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"abstract": "Histiocytic sarcoma (HS) is an extremely rare and aggressive hematopoietic tumor. Although it can be seen at any anatomic location, the most common primary sites are skin as extranodal region, locations including the lymph nodes and gastrointestinal tract. To the best of our knowledge, in light of PubMed search, this is the first primary tonsillar HS case presented with disseminated metastases at the time of diagnosis. A 58-year-old male patient applied with swelling on the right side of the neck, difficulty in swallowing, and weight loss. Positron emission tomography computed tomography was performed and increased pathological 18F fluorodeoxy D glucose uptake was detected in the right palatine tonsil, bilateral cervical multiple lymph nodes, liver masses, intra abdominal lymph nodes, and nodular lesion in the left adrenal gland. Tonsillectomy was performed and the pathological result was reported as HS. The patient did not respond to any treatment and had died after 5 months from the date of diagnosis. In conclusion, HS is generally diagnosed at advanced stage, it has limited chemotherapy response and high mortality rates. To understand this rare disease's pathophysiological and clinical features, further investigations are needed.",
"affiliations": "Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey.",
"authors": "Aytekin|Aydin|A|;Ozet|Ahmet|A|;Bilgetekin|Irem|I|;Ogut|Betul|B|;Ciltas|Aydin|A|;Benekli|Mustafa|M|",
"chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "India",
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"doi": "10.4103/0973-1482.188435",
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"issn_linking": "1998-4138",
"issue": "16(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "Histiocytes; histiocytic sarcoma; metastatic; tonsil",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D003131:Combined Modality Therapy; D019788:Fluorodeoxyglucose F18; D054747:Histiocytic Sarcoma; D006801:Humans; D008113:Liver Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011379:Prognosis; D019275:Radiopharmaceuticals; D014067:Tonsillar Neoplasms",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "665-667",
"pmc": null,
"pmid": "32719287",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A metastatic histiocytic sarcoma case with primary involvement of the tonsil.",
"title_normalized": "a metastatic histiocytic sarcoma case with primary involvement of the tonsil"
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"abstract": "Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.",
"affiliations": "Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo-shi, Japan.;Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, Hakodate-shi, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo-shi, Japan.",
"authors": "Shijubou|Naoki|N|0000-0001-8005-1745;Sumi|Toshiyuki|T|0000-0002-2540-5878;Kamada|Koki|K|;Sawai|Takeyuki|T|;Yamada|Yuichi|Y|;Nakata|Hisashi|H|;Mori|Yuji|Y|;Chiba|Hirofumi|H|",
"chemical_list": "D000077716:Afatinib; D066246:ErbB Receptors",
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"doi": "10.1111/1759-7714.13869",
"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\n33533191\n10.1111/1759-7714.13869\nTCA13869\nCase Report\nCase Reports\nLong‐term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation‐positive lung adenocarcinoma\nShijubou et al.\nShijubou Naoki https://orcid.org/0000-0001-8005-1745\n1 2 shjibou.1229@gmail.com\n\nSumi Toshiyuki https://orcid.org/0000-0002-2540-5878\n1 2\nKamada Koki 1 2\nSawai Takeyuki 2\nYamada Yuichi 1\nNakata Hisashi 1\nMori Yuji 1\nChiba Hirofumi 2\n1 Department of Respiratory Medicine Hakodate Goryoukaku Hospital Hakodate‐shi Japan\n2 Department of Respiratory Medicine and Allergology Sapporo Medical University School of Medicine Sapporo‐shi Japan\n* Correspondence\nNaoki Shijubou, Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, 38‐3 Goryoukaku‐cho Hakodate‐shi, Hokkaido 040‐8611, Japan.\nEmail: shjibou.1229@gmail.com\n\n03 2 2021\n3 2021\n12 6 10.1111/tca.v12.6 989992\n16 12 2020\n12 1 2021\n13 1 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%–23% of EGFR mutation‐positive NSCLC. The treatment of uncommon EGFR mutation‐positive NSCLCs is controversial. Here, we present the case of an 81‐year‐old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation‐induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.\n\nA large number of compound mutations have been observed in patients with uncommon EGFR mutation‐positive NSCLC. Compound mutation‐induced cells are most susceptible to afatinib, suggesting the efficacy of afatinib in clinical practice. Afatinib may be administered to elderly patients with appropriate dose adjustments\n\nafatinib\nelderly\nlung cancer\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:12.03.2021\nShijubou N , Sumi T , Kamada K , et al. Long‐term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation‐positive lung adenocarcinoma. Thorac Cancer. 2021;12 :989–992. 10.1111/1759-7714.13869\n==== Body\nINTRODUCTION\n\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7\n\nHere, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.\n\nCASE REPORT\n\nAn 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).\n\nFIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)\n\nExamination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.\n\nFIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor\n\nDISCUSSION\n\nThe elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.\n\nAn integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9\n\nSince the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.\n\nIn conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.\n\nCONFLICT OF INTEREST\n\nAll authors declare that they have no conflicts of interest.\n\nACKNOWLEDGMENTS\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n==== Refs\nREFERENCES\n\n1 Maemondo M , Inoue A , Kobayashi K , Sugawara S , Oizumi S , Isobe H , et al. Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR . N Engl J Med. 2010;362 :2380–8.20573926\n2 Wu YL , Zhou C , Hu CP , Feng J , Lu S , Huang Y , et al. Afatinib versus cisplatin plus gemcitabine for first‐line treatment of Asian patients with advanced non‐small‐cell lung cancer harbouring EGFR mutations (LUX‐lung 6): an open‐label, randomised phase 3 trial. Lancet Oncol. 2014;15 :213–2.24439929\n3 Soria JC , Ohe Y , Vansteenkiste J , Reungwetwattana T , Chewaskulyong B , Lee KH , et al. Osimertinib in untreated EGFR‐mutated advanced non‐small‐cell lung cancer. N Engl J Med. 2018;378 :113–25.29151359\n4 Yang CHJ , Schuler M , Popat S , Miura S , Heeke S , Park K , et al. Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases. J Thorac Oncol. 2020;15 :803–15.31931137\n5 Yang JC , Sequist LV , Geater SL , Tsai CM , TSK M , Schuler M , et al. Clinical activity of afatinib in patients with advanced non‐small‐cell lung cancer harbouring uncommon EGFR mutations: a combined post‐hoc analysis of LUX‐lung 2, LUX‐lung 3, and LUX‐lung 6. Lancet Oncol. 2015;16 :830–8.26051236\n6 Cho JH , Lim SH , An JH , Kim KH , Park KU , Kang EJ , et al. Osimertinib for patients with non‐small‐cell lung cancer harboring uncommon EGFR mutations: a multicenter, open‐label, phase II trial. (KCSG‐LU15‐09). J Clin Oncol. 2020;10 :488–95.\n7 Minuti G , D'Incecco A , Cappuzzo F . Current and emerging options in the management of EGFR mutation‐positive non–small‐cell lung cancer: considerations in the elderly. Drugs Aging. 2015;32 :907–16.26446154\n8 Kohsaka S , Nagano M , Ueno T , Suehara Y , Hayashi T , Shimada N , et al. A method of high‐throughput functional evaluation of EGFR gene variants of unknown significance in cancer. Sci Transl Med. 2017;9 :eaan6566.29141884\n9 Sato H , Offin M , Kubota D , Yu HA , Wilhelm C , Toyooka S , et al. Allele‐specific role of ERBB2 in the oncogenic of EGFR L861Q in EGFR‐mutant lung cancers. J Thorac Oncol. 2020;S1556‐0864 (20 ):30765–6.\n10 Wu YL , Sequist LV , Tan EH , Geater SL , Orlov S , Zhang L , et al. Afatinib as first‐line treatment of older patients with EGFR mutation‐positive non‐small‐cell lung cancer: subgroup analyses of the LUX‐lung 3, LUX‐lung 6, and LUX‐lung 7 trials. Clin Lung Cancer. 2018;19 :e465–79.29653820\n11 Yang JC , Sequist LV , Zhou C , Schuler M , Geater SL , Mok T , et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation‐positive lung adenocarcinoma: post hoc analyses of the randomized LUX‐lung 3 and 6 trials. Ann Oncol. 2016;27 :2103–10.27601237\n12 Yokoyama T , Yoshioka H , Fujimoto D , Demura Y , Hirano K , Kawai T , et al. A phase II study of low starting dose of afatinib as first‐line treatment in patients with EGFR mutation‐positive non‐small‐cell lung cancer (KTORG1402). Lung Cancer. 2019;135 :175–80.31446992\n13 Tanaka H , Taima K , Tanaka Y , Itoga M , Ishioka Y , Nakagawa H , et al. A phase I study of afatinib for patients aged 75 or older with advanced non‐small cell lung cancer harboring EGFR mutations. Med Oncol. 2018;35 (3 ):34.29423683\n14 Imai H , Kaira K , Suzuki K , Anzai M , Tsuda T , Ishizuka T , et al. A phase II study of afatinib treatment for elderly patients with previously untreated advanced non‐small‐cell lung cancer harboring EGFR mutations. Lung Cancer. 2018;126 :41–7.30527191\n15 Iida Y , Kumasawa F , Shimizu T , Shintani Y , Takahashi N , Gon Y . Successful treatment of an elderly patient with an uncommon L861Q epidermal growth factor receptor mutation with low‐dose afatinib: a case report. Thorac Cancer. 2020;11 (2 ):447–50.31779047\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "12(6)",
"journal": "Thoracic cancer",
"keywords": "afatinib; elderly; lung cancer",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000369:Aged, 80 and over; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009154:Mutation",
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"pages": "989-992",
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"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.",
"title_normalized": "long term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation positive lung adenocarcinoma"
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"abstract": "While localized penile cancers are typically treated surgically and metastatic penile cancers benefit from standard chemotherapy, there have been studies on the horizon demonstrating immunotherapy as a novel approach to metastatic penile cancers that have failed standard chemotherapy. We report a case series of two patients who improved on immunotherapy after progressing with standard chemotherapy regimens. The first case describes a 64-year-old male with a penile mass and significant lymphadenopathy who had surgical resection and adjuvant chemotherapy prior to continued disease progression. He was started on anti-EGFR treatment and improved initially, but he eventually had progression of disease. The second case describes a 79-year-old male with a penile mass who was treated with surgical resection and started on adjuvant chemoradiation, but he developed recurrence and nodal involvement. Therefore, second-line therapy of the PD-L1 inhibitor was started in this patient. There were no available clinical trials for penile cancer patients who progressed beyond the standard surgical therapy and chemotherapy.",
"affiliations": "UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USA.;UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USA.;UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USA.;UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USA.;UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USA.",
"authors": "Hui|Gavin|G|0000-0002-4818-4254;Ghafouri|Sanaz N|SN|;Shen|John|J|;Liu|Sandy|S|;Drakaki|Alexandra|A|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2019/8349793Case ReportTreating Penile Cancer in the Immunotherapy and Targeted Therapy Era http://orcid.org/0000-0002-4818-4254Hui Gavin ghui@mednet.ucla.eduGhafouri Sanaz N. Shen John Liu Sandy Drakaki Alexandra UCLA Medicine Education Office, RRUCLA Medical Center, 757 Westwood Plaza, Suite 7501, Los Angeles, CA 90095-7417, USAAcademic Editor: Ossama W. Tawfik\n\n2019 25 3 2019 2019 834979317 10 2018 18 2 2019 Copyright © 2019 Gavin Hui et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.While localized penile cancers are typically treated surgically and metastatic penile cancers benefit from standard chemotherapy, there have been studies on the horizon demonstrating immunotherapy as a novel approach to metastatic penile cancers that have failed standard chemotherapy. We report a case series of two patients who improved on immunotherapy after progressing with standard chemotherapy regimens. The first case describes a 64-year-old male with a penile mass and significant lymphadenopathy who had surgical resection and adjuvant chemotherapy prior to continued disease progression. He was started on anti-EGFR treatment and improved initially, but he eventually had progression of disease. The second case describes a 79-year-old male with a penile mass who was treated with surgical resection and started on adjuvant chemoradiation, but he developed recurrence and nodal involvement. Therefore, second-line therapy of the PD-L1 inhibitor was started in this patient. There were no available clinical trials for penile cancer patients who progressed beyond the standard surgical therapy and chemotherapy.\n==== Body\n1. Introduction\nIn developed countries, penile cancer is considered to be a rare neoplasm that typically affects elderly males. In the U.S., there are about 2300 new cases and 400 deaths from penile cancer annually [1]. Risk factors include phimosis, HPV, HIV, smoking exposure, and lack of circumcision that leads to poor body hygiene. More than 95% of penile cancers are classified histologically as squamous cell carcinomas, while the remaining include adenocarcinoma, melanoma, sarcoma, basal cell carcinoma and lymphoma [2]. The treatment and prognosis depend on the stage of the disease and in particular, the presence and extent of lymph node involvement.\n\nWhile primary penile tumors can be treated with surgical excision, laser ablation, local radiation, and partial or total penectomy, more advanced tumors, such as those with recurrence or metastasis, benefit from chemotherapy [2]. Penile cancer can spread through the lymphatic system to the inguinal, pelvic, and retroperitoneal lymph nodes [3]. According to National Comprehensive Cancer Network (NCCN) guidelines, penile cancers with unfavorable features such as bulky, fixed lymph nodes, greater than 4 cm in size, portend poorer prognosis and oftentimes warrant neoadjuvant chemotherapy. Evaluation includes fine needle aspiration (FNA) followed by excisional biopsy if FNA results as negative. If either of these biopsies are positive, neoadjuvant chemotherapy is recommended with subsequent inguinal and pelvic lymph node dissection.\n\nThe standard neoadjuvant regimen is TIP, which consists of four cycles of paclitaxel, ifosfamide, and cisplatin [4]. According to the phase II study by Pagliaro et al., patients with metastatic penile cancer showed meaningful clinical responses when given neoadjuvant TIP. Of the thirty men who received TIP chemotherapy, 15 (50%) of them had objective response. Nine (30%) of them were alive and free of disease recurrence at median follow-up of 34 months [5]. An alternative regimen is TPF, and consists of docetaxel, cisplatin and fluorouracil. Following neoadjuvant therapy, patients with responses are recommended to undergo surgical resection. However, there are very few standardized treatments for those with continued tumor progression or metastatic disease beyond the TIP or TPF regimen.\n\nTumor progression after chemotherapy indicates very poor prognosis, with median overall survival (OS) less than 6 months [6]. Therefore, basket clinical trials with targeted therapies for molecular markers such as epidermal growth receptor factor (EGFR), programmed death-1 (PD-1), and programmed death-1 ligand (PD-L1) are imperative in these circumstances. EGFR is a transmembrane tyrosine kinase receptor involved in many cell functions, and it is found to be commonly expressed in penile carcinomas [7]. This suggests the EGFR pathway plays a significant role in penile carcinogenesis, and the literature has shown response in penile cancer patients treated with anti-EGFR monoclonal antibodies [7, 8]. There are currently several studies and clinical trials on epidermal growth factor receptor (EGFR) targets, such as panitumumab and cetuximab.\n\nImmunotherapies targeting the PD-1 and PD-L1 pathways, important for escaping the immune response by tumors, are another promising immunotherapy targets in penile cancer. Udager et al. reported frequent PD-L1 expression (62%, 23/37) in penile cancer [9]. PD-L1 is a ligand that binds to PD-1, an inhibitory T cell surface receptor, to promote self-tolerance and suppress T cell activation. PD-1 inhibitor drugs act by preventing tumor-expressed PD-L1 from suppressing immune response. Two PD-1 inhibitor drugs are nivolumab and pembrolizumab, and they are both IgG4 subclass antibodies that block interaction of PD-1 with PD-L1 [10]. IgG1 antibodies that bind to PD-L1 to inhibit PD-1 contact include atezolizumab, avelumab, and durvalumab. There are currently no large studies or data regarding PD-L1 immunotherapy. However, clinical trials are ongoing.\n\nIn this case series, we present two patients with penile cancer metastatic to regional lymph nodes. In both cases, the patients ultimately progressed on chemotherapy, and they received compassionate use of an EGFR inhibitor and a PD-1 inhibitor.\n\n2. Case One\nA 64-year-old male presented with a two month history of difficulty urinating and was found to have a fungating penile mass involving 50% of his penis. The mass was hard and fixed and extended from the glans proximally up the shaft. He also had bilateral palpable inguinal lymphadenopathy. There were no associated constitutional symptoms. Given there was a high suspicion for malignancy, the patient underwent partial penectomy within a month of presentation. Biopsy results confirmed a pT2 tumor with invasive keratinizing squamous cell carcinoma, poorly differentiated, and tumor size of 5 × 4 × 2.5 cm, with corpus spongiosum and lymphovascular involvements.\n\nFollowing the procedure, the patient had PET-CT for staging, and imaging revealed enlarged hypermetabolic bilateral axillary lymph nodes concerning for metastatic disease. In addition, there was a large centrally necrotic lymph node conglomerate in his left groin that had increased FDG avidity. The patient had left inguinal and bilateral pelvic lymph node dissections revealing metastatic squamous cell carcinoma in multiple lymph nodes. The left inguinal mass was also found to be metastatic well-differentiated SCC. His diagnosis was staged at T2N3M0.\n\nAfter his surgical procedures, patient was started on adjuvant chemotherapy. He began first line chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP). He underwent 4 cycles of TIP but eventually developed disease progression on repeat imaging. At this point, the patient was started on cetuximab given EGFR amplification on tumor analysis with the FoundationOne testing platform. However, the patient had an allergic reaction to cetuximab, so his treatment was changed to panitumumab. The patient had stable disease and a progression-free survival of 6 months with anti-EGFR treatment, which is clinically significant given that this treatment was given in the second-line setting for an aggressive tumor type that other than chemotherapy there is no other approved drug to date.\n\nThe patient was ultimately started on the PD-1 inhibitor nivolumab. He had initial response to immunotherapy followed by stable disease, so he had a disease control rate of an additional 6 months with this investigational agent at that time. Ultimately, he was placed on hospice and passed away two years from the the time of diagnosis.\n\n3. Case Two\nA 79-year-old male with longstanding history of advanced prostate cancer on androgen deprivation therapy presented to his urologist after noticing a mass on the tip of his urethral meatus. A subsequent biopsy of the mass was positive for SCC, and the patient underwent partial penectomy and lymph node dissection that revealed positive right inguinal lymph nodes (three out of seven) revealing pathologic T2N2M0 disease. He received adjuvant chemotherapy by extrapolating data of its benefit when given in the neoadjuvant setting. The standard TIP regimen was not pursued given patient's concern for side effects. The patient proceeded with alternative plan of chemoradiation with 5 weeks of weekly low dose carboplatin and paclitaxel. In addition, he received radiation with a total dose of 5000 cGy over 25 fractions to the right inguinal region. However, the patient developed disease recurrence with nodal involvement nine months later. On restaging CT imaging, the patient was found to have new involvement of the left pelvis. A nodal conglomerate measuring 31×58 mm with central necrotic change was identified in the left inguinal region.\n\nGiven the patient's age, performance status, and local recurrence of disease, he was started on therapy with chemoradiation with curative intent one month later. Treatment with an additional round of chemoradiation with low dose carboplatin and paclitaxel was given for 5 weeks. He had radiation with a total dose of 5000 cGy over 25 fractions to the left pelvic region. He had stable disease with chemoradiation, but he eventually developed disease progression within a year from the end of chemotherapy. At that point, he was considered for second-line therapy with the PD-L1 inhibitor atezolizumab. After being on atezolizumab for approximately 2 years, he developed biopsy-proven bullous pemphigoid, an immune-mediated toxicity of the skin that has been described with those agents. A restaging scan at approximately 2 years showed near complete response, so patient has been placed on treatment holiday at the time of this report. He was started on prednisone 1 mg/kg per immune-mediated management guidelines and had quick resolution of his blistering symptoms [11].\n\n4. Discussion\nThe standard neoadjuvant regimen of TIP, consisting of paclitaxel, ifosfamide, and cisplatin, has been found to be one of the most efficacious regimens for patients with penile cancer. In a study of 61 patients, 54 (90%) of them received chemotherapy with TIP. 39 (65%) of these patients had either partial or complete response to the treatment. This study showed that about 50% of patients with response to treatment who also have consolidative lymphadenectomy remained alive at 5 years [4]. However, there are very few standardized treatments for patients with continued disease progression after the standard neoadjuvant treatment. Therefore, there is an unmet need to identify other therapeutic options that could include either targeted therapies or immune checkpoint inhibitors like those that were offered to our patients.\n\nThe overexpression of epidermal growth factor receptor (EGFR) is frequently observed in epithelial cancers, including penile SCC [12]. A study of penile SCC case series showed EGFR amplification in 4 (20%) of 20 patients. Furthermore, heterogeneous EGFR amplification was identified in 4 (29%) of 14 cases of primary penile SCC and lymph node metastases [12]. In fact, a small study of 30 patients has suggested that EGFR expression has been found to be strongly related to increased risk of recurrence and poorer prognosis in patients with penile SCC [13]. Given that EGFR overexpression is common and associated with poor prognosis, it is a therapeutic target in systemic penile cancer treatment.\n\nTherapy targeted towards EGFR includes monoclonal antibodies cetuximab and panitumumab. For patients with tumors overexpressing EGFR, there are previous reports showing promising clinical benefit with EGFR inhibitor treatment [7]. In a retrospective study of 17 patients treated with cetuximab either alone or with cisplatin, there were 4 (23.5%) partial responses. Another study with 28 patients receiving anti-EGFR drugs such as cetuximab, panitumumab, and nimotuzumab had 50% of patients showing a response to treatment. 15 of 28 patients were receiving anti-EGFR therapy as second-line therapy. Overall, 50% of the patients showed response to treatment with median PFS of 3 months [7].\n\nIn addition to anti-EGFR therapy, immune checkpoint inhibition with PD-1 and PD-ligand 1 (PD-L1) is an important therapeutic target for penile cancer among other malignancies. Udager et al. found that 23 (62.2%) of 37 primary penile SCC tumors were positive for PD-L1 expression. Furthermore, they found significant association between PD-L1 expression and regional lymph node metastasis as well as decreased cancer-specific survival [9]. Another study by Cocks et al. found 21 (40%) of 53 penile SCC tumors expressing PD-L1 [14]. These small studies suggest rational for checkpoint inhibitors as therapeutic targets. Pembrolizumab and nivolumab are two monoclonal antibodies against PD-1 that are FDA-approved in other cancers, such as melanoma. Atezolizumab and durvalumab are two drugs of monoclonal antibodies against PD-L1 that are FDA-approved for urothelial and non-small-cell lung cancer. Avelumab, a PD-L1 inhibitor, is approved for metastatic Merkel cell carcinoma. There are ongoing clinical trials studying the use of pembrolizumab and nivolumab in penile SCC.\n\nIn this case series, we describe two patients who developed metastatic penile cancer, which progressed after surgery and chemotherapeutic approach. However, while there were no clinical trials available for their treatment at the time of progression, they were treated with EGFR inhibitors and immune checkpoint inhibitors with compassionate use that prolonged their survival. The first patient had an additional 12 months of survival after starting anti-EGFR therapy upon failing primary chemotherapy. This was significant given that tumor progression beyond primary chemotherapy has been noted to have median overall survival (OS) of less than six months. It is imperative to include patients with rare tumors such as penile cancer in the multiple ongoing basket trials that are running in most institutions with the hope to offer novel therapies to this patient population.\n\nAcknowledgments\nAppreciation and gratitude are due to the patients and UCLA Health.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest regarding the publication of this article.\n\nAuthors' Contributions\nAll authors contributed equally, with Gavin Hui as the first author.\n==== Refs\n1 Siegel R. L. Miller K. D. Jemal A. Cancer Statistics, 2018 CA: A Cancer Journal for Clinicians 2018 68 1 7 30 10.3322/caac.21442 2-s2.0-85040049759 29313949 \n2 Mosconi A. M. Roila F. Gatta G. Theodore C. Cancer of the penis Critical Reviews in Oncology/Hematology 2005 53 2 165 177 10.1016/j.critrevonc.2004.09.006 2-s2.0-12344287994 15661566 \n3 Marconnet L. Rigaud J. Bouchot O. Long-term followup of penile carcinoma with high risk for lymph node invasion treated with inguinal lymphadenectomy Journal of Urology 2010 183 6 2227 2232 10.1016/j.juro.2010.02.025 2-s2.0-77951877932 20399455 \n4 Dickstein R. J. Munsell M. F. Pagliaro L. C. Pettaway C. A. Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy BJU International 2016 117 1 118 125 10.1111/bju.12946 2-s2.0-84951570585 25294319 \n5 Pagliaro L. C. Williams D. L. Daliani D. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study Journal of Clinical Oncology 2010 28 24 3851 3857 10.1200/JCO.2010.29.5477 2-s2.0-77956233851 20625118 \n6 Wang J. Pettaway C. A. Pagliaro L. C. Treatment for metastatic penile cancer after first-line chemotherapy failure: analysis of response and survival outcomes Urology 2015 85 5 1104 1110 10.1016/j.urology.2014.12.049 2-s2.0-84930819988 25819619 \n7 Carthon B. C. Ng C. S. Pettaway C. A. Pagliaro L. C. Epidermal growth factor receptor–targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis BJU International 2014 113 6 871 877 10.1111/bju.12450 2-s2.0-84891915793 24053151 \n8 Necchi A. Nicolai N. Colecchia M. Proof of activity of anti-epidermal growth factor receptor-targeted therapy for relapsed squamous cell carcinoma of the penis Journal of Clinical Oncology 2011 29 22 e650 e652 10.1200/JCO.2011.34.8367 2-s2.0-80051633427 21632506 \n9 Udager A. M. Liu T. Y. Skala S. L. Frequent PD-L1 Expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches Annals of Oncology 2016 27 9 1706 1712 10.1093/annonc/mdw216 2-s2.0-84995543446 27217541 \n10 Fessas P. Lee H. Ikemizu S. Janowitz T. A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab Seminars in Oncology 2017 44 2 136 140 10.1053/j.seminoncol.2017.06.002 2-s2.0-85026632244 28923212 \n11 Brahmer J. R. Lacchetti C. Schneider B. J. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline Journal of Clinical Oncology 2018 36 17 1714 1768 10.1200/JCO.2017.77.6385 2-s2.0-85048283183 29442540 \n12 Gu W. Zhu Y. Ye D. Beyond chemotherapy for advanced disease—the role of EGFR and PD-1 inhibitors Translational Andrology and Urology 2017 6 5 848 854 10.21037/tau.2017.03.92 2-s2.0-85032263558 29184782 \n13 Di Lorenzo G. Perdonà S. Buonerba C. Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study Journal of Translational Medicine 2013 11 1 p. 161 10.1186/1479-5876-11-161 2-s2.0-84879824803 23819610 \n14 Cocks M. Taheri D. Ball M. W. Immune-checkpoint status in penile squamous cell carcinoma: a North American cohort Human Pathology 2017 59 55 61 10.1016/j.humpath.2016.09.003 2-s2.0-84995810176 27663086\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "8349793",
"pmc": null,
