline use (ie, ≥14 days) is associated with a substantial risk of incident neutropenia of approximately 12%, which appears higher than for other β-lactam antibiotics. In our review, the median time from ceftaroline initiation to neutropenia (range) was 25 (8–125) days, with only 2 cases with a duration of ≤14 days of use. It is unlikely that neutropenia would have an onset before 7 days, based on the lack of neutropenia in phase III trials, where the approximate mean/median duration was 7 days [5–8]. The reason for variance in the percentage of ceftaroline-associated neutropenia (range, 7%–18%) between studies is unknown but is likely related to differences in study populations or an unrecognized risk factor.\n\nAlthough studies have examined risk factors and their association with neutropenia during ceftaroline use, data thus far remain inconclusive. Single studies have suggested antibiotic duration [16], female sex [17], low BMI [17], younger age [28], and bone and joint infections [28] to be significant factors in neutropenia development; however, these factors have not been replicated by other studies. Interestingly, almost half of our cases were being treated for bone and/or joint infections, and previous studies have observed neutropenia in patients being treated with antimicrobials for bone-related infections [30, 31]. This may be related to extended duration of treatment for these types of infection (eg, often for 6 weeks). There are other possible risk factors including the daily dose of ceftaroline, particularly in those with renal insufficiency, as ceftaroline’s primary route of elimination is renal (88%) [21]. Both the half-life and area under the concentration-time curve (AUC) increase with renal impairment compared with normal renal function (CrCl > 80 mL/min) by 1.27 and 1.58 times for half-life, and 1.19 and 1.52 times for AUC with mild (CrCl > 50–80 mL/min) and moderate (CrCl > 30–50 mL/min) renal impairment, respectively [32]. Additionally, concomitant medications and pretreatment exposure to other agents (including prior antibiotics) with residual bone marrow effects may be potential risk factors [33, 34]. Forty percent (12/30) of cases were on concurrent antibiotics, with 67% (8/12) of these receiving antibiotics associated with neutropenia, notably trimethoprim-sulfamethoxazole, clindamycin, rifampin, linezolid, metronidazole, and vancomycin [33, 34]. However, the role of these prior drugs/antibiotics in the development of neutropenia remains unclear as these factors were not investigated in prior ceftaroline case:control data analyses [16, 17, 28]. As ceftaroline is often used as salvage therapy, other patient and disease factors may play a role; however, at least 1 study has questioned this by examining similar agents used for salvage therapy [17].\n\nAlthough all β-lactams may be associated with neutropenia, the risk of ceftaroline appears higher than reported in the literature for other cephalosporins. It is important to recognize that the reported incidence varies in the literature based on study population and study design. For cefazolin, several studies have suggested that the incidence of neutropenia is 2%–4% in those receiving longer than 2 weeks of therapy [28, 35]. Other comparative drugs (vancomycin, daptomycin, nafcillin, linezolid) had substantially lower incidence of neutropenia [28].\n\nThe mechanism whereby ceftaroline (or other cephalosporins) leads to neutropenia remains unclear; however, both immune-mediated and bone marrow effects (via immune-mediated processes and/or direct damage to the myeloid cell line) have been proposed [36–38]. Of note, some cases of ceftaroline-associated neutropenia also had notable reductions in red blood cell and platelet counts, although this was not universal, suggesting a possible diffuse bone marrow effect. Some cases also had fever, rash, and/or eosinophilia, suggesting a potential immune or IgE-mediated phenomena [13].\n\nClinical applications of these data include the need for regular complete blood counts (CBCs) while receiving ceftaroline. The rapid rate of ANC decline in many of the cases is notable (Figure 1A–D); hence close follow-up is needed. We recommend that CBCs be obtained at baseline and at least weekly. If a decline in the ANC is detected, then biweekly or more frequent monitoring should be instituted. The current study also advocates for clinician awareness regarding the risk of neutropenia, which exceeds that stated in the package insert for ceftaroline (<2%) [21], particularly when utilized for durations ≥14 days.\n\nThe clinical management of ceftaroline-associated neutropenia includes rapid antibiotic discontinuation after ruling out other causes, especially if the ANC is <1500 cells/mm3 [33]. However, even earlier discontinuation should be considered. It is notable that 27% developed an ANC nadir of 0 cells/mm3. G-CSF was utilized in 30% of the cases in the literature to assist in neutrophil recovery. Even though there are limited trials evaluating the use of G-CSF for drug-induced neutropenia, G-CSF may be considered in high-risk patients including those with ANCs of less than 100 cells/mm3 due to increased risk of mortality in these patients [33, 39]. Various reports demonstrate a reduction in duration of neutropenia, antibiotic therapy, and length of hospital stay with the use of G-CSF [33, 39]. Although neutropenic complications in cases in this review were uncommon and all patients had favorable outcomes, clinical vigilance is advised, especially in the setting of severe infections (eg, bacteremia, endocarditis).\n\nThis review has several strengths, including being the most comprehensive review on ceftaroline-associated neutropenia to date. In addition, as several of the reports lacked detailed and/or individualized data, this review included additional data obtained after contacting authors of prior reports. The limitations of our study include the overall small number of patients in the published literature who have received extended durations of ceftaroline in which neutropenia was described. Additionally, data for the literature review originated from multiple studies with diverse demographic distributions, patient comorbidities, and study designs, which is important to consider when interpreting the combined findings. As the practice of using ceftaroline for ≥14 days is increasingly common, more studies are needed to more precisely define the incidence of neutropenia in this setting and to identify risk factors for its occurrence. Furthermore, there was notable heterogeneity among published reports in the data available, including complete host comorbidities, definitions of neutropenia utilized, and the timing (as the first agent vs as a salvage regimen) and duration of ceftaroline use. Finally, although scoring systems (eg, Naranjo), temporal associations, and the resolution of neutropenia after drug discontinuation support the associations between ceftaroline and the development of neutropenia, a causative relationship cannot be proven without a prospective trial.\n\nIn summary, ceftaroline-associated neutropenia is an overall common phenomenon when utilized for ≥14 days. Thrombocytopenia, anemia, and eosinophilia are also possible. Complete blood count monitoring is recommended during ceftaroline use, and twice-weekly monitoring should be considered with duration ≥14 days and/or when an ANC reduction is detected. A reduction in ANC should prompt rapid drug discontinuation as agranulocytosis may rapidly occur. Postmarketing data on possible adverse events associated with novel antibiotics are critically important, especially when utilized off-label for extended durations. Further research is needed to determine the mechanism and risk factors for the high incidence of neutropenia associated with long-term ceftaroline use.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nofz168_suppl_supplementary_table_1 Click here for additional data file.\n\n Acknowledgments\n\nAuthor contributions. All authors contributed to the writing of the manuscript. The named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. \n\n\nPotential conflicts of interest. The authors have no conflicts of interest to report, except that Dr. Nancy Crum-Cianflone has received speaking honoraria from Allergan. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n\n\nFinancial support. None.\n\nPrior presentation. This information was presented as poster #2426 at IDWeek 2018; October 6, 2018; San Francisco, CA.\n==== Refs\nReferences\n1. \nNaber CK \nStaphylococcus aureus bacteremia: epidemiology, pathophysiology, and management strategies\n. Clin Infect Dis 2009 ; 48 (Suppl 4 ):S231 –7\n.19374578 \n2. \nBergin SP , Holland TL , Fowler VG Jr, Tong SYC \nBacteremia, sepsis, and infective endocarditis associated with Staphylococcus aureus\n. Curr Top Microbiol Immunol 2017 ; 409 :263 –96\n.26659121 \n3. \nBritt RS , Evoy KE , Lee GC , et al. \nEarly use of ceftaroline fosamil in the United States Veterans Health Care System\n. Drugs 2017 ; 77 :1345 –51\n.28664412 \n4. \nMeaney CJ , Hynicka LM , Tsoukleris MG \nVancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors\n. Pharmacotherapy 2014 ; 34 :653 –61\n.24700598 \n5. \nFile TM Jr, Low DE , Eckburg PB , et al. \nFOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia\n. J Antimicrob Chemother 2011 ; 66 (Suppl 3 ):iii19 –32\n.21482566 \n6. \nLow DE , File TM Jr, Eckburg PB , et al. \nFOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia\n. J Antimicrob Chemother 2011 ; 66 (Suppl 3 ):iii33 –44\n.21482568 \n7. \nCorey GR , Wilcox MH , Talbot GH , et al. \nCANVAS 1: the first phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections\n. J Antimicrob Chemother 2010 ; 65 (Suppl 4 ):iv41 –51\n.21115454 \n8. \nWilcox MH , Corey GR , Talbot GH , et al. \nCANVAS 2: the second phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections\n. J Antimicrob Chemother 2010 ; 65 (Suppl 4 ):iv53 –iv65\n.21115455 \n9. Allergan. Allergan Announces FDA Approval of updated label for TEFLARO® (ceftaroline fosamil). https://www.allergan.com/news/news/thomson-reuters/allergan-announces-fda-approval-of-updated-lab-(1). Accessed 1 May 2018 .\n10. \nCosimi RA , Beik N , Kubiak DW , Johnson JA \nCeftaroline for severe methicillin-resistant Staphylococcus aureus infections: a systematic review\n. Open Forum Infect Dis 2017 ; 4 (X):XXX–XX.\n11. \nVidaillac C , Leonard SN , Rybak MJ \nIn vitro activity of ceftaroline against methicillin-resistant Staphylococcus aureus and heterogeneous vancomycin-intermediate S. aureus in a hollow fiber model\n. Antimicrob Agents Chemother 2009 ; 53 :4712 –7\n.19738009 \n12. \nMatzneller P , Lackner E , Lagler H , et al. \nSingle- and repeated-dose pharmacokinetics of ceftaroline in plasma and soft tissues of healthy volunteers for two different dosing regimens of ceftaroline fosamil\n. Antimicrob Agents Chemother 2016 ; 60 :3617 –25\n.27044549 \n13. \nOlaison L , Belin L , Hogevik H , Alestig K \nIncidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis\n. Arch Intern Med 1999 ; 159 :607 –15\n.10090118 \n14. \nJain R , Chan JD , Rogers L , et al. \nHigh incidence of discontinuations due to adverse events in patients treated with ceftaroline\n. Pharmacotherapy 2014 ; 34 :758 –63\n.24807197 \n15. \nVarada NL , Sakoulas G , Lei LR , Chua J \nAgranulocytosis with ceftaroline high-dose monotherapy or combination therapy with clindamycin\n. Pharmacotherapy 2015 ; 35 :608 –12\n.26037689 \n16. \nFurtek KJ , Kubiak DW , Barra M , et al. \nHigh incidence of neutropenia in patients with prolonged ceftaroline exposure\n. J Antimicrob Chemother 2016 ; 71 :2010 –3\n.27076105 \n17. \nLaVie KW , Anderson SW , O’Neal HR Jr, et al. \nNeutropenia associated with long-term ceftaroline use\n. Antimicrob Agents Chemother 2016 ; 60 :264 –9\n.26503657 \n18. \nDellabella A , Roshdy D , Martin KE \nHigh incidence of adverse effects with extended use of ceftaroline\n. Ann Pharmacother 2016 ; 50 :1068 –9\n.27586432 \n19. \nNaranjo CA , Busto U , Sellers EM , et al. \nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther 1981 ; 30 :239 –45\n.7249508 \n20. \nBlumenthal KG , Kuhlen JL Jr, Weil AA , et al. \nAdverse drug reactions associated with ceftaroline use: a 2-center retrospective cohort\n. J Allergy Clin Immunol Pract 2016 ; 4 :740 –6\n.27130709 \n21. \nTEFLARO \n(ceftaroline fosamil) package insert. \nhttps://www.allergan.com/assets/pdf/teflaro_pi. Accessed 23 March 2018 .\n22. \nMajumdar R , Crum-Cianflone NF \nTelavancin for MRSA endocarditis: case report and review of the literature\n. Infect Dis Clin Pract 2017 ; 25 :176 –183\n.\n23. \nRimawi RH , Frenkel A , Cook PP \nCeftaroline - a cause for neutropenia\n. J Clin Pharm Ther 2013 ; 38 :330 –2\n.23590618 \n24. \nYam FK , Kwan BK \nA case of profound neutropenia and agranulocytosis associated with off-label use of ceftaroline\n. Am J Health Syst Pharm 2014 ; 71 :1457 –61\n.25147169 \n25. \nSahar N , Ratajczak T , Conger NG \nCeftaroline-induced agranulocytosis\n. J Med Cases 2016 ; 7 :197 –201\n.\n26. \nPhull P , Lerner A \nAgranulocytosis secondary to ceftaroline use: a case report and review of the literature\n. J Hematol 2016 ; 5 :103 –105\n.\n27. \nKhan U , Hadid T \nFever, rash and agranulocytosis\n. BMJ Case Rep . 2017; doi:10.1136/bcr-2017-219403.\n28. \nTurner RB , Wilson DE , Saedi-Kwon H , et al. \nComparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline\n. J Antimicrob Chemother 2018 ; 73 :772 –8\n.29237024 \n29. \nZasowski EJ , Trinh TD , Claeys KC , et al. \nMulticenter observational study of ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bloodstream infections\n. Antimicrob Agents Chemother . 2017; doi: 10.1128/AAC.02015-16 .\n30. \nMcCluskey WP , Esterhai JL Jr, Brighton CT , Heppenstall RB \nNeutropenia complicating parenteral antibiotic treatment of infected nonunion of the tibia\n. Arch Surg 1989 ; 124 :1309 –12\n.2818186 \n31. \nPeralta FG , Sánchez MB , Roíz MP , et al. \nIncidence of neutropenia during treatment of bone-related infections with piperacillin-tazobactam\n. Clin Infect Dis 2003 ; 37 :1568 –72\n.14614681 \n32. \nSteed ME , Rybak MJ \nCeftaroline: a new cephalosporin with activity against resistant gram-positive pathogens\n. Pharmacotherapy 2010 ; 30 :375 –89\n.20334458 \n33. \nAndrès E , Mourot-Cottet R \nNon-chemotherapy drug-induced neutropenia - an update\n. Expert Opin Drug Saf 2017 ; 16 :1235 –42\n.28879784 \n34. \nCurtis BR \nNon-chemotherapy drug-induced neutropenia: key points to manage the challenges\n. Hematology Am Soc Hematol Educ Program 2017 ; 2017 :187 –93\n.29222255 \n35. \nYoungster I , Shenoy ES , Hooper DC , Nelson SB \nComparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting\n. Clin Infect Dis 2014 ; 59 :369 –75\n.24785233 \n36. \nMurphy MF , Minchinton RM , Metcalfe P , et al. \nNeutropenia due to beta lactamine antibodies\n. Br Med J 1984 ; 288 :795 .\n37. \nDeldar A , Lewis H , Bloom J , Weiss L \nCephalosporin-induced changes in the ultrastructure of canine bone marrow\n. Vet Pathol 1988 ; 25 :211 –8\n.3394212 \n38. \nNeftel KA , Hübscher U \nEffects of beta-lactam antibiotics on proliferating eucaryotic cells\n. Antimicrob Agents Chemother 1987 ; 31 :1657 –61\n.3324959 \n39. \nAndrès E , Maloisel F , Zimmer J \nThe role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis\n. Br J Haematol 2010 ; 150 :3 –8\n.20151980\n\n",
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"keywords": "ceftaroline; incidence; neutropenia; review; side effects",
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"title": "Ceftaroline-Associated Neutropenia: Case Series and Literature Review of Incidence, Risk Factors, and Outcomes.",
"title_normalized": "ceftaroline associated neutropenia case series and literature review of incidence risk factors and outcomes"
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"abstract": "A 15-year-old girl with Graves' disease presented with hypotension after methimazole and propranolol were re-started for hyperthyroidism. She was found to have pulmonary artery hypertension resulting in obstructive shock. Thyroid storm was diagnosed according to Burch and Wartofsky score. She was promptly treated with anti-thyroid drugs, inorganic iodide, corticosteroid, and respiratory support. Pulmonary hypertension was treated with inhaled nitric oxide until the clinical status improved. Propranolol was withdrawn due to poor cardiac function. We herein present a unique case of a difficult-to-treat Graves' disease presenting with severe pulmonary hypertension resulting in low cardiac output thyroid storm.",
"affiliations": "Division of Critical Care Medicine, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. marut.cha@mahidol.ac.th.;Division of Cardiology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Chantra|Marut|M|;Limsuwan|Alisa|A|;Mahachoklertwattana|Pat|P|",
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"issue": "58(10)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "Graves’ disease; hyperthyroidism; pulmonary hypertension; pulmonary hypertensive crisis; thyroid storm",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D002303:Cardiac Output, Low; D004452:Echocardiography; D005260:Female; D006111:Graves Disease; D006801:Humans; D013902:Radiography, Thoracic; D013318:Stroke Volume; D013958:Thyroid Crisis",
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"publication_types": "D002363:Case Reports",
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"title": "Low cardiac output thyroid storm in a girl with Graves' disease.",
"title_normalized": "low cardiac output thyroid storm in a girl with graves disease"
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"abstract": "We present a 38-year-old white British man who was taking long-term immunosuppressive medication following kidney transplantation. On routine review, he was noted to have an isolated and asymptomatic rise in alanine aminotransferase. After thorough investigation, he was found to have positive IgM and IgG serology to hepatitis E virus-and given the duration of his transaminitis, he was determined to have chronic hepatitis E infection. Treatment options were complicated by the presence of his kidney transplant, by chronic anaemia and by his wish for concomitant fertility treatment. Ribavirin therapy was instituted with a dramatic and immediate drop in serum viral load, although stool viraemia persisted. No clear protocols guide duration of treatment in chronic hepatitis E infection, but protracted faecal virus shedding predicts viral recrudescence, and treatment should continue at least until the stool is clear of virus.",
"affiliations": "Guy's and St Thomas' NHS Foundation Trust, London, UK.;Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, UK.",
"authors": "Evans|Terry John|TJ|;Hilton|Rachel|R|;Douthwaite|Sam|S|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223592",
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"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D000998:Antiviral Agents; D005243:Feces; D016751:Hepatitis E; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D009894:Opportunistic Infections; D012254:Ribavirin; D016896:Treatment Outcome; D019562:Viral Load; D017201:Virus Shedding",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24645943;27537905;20336757;28795981;23982238;28582320;25249523;23013075",
"title": "Treating chronic hepatitis E: when is enough enough?",
"title_normalized": "treating chronic hepatitis e when is enough enough"
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"companynumb": "GB-MYLANLABS-2018M1033191",
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"abstract": "Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a \"3+3\" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.",
"affiliations": "Internal Medicine Oncology/Hematology, 987680 Nebraska Medical Center, Omaha, NE, 68198, USA, Jue.Wang@DignityHealth.org.",
"authors": "Wang|J|J|;McGuire|T R|TR|;Britton|H C|HC|;Schwarz|J K|JK|;Loberiza|F R|FR|;Meza|J L|JL|;Talmadge|J E|JE|",
"chemical_list": "D000970:Antineoplastic Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D013792:Thalidomide; D003520:Cyclophosphamide; D017430:Prostate-Specific Antigen; D000077269:Lenalidomide",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D007962:Leukocytes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D022423:Myeloid Cells; D009360:Neoplastic Cells, Circulating; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D013792:Thalidomide; D013997:Time Factors; D016896:Treatment Outcome",
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"pubdate": "2015-02",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17570320;18446337;9116614;18829513;7828662;23321256;20206921;23765229;1424294;10639195;21159885;17869609;10037394;24238760;24060865;15453805;19965623;19362167;19937382;22560674;21148040;17404082;23507634;2830969;3697996;25085111;10397252;22842478;24712857;24389335;10037051;23418320;18423743;24101153;19451403;19902470;8831996;2658084;19097774;8673041;10334386;24668612;19440214;24083084;23510862;24053309;24514956;22576342;19009291;23223128;11312117;23489938;23221564;16838411;9129207;17289886;22215137;10477909;20818862;17308271;22609473;15003923",
"title": "Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer.",
"title_normalized": "lenalidomide and cyclophosphamide immunoregulation in patients with metastatic castration resistant prostate cancer"
} | [
{
"companynumb": "US-CELGENE-USA-2015020229",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nClozapine is an antipsychotic agent used when patients experience excessive extrapyramidal side effects from other antipsychotic agents or for therapy resistant schizophrenia. However, clozapine is also known for its serious adverse effects e.g. granulocytopenia and agranulocytosis.\n\n\nMETHODS\nA 40-year-old male with known schizophrenia, presented with severe diarrhea and eosinophilia in the peripheral blood examination result, arising 2 weeks after starting clozapine. Histopathological examination demonstrated an eosinophilic colitis. After the patient discontinued clozapine, the symptoms disappeared completely.\n\n\nCONCLUSIONS\nEosinophilic colitis is a rare adverse effect of clozapine. It is only possible to diagnose this using endoscopy and biopsy, so that the complaint is often not recognised. The exact pathophysiology underlying this eosinophilic colitis is not known.",
"affiliations": "Sint Lucas Andreas Ziekenhuis, afd. Psychiatrie, Amsterdam.",
"authors": "de Raad|A W|AW|;Siegersma|N C|NC|;Clahsen|P C|PC|;Hagestein-de Bruijn|C|C|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "155(36)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D003092:Colitis; D004802:Eosinophilia; D006801:Humans; D008297:Male; D012559:Schizophrenia",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A3620",
"pmc": null,
"pmid": "21914234",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Eosinophilic colitis caused by clozapine.",
"title_normalized": "eosinophilic colitis caused by clozapine"
} | [
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"companynumb": "PHHY2011NL87321",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Here, we report the presentation and management of a rare case of sight-threatening bilateral panuveitis with secondary chronic hypotony, subcapsular cataracts, exudative retinal detachments, and choroidal detachments, following initiation of pembrolizumab immunotherapy for metastatic melanoma. An 82-year-old white woman presented with painful, blurry vision 3 days after initiation of pembrolizumab immunotherapy. She had developed a marked panuveitis causing secondary hypotony. The fundal view was entirely limited by acutely dense cataracts and small, uveitic pupils unresponsive to topical dilation. Urgent cataract surgery with intravitreal dexamethasone implant (Ozurdex) was completed successfully and allowed a fundal examination. This revealed bilateral, symmetrical, inferior exudative retinal detachments, and choroidal detachments secondary to chronic hypotony. After 3 months of observation and cessation of oral steroids, the panuveitis remains quiescent, hypotony persists, and the choroidal and retinal detachments are showing progressive self-resolution. The current best-corrected visual acuity is 6/24 OU. She remains under close monitoring. The immune checkpoint inhibitor, pembrolizumab, has been reported to cause sight-threatening adverse effects. We report a rare case of profound bilateral complications treated successfully with oral and intravitreal steroids. To the authors' knowledge, this has not previously been reported in the literature. Ophthalmologists and oncologists should be aware of the ocular effects of pembrolizumab and be able to identify various complications early. Here, cataract surgery with a steroid implant has been an effective sight-saving intervention. The promising visual outcome makes this an unusual success story.",
"affiliations": "Maidstone & Tunbridge Wells Hospitals NHS Trust, London, UK.",
"authors": "Golash|Vidushi|V|;Almeida|Goncalo|G|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003907:Dexamethasone; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "43(9)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002386:Cataract; D002387:Cataract Extraction; D000080324:Choroidal Effusions; D003907:Dexamethasone; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008545:Melanoma; D015814:Ocular Hypotension; D012163:Retinal Detachment; D063189:Symptom Assessment; D016896:Treatment Outcome; D014605:Uveitis",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "283-285",
"pmc": null,
"pmid": "32740318",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pembrolizumab-related Bilateral Ocular Hypotony, Uveitis, Cataracts, Exudative Retinal, and Choroidal Detachments: An Unusual Success Story.",
"title_normalized": "pembrolizumab related bilateral ocular hypotony uveitis cataracts exudative retinal and choroidal detachments an unusual success story"
} | [
{
"companynumb": "GB-009507513-2008GBR008359",
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"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 64-year-old male presented with increased abdo-minal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for α-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.",
"affiliations": "Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Clinical Radiology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-0065, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka 812-8582, Japan.;Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.",
"authors": "Inadomi|Kyoko|K|;Kumagai|Hozumi|H|;Takayoshi|Kotoe|K|;Ariyama|Hiroshi|H|;Kusaba|Hitoshi|H|;Nishie|Akihiro|A|;Yamamoto|Hidetaka|H|;Takase|Ken|K|;Tanaka|Mamoru|M|;Sagara|Kosuke|K|;Okumura|Yuta|Y|;Nio|Kenta|K|;Nakano|Michitaka|M|;Arita|Shuji|S|;Oda|Yoshinao|Y|;Akashi|Koichi|K|;Baba|Eishi|E|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2015.3708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "10(5)",
"journal": "Oncology letters",
"keywords": "anaplastic lymphoma kinase rearrangement negative; chemotherapy; inflammatory pseudotumor; metastatic inflammatory myofibroblastic tumor",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "2981-2985",
"pmc": null,
"pmid": "26722275",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": "19890966;17938159;15991185;16160477;15086369;10934142;23448776;12713619;25210080;19097774;22614325;20431481;16967468;23669730;20979472;21496520;7611533;1746682",
"title": "Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report.",
"title_normalized": "successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor a case report"
} | [
{
"companynumb": "JP-ALVOGEN-2016-ALVOGEN-020843",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Delirium is a common cause for hospital admission among elderly patients. Although infection is the most common explanation, there is a large number of other potential causes. We present a case of acute delirium due to serotonin syndrome, precipitated by concomitant prescription of clarithromycin and fluoxetine. The symptoms improved following treatment with a benzodiazepine and discontinuation of the fluoxetine. The diagnosis and management of serotonin syndrome is discussed.",
"affiliations": "Queen Elizabeth Foundation Hospital Kings Lynn NHS Trust, UK. garymisselbrook@doctors.org.uk",
"authors": "Misselbrook|G P|GP|;Shekhar|R|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4884",
"issue": "10(4)",
"journal": "Acute medicine",
"keywords": null,
"medline_ta": "Acute Med",
"mesh_terms": "D000208:Acute Disease; D000369:Aged, 80 and over; D003221:Confusion; D003937:Diagnosis, Differential; D003943:Diagnostic Techniques, Neurological; D005260:Female; D005334:Fever; D005500:Follow-Up Studies; D006801:Humans; D020230:Serotonin Syndrome",
"nlm_unique_id": "101553725",
"other_id": null,
"pages": "206-8",
"pmc": null,
"pmid": "22111101",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonin syndrome: an unusual cause of acute confusion and fever in the elderly.",
"title_normalized": "serotonin syndrome an unusual cause of acute confusion and fever in the elderly"
} | [
{
"companynumb": "GB-RANBAXY-2012RR-52879",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE\\FLUOXETINE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "We present a case of a 10-year-old boy, who had severe relapsing pancreatitis, three times in two months within 3 weeks after starting treatment with methylphenidate (Ritalin) due to attention deficit hyperactivity disorder (ADHD). Pancreatitis due to the use of (methylphenidate) Ritalin was never published before. Attention must be made by the physicians regarding this possible complication, and this complication should be taken into consideration in every patient with abdominal pain who was newly treated with Ritalin.",
"affiliations": "Department of Radiology, Nazareth Hospital, EMMS, Faculty of Medicine, Bar-Ilan University, Israel ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.;Department of Nuclear Medicine, Meir Hospital, 44410 Betah Tekva, Israel.;Department of Internal Medicine, EMMS Hospital, 16100 Nazareth, Israel.;Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel ; Department of Internal Medicine, EMMS Hospital, 16100 Nazareth, Israel.;Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel ; Department of Internal Medicine, EMMS Hospital, 16100 Nazareth, Israel.;Pediatric Department, Nazareth Hospital, Israel.",
"authors": "Artul|Suheil|S|0000-0002-8621-6034;Artoul|Faozi|F|0000-0001-6273-012X;Habib|George|G|0000-0001-8134-8575;Nseir|William|W|0000-0003-4091-6948;Bisharat|Bishara|B|;Nijim|Yousif|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/319162",
"fulltext": "\n==== Front\nCase Rep Gastrointest MedCase Rep Gastrointest MedCRIGMCase Reports in Gastrointestinal Medicine2090-65282090-6536Hindawi Publishing Corporation 10.1155/2014/319162Case ReportSevere Recurrent Pancreatitis in a Child with ADHD after Starting Treatment with Methylphenidate (Ritalin) http://orcid.org/0000-0002-8621-6034Artul Suheil \n1\n\n2\n*http://orcid.org/0000-0001-6273-012XArtoul Faozi \n3\nhttp://orcid.org/0000-0001-8134-8575Habib George \n4\nhttp://orcid.org/0000-0003-4091-6948Nseir William \n2\n\n4\nBisharat Bishara \n2\n\n4\nNijim Yousif \n5\n1Department of Radiology, Nazareth Hospital, EMMS, Faculty of Medicine, Bar-Ilan University, Israel2Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel3Department of Nuclear Medicine, Meir Hospital, 44410 Betah Tekva, Israel4Department of Internal Medicine, EMMS Hospital, 16100 Nazareth, Israel5Pediatric Department, Nazareth Hospital, Israel*Suheil Artul: suheilartul@nazhosp.comAcademic Editors: H. Kawaratani, J. Vecht, and Ö. Yönem\n\n2014 11 2 2014 2014 3191629 11 2013 5 1 2014 Copyright © 2014 Suheil Artul 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.We present a case of a 10-year-old boy, who had severe relapsing pancreatitis, three times in two months within 3 weeks after starting treatment with methylphenidate (Ritalin) due to attention deficit hyperactivity disorder (ADHD). Pancreatitis due to the use of (methylphenidate) Ritalin was never published before. Attention must be made by the physicians regarding this possible complication, and this complication should be taken into consideration in every patient with abdominal pain who was newly treated with Ritalin.\n==== Body\n1. Case Presentation\nA case of a 10-year-old boy was referred to emergency department because of an abrupt onset of aggravating abdominal pain and vomiting. The boy was generally healthy except for that he was newly diagnosed with ADHD and started the use of methylphenidate (Ritalin) for the past three weeks at a dose of 30 mg daily. Physical examination on admission revealed that the boy looks suffering and afebrile and has diffuse tenderness of abdomen without rebound and no dyspnoea. Laboratory tests showed high level of serum amylase 5824 U/L (amylase normal value: 30–110 U/L), high level of lipase 1950 U/L (normal value: 10/140 U/L), high levels of liver enzymes, AST 1259 (normal range 5–43), ALT 769 (normal range 5–40), and normal levels of electrolytes, cholesterol, triglycerides, bilirubin. There was no metabolic acidosis. Ultrasound of abdomen (Figure 1(a)) showed edematous and enlarged pancreas, big amount of free fluid in the abdomen (Figure 1(b)), thickened gallbladder wall up to 6 mm without intraluminal stones (Figure 2), and no intrahepatic or extrahepatic biliary dilatation. There was no anamnestic familial history of pancreatitis.\n\nThe boy was admitted to intensive care unit with the diagnosis of acute pancreatitis and was started workup to investigate the etiology which revealed no alcohol use, transesophageal ultrasound (EUS) followed by magnetic resonance cholangiopancreatography (MRCP) (Figure 3) no biliary stone or any congenital or acquired malformation, and normal levels of immunoglobulins which excluded autoimmune pancreatitis. Other possible causes such as viral, bacteria, and parasites screening were all negative.\n\nThe boy was treated with intravenous rehydration and fasting with nasogastric tube. The boy improved slowly and discharged with the diagnosis of idiopathic pancreatitis from hospital after one week in good condition, free of symptoms, and with normalization of laboratory tests. Three weeks later, the boy was readmitted to the hospital again with more severe similar clinical scenario, received the same palliative treatment, and discharged after two weeks with good condition. After 5 days he was readmitted again to the hospital with the same clinical presentation of severe pancreatitis. This admission lasted for one week and on discharge the family reported on the use of Ritalin and therefore it was recommended to stop taking Ritalin.\n\nThe boy is now free of symptoms for one year and half after stopping taking Ritalin.\n\n2. Discussion\nThe use of Ritalin is noticeably increased worldwide in the last few years and is prescribed for several indications such as ADHD, behavior disorder, and even for improving scholar achievement [1].\n\nThe incidence of pediatric pancreatitis has increased significantly in the past two decades. It is estimated that 2 to 13 new cases occur annually per 100,000 children [2].\n\nPancreatitis affects a heterogeneous population of children, and symptoms range from mild to life threatening.\n\nIn acute pancreatitis, although the pathophysiology and functional consequences in children are identical to those observed in adults, its etiology differs significantly, although most of pediatric pancreatitis still idiopathic [3]. The common known causes of pancreatitis in children include (1) systemic diseases, such as systemic lupus erythematosus, Henoch-Schönlein purpura, Kawasaki disease, Crohn's disease, hyperlipoproteinemia, and hypertriglyceridemia; (2) different drugs and toxins, such as thiazides, furosemide, cimetidine, estrogen, and tetracycline; (3) infections; (4) obstructive diseases; (5) trauma; (6) hereditary pancreatitis; (7) autoimmune pancreatitis. In about 15% of cases the cause remains unknown after thorough investigation [4].\n\nUnofficial data states that according to FDA reports published on the Internet in June 2013, 41 people of 8668 (0.47%) users of Ritalin in the United States declared to have pancreatitis within one month after starting the treatment. But we do not know if these 41 people have another underlying disease for developing pancreatitis.\n\nWe believe that the number of persons suffering from pancreatitis due to the use of Ritalin is more than this published case.\n\nPhysicians must pay attention regarding this possible complication and it should be taken into consideration in every patient with abdominal pain who started consuming Ritalin.\n\nBecause of clinical various degrees of presentation of pancreatitis, a lot of these patients are undiagnosed.\n\n3. Conclusion\nAcute pancreatitis in pediatric age could be due to the use of Ritalin. Because of increased use of this drug, physicians must be aware of this possibility and they must include this entity in the differential diagnosis in every child suffering from abdominal pain and who was also recently started to take this medicine. We suggest further investigation in this issue.\n\nAbbreviations\nADHD:Attention deficit hyperactivity disorder.\n\nConflict of Interests\nThe authors have no conflicts of interest to disclose.\n\nAuthors' Contribution\nSuheil Artul conceptualized and designed the study, drafted the initial paper, and approved the final paper as submitted. All the other authors reviewed and revised the paper and approved the final paper as submitted.\n\nFigure 1 (a) Ultrasound of epigastrium region showing edematous pancreas (white arrows) and (b) ultrasound of lower abdomen showing free fluid (blue arrow).\n\nFigure 2 Ultrasound of the right upper quadrant showing the gallbladder free of stones (blue arrow) and thickening of gallbladder wall (white arrows).\n\nFigure 3 Coronal T2 MRI (as part of the MRCP STUDY) showing no dilatation and normal position of choledochus.\n==== Refs\n1 Mazzone L Postorino V Reale L Self-esteem evaluation in children and adolescents suffering from ADHD Clinical Practice and Epidemiology in Mental Health 2013 9 96 102 23878614 \n2 Bălănescu NR Topor L Ulici A Acute pancreatitis secondary to hyperlipidemia in an 11-year-old girl: a case report and review of literature Journal of Medicine and Life 2013 6 1 2 6 23599811 \n3 Giordano S Serra G Dones P Acute pancreatitis in children and rotavirus infection. Description of a case and minireview New Microbiologica 2013 36 1 97 101 23435823 \n4 Cappell MS Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy Medical Clinics of North America 2008 92 4 889 923 2-s2.0-44949175978 18570947\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2014()",
"journal": "Case reports in gastrointestinal medicine",
"keywords": null,
"medline_ta": "Case Rep Gastrointest Med",
"mesh_terms": null,
"nlm_unique_id": "101580185",
"other_id": null,
"pages": "319162",
"pmc": null,
"pmid": "24711932",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "18570947;23435823;23599811;23878614",
"title": "Severe recurrent pancreatitis in a child with ADHD after starting treatment with methylphenidate (Ritalin).",
"title_normalized": "severe recurrent pancreatitis in a child with adhd after starting treatment with methylphenidate ritalin"
} | [
{
"companynumb": "PHHY2015IL123485",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "BACKGROUND\nCurrent literature estimates the risk of delayed intracranial hemorrhage as between 0.6 and 6% after mild head injury for patients on warfarin. Due to resource allocation issues, the need to actually diagnose delayed intracranial haemorrhage has been questioned, especially if it does not require surgery. The purpose of our case report is to consider the functional implications during the six months following a mild traumatic brain injury complicated by delayed intracranial hemorrhage in a patient undergoing warfarin therapy. To the best of our knowledge, the rehabilitative and functional considerations of delayed intracranial haemorrhage in head injury have not been previously described in the literature.\n\n\nMETHODS\nA previously independent 74-year-old Lebanese man living in Australia sustained mild traumatic brain injury following an unwitnessed fall from the height of two meters while on warfarin therapy, with an international normalized ratio of 4.2. He was found to have amnesia of the event and extensive facial bruising. His Glasgow Coma Scale score was 14 to 15 throughout observation. Following a non-diagnostic initial computerised tomography scan, a repeat scan at 24 hours from the injury identified large intracerebral, subdural and subarachnoid hemorrhages. A detailed examination demonstrated visuospatial and cognitive impairments. He required inpatient rehabilitation for three weeks, and outpatient rehabilitation for two months. By six months, he had returned to his pre-injury level of functioning, but was unable to resume driving.\n\n\nCONCLUSIONS\nWe describe rehabilitation outcomes of delayed intracranial haemorrhage and mild traumatic brain injury, with diminishing disability over six months. In our case report, the complication of the delayed intracranial haemorrhage resulted in significant activity limitations and participation restrictions, which affected the clinical management, including the need for multidisciplinary rehabilitation. The risk of delayed intracranial haemorrhage in mild head injury remains a significant problem requiring further research.",
"affiliations": "The University of Melbourne, Department of Rehabilitation Medicine, Royal Melbourne Hospital, 34-54 Poplar Road, Parkville, Melbourne, VIC, 3052, Australia. pearl.chung@mh.org.au.;The University of Melbourne, Department of Rehabilitation Medicine, Royal Melbourne Hospital, 34-54 Poplar Road, Parkville, Melbourne, VIC, 3052, Australia. fary.khan@mh.org.au.",
"authors": "Chung|Pearl|P|;Khan|Fary|F|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0652-2",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 65210.1186/s13256-015-0652-2Case ReportMild traumatic brain injury presenting with delayed intracranial hemorrhage in warfarin therapy: a case report Chung Pearl pearl.chung@mh.org.au Khan Fary fary.khan@mh.org.au The University of Melbourne, Department of Rehabilitation Medicine, Royal Melbourne Hospital, 34-54 Poplar Road, Parkville, Melbourne, VIC 3052 Australia 18 8 2015 18 8 2015 2015 9 17310 2 2015 13 7 2015 © Chung and Khan. 2015\nOpen Access This 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.Introduction\nCurrent literature estimates the risk of delayed intracranial hemorrhage as between 0.6 and 6% after mild head injury for patients on warfarin. Due to resource allocation issues, the need to actually diagnose delayed intracranial haemorrhage has been questioned, especially if it does not require surgery. The purpose of our case report is to consider the functional implications during the six months following a mild traumatic brain injury complicated by delayed intracranial hemorrhage in a patient undergoing warfarin therapy. To the best of our knowledge, the rehabilitative and functional considerations of delayed intracranial haemorrhage in head injury have not been previously described in the literature.\n\nCase presentation\nA previously independent 74-year-old Lebanese man living in Australia sustained mild traumatic brain injury following an unwitnessed fall from the height of two meters while on warfarin therapy, with an international normalized ratio of 4.2. He was found to have amnesia of the event and extensive facial bruising. His Glasgow Coma Scale score was 14 to 15 throughout observation. Following a non-diagnostic initial computerised tomography scan, a repeat scan at 24 hours from the injury identified large intracerebral, subdural and subarachnoid hemorrhages. A detailed examination demonstrated visuospatial and cognitive impairments. He required inpatient rehabilitation for three weeks, and outpatient rehabilitation for two months. By six months, he had returned to his pre-injury level of functioning, but was unable to resume driving.\n\nConclusions\nWe describe rehabilitation outcomes of delayed intracranial haemorrhage and mild traumatic brain injury, with diminishing disability over six months. In our case report, the complication of the delayed intracranial haemorrhage resulted in significant activity limitations and participation restrictions, which affected the clinical management, including the need for multidisciplinary rehabilitation. The risk of delayed intracranial haemorrhage in mild head injury remains a significant problem requiring further research.\n\nKeywords\nMild traumatic brain injurymTBIMild head injuryDelayed intracranial hemorrhageAnticoagulationWarfarinissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nFollowing a mild head injury, between 0.6 and 6% of people undergoing warfarin therapy may develop delayed intracranial hemorrhage (DICH), despite a non-diagnostic initial computerised tomography (CT) scan of the brain [1–4]. The overall incidence of mild traumatic brain injury (mTBI) in older adults aged 65 and over is estimated to be as high as 537 per 100,000 person-years, of which 509 per 100,000 person-years are due to falls [5]. The definition for mTBI is widely variable in the literature, making the evidence synthesis difficult [6, 7]. For someone who sustains a TBI, as evidenced by an alteration in the brain function caused by an external force [8], a mTBI could be defined as: a Glasgow Coma Scale (GCS) score of 13 or above, any loss of consciousness (LOC) lasting less than 30 minutes and any post-traumatic amnesia (PTA) lasting less than 24 hours [6, 7]. The definitions for mild (or minor) head injury are broader than that for mTBI; the history of head trauma is the primary basis for mild head injury, without necessarily demonstrating LOC, PTA or evidence of craniofacial trauma [1, 2, 4]. To the best of our knowledge, all of the studies examining the risk of DICH have been in mild head injury, while our patient more specifically met the criteria for mTBI.\n\nDifferent potential mechanisms for post-traumatic DICH have been described. The risk of developing subdural haemorrhage due to shearing of the bridging veins, with associated cerebral atrophy of the elderly, may be exacerbated by a delayed compensatory hypertension for hypercapnia and local neurometabolic processes [9–11]. Estimating the traumatic forces involved in unwitnessed injuries may be difficult, especially if retrograde amnesia is also present. Currently used neurological and functional markers of severity in mTBI have limited predictive value, and imaging modalities in routine practice lack sensitivity for detecting very subtle changes for predicting the likelihood of DICH [12].\n\nThe small risk of DICH is a difficult dilemma from safety and resource allocation perspectives. In terms of safety, severe disability and death are real consequences of DICH, and very late presentations of DICH contribute to worse outcomes [1, 13, 14]. In terms of resource allocation, this is a rare complication of a common problem: the cost of routine hospitalizations for 24-hour observation and for repeat CT scans is difficult to justify with an estimated number needed to treat of up to 61 persons [15]. Further, even after 24 hours, it is possible to develop DICH [4]. The clinical relevance of diagnosing an asymptomatic DICH is questionable, especially if surgery is not needed [1, 4]. Recent reviews of this clinical problem have not recommended routine observations or another CT scan at 24 hours for DICH after the initial scan [16, 17], but observation for 24 hours was recommended in the recent Scandinavian guidelines, with a view to repeating the CT scan if clinically indicated [18]. The purpose of our case report is to continue these discussions regarding the management of the risk of DICH in persons on oral anticoagulation who sustain head injury, based on the lessons learned from a rehabilitation perspective.\n\nCase presentation\nA 74-year-old Lebanese man living with his wife in Melbourne, Australia, who was previously independent with all activities of daily living, mobility and driving a car, sustained an unwitnessed fall resulting in mild TBI, with an initial GCS score of 15 on presentation. He was on warfarin and sotalol for chronic atrial fibrillation, with a target international normalized ratio (INR) of two to three, and a past history of transient ischaemic attack eight years earlier. He was also treated for hypertension. On the day of the injury, he was last seen in his garden pruning a tree on a ladder at a height of two meters. He had no recollection of immediate events leading up to the fall, or the fall itself. His wife noticed extensive right facial bruising when he entered the house, which led to the presentation to his usual local medical officer, who referred him on to the Emergency Department at the Royal Melbourne Hospital (Victoria, Australia), a major trauma centre. The initial CT scan of his brain was performed at five hours from the injury due to the above delays in presentation. This was non-diagnostic for intracranial hemorrhage (Fig. 1). His INR was elevated at 4.2. He was assessed by the neurosurgical team, and was admitted for a 24-hour observation period, with a planned repeat CT brain scan prior to discharge to home to the care of his family. His GCS score remained at 14 to 15 throughout the observation period, due to mildly confused speech at times throughout the night. He complained of a mild headache, which was managed with paracetamol as required.Fig. 1 Computerised tomography scan at five hours from injury, with Glasgow Coma Scale score of 15, demonstrating right facial hematoma, but no acute intracranial hemorrhage\n\n\n\nOn the following day, the repeat CT scan of his brain at 24 hours demonstrated a large right posteromedial parietal intraparenchymal hemorrhage with vasogenic edema, subarachnoid and subdural extension, and right anterolateral subdural hematoma (Fig. 2). He received urgent fresh frozen plasma, human prothrombin complex (Prothrombinex®-VF) (CSL Behring, Melbourne, Australia), and Vitamin K to reverse the anticoagulation, and he was admitted to the Stroke Care Unit, with a multidisciplinary team involved in his care. Further repeat scans did not demonstrate an extension of DICH, and surgical intervention was not required. During his admission, he sustained a fall due to left homonymous hemianopia, impulsivity and vertigo. He was found to have episodes of bradycardia, and his sotalol dosage was ceased. A subsequent CT scan of his brain did not demonstrate additional intracranial pathology. He was referred for inpatient rehabilitation.Fig. 2 Computerised tomography scan at 24 hours from injury, with Glasgow Coma Scale score of 14 to 15, demonstrating right posteromedial parietal intraparenchymal hemorrhage (30×31×46mm) with vasogenic edema, subarachnoid and subdural extension, and right anterolateral subdural hematoma\n\n\n\nOn the 11th day after the injury, he was transferred to the Rehabilitation Unit at Royal Park Campus, Royal Melbourne Hospital, for multidisciplinary rehabilitation. On the 15th day, warfarin therapy was recommenced with close monitoring, with a target INR of two to three. His headache was minimal and his vertigo had resolved. He remained motivated and euthymic. A multidisciplinary assessment in the Rehabilitation Unit demonstrated the following problems: fatigue; mildly impaired arousal, attention, orientation, insight, processing speed, working memory and verbal learning; left homonymous hemianopia; decreased functioning, with minimal assistance of one person required for personal activities of daily living, including assisted showering and toileting; and decreased mobility with constant supervision required due to impulsivity and ongoing risk of falls, with minimal assistance of one person required for transfers and walking. He underwent an intensive three-week inpatient multidisciplinary rehabilitation program to address these problems.\n\nBy discharge, his fatigue and cognitive functioning had improved, and his family were educated on his supervision needs. A formal orthoptics assessment demonstrated full Bjerrum visual fields. However, in functional tasks and ambulation, he demonstrated left neglect and veered to the right side. He was independent with personal activities of daily living, and necessary home equipment was prescribed by his discharge. He was independent with transfers and ambulation indoors, without exercise tolerance limitations, but required supervision for outdoor mobility due to an ongoing visuospatial problem. He was also advised against driving on discharge for the same reason.\n\nHe attended a further two months’ outpatient multidisciplinary rehabilitation program at the Royal Park Campus, Royal Melbourne Hospital to address participation restrictions, with the goal of independent local community access. He was assessed in the outpatient clinic at three months from the injury, and by this stage, he was safely walking to the nearby shops alone, with increased independence in personal and domestic activities of daily living. However, the changed family roles as a result of the injury led to increasing caregiver stress, with ongoing driving restrictions and supervision needs. At his six-month review, he had no residual activity limitations, but his overall participation was restricted by his inability to return to driving.\n\nDiscussion\nWe describe one case of DICH with limited applicability for the broader discussion in DICH. The management of the risk of DICH for persons on oral anticoagulation remains a difficult issue. The incidence of DICH in surveillance studies were variable, and has been reported to be 0.6% (n=4 out of 687) [1], 1% (n=4 out of 362) and 6% (n=5 out of 87) [4]. The first study used follow-up phone calls and medical records to detect cases, while the second and third studies (with higher incidences) used routine CT rescanning to detect cases at six hours and 24 hours from the injury, respectively. In all three studies, the case definition for head injury was non-specific, with no minimum criteria for the severity of the injury sustained. The timing of repeat scans also differed in surveillance studies, making it difficult to pool the data reliably. The question of whether very advanced age; an INR over three; LOC; or PTA increases risk of DICH remains unclear [1, 4], since persons with recognized poor prognostic factors for a poor outcome would presumably have had ICH detected on the initial scan. This is also complicated by the risk of DICH extending beyond 24 hours [4].\n\nIn light of the evidence, and as reflected by our case report, it is unsettling that current practices accept a small but real risk of DICH in mild head injury. A time-limited clear window of opportunity exists for clinicians to detect, or even to prevent DICH, but it is current routine practice for patients to remain anticoagulated, potentially at supratherapeutic INR levels. Initial management may differ if advanced imaging options are considered, such as magnetic resonance imaging (MRI), which may demonstrate subtle shear injuries not seen on CT scans [19]. However, the use of MRI for such a common presentation is just as difficult a problem from resource allocation and resource utilisation perspectives. Our understanding of acute injury variables contributing to DICH remains limited. Further, there is little known regarding the risk of DICH with novel oral anticoagulants, which are increasingly used [17]. Finally, for older persons who sustain mild head injuries from a fall, as in our patient, a thorough review of fall history and the individualized long term risk of further injuries should be carefully weighed against the overall indications for therapeutic anticoagulation.\n\nOur patient was found to have significant neurological impairments from the DICH after his head injury; yet his cognitive and visuospatial deficits were subtle, and not detected as a significant deterioration, even by neurological observations. However, these problems resulted in activity limitations and participation restrictions compared with his pre-injury status, which significantly improved following the multidisciplinary rehabilitation. Is it relevant if a DICH is missed, is minimal and does not require surgical evacuation [16]? From the perspectives of providing patient-centred care to improve quality of life, it would seem relevant for patients and families to be given a clear diagnosis for their symptoms, as well as for any associated impairments to be identified, and for appropriate and timely rehabilitation care to be provided to prevent further complications and to treat any persistent deficits.\n\nConclusions\nAlthough small, the risk of DICH after mild head injury exists for persons on oral anticoagulation with warfarin. The optimal management for the risk of DICH remains unclear in the literature, and further studies are needed to clarify those who are at increased risk of DICH. Identification of DICH, even if not requiring surgical management, is highly relevant to providing patient-centered care, to functioning and to minimise disability.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCTComputerised tomography\n\nDICHDelayed intracranial hemorrhage\n\nGCSGlasgow Coma Scale\n\nINRInternational normalized ratio\n\nLOCLoss of consciousness\n\nMRIMagnetic resonance imaging\n\nmTBIMild traumatic brain injury\n\nPTAPost-traumatic amnesia\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nPC assessed the patient, analyzed the patient data and performed the literature review. FK was a major contributor in writing the manuscript. Both authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank the patient for allowing this case report to be published.\n==== Refs\nReferences\n1. Nishijima DK Offerman SR Ballard DW Vinson DR Chettipally UK Rauchwerger AS Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use Ann Emerg Med 2012 59 460 8 10.1016/j.annemergmed.2012.04.007 22626015 \n2. Peck KA Sise CB Shackford SR Sise MJ Calvo RY Sack DI Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? J Trauma. 2011 71 1600 4 10.1097/TA.0b013e31823b9ce1 22182870 \n3. Kaen A Jimenez-Roldan L Arrese I Delgado MA Lopez PG Alday R The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury J Trauma. 2010 68 895 8 20016390 \n4. Menditto VG Lucci M Polonara S Pomponio G Gabrielli A Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol Ann Emerg Med. 2012 59 451 5 10.1016/j.annemergmed.2011.12.003 22244878 \n5. Feigin VL Theadom A Barker-Collo S Starkey NJ McPherson K Kahan M Incidence of traumatic brain injury in New Zealand: a population-based study Lancet Neurol. 2013 12 53 64 10.1016/S1474-4422(12)70262-4 23177532 \n6. Carroll LJ Cassidy JD Holm L Kraus J Coronado VG Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury J Rehabil Med. 2004 43 Suppl 113 25 10.1080/16501960410023877 15083875 \n7. Chung P Khan F Traumatic brain injury (TBI): overview of diagnosis and treatment J Neurol Neurophysiol. 2013 5 182 \n8. Menon DK Schwab K Wright DW Maas AI Position statement: definition of traumatic brain injury Arch Phys Med Rehabil. 2010 91 1637 40 10.1016/j.apmr.2010.05.017 21044706 \n9. Itshayek E Rosenthal G Fraifeld S Perez-Sanchez X Cohen JE Spektor S Delayed posttraumatic acute subdural hematoma in elderly patients on anticoagulation Neurosurgery 2006 58 E851 856 10.1227/01.NEU.0000209653.82936.96 16639305 \n10. Schaller B Radziwill AJ Wasner M Gratzl O Steck AJ Intermittent paraparesis as manifestation of a bilateral chronic subdural hematoma Schweiz Med Wochenschr. 1999 129 1067 72 10464909 \n11. Brunetti J Zingesser L Dunn J Rovit RL Delayed intracerebral hemorrhage as demonstrated by CT scanning Neuroradiology. 1979 18 43 6 10.1007/BF00346211 514495 \n12. Bazarian JJ Zhong J Blyth B Zhu T Kavcic V Peterson D Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: a pilot study J Neurotrauma. 2007 24 1447 59 10.1089/neu.2007.0241 17892407 \n13. Beynon C Orakcioglu B Winkler H Geis NA Unterberg AW Sakowitz OW Delayed anticoagulation-related intracranial haemorrhage after minor head injury Case Rep Med. 2013 2013 412931 24368918 \n14. Docimo S Jr Demin A Vinces F Patients with blunt head trauma on anticoagulation and antiplatelet medications: can they be safely discharged after a normal initial cranial computed tomography scan? Am Surg. 2014 80 610 3 24887801 \n15. Li J Validation of the dime Ann Emerg Med. 2012 59 469 70 10.1016/j.annemergmed.2012.04.017 22626016 \n16. Rendell S Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: observation is unnecessary following a normal CT brain in warfarinised head injuries: an update Emerg Med J 2014 31 339 42 10.1136/emermed-2014-203646.3 24623731 \n17. Cohn B Keim SM Sanders AB Can anticoagulated patients be discharged home safely from the emergency department after minor head injury? J Emerg Med. 2014 46 410 7 10.1016/j.jemermed.2013.08.107 24360352 \n18. Unden J Ingebrigtsen T Romner B Scandinavian NC Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update BMC Med. 2013 11 50 10.1186/1741-7015-11-50 23432764 \n19. Niogi SN Mukherjee P Diffusion tensor imaging of mild traumatic brain injury J Head Trauma Rehabil. 2010 25 241 55 10.1097/HTR.0b013e3181e52c2a 20611043\n\n",
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"title": "Mild traumatic brain injury presenting with delayed intracranial hemorrhage in warfarin therapy: a case report.",
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"abstract": "Although hyponatremia has been reported with the use of various antidepressants, the association of hyponatremia with bupropion has been limited to two case reports. In this case report, we present the case of a 75-year-old man who developed hyponatremia with the use of bupropion, which improved with stoppage of bupropion.",