"pmid": "31019822",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15661566;20399455;20625118;21632506;23819610;24053151;25294319;25819619;27217541;27663086;28923212;29184782;29313949;29442540",
"title": "Treating Penile Cancer in the Immunotherapy and Targeted Therapy Era.",
"title_normalized": "treating penile cancer in the immunotherapy and targeted therapy era"
} | [
{
"companynumb": "US-AMGEN-USASP2019090246",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEvidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease.\n\n\nMETHODS\nWe did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940.\n\n\nRESULTS\nWe randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group.\n\n\nCONCLUSIONS\nAddition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted.\n\n\nBACKGROUND\nJapanese Ministry of Health, Labour and Welfare.",
"affiliations": "Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan. torukoba@nifty.com",
"authors": "Kobayashi|Tohru|T|;Saji|Tsutomu|T|;Otani|Tetsuya|T|;Takeuchi|Kazuo|K|;Nakamura|Tetsuya|T|;Arakawa|Hirokazu|H|;Kato|Taichi|T|;Hara|Toshiro|T|;Hamaoka|Kenji|K|;Ogawa|Shunichi|S|;Miura|Masaru|M|;Nomura|Yuichi|Y|;Fuse|Shigeto|S|;Ichida|Fukiko|F|;Seki|Mitsuru|M|;Fukazawa|Ryuji|R|;Ogawa|Chitose|C|;Furuno|Kenji|K|;Tokunaga|Hirohide|H|;Takatsuki|Shinichi|S|;Hara|Shinya|S|;Morikawa|Akihiro|A|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007136:Immunoglobulins; D011239:Prednisolone; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(11)61930-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "379(9826)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D001241:Aspirin; D002675:Child, Preschool; D003324:Coronary Artery Disease; D003330:Coronary Vessel Anomalies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D011239:Prednisolone; D011446:Prospective Studies",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1613-20",
"pmc": null,
"pmid": "22405251",
"pubdate": "2012-04-28",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.",
"title_normalized": "efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe kawasaki disease raise study a randomised open label blinded endpoints trial"
} | [
{
"companynumb": "JP-BEH-2016070086",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Voriconazole-related periostitis has been increasingly described in the literature over the last several years as a recognizable disease entity, especially in lung transplant patients. This relationship should be considered when approaching immunosuppressed patients presenting with diffuse bone pain and imaging findings of periostitis. We present a case of voriconazole-associated periostitis, capsular and enthesial ossification and glenuhumeral capsulitis in a patient with a hematologic malignancy. To the authors' knowledge, soft tissue ossification associated with voriconazole has not been described in the radiology literature.",
"affiliations": "Department of Diagnostic Imaging, Musculoskeletal Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA, meera.raghavan@moffitt.org.",
"authors": "Raghavan|Meera|M|;Hayes|Alex|A|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00256-014-1865-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-2348",
"issue": "43(9)",
"journal": "Skeletal radiology",
"keywords": null,
"medline_ta": "Skeletal Radiol",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D002062:Bursitis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009999:Ossification, Heterotopic; D010522:Periostitis; D012216:Rheumatic Diseases; D012785:Shoulder Joint; D014057:Tomography, X-Ray Computed; D065819:Voriconazole",
"nlm_unique_id": "7701953",
"other_id": null,
"pages": "1301-5",
"pmc": null,
"pmid": "24699891",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22049971;20652242;19770293;19845595;24263147;22777747;23663268;21285691;18815860;21169844;22859610;21969513;21239842;6849029",
"title": "Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis.",
"title_normalized": "voriconazole associated soft tissue ossification an undescribed cause of glenohumeral joint capsulitis"
} | [
{
"companynumb": "US-MYLAN-2014M1002572",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of TNBC treated effectively with a platinum-based regimen after developing resistance to anthracycline and taxane-based neoadjuvant chemotherapy(NAC). A 59-year-old woman with a right breast mass and high fever visited our clinic and was diagnosed as having inflammatory triple negative breast cancer(iTNBC). She was treated with NAC of docetaxel, doxorubicin, and cyclophosphamide(TAC)using pegfilgrastim. After 5 courses of TAC, the therapy failed and the disease progressed. Thus, a combination regimen of gemcitabine and carboplatin(GC)was administered. The treatment was successful, and the patient underwent a curative operation after 6 courses of the GC therapy.",
"affiliations": "Dept. of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University.",
"authors": "Yamada|Mai|M|;Kubo|Makoto|M|;Kai|Masaya|M|;Yamamoto|Hidetaka|H|;Nakamura|Masafumi|M|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide; C056507:gemcitabine; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D003520:Cyclophosphamide; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D043823:Taxoids; D014057:Tomography, X-Ray Computed; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "703-705",
"pmc": null,
"pmid": "28860445",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy of GC Therapy for the Patient of iTNBC with Resistance to TAC Therapy.",
"title_normalized": "efficacy of gc therapy for the patient of itnbc with resistance to tac therapy"
} | [
{
"companynumb": "JP-TEVA-2018-JP-879421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Objective: We aimed to evaluate the effectiveness of an mEOX (modified epirubicin, oxaliplatin plus capecitabine)\nregimen as second line therapy after failure of mDCF (modified docetaxel, cisplatin plus fluorouracil). Methods: Gastic\ncancer patients for whom first-line therapy was unsuccessful and who subsequently received mEOX (epirubicin 50 mg/\nm2 on day 1, oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2, p.o. for 2 weeks) every 3\nweeks until disease progression or unacceptable toxicity, were retrospectively analyzed. Results: The study population\ncomprised 129 cases with a median age of 55 years (range= 27-78), the majority being male (76 %). Most (75.2%)\nhad ≥ 2 sites of metastasis. The median number of chemotherapy courses was five (range= 2–9). Forty-nine achieved\na partial response and 33 showed stable disease, resulting in a ORR (overall response rate) of 38% and a DCR (disease\ncontrol rate) of 63.6%. The most frequent features of grade 3-4 hematological and non-hematological toxicity were\nneutropenia (8.5%) and nausea/vomiting (5.4%). None of the patients suffered death due to toxicity. The median PFS\nwas 4.7 months (95% CI, 4.1–5.3) and the OS was 7.4 months (95% CI, 6.3–8.5). On multivariate analysis, age ≥ 60\nyears and ECOG performance status (0-1) were independent prognostic factors affecting PFS and OS. Conslusions:\nIn advanced gastric cancer patients, who progress after first line chemotherapy and have an ECOG performance status\nof 0-1, mEOX is a well tolerated triple regimen associated with a promising OS and PFS.",
"affiliations": "Department of Medical Oncology, SBÜ Ankara Numune Education and Research Hospital, , Ankara, Turkey. Email: dr_yakupbozkaya@hotmail.com",
"authors": "Bozkaya|Yakup|Y|;Özdemir|Nuriye Yıldırım|NY|;Yazıcı|Ozan|O|;Demirci|Nebi Serkan|NS|;Kurtipek|Alican|A|;Erdem|Gökmen Umut|GU|;Ergün|Yakup|Y|;Zengin|Nurullah|N|",
"chemical_list": null,
"country": "Thailand",
"delete": false,
"doi": "10.22034/APJCP.2018.19.1.283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1513-7368",
"issue": "19(1)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": "Modified EOX; gastric cancer; modified DCF; second−line therapy",
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": null,
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "283-290",
"pmc": null,
"pmid": "29374414",
"pubdate": "2018-01-27",
"publication_types": "D016428:Journal Article",
"references": "24190112;17298958;21742485;16782930;22412140;17075117;18172173;24094768;25240821;15830569;23192279;27157491;22040543;23942775;24704535;18669868;20238327;12840796;9660027;23314560;25651787;27664260;18971936;21181464;19097774;12643005;24688534;15930889;11984734;24649240;24560487;24399786;20042971;20728210;24330513;26839542",
"title": "A Modified Epirubicin and Oxaliplatin Plus Capecitabine (EOX) Regimen as a Second- Line Therapy in Patients with Advanced Gastric Cancer",
"title_normalized": "a modified epirubicin and oxaliplatin plus capecitabine eox regimen as a second line therapy in patients with advanced gastric cancer"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2018-00396",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dru... |
{
"abstract": "Hepatitis B virus (HBV) infection is common across the world, especially in Asia, Africa, Southern Europe, and Latin America. The association of HBV infection in patients suffering from different oncological conditions is well established. Many cases of HBV reactivation have been reported in patients on immunosuppressive chemotherapy and in patients undergoing hematopoietic bone marrow transplantations. Only one case has been reported so far of HBV reactivation in a patient treated with programmed cell death receptor 1 (PD-1) checkpoint inhibitors in the setting of HIV status. We report a case of a 51-year-old male, former smoker, diagnosed with stage IV poorly differentiated adenocarcinoma of the lung, and started on pembrolizumab, who developed reactivation of chronic hepatitis requiring antiviral therapy.",
"affiliations": "Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USA.;Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USA.;Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USA.;Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USA.;Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USA.",
"authors": "Pandey|Anita|A|0000-0001-9703-1396;Ezemenari|Susan|S|;Liaukovich|Maksim|M|;Richard|Ivan|I|;Boris|Avezbakiyev|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/5985131",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/5985131Case ReportA Rare Case of Pembrolizumab-Induced Reactivation of Hepatitis B http://orcid.org/0000-0001-9703-1396Pandey Anita anita_pande@hotmail.comEzemenari Susan Liaukovich Maksim Richard Ivan Boris Avezbakiyev Department of Hematology and Oncology, Brookdale University Hospital, Medical Center, Brooklyn, USAAcademic Editor: Jeanine M. Buchanich\n\n2018 17 10 2018 2018 59851314 6 2018 6 9 2018 27 9 2018 Copyright © 2018 Anita Pandey et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatitis B virus (HBV) infection is common across the world, especially in Asia, Africa, Southern Europe, and Latin America. The association of HBV infection in patients suffering from different oncological conditions is well established. Many cases of HBV reactivation have been reported in patients on immunosuppressive chemotherapy and in patients undergoing hematopoietic bone marrow transplantations. Only one case has been reported so far of HBV reactivation in a patient treated with programmed cell death receptor 1 (PD-1) checkpoint inhibitors in the setting of HIV status. We report a case of a 51-year-old male, former smoker, diagnosed with stage IV poorly differentiated adenocarcinoma of the lung, and started on pembrolizumab, who developed reactivation of chronic hepatitis requiring antiviral therapy.\n==== Body\n1. Introduction\nReactivation of HBV is defined as a more than 10-fold rise in HBV DNA, detection of HBV DNA in a patient that was previously undetectable, or when reverse seroconversion occurs (i.e., when an HBsAg-negative/anti-HBc positive patient becomes HBsAg positive) [1]. HBV reactivation is a well-known complication of immunosuppressive therapy which can present as fulminant hepatitis, liver failure, and even death [2, 3]. Approximately 240 million people are positive for HBsAg worldwide [4]. The incidence rate of HBV infection reactivation during immunosuppressive chemotherapy is 14–72% [5]. There is strong evidence that reactivation of HBV can be prevented by screening and prophylaxis in patients on immunosuppressive therapy [6, 7]. Most reported cases of HBV reactivation have involved hematological malignancies treated with chemotherapy [8]. However, corresponding data for patients suffering from adenocarcinoma of the lung and treated with PD-1/PDL-1 inhibitors is not known except for one case report of an HBV flare in a patient with HIV and stage III non-small cell lung cancer (NSCLC) treated with nivolumab [9]. We report a case of HBV reactivation in a patient diagnosed with adenocarcinoma of the lung, treated with pembrolizumab. After initiating antiviral treatment, our patient had complete resolution of his acute hepatitis and continues his immunotherapy treatment till date.\n\n2. Case Presentation\nA 51-year-old male, former smoker and former alcoholic, presented to our emergency department with a few weeks' history of headache associated with left-sided weakness, without fever, seizures, nausea, or visual impairment. A neurological exam was significant for left hemiparesis. CT head was remarkable for multiple isodense and hypodense lesions in the frontal lobes, right parietal lobes, and cerebellum suspicious for metastatic lesions. CT chest was significant for a nodular density in the medial right upper lobe and right hilar lymph node. Biopsy of the lung mass and the hilar lymph node revealed poorly differentiated adenocarcinoma. Immunohistochemistry was positive for TTF-1 (thyroid transcription factor-1), Napsin, and PDL-1 expression of >95% PDL-1. NGS (next-generation sequencing) was negative for EGFR mutation. Treatment for metastatic adenocarcinoma of the lung was initiated based on these findings.\n\nAfter the completion of whole brain radiation, the patient was started on pembrolizumab as the first-line therapy. His baseline complete blood count (CBC), comprehensive metabolic panel (CMP), and thyroid stimulating hormone (TSH) were normal. In the setting of the normal liver function test and absence of symptoms, hepatitis panel was not indicated and not performed at baseline. Following the first cycle of pembrolizumab, a rise in ALT (Alanine aminotransferase) to 528 U/L (normal range: 9–52 U/L) and AST (Aspartate aminotransferase) to 342 U/L (normal range: 14–36 U/L) was noted. Consequently, pembrolizumab was held, and over the next few days, ALT peaked to 994 U/L and AST to 670 U/L. Total bilirubin and alkaline phosphatase were normal. Treatment for probable autoimmune hepatitis was started with high-dose steroids tapered over 3 weeks. The patient's liver enzymes remained elevated in spite of the steroids. Hepatitis workup was sent which revealed HBsAg positive, anti-HBsAb negative, and total anti-HBc positive while IgM anti-Hbc was negative, HbeAg was nonreactive, and HbeAb was reactive which was consistent with chronic hepatitis B. In addition to the serological markers, presence of newly elevated transaminases and HBV DNA RT-PCR (real-time polymerase chain reaction) of >8.23 log was consistent with HBV reactivation. Other tests including ANA, smooth muscle antibody, and ferritin were within normal limits.\n\nAfter the initiation of tenofovir treatment, liver enzymes started to trend downward. Pembrolizumab was reintroduced and continued without any further significant events. Liver enzymes returned to normal range within a 10-week period, and HBV DNA was undetectable.\n\n3. Discussion\nThe HBV virus is a double-stranded DNA virus which induces host immune response in hepatocytes via MCH II-CD4+ helper T cells and MCH I-CD8+ cytotoxic T cells [10]. The release of IFN-gamma, TNF-alpha, and chemokines downregulates viral replication in liver cells. When the cytotoxic T cell response cannot clear the virus completely, chronic infection persists. HBV exhibits immune tolerance during chronic infection by depleting virus-specific T cells [10]. Intrahepatic covalently closed circular DNA (cccDNA) in chronic carriers is vital for HBV replication while on conventional chemotherapy [11]. These chemoagents suppress the immune system thus encouraging viral replication and increasing viral DNA levels. Additionally, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), a key regulator of cellular processes like gluconeogenesis and fatty acid oxidation in hepatocytes, is linked to HBV induction [11, 12]. It has been postulated that high-dose steroids stimulate glucocorticoid-responsive elements in the HBV genome resulting in an increase in transcriptional activity [13], whereas monoclonal antibodies like rituximab and alemtuzumab cause prolonged B and T cell depletion, increasing the risk of HBV reactivation-linked fatal hepatitis along with other severe infections [14]. The pathophysiology behind immunotherapy-induced reactivation may not be parallel with conventional chemotherapies and immunosuppressant-induced reactivation as it is a promoter of T cells which is responsible for the clearance of the virus from the host. Therefore, further molecular studies are needed to explore and clarify the mechanism.\n\nPembrolizumab is a humanized monoclonal antibody which inhibits PD-1 activity by binding to the PD-1 receptor in T cells, therefore reversing T cell immune suppression and promoting T cell proliferation and cytotoxicity [15, 16]. With the extended FDA approval of pembrolizumab for all solid tumors with high microsatellite instability (MSI-H), indications for the drug have broadened beyond NSLC (non-small cell lung cancer) [17]. With the increased use of pembrolizumab, the incidence of cases similar to that which we report will probably rise. Though the prevalence of HBV will vary in different populations, we strongly feel that screening for chronic HBV infection by checking HBsAg and anti-HBc should be a standard practice prior to starting immunotherapy. However, two vital questions require further evaluation. First, should the entire patient population that has screened positive for chronic hepatitis be placed on antiviral therapy prior to starting immunotherapy? Second, what should be the duration of antiviral therapy?\n\nPatients who had prior infection with HBV virus (positive for HBsAg or anti-HBc antibody) and are receiving immunosuppressive therapy for malignancy, autoimmune disease, or solid organ/hematopoietic stem cell transplant are at high risk for reactivation and are therefore indicated for antiviral prophylaxis [18, 19]. In most cases, antiviral therapy was held after 6 months of completion of immunosuppression [14].\n\nIn conclusion, immunotherapy can lead to HBV reactivation and systematic screening for chronic hepatitis before initiating therapy is justifiable. Our patient has stage IV lung adenocarcinoma and will probably remain on immunotherapy until the progression of his disease or until the evidence of toxicity. His viral load is undetectable, and his treatment regimen continues to include tenofovir therapy.\n\n4. Our Recommendations\nScreen all patients receiving pembrolizumab for evidence of chronic hepatitis B infection by testing for HBsAg and anti-HBcAb. Concurrent administration of antiviral prophylaxis (i.e., tenofovir or entecavir) in patients with moderate to high risk for HBV reactivation should be considered.\n\nAcknowledgments\nWe would like to acknowledge the Hematology-Oncology Department of Brookdale University hospital for their motivation and support.\n\nConflicts of Interest\nThe authors declare that they have no conflict of interest.\n==== Refs\n1 Hui C.–. K. Cheung W. W. W. Zhang H.–. Y. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy Gastroenterology 2006 131 1 59 68 10.1053/j.gastro.2006.04.015 2-s2.0-33745014414 16831590 \n2 Lin C. L. Kao J. H. Hepatitis B reactivation in patients receiving immunosuppressive therapy: a hidden menace Hepatology International 2017 11 1 31 33 10.1007/s12072-016-9782-x 2-s2.0-85008514557 28058576 \n3 Yeo W. Chan P. K. S. Zhong S. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors Journal of Medical Virology 2000 62 3 299 307 10.1002/1096-9071(200011)62:3<299::AID-JMV1>3.0.CO;2-0 11055239 \n4 Ott J. J. Stevens G. A. Groeger J. Wiersma S. T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity Vaccine 2012 30 12 2212 2219 10.1016/j.vaccine.2011.12.116 2-s2.0-84857358267 22273662 \n5 Liu C. J. Chen P. J. Chen D. S. Kao J. H. Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management Hepatology International 2013 7 2 316 326 10.1007/s12072-011-9279-6 2-s2.0-84984555373 21670970 \n6 Ludwig E. Cohen N. Papanicolaou G. A. Seo S. K. Screening and prevention of hepatitis B virus reactivation during chemotherapy Oncology 2015 29 12 937 940 943 26676897 \n7 Lubel J. S. Testro A. G. Angus P. W. Hepatitis B virus reactivation following immunosuppressive therapy: guidelines for prevention and management Internal Medicine Journal 2007 37 10 705 712 10.1111/j.1445-5994.2007.01479.x 2-s2.0-34748814273 17894766 \n8 Voican C. S. Mir O. Loulergue P. Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment Annals of Oncology 2016 27 12 2172 2184 10.1093/annonc/mdw414 2-s2.0-85017387311 27803003 \n9 Lake A. C. Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy AIDS 2017 31 15 2115 2118 10.1097/QAD.0000000000001599 2-s2.0-85029740165 28906278 \n10 Larrubia J. R. Lokhande M. U. García-Garzón S. Miquel J. Subirá D. Sanz-de-Villalobos E. Role of T cell death in maintaining immune tolerance during persistent viral hepatitis World Journal of Gastroenterology 2013 19 12 1877 1889 10.3748/wjg.v19.i12.1877 2-s2.0-84875623442 23569333 \n11 Mouler Rechtman M. Burdelova E. O. Bar-Yishay I. The metabolic regulator PGC-1α links anti-cancer cytotoxic chemotherapy to reactivation of hepatitis B virus Journal of Viral Hepatitis 2013 20 1 34 41 10.1111/j.1365-2893.2012.01622.x 2-s2.0-84871023873 23231082 \n12 Tian X. Zhao F. Sun W. CRTC2 enhances HBV transcription and replication by inducing PGC1α expression Virology Journal 2014 11 1 p. 30 10.1186/1743-422X-11-30 2-s2.0-84896744702 24529027 \n13 Wijaya I. Hasan I. Reactivation of hepatitis B virus associated with chemotherapy and immunosuppressive agent Acta Medica Indonesiana 2013 45 1 \n14 Iannitto E. Minardi V. Calvaruso G. Hepatitis B virus reactivation and alemtuzumab therapy European Journal of Hematology 2005 74 3 254 258 10.1111/j.1600-0609.2004.00375.x 2-s2.0-20044371014 15693796 \n15 McDermott J. Jimeno A. Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer Drugs of Today 2015 51 1 7 20 10.1358/dot.2015.51.1.2250387 2-s2.0-84922339585 25685857 \n16 Arasanz H. Gato-Cañas M. Zuazo M. PD1 signal transduction pathways in T cells Oncotarget 2017 8 31 51936 51945 10.18632/oncotarget.17232 2-s2.0-85026750421 28881701 \n17 Diaz L. A. Marabelle A. Delord J.-P. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC Journal of Clinical Oncology 2017 35 Supplement 15 p. 3071 10.1200/jco.2017.35.15_suppl.3071 \n18 Huang H. Li X. Zhu J. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial JAMA 2014 312 23 2521 2530 10.1001/jama.2014.15704 2-s2.0-84919332882 25514302 \n19 Yeo W. Zee B. Zhong S. Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy British Journal of Cancer 2004 90 7 1306 1311 10.1038/sj.bjc.6601699 2-s2.0-2342560548 15054446\n\n",
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"title": "A Rare Case of Pembrolizumab-Induced Reactivation of Hepatitis B.",
"title_normalized": "a rare case of pembrolizumab induced reactivation of hepatitis b"
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"abstract": "OBJECTIVE\nTo evaluate the long-term effectiveness and late toxicities of paclitaxel (PTX) plus cisplatin (DDP) with concurrent radiotherapy for locally advanced esophageal squamous cancer.\n\n\nMETHODS\nBetween 2008 and 2011, 76 patients were enrolled in a phase II study on the treatment of loco-regionally advanced esophageal cancer with radiotherapy (68.4 Gy/44 fractions or 61.2 Gy/34 fractions) combined with 4-cycle chemotherapy consisting of DDP (25 mg/m2 per day for 3 d) and PTX (175 mg/m2 for 3 h). The primary endpoints were overall survival and progression-free survival, and the secondary endpoints were toxicity and the treatment failure pattern.\n\n\nRESULTS\nA total of 76 patients were enrolled in this study, of whom 63.2% finished the whole regimen. The 5-year survival rates for the per-protocol population and intent-to-treat population were 25.4% and 26.4%, respectively, and the median survival rates were 23.7 mo and 28.5 mo, respectively. Grade 3 or 4 late toxicity was observed in only one patient (heart failure). In log-rank analysis, the pretreatment stage (stage II + III: 36.1 mo vs stage IV: 14.9 mo) and the completed cycle (1-3 cycles: 16.1 mo vs 4 cycles: 35.5 mo) were significant prognostic factors (P = 0.037 < 0.05 and P = 0.013 < 0.05).\n\n\nCONCLUSIONS\nRadiotherapy combined with chemotherapy consisting of PTX and DDP is a safe and effective definitive treatment for loco-regionally advanced esophageal squamous cancer.",
"affiliations": "Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.",
"authors": "Zhu|Han-Ting|HT|;Ai|Da-Shan|DS|;Tang|Hua-Rong|HR|;Badakhshi|Harun|H|;Fan|Jian-Hong|JH|;Deng|Jia-Ying|JY|;Zhang|Jun-Hua|JH|;Chen|Yun|Y|;Zhang|Zhen|Z|;Xia|Yi|Y|;Guo|Xiao-Mao|XM|;Jiang|Guo-Liang|GL|;Zhao|Kuai-Le|KL|",