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"abstract": "We evaluated the efficacy and safety of dalbavancin in ABSSSI and 'other sites' infections' (OTA).\n\n\n\nObservational study involving 11 Italian hospitals including patients that received ≥1 dose of dalbavancin in 2016-2019. The outcome was end-of-treatment efficacy and safety in ABSSSI and OTA in a real-life setting.\n\n\n\n206 patients enrolled (males 50%, median age 62 [IQR 50-76] years), 60.2% ABSSSI, 39.8% OTA. 69.7% ABSSSI vs 90.7% OTA (p = 0.003) and 46.3% ABSSSI vs 37.2% OTA (p = 0.786) received previous and concomitant antibiotics, respectively. 82.5% reached clinical cure . Eleven (5.4%) patients had non-serious adverse events (AE). OTA patients showed longer hospitalization (13.5 days, 5.5-22 vs 3, 0-11.7; p<0.0001) and received longer previous (18 days, 9-30 vs 11, 7-19; p = 0.007)/concomitant antibiotic treatments (21 days, 14-52 vs 11, 8-14; p < 0.0001), compared to ABSSSI. ABSSSI and OTA showed similar efficacy (85.5% vs 75%, p = 0.459) and safety (no AE: 81.5% vs 64.3%, p = 0.258); efficacy was independent of previous/concomitant therapies.\n\n\n\nDalbavancin demonstrated a success rate of >80%, with similar efficacy/safety in ABSSSI and off-label indications. The preferential use of dalbavancin as second-line or combination therapy would seem to suggest the need for in-depth studies focused on its off-label use.",
"affiliations": "Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan , Milan, Italy.;Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan , Milan, Italy.;Clinic of Infectious Diseases, Department of Internal Medicine, University Hospital of Padua , Padua, Italy.;Clinic of Infectious Diseases, Department of Internal Medicine, University Hospital of Padua , Padua, Italy.;Clinic of Infectious Diseases, Department of Internal Medicine, University Hospital of Padua , Padua, Italy.;Clinic of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Infectious Diseases Unit, Hospital Health Direction, Humanitas Clinical and Research Center , Milan, Italy.;Infectious Diseases Unit, Hospital Health Direction, Humanitas Clinical and Research Center , Milan, Italy.;Infectious Diseases Unit, ASST Papa Giovanni XXIII, Bergamo Hospital , Bergamo, Italy.;Infectious Diseases Unit, ASST Papa Giovanni XXIII, Bergamo Hospital , Bergamo, Italy.;Infectious Diseases Unit, Department of Clinical and Epidemiological Science, ASST Spedali Civili, University of Brescia , Brescia, Italy.;Infectious Diseases Unit, Department of Clinical and Epidemiological Science, ASST Spedali Civili, University of Brescia , Brescia, Italy.;Infectious Diseases Unit, San Gerardo Hospital , Monza, Monza E Brianza, Italy.;Infectious Diseases Unit, ASST Valle Olona, Busto Arsizio Hospital , Busto Arsizio, Varese, Italy.;Department of Infectious Diseases, ASST Fatebenefratelli, Luigi Sacco Hospital , Milan, Italy.;University of Bari 'Aldo Moro', Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari , Bari, Italy.;Dipartimento Di Promozione Della Salute, Materno-Infantile, Di Medicina Interna E Specialistica Di Eccellenza \"G. D'Alessandro\", University of Palermo , Palermo, Italy.;Clinic of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan , Milan, Italy.;Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan , Milan, Italy.",
"authors": "Bai|Francesca|F|;Aldieri|Chiara|C|;Cattelan|AnnaMaria|A|;Raumer|Francesca|F|;Di Meco|Eugenia|E|;Moioli|Maria Cristina|MC|;Tordato|Federica|F|;Morelli|Paola|P|;Borghi|Federica|F|;Rizzi|Marco|M|;Van Hauwermeiren|Evelyn|E|;Castelli|Francesco|F|;Migliorino|Guglielmo|G|;Menzaghi|Barbara|B|;Rizzardini|Giuliano|G|0000-0002-5183-7818;Saracino|Annalisa|A|;Cascio|Antonio|A|0000-0002-1992-1796;Puoti|Massimo|M|;d'Arminio Monforte|Antonella|A|;Marchetti|Giulia|G|",
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"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000900:Anti-Bacterial Agents; D005260:Female; D006760:Hospitalization; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D012189:Retrospective Studies; D017192:Skin Diseases, Bacterial; D017334:Teicoplanin",
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"title": "Efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and other infections in a real-life setting: data from an Italian observational multicentric study (DALBITA study).",
"title_normalized": "efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections absssis and other infections in a real life setting data from an italian observational multicentric study dalbita study"
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"abstract": "In recent years, human immunodeficiency virus(HIV)-negative Pneumocystis pneumonia(PCP)onset has been occasionally seen in breast cancer. In particular, dose-dense epirubicin and cyclophosphamide(EC: ddEC)therapy, in which EC is administered every 2 weeks, has been generally used in clinical practice for early stage breast cancers. PCP may develop before and during postoperative chemotherapy. We report the cases of 2 patients who developed PCP during postoperative adjuvant chemotherapy. Case 1: A 62-year-old woman, who underwent postoperative EC therapy, developed PCP during the 4th EC cycle. During EC therapy, steroids(prednisolone[PSL])were administered at an average dose of 11.4mg/day, and the number of lymphocytes at the initiation of the 4th EC cycle was 516/mL. Case 2: After receiving 4 cycles of postoperative ddEC, a 27-year-old woman developed PCP after 1 cycle of docetaxel(DTX)administration. During ddEC therapy, PSL was administered at a dose of 17.14mg/day, and the number of lymphocytes at DTX administration was 311/mL. The onset of PCP is presumed to be related to the steroid dose administered and the number of lymphocytes. Therefore, determining effective indicators in patients at a high risk of PCP onset is important.",
"affiliations": "Dept. of Endocrine and Breast Surgery, Tokai University School of Medicine.",
"authors": "Yokoyama|Kozue|K|;Sakaeda|Saeko|S|;Ishida|Rie|R|;Terao|Mayako|M|;Morioka|Toru|T|;Tsuda|Banri|B|;Okamura|Takuho|T|;Niikura|Naoki|N|",
"chemical_list": "D015251:Epirubicin; D003520:Cyclophosphamide",
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"title": "Two Cases of Pneumocystis Pneumonia during Adjuvant Chemotherapy for Breast Cancer.",
"title_normalized": "two cases of pneumocystis pneumonia during adjuvant chemotherapy for breast cancer"
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"abstract": "Immune checkpoint inhibitors with chemotherapy have been shown to exhibit remarkable efficacy for advanced non-small-cell lung carcinoma and are under investigation as an induction therapy. However, the significance of preoperative therapy with pembrolizumab + chemotherapy for surgically resectable non-small-cell lung carcinoma still remains unclear. Here, we report a case of stage IIIB non-small-cell lung carcinoma that underwent salvage surgery after three cycles of pembrolizumab + carboplatin + nab-paclitaxel. Computed tomography revealed the remarkable decrease in tumor volume by 81%. A pathological examination showed that viable neoplastic cells were observed in <1% of the total tumorous lesion suggesting near pathological complete response. This case suggests that this regimen might be a good option as induction therapy for non-small-cell lung carcinoma.",
"affiliations": "Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Pathology, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.;Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.",
"authors": "Saito|Shunichi|S|;Toyokawa|Gouji|G|;Momosaki|Seiya|S|;Kozuma|Yuka|Y|;Shoji|Fumihiro|F|;Yamazaki|Koji|K|;Takeo|Sadanori|S|",
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"doi": "10.1111/1759-7714.14051",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34151529\n10.1111/1759-7714.14051\nTCA14051\nCase Report\nCase Reports\nDramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient\nSaito et al.\nSaito Shunichi 1\nToyokawa Gouji 1\nMomosaki Seiya 2\nKozuma Yuka 1\nShoji Fumihiro 1\nYamazaki Koji 1 yamakan521@gmail.com\n\nTakeo Sadanori 1\n1 Department of Thoracic Surgery Clinical Research Institute, National Hospital Organization, Kyushu Medical Center Fukuoka Japan\n2 Department of Pathology Clinical Research Institute, National Hospital Organization, Kyushu Medical Center Fukuoka Japan\n* Correspondence\nKoji Yamazaki, Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 1‐8‐1 Jigyohama, Chuo‐ku, Fukuoka, 810‐8563, Japan.\nEmail: yamakan521@gmail.com\n\n21 6 2021\n8 2021\n12 15 10.1111/tca.v12.15 22172220\n21 5 2021\n23 4 2021\n25 5 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nImmune checkpoint inhibitors with chemotherapy have been shown to exhibit remarkable efficacy for advanced non‐small‐cell lung carcinoma and are under investigation as an induction therapy. However, the significance of preoperative therapy with pembrolizumab + chemotherapy for surgically resectable non‐small‐cell lung carcinoma still remains unclear. Here, we report a case of stage IIIB non‐small‐cell lung carcinoma that underwent salvage surgery after three cycles of pembrolizumab + carboplatin + nab‐paclitaxel. Computed tomography revealed the remarkable decrease in tumor volume by 81%. A pathological examination showed that viable neoplastic cells were observed in <1% of the total tumorous lesion suggesting near pathological complete response. This case suggests that this regimen might be a good option as induction therapy for non‐small‐cell lung carcinoma.\n\nSignificance of preoperative therapy with pembrolizumab + chemotherapy for surgically resected non‐small‐cell lung carcinoma still remains unclear. This regimen showed a drastic response in a case of stage IIIB non‐small‐cell lung carcinoma that underwent salvage surgery after three cycles. A pathological examination showed that viable neoplastic cells were observed in <1% of the total tumorous lesion suggesting near pathological complete response.\n\nImmunotherapy\nlung cancer\nneoadjuvant therapy\nsalvage surgery\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:02.08.2021\nSaito S , Toyokawa G , Momosaki S , et al. Dramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient. Thorac Cancer. 2021;12 :2217–2220. 10.1111/1759-7714.14051\n==== Body\nINTRODUCTION\n\nImmune checkpoint inhibitors (ICIs) are under investigation in the neoadjuvant setting. Several trials suggested that neoadjuvant ICI with chemotherapy exhibits remarkable efficacy for non‐small‐cell lung carcinoma (NSCLC); however, significance of the preoperative pembrolizumab with chemotherapy has yet to be clarified. 1 , 2 , 3 , 4 We report a case of a patient with locally advanced NSCLC who was successfully treated with surgical resection following pembrolizumab + carboplatin + nab‐paclitaxel.\n\nCASE REPORT\n\nThe patient was a 50‐year‐old man with a 32‐pack/year smoking history. Chest X‐ray of the medical check‐up showed a mass shadow in the left upper lung field without any chief complaints (Figure 1(a)) without any pain in the chest and back, and the patient was referred to our hospital. Laboratory examinations revealed remarkable elevation of the serum level of carcinoembryonic antigen (CEA; 1253.2 ng/mL). Chest computed tomography (CT) revealed a huge mass shadow of 132 mm in size (Figure 1(b)), in the left upper lobe with invasion into the lower lobe and main pulmonary artery. The hilar and mediastinal lymph nodes were also swollen. Positron emission tomography/CT revealed a high uptake in the mass, with a maximum standardized uptake value of 19.85 (Figure 1(c)). The patient underwent transbronchial biopsy and was diagnosed with NSCLC (cT4N2M0, cStage IIIB; Figure 2(a)). No genetic alterations were identified in epidermal growth factor receptor, anaplastic lymphoma kinase, or c‐ROS oncogene 1. Two percent of the tumor cells exhibited the expression of programmed death‐ligand 1 (PD‐L1; 22C3; Figure 2(b)). Carboplatin + nab‐paclitaxel + pembrolizumab were administered. During the second cycle, an adverse event (neutropenia: grade three) occurred and the patient could not receive nab‐paclitaxel on day 15. After the second cycle, the patient's serum level of CEA decreased to 202.6 ng/mL. After the administration of pembrolizumab in the third cycle, an immune‐related adverse event (infusion reaction: grade 2) occurred and we judged that drug therapy could not be continued. After the third cycle, laboratory examinations revealed that the patient's serum level of CEA had decreased to 20.8 ng/mL. CT revealed that the mass shadow was reduced to 104 mm in size (−21%: stable disease) and three‐dimensional CT showed a remarkable decrease in tumor volume from 448 859 to 85 081 mm3 (−81%). No distant metastasis was present. The patient's good physical capacity, including his pulmonary function, suggested that he could undergo left pneumonectomy. Left pneumonectomy with open thoracotomy was electively performed in combination with the resection of the parietal pleura because of adhesion between the left upper lung and parietal pleura (Figure 2(c)). There was adhesion between parietal pleura, aorta, and left upper lung without fibrosis and necrosis of vessels and the bronchi, although we did not encounter any dilemmas in managing with hilar adhesions/dense fibrosis. The hilar and mediastinal lymph nodes were also dissected. The postoperative course was uneventful with no postoperative complications. Pneumonectomy had an insignificant effect on the patient's quality of life. The tumorous lesion in the left upper lung exhibited massive necrosis, fibrosis with hyalinization and inflammation. Viable neoplastic cells were observed in <1% of the total tumorous lesion, suggesting a near pathological complete response (pCR; Figure 2(d), arrow). In addition, no viable cells were identified in the dissected lymph nodes. After surgery, a laboratory examination revealed a further decrease in CEA (1.3 ng/mL; Figure 3). Because of the occurrence of an infusion reaction, we decided to follow‐up without postoperative therapy. Twelve months have passed without recurrence.\n\nFIGURE 1 Chest X‐ray revealed a mass shadow in the left upper lung field (a). Chest computed tomography (CT) revealed a huge mass shadow, measuring 132 mm in size, in the left upper lobe with invasion into the lower lobe and main pulmonary artery (b). Positron emission tomography/CT revealed an avid uptake in the mass, with a maximum standardized uptake value of 19.85 (c). After three cycles of carboplatin + nab‐paclitaxel + pembrolizumab, chest X‐ray revealed that the mass shadow in the left upper lung field had decreased in size (d), and CT revealed that the mass shadow reduced to 104 mm in size (−21%: stable disease) (e). Scale bar: 1.0 cm\n\nFIGURE 2 The pathological examination of a transbronchial biopsy specimen revealed non‐small‐cell lung carcinoma (NSCLC) (a), and 2% of the tumor cells expressed programmed death‐ligand 1 (22C3) (b). The patient underwent left pneumonectomy combined with the resection of the parietal pleura (c). The tumorous lesion in the left upper lung exhibited massive necrosis, fibrosis with hyalinization and inflammation. Viable neoplastic cells were observed in <1% of the total tumorous lesion (d) (arrow)\n\nFIGURE 3 Changes in carcinoembryonic antigen. CEA, carcinoembryonic antigen; CBDCA, carboplatin; nab‐PTX, nab‐paclitaxel\n\nDISCUSSION\n\nICIs are generally administered to patients with advanced‐stage NSCLC and their significance in induction therapy is under investigation. 5 , 6 , 7 , 8 , 9 , 10 Forde et al. reported that neoadjuvant nivolumab therapy led to a major pathological response (MPR) in 9 of 20 patients (45%) and a pCR in 3 of 20 patients (15%). 1 Furthermore, neoadjuvant therapy with atezolizumab + carboplatin + nab‐paclitaxel was tested in patients with resectable NSCLC and among 22 patients, 12 (54.5%) and 7 patients (32%) demonstrated an MPR and pCR, respectively. 3 Therefore, ICI + chemotherapy may have a remarkable efficacy as induction therapy for resectable NSCLC, although the survival benefits are yet to be determined. Some studies showed that pCR after neoadjuvant chemotherapy brings long overall survival for the patients with NSCLC. 11 , 12 , 13 Pembrolizumab and chemotherapy are also being examined in patients with resectable NSCLC, but the result has not been reported (NCT03425643).\n\nThe present case was initially diagnosed as stage IIIB NSCLC and pembrolizumab + carboplatin + nab‐paclitaxel were administrated. Paz‐Ares et al. reported that the addition of pembrolizumab to standard chemotherapy with carboplatin and either paclitaxel or nab‐paclitaxel, in comparison to chemotherapy alone, prolonged median overall survival by 4.6 months (15.9 months vs. 11.3 months) and median progression‐free survival by 1.6 months (6.4 months vs. 4.8 months) in patients with untreated metastatic squamous NSCLC. 14 Because of the immune‐related toxicity, we considered that it was not possible to continue this regimen any further and performed salvage surgery. The achievement of a near pCR with pembrolizumab with carboplatin + nab‐paclitaxel indicates that this combination therapy might be a good option for induction therapy for NSCLC, although this regimen is not currently being investigated for this application. In summary, we report the case of a patient with NSCLC who was successfully treated with carboplatin + nab‐paclitaxel + pembrolizumab followed by salvage surgery.\n\nCONFLICT OF INTEREST\n\nThe authors declare that they have no competing interests.\n\nACKNOWLEDGMENTS\n\nWe thank Brian Quinn for his critical comments on the manuscript. The authors have no sources of funding for the report.\n==== Refs\nREFERENCES\n\n1 Forde PM , Chaft JE , Smith KN , Anagnostou V , Cottrell TR , Hellmann MD , et al. Neoadjuvant PD‐1 blockade in resectable lung cancer. N Engl J Med. 2018;378 :1976–86.29658848\n2 Uprety D , Mandrekar SJ , Wigle D , Roden AC , Adjei AA . Neoadjuvant immunotherapy for NSCLC: current concepts and future approaches. J Thorac Oncol. 2020;15 :1281–97.32522713\n3 Shu CA , Gainor JF , Awad MM , Chiuzan C , Grigg CM , Pabani A , et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non‐small‐cell lung cancer: an open‐label, multicentre, single‐arm, phase 2 trial. Lancet Oncol. 2020;6 :786–95.\n4 Provencio M , Nadal E , Insa A , Garcia‐Campelo R , Casal Rubio J , Domine M , et al. NEO‐adjuvant chemo‐immunotherapy for the treatment of STAGE IIIA resectable non‐small‐cell lung cancer (NSCLC): a phase II multicenter exploratory study‐final data of patients who underwent surgical assessment. J Clin Oncol. 2019;37 (15_suppl ):8509.\n5 Gandhi L , Rodríguez‐Abreu D , Gadgeel S , Esteban E , Felip E , De Angelis F , et al. Pembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer. N Engl J Med. 2018;378 :2078–92.29658856\n6 Reck M , Rodríguez‐Abreu D , Robinson A , Hui R , Csoszi T , Fulop A , et al. Updated analysis of KEYNOTE‐024: pembrolizumab versus platinum‐based chemotherapy for advanced non‐small‐cell lung cancer with PD‐L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37 :537–46.30620668\n7 Borghaei H , Paz‐Ares L , Horn L , Spigel DR , Steins M , Ready NE , et al. Nivolumab versus docetaxel in advanced nonsquamous non‐small‐cell lung cancer. N Engl J Med. 2015;373 :1627–39.26412456\n8 Brahmer J , Reckamp KL , Baas P , Crinò L , Eberhardt WEE , Poddubskaya E , et al. Nivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer. N Engl J Med. 2015;373 :123–35.26028407\n9 Socinski MA , Jotte RM , Cappuzzo F , Orlandi F , Stroyakovskiy D , Nogami N , et al. Atezolizumab for first‐line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378 :2288–301.29863955\n10 Lim E , Harris G , Patel A , Adachi I , Edmonds L , Song F . Preoperative versus postoperative chemotherapy in patients with resectable non‐small cell lung cancer: systematic review and indirect comparison meta‐analysis of randomized trials. J Thorac Oncol. 2009;4 :1380–8.19861907\n11 Pataer A , Kalhor N , Correa AM , Raso MG , Erasmus JJ , Kim ES , et al. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol. 2012;7 :825–32.22481232\n12 Junker K , Langner K , Klinke F , Bosse U , Thomas M . Grading of tumor regression in non‐small cell lung cancer: morphology and prognosis. Chest. 2001;120 :1584–91.11713138\n13 Melek H , Çetinkaya G , Özer E , Yentürk E , Sevinç TE , Bayram AS , et al. Pathological complete response after neoadjuvant/induction treatment: where is its place in the lung cancer staging system? Eur J Cardiothorac Surg. 2019;56 :604–11.30809654\n14 Paz‐Ares L , Luft A , Vicente D , Tafreshi A , Gümüş M , Mazières J , et al. Pembrolizumab plus chemotherapy for squamous non‐small‐cell lung cancer. N Engl J Med. 2018;379 :2040–51.30280635\n\n",
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"title": "Dramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient.",
"title_normalized": "dramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient"
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"abstract": "The aim of this study is to compare the risk of treatment-related toxicities and long-term survival between obese and nonobese patients with non-Hodgkin lymphoma when treated with full uncapped doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. A total of 133 patients and 733 cycles of chemotherapy were analyzed. Obese patients did not experience an increased risk of acute treatment-related toxicities (adjusted odds ratio 0.825, p = 0.197), or delayed toxicities (adjusted odds ratio 0.819, p = 0.779). In the subgroup of diffuse large B-cell lymphoma patients (n = 109), treatment response rate was similar between the two body mass index (BMI) groups, and obese patients tended to have superior overall and progression-free survivals, albeit not statistically significant. Full uncapped doses of R-CHOP chemotherapy administered to obese patients with non-Hodgkin lymphoma (NHL) are safe, well tolerated, and do not lead to inferior treatment response or long-term outcomes.",
"affiliations": "a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;;a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;;b Department of Statistics , University of Auckland , Auckland , New Zealand.;a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;;a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;;a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;;a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;",
"authors": "Chan|Henry|H|;Jackson|Sharon|S|;McLay|Jessica|J|;Knox|Angela|A|;Lee|Jae|J|;Wang|Sarah|S|;Issa|Samar|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
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"issue": "57(11)",
"journal": "Leukemia & lymphoma",
"keywords": "Chemotherapy; non-Hodgkin lymphoma; obesity",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009765:Obesity; D011241:Prednisone; D011379:Prognosis; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
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"title": "Obese non-Hodgkin lymphoma patients tolerate full uncapped doses of chemotherapy with no increase in toxicity, and a similar survival to that seen in nonobese patients.",
"title_normalized": "obese non hodgkin lymphoma patients tolerate full uncapped doses of chemotherapy with no increase in toxicity and a similar survival to that seen in nonobese patients"
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"abstract": "Polypharmacy is increasingly common in older adults, placing them at risk of medication-related harm (MRH). Patients are particularly vulnerable to problems with their medications in the period following hospital discharge due to medication changes and poor information transfer between hospital and primary care. The aim of the present study was to investigate the incidence, severity, preventability and cost of MRH in older adults in England postdischarge.\n\n\n\nAn observational, multicentre, prospective cohort study recruited 1280 older adults (median age 82 years) from five teaching hospitals in Southern England, UK. Participants were followed up for 8 weeks by senior pharmacists, using three data sources (hospital readmission review, participant telephone interview and primary care records), to identify MRH and associated health service utilization.\n\n\n\nOverall, 413 participants (37%) experienced MRH (556 MRH events per 1000 discharges), of which 336 (81%) cases were serious and 214 (52%) potentially preventable. Four participants experienced fatal MRH. The most common MRH events were gastrointestinal (n = 158, 25%) or neurological (n = 111, 18%). The medicine classes associated with the highest risk of MRH were opiates, antibiotics and benzodiazepines. A total of 328 (79%) participants with MRH sought healthcare over the 8-week follow-up. The incidence of MRH-associated hospital readmission was 78 per 1000 discharges. Postdischarge MRH in older adults is estimated to cost the National Health Service £396 million annually, of which £243 million is potentially preventable.\n\n\n\nMRH is common in older adults following hospital discharge, and results in substantial use of healthcare resources.",
"affiliations": "Academic Department of Geriatric Medicine, Brighton and Sussex Medical School, Brighton, Sussex, UK.;Academic Department of Geriatric Medicine, Brighton and Sussex Medical School, Brighton, Sussex, UK.;Institute of Pharmaceutical Science, Kings College London, London, UK.;Institute of Pharmaceutical Science, Kings College London, London, UK.;Department of Ageing and Health, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Academic Department of Geriatric Medicine, Brighton and Sussex Medical School, Brighton, Sussex, UK.;Pharmacy Department, The Royal Marsden NHS Foundation Trust, London, UK.;Department of Medicine, University of Southampton, Southampton, UK.;Academic Department of Geriatric Medicine, Brighton and Sussex Medical School, Brighton, Sussex, UK.",
"authors": "Parekh|Nikesh|N|0000-0002-9988-3717;Ali|Khalid|K|;Stevenson|Jennifer M|JM|;Davies|J Graham|JG|;Schiff|Rebekah|R|;Van der Cammen|Tischa|T|;Harchowal|Jatinder|J|;Raftery|James|J|;Rajkumar|Chakravarthi|C|;|||",
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"fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin Pharmacol10.1111/(ISSN)1365-2125BCPBritish Journal of Clinical Pharmacology0306-52511365-2125John Wiley and Sons Inc. Hoboken 10.1111/bcp.13613BCP13613MP-00116-18.R1Original ArticleOriginal ArticlesIncidence and cost of medication harm in older adults following hospital discharge: a multicentre prospective study in the UK Incidence and cost of medication harm in older adultsN. Parekh et al.Parekh Nikesh http://orcid.org/0000-0002-9988-3717\n1\n\n2\nAli Khalid \n1\n\n2\nStevenson Jennifer M. \n3\nDavies J. Graham \n3\nSchiff Rebekah \n4\nVan der Cammen Tischa \n1\n\n5\nHarchowal Jatinder \n6\nRaftery James \n7\nRajkumar Chakravarthi c.rajkumar@bsms.ac.uk \n1\n\n2\non behalf of the PRIME study group \n†\n\n1 \nAcademic Department of Geriatric Medicine\nBrighton and Sussex Medical School\nBrighton\nSussex\nUK\n\n2 \nDepartment of Elderly Medicine\nBrighton and Sussex University Hospitals NHS Trust\nSussex\nUK\n\n3 \nInstitute of Pharmaceutical Science, Kings College London\nLondon\nUK\n\n4 \nDepartment of Ageing and Health\nGuy's and St Thomas' NHS Foundation Trust\nLondon\nUK\n\n5 \nFaculty of Industrial Design Engineering\nDelft University of Technology\nDelft\nThe Netherlands\n\n6 \nPharmacy Department\nThe Royal Marsden NHS Foundation Trust\nLondon\nUK\n\n7 \nDepartment of Medicine\nUniversity of Southampton\nSouthampton\nUK\n* \nCorrespondence\n\nProfessor Chakravarthi Rajkumar, Chair in Geriatric and Stroke Medicine, Brighton and Sussex Medical School, Audrey Emerton Building, Eastern Road, Brighton, Sussex, BN2 5BE, UK.\n\nTel.: +44 (0) 12 7352 3360\n\nFax: +44 (0) 12 7352 3366\n\nE‐mail: c.rajkumar@bsms.ac.uk\n† \nThe PRIME study group: Coordinating team: K. Ali (co‐lead investigator), C. Rajkumar (co‐lead investigator), J. G. Davies (chief trial pharmacist), J. Harchowal (trial pharmacist), J. Timeyin (trial coordinator); Steering committee: K. Ali, C. Rajkumar, J. G. Davies, R. Schiff, J. M. Stevenson, T. van der Cammen; Data monitoring committee: K. Ali, C. Rajkumar, J. Timeyin, L. Klus, D. Fatz; End points committee: K. Ali, C. Rajkumar, J. G. Davies, R. Schiff; Lead investigators: K. Ali (Princess Royal Hospital, Haywards Heath, Brighton and Sussex University Hospitals NHS Trust), C. Rajkumar (Royal Sussex County Hospital, Brighton, Brighton and Sussex University Hospitals NHS Trust), R.Schiff (St Thomas' Hospital, London), A.Chauhan (Queen Alexandra Hospital, Portsmouth), D.Hunt (Worthing Hospital, Worthing); Trial pharmacists: J. M. Stevenson, K. Le Bosquet, St Thomas' Hospital; J. Allen, N. Henderson, Brighton and Sussex University Hospitals NHS Trust, C. Gonzalaz‐Cuevas, S. Burke‐Adams, Worthing Hospital; N. Khan, K. Yip, Queen Alexandra Hospital; Trial nurses: J. Timeyin, J. Breeds, J. Gaylard, J. Newman, Brighton and Sussex University Hospitals NHS Trust; T. Pettifer, St Thomas' Hospital; H. Fox, M. G. Metiu, Worthing Hospital; D. Foord, S. Valentine, T. Dobson, Queen Alexandra Hospital.\n\n31 5 2018 8 2018 31 5 2018 84 8 10.1111/bcp.v84.81789 1797 13 2 2018 03 4 2018 08 4 2018 © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Aims\nPolypharmacy is increasingly common in older adults, placing them at risk of medication‐related harm (MRH). Patients are particularly vulnerable to problems with their medications in the period following hospital discharge due to medication changes and poor information transfer between hospital and primary care. The aim of the present study was to investigate the incidence, severity, preventability and cost of MRH in older adults in England postdischarge.\n\nMethods\nAn observational, multicentre, prospective cohort study recruited 1280 older adults (median age 82 years) from five teaching hospitals in Southern England, UK. Participants were followed up for 8 weeks by senior pharmacists, using three data sources (hospital readmission review, participant telephone interview and primary care records), to identify MRH and associated health service utilization.\n\nResults\nOverall, 413 participants (37%) experienced MRH (556 MRH events per 1000 discharges), of which 336 (81%) cases were serious and 214 (52%) potentially preventable. Four participants experienced fatal MRH. The most common MRH events were gastrointestinal (n = 158, 25%) or neurological (n = 111, 18%). The medicine classes associated with the highest risk of MRH were opiates, antibiotics and benzodiazepines. A total of 328 (79%) participants with MRH sought healthcare over the 8‐week follow‐up. The incidence of MRH‐associated hospital readmission was 78 per 1000 discharges. Postdischarge MRH in older adults is estimated to cost the National Health Service £396 million annually, of which £243 million is potentially preventable.\n\nConclusions\nMRH is common in older adults following hospital discharge, and results in substantial use of healthcare resources.\n\nhealth economicshealth service usehospital dischargemedication harmolder adultspharmacoepidemiologyNational Institute for Health ResearchPB‐PG‐0711‐25094 source-schema-version-number2.0component-idbcp13613cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:16.07.2018\n\n\nParekh , N. \n, \nAli , K. \n, \nStevenson , J. M. \n, \nDavies , J. G. \n, \nSchiff , R. \n, \nVan der Cammen , T. \n, \nHarchowal , J. \n, \nRaftery , J. \n, \nRajkumar , C. \n, and \non behalf of the PRIME study group \n(2018 ) Incidence and cost of medication harm in older adults following hospital discharge: a multicentre prospective study in the UK . Br J Clin Pharmacol , 84 : 1789 –1797 . 10.1111/bcp.13613 .\n==== Body\nWhat is Already Known about this Subject\n\nPolypharmacy is increasingly common in older adults in the UK.\n\nOlder adults are vulnerable to medication‐related problems during transitions of care from hospital into the community.\n\n\n\n\nWhat this Study Adds\n\nMedication‐related harm affects one in three older adults following hospital discharge, of which at least 10% is preventable.\n\nNon‐adherence is implicated in one quarter of cases of medication harm.\n\nThe cost to the NHS of postdischarge medication harm in older adults is estimated at £396 million, of which over 90% is attributable to hospital readmissions.\n\n\n\n\nIntroduction\nHarm from medicines is a common cause of preventable morbidity and mortality in patients worldwide 1. The European Medicines Agency describes adverse drug reactions (ADRs) as ‘a response to a medicinal product that is noxious and unintended’ 2. In England, between 2008 and 2015, emergency hospital admissions due to ADRs increased by 53%, from 60 055 to 92 114 3. Based on data from a major UK study conducted in 2002 4, the National Institute for Health and Care Excellence (NICE) estimated an annual cost to the National Health Service (NHS) in 2015 of £530 million from preventable ADR‐related hospital admissions 5.\n\nOlder people are highly susceptible to harm from medicines, due to polypharmacy and ageing‐related changes in pharmacokinetics and pharmacodynamics 6, 7. Furthermore, non‐adherence to medicines for chronic disease was found in 30% of participants (median age 67 years) in one UK study 8. Non‐adherence to medicine is strongly associated with poor health outcomes 9, including mortality 10, and high healthcare costs 11. A systematic review found that 16% of community‐dwelling older adults experience harm from their medicines at any one time, compared with 5% of younger adults 12.\n\nThe transition period from hospital to home following hospital discharge has rarely been explored, despite the vulnerability of patients to medication problems during this period. For instance, patients often experience medication changes 13 with limited involvement in these decisions 14. Provision of information about possible side effects can be poor 15, and communication is often lacking between secondary and primary care 16. Furthermore, this is a time of heightened physiological stress for patients, due to the lingering impact of acute illness and deconditioning from their hospital stay 17.\n\nIn England, medication‐related harm (MRH) in the postdischarge period has not been studied in an older population. The aims of the present study were: (i) to determine the incidence, severity and preventability of MRH postdischarge in older adults; (ii) to describe the main types of MRH and implicated drugs; (iii) to describe health service utilization and cost associated with MRH.\n\nMethods\nThe study was approved by the National Research Ethics Service, East of England (REC Reference 13/EE/0075).\n\nDesign, setting and participants\nDetailed methods for the study have been published previously 18. In brief, this multicentre, prospective cohort study recruited adults aged 65 years and over. Between September 2013 and November 2015, research nurses invited patients to participate from medical wards in five NHS teaching hospitals in Southern England, near to the time of hospital discharge. The nurses collected baseline information, including demographic, clinical and social data, from consenting patients. Senior, trained research pharmacists followed discharged participants for 8 weeks to determine if they experienced MRH. An 8‐week observation period was chosen as previous research outside of the UK has shown that this is a reasonable time frame for capturing most postdischarge MRH events 19, 20, 21. We excluded patients if they were terminally ill, lacked capacity and had no nominated consultee, or were transferred to other acute healthcare units.\n\nMRH assessment\nWe defined MRH as an ADR or harm arising from a failure to receive medication owing to non‐adherence. Harm arising from medication error was included where reported. Intentional overdose was excluded. This is a modified version of the definition by Strand et al. 22. A medicine was defined by its inclusion in the World Health Organization–Anatomical Therapeutics Coding (WHO‐ATC) system 23.\n\nWe determined MRH incidence using three sources of follow‐up information: (i) participant and/or carer telephone interview at 8 weeks, using a structured questionnaire; (ii) general practitioner (GP) records; and (iii) prospective review of hospital readmissions, in consultation with the admitting medical consultant.\n\nIf an ADR was suspected, the validated Naranjo algorithm 24 was used to assess causality, in conjunction with the British National Formulary and Summary of Product Characteristics. For MRH associated with non‐adherence to medicine, we used a modified version of a validated questionnaire to assess participant non‐adherence 25. We classified events as ‘possible’, ‘probable’ or ‘definite’ MRH, or ‘doubtful’ when no harm occurred 26, 27, 28. We graded severity of MRH using the approach of Morimoto et al. 29: fatal, life‐threatening, serious (requires therapy change and/or treatment by a health professional) and significant. The preventability of MRH was assessed using the criteria of Hallas et al. 30: ‘definitely preventable’ (treatment inconsistent with best practice or unrealistic), ‘possibly preventable’ (preventable with efforts exceeding obligatory clinical demands), ‘not preventable’, or ‘not able to evaluate’. Two senior study pharmacists provided case‐based training to research pharmacists involved in data collection at all participating sites, to optimize the reliability of MRH assessments. Additionally, cross‐site case discussions were held regularly between the research pharmacists to ensure the standardization of MRH assessments.\n\nAn end‐point committee independent from data collection, consisting of three senior geriatricians and a senior researcher in clinical pharmacy, was provided with the structured case summaries of all cases of MRH by the research pharmacists. The role of the committee was to review, scrutinize and finally confirm or reject cases of MRH by consensus. Implicated medicines were classified according to the World Health Organization–Anatomical Therapeutic Chemical (WHO‐ATC) classification system.\n\nHealthcare utilization and cost analysis\nThe three sources of data collected (participant interviews, GP records, hospital readmissions) provided information on NHS use over the 8‐week follow‐up (including emergency department visits, hospital admission, outpatient clinics, GP visits and out‐of‐hours care). The date and reason for consultation were used to determine NHS utilization associated with MRH.\n\nWe used the Department of Health's 2013/14 payment by results NHS tariff data to cost episodes of healthcare utilization by linking them to Healthcare Resource Groups (HRGs) 31. When in doubt, we took the most cautious approach, such as for emergency department visits and out‐of‐hours care.\n1 With no investigations and no treatment in the emergency department, costing £58 per episode 31. Out‐of‐hours medical visits associated with MRH were costed at £53.60 using data from the National Audit Office 32, which reports that 50% of visits cost £53.60 to £86.30. This cautious approach avoided false assumptions about the extent of investigation and treatment.\n\n\n\n\nTo estimate the annual cost in England of postdischarge MRH in older adults, we multiplied the average excess cost related to MRH per discharged participant in our study by the estimated number of unplanned admissions of older people in 2013/14 in England 33.Furthermore, we disaggregated the costs of MRH‐associated healthcare use by preventability.\n\nStatistical analysis\nWe examined variable distributions for normality and compared the characteristics of the cohort included in the final analysis with those of patients lost to follow‐up, using the Mann–Whitney U‐test. Fisher's exact test was used to compare categorical variables.\n\nThe incidence of MRH is reported as: (i) the incidence proportion (number of participants experiencing MRH/total sample) and (ii) the incidence of events per 1000 discharged participants (number of events × 1000/total sample). Other descriptive statistics are based on frequency calculations. Incidence proportions are presented with accompanying 95% confidence intervals. We analysed data using IBM SPSS Statistics, version 22 (IBM Corp., Armonk, NY).\n\nResults\nParticipant characteristics\nThe study recruited 1280 older adults at hospital discharge and followed up participants for 8 weeks. Research pharmacists completed a telephone interview with 873 participants (68.2%) and retrieved the GP records of 922 participants (72.0%). From the 1280 recruited participants, 17 (1.3%) died without follow‐up, and 147 participants (11.5%) were lost to follow‐up because they were not readmitted, their GP records were unavailable or they could not be contacted. Therefore, our final cohort included 1116 (87.2%) participants (see Table 1).\n\nTable 1 Baseline participant characteristics\n\n\nCharacteristic\n\t\nIncluded participants\na\n(n = 1116)\n\t\nExcluded participants (n = 164)\n\t\nP value\nb\n\t\n\nAge, median (IQR), years\n\t81.9 (75.5–86.9)\t80.5 (74.7–86.2)\t0.123\t\n\nGender, n (%)\n\t\n\nWomen\n\t652 (58.4)\t93 (56.7)\t0.673\t\n\nMen\n\t464 (41.6)\t71 (43.3)\t\t\n\nHospital stay, median (IQR), days\n\t7 (3–14)\t7 (3–13)\t0.595\t\n\nNumber of Charlson Index comorbidities (%)\n\t\n\n0–1\n\t541 (48.5)\t88 (53.7)\t\t\n\n≥2\n\t575 (51.5)\t76 (46.3)\t0.242\t\n\nSelected comorbidities, n (%)\n\t\n\nHypertension\n\t611 (54.7)\t86 (52.4)\t0.615\t\n\nCLD\n\t326 (29.2)\t56 (34.1)\t0.202\t\n\nAtrial fibrillation\n\t279 (25.0)\t43 (26.2)\t0.773\t\n\nDiabetes\n\t269 (24.1)\t31 (18.9)\t0.167\t\n\nIHD\n\t224 (20.1)\t38 (23.2)\t0.352\t\n\nCKD\n\t153 (13.7)\t21 (12.8)\t0.808\t\n\nCCF\n\t150 (13.4)\t20 (12.2)\t0.713\t\n\nDepression\n\t95 (8.5)\t12 (7.3)\t0.762\t\n\nDementia\n\t51 (4.6)\t6 (3.7)\t0.839\t\n\nCharlson index, median (IQR)\n\t2 (1–3)\t1 (1–3)\t0.087\t\n\nBarthel score, median (IQR)\n\t17 (13–20)\t18 (14–20)\t0.035\t\n\nNumber of discharge medicines, median (IQR)\n\t9 (7–12)\t9 (6–12)\t0.393\t\n\nMulticompartment compliance aid, n (%)\n\t371 (33.2)\t43 (26.2)\t0.074\t\n\nDischarge to care home, n (%)\n\t30 (2.7)\t8 (4.9)\t0.136\t\n\nLiving alone after discharge, n (%)\n\t551 (49.4)\t80 (48.8)\t>0.999\t\nCCF, congestive cardiac failure; CLD, chronic lung disease; CKD, chronic kidney disease; IHD, ischaemic heart disease; IQR, interquartile range\n\na Ten participants were included following readmission which was not associated with medication‐related harm, for whom general practitioner records were not available and were uncontactable at 8 weeks (median follow‐up 29 days after recruitment)\n\nb Mann–Whitney U test for continuous variables and Fisher's exact test for categorical variables\n\nThe median age of the cohort was 82 years [interquartile range (IQR) 76–87], 58% were female and the median number of discharge medicines was nine (IQR 7–12).\n\nIncidence of MRH\nOverall, 413 participants [37.0% (95% CI 34.2–39.9%)] experienced MRH in the 8‐week follow‐up period, with 856 medicines implicated in 621 events. This represents an MRH incidence of 556 events per 1000 participants over an 8‐week time frame. A total of 460 MRH events (74%) were attributable to medicines prescribed at hospital discharge, with the remainder prescribed in the community during the 8‐week observation period. Of the 413 participants whom we classified as having MRH, 246 (60%) experienced at least one MRH event considered ‘probable’ (n = 110) or ‘definite’ (n = 136). The remaining cases were ‘possible’ (n = 167). The prevalence of non‐adherence in our cohort was 29.1% at follow‐up (325 out of 1112 participants with adherence data).\n\nADRs were solely responsible for MRH in 301 out of 413 cases (72.9%), non‐adherence in 45 cases (10.9%) and a medication error in 14 cases (3.4%). In five cases (1.2%), the patient experienced harm from both an ADR and a medication error. The underlying medication error was at the stage of prescribing in 11 cases, dispensing in four cases, administration by a carer in three cases and patient error in the use of a medicine administration device in one case. In 48 cases (11.6%), harm was due to both an ADR and non‐adherence. For example, a participant who experienced a gastric bleed associated with antiplatelet therapy was non‐adherent to their proton‐pump inhibitor. One quarter of ADRs occurred in the first week postdischarge, and 68% within 30 days of discharge.\n\nSeverity and preventability of MRH\nFour participants (1.0%) experienced a fatal event associated with the MRH; one died following a fall and fractured neck of femur associated with lorazepam use, one from a major gastrointestinal bleed associated with use of apixaban, one from a stroke associated with non‐adherence to warfarin and one from a lower respiratory tract infection associated with prednisolone‐induced immunosuppression. Nine participants (2.2%) had a life‐threatening event, and MRH was serious in a further 323 participants (78.2%). We classified medication harm as ‘definitely’ preventable in 44 cases [(95% CI 7.8–14.0%)] and ‘possibly’ preventable in 170 MRH cases [(36.4–46.1%); see Appendix 1].\n\nTypes of MRH and implicated medicines\nThe body systems affected by MRH are shown in Table 2. The main body systems affected by MRH were gastrointestinal (25.4%) or neurological (17.9%). The most common events were diarrhoea (n = 55; 8.9%), constipation (n = 52; 8.4%), falls (n = 35; 5.6%) and bleeding (n = 31; 5.0%).\n\nTable 2 Medication‐related harm by body system and implicated medicine\n\n\nBody system\n\t\nTotal events (n = 612), n (%)\n\t\nMedication‐related harm (n)\n\t\nCommonly implicated medicines\na\n(n)\n\t\n\nGastrointestinal\n\t158 (25.4)\tDiarrhoea, 54; constipation, 52; nausea, 21; vomiting, 13; acid reflux, 12; abdominal pain, 5; acute liver injury, 1\tOpiates, 49; senna, 16; iron, 10; macrogol, 9; alendronate, 8; clopidogrel, 8\t\n\nNeurological\n\t111 (17.9)\tDizziness, 25; confusion, 19; fatigue, 19; drowsiness, 14; headache, 14; sleep disturbance, 11; involuntary movements, 4; paraesthesia, 4; seizure, 1\tOpiates, 23; amlodipine, 10; bisoprolol, 9; ramipril, 6; amitriptyline, 5\t\n\nCardiovascular\n\t68 (11.0)\tPeripheral oedema, 26; postural hypotension, 17; syncope, 9; exacerbation of cardiac failure, 7; arrhythmia, 5; thrombotic event, 4\tAmlodipine, 15; furosemide, 10; bisoprolol, 8; bumetanide, 7; ramipril, 6\t\n\nMusculoskeletal\n\t65 (10.5)\tFall, 35; musculoskeletal pain, 27; gout, 2; fracture, 1\tOpiates, 18; bisoprolol, 10; furosemide, 8; ramipril, 7; simvastatin, 5\t\n\nDermatology\n\t47 (7.6)\tRashes and skin lesions, 20; pruritus, 13; candidiasis, 9; alopecia, 3; facial swelling, 1; unresolving infection, 1\tClarithromycin, 4; amoxicillin, 3; flucloxacillin, 3; rivaroxaban, 3; furosemide, 3\t\n\nHaematology\n\t45 (7.2)\tBleeding, 31; bruising, 9; anaemia, 4; immunosuppression, 1\tClopidogrel, 12; rivaroxaban, 10; warfarin, 8; aspirin, 8; dalteparin, 4\t\n\nRespiratory\n\t31 (5.0)\tDyspnoea, 19; cough, 11; unresolving infection, 1;\tRamipril, 9; salbutamol, 7; tiotropium, 7; seretide, 5; symbicort, 3\t\n\nRenal\n\t26 (4.2)\tAcute kidney injury, 15; electrolyte disturbance, 11\tFurosemide, 11; spironolactone, 6; ramipril, 6; bumetanide, 5; omeprazole, 2\t\n\nEndocrine\n\t25 (4.0)\tHypoglycaemia, 12; hyperglycaemia, 11; gynaecomastia, 1, hot flushes, 1\tInsulin, 15; gliclazide, 6; metformin, 3; prednisolone, 3; liraglutide, 2\t\n\nPsychiatric\n\t16 (2.6)\tMood or behavioural disturbance, 16\tOpiates, 6; prednisolone, 3; zopiclone, 2; gabapentin, 2;\t\n\nEar nose & throat\n\t14 (2.3)\tDry mouth, 8; taste disturbance, 4; hoarseness, 1; oral ulceration, 1\tOmeprazole, 2; tiotropium, 2\t\n\nGenitourinary\n\t9 (1.4)\tIncontinence, 4; urinary retention, 4; urine discolouration, 1\tFurosemide, 3\t\n\nOphthalmology\n\t6 (1.0)\tDry or sore eyes, 3; visual disturbance, 3\tPrednisolone, 2\t\na Top five medicines listed, except when the number of events caused by a medicine was <2. Given multiple formulations of codeine and morphine‐related medicines, these are grouped into opiates\n\nAntihypertensives and opiates were implicated in the highest proportion of MRH events (22.4% and 17.2%, respectively). However, MRH risk (incidence per 1000 prescriptions) was greatest for opiates (399), followed by antibiotics (189). The risk of MRH by medicine class is shown in Table 3.\n\nTable 3 Incidence of harm by medicine class\n\n\nMedicine class\na\n\t\nPrescriptions (n)\n\t\nMRH events (n)\n\t\nProportion of MRH by medicine class (%)\n\t\nRisk of MRH by medicine class (events per 1000 prescriptions)\n\t\n\nOpiates\n\t268\t107\t17.2\t399.3\t\n\nAntibiotics\n\t344\t65\t10.5\t189.0\t\n\nBenzodiazepines\n\t81\t15\t2.4\t185.2\t\n\nDiuretics\n\t496\t76\t12.2\t153.2\t\n\nAntiepileptic agents\n\t147\t21\t3.4\t142.9\t\n\nCorticosteroids\n\t158\t21\t3.4\t132.9\t\n\nAnticoagulants\n\t311\t41\t6.6\t131.8\t\n\nAntidepressants\n\t269\t34\t5.5\t126.4\t\n\nAntihypertensive agents\n\t1163\t139\t22.4\t119.5\t\n\nHypoglycaemic agents\n\t314\t34\t5.5\t108.3\t\n\nAnticholinergic agents\n\t173\t12\t1.9\t69.4\t\n\nLaxatives\n\t616\t41\t6.6\t66.6\t\n\nAntiplatelet agents\n\t582\t38\t6.1\t65.3\t\nMRH, medication‐related harm\n\na Benzodiazepines include benzodiazepine‐related drugs; World Health Organization–Anatomical Therapeutics Coding codes C03A and C03B are under both antihypertensive agents and diuretics\n\nOf the 413 participants with MRH, 85 (20.6%), who experienced 105 MRH events, managed their adverse event(s) without seeking healthcare input. The most common events were diarrhoea (n = 13; 12.4%), constipation (n = 11; 10.5%), dizziness (n = 8; 7.6%) and peripheral oedema (n = 8; 7.6%).\n\nHealth service utilization and cost\nOut of the 413 MRH cases, 328 [95% CI (75.2–83.2%)] had at least one NHS service use associated with MRH, and 87 participants [95% CI (6.3–9.5%)] had an MRH‐associated hospital readmission. A total of 328 participants received 441 NHS consults [GP consultation (n = 316; 71.7%), hospital readmission (n = 96; 21.8%], outpatient clinic attendance (n = 12; 2.7%], emergency department attendance (n = 9; 2.0%), out‐of‐hours visit (n = 8; 1.8%)]. The cumulative NHS cost, over the 8‐week period after hospital discharge, was £225 747, an average cost per participant with MRH of £546.60. Hospital readmissions accounted for 93% of total costs. The estimated annual cost to the NHS of MRH postdischarge in older adults is £395.5 million. The cost of preventable MRH lies between £51.6 million per year (only MRH classified as ‘definitely preventable’) and £243.4 million per year (MRH ‘definitely’ or ‘possibly’ preventable).\n\nDiscussion\nThis was the first UK study to investigate medication harm in older adults following hospital discharge. Our key findings were that MRH affects one in three older adults, and that 80% of cases were serious, and at least 10% preventable. Four out of five participants with MRH consulted an NHS service within 8 weeks postdischarge. We estimated that postdischarge MRH to the older population incurs an annual cost in the region of £400 million to the NHS, and that most of this cost is attributable to hospital readmissions.\n\nADRs are the main form of MRH, and 25% manifest in the first week postdischarge. A large proportion of older adults (29%) are non‐adherent in the postdischarge period, and the present study clearly demonstrated the harms associated with this; non‐adherence was implicated in 23% of MRH cases, including one death. While the study did not seek to identify medication errors, harm attributable to a medication error was recorded and represented a very small proportion of the overall MRH burden (<5%). In the majority of these cases, the medication error was made at the prescribing stage.\n\nStrengths and limitations\nThe main strengths of the study were the comprehensive data collection (participant interview, primary care records and readmission review) and the fact that we recruited a large, multicentre cohort of older adults (average age >80 years). Our definition of MRH reflects ‘real‐life’ for patients by including harm from non‐adherence (as opposed to only ADRs), and, we employed a robust approach to ascribe MRH causality using a validated algorithm 24 and the clinical expertise of senior pharmacists and geriatricians.\n\nHowever, there were also several limitations. Participants' involvement in the study might have heightened their awareness of potential ADRs. They might therefore have been more attentive to medicines‐related information and usage instructions, or more likely to seek healthcare when MRH was suspected. However, this increased knowledge might also have enabled participants to attribute and report MRH more accurately.\n\nRetrospective participant interviews may have resulted in under‐reporting of MRH due to poor recall, and GPs may not have recorded all MRH encountered owing to time pressures or a perceived lack of severity 34. Harm arising from medication errors might have been underestimated as we did not look actively for postdischarge medication reconciliation errors and assess their impact. It is possible, therefore, that some MRH was misclassified as an ADR, rather than a harm due to medication error. Nonetheless, a very small proportion of medication errors actually lead to patient harm 35.\n\nThe NHS costs we report are an approximation based on the incidence and types of MRH in the present study. We recorded NHS utilization associated with MRH, and could not infer causality. Nonetheless, hospital readmissions accounted for 93% of overall cost, and in these cases the MRH was verified as a principal driver for admission by the medical consultant in charge.\n\nComparison with other studies\nThe proportion of participants experiencing MRH (37%) in our study was higher than previously reported 36. This was probably due to methodological differences as opposed to any peculiarities in our study population or the healthcare system. A retrospective analysis of 1000 older patients in the United States found that 18.7% experienced MRH over a 45‐day period following hospital discharge 21. This study identified events through review of medical notes, contrasting with our prospective methods, which additionally included participant interviews. Retrospective studies and studies that exclude participant interviews tend to report a lower incidence of MRH 12, 37. A prospective European study of 209 patients (average age 74 years) found that 30% of their cohort experienced an ADR over a 30‐day postdischarge period 38. This finding was comparable to our results, although our slightly higher incidence of 37% probably reflected the inclusion of MRH from non‐adherence.\n\nWe found that 11% of participants experiencing MRH had an event that was definitely preventable. Nevertheless, we believe that the true proportion is likely to be higher as 41% of MRH cases were possibly preventable. A systematic review published in 2011 by Taché et al. reported that 16.5% of MRH events in the community were preventable, based on all age groups 12. The high proportion of preventable events in our study reflected the particularly challenging period (i.e. postdischarge) we investigated in an older population, and our inclusion of harm from non‐adherence to medicines.\n\nThe systematic review by Taché et al. 12 found cardiovascular medicines to be most implicated in MRH in the community setting, reflecting the high prevalence of their use. Our study found that 22% of MRH was associated with antihypertensive medicines. However, the highest risk of MRH was associated with opiates. Concerns have been raised about the potential harm related to overuse of opiates in noncancer patients in the UK 39, and our study demonstrated the actual harm associated with opiate use in older adults.\n\nImplications for practitioners and policy makers\nGiven the high proportion of preventable MRH in our study, there is considerable scope for improving patient safety. The lack of prescriber knowledge of harms is a key driver of medicines overuse 40, and, clinicians are more likely to overestimate the benefits of treatment and underestimate the harms 41. The present study highlights the extent of MRH during a critical juncture of healthcare provision, and supports the need for increased pharmacovigilance among clinicians in secondary and primary care. While most MRH in the postdischarge period was attributable to medicines prescribed in the hospital setting, one‐quarter of implicated medicines were prescribed in the community. It is crucial to reconcile the medicines that patients receive on discharge from hospital, with those already listed on the repeat prescription from the GP, and any additional medicines which the patient takes at home. Prescribers in the community must be wary of the heightened vulnerability of patients to harm in the immediate postdischarge period, as physiological systems remain impaired during recovery from acute illness and the stressors associated with hospitalization (e.g. poor nourishment, deconditioning, sleep disturbance, delirium) 17.\n\nThere are numerous lists of potentially inappropriate medicines for older adults 42 [e.g. Screening Tool of Older Persons' Potentially inappropriate Prescriptions (STOPP), Beers, (European Union Potentially Inappropriate Medications (EU‐PIM)]. While these have merit, a ‘hard and fast’ rules‐based approach does not account for the biopsychosocial complexity of patients 43, 44. Simple guiding principles that support clinical judgement for the safe initiation of medicine [e.g. the BEGIN (1. Basis for therapy; 2. Evaluate risk of interactions; 3. Given agreement; 4. Intended benefit likely; 5. No better alternative) algorithm 45 or the Medication Appropriateness Index 46] may be more practical and effective 47. When prescribers initiate new medicines, a tentative stop or review date should always be specified. While it remains unclear from randomized trials if medication review on its own reduces MRH in older adults, multicomponent interventions incorporating patient education have demonstrated success during transitions of care 13, 48.\n\nIn addition, there are several risk prediction tools to identify patients at high risk for MRH, although these have been largely developed for a hospitalized population 49. In the present study, we showed that the risk of MRH is highest in the community setting following hospital discharge. Future work should focus on developing a tool to identify high‐risk patients during this particularly vulnerable period.\n\nOur national cost estimate of almost £400 million per year is a conservative estimate. It excludes the indirect costs from wasted medicines (non‐adherence and poor therapeutic value, or medicines that must be stopped owing to adverse effects) and the social costs of additional formal and informal care (e.g. time taken away from work by relatives to support participants). The bulk of the cost arises from hospital readmissions. Therefore, early recognition of medication‐related problems and community management as far as possible could generate large savings.\n\nIn conclusion, medication harm in older adults is a common and costly phenomenon following hospital discharge. Increased vigilance to high‐risk prescribing, and supporting the appropriate use of medicines in the community, might reduce this problem.\n\nCompeting Interests\nThere are no competing interests to declare.\n\n\nWe are grateful to Dr Stephen Bremner, senior lecturer in medical statistics, Brighton and Sussex Medical School, UK, for statistical support. This study was funded by the\nNational Institute for Health Research\n(NIHR) – Research for Patients Benefit Scheme (\nPB‐PG‐0711‐25094\n). The sponsor was Brighton and Sussex University Hospitals NHS Trust. The funder and sponsor had no role in the study design; data collection, analysis or interpretation; the writing of the report; or the decision to submit the article for publication. The views expressed are those of the authors and not those of the funder, or the organizations they represent.\n\nContributors\nJ.G.D., J.M.S., K.A., J.H., R.S. and C.R. conceived the study. J.G.D., J.M.S., N.P., K.A., J.H., R.S. and C.R. designed the study and analysed the data. J.M.S., N.P. and J.H. were involved in data collection. J.G.D., K.A., R.S. and C.R. verified end‐points. N.P., J.G.D., J.M.S., K.A., J.H. and C.R. analysed and interpreted the data. T.C. provided expert guidance. All authors contributed to the preparation of the manuscript and approved the final manuscript for submission. C.R. and K.A. are guarantors.\n\nAppendix 1 Case examples of medication‐related harm (MRH)\n\nCase 1: Adverse drug reactions\n\t\nLikelihood MRH: definite; severity: serious; preventable: definitely\t\nPast history of MI, severe aortic stenosis, angina, COPD, diabetes. Participant sitting in chair and began to shake, and with central chest pain and shortness of breath. Felt dizzy with pain, and thought she was going to collapse. Readmitted 15 days postdischarge with negative troponin. Participant experienced a similar presyncopal episode after morning medicines as inpatient, with BP dropping to 76/35 mmHg. Impression: participant suffered a hypotensive episode secondary to a combination of medicines which lower blood pressure: losartan, ISMN, nicorandil and diltiazem.\t\n\nCase 2: Medication error\n\t\nLikelihood MRH: definite; severity: serious; preventable: definitely\t\nPast history of heart failure, COPD and dementia. Participant experienced increased shortness of breath and bilateral leg swelling. Discharged 7 days previously with increased bumetanide dose. At home, carer administered medicines from old dosette box containing lower dose of bumetanide. Symptoms responded well to increased diuretics. Impression: exacerbation of heart failure due to administration of incorrect bumetanide dose.\t\n\nCase 3: Adverse drug reaction and non‐adherence\n\t\nLikelihood MRH: definite; severity: serious; preventable: possibly\t\nPast history of AF, diabetes, PVD, reduced mobility, grade 3 pressure sore. Daughter requested GP visit for participant 6 days post‐discharge. Participant experienced nausea and constipation. No urinary symptoms, negative MSU. Had been prescribed buprenorphine patch and dihydrocodeine from hospital following fractured neck of femur. Has laxido but does not take it. Impression: constipation secondary to opioids and non‐adherence to laxatives.\t\nAF, atrial fibrillation; BP, blood pressure; COPD: chronic obstructive pulmonary disease; GP, general practitioner; ISMN, isosorbide mononitrate; MI, myocardial infarction; MSU, midstream urine; PVD, peripheral vascular disease\n==== Refs\nReferences\n1 \n\nAngamo \nMT \n, \nChalmers \nL \n, \nCurtain \nCM \n, \nBereznicki \nLRE \n. Adverse‐drug‐reaction‐related hospitalisations in developed and developing countries: a review of prevalence and contributing factors . Drug Saf \n2016 ; 39 : 847 –857 .27449638 \n2 \nEuropean Medicines Agency \n. Guideline on good pharmacovigilance practices (GVP) – Annex I – Definitions (Rev 4) . 2017 Available at https://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp&mid=WC0b01ac058058f32c (last accessed 10 May 2018).\n3 \n\nVeeren \nJC \n, \nWeiss \nM \n. Trends in emergency hospital admissions in England due to adverse drug reactions: 2008–2015 . J Pharm Health Serv Res \n2017 ; 8 : 5 –11 .\n4 \n\nPirmohamed \nM \n, \nJames \nS \n, \nMeakin \nS \n, \nGreen \nC \n, \nScott \nAK \n, \nWalley \nTJ \n, et al\nAdverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients . BMJ \n2004 ; 329 : 15 –19 .15231615 \n5 \nNational Institute for Health and Care Excellence \n. Costing statement: medicines optimisation implementing the NICE guideline on medicines optimisation (NG5) . Putting NICE guidance into practice 2015 Available at https://www.nice.org.uk/guidance/ng5/resources/costing-statement-6916717 (last accessed 10 May 2018).\n6 \n\nGuthrie \nB \n, \nMakubate \nB \n, \nHernandez‐Santiago \nV \n, \nDreishculte \nT \n. The rising tide of polypharmacy and drug‐drug interactions: population database analysis 1995–2010 . BMC Med \n2015 ; 13 : 1 –10 .25563062 \n7 \n\nMangoni \nA \n, \nJackson \nS \n. Age‐related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications . Br J Clin Pharmacol \n2003 ; 57 : 6 –14 .\n8 \n\nBarber \nN \n, \nParsons \nJ \n, \nClifford \nS \n, \nDarracott \nR \n, \nHorne \nR \n. Patients' problems with new medication for chronic conditions . Qual Saf Health Care \n2004 ; 13 : 172 –175 .15175485 \n9 \n\nChowdhury \nR \n, \nKhan \nH \n, \nHeydon \nE \n, \nShroufi \nA \n, \nFahimi \nS \n, \nMoore \nC \n, et al\nAdherence to cardiovascular therapy: a meta‐analysis of prevalence and clinical consequences . Eur Heart J \n2013 ; 34 : 2940 –2948 .23907142 \n10 \n\nSimpson \nSH \n, \nEurich \nDT \n, \nMajumdar \nSR \n, \nPadwal \nRS \n, \nTsuyuki \nRT \n, \nVarney \nJ \n, et al\nA meta‐analysis of the association between adherence to drug therapy and mortality . BMJ \n2006 ; 333 : 15 .16790458 \n11 \n\nCutler \nRL \n, \nFernandez‐Llimos \nF \n, \nFrommer \nM \n, \nBenrimoj \nC \n, \nGarcia‐Cardenas \nV \n. Economic impact of medication non‐adherence by disease groups: a systematic review . BMJ Open \n2018 ; 8 : e016982.\n12 \n\nTaché \nSV \n, \nSönnichsen \nA \n, \nAshcroft \nDM \n. Prevalence of adverse drug events in ambulatory care: a systematic review . Ann Pharmacother \n2011 ; 45 : 977 –989 .21693697 \n13 \n\nKwan \nJL \n, \nLo \nL \n, \nSampson \nM \n, \nShojania \nKG \n. Medication reconciliation during transitions of care as a patient safety strategy: a systematic review . Ann Intern Med \n2013 ; 158 : 397 –403 .23460096 \n14 \n\nKnight \nDA \n, \nThompson \nD \n, \nMathie \nE \n, \nDickinson \nA \n. ‘Seamless care? Just a list would have helped!’ Older people and their carer's experiences of support with medication on discharge home from hospital . Health Expect \n2013 ; 16 : 277 –291 .21838834 \n15 \n\nForster \nAJ \n, \nMurff \nHJ \n, \nPeterson \nJF \n, \nGandhi \nTK \n, \nBates \nDW \n. Adverse drug events occurring following hospital discharge . J Gen Intern Med \n2005 ; 20 : 317 –323 .15857487 \n16 \n\nKattel \nS \n, \nManning \nDM \n, \nErwin \nPJ \n, \nWood \nH \n, \nKashiwagi \nDT \n, \nMurad \nMH \n. Information transfer at hospital discharge . J Patient Saf \n2016 ; 1 .\n17 \n\nKrumholz \nHM \n. Post‐hospital syndrome – an acquired, transient condition of generalized risk . N Engl J Med \n2013 ; 368 : 100 –102 .23301730 \n18 \n\nStevenson \nJ \n, \nParekh \nN \n, \nAli \nK \n, \nTimeyin \nJ \n, \nBremner \nS \n, \nVan Der Cammen \nT \n, et al\nProtocol for a Prospective (P) study to develop a model to stratify the risk (RI) of medication (M) related harm in hospitalized elderly (E) patients in the UK (The PRIME study) . BMC Geriatr \n2016 ; 16 : 22 .26787530 \n19 \n\nDormann \nH \n, \nNeubert \nA \n, \nCriegee‐Rieck \nM \n, \nEgger \nT \n, \nRadespiel‐Tröger \nM \n, \nAzaz‐Livshits \nT \n, et al\nReadmissions and adverse drug reactions in internal medicine: the economic impact . J Intern Med \n2004 ; 255 : 653 –663 .15147529 \n20 \n\nKellaway \nGS \n, \nMcCrae \nE \n. Intensive monitoring for adverse drug effects in patients discharged from acute medical wards . N Z Med J \n1973 ; 78 : 525 –528 .4205889 \n21 \n\nKanaan \nA \n, \nDonovan \nJ \n, \nDuchin \nN \n, \nField \nT \n, \nTjia \nJ \n, \nCutrona \nS \n, et al\nAdverse drug events post‐hospital discharge in older patients: types, severity, and involvement of Beers criteria medications . J Am Geriatr Soc \n2013 ; 61 : 1894 –1899 .24116689 \n22 \n\nStrand \nLM \n, \nMorley \nPC \n, \nCipolle \nRJ \n, \nRamsey \nR \n, \nLamsam \nGD \n. Drug‐related problems: their structure and function . DICP \n1990 ; 24 : 1093 –1097 .2275235 \n23 \nWorld Health Organisation Collaborating Centre for Drug Statistics Methodology \n. WHOCC – ATC/DDD Index 2017 [online]. Available at https://www.whocc.no/atc_ddd_index (last accessed 3 September 2017).\n24 \n\nNaranjo \nCA \n, \nBusto \nU \n, \nSellers \nEM \n, \nSandor \nP \n, \nRuiz \nI \n, \nRoberts \nEA \n, et al\nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther \n1981 ; 30 : 239 –245 .7249508 \n25 \n\nMorisky \nDE \n, \nGreen \nLW \n, \nLevine \nDM \n. Concurrent and predictive validity of a self‐reported measure of medication adherence . Med Care \n1986 ; 24 : 67 –74 .3945130 \n26 \n\nTangiisuran \nB \n, \nDavies Graham \nJ \n, \nWright \nE \n, \nRajkumar \nC \n. Adverse drug reactions in a population of hospitalized very elderly patients . Drugs Aging \n2012 ; 29 : 669 .22775477 \n27 \n\nHakkarainen \nKM \n, \nGyllensten \nH \n, \nJönsson \nAK \n, \nAndersson Sundell \nK \n, \nPetzold \nM \n, \nHägg \nS \n. Prevalence, nature and potential preventability of adverse drug events – a population‐based medical record study of 4970 adults . Br J Clin Pharmacol \n2014 ; 78 : 170 –183 .24372506 \n28 \n\nHanlon \nJT \n, \nPieper \nCF \n, \nHajjar \nER \n, \nSloane \nRJ \n, \nLindblad \nCI \n, \nRuby \nCM \n, et al\nIncidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay . J Gerontol A Biol Sci Med Sci \n2006 ; 61 : 511 –515 .16720750 \n29 \n\nMorimoto \nT \n, \nGandhi \nTK \n, \nSeger \nAC \n, \nHsieh \nTC \n, \nBates \nDW \n. Adverse drug events and medication errors: detection and classification methods . Qual Saf Health Care \n2004 ; 13 : 306 –314 .15289635 \n30 \n\nHallas \nJ \n, \nHarvald \nB \n, \nGram \nLF \n, \nGrodum \nE \n, \nBrosen \nK \n, \nHaghfelt \nT \n, et al\nDrug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention . J Intern Med \n1990 ; 228 : 83 –90 .2394974 \n31 \nDepartment of Health \n. Payment by results in the NHS: tariff for 2013 to 2014 [online]. Available at https://www.gov.uk/government/publications/payment-by-results-pbr-operational-guidance-and-tariffs (last accessed 24 July 2017).\n32 \nNational Audit Office \n. Out‐of‐hours GP services in England . 2014 Available at https://www.nao.org.uk/report/hours-gp-services-england-2/ (last accessed 10 May 2018).\n33 \nHospital Episode Statistics Analysis Health and Social Care Information Centre \n. Hospital Episode Statistics, admitted patient care, England – 2014–15 . Available at https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/hospital-episode-statistics-admitted-patient-care-england-2014-15 (last accessed 10 May 2018).\n34 \n\nWilliams \nD \n, \nFeely \nJ \n. Underreporting of adverse drug reactions: attitudes of Irish doctors . Ir J Med Sci \n1999 ; 168 : 257 –261 .10624366 \n35 \n\nFerrah \nN \n, \nLovell \nJJ \n, \nIbrahim \nJE \n. Systematic review of the prevalence of medication errors resulting in hospitalization and death of nursing home residents . J Am Geriatr Soc \n2017 ; 65 : 433 –442 .27870068 \n36 \n\nGarcia‐Caballos \nM \n, \nRamos‐Diaz \nF \n, \nJimenez‐Moleon \nJJ \n, \nBueno‐Cavanillas \nA \n. Drug‐related problems in older people after hospital discharge and interventions to reduce them . Age Ageing \n2010 ; 39 : 430 –438 .20497947 \n37 \n\nThomsen \nLA \n, \nWinterstein \nAG \n, \nSøndergaard \nB \n, \nHaugbølle \nLS \n, \nMelander \nA \n. Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care . Ann Pharmacother \n2007 ; 41 : 1411 –1426 .17666582 \n38 \n\nMarusic \nS \n, \nSicaja \nM \n, \nObreli Roque \nN \n, \nFranic \nM \n, \nMarinovic \nI \n, \nBacic‐Vrca \nV \n. Adverse drug reactions in elderly patients following discharge from an internal medicine clinic . Int J Clin Pharmacol Ther \n2014 ; 52 : 906 –913 .25066228 \n39 \n\nStannard \nC \n. Opioids in the UK: what's the problem? \nBMJ \n2013 ; 347 : f5108 .23950198 \n40 \n\nMorgan \nDJ \n, \nBrownlee \nS \n, \nLeppin \nAL \n, \nKressin \nN \n, \nDhruva \nSS \n, \nLevin \nL \n, et al\nSetting a research agenda for medical overuse . BMJ \n2015 ; 351 : h4534.26306661 \n41 \n\nHoffmann \nTC \n, \nDel Mar \nC \n. Clinicians' expectations of the benefits and harms of treatments, screening, and tests . JAMA Intern Med \n2017 ; 177 : 407 –419 .28097303 \n42 \n\nKaufmann \nCP \n, \nTremp \nR \n, \nHersberger \nKE \n, \nLampert \nML \n. Inappropriate prescribing: a systematic overview of published assessment tools . Eur J Clin Pharmacol \n2014 ; 70 : 1 –11 .24019054 \n43 \n\nDalleur \nO \n, \nBoland \nB \n, \nDel Groot \nA \n, \nVaes \nB \n, \nBoeckxstaens \nP \n, \nAzermai \nM \n, et al\nDetection of potentially inappropriate prescribing in the very old: cross‐sectional analysis of the data from the BELFRAIL observational cohort study . BMC Geriatr \n2015 ; 15 : 156 .26630873 \n44 \n\nSteinman \nMA \n, \nRosenthal \nGE \n, \nLandefeld \nCS \n, \nBertenthal \nD \n, \nKaboli \nPJ \n. Agreement between drugs‐to‐avoid criteria and expert assessments of problematic prescribing . Arch Intern Med \n2009 ; 169 : 1326 –1332 .19636035 \n45 \n\nParekh \nN \n, \nPage \nA \n, \nAli \nK \n, \nDavies \nK \n, \nRajkumar \nC \n. A practical approach to the pharmacological management of hypertension in older people . Ther Adv Drug Saf \n2017 ; 8 : 117 –132 .28439398 \n46 \n\nHanlon \nJT \n, \nSchmader \nKE \n, \nSamsa \nGP \n, \nWeinberger \nM \n, \nUttech \nKM \n, \nLewis \nIK \n, et al\nA method for assessing drug therapy appropriateness . J Clin Epidemiol \n1992 ; 45 : 1045 –1051 .1474400 \n47 \n\nHanlon \nJT \n, \nSchmader \nKE \n. The medication appropriateness index at 20: where it started, where it has been, and where it may be going . Drugs Aging \n2013 ; 30 : 893 –900 .24062215 \n48 \n\nGray \nSL \n, \nHart \nLA \n, \nPerera \nS \n, \nSemla \nTP \n, \nSchmader \nKE \n, \nHanlon \nJT \n. Meta‐analysis of interventions to reduce adverse drug reactions in older adults . J Am Geriatr Soc \n2017 ; 66 : 282 –288 .29265170 \n49 \n\nStevenson \nM \n, \nWilliams \nL \n, \nBurnham \nG \n, \nPrevost Toby \nA \n, \nSchiff \nR \n, \nErskine David \nS \n, et al\nPredicting adverse drug reactions in older adults: a systematic review of the risk prediction models . Clin Interv Aging \n2014 ; 9 : 1581 .25278750\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0306-5251",
"issue": "84(8)",
"journal": "British journal of clinical pharmacology",
"keywords": "health economics; health service use; hospital discharge; medication harm; older adults; pharmacoepidemiology",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000359:Aftercare; D000368:Aged; D000369:Aged, 80 and over; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D017048:Health Care Costs; D006784:Hospitals, Teaching; D006801:Humans; D057970:Inappropriate Prescribing; D015994:Incidence; D008297:Male; D010351:Patient Discharge; D063886:Patient Discharge Summaries; D010359:Patient Readmission; D010607:Pharmacy Service, Hospital; D019338:Polypharmacy; D011446:Prospective Studies; D013222:State Medicine; D006113:United Kingdom",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1789-1797",
"pmc": null,
"pmid": "29790202",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "27449638;23950198;25278750;7249508;4205889;2394974;16720750;23907142;29358417;2275235;15147529;26741789;24019054;26306661;24372506;15175485;15857487;19636035;21838834;21693697;29265170;23301730;25066228;10624366;28097303;17666582;20497947;24062215;23460096;22775477;16790458;1474400;15231615;24116689;15289635;14678335;29790202;27870068;25889849;28439398;26630873;26787530;3945130",
"title": "Incidence and cost of medication harm in older adults following hospital discharge: a multicentre prospective study in the UK.",
"title_normalized": "incidence and cost of medication harm in older adults following hospital discharge a multicentre prospective study in the uk"
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"activesubstancename": "LORAZEPAM"
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"abstract": "This is a case of a 54-year-old female with a history of mechanical aortic valve replacement who presented in cardiogenic shock. Her primary care provider started her on rivaroxaban for anticoagulation therapy. An urgent transesophageal echocardiogram revealed a significant gradient and thrombosis on one leaflet of the valve that was immobile. Given that she was not a surgical candidate, she underwent thrombolysis. However, she later died due to complications from the thrombotic valve. The utility of target-specific oral anticoagulants has yet to be established in clinical practice.",
"affiliations": "University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.;University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota.",
"authors": "Kumar|Vishesh|V|;Kelly|Shawn|S|;Raizada|Amol|A|;Yee|Jimmy|J|;Anuwatworn|Amornpol|A|;Stys|Adam|A|;Stys|Maria|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.14797/mdcj-13-2-73",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1947-6108",
"issue": "13(2)",
"journal": "Methodist DeBakey cardiovascular journal",
"keywords": "anticoagulation; dabigatran; mechanical valve thrombosis; oral anticoagulant; rivaroxaban",
"medline_ta": "Methodist Debakey Cardiovasc J",
"mesh_terms": "D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D018618:Echocardiography, Doppler, Color; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D017809:Fatal Outcome; D005260:Female; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008875:Middle Aged; D056687:Off-Label Use; D000069552:Rivaroxaban; D015912:Thrombolytic Therapy; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "101508600",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "28740586",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21429525;26304938;21773837;24306948;23991661;23021328;21937274",
"title": "Mechanical Valve Thrombosis on Rivaroxaban: Are Novel Anticoagulants Really an Option?",
"title_normalized": "mechanical valve thrombosis on rivaroxaban are novel anticoagulants really an option"
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{
"companynumb": "US-JNJFOC-20170801543",
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"activesubstancename": "RIVAROXABAN"
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{
"abstract": "BACKGROUND\nBreast cancer in the elderly is associated with high recurrence and death rates, due mostly to undertreatment. Human epidermal growth factor receptor type 2 (HER2) overexpression is infrequent in older patients. Trastuzumab-based chemotherapy is often withheld from elderly patients because of its cardiotoxicity.\n\n\nMETHODS\nMedical records of consecutive HER2-positive breast cancer patients aged ≥70 years old treated between 2005 and 2010 in the participating centers were retrospectively reviewed. All patients underwent multidimensional geriatric assessment (MGA).\n\n\nRESULTS\nAmong 59 patients identified, 51 patients were evaluable (median age 76 years). The rate of any adverse event was 20% (10/51). The most relevant cardiac adverse event consisted of symptomatic congestive heart failure (CHF; n = 1, 2%) followed by asymptomatic decreases of left ventricular ejection fraction (LVEF; n = 6, 12%). Other toxicities included moderate hypersensitivity reactions during trastuzumab infusions (n = 3, 6%). Hypertension, obesity, prior anthracyclines exposure and concurrent chemotherapy were associated with a higher incidence of toxic events. Previous radiotherapy, concurrent endocrine therapy and different trastuzumab-based regimens did not seem to influence toxicity.\n\n\nCONCLUSIONS\nOur data suggest that trastuzumab has a good safety profile in nonfrail women aged 70 years and older. These favorable findings may be related to a limited number of anthracycline pretreatments, patient selection and a close cardiologic monitoring.",
"affiliations": "Department of Human Pathology, Medical Oncology Unit, University of Messina, Messina, Italy.",
"authors": "Adamo|Vincenzo|V|;Ricciardi|Giuseppina Rosaria Rita|GR|;Adamo|Barbara|B|;Ferraro|Giuseppa|G|;Franchina|Tindara|T|;Rossello|Rosalba|R|;Zanghì|Mariangela|M|;Cicero|Giuseppe|G|;Rizzo|Sergio|S|;Caristi|Nicola|N|;Russo|Antonio|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000353450",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "86(1)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D000068878:Trastuzumab; D016277:Ventricular Function, Left",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "16-21",
"pmc": null,
"pmid": "24335608",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The risk of toxicities from trastuzumab, alone or in combination, in an elderly breast cancer population.",
"title_normalized": "the risk of toxicities from trastuzumab alone or in combination in an elderly breast cancer population"
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"abstract": "Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.",
"affiliations": "Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, China.;Department of Stomatology, Union Hospital, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.;Department of Respiratory and Critical Care Medicine, Wuhan Pulmonary Hospital, No. 28 Baofeng Road, Wuhan, China. drliming1992@outlook.com.;Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, China. tjhdongll@163.com.",
"authors": "Cai|Shaozhe|S|;Sun|Wei|W|;Li|Ming|M|;Dong|Lingli|L|http://orcid.org/0000-0003-2017-1125",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D006886:Hydroxychloroquine; D000077339:Leflunomide; D008775:Methylprednisolone",
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"fulltext": "\n==== Front\nClin Rheumatol\nClin Rheumatol\nClinical Rheumatology\n0770-3198\n1434-9949\nSpringer International Publishing Cham\n\n32562070\n5234\n10.1007/s10067-020-05234-w\nCase Based Review\nA complex COVID-19 case with rheumatoid arthritis treated with tocilizumab\nCai Shaozhe 1\nSun Wei 2\nLi Ming drliming1992@outlook.com\n\n3\nhttp://orcid.org/0000-0003-2017-1125\nDong Lingli tjhdongll@163.com\n\n1\n1 grid.33199.31 0000 0004 0368 7223 Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030 China\n2 grid.33199.31 0000 0004 0368 7223 Department of Stomatology, Union Hospital, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022 Hubei China\n3 grid.508271.9 Department of Respiratory and Critical Care Medicine, Wuhan Pulmonary Hospital, No. 28 Baofeng Road, Wuhan, China\n19 6 2020\n19 6 2020\n2020\n39 9 27972802\n17 5 2020\n2 6 2020\n9 6 2020\n© The Author(s) 2020\nOpen Access This 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/.\nRecurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s10067-020-05234-w) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nCoronavirus disease 2019\nRheumatoid arthritis\nSecondary opportunistic infection\nTocilizumab\nhttp://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81771754 Dong Lingli Tongji Hospital Clinical Research Flagship Program2019CR206 Dong Lingli issue-copyright-statement© International League of Associations for Rheumatology (ILAR) 2020\n==== Body\nCoronavirus disease 2019 (COVID-19) has progressed to a worldwide pandemic situation, and millions of people are suffering from this lethal disease. Many cytokines involved in the pathogenesis of rheumatic diseases (particularly rheumatoid arthritis, RA), such as IL-6, were elevated in COVID-19 [1–3]. Persistent and dramatic elevation of serum IL-6 level was associated with higher mortality in COVID-19 patients [4]. It seems that administration of tocilizumab can be a perfect solution to treat COVID-19 and RA at the same time. However, every coin has two sides. Application of tocilizumab may bring unsuspected effects. Here, we first reported the complex treatment process of a COVID-19 patient with RA history and illustrated the importance of recognizing the feasibility of tocilizumab application in the therapeutic process.\n\nCase presentation\n\nThe case we reported here was a 72-year-old female with a history of RA for nearly 30 years. She had taken leflunomide (LEF, 20 mg po qd) for 10 years and hydroxychloroquine (HCQ, 0.2 g po bid) for 1 year. Based on the clinical characteristics and therapeutic processes, this report was divided into two parts.\n\nPart 1 (Fig. 1)\n\nFever of unknown reason (< 38 °C) emerged in this case on January 5, 2020, accompanied with cough, expectoration (white, but little), and mild shortness of breath. Chest CT showed pneumonia in the right upper lobe of her lungs. Positivity of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) RNA was detected in her swab samples (January 28), and chest CT on the day before showed progression of the lesions in her right upper lobe (RUL) (Fig. 1a (b1)). Thus, a diagnosis of COVID-19 was made. After administration of antiviral agents (oseltamivir phosphate and lopinavir and ritonavir) and methylprednisolone (40 mg po qd) for 5 days, a significant relief of cough and breath shortness was observed. Chest CT on February 3 showed significant absorption lesions in her lungs (Fig. 1a (b2)). Dosage of glucocorticoids started to be tapered since January 31, and usage of antiviral agents was stopped on February 4. However, when usage of methylprednisolone was quickly tapered to 4 mg/day (February 11) within 11 days, her body temperature rebounded to 38.4 °C and ground glass opacities (GGOs) and patchy shadows appeared in both of her lungs (Fig. 1a (b3)). Antiviral treatment (lopinavir and ritonavir) restarted and dosage of methylprednisolone was elevated to 16 mg/day. Six days later, her body temperature returned to normal, and lesions in her lungs were absorbed totally (Fig. 1a (b4)). Administration of lopinavir and ritonavir was then stopped (February 18), and taper of methylprednisolone started. But fever emerged again after usage of methylprednisolone (10 days) was stopped (February 23). Then, another similar round of therapy was made. On March 2, she presented at the outpatient station with mild fever (37.7 °C), accompanied with chest tightness and shortness of breath. Due to the recurrence and progression of the disease, she was received in Wuhan pulmonary hospital on March 3rd (Figs. 1 (b5) and 3a).Fig. 1 The 1st part of therapeutic processes of the case reported in this study. a Important events, medication, and radiologic features of this case before March 3, 2020 (Part 1). b Images of chest CT indicated in the corresponding panel of a\n\nPart 2 (Figs. 2 and 3)\n\nThe laboratory indices showed a decreased lymphocyte count (0.34 * 109/L) in peripheral blood and elevated levels of erythrocyte sedimentation rate (ESR, 39 mm/h) and C-reactive protein (CRP, 20.53 mg/L). The serum IL-6 level (6.77 pg/mL) was in normal range (< 7 pg/mL). Detection of anti-SARS-CoV-2 antibody showed negativity of IgM subtype, but strong positivity of IgG subtype. Four days later (March 7), her ESR elevated to 66 mm/h, and serum IL-6 level elevated to 115.4 pg/mL. Chest CT showed increased lesions in both of her lungs (Fig. 3b). Severe type of COVID-19 was considered and tocilizumab (400 mg iv drip), which was intended to target both COVID-19 and RA, was used in this case. Dosage of glucocorticoid use was also increased. Despite the escalation of treatment, the patient’s serum IL-6 level was still maintained on a high level, and her condition went down sharply on March 10 (Fig. 3c). On March 14, her serum IL-6 level elevated to 260.1 pg/mL, and chest CT showed even worse condition on both her upper lungs (Fig. 3d). Tocilizumab (400 mg iv drip) was then administrated for the second time. Unfortunately, this patient’s condition was going from bad to worse: on March 17, her dyspnea severed (oxygen flow was escalated to 40 to 50 L/min, and she could not even move on the bed), serum concentration of IL-6 surged to 2055 pg/mL, and obvious aggravation of lesions was observed on her upper lungs (Fig. 3e). This alerted the physicians, that the clinical manifestations of this case and the disease aggravation could not be explained, at least solely, by the potential infection of SARS-CoV-2. Therefore, a multiple disciplinary team (MDT) including rheumatologists was formed and discussed to find out the potential reasons leading to the current situation of this case. Infection of other pathogens due to her over suppressed immune systems (resulted from the administration of tocilizumab and/or glucocorticoids) was considered as the most possible reason. We started to detect the presence of potential pathogenic pathogens in this case immediately. Administration of LEF was stopped, and antiviral (ganciclovir sodium, 500 mg qd ivdrip), antibacterial (cefoperazone sodium sulbactam sodium, 3 g bid ivdrip), and antifungal (caspofungin acetate, 70 mg [for the first day]/50 mg qd ivdrip) agents were then administrated at the same time. Meanwhile, we also noticed that the serum ferritin level of this case was abnormally high (2442 μg/L), platelet count decreased continuously to 83 * 109/L, and hypofibrinogenemia presented (1.9 g/L). All these indicated the tendency of secondary hemophagocytic lymphohistiocytosis (sHLH) characterized by a cytokine storm (which was authenticated by the elevated serum IL-6, IL-2R, IL-8, and TNF-α level detected several days later on March 21), hemophagocytosis, and further multi-organ damage. Thus, the administration of methylprednisolone was also escalated. The situation seemed to be turning: absorption of lesions was observed on chest CT on March 20 (Fig. 3f). On March 22, the high throughput sequencing analysis reported detection of Pneumocystis jirovecii and Aspergillus fumigatus. Chest CT on March 24 showed improvement (Fig. 3g), and levels of serum cytokines dropped significantly. In combination with antimicrobial treatment and application of blood products, this case was brought back from death: her chest CT on March 31 (Fig. 3h) and April 8 (Fig. 3i) both showed significant absorption of lesions on her lungs, and the oxygen flow was gradually reduced to 2 L/min: she could finish daily activity without too much effort. After the final detection of SARS-CoV-2 (RNA−, IgM−, IgG±) and CMV (DNA−), she was discharged on April 14. The detailed medication in this part was recorded in Supplementary Fig. 1.Fig. 2 The 2nd part of therapeutic processes of the case reported in this study. Details of therapeutic process of this case after the hospitalization on March 3 due to disease recurrence and progression (Part 2). RUL right upper lobe, RLL right lower lobe, ESR erythrocyte sedimentation rate, CRP C-reactive protein, IL interleukin, TNF tumor necrosis factor, Lym lymphocyte, PLT platelet, SaO2 arterial oxygen saturation\n\nFig. 3 Radiology (Chest CT) of the case reported in this study during the hospitalization after March 3. The date of examination and the corresponding disease status at that time were recorded in Fig. 2\n\nReview and discussion\n\nUp to the end of April 2020, more than 2.5 million people in the world had been infected with SARS-CoV-2 under the pandemic situation of COVID-19 [5]. As a large population with underlying dysregulated immune system, rheumatic patients infected with SARS-CoV-2 are not rare. How to improve the therapeutic efficacy for patients in this situation is an important task and challenges for physicians.\n\nTherapy with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs) and glucocorticoids\n\nHCQ and LEF are both important components of cs-DMARD in treating rheumatic diseases. Besides that, both of them showed antiviral properties, particularly HCQ, whose analogue chloroquine (CQ) is effective in inhibiting the infection and spread of SARS coronavirus (SARS-CoV) via interfering with terminal glycosylation of ACE2, which is also the entry receptor of SARS-CoV-2 [6, 7]. Some clinical investigations also showed efficacy of HCQ in treating mild to moderate COVID-19 patients [8, 9]. Thus, we applied these two agents in this case at the beginning of the treatment and intended to intervene with her COVID-19 and RA at the same time. However, with the deepening of research, side effects (e.g., cardiotoxicity) in chloroquine- or hydroxychloroquine-treated COVID-19 patients, especially when used at a high dose, were reported [10, 11]. There was also report showing no effects of HCQ in patients hospitalized for COVID-19 infection with oxygen requirement [12].\n\nGlucocorticoids are another agent commonly seen in the treatment of both rheumatic diseases and COVID-19. The anti-inflammatory effects of glucocorticoids are always rapid and significant and are commonly used in the suppression of strong and harmful inflammatory process in pathophysiologic conditions. However, slow-down of the clearance of virus (including SARS-CoV-2) is always observed in the infected cases with systemic usage of glucocorticoids [13–15]. This might be the reason why the recurrence of COVID-19 happened in the case we reported here.\n\nCOVID-19 and rheumatic diseases share similar pathogenic cytokines\n\nAt the level of pathogenic mechanisms, cytokines play important role in the progress of both COVID-19 and rheumatic diseases: Huang et al. revealed elevated serum level of many cytokines (including IL-1β, IL-7, IL-8, IL-10, GM-CSF, IFN-γ, TNF-α, etc.) in COVID-19 patients compared with healthy people, and these cytokines are also the pathogenic factors in many rheumatic diseases, including RA, systemic lupus erythematosus (SLE), and primary Sjögren’s syndrome (pSS) [2, 3, 16, 17]. Thus, targeting these potential pathogenic proinflammatory cytokines is logical and can be a good strategy to realize the win-win mode to treat both COVID-19 and the underlying rheumatic conditions. Among all these candidate target cytokines, IL-6 seems to be one of the best choices, particularly for COVID-19 patients with RA: from the aspects of either availability of the products or the current evidences supporting the benefits in treating both of the diseases [4, 18–21].\n\nFunction of IL-6 and consideration needed in the administration of tocilizumab\n\nIL-6 is an important cytokine in immune reactions, which can enhance the immune response (e.g., via promoting antibody production, differentiation of cytotoxic T cell or type 17 helper T cell, etc.), and always acts as a mediator notifying the occurrence of some emergent event elicited by either pathogen-associated molecular pattern (PAMPs) and damage-associated molecular patterns (DAMPs) [22]. Its elevation can be a sign of cytokine release syndrome (CRS), which is always observed in severe COVID-19 patients [1–3, 23]. However, every coin has two sides; it can also be a part of sHLH, which can be triggered by malignancy, infection (particularly viral infection), autoinflammation alone, or a combination of these factors [24]. Due to the high mortality of sHLH, early identification and the following aggressive treatment to suppress the overactivated immune system and the underlying triggers are required. In this case, after we observed the abnormal elevation of serum ferritin level, and decrease of platelet count in the context of infections and probable autoinflammatory status, we perceived the tendency of sHLH and applied decisively large-dosage glucocorticoids (methylprednisolone) and antimicrobial agents, which were finally authenticated as the key treatment saving this patient from death. It is interesting and worth mentioning that the tendency of sHLH was identified by a rheumatologist, who might have more chances to deal with a specific form of sHLH occurring in the context of autoimmunity, that is, macrophage activation syndrome (MAS) [24].\n\nElectronic supplementary material\n\nESM 1 (DOCX 269 kb).\n\nFunding information\n\nThis work was supported by grants from the National Natural Science Foundation of China (No. 81771754) and the Tongji Hospital Clinical Research Flagship Program (No. 2019CR206).\n\nCompliance with ethical standards\n\nDisclosures\n\nNone.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case study and any accompanying images related.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nShaozhe Cai and Wei Sun contributed equally to this work.\n==== Refs\nReferences\n\n1. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ (2020) The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents:105954. 10.1016/j.ijantimicag.2020.105954\n2. Huang C Wang Y Li X Ren L Zhao J Hu Y Zhang L Fan G Xu J Gu X Cheng Z Yu T Xia J Wei Y Wu W Xie X Yin W Li H Liu M Xiao Y Gao H Guo L Xie J Wang G Jiang R Gao Z Jin Q Wang J Cao B Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 10223 497 506 10.1016/s0140-6736(20)30183-5 31986264\n3. Smolen JS Aletaha D McInnes IB Rheumatoid arthritis Lancet 2016 388 10055 2023 2038 10.1016/s0140-6736(16)30173-8 27156434\n4. Luo P Liu Y Qiu L Liu X Liu D Li J Tocilizumab treatment in COVID-19: a single center experience J Med Virol 2020 92 814 818 10.1002/jmv.25801 32253759\n5. Dong E Du H Gardner L An interactive web-based dashboard to track COVID-19 in real time Lancet Infect Dis 2020 20 533 534 10.1016/s1473-3099(20)30120-1 32087114\n6. Vincent MJ Bergeron E Benjannet S Erickson BR Rollin PE Ksiazek TG Seidah NG Nichol ST Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Virol J 2005 2 69 10.1186/1743-422X-2-69 16115318\n7. Hoffmann M Kleine-Weber H Schroeder S Kruger N Herrler T Erichsen S Schiergens TS Herrler G Wu NH Nitsche A Muller MA Drosten C Pohlmann S SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 181 271 280.e8 10.1016/j.cell.2020.02.052 32142651\n8. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z (2020) Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv. 10.1101/2020.03.22.20040758\n9. 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Mahevas M, Tran V-T, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel T-A, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski J-M, Michel M, Perrodeau E, Carlier N, Roche N, Lastours VD, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N (2020) No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. MedRxiv. 10.1101/2020.04.10.20060699\n13. Baringer JR Klassen T Grumm F Experimental herpes simplex virus encephalitis. Effect of corticosteroids and pyrimidine nucleoside Arch Neurol 1976 33 6 442 446 10.1001/archneur.1976.00500060048010 180935\n14. Chai Z Zhang X Dobbins AL Rigsbee KM Wang B Samulski RJ Li C Optimization of dexamethasone administration for maintaining global transduction efficacy of adeno-associated virus serotype 9 Hum Gene Ther 2019 30 7 829 840 10.1089/hum.2018.233 30700148\n15. Ling Y Xu SB Lin YX Tian D Zhu ZQ Dai FH Wu F Song ZG Huang W Chen J Hu BJ Wang S Mao EQ Zhu L Zhang WH Lu HZ Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients Chin Med J 2020 133 1039 1043 10.1097/CM9.0000000000000774 32118639\n16. Tsokos GC Lo MS Costa Reis P Sullivan KE New insights into the immunopathogenesis of systemic lupus erythematosus Nat Rev Rheumatol 2016 12 12 716 730 10.1038/nrrheum.2016.186 27872476\n17. Nocturne G Mariette X Advances in understanding the pathogenesis of primary Sjogren's syndrome Nat Rev Rheumatol 2013 9 9 544 556 10.1038/nrrheum.2013.110 23857130\n18. Smolen JS Aletaha D Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants Arthritis Rheum 2011 63 1 43 52 10.1002/art.27740 21204103\n19. Di Giambenedetto S, Ciccullo A, Borghetti A, Gambassi G, Landi F, Visconti E, Zileri Dal Verme L, Bernabei R, Tamburrini E, Cauda R, Gasbarrini A, group GAC (2020) Off-label use of tocilizumab in patients with SARS-CoV-2 infection. J Med Virol. 10.1002/jmv.25897\n20. 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Singh JA Saag KG Bridges SL Jr Akl EA Bannuru RR Sullivan MC Vaysbrot E McNaughton C Osani M Shmerling RH Curtis JR Furst DE Parks D Kavanaugh A O'Dell J King C Leong A Matteson EL Schousboe JT Drevlow B Ginsberg S Grober J St Clair EW Tindall E Miller AS McAlindon T 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis Arthritis Rheumatol 2016 68 1 1 26 10.1002/art.39480 26545940\n22. Tanaka T Narazaki M Kishimoto T IL-6 in inflammation, immunity, and disease Cold Spring Harb Perspect Biol 2014 6 10 a016295 10.1101/cshperspect.a016295 25190079\n23. Fu B Xu X Wei H Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 2020 18 1 164 10.1186/s12967-020-02339-3 32290839\n24. Carter SJ Tattersall RS Ramanan AV Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment Rheumatology (Oxford) 2019 58 1 5 17 10.1093/rheumatology/key006 29481673\n\n",
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"issn_linking": "0770-3198",
"issue": "39(9)",
"journal": "Clinical rheumatology",
"keywords": "Coronavirus disease 2019; Rheumatoid arthritis; Secondary opportunistic infection; Tocilizumab",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001172:Arthritis, Rheumatoid; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003371:Cough; D000080424:Cytokine Release Syndrome; D000069340:Deprescriptions; D018450:Disease Progression; D004417:Dyspnea; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D000077339:Leflunomide; D008168:Lung; D051359:Lymphohistiocytosis, Hemophagocytic; D008775:Methylprednisolone; D010102:Oxygen Inhalation Therapy; D058873:Pandemics; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011024:Pneumonia, Viral; D055732:Pulmonary Aspergillosis; D012008:Recurrence; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed",
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"pages": "2797-2802",
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"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab.",
"title_normalized": "a complex covid 19 case with rheumatoid arthritis treated with tocilizumab"
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... |
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"abstract": "OBJECTIVE\nPrevious studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone.\n\n\nMETHODS\nA chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded.\n\n\nRESULTS\nA total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period.\n\n\nCONCLUSIONS\nThis study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.",
"affiliations": "From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA. arthur.lau@medportal.ca.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.;From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA.",
"authors": "Lau|Arthur N|AN|;Wong-Pack|Matthew|M|;Rodjanapiches|Rod|R|;Ioannidis|George|G|;Wade|Sally|S|;Spangler|Leslie|L|;Balasubramanian|Akhila|A|;Pannacciulli|Nicola|N|;Lin|Celia J F|CJF|;Roy-Gayos|Patrick|P|;Bensen|William G|WG|;Bensen|Robert|R|;Adachi|Jonathan D|JD|",
"chemical_list": "D018501:Antirheumatic Agents; D001688:Biological Products; D050071:Bone Density Conservation Agents; D014409:Tumor Necrosis Factor-alpha; D000069448:Denosumab",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.161270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "45(2)",
"journal": "The Journal of rheumatology",
"keywords": "DISEASE-MODIFYING ANTIRHEUMATIC DRUGS; INFECTION; OSTEOPOROSIS; RANK LIGAND; RHEUMATOID ARTHRITIS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D050071:Bone Density Conservation Agents; D002170:Canada; D015331:Cohort Studies; D000069448:Denosumab; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D010024:Osteoporosis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "170-176",
"pmc": null,
"pmid": "29142041",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.",
"title_normalized": "occurrence of serious infection in patients with rheumatoid arthritis treated with biologics and denosumab observed in a clinical setting"
} | [
{
"companynumb": "CA-JNJFOC-20180239724",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Alpha-1-antitrypsin deficiency (AATD)-related panniculitis is an extremely rare and underdiagnosed entity, and there is a paucity of data on its treatment. We report two cases of AATD-related panniculitis. The first was a 24-year-old woman with known AATD who presented with painful leg ulcers refractory to treatment with corticosteroids and colchicine. She had a good response to α1-antitrypsin infusions but required dose adjustment due to flares in disease activity. The second case was a 38-year-old woman who presented with painful nodules on the legs refractory to corticosteroid therapy. Laboratory investigations revealed severe AATD. She had an excellent response to colchicine therapy. In both these cases of AATD, panniculitis was the first clinical manifestation of the disease. AATD-related panniculitis may have none of the typical clinical clues for AATD, such as a family history, cirrhosis or emphysema. Early identification may help prevent these complications from developing.",
"affiliations": "Department of Dermatology, Galway University Hospital, Galway, Ireland.;Department of Dermatology, Galway University Hospital, Galway, Ireland.;Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland.;Department of Pathology, Galway University Hospital, Galway, Ireland.;Department of Dermatology, Galway University Hospital, Galway, Ireland.;Department of Dermatology, Galway University Hospital, Galway, Ireland.",
"authors": "Storan|E R|ER|;O' Gorman|S M|SM|;Hawkins|P|P|;Aalto|L|L|;Murphy|A|A|;Markham|T|T|",
"chemical_list": "D050257:Tubulin Modulators; D000515:alpha 1-Antitrypsin; D003622:Dapsone; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1111/ced.13102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "42(5)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000328:Adult; D003078:Colchicine; D003622:Dapsone; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015434:Panniculitis; D050257:Tubulin Modulators; D055815:Young Adult; D000515:alpha 1-Antitrypsin; D019896:alpha 1-Antitrypsin Deficiency",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "520-522",
"pmc": null,
"pmid": "28512995",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Alpha-1-antitrypsin deficiency-related panniculitis: two cases with diverse clinical courses.",
"title_normalized": "alpha 1 antitrypsin deficiency related panniculitis two cases with diverse clinical courses"
} | [
{
"companynumb": "IE-CONCORDIA PHARMACEUTICALS INC.-GSH201701-000411",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "BACKGROUND\nRestorative proctocolectomy with ileal pouch-anal anastomosis is considered the procedure of choice in patients with ulcerative colitis refractory to medical therapy. Subsequent inflammation of the pouch is a common complication and in some cases, pouchitis fails to respond to antibiotics, the mainstay of treatment. In such cases, corticosteroids, immunomodulatory or biologic treatments are options. However, our understanding of the efficacy of anti-tumour necrosis factor medications in both chronic pouchitis and Crohn's-like inflammation is based on studies that include relatively small numbers of patients.\n\n\nMETHODS\nThis was an observational, retrospective, multi-centre study to assess the long-term effectiveness and safety of infliximab (IFX) for inflammatory disorders related to the ileoanal pouch. The primary outcome was the development of IFX failure defined by early failure to IFX or secondary loss of response to IFX.\n\n\nRESULTS\nThirty-four patients met the inclusion criteria; 18/34 (53%) who were initiated on IFX for inflammatory disorders of the pouch had IFX failure, 3/34 (8%) had early failure and 15/34 (44%) had secondary loss of response with a median follow-up of 280 days (range 3-47 months). In total, 24/34 (71%) avoided an ileostomy by switching to other medical therapies at a median follow-up of 366 days (1-130 months).\n\n\nCONCLUSIONS\nInitial IFX therapy for pouch inflammatory conditions is associated with IFX failure in just over half of all patients. Despite a high failure rate, an ileostomy can be avoided in almost three-quarters of patients at four years by using other medical therapies.",
"affiliations": "a St Mark's Hospital , Harrow , UK.;a St Mark's Hospital , Harrow , UK.;a St Mark's Hospital , Harrow , UK.;a St Mark's Hospital , Harrow , UK.;d Department of Gastroenterology, The Royal Bournemouth and Christchurch Hospitals , Bournemouth , UK.;e Division of Digestive Diseases , St Mary's Hospital Campus, Imperial College , London , UK.;f Institute of Translational Medicine, University of Birmingham , Birmingham , UK.;h Department of Gastroenterology , St Vincent's Hospital , Melbourne , Australia.;h Department of Gastroenterology , St Vincent's Hospital , Melbourne , Australia.;i Department of Gastroenterology , Queen Alexandra Hospital , Portsmouth , UK.;j Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust , London , UK.;j Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust , London , UK.;a St Mark's Hospital , Harrow , UK.;a St Mark's Hospital , Harrow , UK.;a St Mark's Hospital , Harrow , UK.",
"authors": "Segal|Jonathan P|JP|http://orcid.org/0000-0002-9668-0316;Penez|Lawrence|L|;Mohsen Elkady|Soad|S|;Worley|Guy H T|GHT|;McLaughlin|Simon D|SD|;Mullish|Benjamin H|BH|http://orcid.org/0000-0001-6300-3100;Quraishi|Mohammed N|MN|;Ding|Nik S|NS|http://orcid.org/0000-0002-6232-1948;Glyn|Tamara|T|;Kandiah|Kesavan|K|;Samaan|Mark A|MA|;Irving|Peter M|PM|;Faiz|Omar D|OD|;Clark|Susan K|SK|;Hart|Ailsa L|AL|",
"chemical_list": "D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/00365521.2018.1496271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "53(9)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Ileoanal pouch; biologics; infliximab; pouchitis",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000328:Adult; D003093:Colitis, Ulcerative; D039021:Colonic Pouches; D005260:Female; D006801:Humans; D007081:Ileostomy; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D019449:Pouchitis; D016737:Proctocolectomy, Restorative; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "1051-1058",
"pmc": null,
"pmid": "30270685",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Long term outcomes of initial infliximab therapy for inflammatory pouch pathology: a multi-Centre retrospective study.",
"title_normalized": "long term outcomes of initial infliximab therapy for inflammatory pouch pathology a multi centre retrospective study"
} | [
{
"companynumb": "GB-JNJFOC-20180404776",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CODEINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmogenic disorder characterized by adrenergically induced ventricular tachycardia manifesting as stress-induced syncope and sudden cardiac death. While CPVT is not associated with dilated cardiomyopathy (DCM) in most cases, the combination of both disease entities poses a major diagnostic and therapeutic challenge.\nWe present the case of a young woman with CPVT. The clinical course since childhood was characterized by repetitive episodes of exercise-induced ventricular arrhythmias and a brady-tachy syndrome due to rapid paroxysmal atrial fibrillation and sinus bradycardia. Medical treatment included propranolol and flecainide until echocardiography showed a dilated left ventricle with severely depressed ejection fraction when the patient was 32 years old. Cardiac magnetic resonance imaging revealed non-specific late gadolinium enhancement. Myocardial inflammation, however, was excluded by subsequent endomyocardial biopsy. Genetic analysis confirmed a mutation in the cardiac ryanodine receptor but no pathogenetic variant associated with DCM. Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next months, the patient developed progressive heart failure symptoms that were finally managed by heart transplantation.\nManagement in patients with CPVT and DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic internal cardioverter-defibrillator implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.",
"affiliations": "Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.;Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.;Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.;Clinic of Internal Medicine III, Department of Cardiology and Angiology, University Hospital Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.",
"authors": "Christina|Granitz|G|;Peter|Jirak|J|;Bernhard|Strohmer|S|;Gerhard|Pölzl|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa299",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa299\nytaa299\nClinical Case Gallery Reports\nHeart Failure\nAcademicSubjects/MED00200\nCatecholaminergic polymorphic ventricular tachycardia complicated by dilated cardiomyopathy: a case report\nChristina Granitz 1 Peter Jirak 1 Bernhard Strohmer 1 Gerhard Pölzl 2 1 \nClinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria\n2 \nClinic of Internal Medicine III, Department of Cardiology and Angiology, University Hospital Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria\nCamm Christian Fielder Handling Editor Corresponding author. Tel: +43 57255 57455, Fax: +43 57255 25785, Email: c.granitz@salk.at\n12 2020 \n05 11 2020 \n05 11 2020 \n4 6 1 6\n02 5 2020 17 6 2020 05 8 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground \nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmogenic disorder characterized by adrenergically induced ventricular tachycardia manifesting as stress-induced syncope and sudden cardiac death. While CPVT is not associated with dilated cardiomyopathy (DCM) in most cases, the combination of both disease entities poses a major diagnostic and therapeutic challenge.\n\nCase summary \nWe present the case of a young woman with CPVT. The clinical course since childhood was characterized by repetitive episodes of exercise-induced ventricular arrhythmias and a brady-tachy syndrome due to rapid paroxysmal atrial fibrillation and sinus bradycardia. Medical treatment included propranolol and flecainide until echocardiography showed a dilated left ventricle with severely depressed ejection fraction when the patient was 32 years old. Cardiac magnetic resonance imaging revealed non-specific late gadolinium enhancement. Myocardial inflammation, however, was excluded by subsequent endomyocardial biopsy. Genetic analysis confirmed a mutation in the cardiac ryanodine receptor but no pathogenetic variant associated with DCM. Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next months, the patient developed progressive heart failure symptoms that were finally managed by heart transplantation.\n\nDiscussion \nManagement in patients with CPVT and DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic internal cardioverter-defibrillator implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.\n\nCPVTHeart failureDilated cardiomyopathyCase report\n==== Body\nLearning points\nEven though catecholaminergic polymorphic ventricular tachycardia (CPVT) normally occurs in the absence of structural heart disease the clinical course can be complicated by dilated cardiomyopathy.\n\nTo emphasize the need for a multidisciplinary diagnostic and therapeutic approach in patients with complex cardiac diseases.\n\nTo highlight the importance of regular echocardiographic screening in patients with CPVT.\n\nTo point out the difficulties in the management of a patient with both CPVT and heart failure with reduced ejection fraction.\n\n\n\n\nBackground\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by the induction of polymorphic ventricular arrhythmias in response to adrenergic stress. Mutations in the Ryanodine receptor gene (RyR2—dominant form) or in the Calsequestrin 2 gene (CASQ2—recessive form) are associated with CPVT.1 Both receptors are located in the sarcoplasmic reticulum and are involved in intracellular calcium handling and homeostasis.1 Despite the early onset of the disease (most patients experience stress-induced syncope or cardiac arrest already in their childhood), diagnosis is often delayed. This can be explained by a normal resting electrocardiogram (ECG) as well as the absence of structural cardiac abnormalities.1,2 Catecholaminergic polymorphic ventricular tachycardia can be unmasked by a treadmill stress test inducing ventricular ectopy. Additionally, a history of sudden cardiac death or stress-induced syncope in first-degree family members is a frequent finding.1,2 The diagnosis of CPVT can be confirmed by genetic testing.1,2 As alternative diagnoses, long QT syndrome, arrhythmogenic right ventricular (RV) cardiomyopathy, and Andersen–Tawil syndrome must be considered.2Beta-blockers (nadolol and propranolol) still represent the most relevant therapeutic option. In patients with insufficient arrhythmia suppression, sodium channel blockers such as flecainide can be added.2 Patients are counselled to avoid strenuous exercise or competitive sports to prevent arrhythmogenic events.1,2\n\nTimeline\nYear\tEvent\t\n1990\tDiagnosis of catecholaminergic polymorphic ventricular tachycardia, start of propranolol\t\n2007\tCardiac magnetic resonance imaging (MRI) and echocardiography without relevant structural or functional pathology\t\n2016\tRoutine echocardiography—severely reduced left ventricular ejection fraction and dilated left ventricle\t\n2016\tGuideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF) is initiated\t\n2016\tDiagnostic workup: cardiac MRI, endomyocardial biopsy, left heart catheterization, genetic analysis\t\n2016–2017\tAetiology of heart failure remains elusive, progressive heart failure symptoms\t\n2017\tSuccessful heart transplantation\t\nPatient presentation \nWe present the case of a 36-year-old woman with a long-standing genetically confirmed diagnosis of CPVT. The diagnosis was established at the age of six (in 1990) when she suffered a syncopal episode during a sports event. Anticonvulsive therapy was started initially for a suspected epileptic seizure. Further cardiologic testing was prompted by the patient’s history of palpitations precipitated by emotional or physical stress that was associated with dyspnoea and occasional vertigo. Electrocardiography demonstrated a normal QT interval and frequent premature atrial and ventricular contractions. During exercise testing, a bidirectional ventricular tachycardia (VT) at a rate of 160 b.p.m. was observed (Figure 1). Genetic testing revealed CPVT. Her family history was unremarkable for sudden cardiac death; family screening for CPVT was negative. She was started on propranolol (30–40–40 mg) and counselled to avoid competitive sports and strenuous exercise. Flecainide (50 mg bid) was added on top of propranolol in 2012 for further arrhythmia suppression. Apart from the complex ventricular arrhythmias, frequent episodes of paroxysmal rapid atrial fibrillation manifested as brady-tachy syndrome. Repeated echocardiography and a cardiac magnetic resonance imaging (MRI) in 2007 revealed no relevant structural or functional pathology. Regular clinical follow-ups with Holter ECG were conducted in the arrhythmia outpatient clinic. Symptoms including palpitations and lightheadedness improved significantly since the introduction of flecainide. Simultaneously, the dosage of propranolol had to be reduced as symptomatic sinus bradycardia and sinus arrests up to 4 s were documented on Holter ECG. Following a flu-like illness (in 2015), event recording revealed ventricular bigeminy, paroxysmal atrial fibrillation, and sinus bradycardia (34 b.p.m.) resulting in episodes of dizziness.\n\n\nFigure 1 Bidirectional ventricular tachycardia can occur in patients with catecholaminergic polymorphic ventricular tachycardia and is considered to result from intracellular calcium overload leading to delayed afterdepolarizations causing triggered activity. The delayed afterdepolarizations induce epicardial extrasystoles by increasing transmural dispersion of depolarization. This creates the substrate for reentry-based rapid polymorphic ventricular tachycardia. Biventricular tachycardia is caused by alternating epicardial/endocardial beats. The hallmark of this form of ventricular tachycardia is a fast but regular rhythm with a different axis of every other beat.\n\nIn 2016, our patient was referred to the heart failure outpatient clinic for routine echocardiography. She presented in good general health without acute distress, height 158 cm, weight 54 kg, blood pressure 106/63 mmHg. In the clinical exam, no peripheral oedema or jugular venous distension was evident. Cardiac auscultation revealed a holosystolic murmur with punctum maximum at the apex while pulmonary auscultation remained without any abnormalities. Laboratory results showed a significant elevation of N-terminal prohormone of brain natriuretic peptide levels (5648 pg/mL) without any other relevant abnormalities. Transthoracic echocardiography showed a dilated left ventricle and a severely depressed left ventricular (LV) function without regional wall motion abnormalities. Further findings included RV dilatation and moderate to severe functional mitral regurgitation (Figure 2A and B).\n\n\nFigure 2 Transthoracic echocardiography showing left ventricular dilatation and moderate to severe functional mitral regurgitation. (A) Four-chamber view and (B) parasternal short-axis view.\n\nInitial workup\nAs a consequence of these findings, the patient was admitted to our inpatient clinic and underwent an extensive diagnostic workup to determine the underlying cause of de novo cardiomyopathy.3 Cardiac MRI showed a severely depressed left ventricular ejection fraction (LVEF) and marked biventricular dilatation [LVEF: 18%, LV end diastolic volume (EDV): 179 mL, LV end systolic volume (ESV): 147 mL, cardiac index (CI): 1.1 L/min/m2]. Post-gadolinium studies revealed a patchy subepicardial and transmural late enhancement. T2 relaxation time was within normal limits excluding acute oedema. T1 mapping and extracellular volume (ECV) for quantification of diffuse myocardial fibrosis were not available (Figure 3A–C). Endomyocardial biopsy revealed no signs of myocarditis. Masson trichrome staining revealed hypertrophic and degenerated myocytes and interstitial fibrosis, typical for dilated cardiomyopathy (DCM). No inflammatory infiltration was found in immunohistochemical staining, as exemplary shown for CD3 T-cell staining. Nested polymerase chain reaction (PCR) revealed a low-level myocardial parvovirus B19 persistence, which was not regarded as significant (Figure 4A and B). Left heart catheterization excluded the presence of coronary artery disease. Genetic analysis was repeated because the original report of genetic testing in childhood was not available anymore and because of the atypical phenotypic features for CPVT. Next-generation sequencing disclosed a pathogenic mutation in the cardiac ryanodine receptor 2 gene (c.12006G>A, p. Met4002lle), but did not identify a pathogenic gene variant typically associated with DCM.\n\n\nFigure 3 Late gadolinium enhancement in (A) four-chamber view, (B) short-axis view, and (C) two-chamber view: thinned left ventricular myocardium with subendocardial late enhancement along the lateral and anterior wall of the left ventricle (arrows).\n\nFigure 4 Endomyocardial biopsy. (A) Masson trichrome staining reveals hypertrophic, degenerated myocytes, and interstitial fibrosis, typical for dilated cardiomyopathy. (B) No inflammation is found in immunohistochemical stainings, as exemplarily shown for CD3 T-cell staining.\n\nDisease course\nAs Class I antiarrhythmic drugs are not recommended in patients with structural heart disease, the sodium channel blocker flecainide was reduced to 25 mg bid.3 Holter ECG monitoring demonstrated a brady-tachy syndrome with functional sinus bradycardia (<30 b.p.m.) due to blocked atrial bigeminy, atrial tachycardia, atrial fibrillation, pauses of 3.3 s and non-sustained monomorphic VT at a CI 340 ms (Figure 5). Internal cardioverter-defibrillator (ICD) implantation for primary prevention had been considered repeatedly throughout the course of the disease. After extensive discussion, the patient and her parents declined an ICD even at this stage of disease progression.4Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next few months, the patient developed rapid progression of heart failure with increasing dyspnoea on exertion and fluid overload and ultimately required hospitalization for acute decompensated heart failure. Right heart catheterization demonstrated severely decreased cardiac output with a CI of 1.7 L/min/m2 and postcapillary pulmonary hypertension [systolic pulmonary artery pressure (sPAP) 50 mmHg, mean pulmonary artery pressure (mPAP) 31 mmHg, pulmonary capillary wedge pressure 21 mmHg, pulmonary vascular resistance (PVR) 4.2 WU]. Because of rapid disease progression including heart failure symptoms and electrical instability, the patient was finally listed for cardiac transplantation. She was successfully transplanted in 2017 and continues to do well since then.\n\n\nFigure 5 Holter electrocardiogram showing blocked atrial bigeminy, atrial tachycardia, and non-sustained monomorphic ventricular tachycardia.\n\nDiscussion\nIn our patient, despite an extensive diagnostic workup, the aetiology of heart failure remained elusive. While a correlation between disturbances in calcium handling and the initiation and progression of heart failure is reported in the literature, no evidence exists for an association of RyR2 and CASQ2 mutations with DCM.5,6 A possible history of myocarditis, tachycardiomyopathy due to severe and persistent arrhythmias and DCM were considered as differential diagnoses.3 On top of the hereditary arrhythmogenic syndrome, an additional risk for sudden cardiac death was present due to symptomatic HFrEF (LVEF < 35%). In CPVT, however, ICDs are primarily recommended in patients with episodes of cardiac arrest, recurrent syncope, or polymorphic/bidirectional VT despite optimal therapy, as the device therapy is associated with a high burden of shocks and complications. Although the ICD intuitively seems to be a logical option in the management of a potentially lethal cardiac condition, nuances that are unique to CPVT make the utilization controversial. It has to be considered that painful, adrenaline-provoking shocks are potentially pro-arrhythmic in CPVT, that complex atrial and ventricular arrhythmias may trigger inappropriate shocks, and that the typically young age of CPVT onset accentuates the lifetime risk of device complications, such as infections and lead failure.\n\nConclusion\nCatecholaminergic polymorphic ventricular tachycardia is a severe genetic arrhythmogenic disorder characterized by adrenergically induced VT manifesting as stress-induced syncope and sudden cardiac death. In most cases CPVT is not associated with DCM. Management in patients with CPVT who develop DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic ICD implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.\n\nQuestions\nQuestion 1: What is the correct diagnosis of the arrhythmia shown on the monitor strip (Figure 1)?\n\n\nTorsades de pointes.\n\n\nBidirectional ventricular tachycardia.\n\nMultifocal ventricular premature beats.\n\nPre-excited atrial fibrillation.\n\nQuestion 2: What is shown on the following echo-loops (Figure 2)?\n\n\nModerate to severe functional mitral regurgitation.\n\nBiventricular dilatation.\n\nSeverely depressed LV function.\n\n\nAll of the above.\n\nQuestion 3: Which of the findings below is not typical for CPVT?\n\n\nSyncope or cardiac arrest in the childhood.\n\nStructurally normal heart.\n\nNormal baseline electrocardiogram.\n\n\nDilated cardiomyopathy (DCM).\n\n\nQuestion 4: Which statement regarding genetic testing is not correct according to the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure?\n\n\nDCM is idiopathic in 50% of cases, about one-third of which are hereditary.\n\nThe most frequent genes associated with DCM are titin (TTN), lamin (LMNA), and desmin (DES).\n\n\nIn most patients with a definite clinical diagnosis of HF, there is a confirmatory role for routine genetic testing to establish the diagnosis.\n\n\nLamin and phospholamban mutations are related to a poorer prognosis.\n\nQuestion 5: According to the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, ICD implantation is not recommended…\n\n\nIn patients who have recovered from a ventricular arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status.\n\nIn patients with symptomatic heart failure (NYHA Class II–III) and an LVEF ≤35% despite ≥3 months of optimal medical therapy.\n\n\nIn patients who had a myocardial infarction in the prior 40 days.\n\n\nLead author biography\nChristina Granitz: Current position: Senior Cardiologist, Head of Heart Failure Outpatient Clinic University Hospital Salzburg, Division of Cardiology. November 2015–November 2017: Fellowship Intensive Care, Board Certification. November 2013–October 2015: Fellowship Cardiology, Board Certification. May 2007–October 2013: Residency Internal Medicine, University Hospitals Graz and Salzburg, Board Certification. February–May 2007: Post-Doc Research Fellow, University Hospital Graz, Division of Rheumatology. December 2006: Graduation from Medical University Graz. European Certifications in Heart Failure, Transthoracic Echocardiography and Cardiac MRI Level I (European Society of Cardiology).\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared. \n\nSupplementary Material\nytaa299_Supplementary_Data Click here for additional data file.\n\n \nThe article was initially submitted to the European Society of Cardiology Clinical Case Gallery and was peer reviewed by that group.\n==== Refs\nReferences\n1 \nBaltogiannis GG , Lysitsas DN , di Giovanni G , Ciconte G , Sieira J , Conte G \net al\nCPVT: arrhythmogenesis, therapeutic management, and future perspectives. A brief review of the literature\n. Front Cardiovasc Med 2019 ;6 :92 .31380394 \n2 \nPriori SG , Blomström-Lundqvist C , Mazzanti A , Blom N , Borggrefe M , Camm J \net al\n2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)\n. Eur Heart J 2015 ;36 :2793 –2867\n.26320108 \n3 \nPonikowski P , Voors AA , Anker SD , Bueno H , Cleland JGF , Coats AJS \net al; ESC Scientific Document Group. \n2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure\n. Eur Heart J 2016 ;37 :2129 –2200\n.27206819 \n4 \nRoston TM , Jones K , Hawkins NM , Bos JM , Schwartz PJ , Perry F \net al\nImplantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: a systematic review\n. Heart Rhythm 2018 ;15 :1791 –1799\n.30063211 \n5 \nvan den Hoogenhof MMG , Beqqali A , Amin AS , van der Made I , Aufiero S , Khan MAF \net al\nRBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling\n. Circulation 2018 ;138 :1330 –1342\n.29650543 \n6 \nDavlouros PA , Gkizas V , Vogiatzi C , Giannopoulos G , Alexopoulos D , Deftereos S. \nCalcium homeostasis and kinetics in heart failure\n. Med Chem 2016 ;12 :151 –161\n.26411602\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "4(6)",