"chemical_list": "D000970:Antineoplastic Agents; D017239:Paclitaxel; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v23.i3.540",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i3.pg54010.3748/wjg.v23.i3.540Prospective StudyLong-term results of paclitaxel plus cisplatin with concurrent radiotherapy for loco-regional esophageal squamous cell carcinoma Zhu Han-Ting Ai Da-Shan Tang Hua-Rong Badakhshi Harun Fan Jian-Hong Deng Jia-Ying Zhang Jun-Hua Chen Yun Zhang Zhen Xia Yi Guo Xiao-Mao Jiang Guo-Liang Zhao Kuai-Le Han-Ting Zhu, Da-Shan Ai, Jia-Ying Deng, Jun-Hua Zhang, Yun Chen, Zhen Zhang, Yi Xia, Xiao-Mao Guo, Guo-Liang Jiang, Kuai-Le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaHua-Rong Tang, Department of Radiation Oncology, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou 310022, Zhejiang Province, ChinaHarun Badakhshi, Department of Radiation Oncology, Charité School of Medicine and Centre for Cancer Medicine, 14195 Berlin, GermanyJian-Hong Fan, Department of Gynecology, Renhe Hospital, Shanghai 443001, ChinaAuthor contributions: Zhu HT and Ai DS contributed equally to this work; Zhu HT, Ai DS, Tang HR, Badakhshi H, Fan JH, Deng JY, Zhang JH, Chen Y, Xia Y and Zhao KL designed and performed the research; Zhu HT, Ai DS, Tang HR, Badakhshi H, Fan JH, Deng JY, Zhang JH, Chen Y and Xia Y collected the data; Zhu ht and Ai ds analyzed the data and wrote the manuscript; Tang hr, Badakhshi H, Fan JH, Deng JY, Zhang JH, Chen Y, Zhang Z, Xia Y, Guo XM, Jiang GL and Zhao KL revised the manuscript.\n\nSupported by National Natural Science Foundation of China, No. 21172043 and No. 21441010.\n\nCorrespondence to: Dr. Kuai-le Zhao, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China. kuaile_z@sina.com\n\nTelephone: +86-21-64175590-6726 Fax: +86-21-64174774\n\n21 1 2017 21 1 2017 23 3 540 546 10 11 2016 16 12 2016 21 12 2016 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.AIM\nTo evaluate the long-term effectiveness and late toxicities of paclitaxel (PTX) plus cisplatin (DDP) with concurrent radiotherapy for locally advanced esophageal squamous cancer.\n\nMETHODS\nBetween 2008 and 2011, 76 patients were enrolled in a phase II study on the treatment of loco-regionally advanced esophageal cancer with radiotherapy (68.4 Gy/44 fractions or 61.2 Gy/34 fractions) combined with 4-cycle chemotherapy consisting of DDP (25 mg/m2 per day for 3 d) and PTX (175 mg/m2 for 3 h). The primary endpoints were overall survival and progression-free survival, and the secondary endpoints were toxicity and the treatment failure pattern.\n\nRESULTS\nA total of 76 patients were enrolled in this study, of whom 63.2% finished the whole regimen. The 5-year survival rates for the per-protocol population and intent-to-treat population were 25.4% and 26.4%, respectively, and the median survival rates were 23.7 mo and 28.5 mo, respectively. Grade 3 or 4 late toxicity was observed in only one patient (heart failure). In log-rank analysis, the pretreatment stage (stage II + III: 36.1 mo vs stage IV: 14.9 mo) and the completed cycle (1-3 cycles: 16.1 mo vs 4 cycles: 35.5 mo) were significant prognostic factors (P = 0.037 < 0.05 and P = 0.013 < 0.05).\n\nCONCLUSION\nRadiotherapy combined with chemotherapy consisting of PTX and DDP is a safe and effective definitive treatment for loco-regionally advanced esophageal squamous cancer.\n\nChemoradiotherapyLong-term resultLoco-regionally advanced esophageal cancerPhase II trial\n==== Body\nCore tip: This was a prospective phase II trial with 76 patients to evaluate the effect of paclitaxel plus cisplatin combined with concurrent radiotherapy for locally advanced esophageal squamous cancer. Our results showed a good survival rate, which seemed comparable or even better than those of other studies of patients undergoing definitive paclitaxel-based chemoradiotherapy.\n\nINTRODUCTION\nConcurrent chemoradiotherapy has been recognized as a standard treatment for loco-regionally advanced unresectable esophageal cancers[1,2]. The combination of 5-fluorouracil (5-FU) plus cisplatin (DDP) is most commonly used, with a median survival time of 16 mo. However, the standard regimen remains controversial, as more radiosensitive chemotherapeutic drugs, such as paclitaxel (PTX), have been investigated in esophageal cancer[3-6]. Moreover, with the development of radiation techniques, the appropriate irradiation field and total dosage have not been clarified[7-9].\n\nIn 2008, a phase II clinical trial commenced to observe the safety and effectiveness of PTX plus DDP combined with concurrent radiotherapy for locally advanced esophageal squamous cancer. The acute toxicity and 3-year survival rates were reported in 2014[10]. Now, the aim of the present study was to update the results to show the long-term survival and late toxicity of the study for loco-regional esophageal squamous cancer. To the best of our knowledge, few long-term prospective studies have been reported to date.\n\nMATERIALS AND METHODS\nThe study was performed between July 2008 and November 2011 in Fudan University Shanghai Cancer Center. Patients were eligible for this trial if they were histologically confirmed to have loco-regional esophageal squamous cancer with no metastasis [stage II-IVa and stage IVb without viscera metastasis, Union for International Cancer Control (UICC) 6th], an age ≤ 75 years, a Karnofsky performance score ≥ 80, a neutrophil count of at least 1.5 × 109/L, a leukocyte count of at least 3 × 109/L, a platelet count of at least 100 × 109/L, a serum creatinine level ≤ 1.2 mg/dL, and a serum urea nitrogen level ≤ 25 mg/dL. The patients did not receive prior operation/radiotherapy/chemotherapy/targeted therapy, and they had no complete obstruction or tracheoesophageal fistula.\n\nInterventions\nWe designed a phase II study of TP regimen (PTX + DDP) combined with concurrent radiotherapy for patients with loco-regional esophageal squamous cancer. The purpose of this study was to evaluate the safety and effectiveness of a four-week regimen of TP plus concurrent radiotherapy (Figure 1).\n\nFigure 1 Schedule of the chemoradiotherapy protocol. LCAF radiotherapy consisted of 41.4 Gy (1.8 Gy/fraction, q.d.) using large fields, and 27 Gy (1.5 Gy/fraction, b.i.d.) using reduced fields, with a total dose of 68.4 Gy/41 fractions in 44 d. CF radiotherapy consisted of 61.2 Gy/34 fractions in 48 d (1.8 Gy/fraction, q.d.). The chemotherapy regimen included PTX at 175 mg/m2, D1 and DDP at 25 mg/m2, D1-3. RT: radiotherapy; LCAF: late-course accelerated radiotherapy; CF: conventional radiotherapy; CT: Computed tomography; DDP: Cisplatin; PTX: Paclitaxel.\n\nAt the beginning of this study, late-course accelerated radiotherapy (LCAF) was utilized because we had completed some studies of LCAF and obtained higher local control and overall survival[11,12]. The regimen of LCAF was as follows: the first phase of radiation was 41.4 Gy/ 23 fractions over 4.6 wk (1.8 Gy/fraction, 5 fractions per week). The second phase of irradiation was the accelerated hyperfractionated session of 27 Gy/18 fractions in 1.6 wk (1.5 Gy/fraction, twice daily with a minimum interval of 6 h). The total dose of LCAF was 68.4 Gy/41 fractions in 44 d. After 16 patients had completed LCAF radiotherapy, fractionated radiotherapy (twice a day) was prohibited because of the increased number of patients and the limited number of radiation machines; in particular, it was impossible for patients to receive radiation therapy twice per day. Therefore, conventional radiotherapy (CF) had to be used instead of LCAF. These patients received 61.2 Gy/34 fractions in 48 d, with 1.8 Gy/fraction 5 times per week. The regimen for TP was the same as previously described.\n\nFor all patients, the radiotherapeutic technique was the 3-dimensional planning technique or intensity-modulated radiation therapy. The megavoltage photon energy of 6 MV was used. The target volume was localized by computed tomography (CT) planning. The gross tumor volume (GTV) included the primary tumor and nodal metastasis. The clinical target volume (CTV) contained a 2 to 3-cm cephalad and caudad margin beyond the GTV. The planning target volume (PTV) was defined as having a 1-cm margin around the CTV. No prophylactic irradiation was given to any patient.\n\nThe study protocol was reviewed and approved by the Ethics Committee of the Cancer Hospital Affiliated to Fudan University (No. 081065). Written informed consent was obtained from all participants.\n\nFollow-up and statistics\nFollow-up evaluations were performed every 3 mo during the first year, every 6 mo for the next 2 years, and once a year thereafter. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 3.0).\n\nThe treatment completion was defined as the fulfillment of 4 cycles of full-dose PTX + DDP along with a planned total dose of 68.4 Gy or 61.2 Gy radiotherapy.\n\nSurvival rates were calculated by the Kaplan-Meier model from the first day of treatment until death, and differences between rates were compared using the log-rank test. Age (65 years or less vs more than 65 years), gender (male vs female), stage (II-III vs IV: UICC 6th), number of cycles of chemotherapy (1-3 vs 4), pattern of radiotherapy (LCAF vs CF) and number of recurrent regions (one region vs multiple regions) were included into the log-rank test. A P value less than 0.05 was considered significant. All analyses were performed using SPSS22.0.\n\nAll patients who received treatment at least once were summarized in the intention to treat (ITT) analysis. The per-protocol (PP) analysis consisted of all treated patients without any protocol violation. The overall survival (OS) and progression-free survival (PFS) rates were analyzed based on ITT and PP populations, respectively. The primary endpoints of this study were OS and PFS, and the secondary endpoints were toxicity and the treatment failure pattern.\n\nRESULTS\nSeventy-six patients (median age, 58 years; age range, 37 to 74 years) were enrolled in this phase II study from 2008 to 2011 (Table 1). Forty-eight (63.2%) patients completed the whole regimen of chemotherapy without reduction. The median follow-up time was 78.5 mo (range: 67.2-89.8 mo). In July 2016, 6 patients were lost to follow-up because they changed their phone number; 76 (100%) patients were included in the ITT population and 70 (92.1%) in the PP population. In the PP population, 17 patients were alive, and 16 had no evidence of disease progression. Among the 54 of 70 patients with treatment failure, 17 had only local recurrence, 23 had distant metastasis only, 8 had concurrent local recurrence/distant failure, and 6 had failure due to other reasons, including second primary cancer (2 patients), second primary cancer progression (3 patients), and heart failure (1 patient).\n\nTable 1 Patients’ characteristics\n\nCharacteristic\tn (%)\t\nAge (yr)\t\t\nMedian\t58 (37-74)\t\nGender\t\t\nMale\t63 (82.9)\t\nFemale\t13 (17.1)\t\nStage1\t\t\nII\t21 (27.6)\t\nIII\t27 (35.5)\t\nIV\t28 (30.3)\t\nFraction regimen\t\t\nLCAF\t16 (21.1)\t\nCF\t60 (78.9)\t\nNumber of chemotherapy cycles\t\t\n1\t8 (10.5)\t\n2\t13 (17.1)\t\n3\t7 (9.2)\t\n4\t48 (63.2)\t\nStatus\t\t\nSurvival\t17 (22.4)\t\nDead\t53 (69.7)\t\nLost to follow-up\t6 (7.9)\t\n1 UICC 6th. LCAF: Late-course accelerated radiotherapy; CF: Conventional radiotherapy; UICC: Union for International Cancer Control. \n\nThe 1-, 2-, 3-, 4-, and 5-year survival rates in the PP population were 72.9%, 50%, 40%, 28.6%, and 25.4%, respectively, while those in the ITT population were 75%, 53.9%, 44.7%, 34.2%, and 26.4%, respectively. The median OS and PFS times were 23.7 mo (95%CI: 13.0-34.4) and 13.3 mo (95%CI: 9.7-16.9) in the PP population, and 28.5 mo (95%CI: 15.2-41.8) and 14.7 mo (95%CI: 10.7-18.7) in the ITT population, respectively (Figure 2).\n\nFigure 2 Overall survival and progression-free survival rates in patients with loco-regionally advanced esophageal cancer (Kaplan-Meier method). A: ITT analysis; B: PP analysis. ITT: Intention to treat; PP: Per-protocol; OS: Overall survival; PFS: Progression-free survival.\n\nIn log-rank analysis, the difference between the OS rate in the pretreatment stage (P = 0.037; stage II + III: 36.1 mo, 95%CI: 22.9-49.2 vs stage IV: 14.9 mo, 95%CI: 11.9-17.9) and the completed cycle (P = 0.013; 1-3 cycles: 16.1 mo, 95%CI: 10.2-22.1 vs 4 cycles: 35.5 mo, 95%CI: 22.3-48.7) was statistically significant (Table 2).\n\nTable 2 Prognostic factors for overall survival\n\nFactor\tNo.\tMedian survival t/mo\tLog-rank\t\nCycle(s)\t\t\t0.013\t\n1-3\t26\t16.1\t\t\n4\t50\t35.5\t\t\nStage\t\t\t0.037\t\nII-III\t48\t36.1\t\t\nIV\t28\t14.9\t\t\nGender\t\t\t0.093\t\nMale\t63\t17.3\t\t\nFemale\t13\t35.5\t\t\nAge\t\t\t0.708\t\n< 65 yr\t58\t23.4\t\t\n≥ 65 yr\t18\t27.0\t\t\nRadiation\t\t\t0.626\t\nCF\t60\t23.4\t\t\nLCAF\t16\t28.5\t\t\nCF: Conventional radiotherapy; LCAF: Late-course accelerated radiotherapy. \n\nAs acute toxicities had been reported previously[10], the late toxicities were updated in this article. Only one patient died because of heart failure at 20 mo, although it was not clear whether this was caused by radiotherapy. Other grade 3 or 4 late toxicities were not detected, although grade 1 or 2 focal pulmonary fibrous changes and pericardial effusion were common. Moreover, among the alive patients, only 2 had grade 1 hematological toxicity, which did not need special treatment.\n\nDISCUSSION\nLocalized esophageal carcinoma is often treated with preoperative chemoradiotherapy; however, when carcinoma is unresectable (IV stage) or patients do not want to undergo surgery, concurrent chemoradiotherapy would be a suitable treatment[13-15]. Some trials have revealed the effectiveness of chemoradiotherapy in loco-regionally advanced esophageal cancer[1,2,16,17], and 5-FU plus DDP with concurrent radiotherapy was recognized as the initial strategy. As a promising agent, PTX was reported to be effective in concurrent chemoradiotherapy due to its good response rate of 40%[18,19] and its effect as a radio-sensitizer. Various scientists have reported the efficacy of PTX-based chemoradiotherapy, especially TP (PTX plus DDP) and TF (PTX plus 5-FU). However, the details of the regimen remain controversial, including the dosage and the number of cycles.\n\nIn this study, we investigated the effectiveness of a 4-wk schedule of PTX plus DDP combined with concurrent radiotherapy. Our results showed good survival rates, with 1-, 2-, 3-, 4-, and 5-year survival rates of 75%, 53.9%, 44.7%, 34.2%, and 26.4%, respectively, in the ITT model. These results seemed comparable or even better than those with RTOG 0113 and other studies of patients undergoing definitive PTX-based chemoradiotherapy (Table 3).\n\nTable 3 Results of TP regimen plus radiotherapy for loco-regionally advanced esophageal cancer in past studies\n\nRef.\tNo.\tChemotherapy\tDose and fraction\tGrade ≥ 3 acute hematologic toxicity\tMedian observation period (mo)\tMedian survival t/mo\t2-yr survival rate\t\nJingu et al[22]\t84\tPTX 135 mg/m2\t50.4 Gy/28 fractions\t40.00%\tNA\t14.9\t37.00%\t\n\t\tDDP 75 mg/m2\t\t\t\t\t\t\n\t\t3-wk based\t\t\t\t\t\t\nTu et al[21]\t36\tPTX 135 mg/m2\t52-70 Gy/1.8-2 fractions\t13.90%\t14\t18\t42.80%\t\n\t\tDDP 75 mg/m2\t\t\t\t\t\t\n\t\t3-wk based\t\t\t\t\t\t\nSong et al[20]\t82\tPTX 135 mg/m2\t60 Gy/30 fractions\t30.50%\t20.4\t18.2\t40.80%\t\n\t\tDDP 30 mg/m2\t\t\t\t\t\t\n\t\t4-wk based\t\t\t\t\t\t\nDDP: Cisplatin; PTX: Paclitaxel; RT: Radiotherapy; NA: Not available.\n\nCompared with the study of Song et al[20], who used a similar regimen as in our study, the 2-year survival rate in our study was much higher (53.9% vs 40.8%), while the acute and late toxicities were comparable even with a higher dose of PTX. These differences may be due to the following reasons: (1) the median age in our study was 54, while the previous authors enrolled much older patients; and (2) the radiation delivery schedule was different. However, a few trials have reported the long-term outcome of regimens involving PTX in unresectable esophageal cancer[20,21]. In our study, the 5-year survival rate (26.4% in ITT model) was comparable to that of RTOG 8501 (26%), which used the combination of DDP + 5-FU[2]. This finding supports the idea that 4-wk PTX plus DDP regimen combined with concurrent radiotherapy is effective in treating locally advanced esophageal cancer, easy to perform and saves time spent in transportation to the treatment center.\n\nThe standard radiation regimen is 50.4 Gy/28 fractions in Western countries, and whether a high dosage of radiation can be used in concurrent therapy remains controversial. In the INT 0123 study reported by Minsky et al[1], the higher radiation dose (64.8 Gy) did not increase the OS or local control compared with the standard irradiation dose (50.4 Gy), although the higher dosage did not cause greater late toxicity. However, in Asia, 60-70 Gy radiation doses are widely used. In Jingu's study, the median OS was 39 mo, which was excellent after 60 Gy irradiation[22]. In our study, only 1 patient died of heart failure, and whether this outcome had any relationship with late toxicity was unclear. The most common late toxicity was grade 1 or 2 focal pulmonary fibrous changes. Given a good OS, this result suggests that a radiation dose of more than 60 Gy is appropriate for loco-regionally advanced esophageal cancer[22,23]. Differences in radiation doses between Asian and Western countries might be because of the distinct radiation plans applied.\n\nAt our hospital, LCAF was investigated for more than 10 years and was confirmed to be safe and show a better local control or 5-year OS rate[11,12]. However, phase III trials are still needed to compare this approach with CF. The primary purpose of this study was to assess the effectiveness of TP with concurrent LCAF, but because of the limited number of radiation machines and the large number of patients, it was impossible for one patient to receive radiotherapy twice daily; thus, CF was used instead of LCAF in the other 60 patients. With regard to the final data, there were no significant differences between LCAF and CF, perhaps because of the limited number of patients. Due to economic benefit, CF is recommended for loco-regionally advanced esophageal cancer.\n\nThe combination of 4-wk TP chemotherapy with concurrent radiation (61.2 Gy/34 fractions) is a safe and promising definitive treatment for loco-regionally advanced esophageal squamous cancer. A phase III randomized clinical trial (NCT 02459457) has since been initiated to compare the efficacy among TP, TF (PTX plus 5-FU) and TC (PTX plus carboplatin) to determine the best PTX-based regimen for concurrent chemoradiotherapy.\n\nCOMMENTS\nBackground\nConcurrent chemoradiotherapy has been recognized as a standard treatment for loco-regionally advanced unresectable esophageal cancer. The combination of fluorouracil (5-FU) plus cisplatin (DDP) was mostly used. Paclitaxel (PTX) was investigated to treat esophageal cancer. The current trial was designed to evaluate the safety and effectiveness of PTX plus DDP combined with concurrent radiotherapy for locally advanced esophageal squamous cancer.\n\nResearch frontiers\nVarious scientists have reported the efficacy of PTX-based chemoradiotherapy, especially TP (PTX plus DDP) and TF (PTX plus 5-FU) for locally advanced esophageal squamous cancer, but the details of the regimen remain controversial, including the dosage and the number of cycles. In this study, a 4-cycle TP regimen combined with concurrent radiotherapy showed a good overall survival rate and low toxicity.\n\nInnovations and breakthroughs\nFew long-term prospective studies about locally advanced esophageal squamous cancer have been reported to date.\n\nApplications\nBased on our results, a phase III randomized clinical trial (NCT 02459457) has since been initiated to compare the efficacy among TP, TF (PTX plus 5-FU) and TC (PTX plus carboplatin) to determine the best PTX-based regimen for concurrent chemoradiotherapy.\n\nTerminology\nPaclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, used to treat ovarian, breast, lung, pancreatic and other cancers. Cisplatin reacts in the body, binds to DNA and causes the DNA strands to crosslink, which ultimately triggers cells to die in a programmed way.\n\nPeer-review\nThe authors report the long-term results of a combined chemoradiation regimen for esophageal cancer, which is interesting.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: China\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: This study was reviewed and approved by the Ethics Committee of the Cancer Hospital Affiliated to Fudan University.\n\nClinical trial registration statement: As the study started 8 years ago, we did not register our clinical trial in website.\n\nInformed consent statement: All study participants, or their legal guardian, provided written consent prior to study enrollment.\n\nConflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.\n\nData sharing statement: There are no additional data available.\n\nPeer-review started: November 13, 2016\n\nFirst decision: December 2, 2016\n\nArticle in press: December 21, 2016\n\nP- Reviewer: Bonavina L, Sterpetti AV S- Editor: Ma YJ L- Editor: Wang TQ E- Editor: Liu WX\n==== Refs\n1 Minsky BD Pajak TF Ginsberg RJ Pisansky TM Martenson J Komaki R Okawara G Rosenthal SA Kelsen DP INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy J Clin Oncol 2002 20 1167 1174 11870157 \n2 Cooper JS Guo MD Herskovic A Macdonald JS Martenson JA Al-Sarraf M Byhardt R Russell AH Beitler JJ Spencer S Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group JAMA 1999 281 1623 1627 10235156 \n3 Ilson DH Ajani J Bhalla K Forastiere A Huang Y Patel P Martin L Donegan J Pazdur R Reed C Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus J Clin Oncol 1998 16 1826 1834 9586897 \n4 Adelstein DJ Rice TW Rybicki LA Larto MA Ciezki J Saxton J DeCamp M Vargo JJ Dumot JA Zuccaro G Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy J Clin Oncol 2000 18 2032 2039 10811667 \n5 Hsu FM Lin CC Lee JM Chang YL Hsu CH Tsai YC Lee YC Cheng JC Improved local control by surgery and paclitaxel-based chemoradiation for esophageal squamous cell carcinoma: results of a retrospective non-randomized study J Surg Oncol 2008 98 34 41 18449912 \n6 Polee MB Eskens FA van der Burg ME Splinter TA Siersema PD Tilanus HW Verweij J Stoter G van der Gaast A Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer Br J Cancer 2002 86 669 673 11875723 \n7 Jingu K Ariga H Nemoto K Narazaki K Umezawa R Takeda K Koto M Sugawara T Kubozono M Miyata G Long-term results of radiochemotherapy for solitary lymph node metastasis after curative resection of esophageal cancer Int J Radiat Oncol Biol Phys 2012 83 172 177 22079727 \n8 Tahara M Fuse N Mizusawa J Sato A Nihei K Kanato K Kato K Yamazaki K Muro K Takaishi H Phase I/II trial of chemoradiotherapy with concurrent S-1 and cisplatin for clinical stage II/III esophageal carcinoma (JCOG 0604) Cancer Sci 2015 106 1414 1420 26250827 \n9 Yamoah K Showalter TN Ohri N Radiation Therapy Intensification for Solid Tumors: A Systematic Review of Randomized Trials Int J Radiat Oncol Biol Phys 2015 93 737 745 26530740 \n10 Tang HR Ma HF An SM Badakhshi H Deng JY Zhang JH Chen Y Zhang Z Guo XM Jiang GL A Phase II Study of Concurrent Chemoradiotherapy With Paclitaxel and Cisplatin for Inoperable Esophageal Squamous Cell Carcinoma Am J Clin Oncol 2016 39 350 354 24732811 \n11 Shi XH Yao W Liu T Late course accelerated fractionation in radiotherapy of esophageal carcinoma Radiother Oncol 1999 51 21 26 \n12 Zhao KL Shi XH Jiang GL Wang Y Late-course accelerated hyperfractionated radiotherapy for localized esophageal carcinoma Int J Radiat Oncol Biol Phys 2004 60 123 129 15337547 \n13 Sjoquist KM Burmeister BH Smithers BM Zalcberg JR Simes RJ Barbour A Gebski V Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis Lancet Oncol 2011 12 681 692 21684205 \n14 Fan M Lin Y Pan J Yan W Dai L Shen L Chen K Survival after neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: A meta-analysis Thorac Cancer 2016 7 173 181 27042219 \n15 Jin HL Zhu H Ling TS Zhang HJ Shi RH Neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: a meta-analysis World J Gastroenterol 2009 15 5983 5991 20014464 \n16 Ajani JA Winter K Komaki R Kelsen DP Minsky BD Liao Z Bradley J Fromm M Hornback D Willett CG Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113 J Clin Oncol 2008 26 4551 4556 18574157 \n17 al-Sarraf M Martz K Herskovic A Leichman L Brindle JS Vaitkevicius VK Cooper J Byhardt R Davis L Emami B Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study J Clin Oncol 1997 15 277 284 8996153 \n18 Shirakawa T Kato K Nagashima K Nishikawa A Sawada R Takahashi N Shoji H Sasaki Y Honma Y Iwasa S A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy Cancer Chemother Pharmacol 2014 74 1207 1215 25267597 \n19 Kato K Tahara M Hironaka S Muro K Takiuchi H Hamamoto Y Imamoto H Amano N Seriu T A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy Cancer Chemother Pharmacol 2011 67 1265 1272 20703479 \n20 Song T Zhang X Fang M Wu S Concurrent chemoradiotherapy using paclitaxel plus cisplatin in the treatment of elderly patients with esophageal cancer Onco Targets Ther 2015 8 3087 3094 26543377 \n21 Tu L Sun L Xu Y Wang Y Zhou L Liu Y Zhu J Peng F Wei Y Gong Y Paclitaxel and cisplatin combined with intensity-modulated radiotherapy for upper esophageal carcinoma Radiat Oncol 2013 8 75 23531325 \n22 Jingu K Nemoto K Matsushita H Takahashi C Ogawa Y Sugawara T Nakata E Takai Y Yamada S Results of radiation therapy combined with nedaplatin (cis-diammine-glycoplatinum) and 5-fluorouracil for postoperative locoregional recurrent esophageal cancer BMC Cancer 2006 6 50 16515704 \n23 Zhang J Peng F Li N Liu Y Xu Y Zhou L Wang J Zhu J Huang M Gong Y Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell esophageal cancer Radiat Oncol 2012 7 93 22713587\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1007-9327",
"issue": "23(3)",
"journal": "World journal of gastroenterology",
"keywords": "Chemoradiotherapy; Loco-regionally advanced esophageal cancer; Long-term result; Phase II trial",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017239:Paclitaxel; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "540-546",
"pmc": null,
"pmid": "28210091",
"pubdate": "2017-01-21",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "10386713;25267597;24732811;22713587;11875723;8996153;18449912;10235156;20703479;15337547;21684205;10811667;16515704;27042219;9586897;11870157;23531325;26250827;26543377;26530740;22079727;20014464;18574157",
"title": "Long-term results of paclitaxel plus cisplatin with concurrent radiotherapy for loco-regional esophageal squamous cell carcinoma.",
"title_normalized": "long term results of paclitaxel plus cisplatin with concurrent radiotherapy for loco regional esophageal squamous cell carcinoma"
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"companynumb": "CN-PFIZER INC-2021344479",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "PACLITAXEL"
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... |
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"abstract": "We present a case report of a woman for whom a topical mucosal ulcer drug was prescribed and the pharmacist erroneously dispensed a calcium channel blocker (CCB), resulting in toxicities from the drug and withdrawal symptoms when attempts were made to stop the CCB. The pharmacology and toxicology of CCBs are discussed, particularly in relation to the adverse experiences of the case.",
"affiliations": "Rush Medical College, Chicago, IL, USA.",
"authors": "O'Donnell|||;Mertl|S Y|SY|;Kelly|W N|WN|",
"chemical_list": "D002121:Calcium Channel Blockers; D004110:Diltiazem",
"country": "United States",
"delete": false,
"doi": "10.1097/00045391-199901000-00009",
"fulltext": null,
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"issn_linking": "1075-2765",
"issue": "6(1)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D002121:Calcium Channel Blockers; D002764:Cholecystitis; D003329:Coronary Vasospasm; D004110:Diltiazem; D005260:Female; D005704:Gallbladder; D006801:Humans; D008297:Male; D019300:Medical Errors; D008875:Middle Aged; D011247:Pregnancy; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "61-6",
"pmc": null,
"pmid": "10610244",
"pubdate": "1999-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Calcium-channel blocker withdrawal in a pregnant woman.",
"title_normalized": "calcium channel blocker withdrawal in a pregnant woman"
} | [
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"companynumb": "US-BAUSCH-BL-2022-013408",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DILTIAZEM HYDROCHLORIDE"
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"drugadditional": ... |
{
"abstract": "BACKGROUND\nSpontaneous reports of acute liver injuries (ALI) in patients taking dronedarone triggered an EMA alert in 2011. This study aimed to assess the risk of ALI for class III antiarrhythmic drugs controlling for the use of other potential ALI-inducing drugs.\n\n\nMETHODS\nBetween 2010 and 2014, consecutive ALI cases (≥50 years-old) were identified across Germany. ALI was defined as a new increase in at least one of the transaminases ≥3 times the upper limit of normal (ULN) or ≥2 ULN if alkaline phosphatase, with (\"definite\" case) or without (\"biochemical\" case) suggestive signs/symptoms of ALI, excluding other liver diseases. Recruited community controls were matched to cases on gender, age and inclusion date. Exposure to antiarrhythmic drugs and co-medication up to 2 years before ALI onset was informed by patients and confirmed by physicians' prescriptions. Adjusted Odds Ratios (aOR) were obtained from conditional multivariable logistic regressions, adjusted for a multivariate disease risk score and co-medication.\n\n\nRESULTS\n252 cases and 1081 matched controls were included (59.1% females; mean age: 64 years). Exposure to class III antiarrhythmic drugs was 4.0% in cases and 1.5% in controls, aOR = 3.6 (95% CI: 1.6-8.4). Associations with exposure to dronedarone and amiodarone were respectively 3.1 (95% CI: 0.7-14. 8) and 5.90 (1.7-20.0). Restricting the analysis to definite or severe ALI cases did not change these results.\n\n\nCONCLUSIONS\nClass III antiarrhythmic drugs were associated with ALI, amiodarone displaying the highest risk, and results were robust to case definitions. Continued vigilance is needed for patients taking these drugs.",
"affiliations": "Pharmacoepidemiology, LA-SER, Paris, France, and Honorary Associate Professor, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address: lgrimaldi@laser-core.com.;Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.;Department of Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.;Department of Internal Medicine I, Gastroenterology, Hepatology and Infectious Diseases, Hamburg University Medical Center, Hamburg, Germany.;Department of Biostatistics, Rouen University Hospital, and INSERM U657, Institute for Biomedical Research, University of Rouen, Rouen, France.;Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada.;Montpellier School of Medicine, IRB-INSERM1040, Montpellier, France.;LA-SER Europe Limited and Department of Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.;Groupe Hospitalier Pitié-Salpétrière, Department of Hepatology, AP-HP and Institute of Cardiometabolism and Nutrition (ICAN), INSERM, Paris, France.;Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.",
"authors": "Grimaldi-Bensouda|Lamiae|L|;Wedemeyer|Heiner|H|;Wiegand|Johannes|J|;Lohse|Ansgar W|AW|;Benichou|Jacques|J|;Rossignol|Michel|M|;Larrey|Dominique|D|;Abenhaim|Lucien|L|;Poynard|Thierry|T|;Schott|Eckart|E|;|||",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000077764:Dronedarone; D000638:Amiodarone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2018.04.007",
"fulltext": null,
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"issn_linking": "0167-5273",
"issue": "266()",
"journal": "International journal of cardiology",
"keywords": "Acute liver injury; Antiarrhythmic drugs; Case-referent; Drug-induced",
"medline_ta": "Int J Cardiol",
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"abstract": "•Small cell carcinoma of the endometrium is a rare malignancy with poor survival.•A patient was diagnosed with stage IV small cell carcinoma of the endometrium.•She was treated with surgery, chemotherapy (cisplatin/etoposide) and radiotherapy.•She remains disease free 5 years after completion of her treatments.",