"journal": "European heart journal. Case reports",
"keywords": "CPVT; Case report; Dilated cardiomyopathy; Heart failure",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33447728",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "27206819;29650543;26320108;26411602;30063211;31380394",
"title": "Catecholaminergic polymorphic ventricular tachycardia complicated by dilated cardiomyopathy: a case report.",
"title_normalized": "catecholaminergic polymorphic ventricular tachycardia complicated by dilated cardiomyopathy a case report"
} | [
{
"companynumb": "AT-PFM-2022-03519",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Oral and intravenous (IV) N-acetylcysteine (NAC) are used for the treatment of acetaminophen poisoning. The objective of this multicenter study was to compare the safety of these two routes of administration.\n\n\nMETHODS\nWe conducted a multicenter chart review of all patients treated with NAC for acetaminophen poisoning. The primary safety outcome was the percentage of patients with NAC-related adverse events.\n\n\nRESULTS\nA total of 503 subjects were included in the safety analysis (306 IV-only, 145 oral-only, and 52 both routes). There were no serious adverse events related to NAC for either route. Nausea and vomiting were the most common related adverse events and were more common with oral treatment (23 vs. 9%). Anaphylactoid reactions were more common with IV administration (6 vs. 2%).\n\n\nCONCLUSIONS\nIV and oral NAC are generally mild adverse drug reactions.",
"affiliations": "Toxicology Investigator Network Authorship Group Wilford Hall Medical Center, USA.",
"authors": "Bebarta|Vikhyat S|VS|;Kao|Louise|L|;Froberg|Blake|B|;Clark|Richard F|RF|;Lavonas|Eric|E|;Qi|Ming|M|;Delgado|Joao|J|;McDonagh|John|J|;Arnold|Tom|T|;Odujebe|Oladapo|O|;O'Malley|Gerry|G|;Lares|Claudia|C|;Aguilera|Elizabeth|E|;Dart|Richard|R|;Heard|Kennon|K|;Stanford|Chriss|C|;Kokko|Jamie|J|;Bogdan|Greg|G|;Mendoza|Carrie|C|;Mlynarchek|Sara|S|;Rhyee|Sean|S|;Hoppe|Jason|J|;Haur|William|W|;Tan|Hock Heng|HH|;Tran|Nguyen Nguyen|NN|;Varney|Shawn|S|;Zosel|Amy|A|;Buchanan|Jennifer|J|;Al-Helial|Mohammed|M|",
"chemical_list": "D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2010.486381",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "48(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000707:Anaphylaxis; D004333:Drug Administration Routes; D062787:Drug Overdose; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D009325:Nausea; D012449:Safety; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "424-30",
"pmc": null,
"pmid": "20524832",
"pubdate": "2010-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10736123;15795719;17418449;519312;16625578;1928874;18584360;7469629;14700565;10584588;9470017;9428541;12802041;7946509;3059186;17210206",
"title": "A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose.",
"title_normalized": "a multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose"
} | [
{
"companynumb": "US-JNJFOC-20101004050",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHeart transplantation (HT) success rate is limited by a high incidence of cancer post-HT. Data on kidney cancer following solid organ transplantation, especially HT, are limited, and only a few cases have been reported.\n\n\nOBJECTIVE\nTo report a unique case series of detected kidney cancer following HT.\n\n\nMETHODS\nBetween 1997 and 2018, 265 patients who underwent HT were enrolled and prospectively followed in the HT registry of the Sheba Medical Center.\n\n\nRESULTS\nThe series included 5 patients, 4 men and a woman (age range 35-50 years at HT). The patients were diagnosed with kidney tumors 6-11 years after HT (age range at diagnosis 40-72 years). Two of the men were identical twin brothers. At HT four patients received induction therapy with anti-thymocyte globulin and all received an initial immunosuppressive regimen based on cyclosporine. All male HT recipients had a history of heavy smoking. Two male patients developed allograft vasculopathy, but all had preserved heart function. The 72-year-old woman developed a kidney tumor of the native kidney 5 years after re-HT and kidney transplantation. Two patients had features of multifocal papillary renal cell carcinoma (RCC) and eventually underwent bilateral nephrectomy, while another patient underwent left partial nephrectomy with preserved renal function.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first case series study describing kidney tumors following HT. With the improving outcomes and life expectancy of HT patients, a better understanding of the factors that determine cancer risk is of the utmost importance and may have a major impact on the non-cardiac surveillance.",
"affiliations": "Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.;Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.;Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.;Department of Urology, Sheba Medical Center, Tel Hashomer, Israel.",
"authors": "Peled|Yael|Y|;Ram|Eilon|E|;Lavee|Jacob|J|;Dotan|Zohar|Z|",
"chemical_list": null,
"country": "Israel",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "22(5)",
"journal": "The Israel Medical Association journal : IMAJ",
"keywords": null,
"medline_ta": "Isr Med Assoc J",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011446:Prospective Studies",
"nlm_unique_id": "100930740",
"other_id": null,
"pages": "285-288",
"pmc": null,
"pmid": "32378819",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Kidney Cancer Following Heart Transplantation, a Common Presentation of an Uncommon Malignancy: A Unique Case Series.",
"title_normalized": "kidney cancer following heart transplantation a common presentation of an uncommon malignancy a unique case series"
} | [
{
"companynumb": "IL-PBT-000004",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "We reviewed the clinical records of 3 patients with anal squamous cell carcinoma treated with chemoradiotherapy (CRT). Case 1: The patient was diagnosed with StageI (T1N0M0) and treated with cisplatin (CDDP)+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. She achieved partial response(PR), and underwent a salvage surgery. Seven months after the surgery, she died from other comorbidities. Case 2: The patient was diagnosed with Stage I (T1N0M0) and treated with CDDP+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. He achieved PR, and underwent a salvage surgery. Three years and 7 months after the surgery, he died from other comorbidities. Case 3: The patient was diagnosed with Stage IIIB (T4N1M0) and treated with MMC+S-1+radiation. Chemotherapy was discontinued after the first course because of adverse effects. She achieved complete response (CR) and is still surviving without cancer recurrence. We conclude that CRT is an effective treatment for anal squamous cell carcinoma.",
"affiliations": "Dept. of Surgical Oncology, Tokyo Medical and Dental University Graduate School.",
"authors": "Someno|Yasunori|Y|;Ishikawa|Toshiaki|T|;Iwata|Noriko|N|;Takahashi|Hidenori|H|;Kikuchi|Akifumi|A|;Okazaki|Satoshi|S|;Ishiguro|Megumi|M|;Kobayashi|Hirotoshi|H|;Iida|Satoru|S|;Uetake|Hiroyuki|H|;Sugihara|Kenichi|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1855-7",
"pmc": null,
"pmid": "25731353",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Three cases of anal squamous cell carcinoma treated with chemoradiotherapy.",
"title_normalized": "three cases of anal squamous cell carcinoma treated with chemoradiotherapy"
} | [
{
"companynumb": "JP-ACCORD-029556",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "To evaluate continuing stiripentol treatment in adulthood in Dravet syndrome (DS).\n\n\n\nLongitudinal data were collected from the last visit prior to age 15 years (V15 y ) to the last visit in adulthood (Vadult ) in the 40 DS patients (32 typical, eight atypical) of a French historical cohort (Paris) of subjects who continued stiripentol from childhood or adolescence to adulthood.\n\n\n\nAt Vadult (18-40 years, median = 23 years), all the patients were still receiving stiripentol (exposure = 3-24 years, median = 18 years), associated with clobazam (40/40), valproate (39/40), and topiramate (21/40). Between V15 y and Vadult , stiripentol was interrupted in five patients (two for adverse events) but reintroduced following seizure aggravation. Loss of appetite affected 15 of 40 patients but resolved after reducing the dose of stiripentol or valproate; no other new stiripentol-related adverse events were reported. Mean stiripentol dose was progressively decreased from 39 to 25 mg/kg/d (P = 0.0002), whereas clobazam (0.27 mg/kg/d) and valproate (14 mg/kg/d) remained stable. At Vadult , 37 of 40 patients still had generalized tonic-clonic seizures, but none still had status epilepticus (vs three at V15 y ) and only one had myoclonia. During adulthood, generalized tonic-clonic seizure frequency and duration continued to decrease (P = 0.02, P = 0.008) and 10 patients experienced seizure-free periods ≥ 1 years (up to 5 years). All patients already had intellectual disability at V15 y , but retardation was more severe at Vadult (P = 0.03). Furthermore, neurological/gait condition had declined (two patients became bedridden) and behavior had worsened (P < 0.0002). Nevertheless, the 33 patients on stiripentol from infancy/childhood (<15 years) tended to have better seizure outcome in midadulthood than the seven treated from adolescence (>15 years) and the DS patients treated from adult age or stiripentol-naive subjects reported in the literature.\n\n\n\nThe efficacy and safety of the stiripentol/valproate/clobazam combination started at pediatric age are maintained at very long term during adulthood. Such prolonged stiripentol therapy tends to positively impact the late prognosis of epilepsy, especially when initiated before adolescence.",
"affiliations": "Department of Pediatric Neurology, Inserm U1129, Necker-Enfants Malades Hospital, Paris, France.;ESAT le Val (Center of Readaptation for Adults), Mortagne-au-Perche, France.;Department of Pediatric Neurology, Inserm U1129, Necker-Enfants Malades Hospital, Paris, France.;Department of Pediatrics, Mother and Child Hospital, Limoges, France.;Department of Neurology, Bretonneau Hospital, Tours, France.;Department of Pediatric Neurology, Inserm U1129, Necker-Enfants Malades Hospital, Paris, France.;Department of Pediatric Neurology, Inserm U1129, Necker-Enfants Malades Hospital, Paris, France.;Reference Center for Rare Epilepsies, APHP, Necker-Enfants Malades Hospital, Paris, France.",
"authors": "Chiron|Catherine|C|0000-0002-9096-1694;Helias|Marie|M|;Kaminska|Anna|A|;Laroche|Cecile|C|;de Toffol|Bertrand|B|0000-0002-2006-631X;Dulac|Olivier|O|;Nabbout|Rima|R|;An|Isabelle|I|",
"chemical_list": "D000927:Anticonvulsants; D004148:Dioxolanes; C021092:stiripentol",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.14536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "59(9)",
"journal": "Epilepsia",
"keywords": "antiepileptic drugs; epileptic encephalopathy; orphan drugs; transition to adults",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002648:Child; D004148:Dioxolanes; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1705-1717",
"pmc": null,
"pmid": "30132836",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?",
"title_normalized": "do children with dravet syndrome continue to benefit from stiripentol for long through adulthood"
} | [
{
"companynumb": "FR-ACCORD-071433",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nThe study is a prospective clinical observation of patients after orthotopic heart transplantation in a large academic medical center in relation to COVID-19 morbidity. The study population was comprised of 552 patients. All patients were consulted and advised by telephone as regards the prophylaxis of SARS-CoV-2 infection. Hospital and outpatient follow-ups were limited to the minimum. Preventive modification of immunosuppression was not recommended in relation to the pandemic. Three patients with multiple comorbidities (a woman aged 60, a man aged 59, and another man aged 83; 2.25 years, 5.5 years, and 7.5 years after heart transplantation, respectively) and one patient with concomitant arterial hypertension (a woman aged 48, 5.5 years after heart transplantation) presented with a symptomatic COVID-19 infection. Three of the patients were on tacrolimus immunosuppression, and both female patients were additionally on therapy with mycophenolate mofetil, which was discontinued following the diagnosis of infection. One male patient received combined therapy of cyclosporine A and mycophenolate mofetil. The 60-year-old woman presented with gastrointestinal manifestations of the COVID-19 infection which were of moderate severity. The recovery was achieved. The 59-year-old man presented with myocardial infarction, exacerbated renal insufficiency that required hemodialysis and cardiorespiratory failure complicated by bacterial sepsis. As a result, the patient died. The 83-year-old male patient reporting fever, myalgia, fatigue, cough and dyspnea was admitted to hospital and deceased due to septic shock two days after admission. The 48-year old woman who presented with mild symptoms of the upper respiratory tract infection recovered after two weeks. Symptomatic treatment was used in all the patients. Another male patient (aged 45 years, 8 years after orthotopic heart transplant with no significant comorbidities) was an asymptomatic carrier of SARS-CoV-2 and remained under hospital care.\nOf 552 patients after orthotopic heart transplantation, two SARS-CoV-2-related deaths were reported.",
"affiliations": "Medical University of Silesia, Poland. Department of Cardiac, Vascular and Endovascular Surgery and Transplantology. Faculty of Medical Sciences in Zabrze.;Silesian Center for Heart Diseases in Zabrze, Poland. Heart transplantation outpatient clinic.;Silesian Center for Heart Diseases in Zabrze, Poland. Heart transplantation outpatient clinic.;Cardiac surgery ward. Silesian Center for Heart Diseases in Zabrze, Poland.;Silesian Center for Heart Diseases in Zabrze, Poland. Heart transplantation outpatient clinic.",
"authors": "Kuczaj|Agnieszka|A|;Małyszek|Justyna|J|;Trzcińska|Iwona|I|;Zembala|Michał|M|;Przybyłowski|Piotr|P|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.32394/pe.74.51",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2100",
"issue": "74(4)",
"journal": "Przeglad epidemiologiczny",
"keywords": "COVID-19 infection; SARS-CoV-2; immunosuppression; orthotopic heart transplantation",
"medline_ta": "Przegl Epidemiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D002423:Cause of Death; D015897:Comorbidity; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D011044:Poland; D011446:Prospective Studies",
"nlm_unique_id": "0413725",
"other_id": null,
"pages": "596-605",
"pmc": null,
"pmid": "33860947",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "COVID-19 morbidity in patients after orthotopic heart transplantation - single center clinical observation.",
"title_normalized": "covid 19 morbidity in patients after orthotopic heart transplantation single center clinical observation"
} | [
{
"companynumb": "PL-VISTAPHARM, INC.-VER202105-001251",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadd... |
{
"abstract": "BACKGROUND\nNon-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause drug-induced liver injury. Although patients with drug-induced liver injury from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Recently, a few cases of children with persistent jaundice reported have been linked to the vanishing bile duct syndrome. However, data on adult patients is limited.\n\n\nMETHODS\nWe report herein a case of an adult patient who had persistent cholestasis with hyperlipidemia from the VBDS after ibuprofen use. We described a female patient with severe jaundice after taking ibuprofen, although she had no history of liver disease before. The drug-induced liver injury from ibuprofen was identified by clinical features and liver biopsy, which included the Roussel Uclaf Causality Assessment Method scores of 6 and pathological features of cholestasis with stage four drug-induced injury as well as loss of bile duct structures. The clinical course was featuring with persistently high levels of bilirubin associated with hyperlipidemia over the period of one month, although the laboratory abnormalities were slightly improved spontaneously after the cessation of ibuprofen. Her autoantibodies markers including AMA-M2 ASMA, RO-52, LKM, SLA, and anti-glycoprotein-210 were negative. The second liver biopsy was performed on day 213 due to persistent hyperbilirubinemia. Pathological findings were consistent with the diagnosis of vanishing bile duct syndrome.\n\n\nCONCLUSIONS\nA rare case of ibuprofen-associated vanishing bile duct syndrome in an adult female patient is presented. Clinicians need to be aware of vanishing bile duct syndrome as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.",
"affiliations": "Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University School of Medicine, 132-21 41Ave, Flushing, New York, 11355, USA. Panc01@NYU.edu.",
"authors": "Xie|Wen|W|;Wang|Qi|Q|;Gao|Yuanjiao|Y|;Pan|Calvin Q|CQ|http://orcid.org/0000-0002-3723-6688",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-018-0869-9",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 86910.1186/s12876-018-0869-9Case ReportVanishing bile duct syndrome with hyperlipidemia after ibuprofen therapy in an adult patient: a case report Xie Wen xiewen6218@163.com 1Wang Qi wangqidl04@126.com 1Gao Yuanjiao gyj147005579@126.com 1http://orcid.org/0000-0002-3723-6688Pan Calvin Q. +1-718-888-7728Panc01@NYU.edu 21 0000 0004 0369 153Xgrid.24696.3fCenter of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China 2 Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University School of Medicine, 132-21 41Ave, Flushing, New York 11355 USA 29 9 2018 29 9 2018 2018 18 14217 2 2018 6 9 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNon-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause drug-induced liver injury. Although patients with drug-induced liver injury from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Recently, a few cases of children with persistent jaundice reported have been linked to the vanishing bile duct syndrome. However, data on adult patients is limited.\n\nCase presentation\nWe report herein a case of an adult patient who had persistent cholestasis with hyperlipidemia from the VBDS after ibuprofen use. We described a female patient with severe jaundice after taking ibuprofen, although she had no history of liver disease before. The drug-induced liver injury from ibuprofen was identified by clinical features and liver biopsy, which included the Roussel Uclaf Causality Assessment Method scores of 6 and pathological features of cholestasis with stage four drug-induced injury as well as loss of bile duct structures. The clinical course was featuring with persistently high levels of bilirubin associated with hyperlipidemia over the period of one month, although the laboratory abnormalities were slightly improved spontaneously after the cessation of ibuprofen. Her autoantibodies markers including AMA-M2 ASMA, RO-52, LKM, SLA, and anti-glycoprotein-210 were negative. The second liver biopsy was performed on day 213 due to persistent hyperbilirubinemia. Pathological findings were consistent with the diagnosis of vanishing bile duct syndrome.\n\nConclusions\nA rare case of ibuprofen-associated vanishing bile duct syndrome in an adult female patient is presented. Clinicians need to be aware of vanishing bile duct syndrome as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.\n\nKeywords\nJaundiceIbuprofenDrug-induced liver injuryVanishing bile duct syndromeHyperlipidemiaBeijing Municipal Administration of Hospitals’ grant for the Development of Clinical Medicineissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDrug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from a mild elevation of liver enzymes to acute liver failure and death. The severe form of DILI leads to a long-term liver-related morbidity and mortality in 1% to 3% of cases [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause DILI [2]. Although patients with DILI from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Ibuprofen is a widely used antipyretic and analgesic NSAID. However, cases with sub-fulminant hepatitis requiring liver transplantation following ibuprofen overdose have been reported [3]. It has been suggested that ibuprofen can produce an unpredictable, idiosyncratic, type B reactions as a hypersensitivity reaction (HSR) in susceptible individuals [4]. The true HSR is a systemic disease defined by the triad of fever, rash, and internal organ involvement that starts 1 day to 12 weeks after the initiation of therapy [4]. Recently, several cases of children with persistent jaundice after taking ibuprofen have been linked to liver injury as the targeting organ damage from HSR and developed the vanishing bile duct syndrome (VBDS) [5–8]. However, data on adult patients is limited.\n\nCase presentation\nA woman in her 40s presented with acute onset of marked jaundice that had become progressively worsening over the course of 30 days, after taking ibuprofen intermittently for menalgia. The associated symptoms included profound fatigue and dark urine. No other symptoms were present. Twelve months prior to the onset of jaundice, she had menorrhagia after receiving the diagnosis of adenomyosis of uterus. She started only on ibuprofen 300 mg bid by mouth for 2–3 days each month with a total of six months when menalgia occurred. Her medical history included type II diabetic for one year on oral acarbose 50 mg TID and metformin 500 mg three times daily. She had no other medications. She had a surgical resection for a right ovarian cyst about 20 years ago. At the time, she was a non-smoker and did not consume any alcoholic drinks or recreational drugs. Clinical examination revealed normal vital signs and mental status. Although she has scleral icterus and a soft, non-tender abdomen with a surgical scare, neither signs of ascites nor hepatomegaly were presented. Her spleen was palpable at 3 cm below the left costal margin. There was no asterixis.\n\nInvestigations\nLaboratory testing revealed a normal completed blood count except Hb of 82 g/L (110–150); normal plasma thromboplastin antecedent and partial thromboplastin time; deranged liver function tests (alkaline phosphatase 1598 U/L, alanine transaminase 207 U/L, aspartate transaminase 247 U/L, total bilirubin 103 umol/L with direct bilirubin 75 umol/L, and albumin 30 g/L); abnormal lipid profile (total cholesterol 43 mmol/L, triglyceride 3.6 mmol/L, high-density lipoprotein cholesterol 6.4 mmol/L, low-density lipoprotein cholesterol 35 mmol/L Apolipoprotein-A1 0.6 g/L, Apolipoprotein-B 1.2 g/L); and normal electrolytes except potassium of 3.1 mmol/L. Viral serology was negative for hepatitis A, B, C, and Epstein-Barr virus. Antibody tests for hepatitis E, ASMA, RO-52, LKM, AMA, AMA-M2, SLA, and gp210 were negative. Her ceruloplasmin, ferritin, and iron were normal. The titers of cytoplasmic type and nuclear membrane type of ANA were 1:100 and 1:320, respectively. Her IgG level was 15.9 g/L and cytomegalovirus (CMV) PCR was negative although CMV IgG was > 500.00 U/ml. The patient was admitted and ibuprofen was discontinued. Further investigations included the followings: an MRCP revealed stones in the gallbladder without intrahepatic or extrahepatic bile duct dilatation; a computed tomography scan with contrast on day 10, which showed a few small enhanced patchy lesions on the left hepatic lobe likely due to the abnormal perfusion, mild splenomegaly, but no vascular abnormalities or intraperitoneal free fluid. However, three follow-up MRI exams with contrast on days 100, 185 and 260 showed a normal size of the spleen and normal diameters of both intra/extra-hepatic ducts. There were no signs of lymphoma. On the day of first evaluation, the Roussel Uclaf Causality Assessment Method score (RUCAM) was 6 (R = 0.32, grade III liver injury). A liver biopsy was performed on day 28 from the onset of her jaundice. The pathology slides were presented in Fig. 1, which revealed biliary injury and absence of small terminal bile ducts around hepatic arteries affecting over 50% of sampled portal tracts. In addition, Bile salt deposition was visible among peripheral hepatocytes with no evidence of steatohepatitis or significant fibrosis. The Ishak grading showed necroinflammatory activity score of 5 and fibrosis score of 2. The findings were consistent with DILI and VBDS.Fig. 1 The First Liver-Biopsy Specimens on Day 28. The specimen revealed seven peri-portal areas and lobular plates was intact. Hepatic lobule scattered moderate necrosis with granuloma formation and inflammatory infiltration around central veins. There were mild sinusoidal expansion with a small amount of sinus lymphocytes and eosinophil infiltration although a small quantity of DPAS-positive macrophages was present. In peri-portal area, mild to moderate expansion with mixed inflammatory cell infiltration including lymphocytes and eosinophils were noted. Eosinophilic changes were present in hepatocyte cytoplasm. In portal areas, there were accumulation of epithelium-like cells and interstitial cells, fibrous tissue hyperplasia, and interstitial fibrosis. In addition, interlobular bile duct injury with loss of bile duct structure around hepatic arteries was noticed in more than 50% of lobules. Bile salt deposition was visible among peripheral hepatocytes. The results of Immunohistochemistry stain were the followings: CD10 (+), CD38 (+), CK19 (+), CK7 (+), HBcAg (−), HBsAg (−), HCV (−), Mum-1 (+), Pre-S1 (−), ubiquitin (−); Patent staining results: DPAS (−), Masson (+), PAS (−), reticulocyte staining (+), copper and iron staining (−), rhodanine (−). Ishak grading:necroinflammatory activity score of 5 and fibrosis score of 2. The clinical implications of special markers are the followings: CD10 is a maker of bile canaliculus; CD38 and MUM1 are plasmacytic markers; CK7 and CK19 are biliary markers. CK7-positive hepatocytes indicate cholestatic hepatic changes\n\n\n\nDifferential diagnosis\nThis 40-year-old woman, who had a history of taking ibuprofen, became acutely ill with a rapid progressive jaundice and high cholesterol followed by profound fatigues that developed over a 4-week period. The differential diagnosis included drug-induced liver injury, viral hepatitis, marker-negative autoimmune hepatitis, non-alcoholic steatohepatitis, overlap syndrome, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC). Her initial presentations were consistent with intrahepatic cholestasis. She had laboratory evidence of acute hepatic injury and liver biopsy suggested drug-induced liver injury. Moreover, the histological features also suggested VBDS. Thus, further differential diagnosis for VBDS was needed, which includes not only aforementioned drug-induced liver injury, [9] viral hepatitis, autoimmune hepatitis; but also biliary obstruction, idiopathic adulthood ductopenia, Alagille syndrome, PSC, PBC, lymphoma, and ischemic liver injury [10].\n\nClinical diagnosis\nAs supported by the clinical data and the RUCAM score of 6, which indicated modestly probability of DILI with severe liver injury (stage III), her clinical diagnosis was an ibuprofen-induced liver injury resulting on persistent cholestasis and hyperlipidemia. The pathology diagnosis was DILI at the stage of IV. In addition, the features of bile duct injury and the loss of bile duct structures were consistent with VBDS. She has no hepatic duct dilatation or signs of lymphoma in MRI study on day 260. In addition, her negative test results of AMA-M2 and other autoantibodies did not support the diagnosis of PBC or PSC.\n\nClinical course, treatment, and outcomes\nDue to further deterioration of liver function tests despite the cessation of ibuprofen, the patient was hospitalized and received supportive care with intravenous therapy of polyene phosphatidylcholine 930 mg daily. Her oral medication included silibinin capsule at the dose of 200 mg daily, glutathione 2.4 g daily, and weight-based ursodeoxycholic acid at the dose of 250 mg three times a day. In addition, she continued on acarbose and metformin for her diabetic. Although she had progressively worsening jaundice over the first 7 days, the patient’s fatigue and biochemistry were subsequently improved with her total bilirubin decreased from167 umol/L to 130 umol/L. She had normal prothrombin time (PT) during her hospital stay. She was discharged on day 47 and followed up in outpatient’s clinic with the last visit on day 315. Her hyperbilirubinemia persisted with normal PT during the period of her outpatient visits, although the levels were slowly trending down from over 100 umol/L to 30 umol/L. The changes in biochemistry parameters including bilirubin and alanine aminotransferase (ALT) are shown in Fig. 2. Her ALT levels fluctuated at the range of 70–180 U/L. In addition, the patient had persistent hyperlipidemia during the entire observational period. Her total cholesterol and triglyceride levels both remained at levels above 10 times higher than normal, whereas the low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were always below 10 mmol/L (Fig. 3). Owing to the persistent elevation on the serum levels of bilirubin and ALT, a second liver biopsy was performed on day 213. Pathology report indicated again the absence of small terminal bile ducts, interstitial fibrous tissue hyperplasia, bile salt deposition in the peripheral liver cells, and visible lymphocytes with small amount of plasma cell infiltration; Ishak necroinflammatory activity score of 4 and fibrosis score of 2; keeping with a diagnosis of acute VBDS but some features of autoimmune hepatitis (Fig. 4).Fig. 2 Changes of Biochemistry Parameters after the Onset of Symptoms. The hyperbilirubinemia persisted with normal PT during the period of patient’s outpatient visits, although the levels were slowly trending down from over 100 umol/L to 30 umol/L. Thereafter, the patients’ ALT levels were fluctuated at the range of 70–180 U/L. GGT = gamma-glutamyltransferase (U/L); ALP = alkaline phosphatase (U/L); ALT = alanine aminotransferase (U/L); and Tbil = total bilirubin (umol/L)\n\nFig. 3 Changes of Lipid Profile after the Initial Presentation. The patient had persistent hyperlipidemia during the entire observational period. Her total cholesterol and triglyceride levels both remained at levels above 10 times higher than normal, whereas the low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were always below 10 mmol/L. TC = total cholesterol (mg/ml); LDL-C = low-density lipoprotein cholesterol (mg/ml); TG = triglycerides (mg/ml); and HDL-C = high-density lipoprotein cholesterol (mg/ml)\n\nFig. 4 The Second Liver-Biopsy Specimens on Day 213. The second liver biopsy indicated again the absence of small terminal bile ducts. The specimen shows six peri-portal areas and lobular plates were intact. Hepatic lobule scattered with focal moderate necrosis and small granuloma formation. The cytoplasm of hepatocytes was loose with eosinophilic changes and inflammatory infiltration around central veins. There were mild sinusoidal expansion with a small amount of sinus lymphocytes and eosinophil infiltration. There were bile duct injuries, a loss of bile duct structure around central arteries with visible lymphocytes, and a small amount of plasma cell infiltration. In addition, there was mild interface inflammation, interstitial fibrous tissue hyperplasia, and peripheral hepatocyte bile salt deposition. Immuno-histochemical stains were positive for CD10, CD38, CK19, CK7, Mum-1, Masson, and Copper-rhodanine. However, the stains were negative for HBcAg, HBsAg, PRE-S1, ubiquitin, D-pas, PAS, and iron. Ishak grading:necroinflammatory activity score of 4 and fibrosis score of 2. There are four panels inside the image of Fig. 4 including panel A for the specimen with hematoxylin and eosin stain (manification x 10), panel B for the specimen with Masson stain (manification x 10), panel C for the specimen with hematoxylin and eosin stain (magnification x 40), and panel D for the specimen with CK-7 stain (magnification x10)\n\n\n\nDiscussions and conclusions\nVBDS is a severe cholestatic disease associated with toxic effects of medications [9, 11]. As a complication of acute drug-induced liver injury, VBDS generally manifests 1 to 6 months after the onset of the liver injury [9]. Several diseases or syndromes as the causes for VBDS have been discussed in the section of differential diagnosis. Although DILI is an uncommon etiology for the VBDS, several medications have been reported to be related to the development of VBDS after liver injury. These medications include: antifungals or antibiotics like terbinafine, [12] meropenem, [13] and azithromycin; [11] anti-seizure medications such as valproic acid, [14] carbamazepine, [15] and lamotrigine; [16] and NSAIDs such as loxoprofen, diclofenac, and ibuprofen in pediatric cases [5–8, 17]. Five cases of ibuprofen-induced liver injury with the complication of VBDS have been reported by far and all were children. The first case was reported by Alam at el in 1996, which indicated that VBDS was temporally associated with ibuprofen [8]. Subsequently, Kim et al. reviewed three cases of VBDS from ibuprofen-induced liver injury in patients with ages ranging from 9 months to 10 years old [7]. Among them, two had completed clinical and biochemical recovery in 4 to 7 months after the onset of VBDS; one had persistent jaundice and required transplant evaluation. In a case recently reported by Bastuck et al. VBDS occurred in a 7-year-old child who had toxic epidermal necrolysis after oral ibuprofen intake. However, the patient had a complete recovery within 8 months [6]. These reports suggested that ibuprofen can cause acute VBDS, and weight-based ursodeoxycholic acid was commonly used for VBDS with supportive care, although steroids, immunosuppressive agents, or plasmapheresis were provided occasionally [12, 18]. Similar to the clinical presentations described in children, our case had acute onset of jaundice and VBDS developed approximately at weeks 4–6 from the ibuprofen-induced liver injury. However, unlike the outcomes of completed recovery in the majority of cases reported before, our patient had no significant improvement in biochemistry after a 10-month follow-up. Such different outcomes may be related to the lower liver stem cell or progenitor cell activity in the adult or aging liver when comparing to those in children [19]. In addition, hyperlipidemia was presented in our case. Although hyperlipidemia is an uncommon presentation in VBDS patients, it has been reported in a few pediatric patients. In the case presented by Basturk et al. the child was treated with supportive care, an steroid, and ursodeoxycholic acid, with complete normalization of lipid profile in 8 months [6]. Another case reported by Cho et al. was a 7-year-old boy with VBDS from trimethoprim-sulfamethoxazole combination therapy induced liver injury [20]. At the onset of VBDS, the patient’s total cholesterol level was 490 mg/dL and was improved to 385 mg/dL after nine weeks of ursodeoxycholic acid therapy (30 mg/kg/day) and returned to the normal range after one year. Lastly, Kim et al. reported a 7-month-old infant with ibuprofen associated toxic epidermal necrolysis, followed by severe and rapidly progressive VBDS [7]. She had a total cholesterol level of 760 mg/dL but recovered totally with supportive care in three months. The mechanism of hyperlipidemia in VBDS has not been fully understood. It has been suggested that cholestasis might affect cholesterol metabolism and lead to the formation of lipoprotein X, which is frequently mistaken for LDL on routine clinical tests [21]. Further studies are needed to explore the implications of hyperlipidemia in the setting of VBDS.\n\nIn summary, we report herein a case of an adult patient who had persistent cholestasis from the vanishing bile duct syndrome after ibuprofen use. The highlights of clinical features include acute onset of jaundice and severe hepatic impairment required hospitalization, followed by a very slow recovery with persistence of hyperbilirubinemia and hyperlipidemia. The clinical course differed from those previously reported in children, which was a completed clinical and biochemistry recovery. Clinicians need to be aware of VBDS as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.\n\nAbbreviations\nALPAlkaline phosphatase\n\nALTAlanine aminotransferase\n\nASTAspartate transaminase\n\nCMVCytomegalovirus\n\nDILIDrug-induced liver injury\n\nGGTGamma-glutamyltransferase\n\nHDL-CHigh-density lipoprotein cholesterol\n\nHSRHypersensitivity reaction\n\nLDL-CLow-density lipoprotein cholesterol\n\nNSAIDsNon-steroidal anti-inflammatory drugs\n\nRUCAMRoussel Uclaf Causality Assessment Method\n\nTbilTotal bilirubin\n\nTCTotal cholesterol\n\nTGTriglycerides\n\nVBDSVanishing bile duct syndrome\n\nWe thank the staff in our department for their assistance with data collection and our pathologists for preparing the microscopy slides presented in our case report.\n\nFunding\nOur work is supported by the Beijing Municipal Administration of Hospitals’ grant for the Development of Clinical Medicine, and Beijing Ditan Hospital, Capital Medical University, Beijing, China. The funding bodies had no part in the design or performance of the trial, in the data analysis and interpretation of data, in the writing or editing of the manuscript, or in the decision to submit the manuscript for publication.\n\nAvailability of data and materials\nThe original source documents are available in our division for verifying all data presented in the current report.\n\nAuthors’ contributions\nCQP designed the report; WX, YG, and QW collected the patient’s clinical data; CQP, WX, and QW analyzed the data. CQP wrote the paper. All authors contributed to revision of the draft. CQP performed critical reviews, communicated with the journal, and addressed comments from reviewers. All the authors vouch for the veracity and completeness of the data presented and agreed to submit the manuscript for publication.\n\nEthics approval and consent to participate\nOur Institutional IRB approved the case report. The consent to participate is not applicable in the current case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Saithanyamurthi H Faust AJ Drug-induced liver disease: clinical course Clin Liver Dis 2017 21 1 21 34 10.1016/j.cld.2016.08.007 27842773 \n2. Bessone F Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage? World J Gastroenterol 2010 16 45 5651 5661 10.3748/wjg.v16.i45.5651 21128314 \n3. Laurent S Rahier J Geubel AP Lerut J Horsmans Y Subfulminant hepatitis requiring liver transplantation following ibuprofen overdose Liver 2000 20 1 93 94 10.1034/j.1600-0676.2000.020001093.x 10726966 \n4. Nanau Radu M. Neuman Manuela G. Ibuprofen-induced hypersensitivity syndrome Translational Research 2010 155 6 275 293 10.1016/j.trsl.2010.01.005 20478543 \n5. Taghian M Tran TA Bresson-Hadni S Menget A Felix S Jacquemin E Acute vanishing bile duct syndrome after ibuprofen therapy in a child J Pediatr 2004 145 2 273 276 10.1016/j.jpeds.2004.05.027 15289784 \n6. Basturk A Artan R Yilmaz A Gelen MT Duman O Acute vanishing bile duct syndrome after the use of ibuprofen Arab J Gastroenterol 2016 17 3 137 139 10.1016/j.ajg.2016.08.006 27658326 \n7. Kim HY Yang HK Kim SH Park JH Ibuprofen associated acute vanishing bile duct syndrome and toxic epidermal necrolysis in an infant Yonsei Med J 2014 55 3 834 837 10.3349/ymj.2014.55.3.834 24719156 \n8. Alam I Ferrell LD Bass NM Vanishing bile duct syndrome temporally associated with ibuprofen use Am J Gastroenterol 1996 91 8 1626 1630 8759674 \n9. Bonkovsky HL Kleiner DE Gu J Odin JA Russo MW Navarro VM Fontana RJ Ghabril MS Barnhart H Hoofnagle JH Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements Hepatology (Baltimore, Md) 2017 65 4 1267 1277 10.1002/hep.28967 \n10. Nader K Mok S Kalra A Harb A Schwarting R Ferber A Vanishing bile duct syndrome as a manifestation of Hodgkin's lymphoma: a case report and review of the literature Tumori 2013 99 4 e164 e168 10.1177/030089161309900426 24326854 \n11. Juricic D Hrstic I Radic D Skegro M Coric M Vucelic B Francetic I Vanishing bile duct syndrome associated with azithromycin in a 62-year-old man Basic Clin Pharmacol Toxicol 2010 106 1 62 65 19906050 \n12. Mason M. Adeyi O. Fung S. Millar B.-A. Vanishing bile duct syndrome in the context of concurrent temozolomide for glioblastoma Case Reports 2014 2014 nov28 1 bcr2014208117 bcr2014208117 \n13. Schumaker AL Okulicz JF Meropenem-induced vanishing bile duct syndrome Pharmacotherapy 2010 30 9 953 10.1592/phco.30.9.953 20812433 \n14. Gokce S Durmaz O Celtik C Aydogan A Gulluoglu M Sokucu S Valproic acid-associated vanishing bile duct syndrome J Child Neurol 2010 25 7 909 911 10.1177/0883073809343474 20388938 \n15. Forbes GM Jeffrey GP Shilkin KB Reed WD Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome Gastroenterology 1992 102 4 Pt 1 1385 1388 10.1016/0016-5085(92)90780-3 1551543 \n16. Bhayana H Appasani S Thapa BR Das A Singh K Lamotrigine-induced vanishing bile duct syndrome in a child J Pediatr Gastroenterol Nutr 2012 55 6 e147 e148 10.1097/MPG.0b013e31823c2500 22008955 \n17. Srivastava M Perez-Atayde A Jonas MM Drug-associated acute-onset vanishing bile duct and Stevens-Johnson syndromes in a child Gastroenterology 1998 115 3 743 746 10.1016/S0016-5085(98)70154-4 9721172 \n18. Kawasaki Y Matsubara K Hashimoto K Tanigawa K Kage M Iwata A Nigami H Fukaya T Nonsteroidal anti-inflammatory drug-induced vanishing bile duct syndrome treated with plasmapheresis J Pediatr Gastroenterol Nutr 2013 57 5 e30 e31 10.1097/MPG.0b013e3182a95951 \n19. Zhong HH Hu SJ Yu B Jiang SS Zhang J Luo D Yang MW Su WY Shao YL Deng HL Apoptosis in the aging liver Oncotarget 2017 8 60 102640 102652 10.18632/oncotarget.21123 29254277 \n20. Cho HJ Jwa HJ Kim KS Gang DY Kim JY Ursodeoxycholic acid therapy in a child with trimethoprim-sulfamethoxazole-induced vanishing bile duct syndrome Pediatr Gastroenterol Hepatol Nutr 2013 16 4 273 278 10.5223/pghn.2013.16.4.273 24511525 \n21. Nemes K Aberg F Gylling H Isoniemi H Cholesterol metabolism in cholestatic liver disease and liver transplantation: from molecular mechanisms to clinical implications World J Hepatol 2016 8 22 924 932 10.4254/wjh.v8.i22.924 27574546\n\n",
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"title": "Vanishing bile duct syndrome with hyperlipidemia after ibuprofen therapy in an adult patient: a case report.",
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"pubdate": "2021-12-06",
"publication_types": "D016428:Journal Article",
"references": "32663912;34115170;6751212;34155020;34480607;11865774;29368949;33749854;33301246;34411532",
"title": "A case of trigeminal neuralgia developing after a COVID-19 vaccination.",
"title_normalized": "a case of trigeminal neuralgia developing after a covid 19 vaccination"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-341880",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drug... |
{
"abstract": "Successful management of toxic epidermal necrolysis (TEN) with tumor necrosis factor-α inhibitors has been described in adults, but few cases have been reported in children. To date, only four pediatric cases of TEN treated with infliximab and one with etanercept have been published. We present the case of an 8-year-old boy diagnosed with TEN induced by levetiracetam, successfully treated with etanercept, systemic corticosteroids, and intravenous immunoglobulin.",
"affiliations": "Department of Dermatology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Dermatology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Paediatric Intensive Care, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Dermatology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Paediatric Intensive Care, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Pathology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.;Department of Dermatology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.",
"authors": "Estébanez|Andrea|A|https://orcid.org/0000-0002-5700-6281;Sáez-Martín|Luis Carlos|LC|;Muñoz|Juan Ignacio|JI|;Silva|Esmeralda|E|;Monrabal|Alicia|A|;Monteagudo|Carlos|C|;Ramón|María Dolores|MD|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D014409:Tumor Necrosis Factor-alpha; D000077287:Levetiracetam; D000069285:Infliximab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14179",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "37(4)",
"journal": "Pediatric dermatology",
"keywords": "anti-tumor necrosis factor (TNF); etanercept; levetiracetam; toxic epidermal necrolysis",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000328:Adult; D002648:Child; D000068800:Etanercept; D006801:Humans; D016756:Immunoglobulins, Intravenous; D000069285:Infliximab; D000077287:Levetiracetam; D008297:Male; D013262:Stevens-Johnson Syndrome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "701-705",
"pmc": null,
"pmid": "32319121",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Levetiracetam-induced pediatric toxic epidermal necrolysis successfully treated with etanercept.",
"title_normalized": "levetiracetam induced pediatric toxic epidermal necrolysis successfully treated with etanercept"
} | [
{
"companynumb": "ES-UCBSA-2020018585",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
... |
{
"abstract": "Gastrointestinal (GI) bleeding is a serious complication encountered commonly in patients on chronic anticoagulation and/or antiplatelet agents. There is a lack of guidelines on how to manage antiplatelet/anticoagulant therapy in patients with thrombocytopenia and GI bleeding. This poses a clinical dilemma when a clinician encounters serious GI bleeding in clinical practice. We present a patient with paroxysmal atrial fibrillation and chronic thrombocytopenia who suffered severe GI bleeding less than 2 weeks after a percutaneous coronary intervention while being treated with dual antiplatelet therapy and oral anticoagulation.",
"affiliations": "Department of Cardiology, Saint Vincent Hospital, Worcester, Massachusetts, USA usama_ghafoor@yahoo.com.;Department of Cardiology, Saint Vincent Hospital, Worcester, Massachusetts, USA.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts, USA.;Department of Cardiology, Saint Vincent Hospital, Worcester, Massachusetts, USA.",
"authors": "Ghafoor|Hafiz|H|http://orcid.org/0000-0001-9675-2407;Sharma|Nitish Kumar|NK|http://orcid.org/0000-0002-6766-4501;Alampoondi Venkataramanan|Sai Vikram|SV|;Hadley|Michelle|M|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; gastrointestinal system; haematology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000925:Anticoagulants; D001281:Atrial Fibrillation; D004359:Drug Therapy, Combination; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34162622",
"pubdate": "2021-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post PCI severe gastrointestinal bleeding in the setting of idiopathic thrombocytopenic purpura: a treatment dilemma.",
"title_normalized": "post pci severe gastrointestinal bleeding in the setting of idiopathic thrombocytopenic purpura a treatment dilemma"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-143611",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nTo report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.\n\n\nMETHODS\nThirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.\n\n\nRESULTS\nThe patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.\n\n\nCONCLUSIONS\nThe conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.",
"affiliations": "Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China. jianzhou@zshospital.net",
"authors": "Zhou|Jian|J|;Fan|Jia|J|;Wang|Zheng|Z|;Wu|Zhi-Quan|ZQ|;Qiu|Shuang-Jian|SJ|;Huang|Xiao-Wu|XW|;Yu|Yao|Y|;Sun|Jian|J|;Xiao|Yong-Sheng|YS|;He|Yi-Feng|YF|;Wang|Yu-Qi|YQ|;Tang|Zhao-You|ZY|",
"chemical_list": "D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v12.i19.3114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "12(19)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D019703:Calcineurin; D006528:Carcinoma, Hepatocellular; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins; D051437:Renal Insufficiency; D012189:Retrospective Studies; D020123:Sirolimus; D016559:Tacrolimus; D014180:Transplantation; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "3114-8",
"pmc": null,
"pmid": "16718799",
"pubdate": "2006-05-21",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10759564;15376305;9458349;9679823;10028962;10028970;10071017;10071018;15770715;11510015;11709706;11750382;11773892;12030785;12123209;12200775;12499891;12740787;14526403;15021843;15309896;15899120",
"title": "Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: Report of an initial experience.",
"title_normalized": "conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma report of an initial experience"
} | [
{
"companynumb": "CN-PFIZER INC-2021304159",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "This study evaluated both site dependent differences and time dependent changes in postmortem morphine concentrations in man. In 32 deaths involving morphine, left ventricular blood, femoral blood, and cisternal cerebrospinal fluid, were collected as soon after death as possible (T1), and collected again together with iliac blood at the time of autopsy (T2). Samples were analyzed for morphine by radioimmunoassay. No evidence was found for changes in morphine concentration with respect to time at either central or peripheral sites, or in the cerebrospinal fluid. Ventricular blood morphine concentrations were however consistently higher than those in the peripheral compartment, represented by either femoral or iliac blood. This was particularly true when the ventricular morphine concentration exceeded 0.300 mg/L. At peripheral sites, femoral and iliac blood morphine concentrations were well correlated with each other, making either an appropriate site for collection of peripheral blood for toxicological testing.",
"affiliations": "Washington State Toxicology Laboratory, Department of Laboratory Medicine, University of Washington, Seattle, USA.",
"authors": "Logan|B K|BK|;Smirnow|D|D|",
"chemical_list": "D009020:Morphine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "41(2)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D005260:Female; D005268:Femoral Vein; D006352:Heart Ventricles; D006801:Humans; D007084:Iliac Vein; D008297:Male; D008875:Middle Aged; D009020:Morphine; D011180:Postmortem Changes; D019966:Substance-Related Disorders; D013997:Time Factors",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "221-9",
"pmc": null,
"pmid": "8871380",
"pubdate": "1996-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Postmortem distribution and redistribution of morphine in man.",
"title_normalized": "postmortem distribution and redistribution of morphine in man"
} | [
{
"companynumb": "US-PFIZER INC-2021315197",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "Corpus callosotomy is a palliative therapy for refractory epilepsy, including West syndrome, without a resectable epileptic focus. The surgical outcome of corpus callosotomy is relatively favorable in cryptogenic (non-lesional) West syndrome. Tuberous sclerosis complex (TSC) is a disorder that frequently leads to the development of refractory seizures by multiple cortical tubers. The multiple cortical tubers cause multiple or wide epileptic networks in these cases. Most of West syndrome cases in TSC with multiple tubers need additional resective surgery after corpus callosotomy. We describe a case of TSC in a boy aged 4years and 8months. He had multiple cortical tubers on his brain and developed epileptic spasms. The seizures were controlled with valproate. At the age of 1year and 4months, he presented with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), and had relapsed epileptic spasms one month after the onset of the encephalopathy. The seizures were refractory to multiple antiepileptic drugs. A total corpus callosotomy was performed at the age of 3years and 8months. The patient did not show any seizures after the surgery. During 12months of the follow-up, the patient was free from any seizures. Even in cases of symptomatic WS with multiple lesions, total corpus callosotomy may be a good strategy if the patients have secondary diffuse brain insults.",
"affiliations": "Department of Child Neurology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan. Electronic address: okanishipediatrics@gmail.com.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Department of Child Neurology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Department of Child Neurology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Department of Neurophysiology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Department of Pediatrics, Nippon Medical School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.;Department of Child Neurology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 430-8558, Japan.",
"authors": "Okanishi|Tohru|T|;Fujimoto|Ayataka|A|;Motoi|Hirotaka|H|;Kanai|Sotaro|S|;Nishimura|Mitsuyo|M|;Yamazoe|Tomohiro|T|;Takagi|Atsushi|A|;Yamamoto|Takamichi|T|;Enoki|Hideo|H|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2016.11.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "39(5)",
"journal": "Brain & development",
"keywords": "Acute encephalopathy with biphasic seizures and late reduced diffusion; Corpus callosotomy; Epileptic spasms; Tuberous sclerosis complex; West syndrome",
"medline_ta": "Brain Dev",
"mesh_terms": "D002675:Child, Preschool; D003337:Corpus Callosum; D038524:Diffusion Magnetic Resonance Imaging; D004569:Electroencephalography; D004827:Epilepsy; D006801:Humans; D008297:Male; D014402:Tuberous Sclerosis",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "431-434",
"pmc": null,
"pmid": "27923529",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Total corpus callosotomy for epileptic spasms after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in a case with tuberous sclerosis complex.",
"title_normalized": "total corpus callosotomy for epileptic spasms after acute encephalopathy with biphasic seizures and late reduced diffusion aesd in a case with tuberous sclerosis complex"
} | [
{
"companynumb": "JP-UCBSA-2017019081",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nVulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature.\n\n\nMETHODS\nRetrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected.\n\n\nRESULTS\nFifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor α inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy.\n\n\nCONCLUSIONS\nThe diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor α inhibitors are advised to treat this condition.",
"affiliations": "Departments of aGastroenterology and Hepatology bGynaecology cPediatric Gastroenterology, VU University Medical Center dDepartment of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam eDepartment of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen fDepartment of Gastroenterology and Hepatology, University Medical Center, Utrecht gDepartment of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.",
"authors": "Boxhoorn|Lotte|L|;Stoof|Tom J|TJ|;de Meij|Tim|T|;Hoentjen|Frank|F|;Oldenburg|Bas|B|;Bouma|Gerd|G|;Löwenberg|Mark|M|;van Bodegraven|Adriaan A|AA|;de Boer|Nanne K H|NKH|;|||",
"chemical_list": "D001688:Biological Products; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "29(7)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000465:Algorithms; D001688:Biological Products; D019091:Critical Pathways; D003424:Crohn Disease; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D009426:Netherlands; D010348:Patient Care Team; D011237:Predictive Value of Tests; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D014845:Vulvar Diseases",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "838-843",
"pmc": null,
"pmid": "28430699",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Clinical experience and diagnostic algorithm of vulval Crohn's disease.",
"title_normalized": "clinical experience and diagnostic algorithm of vulval crohn s disease"
} | [
{
"companynumb": "NL-JNJFOC-20170624718",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "The primary objective was to evaluate hydrocortisone's efficacy for decreasing respiratory support in premature infants with developing bronchopulmonary dysplasia (BPD). Secondary objectives included assessment of the impact of intrauterine growth restriction (IUGR), maternal history of chorioamnionitis, side effects and route of administration associated with hydrocortisone's efficacy. Dexamethasone as second-line treatment to decrease respiratory support was reviewed.\n\n\n\nRetrospective chart review of preterm infants requiring respiratory support receiving hydrocortisone.\n\n\n\nA total of 48 patients were included. Successful extubation was achieved in 50% of intubated patients after hydrocortisone treatment with no major complications. In our small study, history of maternal chorioamnionitis, IUGR or route of administration did not affect the response. Rescue dexamethasone after hydrocortisone therapy was ineffective in the ten patients who failed extubation following hydrocortisone.\n\n\n\nHydrocortisone is effective in decreasing respiratory support in patients with developing BPD without major complications. Randomized studies are warranted to confirm our findings.",
"affiliations": "Department of Pharmacy, NYU Winthrop Hospital, New York University Langone Medical Center, Mineola, NY, USA.;Department of Pharmacy, NYU Winthrop Hospital, New York University Langone Medical Center, Mineola, NY, USA.;Department of Pediatrics, NYU Winthrop Hospital, New York University Langone Medical Center, Mineola, NY, USA.;Department of Pediatrics, NYU Winthrop Hospital, New York University Langone Medical Center, Mineola, NY, USA.;Department of Foundations of Medicine, NYU Winthrop Hospital, NYU Long Island School of Medicine, Mineola, NY, USA.;Division of Neonatology, Department of Pediatrics, NYU Winthrop Hospital, NYU Long Island School of Medicine, Mineola, NY, USA.;Division of Neonatology, Department of Pediatrics, NYU Winthrop Hospital, NYU Long Island School of Medicine, Mineola, NY, USA. Caterina.Tiozzo@nyulangone.org.",
"authors": "Clauss|Christie|C|;Thomas|Stacey|S|;Khodak|Igor|I|;Tack|Valentyna|V|;Akerman|Meredith|M|http://orcid.org/0000-0001-7332-635X;Hanna|Nazeeh|N|;Tiozzo|Caterina|C|",
"chemical_list": "D006854:Hydrocortisone",
"country": "United States",
"delete": false,
"doi": "10.1038/s41372-020-0680-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0743-8346",
"issue": "40(9)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
"keywords": null,
"medline_ta": "J Perinatol",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "8501884",
"other_id": null,
"pages": "1349-1357",
"pmc": null,
"pmid": "32382114",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "2235227;3174313;11401896;29551318;7700725;11477202;29063585;29063594;29475879;16396863;18595991;8682178;25173821;10744634;25170598;25469645;12682849;16815375;10521727;16238538;16870913;20150750;15574629;22229038;27239054;8077309;9099763;29432424;12892163;17065571;17848504;15995023;26376074;19851225;23706359;17382109;26916176;2050835;30537393;18245407",
"title": "Hydrocortisone and bronchopulmonary dysplasia: variables associated with response in premature infants.",
"title_normalized": "hydrocortisone and bronchopulmonary dysplasia variables associated with response in premature infants"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02544",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
... |
{
"abstract": "There are many reports about contact dermatitis to nickel and side effects of isotretinoin, but the development of contact dermatitis to a previously tolerated allergen while taking isotretinoin is not well described. We report the case of a 19-year-old man who developed a new nickel allergy during isotretinoin treatment. We theorize that thinning of the stratum corneum by this medication allows for greater antigen presentation and thus sensitization to contact allergens.",
"affiliations": "Department of Dermatology, University of Minnesota Medical School, Minneapolis, Minnesota.",
"authors": "Conely|John|J|;Polcari|Ingrid|I|",
"chemical_list": "D003879:Dermatologic Agents; D009532:Nickel; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12460",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "31(6)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000152:Acne Vulgaris; D017449:Dermatitis, Allergic Contact; D003879:Dermatologic Agents; D006801:Humans; D015474:Isotretinoin; D008297:Male; D009532:Nickel; D055815:Young Adult",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e154-5",
"pmc": null,
"pmid": "25424226",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Novel nickel contact dermatitis in a patient taking isotretinoin.",
"title_normalized": "novel nickel contact dermatitis in a patient taking isotretinoin"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0044953",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nA phase II study was conducted to evaluate the efficacy and toxicity of carboplatin plus paclitaxel (TC)-based postoperative concurrent chemoradiotherapy (CCRT) followed by TC-based consolidation chemotherapy in surgically-treated early-stage cervical cancer patients.\n\n\nMETHODS\nWomen with surgically-treated early-stage cervical cancer with positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic intensity modulated radiotherapy (50.4Gy) and concurrent weekly carboplatin (AUC: 2) and paclitaxel (35mg/m(2)) (TC-based CCRT). Three cycles of consolidation chemotherapy involving carboplatin (AUC: 5) and paclitaxel (175mg/m(2)) were administered after TC-based CCRT.\n\n\nRESULTS\nThirty-one patients were enrolled and treated. Overall, the treatment was well tolerated, and 26 patients (83.9%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up period of 36.5months, 2 patients (6.5%) had developed recurrent disease. The patients' estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 93.8%, respectively. In comparisons with historical control groups, TC-based CCRT followed by TC-based consolidation chemotherapy was found to be significantly superior to CCRT involving a single platinum agent in terms of PFS (p=0.026) and significantly superior to extended-field radiotherapy in terms of both PFS (p=0.0004) and OS (p=0.034).\n\n\nCONCLUSIONS\nIn women with surgically treated early-stage cervical cancer, pelvic TC-based CCRT followed by TC-based consolidation chemotherapy is feasible and highly effective. Future randomized trials are needed to verify the efficacy of this regimen.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: smabuchi@gyne.med.osaka-u.ac.jp.;Radiation Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.;Department of Obstetrics and Gynecology, Kaizuka Municipal Hospital, 3-10-20 Hori, Kaizuka, Osaka, 597-0015, Japan.;Department of Obstetrics and Gynecology, Osaka General Medical Center, 3-1-56 Mandaihigashi, Sumiyoshi, Osaka 558-8558, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.;Department of Obstetrics and Gynecology, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki, Hyogo, 660-8511, Japan.;Department of Obstetrics and Gynecology, Osaka Rosai Hospital, 1179-3 Nagasonecho, Kita-ku, Sakai 591-8025, Japan.;Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.;Department of Obstetrics and Gynecology, Kaizuka Municipal Hospital, 3-10-20 Hori, Kaizuka, Osaka, 597-0015, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.",
"authors": "Mabuchi|Seiji|S|;Isohashi|Fumiaki|F|;Yokoi|Takeshi|T|;Takemura|Masahiko|M|;Yoshino|Kiyoshi|K|;Shiki|Yasuhiko|Y|;Ito|Kimihiko|K|;Enomoto|Takayuki|T|;Ogawa|Kazuhiko|K|;Kimura|Tadashi|T|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2016.02.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "141(2)",
"journal": "Gynecologic oncology",
"keywords": "Carboplatin; Cervical cancer; Consolidation chemotherapy; IMRT; Paclitaxel; Phase II study",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D059186:Chemoradiotherapy, Adjuvant; D060830:Consolidation Chemotherapy; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017239:Paclitaxel; D011182:Postoperative Care; D050397:Radiotherapy, Intensity-Modulated; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "240-246",
"pmc": null,
"pmid": "26883141",
"pubdate": "2016-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase II study of postoperative concurrent carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes.",
"title_normalized": "a phase ii study of postoperative concurrent carboplatin and paclitaxel combined with intensity modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP04886",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.",
"affiliations": "Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.;Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.;Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.;Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.;Department of Neurology, Tokushima University, Tokushima, Japan.;Department of Neurology, Tokushima University, Tokushima, Japan.;Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.;Department of Neurosurgery, Tokushima University, Tokushima, Japan.;Department of Neurology, Tokushima University, Tokushima, Japan.;Department of Pathology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.;Department of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan.",
"authors": "Naito|Nobuhito|N|0000-0001-8748-7648;Kawano|Hiroshi|H|;Yamashita|Yuya|Y|;Kondo|Mayo|M|;Haji|Shotaro|S|;Miyamoto|Ryosuke|R|;Toyoda|Yuko|Y|;Kanematsu|Yasuhisa|Y|;Izumi|Yuishin|Y|;Bando|Yoshimi|Y|;Nishioka|Yasuhiko|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2020.1826626",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2472-5625",
"issue": "5(1)",
"journal": "Modern rheumatology case reports",
"keywords": "Neuropsychiatric systemic lupus erythematosus; cerebellar oedema; decompressive craniectomy; obstructive hydrocephalus; vasculitis",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D002531:Cerebellum; D003520:Cyclophosphamide; D056424:Decompressive Craniectomy; D005260:Female; D006261:Headache; D006801:Humans; D006849:Hydrocephalus; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D020945:Lupus Vasculitis, Central Nervous System; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "52-57",
"pmc": null,
"pmid": "33021438",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy.",
"title_normalized": "neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy"
} | [
{
"companynumb": "JP-PFIZER INC-2021337182",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "A patient with Sézary syndrome developed a diffuse undifferentiated lymphoma of T-cell origin. After becoming resistant to multiple chemotherapeutic agents, the patient was treated with antithymocyte globulin. A 75% reduction in adenopathy and complete resolution of skin erythema was observed during an 8-day period. In addition the percent of circulating T cells and the ability of those cells to respond to phytohemagglutinin and concanavalin A were reduced after antithymocyte globulin therapy. The patient died of an intracerebral hemorrhage secondary to profound thrombocytopenia. The study suggests that tumor lysis may be achieved by passive antibody therapy in certain advanced lymphomas.",
"affiliations": null,
"authors": "Fisher|R I|RI|;Kubota|T T|TT|;Mandell|G L|GL|;Broder|S|S|;Young|R C|RC|",
"chemical_list": "D000961:Antilymphocyte Serum; D037102:Lectins; D003208:Concanavalin A",
"country": "United States",
"delete": false,
"doi": "10.7326/0003-4819-88-6-799",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4819",
"issue": "88(6)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D000961:Antilymphocyte Serum; D003208:Concanavalin A; D003873:Dermatitis, Exfoliative; D006801:Humans; D007167:Immunotherapy; D007645:Keratoderma, Palmoplantar; D037102:Lectins; D008206:Lymphatic Diseases; D008213:Lymphocyte Activation; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D013601:T-Lymphocytes",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "799-800",
"pmc": null,
"pmid": "149512",
"pubdate": "1978-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Regression of a T-cell lymphoma after administration of antithymocyte globulin.",
"title_normalized": "regression of a t cell lymphoma after administration of antithymocyte globulin"
} | [
{
"companynumb": "US-PFIZER INC-2018333131",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nChronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia-Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis.\n\n\nOBJECTIVE\nThis study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment.\n\n\nMETHODS\nPost hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, open-label TDF for up to 240 weeks was evaluated. Patients with both baseline and week 240 liver biopsies were evaluated for histologic changes.\n\n\nRESULTS\nAt baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and non-Asian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-to-treat analysis, 74 % of Asian patients and 76 % of non-Asian patients had HBV DNA <400 copies/mL at the end of week 240 (P = 0.602). No differences were seen in HBeAg loss or seroconversion in Asian versus non-Asian patients. No Asian patient experienced hepatitis B surface antigen loss. Safety and tolerability of TDF through week 240, including changes in renal function and in hip/spine bone mineral density (from weeks 192 to 240), were comparable between Asian and non-Asian patients.\n\n\nCONCLUSIONS\nLong-term virologic and histologic efficacy and safety of TDF are comparable in Asian and non-Asian CHB patients.",
"affiliations": "Department of Medicine, Queens Medical Center, University of Hawaii at Manoa, 550 S. Beretania Street, POB III #405, Honolulu, HI, 96734, USA, naoky@hawaii.edu.",
"authors": "Tsai|Naoky C|NC|;Marcellin|Patrick|P|;Buti|Maria|M|;Washington|Mary Kay|MK|;Lee|Samuel S|SS|;Chan|Sing|S|;Trinh|Huy|H|;Flaherty|John F|JF|;Kitrinos|Kathryn M|KM|;Dinh|Phillip|P|;Charuworn|Prista|P|;Subramanian|G Mani|GM|;Gane|Edward|E|",
"chemical_list": "D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-014-3336-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "60(1)",
"journal": "Digestive diseases and sciences",
"keywords": null,
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000225:Adenine; D004279:DNA, Viral; D004311:Double-Blind Method; D005260:Female; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D057194:Intention to Treat Analysis; D008103:Liver Cirrhosis; D008297:Male; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D012307:Risk Factors; D000068698:Tenofovir",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "260-8",
"pmc": null,
"pmid": "25179493",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22510145;20955704;21396961;18752330;15470215;12037146;22273662;23939953;7308988;19399791;16530509;7560864;23234725;19052126;17981229;16391218;12512035;20600025;21992124;20683932",
"title": "Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B.",
"title_normalized": "viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in asians with chronic hepatitis b"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01320",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditi... |
{
"abstract": "The authors retrospectively analyzed the pattern and characteristics of non-laboratory-based adverse drug reactions (ADRs) induced by intravenous radiocontrast agents in a large-scale hospital in China during 2014-2015. There were 314 ADR cases among 118,208 patients receiving enhanced CT or MRI examinations. The frequency of moderate/severe ADRs defined by Chinese Society of Radiology (ie, severe vomiting, systematic urticaria, facial swelling, dyspnea, vasovagal reaction, laryngeal edema, seizure, trembling, convulsions, unconsciousness, shock, death, and other unexpected adverse reactions) was rare (0.0431%), whereas the mild ADRs were uncommon (0.2225%) and accounted for 83.76% of ADRs. Frequency of ADRs induced by iodinated contrast agents was related with examination site, sex, and type of patient settings (P<0.01) and was higher compared with gadolinium contrast agents (0.3676% vs 0.0504%, P<0.01). From 2014 to 2015, frequencies of total and moderate/severe ADRs induced by iodinated contrast agents decreased significantly (0.4410% vs 0.2947%, P<0.01; 0.0960% vs 0.0282%, P<0.01, respectively). Frequency of ADRs differed among different iodinated contrast and gadolinium contrast (P<0.05) agents. Iopromide's ADR frequency in 2014 was significantly higher compared with iopamidol, ioversol, or iohexol (P<0.01). Frequency of moderate/severe ADRs induced by iodixanol was 4.1-5.4 times that of iohexol, iopromide, or iopamidol. Rash was the predominant ADR subtype (84.39%) and occurred more frequently with iodixanol compared with iohexol, iopamidol, or ioversol (P<0.01). Overall, 21.97% of ADR cases had allergy history or atopy traits, and these cases experienced ADRs earlier than the negative ones (17.19 min vs 85.34 min, P<0.01). The mean time to onset of ADRs was increased in patients receiving iodixanol compared with other iodinated contrast agents (323.77 min vs 42.36 min, P<0.01). Overall, 37.26% of ADRs occurred within 5 min and 84.08% of ADRs occurred within 30 min. Efficient quality improvement in decreasing ADRs induced by radiocontrast agents has been achieved by multidisciplinary collaboration.",
"affiliations": "Radiology Nursing Unit, Division of Nursing.;Department of Quality Management.;Radiology Nursing Unit, Division of Nursing.;Department of Quality Management.;Geriatric VIP Care Ward, Division of Nursing.;Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.;Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.",
"authors": "Chen|Qin-Lan|QL|;Zhao|Xiao-Ying|XY|;Wang|Xiao-Mi|XM|;Lv|Na|N|;Zhu|Ling-Ling|LL|;Xu|Hui-Min|HM|;Zhou|Quan|Q|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S134265",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S134265tcrm-13-565Original ResearchRetrospective analysis of non-laboratory-based adverse drug reactions induced by intravenous radiocontrast agents in a Joint Commission International-accredited academic medical center hospital in China Chen Qin-lan 1Zhao Xiao-ying 2Wang Xiao-mi 1Lv Na 2Zhu Ling-ling 3Xu Hui-min 4Zhou Quan 41 Radiology Nursing Unit, Division of Nursing2 Department of Quality Management3 Geriatric VIP Care Ward, Division of Nursing4 Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No 88, Shangcheng District, Hangzhou 310009, Zhejiang Province, People’s Republic of China, Tel +86 571 8778 4615, Fax +86 571 8702 2776, Email zhouquan142602@zju.edu.cnXiao-ying Zhao, Department of Quality Management, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No 88, Shangcheng District, Hangzhou 310009, Zhejiang Province, People’s Republic of China, Email zrxz@zju.edu.cn2017 26 4 2017 13 565 573 © 2017 Chen et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.The authors retrospectively analyzed the pattern and characteristics of non-laboratory-based adverse drug reactions (ADRs) induced by intravenous radiocontrast agents in a large-scale hospital in China during 2014–2015. There were 314 ADR cases among 118,208 patients receiving enhanced CT or MRI examinations. The frequency of moderate/severe ADRs defined by Chinese Society of Radiology (ie, severe vomiting, systematic urticaria, facial swelling, dyspnea, vasovagal reaction, laryngeal edema, seizure, trembling, convulsions, unconsciousness, shock, death, and other unexpected adverse reactions) was rare (0.0431%), whereas the mild ADRs were uncommon (0.2225%) and accounted for 83.76% of ADRs. Frequency of ADRs induced by iodinated contrast agents was related with examination site, sex, and type of patient settings (P<0.01) and was higher compared with gadolinium contrast agents (0.3676% vs 0.0504%, P<0.01). From 2014 to 2015, frequencies of total and moderate/severe ADRs induced by iodinated contrast agents decreased significantly (0.4410% vs 0.2947%, P<0.01; 0.0960% vs 0.0282%, P<0.01, respectively). Frequency of ADRs differed among different iodinated contrast and gadolinium contrast (P<0.05) agents. Iopromide’s ADR frequency in 2014 was significantly higher compared with iopamidol, ioversol, or iohexol (P<0.01). Frequency of moderate/severe ADRs induced by iodixanol was 4.1–5.4 times that of iohexol, iopromide, or iopamidol. Rash was the predominant ADR subtype (84.39%) and occurred more frequently with iodixanol compared with iohexol, iopamidol, or ioversol (P<0.01). Overall, 21.97% of ADR cases had allergy history or atopy traits, and these cases experienced ADRs earlier than the negative ones (17.19 min vs 85.34 min, P<0.01). The mean time to onset of ADRs was increased in patients receiving iodixanol compared with other iodinated contrast agents (323.77 min vs 42.36 min, P<0.01). Overall, 37.26% of ADRs occurred within 5 min and 84.08% of ADRs occurred within 30 min. Efficient quality improvement in decreasing ADRs induced by radiocontrast agents has been achieved by multidisciplinary collaboration.\n\nKeywords\nallergyatopycontrast mediadrug monitoringgadolinium contrastiodinated contrastquality improvements\n==== Body\nIntroduction\nRadiocontrast agents are used widely to improve medical imaging. Institute for Safe Medication Practices lists intravenous radiocontrast agents as high alert medications, which bear a heightened risk of causing significant harm to the patient when used in error.1 It is clinically important to ensure a proper monitoring of adverse drug reactions (ADRs) induced by radiocontrast agents during and after the procedure. But totally non-ionic iodinated contrast and gadolinium-based contrast agents are highly safe, and severe adverse events seldom occur under appropriate care.2,3\n\nThere is little literature on quality improvements in decreasing ADRs induced by radiocontrast agents. Brown et al reported that a 6-year regional multicenter quality improvement intervention could reduce contrast-induced acute kidney injury after percutaneous coronary interventions.4 Dykes et al reported that a national data registry and practice quality improvement initiative failed to have a statistically significant positive impact on intravenous contrast extravasation during CT.5 The aim of this study was to analyze the nature and incidence of non-laboratory-based ADRs induced by intravenous radiocontrast agents in a Joint Commission International (JCI)-accredited academic medical center hospital in China during a 2-year period, and investigate whether quality improvements in this respect could be achieved through multidisciplinary team’s integrated endeavors.\n\nMethods\nData collection\nA retrospective analysis of ADRs induced by radiocontrast agents was performed in the Second Affiliated Hospital of Zhejiang University (SAHZU), a 3200-bed JCI-accredited academic medical center hospital with 3.5 million outpatient visits and 110,000 discharged patients annually (data in 2016) in Zhejiang Province, which has a population of ~54.4 million. The ADRs induced by radiocontrast agents during 2014–2015 were derived from a mandatory reporting system consisting of detailed written sheets in radiology nursing care unit and brief electronic online reporting. Data mining was performed, focusing on reporter’s diagnosis of subtypes of ADRs, severity rating, injection time, time to onset of ADRs, demographic information (sex, age, body weight, whether patients had allergy history or atopy traits), kind of radiocontrast agent used, examination site, ADR treatment and outcomes.\n\nAccording to guideline for iodinated contrast agents use published by Chinese Society of Radiology (CSR), ADRs induced by iodinated contrast agents could be divided into three categories,6 that is, mild ADRs (eg, cough, sneezing, transient chest tightness, conjunctivitis, rhinitis, nausea, systematic fever, urticaria, itching, and angioneurotic edema), moderate ADRs (eg, severe vomiting, systematic urticaria, facial swelling, dyspnea, and vasovagal reaction), and severe ADRs (eg, laryngeal edema, seizure, trembling, convulsions, unconsciousness, shock, death, and other unexpected adverse reactions). ADRs induced by gadolinium contrast agents were classified by referencing the method for iodinated contrast agents.\n\nIn this present study, we also classified several symptoms not included in the CSR criteria into three types, that is, mild or localized facial swelling, mild trembling or shivering, nasal congestion, single symptom such as mild gastrointestinal discomfort, feeling of binaural blockage, transient blurred vision, dizziness, and numb limbs as mild ADRs; substantial facial swelling, single systematic trembling or shivering, hypertention, chest distress, and palpitation as moderate ADRs; and single trembling or shivering coupled with severe systematic symptoms, oxygen desaturation as severe ADRs. Classification criteria of contrast media-related ADRs were consistent through the whole study period.\n\nDrug and Therapeutics Committee (DTC) and the Ethics Committee of SAHZU approved this study. The Ethics Committee at SAHZU deemed that this program was in compliance with the Declaration of Helsinki and patient consent was unnecessary as this study was a review of previous data and did not involve patient data confidentiality. The data presented in the study are available in the archives of DTC of SAHZU. Access and use of these data need permission from the SAHZU DTC.\n\nStatistical analysis\nA descriptive analysis was performed. Chi-square tests were used for testing differences in occurrence rates between two groups using SPSS software (version 13.0, SPSS Incorporated, Chicago, IL, USA). Fisher’s exact test was used when 2 cells (50.0%) of a contingency table had expected count <5. Pear-son Chi-square continuity correction was used when 1 cell (25.0%) had expected count <5. Pearson chi-square was used when 0 cell had expected count <5. Student’s t-test was used for testing difference between sample means. A P-value <0.05 was considered to be statistically significant. A P-value <0.01 was considered to be highly significant.\n\nResults\nDemographic and clinical information\nThree hundred and fourteen ADR cases induced by radiocontrast agents were identified among 118,208 patients enrolled in various types of enhanced CT or MRI examinations during 2014–2015. Using the Naranjo probability scale,7 all reactions were “probable”. Frequencies of mild and moderate/severe ADRs induced by radiocontrast agents were 0.2225% (263/118,208) and 0.0431% (51/118,208), respectively.\n\nThere was no fatality induced by radiocontrast agents during the study period. The basic principles for the treatments of contrast media-related ADRs followed the guideline published by CSR.6 Adverse events required symptomatic and/or aggressive treatments in 268 cases (85.35%), while 46 cases (14.65%) were not specifically treated but remitted spontaneously. There were 11 patients transferred to emergency department for further observation. Four intra-insitutional first-aid calls were performed at radiology department and the average response time was 2.6 min. Percentage of ADR recovery was 100%.\n\nOral hydration was administered first for the cases with mild ADRs, whereas oral and intravenous hydration were given to the patients with moderate/severe ADRs. There were 243 ADR cases (77.39%) receiving oral hydration and 28 cases (8.92%) receiving sodium lactate ringer’s infusion. Two hundred and sixty-two (83.44%) ADR cases received parenteral corticosteroids, including intravenous dexamethasone 5 mg for 4 cases and 10 mg for 252 cases, intravenous methylprednisolone 40 mg for 3 cases, and intramuscular injection of betamethasone/betamethasone dipropionate (2 mg/5 mg) for 2 cases. Topical corticosteroid ointment was given to 2 ADR cases. Five ADR cases (1.59%) received intramuscular injection of H1 receptor blockers (ie, promethazine 12.5–25 mg for 3 cases and chlorpheniramine 10 mg for 2 cases), whereas 10 ADR cases received oral H1 receptor blockers such as loratadine and cetirizine. Electrocardiogram monitor was applied for 70 ADR cases (22.29%). Oxygen inhalation was performed for 31 ADR cases (9.87%). Epinephrine 0.5–1 mg was applied for 5 cases with severe ADRs. Sublingual nitroglycerin tablets were given to 2 moderate ADR cases. Fifty percent glucose solution (20–100 mL) was orally administrated for 1 ADR case and calcium gluconate 1 g was intravenously injected for 2 cases with urticaria.\n\nDemographic and clinical information were listed in Table 1. There was statistically significant sex difference in frequency of ADRs induced by CT radiocontrast agents in 2014 (0.5792% vs 0.3459%, P<0.01) and during 2014–2015 (0.4628% vs 0.3005%, P<0.01). Female patients were more susceptible to ADRs induced by iodinated contrast agents compared with male patients. Frequency of ADR in outpatients and emergency patients receiving iodinated contrast agents was higher compared with inpatients in 2014 (0.5858% vs 0.3034%, P<0.01) and during 2014–2015 (0.4570% vs 0.2820%, P<0.01). However, the influence of sex or patient setting type was not observed in patients receiving gadolinium contrast agents.\n\nFrom 2014 to 2015, significant reduction in frequency of ADRs induced by iodinated contrast agents was observed in female patients (0.5792% vs 0.3504%, P<0.01), outpatients and emergency patients (0.5858% vs 0.3302%, P<0.01), patients receiving abdominal and pelvic examination (0.5298% vs 0.1515%, P<0.01), and chest examination (0.2899% vs 0.1083%, P<0.01). There was statistically significant difference in frequency of ADRs induced by iodinated contrast agents based on examination sites (limbs > abdomen and pelvic, neck, head and brain > chest, P<0.01).\n\nFrequency of ADRs induced by 12 kinds of radiocontrast agents\nTable 2 lists frequencies of ADRs induced by 12 kinds of radiocontrast agents during 2014–2015. Iodinated contrast agents exhibited a higher frequency of ADRs compared with gadolinium contrast agents (0.3674% vs 0.0504%, P<0.01). From 2014 to 2015, the total frequency of ADRs caused by iodinated contrast agents significantly decreased (0.4410% vs 0.2947%, P<0.01). With respect to moderate/severe ADRs, the frequency also reduced (0.0960% vs 0.0282%, P<0.01). Statistically significant difference in frequencies of ADRs was observed with seven iodinated contrast agents in 2014 (P<0.01), six iodinated contrast agents in 2015 (P<0.01), and three gadolinium contrast agents in 2014 (P<0.05). There was no significant difference in frequencies of ADRs induced by 2 products of iohexol (Ousu® [Yangtze River Pharmaceutical Grou P< Taizhou, Jiangsu, People’s Republic of China] vs Omnipaque® [GE Healthcare Shanghai Pharmaceutical Manufacturing Plant, Pudong, Shanghai, People’s Republic of China]); however, significant difference in frequencies of ADRs was observed among patients receiving 2 products of gadopentetate dimeglumine in 2014 (0.2670% vs 0.0218%, P<0.05). Frequency of ADRs induced by iopromide (0.8115%) and iodixanol (0.6957%) was higher compared with iopamidol (0.2639%), ioversol (0.1976%), or iohexol (0.3072%; P<0.01). Regarding moderate/severe ADRs, iodixanol had a higher frequency compared with iopromide, iopamidol, or iohexol (P<0.01).\n\nSubtypes of ADRs\nTable 3 lists subtypes of ADRs induced by radiocontrast agents during 2014–2015. Rash was the predominant ADR subtype (relative percentage: 84.39; actual frequency: 0.2239%), followed by facial swelling (cheek, lip, and eyelid) (relative percentage: 10.51; actual frequency: 0.0279%), laryngeal edema (relative percentage: 4.46; actual frequency: 0.0118%), gastrointestinal discomfort (relative percentage: 4.46; actual frequency: 0.0118%), shivering (relative percentage: 3.50; actual frequency: 0.0093%), anaphylactic shock (relative percentage: 2.23; actual frequency: 0.0059%), and chest distress and palpitation (relative percentage: 2.23; actual frequency: 0.0059%). There was statistically significant difference in frequency of ADR subtype induced by radiocontrast agents (rash > facial swelling [cheek, lip, and eyelid] > gastrointestinal discomfort, shivering, anaphylactic shock, chest distress, and palpitation, P<0.01). More facial swelling was observed in patients receiving iodixanol compared with iopamidol and iopromide (P<0.01). Higher frequency of rash was observed in patients receiving iodixanol compared with iohexol, iopamidol, or ioversol (P<0.01). Frequency of rash was lower in gadopentetate dimeglumine group compared with gadolinium diamine group (P<0.05).\n\nAllergy history or atopy traits among ADR cases\nTable 4 lists information on allergy history or atopy traits among ADR cases during 2014–2015. Among 314 cases of ADRs induced by radiocontrast agents, 69 patients (21.97%) had allergy history (n=66) or atopy traits (n=3). ADR cases with allergy history of antibacterials accounted for 83.33% (50/60) of patients with drug allergy history. The ratio of number of ADR cases with allergy history of penicillins to all ADR cases (10.51%, 33/314) was higher compared with cephalosporins (2.229%, 7/314) or sulfonamides (1.592%, 5/314) (P<0.01). Among 265 cases of rash, 55 patients had allergy history (20.75%, 55/265). Five patients had allergy history among 14 laryngeal edema patients (35.71%, 5/14), and 4 patients had allergy history among 21 facial swelling patients (19.05%, 4/21).\n\nTime to onset of ADRs\nTable 5 lists time to onset of ADRs related with radio-contrast agents during 2014–2015. Patients with allergy history or atopy traits experienced ADRs earlier than those without allergy history or atopy traits during 2014–2015 (17.19±43.59 min vs 85.34±253.82 min, P<0.01) and in 2014 (20.36±55.07 min vs 115.56±280.20 min, P<0.01). Time to onset of ADRs was increased in patients receiving iodixanol compared with patients receiving non-iodixanol iodinated radiocontrast agents (323.77±386.17 min vs 42.36±186.61 min, P<0.01). A total of 84.08% (264/314) of ADR cases occurred within 30 min. The proportion of delayed ADRs, which occurred over 1 h after contrast medium injection, was less than that within 5 min (9.55% vs 37.26%, P<0.01). There was no significant difference in the proportion of ADR occurrence within 5 min between 2014 and 2015 (38.89% vs 35.07%, P>0.05); however, the proportion of ADR occurred beyond 1 h decreased from 13.89% to 3.73% (2014 vs 2015, P<0.01).\n\nDiscussion\nThe study included 118,208 patients enrolled in various types of enhanced CT or MRI examinations, which could reflect ADR conditions in Chinese population accurately and reliably. Regarding frequency of ADRs, “rare” means the occurrence rate ≥0.01% but <0.1% whereas “uncommon” represents the occurrence rate ≥0.1% but <1%.8 Therefore, moderate or severe ADRs induced by 12 kinds of radiocontrast agents in our study were rare whereas mild ADRs were uncommon and accounted for 83.76% of ADRs (263/314), suggesting that enhanced CT and MRI examinations are highly safe.\n\nIt was anecdotally noted that a substantially lower frequency of ADRs was observed in inpatients compared with outpatients and emergency patients at our institution, indicating radiologists and radiology nurses should maintain close vigilance during CT or MRI examinations for outpatients and emergency patients. Dean et al also observed an unexpected discrepancy between inpatient and outpatient cohorts with respect to frequency of ADRs induced by radiocontrast agents and they supposed the hypotheses that there might be several potential barriers to identifying ADRs within the inpatient workflow or there are more opportunities of identifying skin changes or other manifestations of radiocontrast ADRs for outpatients (eg, the time to change from provided gowns for some MRI examinations to outpatients’ own personal clothing).9 There seems to be no barrier to identify radiocontrast-induced ADRs among inpatients at our institution. Both inpatients and outpatients are usually required to move to a holding area for at least 30 min and obvious non-laboratory ADRs induced by radiocontrast agents can be identified and communicated to the radiology team. If inpatients exhibit ADRs induced by radiocontrast agents after going back to their wards, their ward nurses would enter relevant ADR information into the electronic medical recording system (EMRS) and contact radiology nurses who would read the ADR information via EMRS and then record them on specific written sheets. However, ward nurses’ ADR reporting and communicating with radiology nurses are voluntary and thus it is possible to omit collecting ADRs induced by radiocontrast agents, although JCI-accredited SAHZU has an excellent safety culture. Moreover, an intensive care unit (ICU) patient receiving contrast medium at radiology department would be sent back to ICU immediately and it is possible to neglect whether an ICU patient in coma is allergic to the contrast medium. Further research is needed to delineate the exact etiology of the difference in ADR reporting between patient setting type.\n\nLi et al reported that female patients had significantly higher incidence rates of ADRs caused by non-ionic iodinated contrast media compared with male patients (0.40% vs 0.30%; P<0.01).2 Our study also confirmed that sex could affect the development of ADRs associated with enhanced CT examination to a certain degree. The effect of sex on ADR frequency was not observed in patients receiving gadolinium contrast agents, which was not in accordance with previous findings that adverse events were more likely in women.1 The underlying mechanism is still uncertain.\n\nAn interesting phenomenon was observed in our study, that is, patients with positive allergy history or atopy traits experienced ADRs earlier than those who were negative. To our knowledge, this is the first report to reveal the effect of allergy history or atopy traits on time to onset of ADRs induced by radiocontrast agents. The fact that 37.2% of ADR cases occurred within 5 min and 84.08% of ADRs occurred within 30 min indicates that radiologists and nurses should pay special attention to these patients immediately after radiocontrast injection, during and shortly after examinations. Patients should not leave the CT room until 30 min after the examination. Statistically significant decrease in the relative contribution of ADRs occurred 30 min after medium injection, which might facilitate the management of ADRs in patients.\n\nStatistically significant difference in frequencies of ADRs was observed with iodinated contrast agents in both 2014 and 2015 (P<0.01), indicating these differences among different agents should be considered when selecting a medium and when monitoring patients during and after its use to ensure optimum usage and patient safety. Zhang et al observed that the incidence of acute adverse reactions was higher with Ultravist-370 (iopromide) than with Isovue-370 (iopamidol) (0.38% vs 0.24%, P < 0.001), but only for mild ADRs (0.32% vs 0.16%, P < 0.001).10 In our study, frequency of ADRs induced by iopromide (0.8115%) was higher compared with iopamidol (0.2639%), ioversol (0.1976%), or iohexol (0.3072%) (P<0.01), but this difference was only limited to mild ADRs. Two products of gadopentetate dimeglumine exhibited significant difference in frequencies of ADRs (0.2670% vs 0.0218%, P<0.05), indicating possible difference in quality of pharmaceutical formulations with same generic name. It is noteworthy to further investigate the underlying mechanism.\n\nSince the beginning of 2015, SAHZU has initiated a quality improvement program of reducing ADRs induced by radiocontrast agents. Comprehensive intervention measures were as follows:\nPhysicians are required to pay more attention to clinical indications and contraindications of radiocontrast examinations, assess renal function and obtain informed consent from patients.\n\nRadiology nurses are required to strengthen patient education and pre-examination screening of key information (eg, integrity of signed informed consent, allergy history, atopy traits, comorbidities, renal function, and metformin use). Before 2015, radiology nurses directly initiated radiocontrast injection for patients with bronchial asthma or a history of drug anaphylactic shock if these patients’ signed informed consent were complete. However, a new process was established to decrease allergy risk among such patients since the beginning of 2015, that is, patients with history of drug anaphylactic shock will be re-informed with potential risk of radiocontrast use by radiology nurses. If the patient declines to receive radiocontrast examination, the examination will be canceled and alternative examination will be considered by the prescribing physician. If the patient insists on receiving radiocontrast examination, radiology nurse will contact the prescribing physician to confirm the order. For an asthma patient, radiology nurse will re-assess the patient. If the patient has an allergic asthma, radiocontrast examination must be canceled. Patients with bronchial asthma are generally suggested to avoid the radiocontrast examination except when the patient has been received such examination in the past or the prescribing physician insists on the examination. For such cases, after careful consideration, family members of outpatients and doctor of inpatients are required to accompany them during radiocontrast examination.\n\nSince the beginning of 2015, radiologists have to order personalized dose of contrast medium based on a dose calculation algorithm that combines multiple factors such as examination machine, scanning technique, examination site and body weight. On the contrary, dealing with CT radiocontrast doses was all a matter of experience before 2015 (eg, 80–100 mL for chest and abdomen examinations, 60–80 mL for head and neck examinations).\n\nEmergency management contingency plan was further improved. When ADR occurs, all clinical professionals at the radiology department should perform rapid evaluation, closely monitor vital signs and pulse oxygen saturation, appropriately use the devices and medications to treat the patients, timely request for help, record and follow-up the patients. For patients experiencing severe ADRs, immediate treatment should be performed, and clinicians from the emergency, anesthesia and other related departments should be asked to perform treatments in cooperation. Cardiopulmonary resuscitation should be performed immediately when cardiorespiratory arrest occurs. Basic life and advanced life support should be given in the radiology department. Patients receiving radiocontrast agents should be closely monitored by clinical professionals for at least 30 min after radiocontrast injection. Nurse head would routinely check the implementation of ADRs recording by nurses on duty. All radiocontrast-related ADRs were analyzed monthly and quarterly and discussed at the DTC meeting.\n\nInformation technology was further applied, that is, intelligent warnings of disobeying contraindications of radiocontrast examination during physician’s prescribing via EMR and online ADR report system.\n\nFormulary was updated. According to ADR monitoring data in 2014, frequency of moderate/severe ADRs induced by iodixanol was 4.1–5.4 times that of iohexol, iopromide, or iopamidol. Moreover, time to onset of ADRs induced by iodixanol was ~8 times that of other iodinated radiocontrast agents. After discussion in the DTC meeting, SAHZU took a pragmatic intervention (ie, intravenous iodixanol use in radiocontrast examinations was prohibited in 2015).\n\n\n\nSAHZU witnessed statistically significant reduction in occurrence rate of ADRs as well as moderate/severe ADRs induced by iodinated contrast agents from 2014 to 2015 (P<0.01), indicating successful quality improvement by multidisciplinary collaboration among physicians, pharmacists, radiologists, nurses at radiology nursing unit, information technology engineers, and quality management experts.\n\nLimitations\nOur study has some limitations. First, although information on allergy history or atopy traits for each patient must be documented in the SAHZU’s EMRS, we are unable to collect the information on allergy history or atopy traits of 117,894 patients who did not experience ADRs induced by radiocontrast agents due to inconvenience in accessibility of big data. Therefore, whether patients with allergy history or atopy traits are more susceptible to ADRs induced by radiocontrast agents was not addressed in this study. Nevertheless, we revealed the effect of allergy history or atopy traits on time to onset of ADRs induced by radiocontrast agents. Second, the ADRs collected in this study are not laboratory based, so ADRs such as acute kidney injuries were not our focus. Third, we only focused on the intravenous use of radiocontrast agents in this study. ADRs occurring due to radiocontrast administration via other administration routes are worthy of being investigated in the future.\n\nConclusion\nNon-laboratory-based moderate/severe ADRs induced by radiocontrast agents are rare whereas mild ones were uncommon and accounted for the majority of ADRs. Efficient quality improvement in decreasing frequency of ADRs induced by contrast has been achieved by multidisciplinary collaboration. Detailed knowledge of ADRs induced by contrast media could help in promoting risk management and patient safety.\n\nAcknowledgments\nThis work was supported by Zhejiang Provincial Bureau of Education (application number Y201635841). Also, we would like to thank Professor Xiao-na Dai (Dean of Department of Quality Administration), Mr Guang-wu Li (Inpatient Pharmacy Supervisor), and Wei He (Clinical Pharmacist) for their kind help with medication management and use.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nTable 1 Demographic and clinical information\n\nData\t2014\t2015\t2014 and 2015\t\nRelative percentage of male ADR cases to all ADR cases (%)\t46.11% (83/180)\t48.51% (65/134)\t47.13% (148/314)\t\nAge of ADR cases (year), mean ± SD\t51.6±15.0\t51.13±14.42\t51.42±14.70\t\nBody weight of ADR cases (kg), mean ± SD\t51.13±14.42\t61.36±11.29\t60.38±11.00\t\nRelative percentage of inpatients among all ADR cases\t36.11% (65/180)\t43.28% (58/134)\t39.17% (123/314)\t\nRelative percentage of ADR patients with allergy history or atopy\t23.33% (42/180)\t20.15% (27/134)\t21.97% (69/314)\t\nPercentage of drug intervention\t82.22% (148/180)\t89.55% (120/134)\t85.35% (268/314)\t\nPercentage of ADR recovery\t100%\t100%\t100%\t\nCases of patient complaints\t2\t0\t2\t\nPercentage of morning administration\t46.11% (83/180)\t40.30% (54/134)\t43.63% (137/314)\t\nFrequency of ADR in patients receiving iodinated contrast\t\n Male\t0.3459% (79/22,841)\t0.2549% (58/22,750)\t0.3005% (137/45,591)\t\n Female\t0.5792% (91/15,712)a,c\t0.3504% (57/16,269)\t0.4628% (148/31,981)a\t\nFrequency of ADR in patients receiving iodinated contrast\t\n Inpatients\t0.3034% (60/19,775)\t0.2608% (52/19,938)\t0.2820% (112/39,713)\t\n Outpatients and emergency patients\t0.5858% (110/18,778)b,c\t0.3302% (63/19,081)\t0.4570% (173/37,859)b\t\nFrequency of ADR in patients receiving gadolinium contrast\t\n Male\t0.03797% (4/10,535)\t0.06282% (7/11,143)\t0.05074% (11/21,678)\t\n Female\t0.06445% (6/9,309)\t0.1244% (12/9,649)\t0.09495% (18/18,958)\t\nFrequency of ADR in patients receiving gadolinium contrast\t\n Inpatients\t0.05155% (5/9,699)\t0.05549% (6/10,812)\t0.05363% (11/20,511)\t\n Outpatients and emergency patients\t0.04929% (5/10,145)\t0.1303% (13/9,980)\t0.08944% (18/20,125)\t\nFrequency of ADR induced by iodinated contrast based on examination site\t\n Limbs\t1.1820% (5/423)d\t0.5952% (2/336)\t0.9222% (7/759)d\t\n Abdomen and pelvic\t0.5298% (85/16,043)c,d\t0.1515% (25/16,497)\t0.3380% (110/32,540)d\t\n Neck\t0.4548% (15/3,298)d\t0.2237% (8/3,576)\t0.3346% (23/6,874)d\t\n Head and brain\t0.3641% (13/3,570)d\t0.2421% (9/3,717)\t0.3019% (22/7,287)d\t\n Chest\t0.2899% (44/15,178)c,d\t0.1083% (16/14,773)\t0.2003% (60/29,951)d\t\nNotes:\n\na P<0.01 (female vs male);\n\nb P<0.01 (inpatients vs outpatients and emergency patients);\n\nc P<0.01 (2014 vs 2015);\n\nd P<0.01 (comparison in frequency of ADR regarding different examination sites).\n\nAbbreviations: ADR, adverse drug reaction; SD, standard deviation.\n\nTable 2 Frequencies of ADR induced by 12 different radiocontrast agents during 2014–2015\n\nRadiocontrast agents\t2014\n\t2015\n\t2014 plus 2015\n\t\nFrequency of ADR\tFrequency of moderate/severe ADR\tFrequency of ADR\tFrequency of moderate/severe ADR\tFrequency of ADR\t\nIodinated contrast\t0.4410% (170/38,553)a,b\t0.0960% (37/38,553)a\t0.2947% (115/39,019)b\t0.0282% (11/39,019)\t0.3674% (285/77,572)b\t\n1. Iohexol (Ousu®)\t0.2972% (30/10,093)c\t0.0396% (4/10,093)\t0.3341% (29/8,680)c\t0.0346% (3/8,680)\t\t\n2. Iohexol (Omnipaque®)\t0.3310% (14/4,230)c\t0.0473% (2/4,230)\t0.1862% (16/8,594)c\t0 (0/8,594)\t\t\n3. Ioversol (Optiray®)\t0.1976% (5/2,531)c\t0 (0/2,531)\t0.0733% (2/2,730)c\t0.0366% (1/2,730)\t\t\n4. Ioversol (Hengrui)\t0 (0/0)\t0 (0/0)\t0.9524% (1/105)c\t0 (0/105)\t\t\n5. Iopamidol (Dianbile®)\t0.2639% (23/8,717)c\t0.0688% (6/8,717)\t0.2466% (23/9,327)c\t0.0429% (4/9,327)\t\t\n6. Iodixanol (Visipaque 270®)\t0.3012% (1/332)c\t0 (0/332)\t0 (0/0)\t0 (0/0)\t\t\n7. Iodixanol (Visipaque 320®)\t0.6957% (34/4,887)c\t0.3683% (18/4,887)f\t0 (0/0)\t0 (0/0)\t\t\n8. Iopromide (Ultravist®)\t0.8115% (63/7,763)c,a\t0.0902% (7/7,763)\t0.4466% (44/9,853)c\t0.0304% (3/9,853)\t\t\nGadolinium contrast\t0.0504% (10/19,844)\t0.0050% (1/19,844)\t0.0914% (19/20,792)\t0.0096% (2/20,792)\t0.0504% (29/40,636)\t\n1. Gadopentetate dimeglumine\t0.0218% (2/9,177)d,e\t0 (0/9,177)\t0.0552% (5/9,055)\t0 (0/9,055)\t\t\n2. Gadopentetate dimeglumine\t0.2670% (2/749)d\t0 (0/749)\t0 (0/679)\t0 (0/679)\t\t\n3. Gadolinium diamine (Omniscan®)\t0.0605% (6/9,918)d\t0.0101% (1/9,918)\t0.1279% (14/10,946)\t0.0183% (2/10,946)\t\t\n4. Gadoxetate disodium (Primovist®)\t0 (0/0)\t0 (0/0)\t0 (0/112)\t0 (0/112)\t\t\nNotes: Numerator and denominator in parentheses represent number of patients experiencing ADR induced by corresponding radiocontrast agent and number of patients receiving corresponding radiocontrast agent, respectively.\n\na P<0.01 (data in 2014 vs data in 2015 corresponding to the same indicator);\n\nb P<0.01 (iodinated contrast relevant data vs gadolinium contrast relevant data in the same year);\n\nc P<0.01 (comparison in frequency of ADR regarding seven iodinated contrast in the same year);\n\nd P<0.05 (comparison in frequency of ADR regarding three gadolinium contrast in 2014);\n\ne P<0.05 (comparison in frequency of ADR in 2014, gadopentetate dimeglumine [Guangzhou] vs gadopentetate dimeglumine [Beijing]).\n\nf P<0.01 (comparison in frequency of moderate/severe ADR in 2014, iodixanol [Visipaque 320®] vs iopromide, iopamidol or iohexol).\n\nAbbreviation: ADR, adverse drug reaction.\n\nTable 3 Subtypes of ADRs induced by radiocontrast agents during 2014–2015\n\nRadiocontrast agents\tNumber of patients receiving corresponding radiocontrast\tNumber of ADR cases\tNumber of subtype ADR cases\n\t\nRash (%)\tFacial swelling (cheek, lips, and eyelids) (%)\tLaryngeal edema (%)\tGastrointestinal discomfort (%)\tShivering (%)\tAnaphylactic shock (%)\tChest distress and palpitation (%)\tMiscellaneous\t\nIohexol (Ousu®)\t18,773\t59\t49 (0.2610)\t2 (0.0106)\t5 (0.0266)\t3 (0.0160)\t1 (0.0053)\t0\t3 (0.0160)\t0\t\nIohexol (Omnipaque®)\t12,824\t30\t26 (0.2027)\t1 (0.0078)\t2 (0.0156)\t0\t1 (0.0078)\t0\t0\t0\t\nIoversol (Optiray®)\t5,261\t7\t6 (0.1140)\t0\t0\t0\t0\t1 (0.0190)\t0\t0\t\nIoversol (Hengrui)\t105\t1\t1 (0.9524)\t0\t0\t0\t0\t0\t0\t0\t\nIopamidol (Dianbile®)\t18,044\t46\t37 (0.2051)\t5 (0.0277)\t4 (0.0222)\t2 (0.0111)\t4 (0.0222)\t1 (0.0055)\t1 (0.0055)\tTransient syncope (n=1), dizziness and upper limb numbness (n=1), sneezing (n=1)\t\nIopromide (Ultravist®)\t17,616\t107\t92 (0.5223)\t7 (0.0397)\t1 (0.0057)\t5 (0.0284)\t3 (0.0170)\t4 (0.0227)\t2 (0.0114)\tSneezing with nasal congestion (n=1), blurred vision (n=1), feeling of binaural blockage (n=1)\t\nIodixanol (Visipaque®)\t5,219\t35\t32 (0.6131)b\t17 (0.3257)a\t1 (0.0192)\t1 (0.0192)\t0\t0\t0\tOxygen desaturation (n=1)\t\nGadopentetate dimeglumine\t19,660\t9\t6 (0.0305)c\t0\t0\t2 (0.0102)\t1 (0.0051)\t0\t0\t0\t\nGadolinium diamine\t20,864\t20\t16 (0.0767)\t1 (0.0048)\t1 (0.0048)\t1 (0.0048)\t1 (0.0048)\t1 (0.0048)\t1 (0.0048)\t0\t\n(Omniscan®) Total\t118,366\t314\t265 (0.2239)d\t33 (0.0279)e\t14 (0.0118)\t14 (0.0118)\t11 (0.0093)\t7 (0.0059)\t7 (0.0059)\t6 (0.0051%)\t\nNotes: Data in parentheses represent actual frequency of corresponding subtype ADR.\n\na P<0.01 (frequency of facial edema: iodixanol vs iopromide or iopamidol);\n\nb P<0.01 (frequency of rash: iodixanol vs iopamidol or iohexol or ioversol);\n\nc P<0.05 (frequency of rash: gadopentetate dimeglumine vs gadolinium diamine);\n\nd P<0.01 (rash vs other subtype ADR);\n\ne P<0.01 (facial edema vs gastrointestinal discomfort, shivering, anaphylactic shock, or chest distress and palpitation).\n\nAbbreviation: ADR, adverse drug reaction.\n\nTable 4 Information on allergy history or atopy traits among ADR cases during 2014–2015\n\nRadiocontrast agents\tThe ratio of ADR cases with allergy history or atopy traits to all ADRs induced by corresponding radiocontrast agent\tDetails\t\nIohexol (Ousu®)\t16.95% (10/59)\t• Drugs involving allergy: antibacterials (n=50, ie, penicillins [n=33]a, cephalosporins [n=7], sulfonamides [n=5], metronidazole [n=1], streptomycin [n=1], gentamicin [n=1], an unknown antibiotics [n=1], ofloxacin [n=1]), Shenmai injection (a traditional Chinese medicine) (n=1), Shuanghuanglian injection (n=1), calcitonin (n=1), procaine (n=1), tetanus antitoxin (n=1), iodine contrast agent (n=1), iodine (n=1), Ultravist (n=1), metamizole sodium (n=1), Contac NT (n=1).\t\nIohexol (Omnipaque®)\t23.33% (7/30)\t\nIopamidol (Dianbile)\t19.57% (9/46)\t\nIopromide (Ultravist®)\t24.30% (26/107)\t\nIodixanol (Visipaque®)\t20.00% (7/35)\t\nIoversol (Optiray®)\t14.29% (1/7)\t\nIoversol (Hengrui)\t100.00% (1/1)\t• Food and other substance: pollen (n=2), mango (n=1), cicadas (n=1), mulberry (n=1), seafood (n=4), adhesive tape (n=2), dust mite (n=2), paint (n=2).\t\nGadopentetate dimeglumine\t33.33% (3/9)\t\nGadolinium diamine (Omniscan®)\t25.00% (5/20)\t• Atopy: history of rubella (n=1), history of eczema (n=1), rhinallergosis (n=1).\t\nNotes:\n\na P<0.01. The ratio of number of ADR cases with allergy history of corresponding category of antibacterials to total number of ADR cases: penicillins (10.51%) vs cephalosporins (2.23%) or sulfonamides (1.59%).\n\nAbbreviation: ADR, adverse drug reaction.\n\nTable 5 Time to onset of ADRs related to radiocontrast agents during 2014–2015\n\nInvestigation items\t2014\n\t2015\n\t2014 and 2015\n\t\nn\tTime to onset of ADRs (min)\tn\tTime to onset of ADRs (min)\tn\tTime to onset of ADRs (min)\t\nPatients with allergy history or atopy traits\t42\t20.36±55.07a\t27\t12.08±8.61\t69\t17.19±43.59a\t\nPatients without allergy history or atopy traits\t138\t115.56±280.20\t107\t46.73±210.48\t245\t85.34±253.82\t\nIodixanol\t35\t323.77±386.17b\t0\t\t35\t323.77±386.17b\t\nNon-iodixanol iodinated radiocontrast*\t135\t40.30±171.90\t115\t\t250\t42.36±186.61\t\nTime to onset of ADRs\t\n ≤5 min\t38.89% (70/180)\t35.07% (47/134)\t37.26% (117/314)\t\n 5–30 min\t41.11% (74/180)\t54.48% (73/134)c\t46.82% (147/314)\t\n >30 min\t19.44% (35/180)e\t11.19% (15/134)c,e\t15.92% (50/314)e\t\n >1 h\t13.89% (25/180)e\t3.73% (5/134)d,e\t9.55% (30/314)e\t\nNotes:\n\n* Non-iodixanol iodinated contrast medium included iopamidol, iohexol, iopromide, and ioversol. Student’s t-test,\n\na P<0.01 (patients with allergy history or atopy vs patients without allergy history or atopy),\n\nb P<0.01 (iodixanol vs non-iodixanol iodinated contrast medium),\n\nc P<0.05,\n\nd P<0.01 (2014 vs 2015),\n\ne P<0.01 (>1 h vs ≤5 min or >30 min vs ≤5 min). Data presented as mean ± standard deviation unless stated otherwise.\n\nAbbreviation: ADR, adverse drug reaction.\n==== Refs\nReferences\n1 ISMP high-alert medications. [webpage on the Internet] Available from: http://www.ismp.org/Tools/highAlertMedicationLists.asp Accessed January 26, 2017 \n2 Li X Chen J Zhang L Clinical observation of the adverse drug reactions caused by non-ionic iodinated contrast media: results from 109,255 cases who underwent enhanced CT examination in Chongqing, China Br J Radiol 2015 88 1047 20140491 25582519 \n3 Prince MR Zhang H Zou Z Staron RB Brill PW Incidence of immediate gadolinium contrast media reactions AJR Am J Roentgenol 2011 196 2 W138 W143 21257854 \n4 Brown JR Solomon RJ Sarnak MJ Reducing contrast-induced acute kidney injury using a regional multicenter quality improvement intervention Circ Cardiovasc Qual Outcomes 2014 7 5 693 700 25074372 \n5 Dykes TM Bhargavan-Chatfield M Dyer RB Intravenous contrast extravasation during CT: a national data registry and practice quality improvement initiative J Am Coll Radiol 2015 12 2 183 191 25245788 \n6 Working group of Chinese Society of Radiology on the safe use of contrast agents Guideline for iodine contrast agent use Natl Med J China 2014 43 3363 3369 \n7 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508 \n8 Eriksson R Aagaard L Jensen LJ Discrepancies in listed adverse drug reactions in pharmaceutical product information supplied by the regulatory authorities in Denmark and the USA Pharmacol Res Perspect 2014 2 3 e00038 25505588 \n9 Dean KE Starikov A Giambrone A Hentel K Min R Loftus M Adverse reactions to intravenous contrast media: an unexpected discrepancy between inpatient and outpatient cohorts Clin Imaging 2015 39 5 863 865 26164404 \n10 Zhang B Dong Y Liang L The incidence, classification, and management of acute adverse reactions to the low-osmolar iodinated contrast media Isovue and Ultravist in contrast-enhanced computed tomography scanning Medicine (Baltimore) 2016 95 12 e3170 27015204\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "13()",
"journal": "Therapeutics and clinical risk management",
"keywords": "allergy; atopy; contrast media; drug monitoring; gadolinium contrast; iodinated contrast; quality improvements",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "565-573",
"pmc": null,
"pmid": "28490883",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "27015204;25245788;25074372;21257854;25582519;7249508;26164404;25505588",
"title": "Retrospective analysis of non-laboratory-based adverse drug reactions induced by intravenous radiocontrast agents in a Joint Commission International-accredited academic medical center hospital in China.",
"title_normalized": "retrospective analysis of non laboratory based adverse drug reactions induced by intravenous radiocontrast agents in a joint commission international accredited academic medical center hospital in china"
} | [
{
"companynumb": "CN-GUERBET-CN-20170021",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IOVERSOL"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nCardiac metastases from renal cell carcinoma are very rare. In this report, we describe a case of ventricular metastases in the absence of vena cava or right atrial involvement.\n\n\nMETHODS\nWe report the case of a 60-year-old man who had a past history of heavy tobacco intake and well-controlled arterial hypertension. He experienced sudden-onset palpitations, lost consciousness and, as a result, was involved in an accident on the public highway. Cardiac arrhythmia was suspected and, therefore, transthoracic echocardiography was suggested, which revealed a large right ventricular mass. Chest and abdominal computed tomography demonstrated a mass in the right ventricle, but without contiguous vena cava involvement, and a right renal mass related to the probable neoplasm. An ultrasound-guided renal biopsy showed a clear-cell renal cell carcinoma. A bone scan revealed a metastatic bone disease. The patient was started on sunitinib treatment, which was well tolerated. However, approximately 8 months later, reevaluation showed pulmonary metastases. The patient was subsequently started on treatment with everolimus, which, however, was poorly tolerated. Two months later, the patient died due to terminal respiratory insufficiency.\n\n\nCONCLUSIONS\nBased on the literature and our observations in this case, targeted antiangiogenic therapy should be considered as a viable therapeutic alternative to metastasectomy for patients with inoperable cardiac metastatic disease as long as there is no baseline systolic or diastolic dysfunction. The case also emphasizes the importance of a thorough history review and physical examination in the workup of patients with syncope.",
"affiliations": "Department of Medical Oncology, Military Hospital My Ismail, Meknès, Morocco.;Department of Medical Oncology, Military Hospital My Ismail, Meknès, Morocco.;Department of Medical Oncology, Military Hospital Med V, Morocco.;Department of Medical Oncology, Military Hospital Med V, Morocco.;Department of Medical Oncology, Military Hospital Med V, Morocco.;Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.",
"authors": "Bazine|Aziz|A|;Fetohi|Mohamed|M|;Tanz|Rachid|R|;Mahfoud|Tarik|T|;Ichou|Mohamed|M|;Errihani|Hassan|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000366292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-6575",
"issue": "7(2)",
"journal": "Case reports in oncology",