"affiliations": "Department of Obstetrics, Gynecology, and Reproductive Science, University of Manitoba, Canada.;Department of Obstetrics, Gynecology, and Reproductive Science, University of Manitoba, Canada.;Department of Obstetrics, Gynecology, and Reproductive Science, University of Manitoba, Canada.",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30046-1\n10.1016/j.gore.2020.100580\n100580\nCase Report\nLong-term survival in a stage IV small cell carcinoma of the endometrium\nViau M. Baragar I. Altman A.D. aaltman@cancercare.mb.ca⁎ Department of Obstetrics, Gynecology, and Reproductive Science, University of Manitoba, Canada\n⁎ Corresponding author at: 665 William Ave, Winnipeg, MB R3E 0L8, Canada. aaltman@cancercare.mb.ca\n06 5 2020 \n5 2020 \n06 5 2020 \n32 1005803 2 2020 25 4 2020 29 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Small cell carcinoma of the endometrium is a rare malignancy with poor survival.\n\n• A patient was diagnosed with stage IV small cell carcinoma of the endometrium.\n\n• She was treated with surgery, chemotherapy (cisplatin/etoposide) and radiotherapy.\n\n• She remains disease free 5 years after completion of her treatments.\n\n\n\nKeywords\nSmall cell carcinoma of the endometriumEndometrial carcinomaChemotherapy\n==== Body\n1 Introduction\nSmall cell carcinoma of the female genital tract comprises less than 2% of all gynecological malignancies, arising most commonly in the cervix (Walenkamp et al., 2009). Endometrial small cell carcinoma is a rare malignancy, with less than 100 cases reported in the literature to date. It often occurs admixed with other histologic tumour types, such as endometrioid or adenosquamous carcinomas (Matsumoto, 2011), however the natural history of the disease is determined by the presence of the small cell component (Walenkamp et al., 2009). Due to its sparse occurrence and aggressive nature (Katahira, 2004), limited evidence exists to guide treatment and survival remains poor, with literature reporting an estimated mean survival of 12 months and median survival of 2 months for those cases presenting at advanced stages. This is a case of stage IV mixed small cell carcinoma of the endometrium mixed with grade 3 endometrioid adenocarcinoma. The patient was treated with surgery, chemotherapy, and radiotherapy, and demonstrates no evidence of disease recurrence at follow-up 5 years after finishing her treatments.\n\n2 Case\nA 60-year-old patient, gravida 4 para 3, was first seen in May 2014 for a recent history of pelvic pressure and pain. She reported two episodes of post-menopausal bleeding in the preceding four months. She had reached menopause twenty years prior and stopped using combined hormone replacement therapy two years before the onset of her symptoms. Her BMI was 31.1. Her most recent cervical cytology (two years prior to presentation) was normal. She had no history of smoking nor any family history of gynecological cancers or Lynch syndrome. A transvaginal ultrasound showed a heterogeneous uterus with significant nodularity of the uterine parenchyma, 1.1 cm endometrial thickness, no adnexal masses, and a small volume of free fluid in the pelvis.\n\nAn endometrial biopsy revealed small cell carcinoma mixed with an endometroid adenocarcinoma. The small cell carcinoma component was comprised of sheets of tumor cells with small to intermediate-sized cells and nuclear molding. The high grade endometrioid carcinoma component was comprised of malignant glands admixed with areas of solid growth pattern. The adenocarcinoma cells were positive for Vimentin and negative for CEA. The small cell carcinoma component was positive for the neuroendocrine markers CD56 and Synaptophysin. Neither component was positive for p63.\n\nFurther work-up included a CT scan of the chest, abdomen and pelvis which revealed enlarged pelvic and para-aortic lymphadenopathy, with lymph nodes measuring up to 2 cm. The uterus was described as bulky and distorted by multiple soft tissue nodules. Bladder invasion was suspected. Tumor marker CA-125 was within normal limits.\n\nIn June 2014, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, omentectomy and removal of tumor on the bladder. The patient was suboptimally debulked, due to fixed bilateral pelvic lymph nodes measuring up to 5 cm.\n\nThe surgical pathology revealed a mixed small cell carcinoma (Fig. 1) and endometrioid carcinoma (Fig. 2) in a background of complex hyperplasia with atypia. There was invasion to the serosal surface and involvement of the left ovary and bladder. The cervix was uninvolved. There was one positive pelvic lymph node. Pelvic washings were positive. On histology, the tumor was composed approximately of 25% of small cell carcinoma component and 75% of endometrioid carcinoma. The latter was characterized by carcinoma with neuroendocrine features demonstrating high nuclear-cytoplasmic ratio, marked hyperchromasia and coarse granular chromatin. Tumor cells in the small cell carcinoma component were positive for CD56, synaptophysin (Fig. 3) and pancytokeratin while being negative for chromogranin and CEA. There was extensive LVSI.Fig. 1 Small cell carcinoma (Magnification 20×).\n\nFig. 2 High grade endometrioid carcinoma (Magnification 20×).\n\nFig. 3 Synaptophysin stain in the small cell carcinoma (Magnification 40×).\n\n\n\nThe post-operative course was complicated by a superficial wound infection and fluid overload corrected with furosemide. The patient received adjuvant chemotherapy with cisplatin at 20 mg/m2 and etoposide at 100 mg/m2 days 1 to 5 for five cycles of 21 days. Filgrastim, treatment delays, and etoposide dose reductions were required to manage her neutropenia. The sixth cycle was cancelled due to hearing loss diagnosed with audiometry and grade 3 peripheral neuropathy. During her chemotherapy treatments, she was diagnosed with bilateral gonadal vein thrombosis and was successfully treated with therapeutic subcutaneous dalteparin for 6 months. Following completion of chemotherapy treatments, she received adjuvant external beam radiation therapy for a total of 4500 cGy in 25 fractions delivered by 3-dimensional conformal 4-field box technique. The Clinical Target Volume included the paraaortic lymph nodes region up to T11-T12 junction, bilateral common iliac, bilateral external and internal iliac, presacral, hypogastric lymph nodes regions as well as uterine bed.\n\nThe patient developed chronic radiation enteritis and episodes of small bowel bacterial overgrowth that were addressed medically. She is still followed-up at the gynecologic oncology clinic and has no evidence of disease 5 years after completion of her treatments.\n\n3 Discussion\nThe proposed diagnostic criteria for small cell carcinoma of the endometrium are: (1) unequivocal evidence of endometrial origin, (2) dense, sheet-like growth of morphologically similar small to intermediate-sized tumor cells, with or without focal areas of spindle-shaped cells and irrespective of the presence/absence of other malignant subtypes, and (3) immunohistochemical reactivity for at least one neuroendocrine marker (van Hoeven, 1995). This case meets these criteria, with histological structure consistent with small cell carcinoma and positive reactivity to CD56 and synaptophysin.\n\nNinety four cases of small cell carcinoma of the endometrium in thirty one publications were found by reviewing the English-language literature since 1982. Among these, twenty three cases were FIGO stage IV disease at presentation. For most of these cases, the patients died of disease or follow-up or outcome information was unavailable (van Hoeven, 1995, D'Antonio, 2016, Huntsman, 1994, Meirmanov, 2003, Ureyen, 2013). Of those with known outcomes, mean and median survival were 10.6 and 8 months respectively, and all patients succumbed to their disease within 12 months with the notable exception of one patient who died at 36 months of respiratory failure in the setting of lung metastases (van Hoeven, 1995, D'Antonio, 2016, Huntsman, 1994, Meirmanov, 2003, Ureyen, 2013, Sato, 2010). Our case is the first reported case of a patient with stage IV disease who has survived for 5 years post-operatively without evidence of ongoing disease or recurrence, even with a suboptimal debulking.\n\nThere has been considerable variation in the reported treatments received by patients with this condition, with essentially all reported cases receiving surgery and the majority also receiving chemotherapy (in various combinations and durations) and/or radiation therapy. (Matsumoto, 2019) Our patient was treated with 5 cycles of adjuvant cisplatin and etoposide and subsequent adjuvant radiation therapy to the pelvis and para-aortic areas as described above. Among the available literature, there were only three publications which described cases of advanced (FIGO stage III or IV) endometrial small cell carcinoma on presentation remaining disease-free at >12 months follow-up, but no clear pattern of treatment can be derived from these to account for such success (Matsumoto, 2011, Ureyen, 2013, Olson et al., 1982). The treatments presented in these cases were: (a) carboplatin/paclitaxel for 6 cycles of 21 days followed by irinotecan for 3 cycles, then presacral/aortic radiotherapy, and lastly by 3 cycles of docetaxel and gemcitabine (Matsumoto, 2011), (b) pelvic radiotherapy followed by cisplatin and adriamycin (Ureyen, 2013), and (c) 2 doses of adriamycin and cyclophosphamide (Olson et al., 1982). There is a similar degree of diversity in the reported literature regarding the treatment of less-advanced disease (FIGO stage I or II). While the relative paucity of cases proves a challenge, further data will be necessary to guide clinicians in developing treatment strategies for patients presenting with this rare but aggressive malignancy.\n\nThis case is unique for having a long follow-up period without recurrence despite that this highly aggressive disease presented at an advanced stage and unfortunately underwent suboptimal debulking. It suggests that multimodal treatment may cure this disease in rare cases. It is, however, not possible to conclude that the regimen used is superior to other combined chemotherapy regimens for patients presenting with small cell carcinoma of the endometrium, as this would have to be tested in a trial which is unlikely to happen considering the rarity of this disease.\n\n4 Consent\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 on request.\n\nCRediT authorship contribution statement\nM. Viau: Conceptualization, Data curation, Resources, Writing - original draft, Writing - review & editing. I. Baragar: Conceptualization, Data curation, Resources, Writing - original draft, Writing - review & editing. A.D. Altman: Conceptualization, Project administration, Supervision, Writing - review & editing.\n\nDeclaration of Competing Interest\nThe authors declared that there is no conflict of interest.\n==== Refs\nReferences\nD'Antonio A. Small cell neuroendocrine carcinoma of the endometrium with pulmonary metastasis: A clinicopathologic study of a case and a brief review of the literature Ann. Med. Surg. (Lond.) 5 2016 114 117 26900464 \nHuntsman D.G. Small-cell carcinoma of the endometrium. A clinicopathological study of sixteen cases Am. J. Surg. Pathol. 18 4 1994 364 375 7511354 \nKatahira A. Small cell carcinoma of the endometrium: report of three cases and literature review Int. J. Gynecol. Cancer 14 5 2004 1018 1023 15361218 \nMatsumoto H. Small cell carcinoma of the endometrium: a report of two cases J. Obstet. Gynaecol. Res. 37 11 2011 1739 1743 21790887 \nMatsumoto H. Clinicopathologic features, treatment, prognosis and prognostic factors of neuroendocrine carcinoma of the endometrium: a retrospective analysis of 42 cases from the Kansai Clinical Oncology Group/Intergroup study in Japan J. Gynecol. Oncol. 30 6 2019 e103 31576694 \nMeirmanov S. Small cell carcinoma of the endometrium: report of a case with analysis of Wnt/beta-catenin pathway Pathol. Res. Pract. 199 8 2003 551 558 14533940 \nOlson N. Twiggs L. Sibley R. Small-cell carcinoma of the endometrium: light microscopic and ultrastructural study of a case Cancer 50 4 1982 760 765 6284342 \nSato H. Small-cell carcinoma of the endometrium presenting as Cushing's syndrome Endocr. J. 57 1 2010 31 38 19834252 \nUreyen I. Small cell carcinoma of the endometrium: A report of three cases J. Turk. Ger. Gynecol. Assoc. 14 2 2013 113 115 24592086 \nvan Hoeven K.H. Small cell neuroendocrine carcinoma of the endometrium Int. J. Gynecol. Pathol. 14 1 1995 21 29 7883422 \nWalenkamp A.M. Sonke G.S. Sleijfer D.T. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma Cancer Treat. Rev. 35 3 2009 228 236 19068273\n\n",
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"abstract": "A case of multidrug-resistant tuberculosis is presented. It highlights the role of whole-genome sequencing, expanded phenotypic drug susceptibility testing, and enhanced case management, offering a more complete understanding of drug susceptibility to Mycobacterium tuberculosis. This approach guides an effective individualized treatment strategy that results in rapid sustained culture conversion.",
"affiliations": "Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa.;King Dinu-Zulu Hospital Complex, South African National Department of Health, eThekwini Health District, Durban, South Africa.;Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa.",
"authors": "Dookie|Navisha|N|;Padayatchi|Nesri|N|;Lessells|Richard J|RJ|;Naicker|Cherise L|CL|;Chotoo|Sunitha|S|;Naidoo|Kogieleum|K|",
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"fulltext": "\n==== Front\nClin Infect Dis\nClin Infect Dis\ncid\nClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America\n1058-4838 1537-6591 Oxford University Press US \n\n32384148\n10.1093/cid/ciaa526\nciaa526\nBrief Reports\nAcademicSubjects/MED00290\nIndividualized Treatment of Multidrug-resistant Tuberculosis Using Whole-Genome Sequencing and Expanded Drug-Susceptibility Testing\nDookie Navisha 12 Padayatchi Nesri 12 Lessells Richard J 13 Naicker Cherise L 12 Chotoo Sunitha 4 Naidoo Kogieleum 12 1 \nCentre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal Durban, South Africa\n2 \nSouth African Medical Research Council-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal Durban, South Africa\n3 \nKwaZulu-Natal Research Innovation and Sequencing, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa\n4 \nKing Dinu-Zulu Hospital Complex, South African National Department of Health, eThekwini Health District, Durban, South Africa\nCorrespondence: N. Dookie, CAPRISA, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Private Bag X7, Congella, 4013, South Africa (navisha.dookie@caprisa.org).\n01 12 2020 \n08 5 2020 \n08 5 2020 \n71 11 2981 2985\n05 12 2019 16 4 2020 04 5 2020 21 7 2020 © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.2020This 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\nA case of multidrug-resistant tuberculosis is presented. It highlights the role of whole-genome sequencing, expanded phenotypic drug susceptibility testing, and enhanced case management, offering a more complete understanding of drug susceptibility to Mycobacterium tuberculosis. This approach guides an effective individualized treatment strategy that results in rapid sustained culture conversion.\n\nMycobacterium tuberculosiswhole genome sequencingindividualised treatmentmulti-drug resistant tuberculosisEuropean and Developing Countries Clinical Trials Partnership10.13039/501100001713TMA2018CDF-2372TMA2018SF-2476\n==== Body\nMultidrug-resistant tuberculosis (MDR-TB) treatment has been recently transformed with the introduction of the standardized short-course (SSC) regimens as the preferred option for treatment [1]. MDR-TB is a global health crisis affecting approximately 500 000 individuals annually and is considerably more difficult to treat than drug-susceptible TB disease. Given the magnitude of the disease, the recommended treatment in high-burden settings remains standardized empirical combination regimens. This has been largely driven by the need to scale-up treatment provision coupled with limited access to laboratory-based drug-susceptibility testing (DST) [1, 2]. Rapid molecular-based DST such as Xpert MTB/RIF Ultra (Xpert; Cepheid, USA) and MTBDRplus and MTBDRsl line probe assays (LPAs; Hain Lifescience GmbH, Nehren, Germany) provides information on a small selection of key drug-resistance mutations. Hence, treatment regimens may contain ineffective and potentially toxic drugs [3]. The recent arrival of the new TB drugs bedaquiline (BDQ) and delamanid holds significant promise in improving drug-resistant TB (DR-TB) treatment success. Clinical trials are currently underway to evaluate the use of these new drugs in various regimens, with the goal of creating shorter, injection-free standardized regimens. These drugs have been incorporated into current regimens since they became available [4]. As a consequence, early reports of resistance to both of these agents are emerging [5]. \n\nA compelling alternative, presented in the case reported here, is to individualize therapy based on whole-genome predictions of susceptibility. Whole-genome sequencing (WGS) technology for Mycobacterium tuberculosis has advanced significantly and has progressed from the research arena to clinical application for diagnosis and management of DR-TB. Leveraging on the advances in WGS technology coupled with enhanced case management by a team of DR-TB clinicians, we portray how the technology can be used to provide personalized care for patients with DR-TB. This approach could potentially impact the prognosis and outcomes of the disease.\n\nCASE REPORT\nA 41-year-old male was referred in March 2019 to the specialist DR-TB referral hospital in KwaZulu-Natal, South Africa, with pulmonary rifampicin-resistant TB, diagnosed with the Xpert Ultra assay. The patient was subsequently enrolled into the effectiveness of individualised multi-(extensively) drug-resistant tuberculosis treatment study (CAPRISA 020 InDEX study) and randomized to receive individualized treatment based on WGS of the cultured M. tuberculosis isolate [6]. The patient presented with classic clinical features associated with active TB, which included a 2-week history of cough, night sweats, chest pain, weight loss, and poor appetite. Chest radiography indicated consolidation in the right upper lobe and bilateral infiltration of lower zones. His past medical history was notable for a previous episode of drug-susceptible TB in 2004, for which he completed 6 months of treatment. He was diagnosed with human immunodeficiency virus in 2004 and commenced on antiretroviral treatment (ART) since his diagnosis. On presentation, his CD4 T-cell count was 172 cells/μL and viral load was <150 copies/mL. On enrollment into the study, MDR-TB was confirmed by the MTBDRplus LPA performed on the sputum sample, demonstrating resistance mutations in rpoB and the inhA promoter region. No mutations were detected on the MTBDRsl LPA, indicating susceptibility to the fluoroquinolones and second-line injectable drugs. He was initiated on a standard, injection-free regimen that contained BDQ (400 mg; loading dose for 2 weeks, 200 mg; 3 doses per week), linezolid (LZD; 600 mg daily), isoniazid (INH) high-dose (INH-HD; 900 mg daily), levofloxacin (LFX; 1 g daily), clofazimine (CFZ; 100 mg daily), pyrazinamide (Z; 1.25 g daily), and ethambutol (E; 1.2 g daily), indicated for 9 months of treatment [7]. His initial ART regimen, which was comprised of tenofovir (300 mg), lamivudine (300 mg), and efavirenz (600 mg), was switched to tenofovir, emtricitabine (200 mg), and nevirapine (200 mg) on commencement of a BDQ-containing regimen, given the interaction between BDQ and efavirenz [8]. LZD was stopped after 1 month due to anemia, corresponding with approximately 25% decrease in hemoglobin from 11.4 g/dL to 8.9 g/dL. His hemoglobin level subsequently increased to 9.7 g/dL. WGS profiling (MiSeq; Illumina V3.0, USA) and bioinformatics analysis (CLC Genomics Workbench v6.0.1, Qiagen, the Netherlands) conducted on the patient’s isolate showed mutations associated with resistance to INH, RIF, Z, E, and ethionamide. As per study protocol, the patient’s WGS results and clinical characteristics were closely reviewed by a panel of local and international drug-resistant TB experts to individualize patient management. Due to the presence of extensive disease, additional INH resistance mutations, and the presence of E and Z resistance, treatment was modified to a regimen of BDQ, LZD (600 mg/daily), LFX, CFZ, and teridizone (750 mg/daily), indicated for 18 months of treatment (6 weeks after initial treatment initiation) [1]. The patient tolerated the reintroduction of LZD (5-week interruption) for the remaining duration of the intensive phase. The patient’s sputum cultures converted to negative at month 2 and remained negative. Figure 1 contains the complete laboratory profiling data (WGS profiling and extended DST) of the patient’s clinical isolate and chest radiographs.\n\nFigure 1. Chest radiographs and complete laboratory profiling of the Mycobacterium tuberculosis isolate. Abbreviations: AFB, acid-fast bacilli; Asn, asparagine; Asp, aspartic acid; Ile, isoleucine; Leu, leucine; LPA, line probe assay; Met, methionine; MIGIT, mycobacteria growth indicator tube; MPT, MPT64 protein detection-based immunochomatographic test; MTBDR, MTBDRplus line probe assay; Ser, serine; Thr, threonine; Val, valine.\n\nDISCUSSION\nWe report on a case of MDR-TB treated using an individualized treatment strategy based on WGS prediction of drug susceptibility to the infecting organism. The case highlights the challenges associated with the lack of appropriate diagnostics to guide the use of the standard MDR-TB regimen. The application of WGS, expanded phenotypic DST, and enhanced case management revealed that the patient was on a regimen that contained 3 drugs with confirmed susceptibility. This included BDQ, LFX, and CFZ, as LZD was discontinued after 1 month of treatment due to anemia. Further, the patient would have received only 2 effective drugs (LFX and CFZ) during the continuation phase of treatment. WGS profiling demonstrated conventional resistance-associated mutations in the inhA promoter region and rpoB gene regions concordant with LPA results. In the case of INH, an additional mutation was detected in the inhA coding region, which is not available on LPA. A combination of the mutations in the promoter and coding regions of the inhA gene results in highly variable minimum inhibitory concentrations (MICs), ranging from 0.5 to 2.0 mg/L [9, 10]. LPA fails to predict the precise level of resistance in cases where additional mutations not present on the test raises the MIC of the isolate. Phenotypic testing confirmed high-level INH resistance. The role of INH-HD in the treatment of MDR-TB and in patients with different genetic variants of INH-resistant TB has yet to be determined. In the absence of this evidence, quantifying the level of INH resistance by phenotypic DST is advised. Given the high background burden of resistance to E and Z, with approximately 50% of MDR-TB patients with documented resistance to Z and 61% to E [11], replacement of these agents with similar sterilizing agents is warranted. This highlights that careful selection of effective companion drugs is warranted as these potentiate the activity of core drugs promoting relapse-free cure. Further, the use of an SSC regimen should be closely monitored, especially when 1 or more of group A drugs are clinically contraindicated, potentially compromising the regimen. In this case, modification of the drug regimen was required because the patient developed anemia.\n\nDR-TB treatment is rapidly transitioning into shorter, injection-free standard regimens that include the novel 6-month combination of BDQ, LZD, and pretomanid for extensively DR-TB and complicated cases of MDR-TB, as well as various novel combinations currently under evaluation [12]. The current case highlights that the eligibility criteria for these regimens require careful consideration and should ideally be guided by individual-level DST and clinical profiling. In this report, WGS and expanded DST were used as diagnostic adjuncts, demonstrating inadequacy of the novel injection-free BDQ-containing regimen. A significant number of DR-TB patients now receive BDQ-containing treatment regimens; however, as a result of increased use of the drug, there are emerging reports of acquired BDQ resistance with cross-resistance to CFZ [5]. This has important implications for the implementation of novel regimen combinations. At present, no rapid assay has the capability of detecting resistance to BDQ, LZD, CFZ, and cycloserine, which are key components of DR-TB [13]. While robust sequencing technology is available, elucidation of the genetic basis for resistance to the newer drugs remains limited and thus warrants confirmation by phenotypic DST in the interim, especially in cases with prior exposure to these drugs.\n\nIn conclusion, the case highlights the shortfalls of current diagnostic platforms in guiding DR-TB treatment. Initiation of treatment based on the standard diagnostic pipeline may inadvertently result in patients receiving suboptimal treatment, amplify resistance, and increase the risk of DR-TB transmission. Large-scale studies to assess the role of diagnostic adjuncts such as WGS, targeted sequencing panels, and expanded phenotypic assays are urgently needed in order to determine adequate treatment selection and personalized care approaches as highlighted in the described case. We strongly support the recommendations by Dowdy et al to address the policy gap regarding implementation of standard regimens. DST should be conducted with at least the core drugs such as BDQ and LZD, and no patient should be continued on the regimen for more than 2 months without documented susceptibility to these agents. Further, prior to the continuation phase, patients should have documented susceptibility to the fluoroquinolone and other key drugs carried into the continuation phase [14]. While standardized treatment approaches improve treatment access at a reduced cost and complexity, we cannot ignore the potential risk of resistance amplification.\n\nNotes\n\nAcknowledgments. The authors thank the laboratory staff for their assistance with handling, processing, and analyzing specimens at the National Institute of Communicable Diseases–Centre for Tuberculosis and the CAPRISA 020 InDEX study team.\n\n\nFinancial support. This work was supported by the European and Developing Countries Clinical Trials Partnership Fellowship (TMA2018CDF-2372 and TMA2018SF-2476).\n\n\nPotential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nWorld Health Organization . Consolidated guidelines on drug-resistant tuberculosis treatment 2019 . Geneva, Switzerland: \nWorld Health Organization , 2019 .\n2. \nWorld Health Organization . Global Tuberculosis report 2019 . Geneva, Switzerland : World Health Organization , 2019 .\n3. \nDookie N , Rambaran S , Padayatchi N , Mahomed S , Naidoo K \nEvolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care\n. J Antimicrob Chemother 2018 ; 73 :1138 –51\n.29360989 \n4. \nStop TB Partnership . Working group for new TB drugs pipeline Available at: https://www.newtbdrugs.org/pipeline/clinical. Accessed 11 October 2019 .\n5. \nde Vos M , Ley SD , Wiggins KB , et al. \nBedaquiline microheteroresistance after cessation of tuberculosis treatment\n. N Engl J Med 2019 ; 380 :2178 –80\n.31141643 \n6. \nCenter for the AIDS Programme of Research in South Africa . Effectiveness of individualized XDR-TB treatment study Available at: https://www.caprisa.org/Pages/CAPRISAStudies. Accessed 6 November 2019 .\n7. \nSouth African National Department of Health . Management of rifampicin-resistant tuberculosis: a clinical reference guide . South Africa : Department of Health , 2019 .\n8. \nvan Heeswijk RP , Dannemann B , Hoetelmans RM \nBedaquiline: a review of human pharmacokinetics and drug-drug interactions\n. J Antimicrob Chemother 2014 ; 69 :2310 –8\n.24860154 \n9. \nLempens P , Meehan CJ , Vandelannoote K , et al. \nIsoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations\n. Sci Rep 2018 ; 8 :3246 .29459669 \n10. \nGhodousi A , Tagliani E , Karunaratne E , et al \nIsoniazid resistance in Mycobacterium tuberculosis is a heterogeneous phenotype composed of overlapping MIC distributions with different underlying resistance mechanisms\n. Antimicrob Agents Chemother 2019 ; 63 :e00092 –19\n.31010866 \n11. \nZignol M , Dean AS , Alikhanova N , et al. \nPopulation-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project\n. Lancet Infect Dis 2016 ; 16 :1185 –92\n.27397590 \n12. \nConradie F , Diacon AH , Ngubane N , et al ; Nix-TB Trial Team \nTreatment of highly drug-resistant pulmonary tuberculosis\n. N Engl J Med 2020 ; 382 :893 –902\n.32130813 \n13. \nChesov D , Lange C , Heyckendorf J \nMolecular-based tuberculosis drug susceptibility testing: one size fits all?\nInt J Tuberc Lung Dis 2019 ; 23 :879 –80\n.31533876 \n14. \nDowdy DW , Theron G , Tornheim JA , Warren R , Kendall EA \nOf testing and treatment: implications of implementing new regimens for multidrug-resistant tuberculosis\n. Clin Infect Dis 2017 ; 65 :1206 –11\n.29554229\n\n",
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"keywords": "Mycobacterium tuberculosis; individualised treatment; multi-drug resistant tuberculosis; whole genome sequencing",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000995:Antitubercular Agents; D024901:Drug Resistance, Multiple, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis; D004364:Pharmaceutical Preparations; D018088:Tuberculosis, Multidrug-Resistant",
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"title": "Individualized Treatment of Multidrug-resistant Tuberculosis Using Whole-Genome Sequencing and Expanded Drug-Susceptibility Testing.",
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"abstract": "Although intralesional steroid injection as a management option for central giant cell granuloma (CGCG) of the mandible is considered safe, central retinal artery occlusion (CRAO) is a dreaded and previously unreported complication of this treatment modality. The present report discusses an iatrogenic case of CRAO that occurred during treatment of CGCG of the mandible. This complication occurred because of high injection pressure, which led to the opening of an anastomosis between the external and internal carotid arteries, leading to retrograde migration of steroid particles. This report also highlights the importance of being aware of such communications.",
"affiliations": "Senior Resident, Department of Ophthalmology, Guru Nanak Eye Centre, Delhi, India. Electronic address: doctor_gauri@yahoo.com.;Senior Resident, Department of Radiodiagnosis, Maulana Azad Medical College, Delhi, India.;Junior Resident, Department of Pediatric Dentistry, Maulana Azad Institute of Dental Sciences, Delhi, India.;Director Professor, Department of Ophthalmology, Guru Nanak Eye Centre, Delhi, India.",
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"title": "Central retinal artery occlusion as an iatrogenic complication of treatment of central giant cell granuloma of the mandible.",