"keywords": "Cardiac metastases; Renal cell carcinoma; Target therapy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "560-4",
"pmc": null,
"pmid": "25232327",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports",
"references": "22379474;24179641;19436786;14998838;17151773;21693362",
"title": "Cardiac metastases of renal cell carcinoma revealed by syncope: diagnosis and treatment.",
"title_normalized": "cardiac metastases of renal cell carcinoma revealed by syncope diagnosis and treatment"
} | [
{
"companynumb": "PHHY2015MA033736",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPTOPRIL"
},
"drugadditional": null,
"drug... |
{
"abstract": "In patients with acute liver failure (ALF), elevated prothrombin time and thrombocytopenia can fuel a perception of a bleeding tendency. However, the incidence, site, risk factors, and clinical significance of bleeding complications have not been quantified in a large cohort of patients with ALF. We studied 1,770 adult patients enrolled in the ALF Study Group Registry between 1998 and 2016. Bleeding complications and blood component transfusions were collected for 7 days after admission. The relationship of bleeding complications to 21-day mortality was assessed. Despite a median international normalized ratio of 2.7 and platelet count of 96 × 109 /L on admission, bleeding complications were observed in only 187 patients (11%), including 173 spontaneous and 22 postprocedural bleeding episodes. Eighty-four percent of spontaneous bleeding episodes were from an upper gastrointestinal source and rarely resulted in red blood cell transfusion. Twenty patients experienced an intracranial bleed; half of these occurred spontaneously and half after intracranial pressure monitor placement, and this was the proximate cause of death in 20% and 50%, respectively. Bleeders and patients who received red blood cell transfusions were more acutely ill from extrahepatic organ system failure but not from hepatocellular failure. Consistent with this observation, bleeding complications were associated with lower platelet counts but not higher international normalized ratio. Transfusion of any blood component was associated with nearly 2-fold increased death or need for liver transplantation at day 21, but bleeding complications were the proximate cause of death in only 5% of cases.\n\n\n\nDespite a perceived bleeding diathesis, clinically significant bleeding is uncommon in patients with ALF; bleeding complications in patients with ALF are markers of severe systemic inflammation rather than of coagulopathy and so portend a poor prognosis. (Hepatology 2018;67:1931-1942).",
"affiliations": "Hume-Lee Transplant Center of Virginia Commonwealth University, Richmond, VA.;Department of Biostatistics, Medical University of South Carolina, Charleston, SC.;Department of Biostatistics, Medical University of South Carolina, Charleston, SC.;Division of Gastroenterology and Hepatology, Yale University, New Haven, CT.;Division of Gastroenterology, University of Michigan, Ann Arbor, MI.;Department of Biostatistics, Medical University of South Carolina, Charleston, SC.;University of Texas-Southwestern Medical Center, Dallas, TX.",
"authors": "Stravitz|R Todd|RT|;Ellerbe|Caitlyn|C|;Durkalski|Valerie|V|;Schilsky|Michael|M|;Fontana|Robert J|RJ|;Peterseim|Carolyn|C|;Lee|William M|WM|0000-0002-2783-5441;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hep.29694",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "67(5)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders; D001803:Blood Transfusion; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D012042:Registries; D016019:Survival Analysis",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "1931-1942",
"pmc": null,
"pmid": "29194678",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "27043883;21703173;22568491;172938;12830375;10401942;25860444;4569003;18549814;23468040;5775820;22735303;24164805;26049071;3805667;23389887;17654741;23515053;26453953;21266777;66425;24369077;15842354;8093756;1904133;23439263;4908702;15726661",
"title": "Bleeding complications in acute liver failure.",
"title_normalized": "bleeding complications in acute liver failure"
} | [
{
"companynumb": "US-JNJFOC-20180514287",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive mesenchymal pediatric tumor. Previously, reported outcomes have been very poor. Here, we report a single-center experience of five patients with UESL treated with upfront gross total resection and adjuvant chemotherapy. We have a median follow-up of 8 years with a range from 5 to 19 years with 100% event-free survival.",
"affiliations": "Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York. mathiasm@mskcc.org.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.",
"authors": "Mathias|Melissa D|MD|;Ambati|Srikanth R|SR|;Chou|Alexander J|AJ|;Slotkin|Emily K|EK|;Wexler|Leonard H|LH|;Meyers|Paul A|PA|;Magnan|Heather|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(12)",
"journal": "Pediatric blood & cancer",
"keywords": "case series; sarcoma; undifferentiated embryonal sarcoma of the liver",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D012509:Sarcoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2246-2248",
"pmc": null,
"pmid": "27427850",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "20352000;18836810;25611111;1702267;9166061;22217489;26925712;24210186;18926232;20925497;25630954;208754;24798662;23138115;25038546;26788276;25674229;11815984;11376805;12972518",
"title": "A single-center experience with undifferentiated embryonal sarcoma of the liver.",
"title_normalized": "a single center experience with undifferentiated embryonal sarcoma of the liver"
} | [
{
"companynumb": "US-TEVA-733870USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Since their introduction in 2006, the tyrosine kinase inhibitors (TKI) Sunitinib and Sorafenib have become the standard of care for many patients with renal cancer. They are generally well tolerated and have not been significantly implicated in renal toxicity. We report the first biopsy confirmed occurrence of acute interstitial nephritis in a patient receiving treatment with Sunitinib for metastatic renal cell cancer. However, two previous descriptions of interstitial nephritis related to treatment with TKIs, combined with this current report suggest that TKI therapy could be associated with this rare but life-threatening complication.",
"affiliations": "Department of Renal Medicine, St Helier Hospital, Carshalton, Surrey SM5 1AA, UK. simon.winn@epsom-sthelier.nhs.uk",
"authors": "Winn|Simon K|SK|;Ellis|Sarah|S|;Savage|Philip|P|;Sampson|Stephen|S|;Marsh|James E|JE|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfn625",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-0509",
"issue": "24(2)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": null,
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D006801:Humans; D007211:Indoles; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib",
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "673-5",
"pmc": null,
"pmid": "19039026",
"pubdate": "2009-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Biopsy-proven acute interstitial nephritis associated with the tyrosine kinase inhibitor sunitinib: a class effect?",
"title_normalized": "biopsy proven acute interstitial nephritis associated with the tyrosine kinase inhibitor sunitinib a class effect"
} | [
{
"companynumb": "GB-PFIZER INC-2008150350",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": nul... |
{
"abstract": "We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.",
"affiliations": "Department of Medicine, VA Medical Center, Cleveland, OH 44106.",
"authors": "Wisnieski|J J|JJ|;Baer|A N|AN|;Christensen|J|J|;Cupps|T R|TR|;Flagg|D N|DN|;Jones|J V|JV|;Katzenstein|P L|PL|;McFadden|E R|ER|;McMillen|J J|JJ|;Pick|M A|MA|",
"chemical_list": "D001323:Autoantibodies; D003165:Complement System Proteins",
"country": "United States",
"delete": false,
"doi": "10.1097/00005792-199501000-00003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7974",
"issue": "74(1)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000368:Aged; D001323:Autoantibodies; D003165:Complement System Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D014581:Urticaria; D014657:Vasculitis",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "24-41",
"pmc": null,
"pmid": "7837968",
"pubdate": "1995-01",
"publication_types": "D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients.",
"title_normalized": "hypocomplementemic urticarial vasculitis syndrome clinical and serologic findings in 18 patients"
} | [
{
"companynumb": "US-PFIZER INC-2020412354",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nTo determine the prognosis of patients with symptomatic intracranial atherosclerosis who fail antithrombotic therapy.\n\n\nBACKGROUND\nThe outcome of patients with symptomatic intracranial atherosclerosis who fail antithrombotic therapy is unknown. These patients may represent the target group for investigation of more aggressive therapies such as intracranial angioplasty.\n\n\nMETHODS\nThe authors performed a chart review and telephone interview of patients with symptomatic intracranial atherosclerosis identified in the Stanford Stroke Center clinical database. A Cox regression model was created to identify factors predictive of failure of antithrombotic therapy. The authors generated Kaplan-Meier survival curves to determine the timing of recurrent TIA, stroke, or death after failure of antithrombotic therapy.\n\n\nRESULTS\nFifty-two patients had symptomatic intracranial atherosclerosis and fulfilled entry criteria. Twenty-nine of the 52 patients (55.8%) had cerebral ischemic events while receiving an antithrombotic agent (antiplatelet agents [55%], warfarin [31%], or heparin [14%]). In a Cox regression model, older age was an independent predictor of failure of antithrombotic therapy, and warfarin use was associated with a decrease in risk. Recurrent TIA (n = 7), nonfatal/fatal stroke (n = 6/1), or death (n = 1) occurred in 15 of 29 (51.7%) of the patients who failed antithrombotic therapy. The median time to recurrent TIA, stroke, or death was 36 days (95% CI 13 to 59).\n\n\nCONCLUSIONS\nPatients with symptomatic intracranial atherosclerosis who fail antithrombotic therapy have extremely high rates of recurrent TIA/stroke or death. Recurrent ischemic events typically occur within a few months after failure of standard medical therapy. The high recurrence risk observed warrants testing of alternative treatment strategies such as intracranial angioplasty.",
"affiliations": "Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University Medical Center, Palo Alto, CA 94304-0117, USA. vthijs@stanford.edu",
"authors": "Thijs|V N|VN|;Albers|G W|GW|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D006493:Heparin; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.55.4.490",
"fulltext": null,
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"issn_linking": "0028-3878",
"issue": "55(4)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001241:Aspirin; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006493:Heparin; D006801:Humans; D002537:Intracranial Arteriosclerosis; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D016016:Proportional Hazards Models; D012008:Recurrence; D018570:Risk Assessment; D020521:Stroke; D016019:Survival Analysis; D015996:Survival Rate; D017211:Treatment Failure; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "490-7",
"pmc": null,
"pmid": "10953179",
"pubdate": "2000-08-22",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy.",
"title_normalized": "symptomatic intracranial atherosclerosis outcome of patients who fail antithrombotic therapy"
} | [
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"companynumb": "US-PFIZER INC-2020395361",
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"activesubstancename": "HEPARIN SODIUM"
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{
"abstract": "A patient taking oral risperidone while using cocaine and alcohol presented with priapism shortly after long-acting, injectable risperidone was prescribed. Another case of priapism was diagnosed in a sickle cell disease patient who was on oral risperidone. A penectomy due to necrosis was required in the first case, while the other patient regained erectile function. Physicians should be aware of priapism-inducing/predisposing factors, such as sickle cell disease, certain medicines or drugs of abuse, and antipsychotic medications. Risperidone is an established cause of priapism. It occurs especially in males with sickle cell disease; use of antipsychotic drugs and/or cocaine further increases risk.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA.",
"authors": "Koirala|Sharad|S|;Penagaluri|Praveen|P|;Smith|Carolyn|C|;Lippmann|Steven|S|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1097/SMJ.0b013e3181c04775",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "102(12)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000293:Adolescent; D000437:Alcoholism; D000755:Anemia, Sickle Cell; D014150:Antipsychotic Agents; D019970:Cocaine-Related Disorders; D006801:Humans; D008297:Male; D008875:Middle Aged; D011317:Priapism; D011618:Psychotic Disorders; D012307:Risk Factors; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "1266-8",
"pmc": null,
"pmid": "20016438",
"pubdate": "2009-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Priapism and risperidone.",
"title_normalized": "priapism and risperidone"
} | [
{
"companynumb": "US-JNJFOC-20130803381",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "Non-tuberculous mycobacteria (NTM) are a group of environmental pathogens, which cause a broad spectrum of disease. The incidence of NTM infection is increasing, especially in immunocompromized patients. The past three decades also saw a rapid increase in the incidence of NTM infection involving otherwise healthy subjects. We report a case of cutaneous NTM infection in a 79-year-old Chinese woman, who was receiving methotrexate for psoriasis. Mycobacterial culture grew Mycobacterium abscessus, and the lesions cleared with a combination of oral clarithromycin, ciprofloxacin and doxycycline. Interestingly, she then developed a second episode of cutaneous NTM infection with Mycobacterium haemophilum over the same body region, five years after stoppage of methotrexate. Both episodes were separated in time and involved different species, indicating that they were independent from each other. We further discuss the risk factors for cutaneous NTM infection, treatment, and highlight the need for diagnostic vigilance.",
"affiliations": "Department of Dermatology, National Skin Centre , Singapore.;Department of Dermatology, National Skin Centre , Singapore.;Department of Dermatology, National University Hospital , Singapore.;Department of Dermatology, National Skin Centre , Singapore.",
"authors": "Chan|Wai Sze Agnes|WS|;Tee|Shang-Ian|SI|;Chandran|Nisha Su Yien|NS|;Pan|Jiun Yit|JY|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/dr.2015.5712",
"fulltext": "\n==== Front\nDermatol ReportsDermatol ReportsDRDermatology Reports2036-73922036-7406PAGEPress Publications, Pavia, Italy 10.4081/dr.2015.5712Case ReportTwo Episodes of Cutaneous Non-Tuberculous Mycobacterial Infection in a Patient with Psoriasis Chan Wai Sze Agnes 1Tee Shang-Ian 1Chandran Nisha Su Yien 2Pan Jiun Yit 11 Department of Dermatology, National Skin Centre, Singapore2 Department of Dermatology, National University Hospital, SingaporeDepartment of Dermatology, National Skin Centre, 1 Mandalay Road, 308205 Singapore. +65.9364.7239 - +65.6352.3225. agneschan@nsc.gov.sgContributions: the authors contributed equally\n\nConflict of interest: the authors declare no potential conflict of interest\n\n15 6 2015 21 5 2015 7 2 571210 11 2014 30 3 2015 26 4 2015 ©Copyright W.S.A. Chan et al.2015Licensee PAGEPress, ItalyThis 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 non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Non-tuberculous mycobacteria (NTM) are a group of environmental pathogens, which cause a broad spectrum of disease. The incidence of NTM infection is increasing, especially in immunocompromized patients. The past three decades also saw a rapid increase in the incidence of NTM infection involving otherwise healthy subjects. We report a case of cutaneous NTM infection in a 79-year-old Chinese woman, who was receiving methotrexate for psoriasis. Mycobacterial culture grew Mycobacterium abscessus, and the lesions cleared with a combination of oral clarithromycin, ciprofloxacin and doxycycline. Interestingly, she then developed a second episode of cutaneous NTM infection with Mycobacterium haemophilum over the same body region, five years after stoppage of methotrexate. Both episodes were separated in time and involved different species, indicating that they were independent from each other. We further discuss the risk factors for cutaneous NTM infection, treatment, and highlight the need for diagnostic vigilance.\n\nKey words\nMycobacterium abscessusMycobacterium hemophilumcutaneousnon tuberculous mycobacteriapsoriasis\n==== Body\nCase Report\nA 79-year-old Chinese female has been on follow-up at a specialist dermatological center in Singapore for psoriasis vulgaris. Following a pustular flare in October 2004, she was commenced on oral methotrexate (MTX) 2.5-7.5 mg weekly. A year later after having consumed a cumulative MTX dose of 390 mg, she noted the appearance of a new rash on the right antecubital fossa. She did not recall any preceding trauma at that region, including acupuncture or tattoos. Physical examination showed a 17×10 cm erythematous coalescent ulcerated plaque studded with pustules. She was treated initially as for irritant contact dermatitis and erysipelas; however, there was no improvement despite six months of therapy with topical steroids and beta-lactam antibiotics. A skin biopsy was then performed, which revealed a suppurative granulomatous infiltrate consisting of neutrophils, histiocytes and Langhans giant cells within the dermis (Figure 1). Acid-fast bacilli were not demonstrated on Ziehl-Neelsen stain; however tissue culture was positive for non-tuberculous mycobacteria (NTM), which was identified as Mycobacterium abscessus on polymerase chain reaction (PCR). MTX was stopped and she was prescribed a combination of oral clarithromycin 500 mg, ciprofloxacin 500 mg and doxycycline 100 mg twice daily for six months with complete resolution of the lesion.\n\nThere were no further infective episodes until August 2011, when she presented with another erythematous papulopustular rash over her right forearm and elbow (Figure 2). She had not received systemic immunosuppressive therapy in the past five years and she did not report any local trauma. There were no findings on history and physical examination to suggest an underlying immunodeficiency disorder. Laboratory tests including fasting blood glucose levels and HIV serology were normal, while total white cell count and differentials were within normal limits. Skin biopsy revealed a dermal granulomatous dermatitis (Figure 3). Tissue culture confirmed the presence of NTM, identified as Mycobacterium haemophilum on PCR. She was treated with clarithromycin 500 mg and ciprofloxacin 500mg twice daily with complete clearance of the lesion after ten months. She remains well on her last follow-up visit with us.\n\nDiscussion\nNon-tuberculous mycobacteria are free living, fastidious aerobic acid fast bacilli organisms widely distributed in the environment. Six clinical syndromes account for most infections caused by NTM including pulmonary disease, lymphadenitis, skin or soft tissue infections, skeletal (bone, joint, tendon), foreign body and central venous catheter infection, and disseminated diseases.1 Infection is more common in patients who are immunocompromized. Runyon identified and divided NTM into slow growing groups, basing on their ability to produce pigment, and rapidly growing groups (RGM) such as M. abcessus, M. fortuitum, and M. chelonae.2 The most common NTM species to cause cutaneous disease are M. marinum and RGM.3\n\nRecent epidemiological studies have confirmed that the incidence of cutaneous NTM infection is increasing worldwide, highlighting the importance of recognizing this entity.4,3 The rising incidence has been attributed to improved diagnostic techniques as well as the popularity of cosmetic and medical procedures, which carry a risk of contamination. Cutaneous infection presents with myriad clinical signs ranging from erythematous plaques, papules or pustules to subcutaneous nodules, abscesses and ulcers. Direct inoculation via penetrating injury is an important route of infection,4 and most cases involve the extremities. Unfortunately a history of antecedent trauma is not always elicited or may be missed, especially given the long incubation period of certain organisms (up to 12 months for M. abscessus).5 This was the case of our patient, whose disease was picked up on skin biopsy only after six months of empirical treatment. AFB staining has a low yield of 36.2%,2 and identification of NTM species may require PCR testing. Indeed, misdiagnosis occurs in up to 82% of cases,6 emphasizing the need for a high index of suspicion, requesting for mycobacterial culture, and repeating biopsies in clinical scenarios where a patient may be at risk.\n\nImmunosuppression is an important risk factor for NTM infection and is likely to have contributed to our patient’s initial episode, having occurred after 14 months of therapy with MTX. Although her cumulative dose was only 390 mg, it has been noted that even low doses of MTX may induce B cell suppression and inhibit differentiation, leading to susceptibility to infection.7 Opportunistic infections such as Pneumocystis carinii pneumonia, Mycobacterium avium-intracellulare pneumonia and disseminated histoplasmosis have been reported after MTX therapy as short as 11 weeks to 17 years duration.8 In immunocompromized hosts, cutaneous NTM infection presents more frequently, sometimes without associated inciting skin injury, and often involving multiple sites and/or deeper tissues. Our patient was infected with a second episode of cutaneous NTM with a different species with M. Haemophilum; hence the two episodes are distinct and not due to re-activation of latent infection. An inciting factor for the second episode is less obvious given the absence of trauma or drug-induced immunosuppression. Moreover, patients with psoriasis usually do not carry an increased risk of skin infection, due to up-regulation of antimicrobial peptides and cathelicidins, compared to patients with eczema or those with normal skin.9 An underlying immunodeficiency syndrome, previously reported in other families susceptible to mycobacteria,10,11 seems unlikely in our patient given the absence of other recurrent infections to suggest defects in her cellular immune response. We instead postulate that her advanced age, along with the presence of dry and fissured psoriatic plaques, has led to skin barrier problems causing an increase in skin fragility, thereby compromising the innate immunity of skin and facilitating entry of mycobacteria with consequent infection.\n\nThe importance of diagnostic vigilance is crucial, as a delay of up to 7.1 months from initial clinical presentation to commencement of treatment has been reported.6 The choice of antimicrobial treatment depends on species identification and the outcome of susceptibility testing. Most studies recommend clarithromycin alone or in combination with fluoroquinolones or tetracyclines for 4 to 6 months to treat rapid-growing mycobacteria such as M. abscessus, with a curative rate of 87%.12\nM. Haemophilum is resistant to isoniazid and ethambutol in vitro, and experts recommend a combination of clarithromycin, ciprofloxacin and a rifamycin antibiotic. Optimal duration of therapy is not known, and common recommendation is to continue treatment for 4 to 6 weeks upon resolution of cutaneous lesion.4,13 Immunocompromized patients have cutaneous lesions which lasts several months longer than immunocompetent patients and are at higher risk of complications such as deep tissue infections;14 duration of treatment should therefore be longer with evaluation for surgical intervention including incision and drainage.\n\nConclusions\nNon tuberculous mycobacterium organisms are widespread in the environment, and exposure is common. We have encountered a patient with psoriasis who was treated for two separate episodes of cutaneous NTM infection; first while she was receiving immunosuppressive therapy, and second, much later on, when she was apparently healthy with no known predisposing factors, with M. abscessus and M. Haemophilum respectively.\n\nWe propose that she was susceptible to cutaneous NTM infection due to advanced age and defective skin barrier, leading to implantation of NTM organism to the skin. Immunosuppressive therapy was an additional risk factor in the first episode. With the rise in incidence of cutaneous NTM infection, physicians must have a high index of suspicion, especially in patients with non-resolving lesions of the upper distal extremities with a history of antecedent trauma, including acupuncture or medical procedures.\n\nFigure 1. This is composed of suppurative granulomas containing aggregates of neutrophils surrounded by histiocytes and lymphocytes (Hematoxylin and Eosin, 200×).\n\nFigure 2. Erythematous papulopustular plaque at flexor surface of the right forearm.\n\nFigure 3. Higher power reveals an infiltrate of histiocytes admixed with Langhans-type giant cells and surrounded by numerous lymphocytes, plasma cells and neutrophils (Hematoxylin and Eosin, 100×).\n==== Refs\nReferences\n1. No authors listed. Diagnosis and treatment of disease caused by nontuberculous mycobacteria: this official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association . Am J Respir Crit Care Med \n1997 ;156 :S1 -25 .9279284 \n2. Runyon EH \nAnonymous mycobacteria in pulmonary disease . Med Clin North Am \n1959 ;43 :273 -304 .13612432 \n3. Hsiao CH Tsai TF Hsueh PR \nCharacteristics of skin and soft tissue infection caused by non-tuberculous mycobacteria in Taiwan . Int J Tuberc Lung Dis \n2011 ;15 :811 -7 .21575304 \n4. Wentworth AB Drage LA Wengnack NL \nIncreased incidence of cutaneous nontubeculous mycobacterial infection, 1980 to 2009: a population- based study . Mayo Clin Proc \n2013 ;88 :38 -45 .23218797 \n5. Fitzgerald DA Smith AG Lees A \nCutaneous infection with mycobacterium abscessus . Br J Dermatol \n1995 ;132 :800 -4 .7772489 \n6. Dodiuk-Gad R Dyachenko P Ziv M \nNontuberculous mycobacterial infections of the skin: a retrospective study of 25 cases . J Am Acad Dermatol \n2007 ;57 :413 -20 .17368631 \n7. Olsen NJ Callahan LF Pincus T. \nImmunologic studies of rheumatoid arthritis patients treated with methotrexate . Arthritis Rheum \n1987 ;30 :481 -8 .3593431 \n8. LeMense GP Sahn SA \nOpportunistic infection during treatment with low dose methotrexate . Am J Respir Crit Care Med \n1994 ;150 :258 -60 .8025760 \n9. Morizane S Gallo RL \nAntimicrobial peptides in the pathogenesis of psoriasis . J Dermatol \n2012 ;39 :225 -30 .22352846 \n10. Newport MJ Huxley CM Huston S \nA mutation in the interferon gamma receptor gene and susceptibility to mycobacterial infection . N Engl J Med \n1996 ;335 :1941 -9 .8960473 \n11. Chetchotisakd P Mootsikapun P Anunnatisiri S \nDisseminated infection due to rapidly growing mycobacteria in immunocompetent hosts presenting with chronic lymphadenopathy: a previous unrecognized clinical entity . Clin Infect Dis \n2000 ;30 :29 -34 .10619729 \n12. Kothavade RJ Dhurat RS Mishra SN \nClinical and laboratory aspects of the diagnosis and management of cutaneous and subcutaneous infections caused by rapidly growing mycobacteria . Eur J Clin Microbiol Infect Dis \n2013 ;32 :161 -88 .23139042 \n13. Wagner D Young LS \nNontuberculous mycobacterial infections: a clinical review . Infection \n2004 ;32 :257 -70 .15624889 \n14. Lee WJ Kang SM Sung H \nNontuberculous mycobacterial infections of the skin: a retrospective study of 29 cases . J Dermatol \n2010 ;37 :965 -72 .21039785\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7392",
"issue": "7(2)",
"journal": "Dermatology reports",
"keywords": "Mycobacterium abscessus; Mycobacterium hemophilum; cutaneous; non tuberculous mycobacteria; psoriasis",
"medline_ta": "Dermatol Reports",
"mesh_terms": null,
"nlm_unique_id": "101566470",
"other_id": null,
"pages": "5712",
"pmc": null,
"pmid": "26236445",
"pubdate": "2015-05-21",
"publication_types": "D002363:Case Reports",
"references": "23218797;23139042;10619729;22352846;17368631;13612432;15624889;21575304;9279284;8025760;3593431;8960473;21039785;7772489",
"title": "Two Episodes of Cutaneous Non-Tuberculous Mycobacterial Infection in a Patient with Psoriasis.",
"title_normalized": "two episodes of cutaneous non tuberculous mycobacterial infection in a patient with psoriasis"
} | [
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"companynumb": "SG-ANTARES PHARMA, INC.-2015-LIT-ME-0096",
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"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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{
"abstract": "Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.",
"affiliations": "Department of Pediatric Metabolism and Nutrition, Diyarbakır Children's Hospital, Diyarbakır, Turkey.;Department of Pediatrics, Diyarbakır Children's Hospital, Diyarbakır, Turkey.;Department of Pediatrics, Diyarbakır Children's Hospital, Diyarbakır, Turkey.;Department of Pediatric Neurology, Diyarbakır Children's Hospital, Diyarbakır, Turkey.;Department of Pediatrics, Diyarbakır Children's Hospital, Diyarbakır, Turkey.;Department of Pediatric Endocrinology, Diyarbakır Children's Hospital, Diyarbakır, Turkey.",
"authors": "Kasapkara|Ciğdem Seher|CS|;Kanğın|Murat|M|;Taş|Funda Feryal|FF|;Topçu|Yasemin|Y|;Demir|Remezan|R|;Ozbek|Mehmet Nuri|MN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1817-1745.123697",
"fulltext": "\n==== Front\nJ Pediatr NeurosciJ Pediatr NeurosciJPNJournal of Pediatric Neurosciences1817-17451998-3948Medknow Publications & Media Pvt Ltd India JPN-8-25010.4103/1817-1745.123697Case ReportUnusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid Kasapkara Çiğdem Seher Kanğın Murat 1Taş Funda Feryal 1Topçu Yasemin 2Demir Remezan 1Özbek Mehmet Nuri 3Department of Pediatric Metabolism and Nutrition, Diyarbakır Children's Hospital, Diyarbakır, Turkey1 Department of Pediatrics, Diyarbakır Children's Hospital, Diyarbakır, Turkey2 Department of Pediatric Neurology, Diyarbakır Children's Hospital, Diyarbakır, Turkey3 Department of Pediatric Endocrinology, Diyarbakır Children's Hospital, Diyarbakır, TurkeyAddress for correspondence: Dr. Çiğdem Seher Kasapkara, Department of Pediatric Metabolism and Nutrition, Diyarbakır Children's Hospital, Diyarbakır, Turkey. E-mail: cskasapkara@gmail.comSep-Dec 2013 8 3 250 252 Copyright: © Journal of Pediatric Neurosciences2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.\n\nCarglumic acidvalproate-induced hyperammonemiavalproate therapy\n==== Body\nIntroduction\nValproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, and partial seizures and psychiatric disorders. Although usually well-tolerated, VPA is known to be associated with idiosyncratic side effects.[1] Valproate-induced hyperammonemia without evidence of hepatotoxicity is an important idiosyncratic side effect and 16-52% of patients receiving VPA treatment may have mild elevations in ammonia.[2] Hyperammonemia can occur in patients receiving usual VPA dosages for short- and long-term treatment and can be successfully treated by single dose of carglumic acid. The mechanism by which valproate induces hyperammonemia remains incompletely understood, but is likely to relate to the urea cycle.[3] We present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.\n\nCase Report\nCase 1\nA 15-year-old male with a 1-month history of epilepsy, headache, and hemiparesis was admitted to the pediatric intensive care unit with altered mental status. The child was managed conservatively along with intravenous antibiotics and was started on intravenous valproate at a dosage of 33 mg/kg and levetiracetam 44 mg/kg was added for breakthrough seizures. He was intubated because of impaired consciousness with increasing confusion and lethargy and increased seizure frequency. The alteration of consciousness was subsequent to the administration of valproate and not due to a progression of the disease. A metabolic encephalopathy was suspected. Laboratory investigations revealed hyperammonemia 283 μg/dl 6 days after initiating valproic acid (VPA) and no signs of hepatotoxicity. There was no family history of any genetic-metabolic disorder. The valproate was ceased and a single dose of carglumic acid 100 mg/kg per day was administered through a nasogastric tube, followed by a rapid improvement in the patient's mental state and a return of the ammonia level to the normal range (50 μg/dl). Blood ammonia remained normal thereafter.\n\nCase 2\nA 17-months-old male has a history of mental and motor retardation, microcephaly, and epilepsy. He was admitted to the intensive care unit with seizure and respiratory depression. Supportive care in the form of mechanical ventilation, hydration, and antibiotics were administered. His medications included valproate (50 mg/kg/day po) and phenobarbital (5 mg/kg/day) for the last 1 year. An electroencephalography revealed hypsarrhythmia. Magnetic resonance imaging showed schizencephaly. He was consulted to department of pediatric metabolism due to diagnostic confusion with nonketotic hyperglycinemia. His metabolic tests were normal including tandem mass spectrometry and urine organic acid analysis. His serum ammonia level was 189 μg/dl. His liver function test results including aspartate aminotransferase and alanine aminotransferase were within normal limits. After discontinuation of VPA and initiation of carglumic acid 100 mg/kg by nasogastric route, his serum ammonia concentration decreased to 69 μg/dl within 12 h. His neurologic status improved within a day.\n\nDiscussion\nHyperammonemia is most commonly caused by liver disease or inborn errors of metabolism. Less common causes include medications like 5-fluorouracil, salicylate, asparaginase, acetazolamide, diuretics, and VPA.[456]\n\nValproate is partly metabolized in the liver by oxidation which produces active metabolites. Significant contribution to hyperammonemia caused by valproate probably results from the reduction of hepatic levels of N-acetylglutamate, a positive allosteric modulator of carbamoyl phosphate synthetase-1 which catalyzes the first step in urea biosynthesis. VPA interferes with this process through direct inhibition of carbamoylphosphate synthetase and indirectly by depleting carnitine.[3] Valproate binds to carnitine preventing transportation and beta oxidation of long chain fatty acids, which in turn leads to increased oxidation of amino acids resulting in elevated serum ammonia level.\n\nThe management of valproate related hyperammonemia is generally supportive, with discontinuation of therapy, supplementation with N-carbamylglutamate, L-carnitine, and frequent monitoring. N-carbamylglutamate is a structural analog of N-acetylglutamate, licensed as an orphan drug for the treatment of hyperammonemia due to N-acetylglutamate synthetase (NAGS) deficiency. Carnitine supplementation tends to normalize elevated plasma ammonia concentrations by binding to VPA and relieving the inhibition of urea synthesis.[78]\n\nComedications with other antiepileptic drugs including phenytoin, phenobarbital, and topiramate increase the risk of valproate related hyperammonemia. Concomitant use of valproate with phenobarbital predisposed to hyperammonemia in the second case we presented. Combination therapy with valproate and levatiracetam can increase vulnerability to hyperammonemia at the initiation of treatment or at high doses and intravenous usage of both drugs. Avoidance of polypharmacy can prevent drug interactions potentially leading to the development of valproate-induced hyperammonemia.[910] According to previous literature, valproate-induced hyperammonemia has been reported to occur almost equally in both genders. Valproate-induced hyperammonemia was noted in two patients with the same gender in this report. There does not seem to be any relationship between the development of valproate-induced hyperammonemia and serum valproate levels.[11]\n\nValproate-induced hyperammonemia can be acute or subacute with progression of lethargy to coma and death. Valproate-induced hyperammonemia typically occurs in the presence of normal liver functions.[12] In case of a patient presenting with encephalopathy, regardless of the duration of therapy, the diagnosis of valproate-induced hyperammonemia should be suspected in any patient on valproate therapy, ammonia levels should be checked, and valproate should be discontinued. Rapid diagnosis and management will help in reducing valproate-induced hyperammonemia-related potentially life-threatening complications.[13]\n\nValproate-induced hyperammonemia can occur in patients receiving usual VPA dosages for short- or long-term treatment, but data on the use of carglumic acid in these patients are limited. In conclusion, this experience suggests that carglumic acid could be considered for the treatment of valproate-induced hyperammonemia. The patients reported here showed a dramatic fall in plasma ammonia concentrations with a single dose of carglumic acid (100 mg/kg). Of course, trials with more patients are needed in order to demonstrate its usefulness.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Blackford MG Do ST Enlow TC Reed MD Valproic Acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine J Pediatr Pharmacol Ther 2013 18 128 36 23798907 \n2 Chan E McQueen F Valproate-induced hyperammonaemia superimposed upon severe neuropsychiatric lupus: A case report and review of the literature Clin Rheumatol 2013 32 403 7 23271612 \n3 Gramage Caro T Vélez-Díaz-Pallarés M Serna Pérez J Bermejo Vicedo T Carglumic acid for treatment of valproic acid-induced hyperammonaemia in a paediatric patient] Farm Hosp 2012 36 437 8 22858088 \n4 Hong L Schutz J Nance M A case of valproate-induced encephalopathy Aust N Z J Psychiatry 2012 46 1200 1 22619383 \n5 Lewis C Deshpande A Tesar GE Dale R Valproate-induced hyperammonemic encephalopathy: A brief review Curr Med Res Opin 2012 28 1039 42 22587482 \n6 Chopra A Kolla BP Mansukhani MP Netzel P Frye MA Valproate-induced hyperammonemic encephalopathy: An update on risk factors, clinical correlates and management Gen Hosp Psychiatry 2012 34 290 8 22305367 \n7 Mock CM Schwetschenau KH Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy Am J Health Syst Pharm 2012 69 35 9 22180549 \n8 Garg R Sunder RA Valproate-induced hyperammonemia and seizures: Perioperative concerns Paediatr Anaesth 2011 21 1084 5 21981101 \n9 Prins MC van Meijel JJ A case of hyperammonaemic encephalopathy due to valproic acid Neth J Med 2011 69 389 91 21978982 \n10 Gomez-Ibañez A Urrestarazu-Bolumburu E Viteri-Torres C Hyperammonemic encephalopathy related to valproate, phenobarbital, and topiramate synergism Epilepsy Behav 2011 21 480 2 21700501 \n11 Khoo CL Naik S Lua R Chai SB Liew A Sim K Valproate-induced hyperammonemia in mental retardation: A case report and review of the literature Prog Neuropsychopharmacol Biol Psychiatry 2010 34 561 2 20184937 \n12 Deutsch SI Burket JA Rosse RB Valproate-induced hyperammonemic encephalopathy and normal liver functions: Possible synergism with topiramate Clin Neuropharmacol 2009 32 350 2 19952878 \n13 Adams EN Marks A Lizer MH Carbamazepine-induced hyperammonemia Am J Health Syst Pharm 2009 66 1468 70 19667003\n\n",
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"issue": "8(3)",
"journal": "Journal of pediatric neurosciences",
"keywords": "Carglumic acid; valproate therapy; valproate-induced hyperammonemia",
"medline_ta": "J Pediatr Neurosci",
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"nlm_unique_id": "101273794",
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"pages": "250-2",
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"pmid": "24470826",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports",
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"title": "Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid.",
"title_normalized": "unusual cause of hyperammonemia in two cases with short term and long term valproate therapy successfully treated by single dose carglumic acid"
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"abstract": "The diagnosis and treatment of antibody-mediated rejection (AMR) after lung transplantation has recently gained recognition within the transplant community. Extracorporeal photopheresis (ECP), currently used to treat chronic lung allograft dysfunction, modulates various pathways of the immune system known to be involved in AMR. We hypothesize that adding ECP to established AMR treatments could prevent the rebound of donor-specific antibodies (DSA).\nThis study aimed to analyze the role of ECP as an add-on therapy to prevent the rebound of DSA.\nLung transplant recipients who received ECP as an add-on therapy for pulmonary AMR between January 2010 and January 2019 were included in this single-center retrospective analysis. Baseline demographics of the patients, as well as their immunological characteristics and long-term transplant outcomes, were analyzed.\nA total of 41 patients developed clinical AMR during the study period. Sixteen patients received ECP as an add-on therapy after first-line AMR treatment. Among the 16 patients, 2 (13%) had pretransplant DSA, both against human leukocyte antigen (HLA) class I (B38, B13, and C06). Fifteen patients (94%) developed de novo DSA (dnDSA), i.e., 10 (63%) against class I and 14 (88%) against class II. The median time to dnDSA after lung transplantation was 361 days (range 25-2,548). According to the most recent International Society of Heart and Lung Transplantation (ISHLT) consensus report, 2 (13%) patients had definite clinical AMR, 6 (38%) had probable AMR, and 7 (44%) had possible AMR. The median mean fluorescence intensity (MFI) of dnDSA at the time of clinical diagnosis was 4,220 (range 1,319-10,552) for anti-HLA class I and 10,953 (range 1,969-27,501) for anti-HLA class II antibodies. ECP was performed for a median of 14 cycles (range 1-64). MFI values of dnDSA against HLA classes I and II were significantly reduced over the treatment period (for anti-class I: 752; range 70-2,066; for anti-class II: 5,612; range 1,689-21,858). The 1-year survival rate was 55%. No adverse events related to ECP were reported in any of the patients.\nECP is associated with a reduction of dnDSA in lung transplant recipients affected by AMR. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of AMR.",
"affiliations": "Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Department of Dermatology, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.;Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Department of Dermatology, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.;Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.",
"authors": "Benazzo|Alberto|A|;Worel|Nina|N|;Schwarz|Stefan|S|;Just|Ulrike|U|;Nechay|Anna|A|;Lambers|Christoph|C|;Böhmig|Georg|G|;Fischer|Gottfried|G|;Koren|Daniela|D|;Muraközy|Gabriela|G|;Knobler|Robert|R|;Klepetko|Walter|W|;Hoetzenecker|Konrad|K|;Jaksch|Peter|P|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000508170",
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"issn_linking": "1660-3796",
"issue": "47(3)",
"journal": "Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie",
"keywords": "Antibody-mediated rejection; Extracorporeal photopheresis; Lung transplantation",
"medline_ta": "Transfus Med Hemother",
"mesh_terms": null,
"nlm_unique_id": "101176417",
"other_id": null,
"pages": "205-213",
"pmc": null,
"pmid": "32595425",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "18096473;27044531;22910399;22622504;23522237;19843031;15636621;24041981;23260706;25130554;20558084;19134538;1498142;9521198;9301537;24906794;15879089;10770423;23220148;23953920;17109725;31932054;29537702;17391128;23142561;29653665;22202499;15203130;23260701;16925566;25447575;23426730;12494410;16619230;12364858;28173620",
"title": "Outcome of Extracorporeal Photopheresis as an Add-On Therapy for Antibody-Mediated Rejection in Lung Transplant Recipients.",
"title_normalized": "outcome of extracorporeal photopheresis as an add on therapy for antibody mediated rejection in lung transplant recipients"
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"abstract": "BACKGROUND\nTumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity.\n\n\nMETHODS\nmCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance.\n\n\nRESULTS\nAmong 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases.\n\n\nCONCLUSIONS\nPL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.",
"affiliations": "Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Interventional Radiology Unit, Department of Diagnostic Imaging and Interventional Radiology, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Department, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy.;BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy.;BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy.;Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.;Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy.",
"authors": "Formica|Vincenzo|V|0000-0002-5380-3144;Lucchetti|Jessica|J|0000-0002-0262-535X;Doldo|Elena|E|;Riondino|Silvia|S|;Morelli|Cristina|C|;Argirò|Renato|R|0000-0002-2878-4658;Renzi|Nicola|N|;Nitti|Daniele|D|;Nardecchia|Antonella|A|;Dell'Aquila|Emanuela|E|;Ferroni|Patrizia|P|0000-0002-9877-8712;Guadagni|Fiorella|F|;Palmieri|Giampiero|G|;Orlandi|Augusto|A|0000-0001-7202-5854;Roselli|Mario|M|",
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"doi": "10.3390/jcm10010087",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383 MDPI \n\n33383664\n10.3390/jcm10010087\njcm-10-00087\nArticle\nClinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients—The Importance of Tissue/Plasma Discordant Cases\nhttps://orcid.org/0000-0002-5380-3144Formica Vincenzo 1* https://orcid.org/0000-0002-0262-535XLucchetti Jessica 1 Doldo Elena 2 Riondino Silvia 1 Morelli Cristina 1 https://orcid.org/0000-0002-2878-4658Argirò Renato 3 Renzi Nicola 1 Nitti Daniele 1 Nardecchia Antonella 1 Dell’Aquila Emanuela 4 https://orcid.org/0000-0002-9877-8712Ferroni Patrizia 56 Guadagni Fiorella 56 Palmieri Giampiero 2 https://orcid.org/0000-0001-7202-5854Orlandi Augusto 2 Roselli Mario 1 1 Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy; jess.lucchetti@gmail.com (J.L.); silviariondino2@gmail.com (S.R.); cristina.morelli89@gmail.com (C.M.); nicola.renzi86@gmail.com (N.R.); dottdanielenitti@gmail.com (D.N.); antonella.nardecchia@gmail.com (A.N.); mario.roselli@uniroma2.it (M.R.)\n2 Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy; elenadoldo.ed@gmail.com (E.D.); giampiero.palmieri@uniroma2.it (G.P.); orlandi@uniroma2.it (A.O.)\n3 Interventional Radiology Unit, Department of Diagnostic Imaging and Interventional Radiology, Tor Vergata University Hospital, Viale Oxford 81, 00133 Rome, Italy; renato.argiro@gmail.com\n4 Medical Oncology Department, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy; e.dellaquila@unicampus.it\n5 BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy; patrizia.ferroni@sanraffaele.it (P.F.); fiorella.guadagni@sanraffaele.it (F.G.)\n6 Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy\n* Correspondence: v.formica1@gmail.com; Tel.: +39-0620908190\n29 12 2020 \n1 2021 \n10 1 8726 11 2020 25 12 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.\n\nmetastatic colorectal cancerctDNAliquid biopsy\n==== Body\n1. Introduction\nSince 1948, when cell-free nucleic acids were first detected in human plasma [1], the interest in the molecular characteristics of the plasma cell-free DNA of cancer patients has increasingly grown in the scientific community.\n\nCell-free DNA is fragmented DNA found in the compartment of non-cellular molecules of the blood. In cancer patients, circulating tumor DNA (ctDNA) is released by cancer cells into the bloodstream and represents a very small fraction of the total cell-free DNA (<1%). ctDNA retains epigenetic characteristics and tumor-specific mutations of the original cancer cells and can be thus assessed in the peripheral blood, also longitudinally for patient management over time [2]. Recent studies have suggested that ctDNA can originate from multiple sources: (1) apoptotic or necrotic tumor cells from the primary tumor; (2) live tumor cells from the primary tumor; and (3) circulating metastatic tumor cells [3,4,5].\n\nctDNA is an ideal diagnostic tool at many time-points (pre-disease screening, early diagnosis, minimal residual disease detection after primary surgery, early recurrence diagnosis and drug resistance monitoring in the metastatic setting). \n\nTumor tissue analysis remains the gold standard for cancer genotyping; however, this diagnostic procedure is often difficult to perform with inherent risk of biopsy complications, especially in relapsed and metastatic patients. Furthermore, it can be expensive and difficult to organize since it might require hospitalization resulting in significant use of healthcare resources. At times, tissue biopsy is inconclusive because of insufficient material for analysis or does not recapitulate intra-tumoral spatial and temporal heterogeneity, which would require invasive re-biopsies to be captured [6].\n\nMoreover, the turnaround time of tumor tissue analysis is usually longer than that of ctDNA analysis, making the latter more attractive also from a technical standpoint. This would be especially useful for metastatic colorectal cancer (mCRC) patients who need rapid molecular profiling in order to receive the optimal targeted agent in a timely fashion [7]. \n\nIndeed, treatment of mCRC has been enriched by the introduction of biological agents targeting angiogenesis or the epidermal growth factor receptor (EGFR) signaling, that are administered in association with standard combination chemotherapy of 5-fluroruracil plus irinotecan and/or oxaliplatin [8]. Activating mutations of KRAS/NRAS (collectively named as RAS) or BRAF genes represent a major intrinsic mechanism of resistance to anti-EGFR agents and their identification is now mandatory to decide whether to use anti-EGFR antibodies or not.\n\nIn mCRC patients treated with anti-EGFR agents, RAS alteration demonstrated in liquid biopsies anticipated the radiological disease progression by approximately 10 months [9,10]. The early discontinuation of anti-EGFR therapy in case of appearance of liquid RAS mutation allows the progressive reduction in the number of circulating mutated RAS clones with the consequent reacquisition of sensitivity to the drug [11].\n\nOn the other hand, the common BRAF V600E mutation, besides being associated with anti-EGFR agent resistance, also forecasts a remarkably poor outcome in mCRC and the use of standard chemotherapy has proven of limited efficacy in this subgroup of disease [12,13]\n\nThe degree of agreement between tissue (T) and plasma (PL) mutational status is a matter of debate. In mCRC, discordant cases might be related not only to the technology used for their evaluation, but also to the patients’ features such as presence or absence of liver or lung metastases, circulating mutational fraction (defined as the fraction of mutant DNA over total cell free DNA), or tumor marker levels [14]. García-Foncillas et al. demonstrated a discordance rate of 8% between PL and T analysis in 236 mCRC patients and the discordance was higher in patients with lung metastasis [15]. Further analyses demonstrated that the maximum lesion diameter and the number of lesions have an impact on the discordance rate [16].\n\nIn the present prospective study, we assessed the clinical utility of PL liquid biopsy for KRAS, NRAS and BRAF mutation testing in mCRC using qualitative Real Time PCR (Easy PGX), in consecutive patients with known T mutational status prior to starting a standard first-line chemotherapy. We compared T and PL mutation profile and evaluated whether liquid biopsy might be useful to further stratify mCRC patient prognosis and treatment response. As RAS/BRAF mutations are both predictive and prognostic in mCRC patients treated with optimal first-line therapy [17,18], progression free survival (PFS) was chosen as a surrogate for the assessment of test usefulness. Furthermore, we investigated possible predictors of discordance between T and PL results.\n\n2. Experimental Section\n2.1. Materials and Methods\n2.1.1. Patients\nBetween September 2018 and February 2020, consecutive mCRC patients referred to the Medical Oncology Unit of Tor Vergata University Hospital (Rome, Italy), were enrolled. Inclusion criteria were age ≥18, histo-pathologically verified adenocarcinoma, and measurable metastatic disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 not amenable to radical surgery [19]. Microsatellite instability (MSI) represented an exclusion criterion. Moreover, since the radiological tumor burden was important for the scope of the present research (see below), patients with non-measurable lesions were not eligible for the study.\n\nResults of tissue KRAS, NRAS and BRAF were available before the start of first-line chemotherapy. Tissue assessment on either primary tumor or metastatic site was allowed, at any moment of the disease history, either at initial diagnosis or disease relapse.\n\nPatients were treated with one of the following standard first-line regimens based on T-RAS/BRAF mutational analysis: RAS/BRAF wild type (WT) patients received panitumumab-FOLFOX (panitumumab, 6 mg/kg intravenous (IV) infusion on day 1 before FOLFOX chemotherapy regimen-oxaliplatin 85 mg/m2 IV on day 1, leucovorin, 200 mg/m2 on day 1 and 5-fluorouracil 400 mg/m2 IV bolus followed by 1200 mg/m2 IV infusion over 22 h on days 1 and 2, every 14 days); mutated patients received bevacizumab-FOLFOX (bevacizumab 5 mg/kg IV on day 1 and FOLFOX chemotherapy regimen -oxaliplatin 85 mg/m2 intravenous (IV) infusion on day 1, leucovorin, 200 mg/m2 on day 1 and 5-fluorouracil 400 mg/m2 IV bolus followed by 1200 mg/m2 IV infusion over 22 h on days 1 and 2, every 14 days). First-line chemotherapy was administered until disease progression, unacceptable toxicity or death, whichever came first.\n\nWhole body computed tomography (CT) with or without iodinated contrast was performed every 12 weeks for tumor assessment and progressive disease (PD) was acknowledged according to RECIST 1.1 criteria. Each CT scan was carefully reviewed by a dedicated radiologist (A.R.). For each patient, the total number of metastatic lesions (TNL) and the sum of the maximum diameter of all lesions (SMD) were calculated at baseline. Of note, TNL refers to all separate lesions identified as tumor masses, which have to be distinguished from the number of metastatic sites referring to the single organs involved.\n\nProgression-free survival (PFS) was set as the primary outcome measure and was defined as the time from chemotherapy start to PD or death from any reason. Participants who were alive but did not meet criteria for progression by the cut-off date were censored at their last evaluable disease assessment.\n\nCommon clinical variables, biochemical tests and tumor markers including carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19.9) were also recorded before treatment and every month thereafter.\n\nWritten informed consent was obtained from all patients and the study procedures were performed in accordance with the Declaration of Helsinki and adhered to the international Good Clinical Practice guidelines.\n\n2.1.2. Molecular Analysis\nCell-Free DNA Extraction and Amplification\nLiquid biopsy samples were collected within two weeks before first-line chemotherapy start. For cell free-DNA (cfDNA) extraction, 3 Ethylenediaminetetraacetic acid (EDTA) tubes containing 3 mL whole blood were centrifuged at 4 °C for 10 min at 3000 rpm within 1 h after blood collection. The supernatant was then transferred into 2 mL tubes, re-centrifuged at 12,000 rpm for 5 min at 4 °C and used for cfDNA extraction by MagCore® Plasma DNA Extraction Kit (RBC Biosciences Corp. Taipei, Taiwan) according to manufacturer’s instructions. After extraction, cfDNA was quantified using the Qubit fluorometer ((ThermoFisher, Foster City, CA, USA), following the manufacturer’s protocol. Easy PGX Real Time PCR (DiatechPharmacogenetics Jesi, Italy) for selective mutations of KRAS and NRAS exons 2, 3 and 4 and BRAF exon 15 was performed and results analyzed using the software “Easy PGX analysis software”. The kit allowed the detection of low percentages of mutated allele in the presence of high amounts of wild-type genomic DNA by real-time amplification with sequence-specific probes marked with (5(6)-carboxyfluorescein and 6-carboxy-2′,4,4′,5′,7,7′-hexachlorofluorescein) FAM and HEX (limit of detection ranging from 0.5 to 5% depending on the mutation).\n\nTissue DNA Extraction and RAS and BRAF Mutational Status\nAn appropriate formalin-fixed paraffin-embedded (FFPE) tissue block was selected for each case. Three to five unstained FFPE tissue sections of the area previously selected by the pathologist (P.G.) were cut at 5 μm each for DNA extraction. DNA was obtained using the MagCore® Genomic DNA FFPE One-Step Kit (Diatech-Pharmacogenetics, Jesi, Italy), according to the manufacturer’s instructions. The method is characterized by a One-Step heating, to dissolve the paraffin and, simultaneously, to lyse the tissue without dangerous substances such as xylene. DNA is extracted through cellulose co-opted with magnetic beads.\n\nExtracted DNA was eluted in the elution buffer and then quantified by a Qubit Fluorometer (Thermofisher) using the Qubit dsDNA Assay kit, according to the manufacturer’s recommendations. Once extracted, exons 2, 3 and 4 of KRAs and NRAS and exon 15 of BRAF were amplified by Real Time PCR (Diatech Pharmacogenetics), and then genotyping of each single mutation was performed by Pyrosequencing technology (Diatech Pharmacogenetics). Using a this system, we detected the main mutations of exon 2 (codons 12, 13), of exon 3 (codons 59, 61) and of exon 4 (codons 117, 146) of KRAS and NRAS genes and main mutations of codon 600 of the gene BRAF.\n\n2.2. Statistical Analysis\nPatients were stratified according to concordance or discordance of tissue and plasma RAS/BRAF mutational status, and analyzed for difference of the primary outcome measure PFS with the Kaplan-Meier method and log-rank test. Hazard Ratios for PFS between patient groups were analyzed with both univariate and multivariate Cox proportional regression model and 95% confidence intervals were derived. An exploratory hypothesis-generating multivariate Cox regression analysis was run including both tissue and plasma mutational status, as well as known prognostic factors. This analysis was not performed to specify a prognostic model. Instead, it was performed to assess the relative contribution of important covariates to PFS estimation in our patient cohort. For this reason, no variable reduction/pre-selection (such as univariate pre-selection) was carried out and no strict rule for the number of variables to be included in the analysis was applied.\n\nSince discordant mutational status was thought to be clinically relevant, a multivariate logistic regression analysis including baseline patient characteristics was performed to identify determinants of discordant results. A Least Absolute Shrinkage and Selection Operator (LASSO) approach was used to select the most significant factor predicting mutational discordance.\n\nFor the logistic regression analysis, continuous variables were optimally dichotomized by means of ROC curve analysis. Differences in variables between concordant and discordant cases were assessed with the chi-square statistics and Odds Ratio calculation.\n\nAll analyses were performed with R software version 3.6.0 (Vienna, Austria—http://www.R-project.org/). Tests were considered statistically significant for two tail p values <0.05.\n\n3. Results\n3.1. Patients’ Characteristics\nBetween September 2018 and February 2020 45 mCRC patients were enrolled (median age 67 y, 16 females, 29 males). Patients’ characteristics are summarized in Table 1). Karnofsky Performance Status (KPS) was 100 in 84% of cases. Only 7 patients had KPS ≤ 80 at the moment of the liquid biopsy, and only for two patients a KPS deterioration was noted since the initial tumor diagnosis.\n\nMore than half of patients had liver metastasis (30 out of 45 patients, 66.67% of total), and 11 had liver limited disease (24.45%). Median TNL was 4 (range 1–56), and median SMD expressed in mm was 122 (range 25–1687 mm).\n\nAccording to tissue mutational status, 6 patients were BRAF mutated (13%), 15 RAS mutated (34%), and 24 RAS/BRAF wild type (53%). As per protocol, 21 patients (47%) received FOLFOX-bevacizumab (RAS or BRAF mutated patients) and 24 (53%) FOLFOX-panitumumab (RAS/BRAF wild type).\n\nIn 62% of cases, tissue sampling for mutational assessment had been performed within the year preceding the liquid biopsy date and first-line chemotherapy start. More ancient tissue sampling (>1 year) was mainly due to metachronous metastatic relapse of initially localized colon cancer. None of the patients were exposed to anti-EGFR agents in the interval time between tissue sampling and liquid biopsy. Tissue source was surgically-removed primary tumor, colonoscopic biopsy and biopsy of a metastatic lesion (mainly liver metastasis) in 16% (n = 7), 55% (n = 25) and 29% (13) of cases, respectively.