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"abstract": "BACKGROUND\nHistoplasmosis is an uncommon systemic fungal infection, but it is potentially fatal in immunosuppressed populations. In Latin America, which is considered an endemic area for this mycosis, there have been no published reports regarding the incidence, clinical presentation, morbidity, and mortality of histoplasmosis in renal transplant patients. The objective of this study was to describe cases of histoplasmosis in renal transplant patients treated at the Pablo Tobon Uribe Hospital (Medellin, Colombia) between 2006 and 2013.\n\n\nMETHODS\nThis is a descriptive, retrospective study.\n\n\nRESULTS\nThe incidence of histoplasmosis in our renal transplant population was 1.1%. The ages of the 9 patients (4 men and 5 women) ranged between 27 and 59 years. In 2 of these patients, histoplasmosis appeared during the first year after transplantation. At the time of transplantation, 66% of patients received induction with alemtuzumab; 88% had a prior rejection episode and required increased immunosuppressive medication; 88% had renal graft dysfunction with creatinine levels >1.5 mg/dL; and the primary clinical presentation was disseminated histoplasmosis followed by the pulmonary form of the disease. Diagnoses were performed by histology in 6 patients, blood culture in 2 patients, and antigenuria in 1 patient. Three patients required treatment with amphotericin B for the severity of their infection, and 2 of these patients died before receiving the cumulative dose of amphotericin B. The 7 remaining patients received itraconazole for 12 months and had a successful treatment response. Regarding complications, 2 patients had hemophagocytic syndrome. At the 1-year follow-up appointment, renal function remained stable in all patients, and no patients had acute rejection or required renal replacement therapy. Thus, the overall mortality rate observed was 22.2%.\n\n\nCONCLUSIONS\nIn this series, histoplasmosis in renal transplant patients presented as an aggressive opportunistic infection with a higher incidence than that previously reported in the literature. The following risk factors have been associated with histoplasmosis: renal graft dysfunction, previous acute rejection, immunosuppression with tacrolimus-mycophenolate, and induction with alemtuzumab. The clinical presentation of histoplasmosis was nonspecific, which complicated disease diagnosis, and the treatment regimens were highly toxic and associated with significant morbidity and mortality rates.",
"affiliations": "Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia. Electronic address: johnfredynieto@gmail.com.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia. Electronic address: lm.serna@hotmail.com.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.;Hospital Pablo Tobon Uribe, Universidad de Antioquia, Medellín-Colombia.",
"authors": "Nieto-Ríos|J F|JF|;Serna-Higuita|L M|LM|;Guzman-Luna|C E|CE|;Ocampo-Kohn|C|C|;Aristizabal-Alzate|A|A|;Ramírez|I|I|;Velez-Echeverri|C|C|;Vanegas-Ruiz|J J|JJ|;Zuleta|J J|JJ|;Zuluaga-Valencia|G A|GA|",
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"mesh_terms": "D000328:Adult; D003105:Colombia; D019353:Endemic Diseases; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006660:Histoplasmosis; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D062606:Tertiary Care Centers",
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"title": "Histoplasmosis in renal transplant patients in an endemic area at a reference hospital in Medellin, Colombia.",
"title_normalized": "histoplasmosis in renal transplant patients in an endemic area at a reference hospital in medellin colombia"
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"abstract": "Ruxolitinib could be considered as an option in the treatment of LONIPCs in children when other treatments are ineffective. Spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children. https://bit.ly/3BmOYfb.",
"affiliations": "Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Pediatric Onco-haematology Unit, Pisa University Hospital, Pisa, Italy.;Pediatric Onco-haematology Unit, Pisa University Hospital, Pisa, Italy.;Dept of Diagnostic Imaging, 2nd Radiology Unit, Pisa University Hospital, Pisa, Italy.;Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.;Pediatric Onco-haematology Unit, Pisa University Hospital, Pisa, Italy.",
"authors": "Di Cicco|Maria|M|https://orcid.org/0000-0002-7027-6817;Del Tufo|Ester|E|;Parolo|Eva|E|;Menconi|Mariacristina|M|;Bernasconi|Sayla|S|;Romei|Chiara|C|;Di Gangi|Alessandro|A|https://orcid.org/0000-0002-2076-4994;Masini|Beatrice|B|;Peroni|Diego|D|;Casazza|Gabriella|G|",
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"fulltext": "\n==== Front\nERJ Open Res\nERJ Open Res\nERJOR\nerjor\nERJ Open Research\n2312-0541\nEuropean Respiratory Society\n\n10.1183/23120541.00407-2021\n00407-2021\nVersion of Record\nResearch Letter\n9\n14\nEffective treatment of late-onset noninfectious pulmonary complication with ruxolitinib in an 8-year-old boy\nEffective treatment of LONIPC with ruxolitinib\nhttps://orcid.org/0000-0002-7027-6817\nDi Cicco Maria 1\nDel Tufo Ester 1\nParolo Eva 1\nMenconi Mariacristina 2\nBernasconi Sayla 2\nRomei Chiara 3\nhttps://orcid.org/0000-0002-2076-4994\nDi Gangi Alessandro 1\nMasini Beatrice 1\nPeroni Diego 1\nCasazza Gabriella 2\n1 Dept of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy\n2 Pediatric Onco-haematology Unit, Pisa University Hospital, Pisa, Italy\n3 Dept of Diagnostic Imaging, 2nd Radiology Unit, Pisa University Hospital, Pisa, Italy\nMaria Di Cicco (maria.dicicco@unipi.it)\n7 2021\n20 9 2021\n7 3 00407-202119 6 2021\n09 7 2021\nCopyright ©The authors 2021\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org\nHaematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant and nonmalignant diseases both in adults and children, but this procedure can be burdened by the so-called “late-onset non-infectious pulmonary complications” (LONIPCs), which are characterised by significant morbidity and mortality [1]. LONIPCs include different forms of inflammatory lung involvement, occurring after 100 days and within 2–3 years following HSCT [2].\n\nRuxolitinib could be considered as an option in the treatment of LONIPCs in children when other treatments are ineffective. Spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children. https://bit.ly/3BmOYfb\n==== Body\npmc To the Editor:\n\nHaematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant and nonmalignant diseases both in adults and children, but this procedure can be burdened by the so-called “late-onset non-infectious pulmonary complications” (LONIPCs), which are characterised by significant morbidity and mortality [1]. LONIPCs include different forms of inflammatory lung involvement, occurring after 100 days and within 2–3 years following HSCT [2]. They have a variable incidence, with similar rates in adults and children [3], and uncertain pathogenesis, even if a strict relationship with chronic graft-versus-host disease (GVHD) has been reported. Pneumonia before 100 days after HSCT is considered as a risk factor [4, 5]. In these patients, unspecific signs and symptoms, such as dry cough or exercise-induced dyspnoea, frequently appear 8–12 months after HSCT [6]. Lung biopsy is considered the gold standard to establish a specific diagnosis; however, it is not always feasible in clinical practice, especially in children. Therefore, the diagnosis of LONIPCs relies upon clinical manifestations, lung imaging, spirometry, and the exclusion of infections [2]. First-line treatment is based on high-dose corticosteroids, while second-line treatment includes immunosuppressive agents such as calcineurin inhibitors [2]. Inhaled corticosteroids and short/long-acting bronchodilators may be slightly effective [7]. Ruxolitinib is a selective inhibitor of JAK1/2 approved for acute GVHD (in patients >12 years of age) [8], which has recently been proposed for chronic GVHD and LONIPCs [9].\n\nHere, we report a case of LONIPCs effectively treated with ruxolitinib in an 8-year-old boy, referred in April 2020 due to dry cough and increasing exercise-induced dyspnoea for 10 days. The patient had a history of B-cell acute lymphoblastic leukaemia diagnosed in August 2015 at 3 years of age, treated accordingly to the AIEOP-BFM-2009 protocol [10]. He obtained a first complete remission and then relapsed in March 2018. He then received additional chemotherapy achieving a second remission and a subsequent haploidentical HSCT from his mother with a peripheral graft and a busulfan-based regimen in November 2018. Neutrophil and platelet engraftment was unremarkable and GVHD prophylaxis included post-transplantation cyclophosphamide, cyclosporin and mycophenolate-mofetil. Early post-HSCT complications were represented by pneumonia treated with empiric therapy. The patient was discharged on cyclosporin and antimicrobial prophylaxis. Within the first year after HSCT, after a persistent increase in liver function tests (LFTs), namely alanine aminotransferase, aspartate aminotransferases and γ-glutamyltransferase, worsened by corticosteroid therapy and nonresponsive to immunosuppression, a liver biopsy showed a vanishing bile-duct syndrome related to drug toxicity with only mild signs of GVHD. Therefore, we tapered immunosuppression with a full suspension of cyclosporin in March 2020. 1 month later, on evaluation the boy was slightly tachypnoeic (respiratory rate 48 breaths per min), chest auscultation showed slightly decreased breathing sounds and oxygen saturation measured by pulse oximetry (SpO2) was 90%. Spirometry showed a restrictive pattern with severe reduction of all the parameters and normal forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (FEV1 48%, z-score −4.25; FVC 48%, z-score −4.35) (figure 1), and a chest computed tomography (CT) showed bilateral multiple peribronchial consolidations associated with bronchiectasis with a peri-lobular distribution. Nasopharyngeal swabs were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), blood examination showed an increase in LFTs, and bronchoalveolar lavage (BAL) cytology showed a predominance of neutrophils. Microbiological testing, including cultures and molecular testing for bacteria, fungi and viruses, were negative on BAL and blood samples, so we suspected a LONIPC. The patient required low-flow oxygen, while cyclosporin, high-dose prednisone and inhaled salmeterol/fluticasone were initiated, with a gradual improvement of both symptoms and spirometry (FEV1 62%, z-score −3.12, FVC 60%, z-score −3.32). 1 month later, chest CT showed a reduction of the parenchymal consolidations, but fibrotic bands were observed in the same areas and were associated with traction bronchiectasis, suggesting a fibrotic evolution. On tapering the steroids, the patient worsened again both clinically (dyspnoea on exertion, SpO2 94%) and at spirometry (FEV1 52%, z-score −3.95). Prednisone was increased again, but it had to be stopped due to a further increase in LFTs. Then, ruxolitinib was introduced (10 mg per day), with subsequent gradual improvement. Remarkably, 7 months later both LFTs and spirometry were normal (FEV1 88%, z-score −1.05; FVC 86%, z-score −1.18) (figure 1). To further characterise the pulmonary damage and in the attempt to avoid additional radiation exposure, lung magnetic resonance imaging (MRI) was performed in February 2021, revealing a reduction of the parenchymal bands and striae. T2-weighted sequences were consistent with chronic inflammatory involvement and initial fibrosis.\n\nFIGURE 1 Lung function testing trend by means of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values.\n\nTo our knowledge, this is the first reported effective treatment of LONIPCs with ruxolitinib in a child younger than 12 years with complete normalisation of lung function testing. LONIPCs is a generic definition including different subtypes of inflammatory lung involvement, potentially leading to aberrant tissue repair [11]. Among them, interstitial disease, bronchiolitis obliterans syndrome (BOS), and cryptogenic organising pneumonia (COP), are the most common [12]. According to the American Thoracic Society/European Respiratory Society guidelines [13], in LONIPCs the flow–volume curve may show an obstructive pattern (BOS), a restrictive pattern (interstitial disease), or even a mixed pattern [4]. CT may show geographic hypoattenuation and air trapping with a subpleural predominance in BOS, airspace consolidation along the bronchovascular bundle or in the subpleural area in COP, or ground-glass areas with reticulation and crazy paving pattern with predominantly peribronchovascular traction bronchiectasis in interstitial disease [14]. In our case, respiratory signs and symptoms appeared more than 1 year after transplantation, when cyclosporin was discontinued, and without any relationship with hepatic toxicity, suggesting the presence of an underlying alloreactive status that was exacerbated by the removal of immunosuppression. Moreover, lung infections were excluded, a restrictive pattern was identified on spirometry, and interstitial damage together with bronchiectasis was shown at CT, while MRI confirmed the presence of chronic inflammatory damage with fibrosis. In the absence of a diriment histological finding, while neither the BOS nor COP criteria were met, interstitial lung disease was a reasonable diagnosis.\n\nRuxolitinib can control alloreactivity through: 1) suppression of pro-inflammatory cytokines, 2) increase in regulatory T-cells, and 3) decrease in memory T-cells [15]. However, its safety and efficacy in children is still uncertain. Data on the effects of ruxolitinib on lung function in LONIPCs are lacking and only one study included five children with BOS showing that steroids were reduced in four patients, a full suspension was achieved in three patients and a 24% increase in FEV1 was observed [16]. Our patient responded to high-dose steroids, but the treatment was discontinued due to hepatic toxicity; since cyclosporin was not sufficient to control lung involvement, ruxolitinib was a valuable and effective option, providing a clinical response and a definite improvement of lung function. We also observed an improvement of lung involvement at the MRI. Our case shows that spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children since lung auscultation may be unremarkable. Our case report suggests that ruxolitinib should be considered as an effective option in the treatment of LONIPCs in children when other treatments are not effective nor feasible. However, more studies are needed to further investigate its efficacy and long-term safety in this age group.\n\nProvenance: Submitted article, peer reviewed.\n\nAuthors contributions: M. Di Cicco, E. Del Tufo, E. Parolo and M. Menconi conceptualised and designed the study, drafted the initial manuscript, contributed to data collection, and reviewed and critically revised the final manuscript. A. Di Gangi, B. Masini and C. Romei contributed to data collection and to the review of the literature, and actively participated in manuscript drafting. S. Bernasconi, G. Casazza and D. Peroni actively participated in manuscript drafting, and reviewed and critically revised the final manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nEthics statement: Written informed consent was obtained from the patient's parents for publication of this case report and any accompanying images.\n\nConflict of interest: The authors have no conflicts of interest relevant to this article to disclose.\n==== Refs\nReferences\n\n1 PatriarcaF, SkertC, SperottoA, et al. Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation. Bone Marrow Transplant 2004; 33 : 751–758. doi:10.1038/sj.bmt.1704426 14755316\n2 CarrerasE, CookeKR. Noninfectious pulmonary complications. In: CarrerasE, DufourC, MohtyM, et al. , eds. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. 7th Edn. Cham, Springer, 2019; pp. 393–407.\n3 PalmasA, TefferiA, MyersJL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998; 100 : 680–687. doi:10.1046/j.1365-2141.1998.00617.x 9531334\n4 HildebrandtGC, FazekasT, LawitschkaA, et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant 2011; 46 : 1283–1295. doi:10.1038/bmt.2011.35 21441964\n5 BergeronA, ChevretS, Peffault de LatourR, et al. Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation. Eur Respir J 2018; 51 : 1702617. doi:10.1183/13993003.02617-2017 29650555\n6 TrisoliniR, BandiniG, StanzaniM, et al. Morphologic changes leading to bronchiolitis obliterans in a patient with delayed non-infectious lung disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28 : 1167–1170. doi:10.1038/sj.bmt.1703303 11803362\n7 De SoyzaA, FisherAJ, SmallT, et al. Inhaled corticosteroids and the treatment of lymphocytic bronchiolitis following lung transplantation. Am J Respir Crit Care Med 2001; 164 : 1209–1212. doi:10.1164/ajrccm.164.7.2011034 11673211\n8 PrzepiorkaD, LuoL, SubramaniamS, et al. FDA approval summary: ruxolitinib for treatment of steroid-refractory acute graft-versus-host disease. Oncologist 2020; 25 : e328–e334. doi:10.1634/theoncologist.2019-0627 32043777\n9 StreilerC, ShaikhF, DavisC, et al. Ruxolitinib is an effective steroid sparing agent in bronchiolitis obliterans due to chronic graft-versus-host-disease. Bone Marrow Transplant 2020; 55 : 1194–1196. doi:10.1038/s41409-019-0662-6 31484991\n10 clinicaltrials.gov. International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia (Phase III). ClinicalTrials.gov Identifier: NCT01117441. https://clinicaltrials.gov/ct2/show/study/NCT01117441 Date last accessed: 6 July 2021.\n11 BarkerAF, BergeronA, RomWN, et al. Obliterative bronchiolitis. N Engl J Med 2014; 370 : 1820–1828. doi:10.1056/NEJMra1204664 24806161\n12 NishioN, YagasakiH, TakahashiY, et al. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant 2009; 44 : 303–308. doi:10.1038/bmt.2009.33 19349954\n13 PellegrinoR, ViegiG, BrusascoV, et al . Interpretative strategies for lung function tests. Eur Respir J 2005; 26 : 948–968. doi:10.1183/09031936.05.00035205 16264058\n14 MerliniL, BorzaniIMO, AnooshiravaniM, et al. Correlation of lung abnormalities on high-resolution CT with clinical graft-versus-host disease after allogeneic versus autologous bone marrow transplantation in children. Pediatr Radiol 2008; 38 : 1201–1209. doi:10.1007/s00247-008-0984-9 18769910\n15 SpoerlS, MathewNR, BscheiderM, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123 : 3832–3842. doi:10.1182/blood-2013-12-543736 24711661\n16 SchoettlerM, DuncanC, LehmannL, et al. Ruxolitinib is an effective steroid sparing agent in children with steroid refractory/dependent bronchiolitis obliterans syndrome after allogenic hematopoietic cell transplantation. Bone Marrow Transplant 2019; 54 : 1158–1160. doi:10.1038/s41409-019-0450-3 30683905\n\n",
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"title": "Effective treatment of late-onset noninfectious pulmonary complication with ruxolitinib in an 8-year-old boy.",
"title_normalized": "effective treatment of late onset noninfectious pulmonary complication with ruxolitinib in an 8 year old boy"
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"abstract": "Immunoglobulin G4-related disease (IgG4-RD) is defined as an inflammatory lymphoproliferative disorder. The relationship between malignancies and IgG4-RD remains unclear. We herein present a case of IgG4-RD that occurred during chemotherapy for advanced breast cancer. In this case, it was challenging to determine which of these diseases was responsible for the patient's mediastinal lymphadenopathy. Lymphadenopathy with IgG4-RD was diagnosed by assessing the reactivity to corticosteroids, which were used as premedication in chemotherapy, over time. The administration of prednisolone, which was initiated to treat active IgG4-RD, led to stable systemic therapy for malignancy. It is imperative to assess the disease activity and consider each treatment.",
"affiliations": "Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan.;Department of Gastroenterology, Hiroshima Prefectural Hospital, Japan.;Department of Pathology, Hiroshima Prefectural Hospital, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan.",
"authors": "Fujii|Yasutoshi|Y|;Doi|Mihoko|M|;Yamane|Hiroaki|H|;Morioka|Takehiko|T|;Komichi|Daisuke|D|;Nishisaka|Takashi|T|;Shinozaki|Katsunori|K|",
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"doi": "10.2169/internalmedicine.3386-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32269187\n10.2169/internalmedicine.3386-19\nCase Report\nOccurrence of Immunoglobulin G4-related Disease during Chemotherapy for Advanced Breast Cancer\nFujii Yasutoshi 1 Doi Mihoko 1 Yamane Hiroaki 1 Morioka Takehiko 1 Komichi Daisuke 2 Nishisaka Takashi 3 Shinozaki Katsunori 1 \n1 Division of Clinical Oncology, Hiroshima Prefectural Hospital, Japan\n\n2 Department of Gastroenterology, Hiroshima Prefectural Hospital, Japan\n\n3 Department of Pathology, Hiroshima Prefectural Hospital, Japan\nCorrespondence to Dr. Yasutoshi Fujii, yasup31@hotmail.com\n\n\n9 4 2020 \n1 7 2020 \n59 13 1649 1654\n23 5 2019 18 2 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Immunoglobulin G4-related disease (IgG4-RD) is defined as an inflammatory lymphoproliferative disorder. The relationship between malignancies and IgG4-RD remains unclear. We herein present a case of IgG4-RD that occurred during chemotherapy for advanced breast cancer. In this case, it was challenging to determine which of these diseases was responsible for the patient's mediastinal lymphadenopathy. Lymphadenopathy with IgG4-RD was diagnosed by assessing the reactivity to corticosteroids, which were used as premedication in chemotherapy, over time. The administration of prednisolone, which was initiated to treat active IgG4-RD, led to stable systemic therapy for malignancy. It is imperative to assess the disease activity and consider each treatment. \n\nIgG4-related diseaseautoimmune pancreatitislymphadenopathybreast cancer\n==== Body\nIntroduction\nImmunoglobulin G4-related disease (IgG4-RD), a novel disease concept that was first described in Japan by Hamano et al. (1), is characterized by an elevation of the serum IgG4 level and the infiltration of IgG4-positive plasma cells in tissues, as well as a chronic lymphoproliferative disorder that presents as fibrous, massive, hypertrophic lesions in several organs. In Japan, the Ministry of Health, Labour and Welfare proposed the Comprehensive Diagnostic Criteria for IgG4-RD in 2011 (2). To date, the precise steps resulting in the establishment of IgG4-RD remain unclear. Typically, lymphadenopathy is accompanied by other manifestations of IgG4-RD, and the differentiation of IgG4-RD from malignant tumors is clinically essential. Conversely, IgG4-RD is reportedly correlated with malignancies (3-6), although the relationship between malignant tumors and IgG4-RD remains under debate. We herein report a case of IgG4-RD that occurred during systemic therapy for advanced breast cancer and which the patient experienced repeated exacerbations and remissions with corticosteroids, which were used as premedication in chemotherapy.\n\nCase Report\nA 68-year-old-female with a history of Graves' disease and who presented with pain and swelling in the right upper limb was diagnosed with right breast invasive ductal carcinoma with metastasis to the right axillary lymph nodes and lungs. An immunohistological study revealed HER2 3+, ER 3+, PgR+, and a Ki-67 labeling index of 19.1%. Accordingly, treatment with paclitaxel (PTX)+trastuzumab (Tmab) was initiated for unresectable advanced breast cancer. The regimen was switched to trastuzumab emtansine (T-DM1) due to the development of peripheral neuropathy as an adverse event. The patient showed an iodinated contrast media-related hypersensitivity reaction (generalized urticaria) during the clinical course.\n\nAfter 2 years and 5 months of chemotherapy, the patient developed painless swelling of the bilateral submaxillary glands. We suspected IgG4-RD because of a high serum IgG4 value (752 mg/dL), but chose to observe the patient without corticosteroid treatment, after confirming that there were no malignant findings in fine needle aspiration cytology, because she had no symptoms and her condition was accompanied by advanced cancer. At the same period, although her tumor lesions had been shrinking, positron emission tomography-computed tomography (PET-CT) still showed an abnormal uptake of fluorodeoxyglucose (FDG) in the right axillary lymph node. In addition, new lymphadenopathies of the mediastinal and paraaortic lymph nodes (Fig. 1 CT-a) and an abnormal uptake of FDG were detected; these lymphadenopathies were considered to represent new metastatic lesions of breast cancer; thus, we changed the regimen to eribulin+Tmab.\n\nFigure 1. Clinical course. T: trastuzumab, P: pertuzumab, PTX: paclitaxel, DTX: docetaxel, T-DM1: trastuzumab emtansine, GEM: gemcitabine, LET: letrozole, MPA: medroxyprogesterone acetate\n\nAfter that, only the right axillary lymph node was enlarged; thus, radiation therapy (39Gy/13fr) was added. The regimen was administered alternately with gemcitabine (GEM)+Tmab and letrozole (LET)+Tmab because of peripheral neuropathy. A follow-up CT scan performed 2 months after the commencement of ongoing LET+Tmab revealed enlargement of mediastinal and paraaortic lymph nodes (Fig. 1 CT-b). We assessed that the breast cancer lesions progressed because of weakness in tumor control in endocrine therapy and returned to GEM+Tmab. Although these lymphadenopathies were reduced (Fig. 1 CT-c), it became difficult to continue GEM due to peripheral neuropathy, and we changed the regimen to medroxyprogesterone acetate (MPA). As a result, these lymphadenopathies enlarged again (Fig. 1 CT-d). At that time, we retrospectively observed that the pancreas and retroperitoneal soft tissue had enlarged and reduced along with these lymphadenopathies following the initiation of LET+Tmab treatment. Conversely, the sites at the first diagnosis that were the primary lesions-the right axillary lymph node and lungs-consistently showed no regrowth over time (Fig. 1 CT-b, c, d). Of note, the patient did not receive corticosteroids in the period in which she received endocrine therapy+Tmab regimen. In addition, salivary gland swelling, which had been pointed out previously, was subjectively reduced with the administration of corticosteroids as premedication for chemotherapy. Based on these findings, the mediastinal and paraaortic lymph nodes, which were initially considered to be new breast cancer lesions, were considered to be IgG4-RD lesions.\n\nEndoscopic ultrasonography (EUS) revealed low echoic diffuse pancreatic enlargement and stranding echoes. Magnetic resonance cholangiopancreatography (MRCP) showed bile duct stenosis and an irregularly narrow segment of the main pancreatic duct and low apparent diffusion coefficient (ADC) of the diffusely enlarged pancreatic parenchyma. The patient's serum bilirubin and liver enzyme levels were not elevated. We performed EUS-guided fine-needle aspiration, and a histopathological examination revealed infiltration of lymphocytes and plasma cells and fibrosis. After an immunohistochemical evaluation, more than 10 IgG4-positive cells were detected in a high-power field and the IgG4/IgG ratio was >40% (Fig. 2). A diagnosis of IgG4-RD was made based on the Comprehensive Diagnostic Criteria for IgG4-RD, 2011. Based on the different clinical response to corticosteroids used as premedication in chemotherapy, the lesions of the pancreas, salivary gland, retroperitoneal soft tissue, and the mediastinal and paraaortic lymph nodes were diagnosed as IgG4-RD.\n\nFigure 2. A: A specimen obtained by EUS-guided fine-needle aspiration. Pathologically, the lesion was found to be composed of inflammatory fibrous tissues with lymphoplasmacytic infiltration (Hematoxylin and Eosin staining, ×400). B: Immunohistochemistry with IgG-positive plasma cells (IgG staining, ×400). C: IgG4-immunostaining revealed more than 10 IgG4-positive cells per high-power field (IgG4 staining, ×400). EUS: endoscopic ultrasonography\n\nThe breast cancer lesions were controlled for long period of time, and prednisolone (PSL; 30 mg) was initiated for IgG4-RD with bile duct stenosis. Thereafter, all lesions showed remission (Fig. 3). Next, we changed the systemic therapy to LET + Tmab because of the contraindication of the combination of MPA and PSL due to the risk of thrombus. Currently, at 6 years since the initiation of chemotherapy, the patient is continuing to stably receive systemic therapy for breast cancer with the administration of PSL to control IgG4-RD.\n\nFigure 3. After starting PSL (30 mg) for IgG4-RD. A: MRCP showed improvement in bile duct stenosis (a), and an ADC map showed an increase in the ADC value (b). B: The size of the lesions of the mediastinal LNs (a), retroperitoneal soft tissue (b) and pancreas (c) were reduced. PSL: prednisolone, MRCP: magnetic resonance cholangiopancreatography, ADC: apparent diffusion coefficient, LN: lymph node\n\nDiscussion\nWe encountered a case of IgG4-RD that developed during several lines of systemic therapy for advanced breast cancer. The IgG4-related lymphadenopathy was noticed due to the different clinical response of plural lymphadenopathy to corticosteroids, which were used as premedication for chemotherapy.