\n\n3.2. Survival Analysis\nTissue mutational status was confirmed to have a statistically significant prognostic value, with median PFS (mPFS) of 4.5, 8.3 and 22.9 months for tissue BRAF V600E mutated, tissue RAS mutated, and tissue RAS/BRAF wild type mCRC patients, respectively, p = 0.00014 (taking BRAF mutated group as reference, Hazard Ratio, HR 0.18, 95%CI 0.05–0.59, p value 0.005 and HR 0.10, 95%CI 0.03–0.35, p value 0.0003, for tissue RAS mutated and tissue RAS/BRAF wild type patients, respectively) (Figure 1A).\n\nAccording to liquid biopsy compared to tissue RAS/BRAF mutational status, we found 100% of concordance for BRAF V600E mutation and 9 discordant cases for RAS mutation. Hence, the combined mutational analysis of tissue and plasma identified the following 5 subgroups: patients BRAF mutated concordant (n = 6), patients RAS wild type (WT) in tissue (T) and mutated in plasma (PL) (RAS WT-T/MUT-PL discordant) (n = 4), patients RAS mutated in T and wild type in PL (RAS MUT-T/WT-PL discordant) (n = 5), patient RAS mutated in both T and PL (RAS MUT concordant) (n = 10), patient RAS wild type in both T and PL (RAS WT concordant) (n = 20).\n\nPlasma RAS mutational status was significantly associated with PFS in both tissue RAS wild type and mutated patients: mPFS of concordant vs. discordant cases was 23.3 vs. 9.6 months, respectively in tissue RAS wild patients (HR 0.23 (95% CI 0.85–0.06), p = 0.02) (Figure 1B); and 7.8 vs. 24.4 months, respectively in tissue RAS mutated patients (HR 10.91 (95% CI 89.85–1.32), p = 0.008) (Figure 1C).\n\nFigure 1D reports survival curves of the five subgroups. PFS for RAS MUT-T/WT-PL was similar to that of RAS wild type concordant cases (p value 0.399) and PFS for RAS WT-T/MUT-PL was similar to that of RAS mutated concordant cases (p value 0.547).\n\nIn an exploratory multivariate cox regression analysis including known prognostic factors such as performance status, CEA and tumor sidedness, liquid mutational status was confirmed to be an independent prognostic factor superior to tissue mutational status (p = 0.0008) (Table 2). Of note, patients with BRAF mutation were excluded from the analysis.\n\n3.3. Predictors of Discordant Cases\nGiven the relevance of RAS discordant cases, a multivariate logistic regression (MLR) analysis with least absolute shrinkage and selection operator (LASSO) approach was performed to identify the most significant predictors of liquid/tissue discordance in both subgroups of tissue RAS mutated and tissue RAS wild type patients.\n\nThe analysis included the following 23 clinical and biochemical variables recorded at baseline: type of tissue source, tissue collection-liquid biopsy interval time, primary sidedness, resection of primary tumor, total number of tumor lesions (TNL), total tumor burden expressed in mm (SMD), presence of liver metastases, age, sex, albumin, red blood cells, hemoglobin, white blood cells, lymphocytes, neutrophils, platelets, d-dimer, C reactive protein, Charlston comorbidity index, CEA, CA19.9, KPS basal score, smoking habit.\n\nBecause of the small size of the patient cohort, individual ROC curve analysis was first performed to optimally dichotomize continuous variables.\n\nAccording to MLR with LASSO, TNL was found to be the most significant predictor of discordance among tissue RAS wild patients (p = 0.05) (Figure 2A), and SMD the most significant predictor of RAS discordance among tissue RAS mutated patients (p = 0.02) (Figure 2B). Of note, SMD and TNL were superior to source of tissue biopsy (biopsy vs. surgical material) and interval time from tissue to plasma collection (< vs. >1 year) in predicting discordance.\n\nThe absolute risk of discordance was 50% vs. 10% in patients with ≥10 vs. <10 total number of lesions in the tissue RAS wild type subgroup (Odds Ratio 9.0, p = 0.05), and was 80% vs. 10% in patients with <140 vs. >140 mm of overall SMD in the tissue RAS mutated subgroup (Odds Ratio 36.0, p = 0.02) (Figure 3).\n\n4. Discussion\nIn the present prospective study, we demonstrated that baseline plasmatic testing of ctDNA RAS/BRAF mutation using Easy PGX Real Time PCR offers meaningful additional information in mCRC patients starting a standard firs-line chemotherapy. In our cohort, plasma RAS assessment was even superior in terms of PFS prediction as compared to tissue RAS assessment (p value at multivariate Cox regression analysis, 0.0008 and 0.702, respectively). BRAF mutation detected in the plasma had a perfect concordance with tissue analysis and was confirmed to be associated with the worst PFS (mPFS 4.5 months) [20].\n\nAlthough the authors acknowledge the small size of the study cohort and that caution should be taken also in interpreting significant results, useful information can be derived from the analysis of predictors of discordant cases for KRAS and NRAS genes. In subjects formally labelled as RAS wild type at the tissue analysis, a high percentage of patients with circulating RAS mutated clones was found when more than 10 tumor lesions were detected at the pre-chemotherapy CT scan (50% of cases). This is probably due to both spatial and temporal heterogeneity since tissue was often collected many months before the disease progression requiring a first-line chemotherapy or on cell clones (mainly from the primary site) that were not representative of the entire disease, especially when a relevant number of metastatic lesions are observed (i.e., >10). We therefore strongly recommend a ‘liquid re-profiling’ when more than 10 distinct tumor masses are displayed at the CT scan before starting a first-line treatment containing an anti-EGFR antibody. Only 13 patients in our cohort had tissue mutational assessment in the metastatic site (mainly the liver), and further assessment of primary vs. metastasis spatial discordance could not be carried out.\n\nOn the other hand, an even higher discordance (80%) was found among tissue RAS mutated patients with a low tumor burden (overall <140 mm as measured by SMD). The most probable explanation of this finding is the higher false negativity rate of liquid biopsy testing observed when a specific mutation present in the tumor tissue is analysed in the plasma of patients with low tumor burden. Modern techniques with improved sensitivity would probably detect circulating mutations also in case of low mutant allele fraction (MAF) [21,22,23].\n\nFrom a biological point of view, it is possible that in some metastatic patients, given the increasing reduction of limit of detection (LoD) for RAS mutation of new generation genotyping techniques, a disease formally labelled as tissue mutated is still constituted for the vast majority of RAS wild type clones, with less aggressive behaviour, and more sensitive to anti-EGFR agents. Liquid biopsy would represent, in this case, the ‘clinically meaningful’ disease with mutated clones confined in limited spatial niches and not shedding in the bloodstream. Interestingly, in this subgroup, the mean diameter of the lesions was higher among the discordant cases (median 34 mm, range 20–100 mm) than among concordant cases (median 29 mm, range 15–80), indicating that this hypothesis might be particularly true in patients with few lesions of big dimensions.\n\nMoreover, the organs involved by metastatic dissemination might be of relevant importance. Among discordant patients with RAS tissue mutated and plasma wild type, only 2 out of 5 had liver metastases. The absence of liver metastasis is a condition more often associated with low cfDNA release in peripheral blood. In fact, as reported in other works using even more sensitive techniques, the absence of liver metastases was the main clinical factor associated with inconclusive ctDNA results [24].\n\nVarious technologies are available for testing known mutations in ctDNA in mCRC. They are classified into PCR-based or sequencing-based technologies (NGS). NGS allows deep sequencing of amplicons and, while the PCR-based methods can detect specific, already-known mutations, NGS has the advantage of detecting novel mutations in addition to the known ones [25,26].\n\nMethods based on real-time PCR, widely used in clinical research, have a limit of detection (LoD) of 0.5–0.1%. Because ctDNA exists at low levels in plasma, more sensitive detection methods, such as the allele-specific quantitative PCR-based Intplex technology, emulsion PCR techniques (such as ddPCR), and the Beads, Emulsion, Amplification and Magnetics (BEAMing) have been developed.\n\nThese methods have a limit of detection of 0.01–0.001%, resulting in a higher ability in detecting low frequency mutations [27]. However, the ability to diagnose rare RAS mutant subclones has uncertain clinical significance and might lead to an over-diagnosis of anti-EGFR resistance [28].\n\nAlthough ctDNA typically constitutes only a small portion (<1%) of the total cfDNA [29,30], it is regarded as a reliable tool in oncology, offering a non- invasive method to evaluate patients’ genomic profiles and consenting repeated evaluations during the course of the disease.\n\nMoreover, its use, in contrast to the analysis of tumor biopsy samples, allows an overview of tumor heterogeneity and evolution. This last point is of the outmost importance, given that tumor heterogeneity, which characterizes cancers in an advanced stage [31], limits the use of tissue biopsy for reliable cancer sequencing [29].\n\nThe same patient might display both an intra-tumoral heterogeneity (in which different areas of the same tumor mass have different genetic profiles), and inter-metastatic heterogeneity when multiple distinct metastatic lesions are present [32].\n\nOur results highlight the importance of the information derived from discordant cases. The vast majority of the studies on ctDNA underline the good level of concordance between the two methods and, indeed in our population, we have observed a significant level of concordance of tissue/plasma mutations (80%), consistent with data reported in the literature [33,34,35]. However, we also suggest that discordant cases might be of clinical relevance, instead of just indicating false negative or false positive errors.\n\nIn some reports, discordant findings are explained by the temporal heterogeneity and the possible acquisition of mutation during targeted treatment with anti-EGFR agents [36]. However, none of the patients enrolled in our study received an anti-EGFR treatment.\n\nA prospective phase II clinical trial (PROSPECT-C) of single agent anti-EGFR therapy in patients with RAS WT metastatic colorectal cancer (mCRC) found that almost half of patients harbored pre-existing alterations in the RAS pathway, detectable at baseline cfDNA evaluation. These patients had a significantly lower PFS and OS as well as a trend toward lack of response compared with patients without baseline RAS alterations on liquid biopsy [37].\n\nThese data are in agreement with those of Vandeputte et al., who observed that mCRC patients with an early decline in mutant DNA fraction during regorafenib and TAS-102 treatment had a longer mPFS than those displaying a persistently high mutant fraction [38].\n\nIn the Italian CRICKET (Cetuximab Rechallenge in Irinotecan-pretreated mCRC, KRAS, NRAS and BRAF Wild-type Treated in 1st Line With Anti-EGFR Therapy) study 27 mCRC patients, with an initial tissue wild type RAS/BRAF status and the subsequent development of acquired resistance during first-line anti-EGFR-based therapy, were re-challenged with irinotecan plus cetuximab in third line after an anti-EGFR-free second-line. At the re-challenge baseline, mutational assessment of ctDNA by droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) predicted a greater efficacy of irinotecan-cetuximab re-challenge [39].\n\nAll these data show how liquid biopsy can be used to optimize therapy management in mCRC and to early detect drug resistance.\n\nWe must acknowledge the following limitations of our study: (1) the low sensitivity of the technique used (LoD 0.5–5%), (2) the small sample size, (3) the absence of serial liquid biopsies during treatment. Despite these limitations, our study is in line with the recently released consensus statement of the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute on the utility of ctDNA in the management of mCRC patients, with the ultimate goal to include it in routine clinical practice [40]. Extension of the present study to enroll a higher number of patients is underway. Prospective comparison of real time PCR to other more sensitive techniques is also being considered.\n\n5. Conclusions\nLiquid biopsy for the assessment of RAS and BRAF mutations using available kits of real time PCR is feasible and effective in clinical management of mCRC patients. Even if the emergence of circulating RAS mutated clones has been previously correlated with anti-EGFR antibody acquired resistance [41], the present study confirms that ctDNA assessment should be taken into consideration also at the baseline in certain chemotherapy-naïve patients.\n\nTogether with clinical information such as the number and dimension of total metastatic lesions, liquid biopsy seems associated with a more informative prognostic value than tissue mutational status alone. Larger sample size is required to confirm these results. Future studies should evaluate the extent by which baseline ctDNA mutational analysis would influence the choice of targeted agents in mCRC.\n\nAcknowledgments\nThis research work has been conducted under the Programme on Experimental System and Medicine (XXXV cycle) at the University of Rome Tor Vergata. This work was partially supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 848098. We acknowledge the precious work performed by Cristiano Serci and Lorena Vergilii for sample collection and handling and data recording. In this section you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nConceptualization, V.F., J.L., E.D. (Elena Doldo), S.R., G.P., A.O., M.R.; methodology, V.F., P.F., F.G.; formal analysis, V.F., J.L., R.A., S.R., P.F.; resources, E.D. (Elena Doldo), N.R., D.N., A.N., E.D. (Emanuela Dell’Aquila); data cura-tion, E.D. (Elena Doldo), N.R., D.N., A.N., E.D. (Emanuela Dell’Aquila); writing, V.F., J.L., E.D. (Elena Doldo), S.R., C.M., P.F., F.G., G.P., A.O., M.R. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nPartially supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No 848098.\n\nData Availability Statement\nMDPI is committed to supporting open scientific exchange and enabling our authors to achieve best practices in sharing and archiving research data. We encourage all authors of articles published in MDPI journals to share their research data. More details in section “MDPI Research Data Policies” at https://www.mdpi.com/ethics.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Progression free survival (PFS) analysis. (A): PFS according to tissue mutational analysis; (B): PFS in the tissue RAS wild type group according to the result of the liquid biopsy, (C): PFS in the tissue RAS mutated group according to the result of the liquid biopsy; (D): PFS in the five subgroups identified by the combined analysis of tissue and liquid biopsy. mPFS is indicated. p value in the bottom left angle refers to p value for trend for (A,D). BRAF V600E mutations were always consistently found both in plasma and in tissue (BRAF mut subgroup).\n\nFigure 2 Path of Multivariate Logistic regression analysis with Least Absolute Shrinkage and Selection Operator (LASSO) approach for RAS discordance.\n\nFigure 3 Mosaic plot of risk of discordance according to total number of tumor lesions (TNL) and sum of the maximum diameter (SMD) of all lesions in tissue RAS wild type (A) (n = 24) and mutated patients(B) (n = 15).\n\njcm-10-00087-t001_Table 1Table 1 Patients characteristics. KPS: Karnosky Performance Status. TNL: total number of tumor lesions. SMD: sum of maximum diameter of all measurable lesions in mm.\n\nCharacteristic\t% of Patients (Total n = 45)\tCharacteristic\t% of Patients (Total n = 45)\t\n\nMedian Age (years, range)\n\t67 (41–89)\t\nMedian Karnofsky Performance Status (KPS) score (range)\n\t100 (60–100)\t\n\nGender\n\t\n\t\nSidedness\n\t\n\t\nFemale\t36% (16)\tRight\t22% (10)\t\nMale\t64% (29)\tLeft\t78% (35)\t\n\nMetastasis\n\t\n\t\nMutational status in tissue\n\t\n\t\nLiver only\t24% (11)\tBRAF mutation\t13% (6)\t\nLiver and others\t67% (30)\tRAS mutation\t34% (15)\t\nNon-liver only\t9% (4)\tRAS/BRAF wild type\t53% (24)\t\n\nTumor burden\n\t\n\t\nTreatment\n\t\n\t\nTNL\t4 (1–56)\tFOLFOX-bevacizumab\t47% (21)\t\nSMD\t122 mm (25–1687)\tFOLFOX-panitumumab\t53% (24)\t\n\nPrimary Resection\n\t\n\t\nTumor markers\n\t\n\t\nYes\t73% (33)\tCarcinoembryonic antigen (CEA) (median ng/mL, range)\t599 (0.62–5580)\t\nNo\t27% (12)\tCA19.9 (median ng/mL, range)\t214 (1–19,032)\t\njcm-10-00087-t002_Table 2Table 2 Multivariate Cox-regression analysis for PFS. In bold variables with independent prognostic value are reported. Coef: beta coefficient, HR: hazard ratio, Se: standard error, Z: z-statistic.\n\nCovariate\tCoef\tHR\tSe (Coef)\tZ\t\np\n\t\nCEA\t0.0001\t1.0001\t0.0002\t0.5390\t0.5899\t\nTissue mutational status\t0.1897\t1.2088\t0.4957\t0.3830\t0.7020\t\n\nPlasmatic mutational status\n\t\n−1.9731\n\t\n0.1390\n\t\n0.5912\n\t\n−3.3370\n\t\n0.0008\n\t\n\nSideness left vs. right\n\t\n−0.0118\n\t\n0.9883\n\t\n0.5185\n\t\n−0.0230\n\t\n0.9818\n\t\n\nKPS\n\t\n−0.0743\n\t\n0.9284\n\t\n0.0281\n\t\n−2.6440\n\t\n0.0082\n==== Refs\nReferences\n1. Mandel P. Metais P. Les acides nucléiques du plasma sanguin chez l’homme CR Seances Soc. Biol. Fil. 1948 142 241 243 \n2. Fan H.C. Blumenfeld Y.J. Chitkara U. Hudgins L. Quake S. R Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing Clin. Chem. 2010 56 1279 1286 10.1373/clinchem.2010.144188 20558635 \n3. Cheng F. Su L. Qian C. 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Henrichsen-Schnack T. Ladelund S. Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis Acta Oncol. 2014 53 852 864 10.3109/0284186X.2014.895036 24666267 \n9. Corcoran R.B. Chabner B.A. Application of cell-free DNA analysis to cancer treatment N. Engl. J. Med. 2018 379 1754 1765 10.1056/NEJMra1706174 30380390 \n10. Misale S. Yaeger R. Hobor S. Scala E. Janakiraman M. Liska D. Valtorta E. Schiavo R. Buscarino M. Siravegna G. Emergence of KRAS mutations and acquired resistance to anti- EGFR therapy in colorectal cancer Nature 2012 486 532 536 10.1038/nature11156 22722830 \n11. Siravegna G. Mussolin B. Buscarino M. Corti G. Cassingena A. Crisafulli G. Ponzetti A. Cremolini C. Amatu A. Lauricella C. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients Nat. Med. 2015 21 795 801 10.1038/nm.3870 26030179 \n12. Hutchins G. Southward K. Handley K. Magill L. Beaumont C. Stahlschmidt J. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer J. Clin. Oncol. 2011 29 1261 1270 10.1200/JCO.2010.30.1366 21383284 \n13. Pietrantonio F. Petrelli F. Coinu A. di Bartolomeo M. Borgonovo K. Maggi C. Cabiddu M. Iacovelli R. Bossi I. Lonati V. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis Eur. J. Cancer 2015 51 587 594 10.1016/j.ejca.2015.01.054 25673558 \n14. Elez E. Chianese C. Sanz-García E. Martinelli E. Noguerido A. Mancuso F.M. Caratù G. Matito J. Grasselli J. Cardone C. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer Mol. Oncol. 2019 13 1827 1835 10.1002/1878-0261.12547 31322322 \n15. García-Foncillas J. Tabernero J. Élez E. Aranda E. Benavides M. Camps C. Jantus-Lewintre E. López R. Muinelo-Romay L. Montagut C. Prospective multicentre real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer Br. J. Cancer 2018 119 1464 1470 10.1038/s41416-018-0293-5 30467411 \n16. Bando H. Kagawa Y. Kato T. Akagi K. Denda T. Nishina T. Komatsu Y. Oki E. Kudo T. Kumamoto H. A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer Br. J. Cancer 2019 120 982 986 10.1038/s41416-019-0457-y 31015557 \n17. Yao J. Zang W. Ge Y. Weygant N. Yu P. Li L. Rao G. Jiang Z. Yan R. He L. RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients Can. J. Gastroenterol. Hepatol. 2018 2018 4248971 10.1155/2018/4248971 29707525 \n18. Garcia-Carbonero N. Martinez-Useros J. Li W. Orta A. Perez N. Carames C. Hernandez T. Moreno I. Serrano G. Garcia-Foncillas J. KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study Cells 2020 9 219 10.3390/cells9010219 \n19. Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L.H. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \n20. Djanani A. Eller S. Öfner D. Troppmair J. Maglione M. The Role of BRAF in Metastatic Colorectal Carcinoma-Past, Present, and Future Int. J. Mol. Sci. 2020 21 9001 10.3390/ijms21239001 \n21. Godsey J.H. Silvestro A. Barrett J.C. Bramlett K. Chudova D. Deras I. Dickey J. Hicks J. Johann D.J. Leary R. Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays: A Joint Consensus Recommendation of the BloodPAC’s Analytical Variables Working Group Clin. Chem. 2020 66 1156 1166 10.1093/clinchem/hvaa164 32870995 \n22. Hosen M.I. Forey N. Durand G. Voegele C. Bilici S. Avogbe P.H. Delhomme T.M. Foll M. Manel A. Vian E. Development of Sensitive Droplet Digital PCR Assays for Detecting Urinary TERT Promoter Mutations as Non-Invasive Biomarkers for Detection of Urothelial Cancer Cancers 2020 12 3541 10.3390/cancers12123541 33260905 \n23. Zhou J. Chang L. Guan Y. Yang L. Xia X. Cui L. Yi X. Lin G. Application of Circulating Tumor DNA as a Non-Invasive Tool for Monitoring the Progression of Colorectal Cancer PLoS ONE 2016 11 e0159708 10.1371/journal.pone.0159708 27459628 \n24. Bachet J.B. Bouché O. Taieb J. Dubreuil O. Garcia M.L. Meurisse A. Normand C. Gornet J.M. Artru P. Louafi S. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: The AGEO RASANC prospective multicenter study Ann. Oncol. 2018 29 1211 1219 10.1093/annonc/mdy061 29438522 \n25. Galvano A. Taverna S. Badalamenti G. Incorvaia L. Castiglia M. Barraco N. Passiglia F. Fulfaro F. Beretta G. Duro G. Detection of RAS mutations in circulating tumor DNA: A new weapon in an old war against colorectal cancer. A systematic review of literature and meta-analysis Ther. Adv. Med. Oncol. 2019 11 1 15 10.1177/1758835919874653 31534493 \n26. Normanno N. Cervantes A. Ciardiello F. De Luca A. Pinto C. The liquid biopsy in the management of colorectal cancer patients: Current applications and future scenarios Cancer Treat. Rev. 2018 70 1 8 10.1016/j.ctrv.2018.07.007 30053724 \n27. Wan J.C. Massie C. Garcia-Corbacho J. Mouliere F. Brenton J.D. Caldas C. Pacey S. Baird R. Rosenfeld N. Liquid biopsies come of age: Towards implementation of circulating tumour DNA Nat. Rev. Cancer 2017 17 223 238 10.1038/nrc.2017.7 28233803 \n28. Vidal J. Bellosillo B. Santos Vivas C. García-Alfonso P. Carrato A. Cano M.T. García-Carbonero R. Élez E. Losa F. Massutí B. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy Ann. Oncol. 2019 30 439 446 10.1093/annonc/mdz005 30689692 \n29. Holdhoff M. Schmidt K. Donehower R. Diaz L.A. Jr. Analysis of circulating tumor DNA to confirm somatic KRAS mutations J. Natl. Cancer Inst. 2009 101 1284 1285 10.1093/jnci/djp240 19641175 \n30. Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Circulating mutant DNA to assess tumor dynamics Nat. Med. 2008 14 985 990 10.1038/nm.1789 18670422 \n31. Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz L.A. Jr. Kinzler K.W. Cancer genome landscapes Science 2013 339 1546 1558 10.1126/science.1235122 23539594 \n32. Thierry A.R. El Messaoudi S. Mollevi C. Raoul J.L. Guimbaud R. Pezet D. Artru P. Assenat E. Borg C. Mathonnet M. Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment Ann. Oncol. 2017 28 2149 2159 10.1093/annonc/mdx330 28911069 \n33. Vidal J. Muinelo L. Dalmases A. Jones F. Edelstein D. Iglesias M. Orrillo M. Abalo A. Rodríguez C. Brozos E. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients Ann. Oncol. 2017 28 1325 1332 10.1093/annonc/mdx125 28419195 \n34. Montagut C. Tsui D.W. Diaz L.A. Jr. Detection of somatic RAS mutations in circulating tumor DNA from metastatic colorectal cancer patients: Are we ready for clinical use? Ann. Oncol. 2018 29 1083 1084 10.1093/annonc/mdy091 29554200 \n35. Diaz L.A. Jr. Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA J. Clin. Oncol. 2014 32 579 586 10.1200/JCO.2012.45.2011 24449238 \n36. Blakely C.M. Watkins T.B.K. Wu W. Gini B. Chabon J.J. McCoach C.E. McGranahan N. Wilson G.A. Birkbak N.J. Olivas V.R. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers Nat. Genet. 2017 49 1693 1704 10.1038/ng.3990 29106415 \n37. Khan K.H. Cunningham D. Werner B. Vlachogiannis G. Spiteri I. Heide T. Mateos J.F. Vatsiou A. Lampis A. Damavandi M.D. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial Cancer Discov. 2018 8 1270 1285 10.1158/2159-8290.CD-17-0891 30166348 \n38. Vandeputte C. Kehagias P. El Housni H. Ameye L. Laes J.F. Desmedt C. Sotiriou C. Deleporte A. Puleo F. Geboes K. Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi- kinase inhibitor Oncotarget 2018 9 17756 17769 10.18632/oncotarget.24879 29707145 \n39. Cremolini C. Rossini D. Dell’Aquila E. Lonardi S. Conca E. Del Re M. Busico A. Pietrantonio F. Danesi R. Aprile G. Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial JAMA Oncol. 2019 5 343 350 10.1001/jamaoncol.2018.5080 30476968 \n40. Dasari A. Morris V.K. Allegra C.J. Atreya C. Benson A.B. 3rd Boland P. Chung K. Copur M.S. Corcoran R.B. Deming D.A. ctDNA applications and integration in colorectal cancer: An NCI Colon and Rectal-Anal Task Forces whitepaper Nat. Rev. Clin. Oncol. 2020 17 757 770 10.1038/s41571-020-0392-0 32632268 \n41. Schmiegel W. Scott R.J. Dooley S. Lewis W. Meldrum C.J. Pockney P. Draganic B. Smith S. Hewitt C. Philimore H. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: Concordance of results from circulating tumor DNA and tissue-based RAS testing Mol. Oncol. 2017 11 208 219 10.1002/1878-0261.12023 28106345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "10(1)",
"journal": "Journal of clinical medicine",
"keywords": "ctDNA; liquid biopsy; metastatic colorectal cancer",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33383664",
"pubdate": "2020-12-29",
"publication_types": "D016428:Journal Article",
"references": "19097774;30476968;29554200;27223063;28106345;22722830;30053724;11694251;29707525;28911069;29700206;20558635;30467411;29707145;29438522;33256240;30166348;31534493;24449238;23539594;32632268;22397650;25673558;26030179;19641175;31952366;27459628;24666267;32870995;30380390;30689692;28419195;18875018;31322322;28233803;18267930;31015557;29106415;21383284;18670422;33260905",
"title": "Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients-The Importance of Tissue/Plasma Discordant Cases.",
"title_normalized": "clinical utility of plasma kras nras and braf mutational analysis with real time pcr in metastatic colorectal cancer patients the importance of tissue plasma discordant cases"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020114342",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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... |
{
"abstract": "BACKGROUND\nImmune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome.\n\n\nMETHODS\nA 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of 99mTc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of 99mTc-pertechnatate and the presence of a \"cool\" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion.\n\n\nCONCLUSIONS\nWe present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.",
"affiliations": "Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy. lemoli.rosario@tiscali.it.;Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.;Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.;Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.;Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.;Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.",
"authors": "Le Moli|Rosario|R|http://orcid.org/0000-0002-1398-9271;Russo|Marco|M|;Malandrino|Pasqualino|P|;Vella|Veronica|V|;Belfiore|Antonino|A|;Frasca|Francesco|F|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D013956:Antithyroid Agents; D016566:Organoselenium Compounds; C517785:methionine selenoxide; D000074323:Alemtuzumab; D008713:Methimazole; D008715:Methionine",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42000-020-00215-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1109-3099",
"issue": "20(1)",
"journal": "Hormones (Athens, Greece)",
"keywords": "Alemtuzumab; Graves’ ophthalmopathy; Immune-reconstitution inflammatory syndrome; Marine-Lenhart syndrome",
"medline_ta": "Hormones (Athens)",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D000074322:Antineoplastic Agents, Immunological; D013956:Antithyroid Agents; D005260:Female; D006111:Graves Disease; D049970:Graves Ophthalmopathy; D006801:Humans; D008713:Methimazole; D008715:Methionine; D009103:Multiple Sclerosis; D016566:Organoselenium Compounds",
"nlm_unique_id": "101142469",
"other_id": null,
"pages": "161-165",
"pmc": null,
"pmid": "32500462",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.",
"title_normalized": "onset of marine lenhart syndrome and graves ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317959",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"dru... |
{
"abstract": "OBJECTIVE\nA patient with a well-healed, functional cochlear implant (CI) experienced a CI and mastoid infection shortly after initiating large-volume nasal irrigations after sinus surgery. The goal of this report is to bring attention to a rare complication and to question if large-volume nasal irrigation is safe in CI recipients.\n\n\nMETHODS\nSingle patient at a tertiary care hospital.\n\n\nMETHODS\nA CI recipient began using large-volume nasal irrigations with saline and budesonide after undergoing sinus surgery.\n\n\nMETHODS\nCI infection and mastoiditis.\n\n\nRESULTS\nTwo weeks after starting nasal irrigations, the patient presented with mastoiditis and CI infection. Mastoid and intranasal middle meatal cultures both grew Group A streptococcus.\n\n\nCONCLUSIONS\nLarge-volume nasal irrigations may be related to our patient's CI infection, ultimately leading to explantation. Though a causal relationship cannot be definitively proven, awareness of this potential safety issue should be disseminated.",
"affiliations": "Department of Otolaryngology, Mayo Clinic, Phoenix, Arizona, U.S.A.",
"authors": "Cain|Rachel B|RB|;Lal|Devyani|D|;Barrs|David M|DM|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D012965:Sodium Chloride; D019819:Budesonide",
"country": "United States",
"delete": false,
"doi": "10.1097/MAO.0000000000000565",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1531-7129",
"issue": "36(1)",
"journal": "Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology",
"keywords": null,
"medline_ta": "Otol Neurotol",
"mesh_terms": "D000281:Administration, Intranasal; D000368:Aged; D000893:Anti-Inflammatory Agents; D019819:Budesonide; D019929:Cochlear Implantation; D003054:Cochlear Implants; D005260:Female; D006801:Humans; D008297:Male; D008417:Mastoiditis; D055556:Nasal Lavage; D010256:Paranasal Sinuses; D012220:Rhinitis; D012852:Sinusitis; D012965:Sodium Chloride",
"nlm_unique_id": "100961504",
"other_id": null,
"pages": "12-3",
"pmc": null,
"pmid": "25226373",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infected cochlear implant after large-volume nasal irrigation.",
"title_normalized": "infected cochlear implant after large volume nasal irrigation"
} | [
{
"companynumb": "US-B. BRAUN MEDICAL INC.-1042474",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nThis video demonstrates surgical repair of a vesicouterine fistula via a robotic, uterine-sparing approach.\n\n\nMETHODS\nIn this video, we present a vesicouterine fistula, which occurred after cesarean delivery. The patient presented with cyclical hematuria 4 years following delivery. She underwent uterine-conserving robotic repair via excision of the fistula tract through an intentional cystotomy. The uterus and bladder were closed in multiple layers.\n\n\nRESULTS\nThe patient tolerated the procedure well, and CT cystogram 6 weeks following surgery demonstrated no concern for defect or recurrent fistulization. The patient was asymptomatic 9 months following her procedure.\n\n\nCONCLUSIONS\nRepair of a vesicouterine fistula may be safely completed via a minimally invasive approach without need for routine hysterectomy.",
"affiliations": "Female Pelvic Medicine and Reconstructive Surgery, Vanderbilt University, 1121 Medical Center Drive, Nashville, TN, 37232, USA. Mary.vm.baker@vumc.org.;Division of Urogynecology, Mayo Clinic, Rochester, MN, USA.;Division of Urogynecology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Baker|Mary V|MV|http://orcid.org/0000-0003-3653-5691;Kisby|Cassandra K|CK|;Occhino|John A|JA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1007/s00192-021-04940-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-3462",
"issue": null,
"journal": "International urogynecology journal",
"keywords": "Robotic surgery; Uterine conservation; Vesicouterine fistula",
"medline_ta": "Int Urogynecol J",
"mesh_terms": null,
"nlm_unique_id": "101567041",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34374804",
"pubdate": "2021-08-10",
"publication_types": "D016428:Journal Article",
"references": "21656476",
"title": "Vesicouterine Fistula: A Robotic Approach.",
"title_normalized": "vesicouterine fistula a robotic approach"
} | [
{
"companynumb": "US-TOLMAR, INC.-21US025562",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nBullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitors (DPP4i). Clinical features, outcomes, and risk of BP for new DPP4i (linagliptin, saxagliptin, and alopgliptin) are not well established. Comparison of risk of BP appearance for DPP4i and other oral antidiabetic drugs (OADs) such as sodium glucose cotransporter 2 inhibitors has not been studied to date.\n\n\nOBJECTIVE\nTo describe the prevalence, sociodemographic, clinical, and histopathological characteristics, and outcome after drug withdrawal in DPP-4i-associated BP cases from our hospital. To review all Spanish spontaneous notifications of BP where DPP4i or OADs were included as suspected drugs and calculate the reporting odds ratios (RORs).\n\n\nMETHODS\nA retrospective observational study was performed examining the association between DDP4i and BP. Clinical features and RORs were analyzed. Data from the Spanish Pharmacovigilance System (SEFV) are included.\n\n\nRESULTS\nIn our center, 28 of 89 patients with BP (31.5%) were under DPP4i treatment; 53.6% were male, and mean age was 80.8 years. BP debuted the first year after DPP4i in 57.2%. BP control was achieved within 3.7 months after drug withdrawal. Regarding SEFV, 22 of 972 spontaneous notifications were related to BP and DPP4i. RORs were superior for DPP4i compared to other OADs. Vildagliptin had the highest ROR.\n\n\nCONCLUSIONS\nWe present the largest DPP4i-induced BP case series in a single center, with a detailed study of the sociodemographic, clinical, and histopathological characteristics of each patient, and their treatment and outcome. Vildagliptin had the highest risk. DPP4i-associated BP does not seem to have specific clinical characteristics.",
"affiliations": "Department of, Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Clinical Pharmacology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Pathology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.;Department of, Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario la Princesa, Madrid, Spain.",
"authors": "Reolid|Alejandra|A|;Muñoz-Aceituno|Ester|E|;Rodríguez-Jiménez|Pedro|P|https://orcid.org/0000-0002-7061-3027;González-Rojano|Esperanza|E|;Llamas-Velasco|Mar|M|;Fraga|Javier|J|;Daudén|Esteban|E|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000069476:Linagliptin; D000077597:Vildagliptin; D000068900:Sitagliptin Phosphate",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.14658",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "59(2)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D016208:Databases, Factual; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005260:Female; D006801:Humans; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D060735:Pharmacovigilance; D012189:Retrospective Studies; D000068900:Sitagliptin Phosphate; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013030:Spain; D000077597:Vildagliptin",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "197-206",
"pmc": null,
"pmid": "31605541",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors. A case series and analysis of cases reported in the Spanish pharmacovigilance database.",
"title_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitors a case series and analysis of cases reported in the spanish pharmacovigilance database"
} | [
{
"companynumb": "NVSC2019ES027562",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
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"abstract": "Lichen planopilaris failed to respond to ustekinumab after 10 months of treatment.",
"affiliations": "Jefferson Medical College, Philadelphia. gfweb@earthlink.net.",
"authors": "Webster|Guy|G|",
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"mesh_terms": "D000368:Aged; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D008010:Lichen Planus; D017211:Treatment Failure; D000069549:Ustekinumab",
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"title": "Failure of lichen planopilaris to respond to ustekinumab.",
"title_normalized": "failure of lichen planopilaris to respond to ustekinumab"
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"abstract": "BACKGROUND\nThe authors present a case of multinodular goiter in an HIV-positive patient affected by lipodystrophy with particular accumulation of adipose tissue in the region of the neck and trunk.\n\n\nMETHODS\nThe patient, a 53-year-old man, presented with multinodular struma with partial retrosternal engagement, as well as multiple thyroid nodules increasing in size; some of the nodules had suspicious characteristics on ultrasound. Needle aspiration biopsy was difficult to use to determine the presence of lipodystrophy; however, even in the absence of cytology, surgical treatment was necessary due to the presence of dyspnea during exercise, the dimension of the goiter with retrosternal engagement, and the ovalization of the tracheal lumen. The patient underwent total thyroidectomy by anterior cervicotomy with particular attention to patient positioning because of the buffalo hump and taurine neck. Histological examination was positive for adenomatous hyperplasia with outbreaks of papillary microcarcinoma.\n\n\nCONCLUSIONS\nThe aim of this case report was to highlight the importance of the perioperative teamwork, with particular attention to patient positioning before surgery, as well as professional collaboration and experience among the operators.",
"affiliations": "Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via Largo del Pozzo n. 71- 41124 Modena, Italy. Electronic address: carreseelena@libero.it.;Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via Largo del Pozzo n. 71- 41124 Modena, Italy. Electronic address: uliano.morandi@unimore.it.;Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via Largo del Pozzo n. 71- 41124 Modena, Italy. Electronic address: alessandro.stefani@unimore.it.;Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via Largo del Pozzo n. 71- 41124 Modena, Italy. Electronic address: beatrice.aramini@unimore.it.",
"authors": "Carrese|Elena|E|;Morandi|Uliano|U|;Stefani|Alessandro|A|;Aramini|Beatrice|B|",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30402-X10.1016/j.ijscr.2019.07.020ArticleTotal thyroidectomy in HIV positive patient with buffalo hump and taurine neck Carrese Elena carreseelena@libero.itMorandi Uliano uliano.morandi@unimore.itStefani Alessandro alessandro.stefani@unimore.itAramini Beatrice beatrice.aramini@unimore.it⁎Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via Largo del Pozzo n. 71- 41124 Modena, Italy⁎ Corresponding author. beatrice.aramini@unimore.it19 7 2019 2019 19 7 2019 61 64 66 12 5 2019 11 7 2019 © 2019 The Author(s)2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• A multinodular goiter in an HIV-positive with lipodystrophy, buffalo hump and taurine neck.\n\n• Needle aspiration biopsy was difficult to use to determine the presence of lipodystrophy.\n\n• The goiter was with retrosternal engagement and the ovalization of the tracheal lumen.\n\n• Surgical treatment was necessary due to the presence of dyspnea during exercise.\n\n• Importance of the perioperative teamwork, in particular to the patient positioning.\n\n\n\nBackground\nThe authors present a case of multinodular goiter in an HIV-positive patient affected by lipodystrophy with particular accumulation of adipose tissue in the region of the neck and trunk.\n\nCase presentation\nThe patient, a 53-year-old man, presented with multinodular struma with partial retrosternal engagement, as well as multiple thyroid nodules increasing in size; some of the nodules had suspicious characteristics on ultrasound. Needle aspiration biopsy was difficult to use to determine the presence of lipodystrophy; however, even in the absence of cytology, surgical treatment was necessary due to the presence of dyspnea during exercise, the dimension of the goiter with retrosternal engagement, and the ovalization of the tracheal lumen. The patient underwent total thyroidectomy by anterior cervicotomy with particular attention to patient positioning because of the buffalo hump and taurine neck. Histological examination was positive for adenomatous hyperplasia with outbreaks of papillary microcarcinoma.\n\nConclusions\nThe aim of this case report was to highlight the importance of the perioperative teamwork, with particular attention to patient positioning before surgery, as well as professional collaboration and experience among the operators.\n\nAbbreviations\nHIV, human immunodeficiency virusHAART, highly active anti-retroviral therapyAZT, zidovudineDdi, didanosined4T, stavudine3TC, lamivudineIDV, indinavirEFV, efavirenzBMI, body mass indexHCV, hepatitis c virusASA, American society of anesthesiologistsPIs, protease inhibitorsNRTIs, nucleoside reverse transcriptase inhibitorsLDL, low-density lipoproteinHDL, high-density lipoproteinnon-NRTIs, non-nucleoside reverse transcriptase inhibitorsKeywords\nThyroidectomyLipodystrophyHighly active anti-retroviral therapy (HAART)HIV positive\n==== Body\n1 Background\nHighly active anti-retroviral therapy (HAART) with associated lipodystrophy syndrome refers to a serious metabolic syndrome in HIV-infected patients receiving highly antiretroviral therapy [4]. It is generally characterized by metabolic changes such as the development of dyslipidemia, insulin resistance, glucose intolerance and abnormal redistribution of body fat (peripheral lipoatrophy and lipohypertrophy) [3]. Lipohypertrophy refers to localized abnormal fat accumulation and most commonly occurs in the intra-abdominal compartment (visceral adipose tissue), breast, dorso-cervical area (buffalo hump) or discretely accumulates under the skin (lipomas). Lipoatrophy is characterized by loss of subcutaneous fat, particularly in the face, buttocks, arm and leg. The coexistence of lipohypertrophy and lipoatrophy is referred to as mixed lipodystrophy [5]. This syndrome was identified in 1998, but its causes are not fully understood; current data suggest a multifactorial pathogenesis, with the major contributing factors being the choice of treatment, duration of treatment and patient-related factors, such as age, BMI, and the level of immunodeficiency [3,5,4].\n\nThe aim of this report was to show perioperative management in an HIV patient affected by lipodystrophy syndrome who underwent thyroidectomy for a multinodular goiter. The work has been reported in line with SCARE criteria has been reported in line with the SCARE criteria [6].\n\n2 Case presentation\nWe present a case of a 53-year-old man who came to our department for a large multinodular goiter with multiple suspicious nodules on ultrasound. The diagnosis was made in 1999 during hospitalization for an episode of thyrotoxicosis. The patient was diagnosed as HIV-positive in 1994 and began antiretroviral treatment with AZT (zidovudine) and Ddi (didanosine) with minimal initial benefit; however, subsequent worsening of the immunological condition was noted. Therefore, beginning in June 1997, therapy was switched to d4T (stavudine) plus 3TC (lamivudine) and IDV (indinavir); this achieved excellent viral replication control and improved the immunological condition. In 1999, a change in HIV treatment was necessary due to the presence of an important lipid dysmetabolism with hypertriglyceridemia, modification of the habitus with an important lipohypertrophy of the cervicodorsal region (buffalo hump and taurine neck) and loss of subcutaneous fat of the legs (Fig. 1A–D). Therapy with AZT (zidovudine)+ 3TC (lamivudine) + EFV (efavirenz) enabled control of viral replication and stability of the lipodystrophic picture. The patient had undergone multiple liposuctions, but they were not effective, likely due to the excessive accumulation of adipose tissue. In our opinion, the most relevant clinical aspect to consider was the large buffalo hump and taurine neck due to lipodystrophy. He also presented with negative thyroid autoimmunity, with normal calcitonin and calcemic blood values. The ultrasound exam showed struma with partial retrosternal engagement and multiple thyroid nodules increasing in size relative to a previous check, as well as suspicious features for neoplasia. The patient had undergone several needle aspirations, which failed due to the thickness and abundancy of the adipose tissue.Fig. 1 A-C-D show a lateral view of the patient affected by lipodystrophy with particular accumulation of adipose tissue in the region of the neck and trunk. Fig. 2B shows a posterior view.\n\nFig. 1\n\nPatient comorbidities were mainly based on the alteration of glucose metabolism (due to diabetes mellitus), alteration of bone metabolism (due to osteopenia), severe obesity (body mass index, BMI, of 34.6), and hypertension, as well as slight limitation in running, weightlifting and playing intense sports. He also reported that a previous HCV hepatopathy had been treated with Harvoni. The indication to remove the thyroid glands was suggested by the patient’s endocrinologist, primarily due to the suspicious nodules. Preoperative anesthesia evaluation predicted an American Society of Anesthesiologists (ASA) anesthetic risk of 3, requiring complex intubation for the patient’s habitus and for the shrinkage of the trachea. Indeed, preoperative chest X-ray showed an ovalization of the tracheal lumen (11 mm) to a plane passing through C7 (Fig. 2).Fig. 2 Chest x-ray shows the ovalization of the tracheal lumen (arrow).\n\nFig. 2\n\nAfter careful positioning (Fig. 3A and B), the patient underwent total thyroidectomy by anterior cervicotomy. Total thyroidectomy was performed with technical difficulties: first, intubation of the patient was required for the operation due to the hyperextension of the neck; second, access to the goiter was difficult due to the amount of adipose tissue, as well as the buffalo hump and taurine neck. Thyroid isolation was complicated on the right side of the gland for the increased volume, particularly due to difficulty in recurring laryngeal nerve isolation. No intraoperative complications and no bleeding loss were observed during or after surgery. The drains were removed on the second postoperative day. Despite the patient’s HIV infection, no complications were noted after surgery, especially around the wound. Calcium blood values stayed in the normal range after surgery. The patient presented with dysphonia; therefore, direct laryngoscopy was performed, which showed fixation of the right vocal string with good phonatory compensation, as well as consistency of the respiratory space. Therefore, the patient was sent to logopedic rehabilitation after discharge from the hospital.Fig. 3 shows the patient positioning before surgery and the anesthesiologist management during intubation.\n\nFig. 3\n\n3 Discussion and conclusion\nLipodystrophy syndrome is an important complication of antiretroviral therapy due to its increased cardiovascular risk as a result of metabolic alterations, as well as the psychological aspects and quality of life.\n\nStudies have shown that protease inhibitors (PIs) and some nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine (d4T), increase the levels of triglycerides, total cholesterol and low-density lipoprotein cholesterol (LDL); however, they reduce high-density lipoprotein (HDL) levels. In contrast, regimens with nevirapine and efavirenz (non-NRTIs, or NNRTIs) show reduced atherogenic effects on lipid profiles [3,1]. PIs and NRTIs appear to cause mitochondrial toxicity, modifying the enzyme activity involved in metabolism [7,8]. Other studies support a direct role for HIV: adipose tissue may serve as reservoir for HIV, altering the local tissue environment and promoting enhanced adipose tissue inflammation. HIV proteins alter adipose tissue function and increase inflammation; therefore, HIV-associated chronic inflammation and immune activation may play a direct role in the development of lipohypertrophy [5].\n\nThe risk of developing lipodystrophy is greater with advanced age, in people who have the longest durations of infection and in patients who have had therapy for longer periods [3,4]. Furthermore, some studies have shown that patients with lipoatrophy have significantly lower BMI than those with lipohypertrophy [2,8].\n\nThe combination of obesity, lipodystrophy, central adiposity, dyslipidemia, and insulin resistance commonly occurs among HIV-infected adults; these constitute risk factors associated with cardiovascular diseases, which represent the third most common cause of death among HIV-positive individuals in Europe. Moreover, lipodystrophic body changes can influence the quality of life, leading to low adherence to HAART and subsequent virologic and clinical failure [3,9,4,5].\n\nIn this case, lipodystrophy syndrome was a complicated obstacle to the necessary intervention. Surgery, despite all of its technical difficulties, was the only method to obtain the diagnosis considering the failed aspiration attempts. Moreover, the patient had shown progression of thyrotoxicosis, which justified the choice of surgical intervention. The surgical indication was correct because the histological examination was positive for papillary carcinoma.\n\nIn conclusion, we believe that every medical or surgical intervention must be aimed at improving or maintaining the patient’s health and quality of life; therefore, we must try to overcome technical complexity where possible. The collaboration of an experienced team is essential to obtain satisfactory results, especially in the most challenging cases.\n\nDeclaration of Competing Interest\nThe authors have no conflicts of interest to disclose.\n\nFunding\nNo funding\n\nEthics approval\nFor single case report NO ethical approval needs. Patient signed a consent for publishing the case report.\n\nConsent\nPatient signed a consent for the publication of this case report.\n\nAuthor contribution\nEC and BA wrote the case report. AS and UM revised the case report.\n\nRegistration of Research Studies\nEthical Board approval is not required for case reports in our Center.\n\nGuarantor\nProf. Uliano Morandi is the Guarantor of this case report.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed\n\nAcknowledgements\nNot applicable.\n==== Refs\nReferences\n1 Jones E. Mazirka P. McNurlan M.A. Darras F. Gelato M.C. Caso G. Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes World J. Virol. 6 3 2017 53 58 Epub 2017 Aug 12 28868243 \n2 Kumar N.S. Shashibhushan J. Malappa Venugopal K. Vishwanatha H. Clin Menon M.J. Lipodystrophy in Human Immunodeficiency Virus (HIV) Patients on Highly Active Antiretroviral Therapy (HAART) Diagn Res. 9 July7 2015 OC05 8 Epub 2015 Jul 1 \n3 Ceccato M.G. Bonolo P.F. Souza Neto A.I. Araújo F.S. Freitas M.I. Antiretroviral therapy-associated dyslipidemia in patients from a reference center in Brazil Braz. J. Med. Biol. Res. 44 November 11 2011 1177-83. Epub 2011 Oct 7 \n4 Balasubramanyam A. Sekhar R.V. Jahoor F. Jones P.H. Pownall H.J. Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of’ systemic steatosis’ Curr. Opin. Lipidol. 15 February 1 2004 59 67 Review 15166810 \n5 Lake J.E. Stanley T.L. Apovian C.M. Bhasin S. Brown T.T. Capeau J. Currier J.S. Dube M.P. Falutz J. Grinspoon S.K. Guaraldi G. Martinez E. McComsey G.A. Sattler F.R. Erlandson K.M. Practical review of recognition and management of obesity and lipohypertrophy in human immunodeficiency virus infection Clin. Infect. Dis. 64 May 10 2017 1422 1429 Review 28329372 \n6 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n7 Esser S. Helbig D. Hillen U. Dissemond J. Grabbe S. Side effects of HIV therapy J. Dermatol. Ges. 5 September 9 2007 745-54. Review \n8 Dell’Isola C. Aprea L. Pizzella T. Izzo C. Effect of anti-retroviral therapy on body composition changes: a literature review Infez. Med. 14 September 1 2006 5 12 16794374 \n9 Falutz J. Therapy insight: body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy Nat. Clin. Pract. Endocrinol. Metab. 3 September 9 2007 651 661 17710086\n\n",
"fulltext_license": "CC BY",
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"keywords": "HIV positive; Highly active anti-retroviral therapy (HAART); Lipodystrophy; Thyroidectomy",
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"title": "Total thyroidectomy in HIV positive patient with buffalo hump and taurine neck.",
"title_normalized": "total thyroidectomy in hiv positive patient with buffalo hump and taurine neck"
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"abstract": "Radicular low back pain is difficult to treat and commonly encountered in the Emergency Department (ED). Pain associated with acute radiculopathy results in limited ability to work, function, and enjoy life, and is associated with increased risk of chronic opioid therapy. In this case report, we describe the first ED-delivered ultrasound-guided caudal epidural steroid injection (ESI) used to treat medication-refractory lumbar radiculopathy, which resulted in immediate and sustained resolution of pain.\n\n\n\nA 56-year old man with a past medical history of chronic lumbar radiculopathy presented to the ED with acute low back and right lower-extremity pain. Based on history and physical examination, a right L5 radiculopathy was suspected. His pain was poorly controlled despite multimodal analgesia, at which point he was offered admission or an ultrasound-guided caudal ESI. The procedure was performed using dexamethasone, preservative-free normal saline, and preservative-free 1% lidocaine solution, after which the patient reported 100% resolution of his pain and requested discharge from the ED. Why Should an Emergency Physician Be Aware of This? The safety and efficacy of ultrasound-guided caudal ESIs have been established, but there is a paucity of literature exploring their application in the ED. We present a case of a refractory lumbar radiculopathy successfully treated with an ultrasound-guided caudal ESI. ED-performed epidurals can be one additional tool in the emergency physician arsenal to treat acute or chronic lumbar radiculopathy.",
"affiliations": "Department of Emergency Medicine, University of California San Diego, San Diego, California.;Department of Emergency Medicine, University of California San Diego, San Diego, California; Department of Anesthesiology & Center for Pain Management, University of California San Diego, La Jolla, California. Electronic address: Jessica.Oswaldem@gmail.com.",
"authors": "Bubic|Irvan J|IJ|;Oswald|Jessica|J|",
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"journal": "The Journal of emergency medicine",
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"title": "Ultrasound-Guided Caudal Epidural Steroid Injection for Back Pain: A Case Report of Successful Emergency Department Management of Radicular Low Back Pain Symptoms.",
"title_normalized": "ultrasound guided caudal epidural steroid injection for back pain a case report of successful emergency department management of radicular low back pain symptoms"
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"abstract": "BACKGROUND\nVenous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy.\n\n\nOBJECTIVE\nWe aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL.\n\n\nMETHODS\nAll patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005-2017 were included.\n\n\nRESULTS\nThere were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0-1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event.\n\n\nCONCLUSIONS\nAmong our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.",
"affiliations": "Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Leslie and Michael Gaffin Center for Neuro-Oncology, Departments of Oncology and Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, NachmiasB@gmail.com.",
"authors": "Gazal|Stav|S|;Lebel|Eyal|E|;Kalish|Yosef|Y|;Makranz|Chen|C|;Gatt|Moshe E|ME|;Goldschmidt|Neta|N|;Nachmias|Boaz|B|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin",
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"title": "Venous Thromboembolism Prophylaxis with Low-Molecular-Weight Heparin in Primary Central Nervous System Lymphoma.",
"title_normalized": "venous thromboembolism prophylaxis with low molecular weight heparin in primary central nervous system lymphoma"
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"abstract": "Balanced translocation between chromosomes 3q26 and 8q24 is a very rare event. Here we report six patients with t(3;8)(q26;q24) either as a sole or as a part of genetic abnormalities. Five of the six patients were men with ages ranging from 41 to 84 years old. One patient had a long history of granulocyte colony stimulating factor (G-CSF) treatment. Three of the patients were initially diagnosed with acute myeloid leukemia, two with myelodysplastic syndrome and one with chronic myelogenous leukemia with blast crisis. The peripheral blood in all patients showed severe to moderate anemia; one had absolute neutropenia, one with neutrophilia; four had thrombocytopenia, two with thrombocytosis. The bone marrows from all patients showed dysmegakaryopoiesis with additional erythroid (three patients) and granulocytic (two patients) dysplasia. Cytogenetics revealed t(3;8)(q26;q24) as the sole abnormality in three patients. The majority of patients (4/6) had a poor clinical course, with an average survival of 10 months.",
"affiliations": "Department of Pathology and Immunology, Washington University in St. Louis , St. Louis, MO , USA.",
"authors": "Xu|Xiangdong|X|;Su|Mu|M|;Levy|Norman B|NB|;Mohtashamian|Arash|A|;Monaghan|Sara|S|;Kaur|Prabhjot|P|;Zaremba|Charles|C|;Garcia|Rolando|R|;Broome|H Elizabeth|HE|;Dell'Aquila|Marie L|ML|;Wang|Huan-You|HY|",
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"issue": "55(11)",
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"keywords": "Acute myeloid leukemia; EVI1; MDS1; myeloid dysplastic syndrome; t(3;8)(q26;q24)",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001752:Blast Crisis; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D059785:Karyotype; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D014178:Translocation, Genetic",
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"title": "Myeloid neoplasm with t(3;8)(q26;q24): report of six cases and review of the literature.",
"title_normalized": "myeloid neoplasm with t 3 8 q26 q24 report of six cases and review of the literature"
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... |
{
"abstract": "Hypocalcaemia is known for its neuromuscular symptoms, which are rapidly alleviated by intravenous supplementation. Calcium is also essential for both cardiac cell excitability and contraction. We present a case of acute heart failure due to hypocalcaemia in a young male with a complex medical history.\nHypocalcaemia is a rare cause of acute heart failure.All clinical decisions, although correct and necessary, may have grave consequences in the short and long term.Childhood cancer survivors have an excess risk of developing multiple complications, namely heart failure and lung fibrosis.",
"affiliations": "Internal Medicine Department, Centro Hospitalar de São João, Porto, Portugal.;Internal Medicine Department, Hospital CUF, Porto, Portugal.;Internal Medicine Department, Hospital CUF, Porto, Portugal.",
"authors": "Costa|Inês Almeida|IA|;Alvelos|Margarida|M|;Bettencourt|Paulo|P|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2017_000745",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2017_000745745-1-4132-1-10-20171010ArticlesHypocalcaemia as a Reversible Cause of Acute Heart Failure in a Long-Term Survivor of Childhood Cancer Costa Inês Almeida 1Alvelos Margarida 2Bettencourt Paulo 2\n1 Internal Medicine Department, Centro Hospitalar de São João, Porto, Portugal\n2 Internal Medicine Department, Hospital CUF, Porto, Portugal2017 11 10 2017 4 10 00074518 9 2017 23 9 2017 © EFIM 20172017This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseHypocalcaemia is known for its neuromuscular symptoms, which are rapidly alleviated by intravenous supplementation. Calcium is also essential for both cardiac cell excitability and contraction. We present a case of acute heart failure due to hypocalcaemia in a young male with a complex medical history.\n\nLEARNING POINTS\nHypocalcaemia is a rare cause of acute heart failure.\n\nAll clinical decisions, although correct and necessary, may have grave consequences in the short and long term.\n\nChildhood cancer survivors have an excess risk of developing multiple complications, namely heart failure and lung fibrosis.\n\nHypocalcaemiaheart failurelong-term survivorchildhood cancer\n==== Body\nCASE DESCRIPTION\nWe present the case of a 23-year-old Caucasian male who was diagnosed with Hodgkin’s lymphoma at the age of 3. He first received chemotherapy with vinblastine, etoposide, bleomycin and prednisone plus radiotherapy, but due to an unsatisfactory response after four cycles he was changed to vincristine, prednisone, procarbazine and doxorubicin. He was considered in full remission at the age of 5.\n\nAbout 10 years later, at a follow-up visit, a new cervical lump was found. The lymph node histology was compatible with thyroid papillary carcinoma and staging showed extra-thyroid invasion, with lung and nodal metastasis. Total thyroidectomy with bilateral cervical lymph node dissection was performed in 2005, combined with eight cycles of radioiodine from 2005 to 2012. After surgery, he was started on levothyroxine, calcium carbonate and calcitriol.\n\nDuring follow-up our patient started complaining of mild exertional dyspnoea. Lung computed tomography (CT) showed diffuse lung fibrosis; pulmonary function tests (PFTs) were suggestive of mainly restrictive lung disease. He was then admitted to our heart failure and pulmonary hypertension specialty clinic in 2013. At admission he complained of fatigability, dyspnoea at rest and orthopnoea.\n\nEchocardiogram estimated a pulmonary artery systolic pressure (PASP) of 60 mmHg, with a markedly dilated right ventricle and mild right systolic dysfunction, but preserved left systolic function. Cardiac catheterization confirmed a PASP of 70 mmHg, a high pulmonary vascular resistance index (7.32 Wood units) but no response to stimulation with iloprost.\n\nA diagnosis of pre-capillary pulmonary hypertension and lung fibrosis due to radiotherapy and chemotherapy was made. Symptomatic treatment with furosemide 80 mg per day was started and he was discharged.\n\nA few weeks later our patient was re-admitted because of severe worsening of dyspnoea, de novo diplopia and muscle cramps. Physical examination showed blood pressure 108/62 mmHg, heart rate 82 beats per minute, and oxygen saturation of 94% with a fraction of inspired oxygen of 0.21; rales were audible in the lower halves of both lungs and there was no peripheral oedema. Trousseau’s sign was elicited while measuring blood pressure. Arterial blood gas analysis showed very low ionized calcium, confirmed by serum measurements: 0.48 mmol/l (normal range: 1.13–1.32 mmol/l). Echocardiogram showed severe systolic cardiac dysfunction, with an estimated ejection fraction of 16%; cardiac magnetic resonance (MR) excluded constrictive pericarditis and confirmed global and severe systolic dysfunction. A diagnosis of acute heart failure and neuromuscular irritability due to severe hypocalcaemia was made. Intravenous calcium supplementation was initiated under close cardiac monitoring.\n\nOur patient showed an uneventful recovery. At discharge he had mild exertional dyspnoea, serum ionized calcium level was 1.16 mmol/l and an echocardiogram showed improved systolic function with an estimated left ventricle ejection fraction of 42%.\n\nDISCUSSION\nWhat is already known\nClinicians are aware of tetany as a hallmark presentation of acute hypocalcaemia. Neuromuscular irritability symptoms – such as muscle spasms and cramps, perioral numbness, paraesthesias of hand and feet, clumsiness and, in severe cases, carpopedal spasm and seizures – must be promptly recognized and addressed. The classic physical findings of this neuromuscular irritability are Chvostek and Trousseau’s signs. Chvostek’s sign is sensitive but less specific, while Trousseau’s sign is less frequent but more specific, and implies more severe and sustained hypocalcaemia[1].\n\nWhat is new\nSevere hypocalcaemia is a rare but possible cause of acute heart failure. The absolute quantity of ionized calcium that crosses the sarcolemma and the transverse tubules of cardiac cells is insufficient to bring about full activation of the contractile apparatus. Calcium influx into the cardiac cell triggers the release of calcium from the sarcoplasmic reticulum, in a process called calcium-induced calcium release. As a consequence, cardiac muscle contraction ensues[2,3]. When hypocalcaemia is present, cardiac performance – estimated by ejection fraction – is reduced. All cases of heart failure due to hypocalcaemia published so far demonstrated full systolic dysfunction recovery with calcium supplementation [2–4].\n\nWhy is it significant\nThis case illustrates how medical iatrogenesis parallels our practice, no matter how thorough and correct it is. This patient presented with acute heart failure due to hypocalcaemia, and we hypothesize that it was precipitated by starting furosemide, since this drug indirectly promotes calcium release to the lumen of the ascending loop of Henle. The literature also suggests that the calcium-lowering effect of furosemide tends to be greater in the presence of established hypoparathyroidism.\n\nThis patient also serves as an example of how live-saving treatments in childhood often have grave consequences in the long run. In fact, Mertens et al. showed that childhood cancer survivors have an all-cause absolute excess risk of 8.8 deaths per 1,000 person-years, which is 10.8 times greater than that in general population[5]. The diminished health status and premature death risk seem to derive from both disease recurrence and other causes of death, 21.3% of which can be attributed to treatments, such as anthracycline-related heart failure and pulmonary restrictive disease and/or lung fibrosis after chemotherapy and radiotherapy exposure[5,6]. It is also known that organ damage might not be clinically evident until many years later[6]. Consequently, long-term follow-up of childhood cancer survivors is vital to quickly detect and address complications and to promote secondary prevention (smoking cessation, weight loss and exercise, for example). Cohort studies and case reports also have a role in determining which treatment modalities carry the highest risk and which co-morbidities are to be expected[6].\n\nIn conclusion, we present a rare cause of acute heart failure in a young patient with a complex medical history. It is also a model case for keeping in mind that all medical decisions, even when live-saving, have consequences in the short and long term.\n\nAcknowledgements\nWe thank Professor Reinold Gans, head and chairman of the Department of Internal Medicine at University Medical Center Groningen (The Netherlands) and president of the UEMS Section of Internal Medicine, for comments that greatly improved the manuscript.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Cooper MS Gittoes NJL Diagnosis and management of hypocalcaemia BMJ 2008 336 1298 1302 18535072 \n2 Newman DB Fidahussein SS Kashiwagi DT Kennel KA Kashani KB Wang Z Reversible cardiac dysfunction associated with hypocalcemia: a systematic review and meta-analysis of individual patient data Heart Fail Rev 2014 19 199 205 23355181 \n3 Catalano A Basile G Lasco A Hypocalcemia: a sometimes overlooked cause of heart failure in the elderly Aging Clin Exp Res 2012 24 400 403 23238316 \n4 Suzuki T Ikeda U Fujikawa H Saito K Shimada K Hypocalcemic heart failure: a reversible form of heart muscle disease Clin Cardiol 1998 21 227 228 9541771 \n5 Mertens AC Yasui Y Neglia JP Potter JD Nesbit ME Jr Ruccione K Late mortality experience in five-year survivors of childhood and adolescent cancer: the childhood cancer survivor study J Clin Oncol 2001 19 3163 3172 11432882 \n6 Oeffinger KC Mertens AC Sklar CA Kawashima T Hudson MM Meadows AT Chronic health conditions in adult survivors of childhood cancer N Engl J Med 2006 355 1572 1582 17035650\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "4(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Hypocalcaemia; childhood cancer; heart failure; long-term survivor",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000745",
"pmc": null,
"pmid": "30755917",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "11432882;17035650;18535072;23238316;23355181;9541771",
"title": "Hypocalcaemia as a Reversible Cause of Acute Heart Failure in a Long-Term Survivor of Childhood Cancer.",
"title_normalized": "hypocalcaemia as a reversible cause of acute heart failure in a long term survivor of childhood cancer"
} | [
{
"companynumb": "PT-FRESENIUS KABI-FK201809845",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPrognosis for relapsed/refractory high-risk neuroblastoma (HR-NBL) remains poor. Bortezomib, a proteasome inhibitor, has shown preclinical activity against NBL as a single agent and in combination with cytotoxic chemotherapy including irinotecan.\n\n\nMETHODS\nEighteen HR-NBL patients with primary refractory (n = 8) or relapsed (n = 10) disease were enrolled in a Phase I study using modified Time To Event Continual Reassessment Method. Bortezomib (1.2 mg/m2 /day) was administered on days 1, 4, 8, and 11 intravenously (IV) and irinotecan was given IV on days 1-5 (35, 40, or 45 mg/m2 /day, on dose levels [DL] 1-3, respectively). The maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and response rate were examined.\n\n\nRESULTS\nEighteen NBL patients were evaluable for toxicity; 17 were evaluable for response assessment. A total of 142 courses were delivered (mean 8.2, median 2, range 1-48), with two patients receiving more than 40 courses of therapy. Two DLTs were reported, including a grade 4 thrombocytopenia (DL2) and a grade 3 irritability (DL3). MTD was estimated as DL3. Two of 17 (12%) evaluable patients showed objective responses (ORs) lasting more than 40 courses, including 1 partial remission and 1 complete remission. Four patients (23%) had prolonged stable disease (SD) lasting six or more courses, with a total of 35% study patients demonstrating clinical benefit in the form of prolonged OR or SD.\n\n\nCONCLUSIONS\nThe combination of bortezomib and irinotecan was well tolerated by patients with relapsed/refractory NBL with favorable toxicity profile. It also showed modest but promising clinical activity and merits further testing in Phase II studies.",
"affiliations": "Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.;Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.",
"authors": "Mody|Rajen|R|;Zhao|Lili|L|;Yanik|Gregory Anthony|GA|;Opipari|Valerie|V|",
"chemical_list": "D000069286:Bortezomib; D000077146:Irinotecan; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26563",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(11)",
"journal": "Pediatric blood & cancer",
"keywords": "irinotecan; proteasome inhibitor; relapsed/refractory high-risk neuroblastoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D002166:Camptothecin; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009447:Neuroblastoma; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28436582",
"pubdate": "2017-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma.",
"title_normalized": "phase i study of bortezomib in combination with irinotecan in patients with relapsed refractory high risk neuroblastoma"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US21535",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nOpioid therapy for pain relief is associated with several adverse effects. Herein, we report the potential consequences of opioid use on the adrenal function.\n\n\nMETHODS\nA 49-year-old woman with sickle cell anemia (Hemoglobin SS) was admitted for the treatment of a vaso-occlusive crisis. Morphine was used for pain management, provided by intravenous intermittent dosing (patient-controlled analgesia). She developed during the hospitalization low blood pressure, due to secondary adrenal insufficiency (cortisol 74 nmol/L; ACTH 2.9pmol/L). Pituitary gland was normal on brain magnetic resonance imaging and adrenal function recovered after morphine discontinuation.\n\n\nCONCLUSIONS\nOpioids suppress cortisol secretion, primarily mediated by direct negative effect on hypothalamus and pituitary gland. Further studies are needed to define the incidence and the clinical significance of opioid-induced adrenal insufficiency, as well as the need for hormone replacement.",
"affiliations": "Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France. Electronic address: edouard.flamarion@aphp.fr.;Service de médecine interne, hôpital Henri-Mondor, université Paris Est Créteil, Assistance publique-Hôpitaux de Paris, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service d'accueil des urgences et département d'aval des urgences, hôpital Henri-Mondor, université Paris Est Créteil, Assistance publique-Hôpitaux de Paris, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France.;Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France.;Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France.;Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France.;Service de médecine interne, hôpital européen Georges-Pompidou, université Paris Descartes, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France.",
"authors": "Flamarion|E|E|;Saada|N|N|;Khellaf|M|M|;Michon|A|A|;Passeron|A|A|;Pouchot|J|J|;Arlet|J-B|JB|;Ranque|B|B|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2019.07.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "40(11)",
"journal": "La Revue de medecine interne",
"keywords": "Drug toxicity; Drépanocytose; Iatrogénie; Insuffisance surrénale secondaire; Opioids; Opioïdes; Secondary adrenal insufficiency; Sickle cell disease",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000309:Adrenal Insufficiency; D000701:Analgesics, Opioid; D000755:Anemia, Sickle Cell; D000818:Animals; D005260:Female; D006801:Humans; D008875:Middle Aged; D009020:Morphine",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "758-763",
"pmc": null,
"pmid": "31444021",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Opioid-induced adrenal insufficiency: Case report and synthesis of the literature.",
"title_normalized": "opioid induced adrenal insufficiency case report and synthesis of the literature"
} | [
{
"companynumb": "FR-PFIZER INC-2019426571",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": "1",
... |
{
"abstract": "Volatile anaesthetic agents are known to cause acute hepatitis and fulminant hepatic failure in susceptible individuals. Four patients were identified with prolonged liver injury due to volatile anaesthetic-induced hepatitis. Three had liver biopsy confirmation and all gave blood for specific diagnostic tests (TFA and CYP 2E1 IgG4 antibodies). The Roussel Uclaf Causality Assessment Method (RUCAM) drug causality scale was used to determine the likelihood of volatile anaesthetics causing the chronic liver injury. We describe four cases of volatile anaesthetic hepatitis in which three evolved into chronic hepatitis. The fourth followed a more typical pattern of acute hepatitis; however, resolution took a few months. These cases all occurred with modern volatile anaesthetics, predominantly sevoflurane, and all cases were proven with specific antibody tests, liver histology and a drug causality scale. This is the first report of chronic liver injury due to volatile anaesthetic exposure.",
"affiliations": "Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. Amanda.nicoll@mh.org.au",
"authors": "Nicoll|Amanda|A|;Moore|David|D|;Njoku|Dolores|D|;Hockey|Brad|B|",
"chemical_list": "D000777:Anesthetics; D008738:Methyl Ethers; D000077149:Sevoflurane",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2012()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000777:Anesthetics; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006505:Hepatitis; D006521:Hepatitis, Chronic; D006801:Humans; D008099:Liver; D017114:Liver Failure, Acute; D008297:Male; D008738:Methyl Ethers; D008875:Middle Aged; D000077149:Sevoflurane; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23131606",
"pubdate": "2012-11-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7286784;8229110;8989020;19362101;12411515;10958225;17133470;8014443;15242813;15684249;16554286;11124828;12637791;9303497;17275868;11124850;19032721;12016546;19155082;21105110;4412436;18300198;3769709;18955056;17555424;17513640;8794896;5091889;8902272;11812677;16467335;5635878;15479268;18052104",
"title": "Repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury.",
"title_normalized": "repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury"
} | [
{
"companynumb": "AU-MYLANLABS-2015M1003108",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.",
"affiliations": "Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan.;Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Division of Respirology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Respiratory Medicine, National Hospital Organization Fukuoka-Higashi Medical Center, Koga, Fukuoka, Japan.;Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Osaka, Japan.;Department of Respiratory Medicine, Steel Memorial Yawata Hospital, Kitakyushu, Japan.;Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan okamotoi@kokyu.med.kyushu-u.ac.jp.",
"authors": "Otsubo|Kohei|K|0000-0002-9476-8840;Sakai|Kazuko|K|;Takeshita|Masafumi|M|;Harada|Daijiro|D|;Azuma|Koichi|K|;Ota|Keiichi|K|;Akamatsu|Hiroaki|H|;Goto|Koichi|K|;Horiike|Atsushi|A|;Kurata|Takayasu|T|;Nakagaki|Noriaki|N|;Nosaki|Kaname|K|;Iwama|Eiji|E|;Nakanishi|Yoichi|Y|;Nishio|Kazuto|K|;Okamoto|Isamu|I|0000-0002-7587-6096",
"chemical_list": "D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; C508053:ERBB2 protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2019-0101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(8)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung; D000074141:Circulating Tumor DNA; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005240:Feasibility Studies; D005260:Female; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D018719:Receptor, ErbB-2",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1022-1026",
"pmc": null,
"pmid": "31023862",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25948633;26141217;25939061;27751847;27354477;27283993;30289575;28177428;28221867;30496436;26473927;23470965;24705333;30187675;18408761;27959700;17463250;22956644;27018799;22888144;29506987;30336693",
"title": "Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA.",
"title_normalized": "genetic profiling of non small cell lung cancer at development of resistance to first or second generation egfr tkis by capp seq analysis of circulating tumor dna"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-101254",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "Early recognition and treatment of seizures is essential for optimal patient outcomes. Seizure activity, particularly in young children, can be subtle and often go unrecognized by providers. This case series retrospectively identified 7 cases of pediatric patients (14 years and younger) who presented to the emergency department with active seizure activity that was unrecognized by the prehospital care providers. The presentation of these patients, their clinical signs of seizure, and emergency department disposition are highlighted in this series.",
"affiliations": "From the Keck School of Medicine of the University of Southern California and, Department of Emergency Medicine, Los Angeles County + University of Southern California Medical Center, Los Angeles, CA.",
"authors": "Rose|Emily|E|;Abramson|Tiffany M|TM|;Kearl|Yvette L|YL|;Loza-Gomez|Angelica|A|",
"chemical_list": "D000927:Anticonvulsants; D008140:Lorazepam",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001941",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "35(10)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D042241:Early Diagnosis; D004632:Emergency Medical Services; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008140:Lorazepam; D015141:Los Angeles; D008297:Male; D012189:Retrospective Studies; D012640:Seizures; D013226:Status Epilepticus",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e177-e180",
"pmc": null,
"pmid": "31524823",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Active Seizures in Children Are Often Subtle and Unrecognized by Prehospital Providers.",
"title_normalized": "active seizures in children are often subtle and unrecognized by prehospital providers"
} | [
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"companynumb": "US-UCBSA-2020006712",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
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{
"abstract": "BACKGROUND\nPulmonary thromboembolism (PTE) is a potentially life-threatening condition with high morbidity and mortality, and computed tomographic pulmonary angiography (CTPA) is an important diagnostic tool for patients in whom PTE is suspected; however, intraoperative PTE is very difficult to diagnose and often has a rapid clinical course. We experienced a case of intraoperative PTE with persistent tachycardia refractory to conventional treatments despite negative preoperative CTPA findings.\nA 53-year-old man with a pelvic bone fracture who had been on bed rest for 10 days underwent open reduction and internal fixation under general anesthesia. He remained tachycardic (heart rate of 120 beats/min) despite treatments with fluid resuscitation, analgesics, and beta-blockers.\nPreoperative CTPA, computed tomography (CT) venography, and transthoracic echocardiography showed no signs of deep vein thrombosis and PTE. However, the levels of D-dimer were elevated. After the start of the surgery, tachycardia (heart rate between 100 and 110 beats/min) could not be treated with fluid resuscitation. Systolic blood pressure was maintained between 90 and 100 mm Hg using continuous infusion of phenylephrine. Ninety minutes after the surgery, systolic and diastolic blood pressures suddenly dropped from 100/60 to 30/15 mm Hg with a decrease in end-tidal carbon dioxide concentration from 29 to 13 mm Hg and development of atrial fibrillation. Arterial blood gas analysis revealed hypercapnia. Under the suspicion of PTE, cardiopulmonary resuscitation (CPR) was immediately initiated. Three CPR cycles raised the blood pressure back to 90/50 mm Hg with sinus tachycardia (115 beats/min). Transesophageal echocardiography showed right ventricular dysfunction and paradoxical septal motion. However, emboli were not found. Postoperative chest CT revealed massive PTE in both pulmonary arteries.\n\n\nMETHODS\nImmediately, surgical embolectomy was performed uneventfully.\n\n\nRESULTS\nThe patient was discharged from the hospital 1 month later without any complications.\n\n\nCONCLUSIONS\nThe patient with moderate risk for PTE (heart rate > 95 beats/min and immobilization, surgery under general anesthesia, and lower limb fracture within 1 month) should be closely monitored and managed intraoperatively even if preoperative CTPA findings are negative. The development of PTE needs to be expected if tachycardia is refractory to conventional treatments.",
"affiliations": "Department of Anesthesiology and Pain Medicine, School of Medicine, Daegu Catholic University.;Department of Anesthesiology and Pain Medicine, School of Medicine, Daegu Catholic University.;Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Anesthesiology and Pain Medicine, School of Medicine, Daegu Catholic University.",
"authors": "Kim|Jong Hae|JH|;Lim|Hyungseop|H|;Kim|Hyun Mi|HM|;Lim|Jung A|JA|0000-0002-7427-5483",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026658",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-03373\n10.1097/MD.0000000000026658\n26658\n3300\nResearch Article\nClinical Case Report\nIntraoperative development of pulmonary thromboembolism in a bedridden patient owing to a pelvic bone fracture with negative preoperative computed tomography pulmonary angiographic findings\nA case report\nKim Jong Hae MD a\nLim Hyungseop MD a\nKim Hyun Mi MD b\nhttp://orcid.org/0000-0002-7427-5483\nLim Jung A. MD a∗\nSaranathan. Maya\na Department of Anesthesiology and Pain Medicine, School of Medicine, Daegu Catholic University\nb Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Korea.\n∗ Correspondence: Jung A. Lim, Department of Anesthesiology and Pain Medicine, School of Medicine, Daegu Catholic University, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472 Republic of Korea (e-mail: definitebud@naver.com).\n23 7 2021\n23 7 2021\n100 29 e266582 5 2021\n7 6 2021\n28 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\nRationale:\n\nPulmonary thromboembolism (PTE) is a potentially life-threatening condition with high morbidity and mortality, and computed tomographic pulmonary angiography (CTPA) is an important diagnostic tool for patients in whom PTE is suspected; however, intraoperative PTE is very difficult to diagnose and often has a rapid clinical course. We experienced a case of intraoperative PTE with persistent tachycardia refractory to conventional treatments despite negative preoperative CTPA findings.\n\nPatient concerns:\n\nA 53-year-old man with a pelvic bone fracture who had been on bed rest for 10 days underwent open reduction and internal fixation under general anesthesia. He remained tachycardic (heart rate of 120 beats/min) despite treatments with fluid resuscitation, analgesics, and beta-blockers.\n\nDiagnoses:\n\nPreoperative CTPA, computed tomography (CT) venography, and transthoracic echocardiography showed no signs of deep vein thrombosis and PTE. However, the levels of D-dimer were elevated. After the start of the surgery, tachycardia (heart rate between 100 and 110 beats/min) could not be treated with fluid resuscitation. Systolic blood pressure was maintained between 90 and 100 mm Hg using continuous infusion of phenylephrine. Ninety minutes after the surgery, systolic and diastolic blood pressures suddenly dropped from 100/60 to 30/15 mm Hg with a decrease in end-tidal carbon dioxide concentration from 29 to 13 mm Hg and development of atrial fibrillation. Arterial blood gas analysis revealed hypercapnia. Under the suspicion of PTE, cardiopulmonary resuscitation (CPR) was immediately initiated. Three CPR cycles raised the blood pressure back to 90/50 mm Hg with sinus tachycardia (115 beats/min). Transesophageal echocardiography showed right ventricular dysfunction and paradoxical septal motion. However, emboli were not found. Postoperative chest CT revealed massive PTE in both pulmonary arteries.\n\nInterventions:\n\nImmediately, surgical embolectomy was performed uneventfully.\n\nOutcomes:\n\nThe patient was discharged from the hospital 1 month later without any complications.\n\nLessons:\n\nThe patient with moderate risk for PTE (heart rate > 95 beats/min and immobilization, surgery under general anesthesia, and lower limb fracture within 1 month) should be closely monitored and managed intraoperatively even if preoperative CTPA findings are negative. The development of PTE needs to be expected if tachycardia is refractory to conventional treatments.\n\nKeywords\n\ncomputed tomographic pulmonary angiography\npelvic bone fracture\npulmonary thromboembolism\ntachycardia\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nPulmonary thromboembolism (PTE) is a rare but potentially life-threatening condition associated with high morbidity and mortality.[1,2] The prevalence of PTE is 4.6% in critically ill trauma patients (n = 153) receiving thromboprophylaxis therapy, among whom patients with pelvic bone fracture had an odds ratio of 3.04 for the development of venous thromboembolism.[3] In addition, the incidence of PTE was the highest (0.78%) in patients undergoing pelvic open reduction and internal fixation among 11,313 adult trauma patients on thromboprophylaxis therapy.[4] Therefore, more attention should be paid to the development of PTE in patients with a pelvic bone fracture.\n\nPerioperatively (before and after surgery), computed tomographic pulmonary angiography (CTPA) and D-dimer test are the mainstay for diagnosing PTE in patients with suspected PTE in the absence of hemodynamic instability.[5] However, intraoperative PTE is very difficult to diagnose and often has a rapid clinical course. Furthermore, the results of preoperative tests do not take effect until the intraoperative period because the physiological milieu changes under both the anesthetic and surgical conditions. Nevertheless, there are limited predictive factors for PTE and no available guidelines for its screening. The obstruction of the pulmonary arteries (the mechanism of PTE) is often accompanied by nonspecific hemodynamic changes, such as normal blood pressure compensated for by tachycardia.[6] Catecholamine-driven tachycardia in combination with right ventricular dilatation is an important compensatory mechanism to maintain cardiac output. However, normal blood pressure with tachycardia may not always indicate PTE because other confounding factors affect intraoperative hemodynamics, such as underlying cardiovascular or autonomic diseases, anesthetics, bleeding, fluid shifting, etc. Therefore, it would be reasonable to suspect the occurrence of PTE in patients at risk for PTE if tachycardia persists even after all the candidate causes other than PTE are ruled out. In addition, given the fact that the development of shock and the severity of hemodynamic compromise are important predictive and prognostic factors for mortality,[7] close monitoring of vital signs to identify and halt the progress of PTE is mandatory.\n\nHerein, we report intraoperative development of PTE preceded by tachycardia refractory to conventional treatments in a bedridden patient owing to a pelvic bone fracture with no evidence of deep vein thrombosis (DVT) and PTE on preoperative CTPA and computed tomography (CT) venography.\n\n2 Case report\n\nA 53-year-old man (height, 180 cm; weight, 76.6 kg), a heavy alcoholic, was admitted to a local medical center under the diagnosis of right acetabular and iliac wing fracture after falling from a tree. The patient was bedridden under conservative treatment. Three days later, he presented with abdominal pain and tenderness and was then transferred to our hospital for further evaluation and management. The systolic/diastolic blood pressure, heart rate on electrocardiogram, and body temperature were 160/94 mm Hg, 120 beats/min, and 37.5°C, respectively. Under the suspicion of dehydration and fracture-induced pain, fluid resuscitation was initiated with Hartmann solution and analgesics were administered. Nonetheless, the heart rate did not decrease. Hence, bisoprolol (5 mg per os) was administered once daily. Thiamine, haloperidol, and quetiapine were administered to treat alcohol withdrawal delirium. Every time the patient became responsive to verbal stimuli, he kept reporting abdominal pain. However, no pulmonary symptoms were present. Anteroposterior chest radiograph and transthoracic echocardiography (TTE) were normal. Abdominal CT revealed retroperitoneal and right iliacus hematoma. However, no injury was found in major vessels or organs. The laboratory findings showed increased levels of D-dimer (26.64 μg/mL), the normal range of which was < 0.1 μg/mL. Because he was immobilized after the injury with elevated levels of D-dimer, combined CT venography and CTPA was performed 7 days after the injury to rule out DVT and PTE; however, the results were negative.\n\nThree days later (10 days after the injury), he presented to the operating room for open reduction and internal fixation of the pelvic bone fracture. Before anesthesia induction, the systolic/diastolic blood pressure, heart rate, and peripheral oxygen saturation (SpO2) were 142/92 mm Hg, 100 beats/min, and 100%, respectively. Anesthesia was induced with bolus administration of 130 mg propofol and continuous infusion of remifentanil at 0.1 μg/kg/min. Endotracheal intubation was facilitated with 50 mg rocuronium. The ventilator was set in the volume-controlled mode to deliver a tidal volume of 6 to 8 mL/kg at a respiratory rate of 10 to 12 breaths/min. The tidal volume and respiratory rate were adjusted to maintain end-tidal carbon dioxide concentration (EtCO2) between 33 and 35 mm Hg. Anesthesia was maintained with sevoflurane (1.5–2.0 vol%) in oxygen/air mixture (inspired oxygen saturation of 50%) to ensure bispectral index values between 40 and 60. The infusion rate of remifentanil (0.1–0.2 μg/kg/min) was adjusted to maintain blood pressure and heart rate within 20% of the baseline values. The right radial artery was catheterized for real-time monitoring of arterial blood pressure and arterial blood sampling. The right internal jugular vein was catheterized for real-time monitoring of central venous pressure, bolus administration of drugs, and continuous infusion of drugs. The results of arterial blood gas analysis after anesthesia induction were as follows: pH, 7.468; partial pressure of arterial carbon dioxide (PaCO2), 37.2 mm Hg; partial pressure of arterial oxygen (PaO2), 193.5 mm Hg; bicarbonate (HCO3−), 26.3 mmol/L; base excess, 2.6 mmol/L; hemoglobin, 8.2 g/dL.\n\nAt 10 minutes before the surgery, 100 μg phenylephrine was bolus administered twice at a 5-minute interval to ensure a systolic blood pressure of > 100 mm Hg. At the beginning of the surgery, phenylephrine was continuously infused at a rate of 0.2 μg/kg/min owing to the transient effects of its bolus administration. To compensate for intraoperative blood loss and preoperative dehydration, 6% hydroxyethyl starch, packed red blood cells, and fresh frozen plasma were administered at a rate of 8 to 10 mL/kg/min, and systolic blood pressure and heart rate were maintained between 90 and 100 mm Hg and between 100 and 110 beats/min, respectively. Ninety minutes after the surgery, systolic/diastolic arterial blood pressure and EtCO2 abruptly decreased from 100/60 to 30/15 mm Hg and from 29 to 13 mm Hg, respectively. The central venous pressure elevated from 10 to 29 mm Hg. The heart rate slightly increased from 105 to 115 beats/min. The normal sinus rhythm on the electrocardiogram turned into atrial fibrillation, after which bradycardia (49 beats/min) ensued. Under the impression of PTE, 3 cycles of cardiopulmonary resuscitation (CPR) were intermittently performed for 25 minutes until spontaneous circulation [systolic/diastolic blood pressure of 80–90/50 mm Hg and sinus tachycardia (115 beats/min)] was achieved (Fig. 1). At the beginning of CPR, epinephrine and norepinephrine were infused at a rate of 0.1 μg/kg/min, and 3 mg epinephrine was bolus administered during CPR. Arterial blood gas analysis performed between the first 2 CPR cycles revealed hypercapnia (pH, 7.287; PaCO2, 55.8 mm Hg; PaO2, 98.7 mm Hg; HCO3−, 26.0 mmol/L; base excess, −0.6 mmol/L; hemoglobin, 8.8 g/dL). At the end of the last CPR cycle, the infusion rate of the fluid was reduced to 3 to 5 mL/kg/min, and a probe for transesophageal echocardiography (TEE) was inserted into the esophagus. TEE showed right ventricular dysfunction with paradoxical septal motion. However, no embolus was found in the main, right, and left pulmonary arteries. Intraoperatively, 500 mL of 6% hydroxyethyl starch, 1250 mL of packed red blood cells, and 450 mL of fresh frozen plasma were administered in total. The amount of blood loss and urine output was 700 and 100 mL, respectively.\n\nFigure 1 Anesthesia record. CPR = cardiopulmonary resuscitation, CVP = central venous pressure, EtCO2 = end-tidal concentration of carbon dioxide.\n\nChest CT performed immediately after the surgery showed emboli in both the pulmonary arteries (Fig. 2). The patient was taken back to the operating room and underwent surgical embolectomy under cardiopulmonary bypass with aortic cross-clamping and cardioplegic arrest. The incision was made in both the main pulmonary arteries, and emboli were removed (Fig. 3). EtCO2 and central venous pressure were elevated from 20 to 31 mm Hg and reduced from 30 to 4 mm Hg, respectively, after weaning from cardiopulmonary bypass. Intraoperative TEE and postoperative TTE showed normalized right ventricular function and septal motion. Anticoagulation therapy with warfarin was commenced from the third postoperative day. The inferior vena cava filter was also placed. One month after the surgery, CTPA and CT venography revealed no DVT and PTE. The patient was then discharged from the hospital without any complications. The patient provided informed consent for the publication of this case.\n\nFigure 2 Chest computed tomography showing the emboli in both pulmonary arteries.\n\nFigure 3 Emboli retrieved from both pulmonary arteries.\n\n3 Discussion\n\nOur patient was immobilized because of a pelvic bone fracture for 10 days before undergoing surgery under general anesthesia. The heart rate was mostly>100 beats/min, and the D-dimer test was positive. On the basis of the above information, the revised Geneva score[8] and Wells score[9] were 10 and 3, respectively, indicating an intermediate and moderate probability of having PTE (27.5–28.5% and 36.1–37.3%), respectively. However, anticoagulation therapy or intermittent pneumatic compression for the prevention of DVT or PTE was not performed because of the risk of bleeding[10] and ischemic events distal to the pelvic bone fracture.[11] Alternatively, CTPA and CT venography were performed to detect any PTE or DVT. Because of its non-invasiveness, availability, and high sensitivity (83%) and specificity (96%), CTPA is widely used in patients at high risk for PTE.[12,13] CTPA combined with CT venography can diagnose DVT and PTE at the same time without using additional radiocontrast and exposure to excessive radiation.[14] As the negative predictive value of CTPA was 89% in patients with a moderate probability (Wells score of 3) based on the results of a previous study,[13] we believed that the negative findings of CTPA and CT venography almost excluded the preoperative development of PTE and DVT in our patient. Accordingly, preoperative echocardiography showed no evidence of PTE (visible embolus or right ventricular global dysfunction). As trauma produces fibrin, the usefulness of the levels of D-dimer is limited for the diagnosis of PTE in this case.[15]\n\nTachycardia occurs frequently in the early stage of PTE. Acute large or multiple PTE increases pulmonary vascular resistance, resulting in an increase in right ventricular afterload. The increased afterload causes right ventricular dysfunction and dilatation that displace the interventricular septum towards the left leading to a reduction in cardiac output and systemic arterial blood pressure, which is compensated for by tachycardia.[16] Accordingly, sustained tachycardia and normal blood pressure were observed in clinical settings.[17] In addition, the Wells score and revised Geneva score that were developed to predict the probability of PTE have heart rate (>100 and ≥ 95 beats/min, respectively) as one of the predictive variables.[8,9] Particularly, the heart rate of ≥95 beats/min has the highest score among the variables included in the revised Geneva score.[8] In our case, until the development of hemodynamic instability attributed to PTE, preoperative and intraoperative heart rates remained > 100 beats/min. Preoperative blood pressure was normal, and intraoperative blood pressure was maintained normal with continuous phenylephrine infusion. Unfortunately, all the perioperative efforts to control the rapid heart rate (administration of analgesics and beta-blockers and fluid management) were unsuccessful. Therefore, it was reasonable to assume that tachycardia was caused by PTE after excluding the candidate causes of tachycardia. However, the evidence of preoperative PTE and DVT was nearly absent on CTPA and CT venography findings. In addition, hypotension after anesthesia induction was easily treated with phenylephrine, and no other significant changes in vital signs were observed until the development of PTE during the surgery. Particularly, general anesthesia and surgery were additional causes of tachycardia (systemic vasodilatation, surgical stimulation, bleeding, preoperative dehydration, insensible loss, etc). Moreover, symptoms related to PTE were masked by general anesthesia. Therefore, it was very challenging to predict the intraoperative development of PTE in our patient.\n\nThus, the intraoperative use of TEE was not indicated for a prompt and accurate diagnosis of PTE in our case. However, it is very regrettable that we did not use TEE after anesthesia induction because PTE actually occurred in our patient. TEE is widely used to confirm the presence of pulmonary emboli and right ventricular dysfunction during surgery without affecting surgical performance.[18–21] It is also helpful in the differential diagnosis of the causes of intraoperative hemodynamic instability, such as hypovolemia, pericardial tamponade, and severe hypokinesia in the left ventricular wall.[22] In a report published in 2004, TEE performed by cardiac anesthesiologists could detect visible emboli immediately before surgery in only 26% of patients undergoing emergent pulmonary embolectomy for severe PTE.[23] However, with advanced technology and increased levels of expertise, a recent study in 2014 reported that the evidence of emboli and the right ventricular strain was found in 87% and 92% of patients with intraoperative massive PTE, respectively.[24] Although delayed, TEE monitoring was commenced after the occurrence of hemodynamic instability, and we found right ventricular dysfunction that indicated the development of PTE. However, pulmonary emboli could not be visualized presumably because of the lack of attending anesthesiologist's proficiency.[25]\n\nAt the beginning of CPR, we infused norepinephrine to increase arterial blood pressure and right ventricular contractility via strong α1 and modest β1 adrenergic effects, respectively. Another beneficial effect of norepinephrine is the restoration of coronary perfusion pressure gradients to the right ventricular subendocardium. In addition, fluid overloading was avoided to reduce right ventricular preload and systolic wall stress that worsen myocardial ischemia and ventricular interdependence. Although systemic administration of vasodilators, such as nitroglycerin or nitroprusside that release nitric oxide, can decrease pulmonary arterial and venous resistance, they may also worsen hypotension and systemic hypoperfusion because their action is not specific to the pulmonary vasculature.[5] Hence, they were not used in our patient. As anticoagulation therapy is indicated for patients with normal blood pressure and right ventricular function,[15] the therapy was not provided to our patient. The presence of hemodynamic instability indicated systemic thrombolysis or surgical embolectomy, and surgical embolectomy was performed because the patient had absolute contraindications to systemic thrombolysis (major trauma or surgery in previous 3 weeks and active bleeding).[5]\n\nOn the basis of our experience, negative CTPA and CT venography findings do not guarantee that intraoperative PTE does not occur in a patient with a moderate probability of having PTE. Although TEE was not used after anesthesia induction in our case, we strongly recommend the intraoperative use of TEE to investigate the causes of hemodynamic instability (including PTE) for patients with a moderate or high probability of having PTE. As tachycardia is an important predictive factor for PTE, anesthesiologists should consider the probability of intraoperative PTE occurrence if tachycardia is refractory to conventional treatments.\n\nIn conclusion, a comprehensive understanding of the risk factors and clinical features of PTE and monitoring and maintaining hemodynamics are mandatory for managing patients at risk of PTE.\n\nAuthor contributions\n\nConceptualization: Jong Hae Kim, Jung A Lim.\n\nData curation: Hyungseop Lim, Hyun Mi Kim, Jung A Lim.\n\nWriting – original draft: Jong Hae Kim, Hyungseop Lim, Jung A Lim.\n\nWriting – review & editing: Jong Hae Kim, Jung A Lim.\n\nAbbreviations: CPR = cardiopulmonary resuscitation, CT = computed tomography, CTPA = computed tomographic pulmonary angiography, DVT = deep vein thrombosis, EtCO2 = end-tidal carbon dioxide concentration, PTE = pulmonary thromboembolism, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography.\n\nHow to cite this article: Kim JH, Lim H, Kim HM, Lim JA. Intraoperative development of pulmonary thromboembolism in a bedridden patient owing to a pelvic bone fracture with negative preoperative computed tomography pulmonary angiographic findings: A case report. Medicine. 2021;100:29(e26658).\n\nThe authors have no conflicts of interest.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Visnjevac O Lee K Bulatovic R . Outcomes-based systematic review for management of massive intra-cardiac or pulmonary thrombotic emboli during surgery. Heart Lung Vessel 2014;6 :24–32.24800195\n[2] Warnaar N Molenaar IQ Colquhoun SD . Intraoperative pulmonary embolism and intracardiac thrombosis complicating liver transplantation: a systematic review. J Thromb Haemost 2008;6 :297–302.18005235\n[3] Hamada SR Espina C Guedj T . High level of venous thromboembolism in critically ill trauma patients despite early and well-driven thromboprophylaxis protocol. Ann Intensive Care 2017;7 :97.28900890\n[4] Lowe JA Mitchell SM Agarwal S Jones CB . The incidence of venous thromboembolism following pelvic and lower extremity trauma despite adherence to modern prophylactic protocols. J Orthop Trauma 2020;34 :418–21.32349027\n[5] Konstantinides SV Meyer G Becattini C . 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019;54 :1901647.31473594\n[6] Capan LM Miller SM . Monitoring for suspected pulmonary embolism. Anesthesiol Clin North Am 2001;19 :673–703.11778377\n[7] Kucher N Rossi E De Rosa M Goldhaber SZ . Massive pulmonary embolism. Circulation 2006;113 :577–82.16432055\n[8] Le Gal G Righini M Roy PM . Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144 :165–71.16461960\n[9] Wells PS Anderson DR Rodger M . Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83 :416–20.10744147\n[10] Magnussen RA Tressler MA Obremskey WT Kregor PJ . Predicting blood loss in isolated pelvic and acetabular high-energy trauma. J Orthop Trauma 2007;21 :603–7.17921834\n[11] Aprahamian C Towne JB Thompson BM . Effect of circumferential pneumatic compression devices on digital flow. Ann Emerg Med 1984;13 :1092–5.6507969\n[12] Moore AJE Wachsmann J Chamarthy MR . Imaging of acute pulmonary embolism: an update. Cardiovasc Diagn Ther 2018;8 :225–43.30057872\n[13] Stein PD Fowler SE Goodman LR . Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354 :2317–27.16738268\n[14] Loud PA Katz DS Bruce DA . Deep venous thrombosis with suspected pulmonary embolism: detection with combined CT venography and pulmonary angiography. Radiology 2001;219 :498–502.11323478\n[15] Cox JC Jablons DM . Operative and perioperative pulmonary emboli. Thorac Surg Clin 2015;25 :289–99.26210925\n[16] Desciak MC Martin DE . Perioperative pulmonary embolism: diagnosis and anesthetic management. J Clin Anesth 2011;23 :153–65.21377083\n[17] Cheta J Long A Marik P . Use of tachycardia in patients with submassive pulmonary emboli to risk stratify for early initiation of thrombolytic therapy: a case series comparing early versus late thrombolytic initiation. J Investig Med High Impact Case Rep 2017;5 :2324709617744232.\n[18] Thys DM Abel MD Brooker RF . Practice guidelines for perioperative transesophageal echocardiography. An updated report by the American Society of Anesthesiologists and the Society of Cardiovascular Anesthesiologists Task Force on Transesophageal Echocardiography. Anesthesiology 2010;112 :1084–96.20418689\n[19] Dudaryk R Benitez Lopez J Louro J . Diagnosis and thrombolytic management of massive intraoperative pulmonary embolism guided by point of care transthoracic echocardiography. Case Rep Anesthesiol 2018;2018 :8709026.29686907\n[20] Krivec B Voga G Zuran I . Diagnosis and treatment of shock due to massive pulmonary embolism: approach with transesophageal echocardiography and intrapulmonary thrombolysis. Chest 1997;112 :1310–6.9367474\n[21] Pruszczyk P Torbicki A Pacho R . Noninvasive diagnosis of suspected severe pulmonary embolism: transesophageal echocardiography vs spiral CT. Chest 1997;112 :722–8.9315806\n[22] Dresden S Mitchell P Rahimi L . Right ventricular dilatation on bedside echocardiography performed by emergency physicians aids in the diagnosis of pulmonary embolism. Ann Emerg Med 2014;63 :16–24.24075286\n[23] Rosenberger P Shernan SK Body SC Eltzschig HK . Utility of intraoperative transesophageal echocardiography for diagnosis of pulmonary embolism. Anesth Analg 2004;99 :12–6.15281493\n[24] Visnjevac O Pourafkari L Nader ND . Role of perioperative monitoring in diagnosis of massive intraoperative cardiopulmonary embolism. J Cardiovasc Thorac Res 2014;6 :141–5.25320660\n[25] Reeves ST Finley AC Skubas NJ . Basic perioperative transesophageal echocardiography examination: a consensus statement of the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr 2013;26 :443–56.23622926\n\n",
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"mesh_terms": "D000075482:Bedridden Persons; D000072226:Computed Tomography Angiography; D003937:Diagnosis, Differential; D050723:Fractures, Bone; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D010388:Pelvis; D011655:Pulmonary Embolism",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Intraoperative development of pulmonary thromboembolism in a bedridden patient owing to a pelvic bone fracture with negative preoperative computed tomography pulmonary angiographic findings: A case report.",
"title_normalized": "intraoperative development of pulmonary thromboembolism in a bedridden patient owing to a pelvic bone fracture with negative preoperative computed tomography pulmonary angiographic findings a case report"
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"abstract": "We report the case of a 65-year-old man with myasthenia gravis, who developed recurrent opportunistic infections following thymectomy and immunosuppressive therapy. Subsequent evaluation including immunological studies, flow cytometry, and bone marrow studies confirmed the diagnosis of Good's syndrome. The patient was successfully treated with intravenous immunoglobulin (IVIG) and has remained stable with a monthly IVIG regimen. Good's syndrome should be strongly suspected when patients with myasthenia gravis develop recurrent opportunistic infections, especially after discontinuation of immunosuppressive therapy. Any delay in diagnosis can be life-threatening in such patients. Serum immunoglobulin levels and flow cytometry should be considered part of the initial diagnostic evaluation in patients with myasthenia gravis and an anterior mediastinal mass prior to the initiation of immunosuppressive therapy.",
"affiliations": "Neurology, University of Missouri, Columbia, USA.;Neurology, University of Missouri, Columbia , USA.;Neurology, University of Missouri, Columbia, USA.;Neurology, University of Missouri, Columbia, USA.",
"authors": "Shankar Kikkeri|Nidhi|N|;Beladakere Ramaswamy|Swathi|S|;Bhagavan|Sachin M|SM|;Govindarajan|Raghav|R|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.3130",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3130NeurologyInfectious DiseaseRheumatologyRecurrent Opportunistic Infections in a Thymectomised Patient with Myasthenia Gravis and Good’s Syndrome Muacevic Alexander Adler John R Shankar Kikkeri Nidhi 1Beladakere Ramaswamy Swathi 2Bhagavan Sachin M 1Govindarajan Raghav 1\n1 \nNeurology, University of Missouri, Columbia, USA \n2 \nNeurology, University of Missouri, Columbia , USA \nNidhi Shankar Kikkeri nidhi.kikkeri@gmail.com10 8 2018 8 2018 10 8 e31306 8 2018 10 8 2018 Copyright © 2018, Shankar Kikkeri et al.2018Shankar Kikkeri et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/14192-recurrent-opportunistic-infections-in-a-thymectomised-patient-with-myasthenia-gravis-and-goods-syndromeWe report the case of a 65-year-old man with myasthenia gravis, who developed recurrent opportunistic infections following thymectomy and immunosuppressive therapy. Subsequent evaluation including immunological studies, flow cytometry, and bone marrow studies confirmed the diagnosis of Good’s syndrome. The patient was successfully treated with intravenous immunoglobulin (IVIG) and has remained stable with a monthly IVIG regimen. Good’s syndrome should be strongly suspected when patients with myasthenia gravis develop recurrent opportunistic infections, especially after discontinuation of immunosuppressive therapy. Any delay in diagnosis can be life-threatening in such patients. Serum immunoglobulin levels and flow cytometry should be considered part of the initial diagnostic evaluation in patients with myasthenia gravis and an anterior mediastinal mass prior to the initiation of immunosuppressive therapy. \n\nmyasthenia gravisgood’s syndromethymomahistoplasmosismycophenolateimmunodeficiencyhypogammaglobulinemiaintravenous immunoglobulinsThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nMyasthenia gravis (MG) is a chronic neuromuscular condition, which is considered a prototype of both synaptic and autoimmune disorders. About 60% of thymomas are associated with MG while only 10% of MG patients have thymoma [1-2]. Good’s syndrome (GS), also known as thymoma with immunodeficiency (TWI), is a rare adult-onset immunodeficiency disorder characterized by thymoma and hypogammaglobulinemia, with defects in B and T cell-mediated immunity [2-5]. It was first reported by Robert A Good, who was a physician and scientist at the University of Minnesota Medical School, USA, in the year 1954 [6]. The hallmark features of GS include recurrent sino-pulmonary, opportunistic fungal and viral infections [3, 7]. Thymoma can manifest clinically in the form of autoimmune (30%) diseases or immunodeficiency (6%-11%) disorders [3-4, 8]. The management of the former requires immunosuppression whereas the latter needs immuno-supplementation. Myasthenia gravis has a favorable outcome following thymectomy, whereas patients with Good’s syndrome might worsen following the surgery [8]. The objective of this case report is to establish the rare co-existence of Good’s syndrome in MG patients with post-thymectomy status who present with recurrent opportunistic infections and to demonstrate the role of intravenous immunoglobulins (IVIG) in their treatment and stabilization.\n\nCase presentation\nA 65-year-old male with a past medical history significant for hypertension initially presented with episodes of double vision, fatigue, dysphagia, and generalized weakness. Neurological examination was remarkable for ptosis of the right eye which improved with the ice pack test. Serology was positive for anti-acetylcholine receptor antibodies. Further workup revealed a decremental response to slow (2Hz) repetitive nerve stimulation of the right spinal accessory nerve. The patient was then diagnosed with myasthenia gravis. A computed tomography (CT) scan of the chest revealed thymoma for which the patient underwent resection and was subsequently placed on a high dose (50 mg daily) oral prednisone, in addition to mycophenolate and pyridostigmine. \n\nFour months after starting the above treatment, the patient presented to the hospital with shortness of breath. A chest X-ray revealed reticulonodular infiltrates. Further workup led to the diagnosis of histoplasmosis. Mycophenolate was then stopped. However, the patient was on a tapering dose of prednisone. The patient then developed refractory diarrhea and was diagnosed with Cytomegalovirus (CMV) colitis. Subsequently, the patient was completely weaned off steroids. However, he continued to develop recurrent pneumococcal infections.\n\nEight months post discontinuation of steroids, the patient developed disseminated candidal infection. Immunological studies were remarkable for hypogammaglobulinemia (immunoglobulin G (IgG): 100 mg/dl; normal IgG: 700-1600 mg/dl). There was cutaneous anergy to intra-dermal antigen challenge. Subsequently, flow cytometry revealed reduced mature circulating B cells, reduced CD4 count, and reversal of the CD4:CD8 ratio (patient value: 0.5; normal CD4/CD8 ratio: 2.0). The patient then underwent a bone marrow biopsy which revealed reduced pre-B cell lineage. This led to the diagnosis of Good’s syndrome. The patient was successfully treated with IVIG (1g/kg) and since then has remained stable on a monthly IVIG regimen which is used to treat both MG and Good's syndrome.\n\nDiscussion\nPatients with myasthenia gravis are commonly treated with corticosteroids, cytotoxic drugs (mycophenolate, azathioprine), alkylating agents (cyclophosphamide), and calcineurin inhibitors (cyclosporine A, tacrolimus) [9]. These immunosuppressive drugs predispose the patients to infections [10]. Hence, during opportunistic infections, the immunosuppressive therapy is gradually weaned off or withdrawn to aid in the recovery from infections [10-11]. Recurrent opportunistic infections after the discontinuation of immunosuppressive therapy should raise the suspicion for an immunodeficiency disorder. \n\nThe incidence of Good’s syndrome is 0.15 cases per 100,000 populations per year, and the average age of the affected patients is 40-70 years [4]. The immunodeficiency spectrum involves both B cells and T cells as reflected by low levels of all types of immunoglobulin, CD4 T-cell lymphopenia, and an abnormal or inverted CD4:CD8+ T-cell ratio [12]. GS is recognized as a distinct entity by the expert committee of the World Health Organization (WHO) / International Union of Immunological Societies on Primary Immunodeficiencies [3]. There are no clear diagnostic criteria for Good’s syndrome. Treatment of Good’s syndrome involves immunoglobulin replacement to maintain adequate trough IgG values [3]. The prognosis of Good’s syndrome appears to be poor. Hermaszewski et al. [13] found that only 33% of patients were alive at the end of 10 years in comparison with 97% of patients with common variable immunodeficiency. \n\nThymoma can be associated with both MG and GS. But their concurrent existence in a thymoma patient is a rare association [11]. There have been very few cases reporting their co-existence. A delay in recognizing GS can lead to an infectious catastrophe as seen in our patient. Hence, serum immunoglobulins and flow cytometry should be considered as a part of the initial diagnostic evaluation in patients with MG and an anterior mediastinal mass, prior to the institution of immunosuppressive therapy.\n\nConclusions\nGood’s syndrome is a rare immunologic disorder characterized by adult onset of immunodeficiency in the setting of thymoma. As it is a rare condition, a high degree of suspicion is needed to diagnose it when a patient with a history of thymectomy presents with recurrent opportunistic infections. The delay in diagnosis can lead to life-threatening infections as seen in our patient. Also, in patients with MG who develop recurrent opportunistic infections with or without immunosuppressive therapy, flow cytometry should be considered to rule out GS. When co-existence of myasthenia gravis and Good's syndrome is confirmed, immediate institution of IVIG therapy is necessary for effective treatment, stabilization, and to prevent the future occurrences of opportunistic infections. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study. MU Institutional Review Board issued approval N/A. Informed consent has been obtained from the patient.\n==== Refs\nReferences\n1 Myasthenia gravis Lancet Vincent A Palace J Hilton-Jones D 2122 2128 30 2001 \n2 Thymoma with immunodeficiency (Good's syndrome) associated with myasthenia gravis and benign IgG gammopathy Arch Intern Med Soppi E Eskola J Röyttä M Veromaa T Panelius M Lehtonen A 1704 1707 145 1985 3896187 \n3 What is Good's syndrome? Immunological abnormalities in patients with thymoma J Clin Pathol Kelleher P Misbah SA 12 16 56 2003 12499426 \n4 Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications Clin Infect Dis Malphettes M Gérard L Galicier L 13 19 15 2015 \n5 Good's syndrome: successful management of thymoma with hypoimmunoglobulinemia Ann Thorac Surg DeBoard ZM Taylor BJ 1903 1905 100 2015 26522540 \n6 Absence of plasma cells from bone marrow and lymph nodes following antigenic stimulation in patients with a gamma globulinemia Rev Hematol Good RA 502 503 9 1954 http://www.robertagoodarchive.com/images/00340001.pdf 14357973 \n7 Good's syndrome: clinical and imaging presentation Diagn Interv Imaging Colin GC Ghaye B Pieters T Knoops L Coche E 487 489 97 2016 26725527 \n8 High prevalence of infections and autoimmunity in patients with thymoma Hum Immunol Holbro A Jauch A Lardinois D Tzankov A Dirnhofer S Hess C 287 290 73 2012 22261388 \n9 Immunosuppressive therapies in myasthenia gravis Autoimmunity Sanders DB Evoli A 428 435 43 2010 20166870 \n10 Myasthenia gravis and treatment with intravenous immunoglobulins Rev Neurol Puy-Nunez A Dacosta-Balboa M Cabo-Lopez I 432 1 2016 https://www.neurologia.com/articulo/2016388/eng \n11 Thymoma with immunodeficiency/good syndrome associated with myasthenia gravis Rinsho Shinkeigaku Takai S Tagawa A Ogawa T Kato H Saito N Okada S 208 213 27 2017 \n12 Thymoma-associated immunodeficiency: a diagnostic challenge for the clinician Asian Cardiovasc Thorac Ann Narahari NK Gongati PK Kakarla B Nizami MI Boddula RP Sattavarapu LR 146 149 25 2017 28068785 \n13 Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications Q J Med Hermaszewski RA Webster AD 31 42 86 1993 8438047\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "10(8)",
"journal": "Cureus",
"keywords": "good’s syndrome; histoplasmosis; hypogammaglobulinemia; immunodeficiency; intravenous immunoglobulins; myasthenia gravis; mycophenolate; thymoma",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e3130",
"pmc": null,
"pmid": "30345189",
"pubdate": "2018-08-10",
"publication_types": "D002363:Case Reports",
"references": "3896187;25828999;28068785;14357973;26725527;8438047;26522540;20166870;27779307;11445126;22261388;12499426;28450687",
"title": "Recurrent Opportunistic Infections in a Thymectomised Patient with Myasthenia Gravis and Good's Syndrome.",
"title_normalized": "recurrent opportunistic infections in a thymectomised patient with myasthenia gravis and good s syndrome"
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