\n\nThe precise steps resulting in the establishment of IgG4-RD remain unclear. IgG4-RD is thought to be an autoimmune condition. The immunological characteristics of IgG4-RD include Th2-cell-dominant immune responses and abundant infiltration of regulatory T (Treg) cells into the involved organs. An excess immunoreaction of Th2 cells is reported to result in the recruitment of Treg cells, that secrete high levels of IL-10, inducing further class-switching to IgG4 and TGF-β, thereby, driving severe fibrosis (7,8). To date, several studies have reported that associations between allergic conditions and IgG4-RD may suggest a shared pathogenesis between the two conditions (9). On the other hand, studies of patients with autoimmune conditions have shown a coincidental pathogenesis between malignancy and the subsequent development of dermatomyositis, systemic sclerosis, and other conditions (10). The presented patient showed an allergic predisposition and an iodinated contrast media-related hypersensitivity reaction at 4 months before the onset of IgG4-RD. Moreover, the patient had a history of treatment for Graves' disease that had been administered for 15 years before the onset of IgG4-RD. The previous dataset of 235 consecutive IgG4-RD patients showed that 30% had a past history of allergic disease and 8.5% had a past history of autoimmune disease, respectively (11). Taken together, the patient may have had an intrinsic risk of developing IgG4-RD.\n\nThe association between malignant tumors and IgG4-RD remains under debate (Table). Wallace et al. (6) reported that a history of invasive malignancy is probably correlated with the subsequent development of IgG4-RD, and proposed that malignancy may be a predisposing condition to IgG4-RD in some patients. One possible explanation is that treatment for malignancy fosters immune dysregulation, leading to IgG4-RD in patients with other risk factors for that condition. The presence of malignancy or its treatment may induce some stimulation, such as pathogen-associated molecular pattern molecules and damage-associated molecular pattern molecules, and could cause excess immunoreaction of Th2 cells. In addition, no IgG4-RD manifestations occurred at the site of a prior malignancy in these studies (6); the condition could not be accounted for by local changes in the immunological milieu associated with malignancy, its treatment, or subsequent damage. Even in the largest cohort, which covered all organ manifestations of IgG4-RD in Japan, with the exception of 2 of 38 cases, IgG4-RD and malignancy diagnosed before or at the presentation of IgG4-RD differed in terms of the organ of origin (11). On the other hand, three of six retrospective cohort studies, reporting the risk of malignancy in IgG4-related disease, reported a marked correlation between IgG4-RD and the occurrence of malignancy (Table) (3-5). Those studies proposed that IgG4-RD could feature aspects of paraneoplastic syndrome, a characteristic of which was that the risk of occurrence of malignancies was the highest within 1 year after the diagnosis of IgG4-RD, and the clinical findings of autoimmune disease enhanced with treatment of the underlying malignancy (4,5). Moreover, the fact that few malignancies occurred at the site of prior IgG4-RD lesions indicates that IgG4-RD may feature aspects of paraneoplastic syndrome. However, in a study reported by Wallace et al. (6) and our case, the development of IgG4-RD was not correlated with the activity of malignancy and did not match the characteristics of paraneoplastic syndrome. Conversely, the other three studies reported that IgG4-RD was not markedly correlated with the occurrence of malignancy (1-13); this discrepancy could be attributed to differences in the analytical methods. Hirano et al. and Inoue et al. excluded subjects who were concurrently diagnosed with IgG4-RD complicated with malignancy.\n\nTable. The Association between Malignant Tumors and IgG4-RD.\n\nReference\tNumber of cases\tFollow up period\tNumber of cases that developed malignant tumor\tCancer type\tStandardised incidence rate (95% CI)\tRelative risk \n(95% CI)\t\n3\t106\taverage \n3.1 years\t11 (10.4%)\tColon(2)Lung(2)ML(2)Breast(1)Kidney(1) Prostate(1)Ovary(1)Tongue(1)\t3.8\t\t\n4\t108 \nAIP only\tmedian \n3.3 years\t15 (13.9%)\tStomach(7)Lung(3)ML(2)Prostate(2) Colon(2)Bile duct(1)Thyroid(1)\t・All 2.7 (1.4-3.9) \n・within 1 year 6.1 (2.9-9.9) \n・1 year or more 1.5 (0.3-2.8)\tAt the time of AIP diagnosis 4.9 (1.7-14.9)\t\n12\t113\tmedian \n6.1 years\t14 (12.4%)\tLung(5)Stomach(2)Pancreas(2) Bile duct(1)Kidney(1)Tongue(1) Breast(1)MM(1)AML(1)\t1.04 (0.57-1.8)\t\t\n13\t116 \nAIP only\tmedian \n3 years\t11 (9.5%)\tProstate(4)ML(2)Kidney(2)Breast(1) Bile duct(1)Pancreas(1)\t\t0.64 (0.27-1.51)\t\n11\t235\tmedian \n3 years\t13 (6%)\tLung(6)Colon(3)Stomach(2) Urinary Bladder(2)Pancreas(1)Kidney(1)\t1.16\t\t\n5\t158\tmedian \n5.95 years\t34 (21.5%)\tLung(5)Colon(5)Prostate(5)Stomach(4) Pancreas(4)Kidney(2)ML(2)Bile duct(1) Liver(1)Esophagus(1)Ovary(1)Breast(1) Thyroid(1)Tongue(1)Skin(1)MS(1)\t・All 2.01 (1.34-2.69) \n・within 1 year 3.53 (1.23-5.83) \n・1 year or more 1.48 (0.99-1.98)\t\t\n\t\nReference\tNumber of cases\tNumber of cases with a history of invasive cancer prior to IgG4-RD diagnosis\tCancer type\tStandardised prevalence rate (95% CI)\tOdds ratio (95% CI)\t\n6\t125\t20 (16.0%)\tProstate(7)ML(4)Colon(2)Lung(2) Testicle(2)Breast(2)Cervix(1)Leukemia(1)\t2.5 (1.1-3.6)\t3.1 (1.6-6.2, p=0.01)\t\nML: malignant lymphoma, MM: malignant melanoma, AML: acute myeloid leukemia, MS: myelodysplastic syndrome, CI: confidence interval\n\nWe initiated corticosteroid treatment (CST) for IgG4-RD that developed during chemotherapy for advanced breast cancer. The early introduction of CST is recommended, especially for patients with progressive fibrosis in the salivary glands and pancreas lesions (14-16). However, CST is associated with a risk of susceptibility to infection during chemotherapy. Observation may be appropriate for advanced cancer patients with asymptomatic lesions; however, if the disease activity of IgG4-RD is high, CST may lead to stable systemic therapy for advanced cancer. In short, it is important that the activity of each disease be precisely assessed. On the other hand, immunosuppressants can interfere with the anticancer response, although no clear evidence exists to support the correlation between malignant tumor progression and corticosteroid therapy. Previous studies have demonstrated that corticosteroids inhibit chemotherapy-induced cell apoptosis, whereas other investigations have reported that they suppress tumor progression and metastasis (17). In breast cancer, the response of breast cancer cells to glucocorticoid signaling may differ among breast cancer subtypes. Preclinical data has revealed that glucocorticoids receptor (GR) activation may reduce estrogen-induced cell proliferation in ER-positive breast cancer (18). On the other hand, in ER-negative breast cancer, the high tumor expression of GR is associated with a poor prognosis and GR activation suppresses chemotherapy-induced apoptosis (19). In our case of ER-positive breast cancer, the shrinkage of the malignant lesions has been maintained, with no abnormal uptake of FDG and without the appearance of new lesions, while controlling IgG4-RD with PSL. Thus, it seems that there have been no adverse effects from PSL.\n\nOverall, this case indicates that malignancy may be a predisposing condition to IgG4-RD, and may not be a characteristic of paraneoplastic syndrome. It is imperative to assess the disease activity and consider each treatment.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Hamano H , Kawa S , Horiuchi A , et al \nHigh serum IgG4 concentrations in patients with sclerosing pancreatitis\n. N Engl J Med \n344 : 732 -738\n, 2001 .11236777 \n2. Okazaki K , Kawa S , Kamisawa T , et al \nComprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) 2011\n. J Jpn Soc Intern Med \n101 : 795 -804\n, 2012 .\n3. Yamamoto M , Takahashi H , Tabeya T , et al \nRisk of malignancies in IgG4-related disease\n. Mod Rheumatol \n22 : 414 -418\n, 2012 .21894525 \n4. Shiokawa M , Kodama Y , Yoshimura K , et al \nRisk of cancer in patients with autoimmune pancreatitis\n. Am J Gastroenterol \n108 : 610 -617\n, 2013 .23318486 \n5. Asano J , Watanabe T , Oguchi T , et al \nAssociation between immunoglobulin G4-related disease and malignancy within 12 years after diagnosis: an analysis after longterm follow up\n. J Rheumatol \n42 : 2135 -2142\n, 2015 .26472416 \n6. Wallace ZS , Wallace CJ , Lu N , Choi HK , Stone JH \nAssociation of IgG4-related disease with history of malignancy\n. Arthritis Rheumatol \n68 : 2283 -2289\n, 2016 .27273903 \n7. Zen Y , Fujii T , Harada K , et al \nTh2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis\n. Hepatology \n45 : 1538 -1546\n, 2007 .17518371 \n8. Yamamoto M , Takahashi H , Shinomura Y \nMechanisms and assessment of IgG4-related disease: lessons for the rheumatologist\n. Nat Rev Rheumatol \n10 : 148 -159\n, 2014 .24296677 \n9. Kamisawa T , Anjiki H , Egawa N , Kubota N \nAllergic manifestations in autoimmune pancreatitis\n. Eur J Gastroenterol Hepatol \n21 : 1136 -1139\n, 2009 .19757521 \n10. Joseph CG , Darrah E , Shah AA , et al \nAssociation of the autoimmune disease scleroderma with an immunologic response to cancer\n. Science \n343 : 152 -157\n, 2014 .24310608 \n11. Inoue D , Yoshida K , Yoneda N , et al \nIgG4-related disease: dataset of 235 consecutive patients\n. Medicine (Baltimore) \n94 : e680 , 2015 .25881845 \n12. Hirano K , Tada M , Sasahira N , Isayama H , Mizuno S , Takagi K , et al \nIncidence of malignancies in patients with IgG4-related disease\n. Intern Med \n53 : 171 -176\n, 2014 .24492683 \n13. Hart PA , Law RJ , Dierkhising RA , Smyrk TC , Takahashi N , Chari ST \nRisk of cancer in autoimmune pancreatitis: a case-control study and review of the literature\n. Pancreas \n43 : 417 -421\n, 2014 .24622072 \n14. Khosroshahi A , Wallace ZS , Crowe JL , et al \nInternational consensus guidance statement on the management and treatment of IgG4-related disease\n. Arthritis Rheumatol \n67 : 1688 -1699\n, 2015 .25809420 \n15. Shimizu Y , Yamamoto M , Naishiro Y , et al \nNecessity of early intervention for IgG4-related disease: delayed treatment induces fibrosis progression\n. Rheumatology \n52 : 679 -683\n, 2013 .23258649 \n16. Hirano K , Tada M , Isayama H , et al \nLong-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment\n. Gut \n56 : 1719 -1724\n, 2007 .17525092 \n17. Lin KT , Wang LH \nNew dimension of glucocorticoids in cancer treatment\n. Steroids \n111 : 84 -88\n, 2016 .26930575 \n18. Karmakar S , Jin Y , Nagaich AK \nInteraction of glucocorticoid receptor (GR) with estrogen receptor (ER) alpha and activator protein 1 (AP1) in dexamethasone-mediated interference of ERalpha activity\n. J Biol Chem \n288 : 24020 -24034\n, 2013 .23814048 \n19. Wu WS , Chaudhuri S , Brickley DR , Pang T , Karrison SD \nMicroarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells\n. Cancer Res \n64 : 1757 -1764\n, 2004 .14996737\n\n",
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"issue": "59(13)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "IgG4-related disease; autoimmune pancreatitis; breast cancer; lymphadenopathy",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D000077733:Immunoglobulin G4-Related Disease; D000072281:Lymphadenopathy; D011239:Prednisolone",
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"title": "Occurrence of Immunoglobulin G4-related Disease during Chemotherapy for Advanced Breast Cancer.",
"title_normalized": "occurrence of immunoglobulin g4 related disease during chemotherapy for advanced breast cancer"
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"abstract": "Asthma therapy with monoclonal antibodies is a promising and effective approach for those with a severe and refractory type of disease. Although such a targeted therapy is considered to be safe, unusual complications may occur. We present a case of a 45 year-old female patient with severe allergic asthma and chronic spontaneous urticaria, who developed autoimmune polyendocrine syndrome type 2 (APS-2) after 26 months of omalizumab administration. The patient was diagnosed with primary adrenal insufficiency (Addison's disease) and Hashimoto's thyroiditis accompanied by autoimmune atrophic gastritis. According to our knowledge this is the first description of APS-2 that developed in conjunction with omalizumab treatment, although we have no evidence that the observed phenomenon indicated a cause-effect relationship to omalizumab.",
"affiliations": "a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.;a Department of Internal Medicine , Jagiellonian University Medical College , Krakow , Poland.",
"authors": "Rams|Anna|A|;Żółciński|Marek|M|;Zastrzeżyńska|Weronika|W|;Polański|Stanisław|S|;Serafin|Agnieszka|A|;Wilańska|Joanna|J|;Musiał|Jacek|J|;Bazan-Socha|Stanisława|S|",
"chemical_list": "D018927:Anti-Asthmatic Agents; D000069444:Omalizumab",
"country": "England",
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"doi": "10.1080/02770903.2017.1414239",
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"issue": "55(12)",
"journal": "The Journal of asthma : official journal of the Association for the Care of Asthma",
"keywords": "Autoimmune polyendocrine syndrome type 2; asthma ; omalizumab",
"medline_ta": "J Asthma",
"mesh_terms": "D018927:Anti-Asthmatic Agents; D001249:Asthma; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate; D008875:Middle Aged; D000069444:Omalizumab; D016884:Polyendocrinopathies, Autoimmune",
"nlm_unique_id": "8106454",
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"title": "Autoimmune polyendocrine syndrome type 2 in patient with severe allergic asthma treated with omalizumab.",
"title_normalized": "autoimmune polyendocrine syndrome type 2 in patient with severe allergic asthma treated with omalizumab"
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"abstract": "This case involves a 62-year-old male with a prior history of epidural abscess and L1-L2 osteodiscitis who was admitted because of low back pain. The patient was previously treated for methicillin-susceptible Staphylococcus aureus (MSSA) discitis in the L1/L2 vertebral region with intravenous (IV) nafcillin through a peripherally inserted central catheter (PICC). However, he returned after four months with recurrent low back pain along with chills and fever. He was admitted for severe sepsis related to the L1-L2 region osteomyelitis and discitis. The Infectious Disease department initially started the patient on IV vancomycin and cefepime; however, routine labs on the second day of IV antibiotics showed concern for pancytopenia with white blood cell count (WBC) decreased to 2.5 thou/mm3, Hgb to 6.2 g/dL, Hct to 20.8%, and platelets to 82 thou/mm3 from baseline values of WBC 3.9 thou/mm3, Hgb 8.3 g/dL, Hct 28%, and platelets 126 thou/mm3. Due to concern for pancytopenia in the setting of severe sepsis, extensive hematologic workup was pursued to evaluate for disseminated intravascular coagulation (DIC) and bone marrow suppression. The patient also had a positive fecal occult blood test, so the Gastroenterology department was consulted for esophagogastroduodenoscopy (EGD) and colonoscopy. Furthermore, despite appropriate outpatient treatment for MSSA osteodiscitis, the patient was bacteremic with Staphylococcus aureus. Hence, the Cardiology department was consulted to rule out cardiac valvular vegetation. This case presents a unique case of pancytopenia involving elements of drug-induced aplastic anemia as well as DIC-related sepsis. The agranulocytosis may have been a consequence of drug reaction to IV vancomycin. The anemia and thrombocytopenia may have been caused by DIC. Repeat computed tomography (CT) guided spinal aspiration confirmed pan-sensitive Staphylococcus aureus infection of the L1/L2 vertebral region. Treatment was reverted to nafcillin monotherapy and fortunately his hematologic function normalized, avoiding the need for advanced treatments such as intravenous immunoglobulin infusion therapy (IVIG) or high dose steroids.",
"affiliations": "Internal Medicine, Ocala Regional Medical Center/ University of Central Florida College of Medicine, Ocala, USA.;Internal Medicine, Ocala Regional Medical Center/ University of Central Florida College of Medicine, Ocala, USA.;Internal Medicine, Ocala Regional Medical Center/ University of Central Florida College of Medicine, Ocala, USA.",
"authors": "Cho|Jake N|JN|;Avera|Stephen|S|;Iyamu|Kenneth|K|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3994Internal MedicineMedical EducationInfectious DiseasePancytopenia as a Consequence of Sepsis and Intravenous Antibiotic Drug Toxicity Muacevic Alexander Adler John R Cho Jake N 1Avera Stephen 1Iyamu Kenneth 1\n1 \nInternal Medicine, Ocala Regional Medical Center/ University of Central Florida College of Medicine, Ocala, USA \nJake N. Cho jake.cho@ucf.edu1 2 2019 2 2019 11 2 e399414 1 2019 1 2 2019 Copyright © 2019, Cho et al.2019Cho 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/17399-pancytopenia-as-a-consequence-of-sepsis-and-intravenous-antibiotic-drug-toxicityThis case involves a 62-year-old male with a prior history of epidural abscess and L1-L2 osteodiscitis who was admitted because of low back pain. The patient was previously treated for methicillin-susceptible Staphylococcus aureus (MSSA) discitis in the L1/L2 vertebral region with intravenous (IV) nafcillin through a peripherally inserted central catheter (PICC). However, he returned after four months with recurrent low back pain along with chills and fever. He was admitted for severe sepsis related to the L1-L2 region osteomyelitis and discitis.\n\nThe Infectious Disease department initially started the patient on IV vancomycin and cefepime; however, routine labs on the second day of IV antibiotics showed concern for pancytopenia with white blood cell count (WBC) decreased to 2.5 thou/mm3, Hgb to 6.2 g/dL, Hct to 20.8%, and platelets to 82 thou/mm3 from baseline values of WBC 3.9 thou/mm3, Hgb 8.3 g/dL, Hct 28%, and platelets 126 thou/mm3. Due to concern for pancytopenia in the setting of severe sepsis, extensive hematologic workup was pursued to evaluate for disseminated intravascular coagulation (DIC) and bone marrow suppression. The patient also had a positive fecal occult blood test, so the Gastroenterology department was consulted for esophagogastroduodenoscopy (EGD) and colonoscopy. Furthermore, despite appropriate outpatient treatment for MSSA osteodiscitis, the patient was bacteremic with Staphylococcus aureus. Hence, the Cardiology department was consulted to rule out cardiac valvular vegetation.\n\nThis case presents a unique case of pancytopenia involving elements of drug-induced aplastic anemia as well as DIC-related sepsis. The agranulocytosis may have been a consequence of drug reaction to IV vancomycin. The anemia and thrombocytopenia may have been caused by DIC. Repeat computed tomography (CT) guided spinal aspiration confirmed pan-sensitive Staphylococcus aureus infection of the L1/L2 vertebral region. Treatment was reverted to nafcillin monotherapy and fortunately his hematologic function normalized, avoiding the need for advanced treatments such as intravenous immunoglobulin infusion therapy (IVIG) or high dose steroids.\n\npancytopeniaagranulocytosisvancomycindrug toxicityanemiasepsisdisseminated intravascular coagulationThe 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\nAcquired agranulocytosis is a rare condition with a reported incidence ranging from one to five cases per million population per year. An association with medications can be found in two-thirds or more of the incidents [1]. Neutropenia is usually a result of decreased production or increased destruction. There are a number of medications implicated as potential causes of neutropenia or agranulocytosis, the most definitive medications being those that cause bone marrow suppression. In this case report, we describe the observation of vancomycin-associated agranulocytosis as well as hemolytic/aplastic anemia. Published case reports have cited vancomycin-induced neutropenia or thrombocytopenia separately, but very few have reported pancytopenia in the setting of sepsis with or without drug toxicity.\n\nCase presentation\nThis case report involves a 62-year-old male with a prior history of epidural abscess and L1-L2 osteodiscitis, who was admitted to the ward because of progressively worsening low back pain. About four months prior (Figures 1A, 1B), the patient was treated via peripherally inserted central catheter (PICC) intravenous (IV) nafcillin (six week course) for methicillin-susceptible Staphylococcus aureus (MSSA) associated discitis in the L1/L2 vertebral region confirmed with CT guided aspiration. The patient reported doing well but two days prior to presentation, he started having severe low back pain again, along with subjective chills and fever. Magnetic resonance imaging (MRI) of the spine was ordered but the MRI study was limited due to the inability of the patient to tolerate being in supine position. The imaging that was obtained did show progression of loss of the L1-L2 vertebral bodies suspicious for osteomyelitis (Figures 2A, 2B). With a temperature of 100°F, elevated CRP > 9 mg/dL and lactic acidosis 2.8 mmol/L, vancomycin 1.25 gm IV and ceftriaxone 2 gm IV were given empirically for severe sepsis on admission (Day 0). The next day (Day 1), the Infectious Disease department was consulted and they recommended vancomycin 1.5 gm Q12H IV and cefepime 2 gm Q12H IV. However, the CBC labs showed pattern concerning for pancytopenia with WBC decreased to 2.5 thou/mm3, Hgb to 6.2 g/dL, Hct to 20.8%, and platelets to 82 thou/mm3 (Table 1). Although the patient was given IV NS fluids overnight, the degree and pattern of reduction was not consistent with hemodilution. Repeat CBC labs confirmed these values. Incidentally, on admission, his prothrombin time (PT) and international normalized ratio (INR) were elevated to 19.5 seconds and 1.72, respectively, but the patient stated that he consumes red yeast rice extract for cholesterol control, which also has anti-clotting properties. Lactate dehydrogenase (LDH) obtained on Day 1 was elevated to 929 unit/L and the total bilirubin on admission was 0.8 mg/dL.\n\nFigure 1 Initial Admission MRI Lumbar\nInitial admission, Figure 1A (MRI T1 w contrast, sagittal): Compression fracture at L2 with retropulsion of the posterior-superior margin. Bone destruction particularly involving the inferior aspect of the L1 vertebra and portions of the L2 vertebra representing discitis and osteomyelitis. Figure 1B (MRI T2 wo contrast, axial): Paravertebral phlegmon (yellow *) extending into left and right psoas muscles (double yellow *) with fluid signal intensity suggesting small abscesses. Moderate ventral thecal sac compression and moderate spinal stenosis. Paraspinal muscles (PS).\n\nFigure 2 Re-admission MRI Lumbar and CT Lumbar\nRe-admission, Figure 2A: (MRI T2 wo contrast, axial): Non-diagnostic as the patient terminated the study after three sequences. Mild improvement in paravertebral abscess (yellow *). Psoas muscles (double yellow *). Paraspinal muscles (PS). Figure 2B (CT lumbar w contrast) Gibbus deformity at this level, discitis most likely reflecting progression of infection. Comparison to prior, progression of loss of vertebral body height of L2 and L1.\n\nTable 1 Complete Blood Count (CBC) Values Longitudinal \nTable 1: CBC Values Longitudinal\t\n \tDay 0 ED admit\tDay 1\tDay 2 (repeat labs)\tDay 3\tDay 4\tDay 5\tDay 6\tDay 7\tDay 8\t\nHemoglobin (g/dL)\t8.0\t8.3\t6.2 (5.9)\t6.9\t7.6\t7.2\t7.3\t7.5\t7.6\t\nHematocrit (%)\t27\t28.3\t20.8 (19.6)\t22.4\t24.2\t22.6\t23\t23.6\t24.7\t\nWhite blood cells (thou/mm3)\t4.6\t3.9\t2.5 (2.6)\t5.7\t8.0\t7.3\t6.7\t6.9\t7.0\t\nPlatelets (Thou/mm3)\t86\t126\t82 (79)\t90\t98\t94\t86\t147\t194\t\nAntibiotics\tVancomycin, Ceftriaxone\tVancomycin, Cefepime\tVancomycin, Cefepime\tNafcillin\tNafcillin\tNafcillin\tNafcillin\tNafcillin\tNafcillin\t\nEvents\t \t \tTransfuse 2 units pRBC\tTransfuse 1 unit pRBC\t \t \t \t \t \t\nDue to the patient's acute anemia on Day 2, a decision was made to transfuse two units of packed RBCs, which mildly improved the patient's Day 3 labs to WBC 5.7 thou/mm3, Hgb 6.9 g/dL, Hct 22%, and Plt 90 thou/mm3 (Table 1) with a D-Dimer of 741 ng/mL (Table 2). To evaluate for disseminated intravascular coagulation (DIC), fibrinogen and fibrin split products (FSP) were ordered on Day 2, but unfortunately, those labs were collected post transfusion. Nevertheless, fibrinogen was 544 mg/dL and FSP was 10-40 mcg/dL and the peripheral smear from Day 2 did not show schistocytes (Table 2). The Infectious Disease department recommended discontinuation of vancomycin and cefepime and resuming nafcillin 12 gm Q24H IV which the patient tolerated during prior admission. The patient received another transfusion on Day 3, which improved Day 4 labs of Hgb to 7.6 g/dL and Plt to 98 thou/mm3. Lactic acid decreased to 0.9 mmol/L; however, the patient continued to have fever spikes of temperature 101.6°F. On Day 3, his reticulocyte count was 0.4 (absolute 0.2), the reticulocyte index was 0.12 and haptoglobin was elevated to 315 mg/dL. The Hematology department was consulted and they ordered serum protein electrophoresis (SPEP), vitB12 and folate (both within normal limits). The SPEP result was obtained several days later, which yielded a kappa/lambda light chain ratio of 0.78 (WNL) and monoclonal immunoglobulin not detected by immune-fixation (Table 2). By Day 7 of monotherapy with nafcillin, CBC continued to improve with WBC of 6.9 thou/mm3, Hgb 7.5 g/dL, Hct 23.6%, and Plt 147 thou/mm3 (Table 1). The blood cultures from admission were positive for MSSA staph and through interventional radiology guided spinal abscess aspiration, microbiology studies yielded a pan-sensitive staph organism. By Day 8, the patient had no fever spikes, but an esophagogastroduodenoscopy (EGD) was performed to rule out a gastrointestinal bleeding source since his fecal occult blood test was positive and due to the acute anemia soon after admission. EGD identified a chronic 2 cm duodenal ulcer, which was ablated, and colonoscopy was WNL. Due to the persistent bacteremia, transesophageal echocardiography (TEE) was also done, which ruled out valvular vegetation as a source for the MSSA bacteremia.\n\nTable 2 Iron Profile/Hematology/SPEP Studies\nSPEP - serum protein electrophoresis, TIBC - total iron binding capacity, FeSat - iron saturation, retic - reticulocyte, LDH - lactate dehydrogenase, PEP - protein electrophoresis, IEP - immunoelectrophoresis.\n\nIron Profile/Hematology/SPEP Studies\t\n \tValues (Day 4)\tReference range\t\nFerritin\t97.1\t24 – 336 ng/mL\t\nTotal iron\t22\t45 – 182 mcg/dL\t\nTIBC\t298\t250 – 450 mcg/dL\t\nFeSat\t8\t20 - 55 %\t\n \tValues (Day 3)\tReference range\t\nFibrinogen\t544\t150 – 400 mg/dL\t\nFibrin degradation products\t10-40\t<10 mcg/dL\t\nD-dimer\t741\t<460 ng/mL\t\nRetic count\t0.4\t0.6 - 2.2%\t\nHaptoglobin\t315\t30-200 mg/dL\t\nLDH\t929\t313 – 618 units/L\t\n \tValues (Day 4)\tReference range\t\nAlpha-2-globulins\t0.85\t0.6 – 1.0 g/dL\t\nBeta globulins\t0.74\t0.7 – 1.2 g/dL\t\nGamma globulins\t0.63\t0.7 – 1.6 g/dL\t\nPEP interpretation\tHypogammaglobulinemia and hypoalbuminemia\t\nIFE kappa light chain\t26.5\t3.3 – 19.4 mg/L\t\nIFE lambda light chain\t33.9\t5.7 – 26.3 mg/L\t\nKappa/lambda ratio\t0.78\t0.26 – 1.65\t\nIEP interpretation\tMonoclonal immunoglobulin is not detected by immunofixation\t\nDiscussion\nThis case presents a unique adverse reaction to vancomycin associated with both agranulocytosis and hemolytic anemia. Although the patient was exposed to vancomycin, ceftriaxone and cefepime, vancomycin was used the longest for three days. Vancomycin is known to have a 2% to 3% chance of being associated with neutropenia, and a less than 1% chance of causing thrombocytopenia [2]. Taking into consideration the Naranjo [3] adverse drug reaction (ADR) probability scale, there is a probable association between vancomycin and neutropenia [4,5] as well as between vancomycin and thrombocytopenia [2,6]. The Naranjo ADR probability scale ranges from doubtful to possible, probable and definite. Although the agranulocytosis and reticulocyte index suggest a bone marrow etiology, the elevated LDH and FSP also point to a hemolytic process such as DIC or immune thrombocytopenia (Table 2). Interestingly, DIC may have been present prior to admission given the sepsis and initial coagulopathy with prothrombin time (PT) of 19 seconds, partial thromboplastin time (PTT) of 30 seconds, and international normalized ratio (INR) of 1.72. The elevated fibrinogen level can be explained due to the post transfusion state or acute phase reactant. However, the low reticulocyte index and pancytopenia suggest a global bone marrow suppression. Although the elevated fibrinogen of 544 mg/dL, D-Dimer of 741 ng/mL and FSP of 10-40 mcg/dL may be confounded by the blood transfusion, DIC can not be ruled out. Similarly, although the peripheral smear was negative for schistocytes, this is not sensitive or specific for DIC [7]. Heparin-induced thrombocytopenia was ruled out since the patient was not on heparin. Multiple myeloma was also ruled out given the SPEP/IPEP data (Table 2). Although EGD identified a duodenal ulcer, this lesion was chronic and not actively bleeding. Furthermore, the patient denied a recent history of hematemesis, hematochezia or melena.\n\nHence, in this case, the pancytopenia may be due to DIC related to sepsis or a combination of initial DIC, exacerbated by drug toxicity to either vancomycin, ceftriaxone or cefepime. As stated earlier, initial lab values support the possibility of the patient having developed pancytopenia secondary to DIC from sepsis prior to admission. For instance, DIC can cause anemia through red blood cell fragmentation, or the anemia can also be associated with anemia of chronic disease in the setting of sepsis [8] as the iron profile showed low total iron, low FeSat, low TIBC, and relatively low ferritin (Table 2).\n\nFurthermore, sepsis is a major risk factor for thrombocytopenia as it is a feature in up to 98% of DIC cases with the platelet count < 50 thou/mm3 in approximately 50% [9]. Leukopenia of 3.9 thou/mm3 also meets systemic inflammatory response syndrome (SIRS) criteria with WBC <4 thou/mm3 (Table 1). However, one argument against sepsis and DIC being the sole factors for the pancytopenia is that the reticulocyte count and retic index are consistent with a hypoproliferative marrow or bone marrow suppression. One would expect a consumptive process such as DIC induced thrombocytopenia to be associated with a hyper-proliferative bone marrow. The etiology of his pancytopenia was further complicated by the fact that his bone marrow began to recover when he was placed on nafcillin monotherapy as well as when the sepsis improved on Day 4 with a lactic acid of 0.9 mmol/L.\n\nThe notion of antibiotic induced aplastic anemia is also still applicable in this case. Given his lab values, this patient certainly fits the definition of acquired aplastic anemia as characterized by anemia, neutropenia, and thrombocytopenia, with a hypo-cellular bone marrow. Acquired, drug-induced aplastic anemia is an idiosyncratic reaction, with unpredictable severity and time to recovery. It has been estimated that 50% of aplastic anemia cases are acquired in nature, but a definitive causative agent cannot be identified in most cases [9]. The three major etiologies of acquired aplastic anemia include direct toxicity, metabolite-driven toxicity, and immune-mediated mechanisms [9]. For instance, a 2018 case report by Gniadek and a 2007 clinical report by Drygalski describe a mechanism of immune thrombocytopenia involving vancomycin dependent platelet reactive antibodies [6,10]. Pancytopenia has also been described to be more likely with both slow and fast rates of infusion as well as lengthy duration of vancomycin infusion [1,4]. Aplastic anemia has been identified in observational studies involving medications such as carbamazepine, methimazole, phenytoin and sulfonamides, whereas chloramphenicol, dapsone and lithium have been mentioned in case reports [9]. In this case, the patient was exposed to vancomycin, cefepime and ceftriaxone before completing his antibiotic course with nafcillin monotherapy.\n\nConclusions\nThis case presents a unique incidence of pancytopenia in that the etiology appeared to involve elements of DIC related to sepsis as well as acquired aplastic anemia. Fortunately, the patient did not require high dose steroids or advanced therapeutics such as intravenous immunoglobulin infusion therapy (IVIG) or plasmapheresis as his hematologic function normalized after consolidating IV antibiotics to nafcillin. The objective of this case report is to emphasize early recognition of pancytopenia through relevant basic labs and hematologic workup. If the patient is undergoing IV antibiotics treatment, the antibiotics will have to be assessed carefully and his allergy list updated if an antibiotic is found to be associated with an adverse drug reaction.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nThis research was supported (in whole or in part) by HCA and/or an HCA affiliated entity. The views expressed in this\npublication represent those of the author(s) and do not necessarily represent the official views of HCA or any of its \naffiliated entities.\n==== Refs\nReferences\n1 Relative incidence of agranulocytosis and aplastic anemia Am J Hematol Kaufman DW Kelly JP Issaragrisil S 65 67 81 2006 16369972 \n2 Vancomycin-induced thrombocytopenia Arch Intern Med Zenon GJ Cadil RM Hamill RJ 995 996 151 1991 2025149 \n3 A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther Naranjo CA Busto U Sellers EM 239 245 30 1981 7249508 \n4 Case report of vancomycin induced pancytopenia Rev Soc Bras Med Trop Gupta S Sharma S Menon N Ahuja S Dahdouh M 258 259 Mar Apr Revista da Sociedade Brasileira de Medicina Tropical 49(2): 258-259 49 2016 27192600 \n5 Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother Black E Lau TTV Ensom MHH 629 638 45 2011 21521866 \n6 Vancomycin-induced immune thrombocytopenia N Engl J Med Drygalski AV Curtis BR Bougie DW 904 910 356 2007 17329697 \n7 Guidelines for the diagnosis and management of disseminated intravascular coagulation Br J Haematol Levi M Toh CH Thachil J Watson HG 24 33 Blackwell Publishing Ltd, British Journal of Haematology 145 2009 19222477 \n8 Hematologic changes in sepsis and their therapeutic implications Semin Respir Crit Care Med Goyette RE Key NS Ely W 645 659 25 2004 16088507 \n9 Chapter 24. Drug-induced hematologic disorders Pharmacotherapy: A Pathophysiologic Approach 9e Rao KV New York McGraw-Hill 2014 https://accesspharmacy.mhmedical.com/content.aspx?bookid=689§ionid=48811451 \n10 Drug induced immune hemolytic anemia associated with anti-vancomycin complicated by a paraben antibody Transfusion Gniadek TJ Arndt PA Leger RM Zydowicz D Cheng EY Zantek ND 181 188 DOI 58 2017 28990203\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(2)",
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"keywords": "agranulocytosis; anemia; disseminated intravascular coagulation; drug toxicity; pancytopenia; sepsis; vancomycin",
"medline_ta": "Cureus",
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"pages": "e3994",
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"pubdate": "2019-02-01",
"publication_types": "D002363:Case Reports",
"references": "16088507;16369972;17329697;19222477;2025149;21521866;27192600;28990203;7249508",
"title": "Pancytopenia as a Consequence of Sepsis and Intravenous Antibiotic Drug Toxicity.",
"title_normalized": "pancytopenia as a consequence of sepsis and intravenous antibiotic drug toxicity"
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"abstract": "A 31-month-old girl required constant intravenous (IV) infusion of naloxone hydrochloride to treat codeine-induced respiratory and CNS depression. The infusion rate was 0.4 mg/hr (27 micrograms/kg/hr) over nine hours, without apparent side effects or evidence of toxic effects, for a total naloxone hydrochloride dose of 4.1 mg (280 micrograms/kg). Constant naloxone hydrochloride infusion at an initial rate of 0.4 mg/hr in pediatric narcotic poisoning should be considered if the patient responds inadequately to an initial 0.01-mg/kg bolus, requires repeated administration to reverse narcotic-induced effects, or has ingested long-acting agents. Continuous IV naloxone infusion is a convenient, safe, and effective method to treat narcotic overdose.",
"affiliations": null,
"authors": "Lewis|J M|JM|;Klein-Schwartz|W|W|;Benson|B E|BE|;Oderda|G M|GM|;Takai|S|S|",
"chemical_list": "D009294:Narcotics; D000082:Acetaminophen; D009270:Naloxone; D003061:Codeine",
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"mesh_terms": "D000082:Acetaminophen; D001143:Arousal; D002675:Child, Preschool; D003061:Codeine; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D009270:Naloxone; D009294:Narcotics; D012119:Respiration",
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"references": null,
"title": "Continuous naloxone infusion in pediatric narcotic overdose.",
"title_normalized": "continuous naloxone infusion in pediatric narcotic overdose"
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"abstract": "Standard medical education dictates that the vast majority of cases of an alanine aminotransferase (ALT) level >1,000 IU/l will be due to acute ischaemia, acute drug-induced liver injury (DILI) (usually paracetamol) or acute viral hepatitis. There are very few references in the literature to other potential causes of an ALT >1,000 IU/l nor to the prognosis ascribed to each aetiology. In this study, we have confirmed that the main causes of a dramatic ALT rise are ischaemic liver injury, DILI and viral hepatitis. Common bile duct stones and hepatitis E are two causes for which there needs to be a high index of suspicion as the necessary tests may not be in the clinician's first-line investigation panel. Failing to find a cause and determining that the cause was ischaemic both have poor prognostic implications.",
"affiliations": "Centre for Liver Diseases, Mater Misericordiae University Hospital, Dublin, Ireland zitagalvin@gmail.com.;Centre for Liver Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.;Centre for Liver Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.;Mater Misericordiae University Hospital, Dublin, Ireland.",
"authors": "Galvin|Zita|Z|;McDonough|Anna|A|;Ryan|John|J|;Stewart|Stephen|S|",
"chemical_list": "D000410:Alanine Transaminase",
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"journal": "Clinical medicine (London, England)",
"keywords": "Alanine aminotransferase; acute hepatitis; aetiology; prognosis; transaminases",
"medline_ta": "Clin Med (Lond)",
"mesh_terms": "D000410:Alanine Transaminase; D005260:Female; D006801:Humans; D008107:Liver Diseases; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "101092853",
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"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "11106350;14073990;15224287;15667485;15684121;18388683;19058303;20513004;2132296;23139615;23188856;24114815;24836400;24842305;5509868;696683;8749903",
"title": "Blood alanine aminotransferase levels >1,000 IU/l - causes and outcomes.",
"title_normalized": "blood alanine aminotransferase levels 1 000 iu l causes and outcomes"
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"abstract": "We report on a rare case of an adult with severe hypercalcemia secondary to the ectopic secretion of parathyroid-related peptide (PTH-rP) from a penile squamous cell cancer (PC). A patient of 47 years old was admitted with warty lesions and areas of ulceration covered by purulent material in a large area of the groin, scrotum and penis. Laboratory tests revealed severe hypercalcemia and elevation of PTH-rP; the biopsy reported PC. Hypercalcemia was successfully treated with zoledronic acid, however, the tumor displayed aggressive behavior, which resulted in a poor prognosis for the patient.",
"affiliations": "Division of Medicine, Instituto Nacional de Ciencias Medicas y Nutricion ?Salvador Zubiran?, Mexico City, Mexico.;Instituto Tecnologico y de Estudios Superiores de Monterrey, Mexico City, Mexico.;Instituto Tecnologico y de Estudios Superiores de Monterrey, Mexico City, Mexico.;Division of Medicine, Instituto Nacional de Ciencias Medicas y Nutricion ?Salvador Zubiran?, Mexico City, Mexico.;Unidad PET/CT, Facultad de Medicina, UNAM, Mexico City, Mexico.",
"authors": "Trejo-Rosales|Rogelio|R|;Nevarez-Barragan|Maria J|MJ|;Rosas-Jurado|Mercedes G|MG|;Perez-Diaz|Ivan|I|;Bezaury|Ana Paula Piana|AP|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D010281:Parathyroid Hormone; D000077211:Zoledronic Acid",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2730",
"issue": "58(6)",
"journal": "Arquivos brasileiros de endocrinologia e metabologia",
"keywords": null,
"medline_ta": "Arq Bras Endocrinol Metabol",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002294:Carcinoma, Squamous Cell; D004164:Diphosphonates; D006801:Humans; D006934:Hypercalcemia; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone; D010388:Pelvis; D010412:Penile Neoplasms; D035583:Rare Diseases; D014057:Tomography, X-Ray Computed; D000077211:Zoledronic Acid",
"nlm_unique_id": "0403437",
"other_id": null,
"pages": "646-9",
"pmc": null,
"pmid": "25211448",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare association between penile squamous cell carcinoma and parathyroid related peptide (PTH-rP) secretion.",
"title_normalized": "rare association between penile squamous cell carcinoma and parathyroid related peptide pth rp secretion"
} | [
{
"companynumb": "PHHY2015MX067128",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "An 85-year-old lady presented to our institution following multiple episodes of transient loss of consciousness. Her admission ECG revealed a junctional bradycardia with significant QT prolongation. Telemetry captured a torsades de pointes arrhythmia. Possible offending drugs (digoxin and hydroxychloroquine) were stopped and she was given intravenous magnesium and potassium. Despite this, she continued to have runs of torsades. An isoprenaline infusion was commenced to increase her resting heart rate. Her QT interval shortened and she had no further arrhythmia. Investigation into the cause of her bradycardia and prolonged QT revealed profound hypothyroidism. Levothyroxine was commenced but the patient remained bradycardia and required a permanent pacemaker. She had no further arrhythmia and was discharged home safely. This is a very rare case of severe primary hypothyroidism presenting with torsades de pointes.",
"affiliations": "Gloucestershire Royal Hospital, Gloucester, UK. raveenkandan@gmail.com",
"authors": "Kandan|Sri Raveen|SR|;Saha|Mrinal|M|",
"chemical_list": "D013974:Thyroxine",
"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; D000369:Aged, 80 and over; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D006321:Heart; D006801:Humans; D007037:Hypothyroidism; D013974:Thyroxine; D016171:Torsades de Pointes",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22987900",
"pubdate": "2012-09-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17923583;16615675;16538077;18990220;11172193;12915662",
"title": "Severe primary hypothyroidism presenting with torsades de pointes.",
"title_normalized": "severe primary hypothyroidism presenting with torsades de pointes"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-GSH201804-001304",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugad... |
{
"abstract": "An 80-year-old woman was diagnosed with pancreatic head cancer, and pancreaticoduodenectomy was performed. Twelve months after the operation, chest CT scans showed the presence ofmultiple nodules in both the lungs. Because ofthe potential negative side effects of anti-cancer drugs, the patient underwent chemotherapy with dose-down biweekly adminis- tration ofgemcitabine (1,000mg/day/body≒750mg/m2. Chest CT examination every 2-3 months revealed no rapid increase in multiple tumors. Nineteen months after starting gemcitabine therapy, there was an elevation in tumor marker and a gradual increase in lung metastases. We performed combination chemotherapy with nab-paclitaxel. However, owing to side effects, only 2 courses of nab-paclitaxel were administered, and the therapy was switched to only gemcitabine administration. Later, respiratory distress accompanied by pleural effusion developed, and the patient died of the original disease 27 months after recurrence. Here, we report a case ofan elderly patient with multiple lung metastases ofpancreatic cancer in whom lung metastases were controlled by biweekly dose-down administration of gemcitabine.",
"affiliations": "Dept. of Surgery, Tokai Memorial Hospital.",
"authors": "Iwata|Tsutomu|T|;Ando|Keichi|K|;Mishima|Hideyuki|H|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1453-1455",
"pmc": null,
"pmid": "31530789",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of an Elderly Patient with Multiple Lung Metastases of Postoperative Pancreatic Cancer in Whom Lung Metastases Were Controlled by Biweekly Dose-Down Administration of Gemcitabine.",
"title_normalized": "a case of an elderly patient with multiple lung metastases of postoperative pancreatic cancer in whom lung metastases were controlled by biweekly dose down administration of gemcitabine"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20191002180",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse.",
"affiliations": "Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Rome, Italy.;Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.",
"authors": "Locatelli|Franco|F|;Strahm|Brigitte|B|",
"chemical_list": "D009363:Neoplasm Proteins",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-09-765214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "131(13)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes; D009363:Neoplasm Proteins",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1406-1414",
"pmc": null,
"pmid": "29438960",
"pubdate": "2018-03-29",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "How I treat myelodysplastic syndromes of childhood.",
"title_normalized": "how i treat myelodysplastic syndromes of childhood"
} | [
{
"companynumb": "IT-CELLTRION INC.-2019IT022126",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute skin toxicity is a frequent finding during combined radiotherapy and chemotherapy in head and neck cancer patients. Its timely and appropriate management is crucial for both oncological results and patient's global quality of life. We herein report clinical data on the use of Hypericum perforatum and neem oil in the treatment of acute skin toxicity during concurrent chemo-radiation for head and neck cancer. A consecutive series of 50 head and neck cancer patients undergoing concomitant radio-chemotherapy with weekly cisplatin was analyzed. Treatment with Hypericum perforatum and neem oil was started in case of G2 acute skin toxicity according to the RTOG/EORTC scoring scale and continued during the whole treatment course and thereafter until complete recovery. The maximum detected acute skin toxicity included Grade 2 events in 62% of cases and G3 in 32% during treatment and G2 and G3 scores in 52 and 8%, respectively, at the end of chemo-radiation. Grade 2 toxicity was mainly observed during weeks 4-5, while G3 during weeks 5-6. Median times spent with G2 or G3 toxicity were 23.5 and 14 days. Patients with G3 toxicity were reconverted to a G2 profile in 80% of cases, while those with a G2 score had a decrease to G1 in 58% of cases. Time between maximum acute skin toxicity and complete skin recovery was 30 days. Mean worst pain score evaluated with the Numerical Rating Scale-11 was 6.9 during treatment and 4.5 at the end of chemo-radiotherapy. Hypericum perforatum and neem oil proved to be a safe and effective option in the management of acute skin toxicity in head and neck cancer patients submitted to chemo-radiation with weekly cisplatin. Further studies with a control group and patient-reported outcomes are needed to confirm this hypothesis.",
"affiliations": "Department of Oncology, Radiation Oncology, University of Turin, Via Genova 3, 10126, Turin, Italy. pierfrancesco.franco@unito.it.;Department of Oncology, Radiation Oncology, AOU Citta' della Salute e della Scienza, Turin, Italy.;2nd Medical Oncology Division, Department of Oncology, AOU Città della Salute e della Scienza, Turin, Italy.;1st Medical Oncology Division, Department of Oncology, AOU Città della Salute e della Scienza, Turin, Italy.;1st ENT Division, Department of Surgical Sciences, University of Turin, Turin, Italy.;Maxillofacial Surgery Division, Department of Surgical Sciences, University of Turin, Turin, Italy.;Maxillofacial Surgery Division, Department of Surgical Sciences, University of Turin, Turin, Italy.;Department of Oncology, Radiation Oncology, University of Turin, Via Genova 3, 10126, Turin, Italy.;Department of Oncology, Radiation Oncology, University of Turin, Via Genova 3, 10126, Turin, Italy.;Department of Oncology, Radiation Oncology, University of Turin, Via Genova 3, 10126, Turin, Italy.;Department of Oncology, Radiation Oncology, AOU Citta' della Salute e della Scienza, Turin, Italy.;Department of Oncology, Radiation Oncology, University of Turin, Via Genova 3, 10126, Turin, Italy.",
"authors": "Franco|Pierfrancesco|P|http://orcid.org/0000-0003-2276-0687;Rampino|Monica|M|;Ostellino|Oliviero|O|;Schena|Marina|M|;Pecorari|Giancarlo|G|;Garzino Demo|Paolo|P|;Fasolis|Massimo|M|;Arcadipane|Francesca|F|;Martini|Stefania|S|;Cavallin|Chiara|C|;Airoldi|Mario|M|;Ricardi|Umberto|U|",
"chemical_list": "D005989:Glycerides; D013729:Terpenes; C002443:neem oil; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-017-0886-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "34(2)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": "Concomitant chemo-radiotherapy; Head and neck cancer; Hypericum perforatum; Neem oil; Skin toxicity",
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D002945:Cisplatin; D003875:Drug Eruptions; D005260:Female; D005989:Glycerides; D006258:Head and Neck Neoplasms; D006801:Humans; D020902:Hypericum; D008297:Male; D008875:Middle Aged; D008517:Phytotherapy; D011855:Radiodermatitis; D013729:Terpenes",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "30",
"pmc": null,
"pmid": "28101834",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "16384753;25544371;15342408;24192693;26187236;11243487;23241224;10741815;24214835;16724685;16893745;27514316;19446902;21030225;20659547;11850844;26504058;27290695;11370698;22743346;27019417;23413284;7713792;25544268;11966833",
"title": "Management of acute skin toxicity with Hypericum perforatum and neem oil during platinum-based concurrent chemo-radiation in head and neck cancer patients.",
"title_normalized": "management of acute skin toxicity with hypericum perforatum and neem oil during platinum based concurrent chemo radiation in head and neck cancer patients"
} | [
{
"companynumb": "IT-ACCORD-049574",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "We aimed to determine whether patients receiving dasatinib or imatinib concurrently with high-dose methotrexate (HDMTX) had slower methotrexate clearance than patients not receiving a tyrosine kinase inhibitor (TKI) during the HDMTX infusion. Patients concurrently receiving dasatinib and HDMTX (N = 7) had significantly slower MTX clearance (P = 0.008) than patients not receiving a TKI (N = 111). Two patients receiving a TKI during a HDMTX infusion required glucarpidase. In vitro studies showed that dasatinib significantly inhibited methotrexate uptake by SLCO1B1-expressing cells (P = 0.009). There may be an interaction between dasatinib and HDMTX, mediated by the transporter SLCO1B1, that causes a delay in MTX clearance.",
"affiliations": "Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.",
"authors": "Ramsey|Laura B|LB|0000-0001-6417-3961;Mizuno|Tomoyuki|T|0000-0002-8471-9826;Vinks|Alexander A|AA|0000-0003-4224-2967;O'Brien|Maureen M|MM|",
"chemical_list": "D000069439:Dasatinib; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(5)",
"journal": "Pediatric blood & cancer",
"keywords": "acute lymphoblastic leukemia; dasatinib; glucarpidase; imatinib; methotrexate; pharmacokinetics",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D014018:Tissue Distribution; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27618",
"pmc": null,
"pmid": "30677213",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib.",
"title_normalized": "delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib"
} | [
{
"companynumb": "US-MYLANLABS-2019M1039700",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugadditional": "3",
... |
{
"abstract": "This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint.",
"affiliations": "Department of Endocrinology, Ospedale Niguarda Ca' Granda Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.;Department of Endocrinology, Ospedale Niguarda Ca' Granda Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.;Department of Endocrinology, Ospedale Niguarda Ca' Granda Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.;Department of Neuroradiology, Ospedale Niguarda Ca' Granda Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.;Department of Endocrinology, Ospedale Niguarda Ca' Granda Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.",
"authors": "Grossrubatscher|Erika|E|;Zampetti|Benedetta|B|;Dalino Ciaramella|Paolo|P|;Doneda|Paola|P|;Loli|Paola|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.321",
"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.321Case ReportsEffectiveness of low-dose pasireotide in a patient with Cushing’s disease: antiproliferative effect and predictivity of a short pasireotide suppression test Grossrubatscher Erika 1Zampetti Benedetta 1Dalino Ciaramella Paolo 1Doneda Paola 2Loli Paola 11 Department of Endocrinology, Ospedale Niguarda Ca’ GrandaPiazza Ospedale Maggiore, 3, 20162, Milan, Italy2 Department of Neuroradiology, Ospedale Niguarda Ca’ GrandaPiazza Ospedale Maggiore, 3, 20162, Milan, ItalyCorrespondence Paola Loli, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. Tel: +3902 6444 7771;, Fax: +3902 6444 4926; E-mail: paola.loli@ospedaleniguarda.itFunding Information No sources of funding were declared for this study.\n\n8 2015 19 7 2015 3 8 718 722 10 2 2015 07 5 2015 21 5 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nThis case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint.\n\nACTH-secreting macroadenomaantiproliferative effectCushing’s diseasepasireotide\n==== Body\nIntroduction\nFirst-line treatment of Cushing’s disease (CD) is pituitary microsurgery; medical treatment has been limited to patients with persistent hypercortisolism after unsuccessful surgery, while awaiting the beneficial effects of radiation therapy or, preoperatively, to control symptoms due to extremely severe hypercortisolism in order to reduce the surgical risk 1. Drugs so far available target adrenal cortisol production via steroidogenesis inhibition (ketoconazole, metyrapone, etomidate) or act by blocking glucocorticoid action at the glucocorticoid receptor (mifepristone) or combine antisteroidogenic and adrenolitic action (mitotane) 2,3 Until short time ago, only cabergoline was an available pituitary targeted therapy 4.\n\nOverall, there is no substantial evidence in support of many of the drugs currently used in treatment of hypercortisolism; many are used off-label, are unavailable in some countries and no reliable predictors of efficacy are identified.\n\nPasireotide is a novel somatostatin analog that acts on specific receptor isoforms with increased affinity toward sstr 5 in comparison with previous analogs 5. In this case report, we show that low doses of pasireotide used as first-line treatment in a patient with CD not eligible for surgery were effective in normalizing cortisol secretion and improving the clinical condition and also in determining substantial tumor volume reduction.\n\nCase Description\nA 63-years-old male patient was referred to emergency room after 2 days of acute onset headache, diplopia, visual impairment, nausea, and vomiting; when admitted to the Hospital only diplopia persisted. The past medical history was unremarkable except for depression since 20 years. At brain CT and CT-angiography performed in the emergency department a pituitary mass was detected; at subsequent gadolinium-enhanced MRI, a pituitary macroadenoma with suprasellar and right parasellar extension dislocating right internal carotid was detected (21 mm × 14.5 mm × 15.7 mm, respectively, postero-anterior, cranio-caudal, and latero-lateral diameters, volume 2.53 cm3), isointense with brain on T1 and hyperintense on T2 weighted images, compressing the normal gland and deviating to the left the pituitary stalk (Fig.1). Opthalmological evaluation was normal. Full-blown cushingoid features were present with newly diagnosed hypertension and impaired glucose regulation (HbA1c 44 mmol/mol) treated, respectively, with hypotensive drug and diet. Densitometric values were consistent with osteopenia.\n\nFigure 1 Gadolinium enhanced MRI studies performed at baseline (left) and after 12 months (right) of treatment with pasireotide 300 μg subcutaneously (s.c.) two times a day (b.i.d).\n\nHigh-normal plasma ACTH levels (88 and 43.2 pg/mL, n.v. 9–52), elevated 24 h urinary free cortisol excretion (UFC) (459 μg/24 h, normal range 36–137) were detected as well as normal thyroid function and normogonadotropic hypogonadism. Hypercortisolism was confirmed by repeated UFC collections (UFC 2601, 1075, 6222 μg/24 h), unsuppressibility of cortisol after low-dose dexamethasone (320 μg/L) and by supranormal midnight plasma cortisol (172 μg/L, n.v. <75 μg/L) (Table1). Plasma ACTH increased by 35% after desmopressin and by 18% after CRH (basal 60 and peak 71 pg/mL at 60 min), whereas plasma cortisol was not responsive (basal 393 and peak 405 μg/L at 15 min); plasma and urinary cortisol decreased by 75.3% and 66.3% after high-dose dexamethasone suppression test.\n\nTable 1 Biochemical and hormonal data at baseline and during treatment with pasireotide\n\n\tUFC1 (μg/24 h)\tACTH (pg/mL)\tHbA1c (mmol/mol)\tTotal cholesterol (mg/dL)\tTryglicerides (mg/dL)\tHDL (mg/dL)\tWeight (kg)\tBMI\tWAIST (cm)\t\nBasal\t3299\t65\t49\t237\t112\t53\t88\t29.4\t105\t\n2 weeks\t564\t47\t\t\t\t\t\t\t\t\nMonth 1\t27\t31\t76\t\t\t\t86\t28.7\t102\t\nMonth 2\t46\t21\t77\t\t\t\t\t\t\t\nMonth 3\t522\t52\t53\t\t\t\t84.4\t28.2\t\t\nMonth 4\t30\t17\t53\t\t\t\t\t\t\t\nMonth 6\t54\t15\t55\t210\t129\t42\t82.5\t27.5\t101\t\nMonth 9\t55\t17\t50\t\t\t\t82\t27.4\t98\t\nMonth 12\t38\t16\t49\t188\t106\t40\t80\t26.7\t97\t\nMonth 14\t218\t51\t45\t\t\t\t\t\t\t\nMonth 15\t38\t40\t\t\t\t\t80\t26.7\t96\t\nMonth 18\t82\t30\t47\t167\t95\t38\t78\t26\t96\t\n1 Mean of four values.\n\nClinical signs and symptoms of overt Cushing’s syndrome were worsening since the first evaluation 2 months before: blood pressure levels had increased, cholesterol levels were higher than before, glycemic control worsened and Hba1c value consistent with overt diabetes was found (HbA1c 49 mmol/mol) (Table1). Metformin was therefore started.\n\nPituitary surgery was recommended: as the patient refused surgery, primary medical treatment with subcutaneous pasireotide (SOM230; Novartis, Basel, Switzerland) was offered at the initial dose of 0.6 μg, bid.\n\nShort Pasireotide Suppression Test\nACTH and cortisol variations after 100 μg octreotide were compared with those recorded after the first dose of pasireotide. Octreotide did not induce changes, whereas a progressive decline in cortisol concentration was recorded with maximal inhibition of 67% at 10 h after administration of pasireotide (Table2, Fig.2).\n\nTable 2 Left: Plasma ACTH and cortisol levels before and hourly for 6 h after a single dose of 100 μg s.c. octreotide. Right: Plasma ACTH and cortisol levels before and every 2 h for 10 h after a single dose of 600 μg s.c. pasireotide\n\n\tShort pasireotide suppression test\t\n\tSerum cortisol (μg/L)\tACTH (pg/mL)\t\nBasal\t315\t110\t\n2\t150\t32\t\n4\t119\t38\t\n6\t143\t45\t\n8\t106\t40\t\n10\t100\t35.6\t\nFigure 2 Left: Plasma ACTH and cortisol levels before and hourly for 6 h after a single dose of 100 μg subcutaneous octreotide Right: Plasma ACTH and cortisol levels before and every 2 h for 10 h after a single dose of 600 μg subcutaneous pasireotide.\n\nTwo weeks later, plasma ACTH normalized (47 pg/mL) and UFC decreased (564 μg/24 h) (Fig.3). A worsening of glycemic control required an increase of metformin dose and addition of sitagliptin.\n\nFigure 3 Urinary-free cortisol (UFC) excretion (normal range: 37–136 μg/24 h) and plasma ACTH (normal range 9–52 pg/mL) values before and during the entire course of pasireotide treatment.\n\nOne month later, the patient complained of fatigue, dizziness, abdominal pain, and diarrhea, consistent with hypoadrenalism; UFC had decreased to subnormal values (27 μg/24 h). Hypotensive drugs were reduced; due to unsatisfactory glycemic control insulin treatment was started.\n\nOn the basis of clinical and biochemical data, pasireotide was reduced to 0.3 μg twice daily.\n\nStarting from the third month of treatment, the improvement of the clinical condition persisted steadily for 18 months (at the present time) in line with normalization of UFC concentrations (Fig.3). Testosterone concentration normalized. Fasting, postprandial glucose, and Hba1c values were satisfactory on long-acting insulin, metformin, and sitaglyptin (fasting glycemia values <130 mg/dL and postprandial values <180 mg/dL); cholesterol profile improved. Blood pressure normalized without treatment, weight decreased by more than 10% and waist circumference from 105 to 96 cm. Antidepressant therapy was also stopped.\n\nOverall the patient reported an improvement in quality of life. Although no specific quality of life measure was utilized, the patient reported improvements in the areas of self confidence, physical appearance, social activities, sleep quality, physical performances, and everyday activities.\n\nAt MRI, the size of the pituitary tumor decreased by 44% at 6 months and up to 52% at 18 months (18.9 mm × 9.8 mm × 11 mm, volume 1.21 cm3) (Fig.1). The BMD values were stable with respect to first evaluation.\n\nDiscussion\nFrom a clinical standpoint, a remarkable finding of this case is the effectiveness of low doses of pasireotide in obtaining a stable control of disease in a patient with clinical and biochemical features of severe hypercortisolism, a finding rarely reported previously in single patients 6,7.\n\nAs reported in the registrative trial 8, normalization of UFC was more likely achieved in patients with mild disease, although the drug was effective also in severe hypercortisolism. If confirmed in other cases, the effectiveness of pasireotide at doses lower than previously suggested has practical implications such as the reduced risk of adverse events and the potential reduction of the costs for managing the disease.\n\nNo gastrointestinal symptoms appeared. Diabetes worsened during treatment, however, surrogate markers of cardiovascular risk improved as a consequence of the remission of hypercortisolism.\n\nTreatment induced hypocortisolism is an adverse event to be considered in any patient on medical treatment for hypercortisolism: alerting the patient on warning symptoms might help in avoiding severe adverse consequences.\n\nThe tumor volume reduction here observed is concordant with the antiproliferative effect already seen in primary cell cultures of human corticotroph adenomas 9,10. The molecular mechanism of suppression of cell growth and the role of specific sstrs in transducing growth inhibitory signals in corticotroph tumors need further study.\n\nData in patients with a measurable tumor support the antiproliferative effect of pasireotide at high doses (900–1200 μg, bid) 8,11; the present case shows that even a lower dose of pasireotide retains an antiproliferative effect.\n\nConclusion\nThis case illustrates the long-term effectiveness of low doses of pasireotide, a tumor-directed therapy, in the biochemical and clinical control of hypercortisolism of CD. Although it is clear that the control of tumoral mass is best achieved with surgery, the surgical outcome in ACTH-secreting macroadenomas is less favorable than in micro. The drug may be an option for long-term treatment in some patients with the disease when surgery is not feasible for many reasons. It might be an option in patients with ACTH-dependent macroadenomas where control of tumor mass is an important clinical endpoint. The treatment might offer better chance of success for subsequent surgery.\n\nConflict of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\nBiller BM Grossman AB Stewart PM Melmed S Bertagna X Bertherat J Treatment of adrenocorticotropin dependent Cushing’s syndrome: a consensus statement J. Clin. Endocrinol. Metab 2008 93 2454 2462 18413427 \nDaniel E Newell Price J Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing’s syndrome Eur. J. Endocrinol 2015 172 263 280 \nFleseriu M Biller BM Findling JW Molitch ME Schteingart DE Gross C Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome J. Clin. Endocrinol. Metab 2012 97 2039 2049 22466348 \nPivonello R De Martino MC Cappabianca P De Leo M Faggiano A Lombardi G The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery J. Clin. Endocrinol. Metab 2009 94 223 230 18957500 \nBruns C Lewis I Briner U Meno-Tetang G Weckbecker G SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile Eur. J. Endocrinol 2002 146 707 716 11980628 \nMacKenzie Feder J Bourdeau I Vallette S Beauregard H Ste-Marie LG Lacroix A Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of phase III Trial Pituitary 2014 17 519 529 24287689 \nTrementino L Cardinaletti M Concettoni C Marcelli G Boscaro M Arnaldi G Up-to 5-year efficacy of pasireotide in a patient with Cushing’s disease and pre-existing diabetes: literature review and clinical practice considerations Pituitary 2015 18 60 67 24482099 \nColao A Petersenn S Newell-Price J Findling JW Gu F Maldonado M A 12-month phase 3 study of pasireotide in Cushing’s disease N. Engl. J. Med 2012 366 914 924 22397653 \nHofland LJ van der Hoek J Feelders R van Aken MO van Koetsveld PM Waaijers M The multiligandsomatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatinreceptor type 5 Eur. J. Endocrinol 2005 152 645 654 15817922 \nBatista DL Zhang X Gejman R Ansell PJ Zhou Y Johnson SA The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas J. Clin. Endocrinol. Metab 2006 91 4482 4488 16940446 \nShimon I Rot L Inbar E Pituitary-directed medical therapy with pasireotide for a corticotrophmacroadenoma: pituitary volume reduction and literature review Pituitary 2012 15 608 613 22918543\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "3(8)",
"journal": "Clinical case reports",
"keywords": "ACTH-secreting macroadenoma; Cushing’s disease; antiproliferative effect; pasireotide",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "718-22",
"pmc": null,
"pmid": "26331021",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports",
"references": "24952218;24287689;18957500;15817922;16940446;22397653;11980628;25637072;22918543;22466348;18413427",
"title": "Effectiveness of low-dose pasireotide in a patient with Cushing's disease: antiproliferative effect and predictivity of a short pasireotide suppression test.",
"title_normalized": "effectiveness of low dose pasireotide in a patient with cushing s disease antiproliferative effect and predictivity of a short pasireotide suppression test"
} | [
{
"companynumb": "IT-BAUSCH-BL-2018-025770",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Two cases of suspected acute and lethal intoxication caused by propofol were delivered by the judicial authority to the Department of Sciences for Health Promotion and Mother-Child Care in Palermo, Sicily. In the first case a female nurse was found in a hotel room, where she lived with her mother; four 10 mg/mL vials and two 20 mg/mL vials of propofol were found near the decedent along with syringes and needles. In the second case a male nurse was found in the operating room of a hospital, along with a used syringe. In both cases a preliminary systematic and toxicological analysis indicated the presence of propofol in the blood and urine. As a result, a method for the quantitative determination of propofol in biological fluids was optimized and validated using a liquid-liquid extraction protocol followed by GC/MS and fast GC/MS-TOF. In the first case, the concentration of propofol in blood was determined to be 8.1 μg/mL while the concentration of propofol in the second case was calculated at 1.2 μg/mL. Additionally, the tissue distribution of propofol was determined for both cases. Brain and liver concentrations of propofol were, respectively, 31.1 and 52.2 μg/g in Case 1 and 4.7 and 49.1 μg/g in Case 2. Data emerging from the autopsy findings, histopathological exams as well as the toxicological results aided in establishing that the deaths were due to poisoning, however, the manner of death in each were different: homicide in Case 1 and suicide in Case 2.",
"affiliations": "Department of Sciences for Health Promotion and Mother-Child Care \"G. D'Alessandro\" Via del Vespro 133, 90127 Palermo, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Department of Sciences for Health Promotion and Mother-Child Care \"G. D'Alessandro\" Via del Vespro 133, 90127 Palermo, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.",
"authors": "Procaccianti|Paolo|P|;Farè|Fiorenza|F|;Argo|Antonella|A|;Casagni|Eleonora|E|;Arnoldi|Sebastiano|S|;Facheris|Sara|S|;Visconti|Giacomo Luca|GL|;Roda|Gabriella|G|;Gambaro|Veniero|V|",
"chemical_list": "D006993:Hypnotics and Sedatives; D015742:Propofol",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(9)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D062787:Drug Overdose; D005260:Female; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006708:Homicide; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D015742:Propofol; D013405:Suicide",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "771-776",
"pmc": null,
"pmid": "28977429",
"pubdate": "2017-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Determination of Propofol by GC/MS and Fast GC/MS-TOF in Two Cases of Poisoning.",
"title_normalized": "determination of propofol by gc ms and fast gc ms tof in two cases of poisoning"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201800623",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAdministration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women.\n\n\nMETHODS\nFourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease.\n\n\nRESULTS\nIn 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003).\n\n\nCONCLUSIONS\nNSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases.",
"affiliations": "County Hospital Turda, Romania. mcmicu@yahoo.com",
"authors": "Micu|Mihaela C|MC|;Micu|Romeo|R|;Ostensen|Monika|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011725:Pyridines; D013450:Sulfones; D004008:Diclofenac; D007052:Ibuprofen; D000077613:Etoricoxib",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.20510",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2151-464X",
"issue": "63(9)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D000077613:Etoricoxib; D005260:Female; D005298:Fertility; D006801:Humans; D007052:Ibuprofen; D007247:Infertility, Female; D007249:Inflammation; D009664:Norway; D006080:Ovarian Follicle; D010060:Ovulation; D011247:Pregnancy; D011446:Prospective Studies; D011725:Pyridines; D012216:Rheumatic Diseases; D018570:Risk Assessment; D012307:Risk Factors; D013450:Sulfones; D014463:Ultrasonography",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "1334-8",
"pmc": null,
"pmid": "21618455",
"pubdate": "2011-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies.",
"title_normalized": "luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies"
} | [
{
"companynumb": "PHHY2015RO041386",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETORICOXIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "We performed a genome-wide association study to investigate the association between single nucleotide polymorphisms and anthracycline-induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2 -300 mg/m2 ) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty-seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23-4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11-5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E-06), rs11894115 (MPP4, P = 4.71E-06), rs58328254 (RPL7, P = 6.09E-06), and rs117299725 (PRUNE2, P = 8.53E-06), although none of these variants reached the Bonferroni-corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E-07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.",
"affiliations": "Biostatistics Collaboration Team, Research Core Center, National Cancer Center, Research Institute, Goyang, Korea.;Division of Translational Science, National Cancer Center, Research Institute, Goyang, Korea.;Branch of Hemato-Oncology, Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Branch of Cardiology, Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Division of Translational Science, National Cancer Center, Research Institute, Goyang, Korea.",
"authors": "Park|Boram|B|https://orcid.org/0000-0003-2683-8795;Sim|Sung Hoon|SH|;Lee|Keun Seok|KS|;Kim|Hak Jin|HJ|;Park|In Hae|IH|",
"chemical_list": "D018943:Anthracyclines",
"country": "England",
"delete": false,
"doi": "10.1111/cas.14446",
"fulltext": "\n==== Front\nCancer Sci\nCancer Sci\n10.1111/(ISSN)1349-7006\nCAS\nCancer Science\n1347-9032 1349-7006 John Wiley and Sons Inc. Hoboken \n\n10.1111/cas.14446\nCAS14446\nOriginal Article\nOriginal Articles\nGenetics, Genomics, and Proteomics\nGenome‐wide association study of genetic variants related to anthracycline‐induced cardiotoxicity in early breast cancer\nPARK et al.Park Boram https://orcid.org/0000-0003-2683-8795\n1\n Sim Sung Hoon \n2\n\n3\n Lee Keun Seok \n3\n Kim Hak Jin \n4\n Park In Hae \n2\n\n3\n\n5\nparkih@korea.ac.kr \n1 \nBiostatistics Collaboration Team\nResearch Core Center\nNational Cancer Center\nResearch Institute\nGoyang\nKorea\n\n\n2 \nDivision of Translational Science\nNational Cancer Center\nResearch Institute\nGoyang\nKorea\n\n\n3 \nBranch of Hemato‐Oncology\nDepartment of Internal Medicine\nNational Cancer Center\nGoyang\nKorea\n\n\n4 \nBranch of Cardiology\nDepartment of Internal Medicine\nNational Cancer Center\nGoyang\nKorea\n\n\n5 \nDivision of Medical Oncology, Department of Internal Medicine\nKorea University College of Medicine, Korea University\nSeongbuk‐gu\nKorea\n\n* Correspondence\n\nIn Hae Park, Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, Korea.\n\nEmail: parkih@korea.ac.kr\n\n20 6 2020 \n7 2020 \n111 7 10.1111/cas.v111.72579 2587\n17 1 2020 29 4 2020 01 5 2020 © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer AssociationThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nWe performed a genome‐wide association study to investigate the association between single nucleotide polymorphisms and anthracycline‐induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2‐300 mg/m2) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty‐seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23‐4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11‐5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E−06), rs11894115 (MPP4, P = 4.71E−06), rs58328254 (RPL7, P = 6.09E−06), and rs117299725 (PRUNE2, P = 8.53E−06), although none of these variants reached the Bonferroni‐corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E−07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.\n\nIn this study, we addressed potent genetic variants related with anthracycline induced cardiotoxicity in Korean early breast cancer patients adjusting various clinical factors with a long follow‐up period. The results of our study showed that in anthracycline treatments with a cumulative dose not exceeding 300 mg/m2, clinical factors were more associated with cardiotoxicity than genetic factors. Several possible genetic variants found in this study may require further study.\n\n\nanthracyclinebreast cancercardiotoxicitycase‐control studygenome‐wide association studyNCCK1940520‐1 source-schema-version-number2.0cover-dateJuly 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.6 mode:remove_FC converted:28.07.2020\n\n\nPark \nB \n, \nSim \nSH \n, \nLee \nKS \n, \nKim \nHJ \n, \nPark \nIH \n. Genome‐wide association study of genetic variants related to anthracycline‐induced cardiotoxicity in early breast cancer\n. Cancer Sci . 2020 ;111 :2579 –2587\n. 10.1111/cas.14446\n==== Body\n1 INTRODUCTION\nAnthracycline has long been used as the primary treatment for breast cancer. Despite its potential benefits, the number of doses of anthracycline needs to be limited due to its adverse effects on the heart, including congestive heart failure.\n1\n, \n2\n Doxorubicin is an anthracycline with an overall incidence of cardiotoxicity in up to 3.3% of patients who received a cumulative dose of at least 450 mg/m2.\n1\n Clinical factors associated with the development of cardiotoxicity include the cumulative dose of doxorubicin, age, and existing heart disease.\n1\n, \n3\n The concomitant use of other chemotherapeutic agents, such as trastuzumab and bevacizumab, with anthracyclines also increases the cardiotoxicity risk.\n4\n, \n5\n\n\n\nAnthracycline‐induced cardiotoxicity (ACT) involves irreversible cardiomyocyte death due to reactive oxygen species produced by doxorubicin metabolism within the cardiomyocytes.\n6\n, \n7\n Many studies have been conducted to identify genetic risk factors that predict the development of cardiotoxicity.\n8\n, \n9\n, \n10\n, \n11\n, \n12\n, \n13\n Results from these studies have not been consistent, however, due to the heterogeneity of the study populations and differences in the definitions of cardiotoxicity.\n\nAnthracyclines have been included as neoadjuvant or adjuvant treatments with or without other chemotherapeutic agents in the treatment of breast cancer. Under such treatment regimens, the cumulative dose of doxorubicin usually does not exceed 300 mg/m2, nevertheless cardiotoxicity occurred in 1.5%‐2.0% of patients who took part in a large clinical trial.\n4\n, \n14\n Given the severity of cardiotoxicity, there is a need to develop reliable predictive biomarkers to identify high‐risk patients.\n\nIn this study, we conducted a genome‐wide association study (GWAS) of patients with early breast cancer to assess single nucleotide polymorphisms (SNPs) across the whole genome. The goal of this GWAS was to identify genetic variants and clinical factors associated with risk of ACT in this population.\n\n2 MATERIALS AND METHODS\n2.1 Study population\nFrom January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Of these patients, 3910 patients received doxorubicin as a neoadjuvant or adjuvant treatment, and 67 were diagnosed with ACT. In this study, cardiotoxicity was defined as a >10% reduction in the left ventricular ejection fraction (LVEF) from baseline and LVEF < 50% on multi‐gated blood pool scan (MUGA), or <55% on echocardiography.\n15\n Among patients in the case group, those who completely recovered from ACT during the follow‐up period were classified into the transient ACT group and those who needed medication and regular monitoring were classified into the persistent ACT group. We analyzed separately genetic differences between the persistent ACT group and the control group.\n\nFor the control group, we selected 317 age‐matched patients with breast cancer who underwent breast surgery before or after doxorubicin‐containing chemotherapy as neoadjuvant/adjuvant treatment. The cardiac function of the control group was normal before and after chemotherapy as confirmed by MUGA or echocardiography. For all patients, clinical data, including age, body weight, height, cancer stage, cumulative dose of doxorubicin, radiation therapy, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. This study was approved by the Institutional Review Board of the National Cancer Center in Korea (IRB no. NCC2017‐0161) and all patients provided written informed consent before participation.\n\n2.2 Genotyping\nPeripheral blood samples were drawn into vacutainer tubes and genomic DNA was extracted from whole blood using the QIAamp DNA Mini Kit (Qiagen, CA) in accordance with the manufacturer's instructions. DNA samples from both the case and control groups were genotyped using the Korea Biobank Array platform (KoreanChip).\n16\n The KoreanChip is comprised of 833 535 markers, including more than 247 000 rare frequency or functional variants based on the sequencing data of 2500 Koreans.\n16\n\n\n\n2.3 Quality control for samples\nSamples were subjected to quality control (QC). Among the 384 samples, 10 samples were excluded due to multidimensional scaling and 30 samples due to a low call rate and excessive heterozygosity rate. An additional 87 samples were further excluded for the following reasons: male patient (n = 1), stage IV cancer (n = 2), anthracycline cumulative dose < 240 mg/m2 (n = 7), no chemotherapy (n = 6), and anthracycline cumulative dose > 300 mg/m2 (n = 71). The final association test was performed with 257 samples (Figure 1A).\n\nFIGURE 1 Consort diagram of quality control (QC) for (A) each samples and (B) SNPs\n\n2.4 Quality control for markers\nSNP QC steps were performed on 833 535 available markers. SNPolisher software designed by Affymetrix was used to select markers for better QC.\n17\n In total, 63 233 markers were removed due to low quality (n = 23 647), SNPolisher failure (n = 16 958), marker call rate < 0.05 (n = 21 920), and Hardy‐Weinberg equilibrium P‐value ≤ 1E−6 (n = 708). Additional SNP QC steps were performed on the final 257 samples included in the analysis. Among the 770 302 remaining markers, SNPs exhibiting monomorphism (n = 125 751) or loss of heterozygosity (n = 102) were first filtered out. Then SNPs with a missing rate > 5% (n = 3562), minor allele frequency (MAF) ≤5% (n = 293 437), or Hardy‐Weinberg equilibrium P‐value < .001 (n = 504) were further excluded. The final marker set included 346 946 SNPs across 257 patients. The P‐value threshold for significance was = α1.44E−07 based on 0.05/346 946 (Figure 1B).\n\n2.5 Statistical analysis\nBefore the study, statistical power was calculated based on a maximum sample size of 60 cases and 240 controls. This sample size (1:4 ratio of cases to controls) was expected to achieve 87.4% and 67.3% power at significance levels of 10−2 and 10−3, respectively, with an assumed odds ratio (OR) of 3.0 in the additive model under a high‐risk allele frequency of 0.1 and disease prevalence of 1.7%. The distribution of clinical characteristics between cases and controls was presented as means ± SD for continuous variables and frequency (percentage) for categorical variables. Differences in clinical variables were tested using the Student t test for continuous variables and Pearson chi‐square test or Fisher exact test for categorical variables. To test the association between ACT and SNPs, we used several genetic models, including the additive, dominant, and recessive models. Univariate and multivariate logistic regression models were applied to perform the association tests with adjustment for significant clinical factors in the multivariate model. Significance of the association of SNPs was examined using the minimum of the P‐value among the additive and dominant genetic models.\n18\n The effective number of SNPs was calculated with respect to the linkage disequilibrium (LD) correlation structure.\n19\n The LD between genetic markers were calculated using the joint probability and the product of the individual allele probabilities. We did this using the LD() function of the ‘genetics’ packages in R software. Regional plots were created using LocusZoom (http://locuszoom.sph.umich.edu/locuszoom/). Expression quantitative trait loci (eQTL) analysis was performed using the Genotype‐Tissue Expression (GTEx) database\n20\n (http://gtexportal.org/). To compare the overall survival between patients in the case and control groups, the difference was tested using the log‐rank test and plotted as Kaplan‐Meier curves.\n\n3 RESULTS\n3.1 Patient characteristics\nForty‐two cases and 215 controls were included in this study after excluding samples for QC. Across all patients, the median follow‐up duration was 8.43 y (interquartile range: 5.15‐10.42 y; maximum: 15.45 y). The median onset time for ACT was 220 d (range: 55‐2472 d) after completion of chemotherapy. Most clinical variables were not significantly different between the case and control groups, however body mass index (BMI) >25 kg/m2 (45.2% vs 25.6%, P = .010), higher weight (61.6 vs 57.5 kg, P = .002), and a history of hyperlipidemia (16.7% vs 6.1%, P = .028) were more frequently observed in the case group. In addition, the number of patients with HER2 amplification (83.3% vs 60.5%, P = .005) and trastuzumab use (76.2% vs 57.7%, P = .025) was significantly higher in the case group (Table 1). Most patients with HER2‐amplified tumors received trastuzumab treatment concurrently with adjuvant chemotherapy, therefore trastuzumab use but not HER2 positivity was included as a factor in the analysis, to account for any interaction between the 2 factors. In the multivariate logistic regression model, BMI ≥ 25 kg/m2 (OR = 2.45, 95% CI, 1.23‐4.88, P = .011) and trastuzumab use (OR = 2.40, 95% CI, 1.11‐5.17, P = .026) remained as significant factors associated with ACT (Table 2). These 2 factors were included as covariates in the adjusted model.\n\nTABLE 1 Distribution of clinical characteristics between case and control\n\nCharacteristics\t\tTotal\tCase\tControl\t\nP‐value\t\n(n = 257)\t(n = 42)\t(n = 215)\t\nAge at diagnosis (mean ± SD)\t\t49.3 ± 9.5\t49.8 ± 8.8\t49.2 ± 9.7\t.720\t\nHeight (cm)\t\t157.2 ± 5.0\t158.1 ± 5.7\t157.0 ± 4.9\t.221\t\nWeight (kg)\t\t58.2 ± 7.9\t61.6 ± 9.2\t57.5 ± 7.5\t.002\t\nBody mass index (BMI)\t<25\t183\t23 (54.8)\t160 (74.4)\t.010\t\n≥25\t74\t19 (45.2)\t55 (25.6)\t\nHypertension\tNo\t214\t34 (81.0)\t180 (83.7)\t.660\t\nYes\t43\t8 (19.0)\t35 (16.3)\t\nHyperlipidemia\tNo\t237\t35 (83.3)\t202 (94.0)\t.028\t\nYes\t20\t7 (16.7)\t13 (6.1)\t\nDiabetes\tNo\t247\t41 (97.6)\t206 (95.8)\t>.999\t\nYes\t10\t1 (2.4)\t9 (4.2)\t\nOther heart disease\tNo\t252\t40 (95.2)\t212 (98.6)\t.189\t\nYes\t5\t2 (4.8)\t3 (1.4)\t\nTaxol\tNo\t85\t11 (26.2)\t74 (34.4)\t.300\t\nYes\t172\t31 (73.8)\t141 (65.6)\t\nER\tNegative\t89\t16 (38.1)\t73 (34.0)\t.606\t\nPositive\t168\t26 (61.9)\t142 (66.0)\t\nPR\tNegative\t104\t17 (40.5)\t87 (40.5)\t.999\t\nPositive\t153\t25 (59.5)\t128 (59.5)\t\nHER2\tNegative\t92\t7 (16.7)\t85 (39.5)\t.005\t\nPositive\t165\t35 (83.3)\t130 (60.5)\t\nRadiotherapy\tNo\t21\t3 (7.1)\t18 (8.4)\t>.999\t\nYes\t236\t39 (92.9)\t197 (91.6)\t\nEndocrine therapy\tNo\t86\t15 (35.7)\t71 (33.0)\t.735\t\nYes\t171\t27 (64.3)\t144 (67.0)\t\nTrastuzumab use\tNo\t101\t10 (23.8)\t91 (42.3)\t.025\t\nYes\t156\t32 (76.2)\t124 (57.7)\t\nDeath\tSurvival\t231\t39 (92.9)\t192 (89.3)\t\t\nDeath from breast cancer\t22\t3 (7.1)\t19 (8.8)\t\t\nDeath from other cause\t4\t0 (0.0)\t4 (1.9)\t\t\nProgress of ACT\tPersistent ACT\t30\t30 (71.4)\t\t\t\nTransient ACT\t12\t12 (28.6)\t\t\t\nAbbreviations: ACT: anthracycline‐induced cardiotoxicity; HER2, human epidermal growth factor receptor 2.\n\nJohn Wiley & Sons, LtdTABLE 2 Univariable and multivariable logistic regression model for clinical variables\n\nCharacteristics\tUnivariate model\tMultivariate model\t\nOR (95% CI)\t\nP‐value\tOR (95% CI)\t\nP‐value\t\nBody mass index (BMI)\t<25\t1 (ref)\t\t1 (ref)\t\t\n≥25\t2.40 (1.22‐4.75)\t.012\t2.45 (1.23‐4.88)\t.011\t\nTrastuzumab use\tNo\t1 (ref)\t\t1 (ref)\t\t\nYes\t2.35 (1.10‐5.02)\t.028\t2.40 (1.11‐5.17)\t.026\t\nAbbreviations: CI, confidence interval; OR, odds ratio.\n\nJohn Wiley & Sons, LtdThirty patients (71.4%) in the case group were classified into the persistent ACT group. In contrast, 12 patients in the case group completely recovered from ACT within a median of 410 d (range: 125‐850 d) and were classified into the transient ACT group. A further analysis of the genes within the persistent ACT group was conducted.\n\n3.2 Genetic association study\nA quantile‐quantile (Q‐Q) plot showed the distribution of the observed P‐value from association testing of 346 946 SNPs and all case and control samples distributed into the same cluster in the principal component analysis (PCA) plot (Figure S1A,B). A Manhattan plot was used to display the 346 946 SNPs that passed QC (Figure 2). None of the SNPs reached the Bonferroni‐corrected significance level (α = 1.44E−07 from 0.05/346 946). We therefore identified 86 SNPs with a minimum P‐value < 1.0E−04 in the crude or adjusted model (Table S1). Because several SNPs selected on the same gene were in LD, we calculated the effective number of 86 SNPs based on LD correlation structure. The effective number was 68.9 due to duplicated genes among the 86 SNPs. We identified 7 SNPs with a minimum P‐value < 1.0E−05 in the adjusted model, corresponding to an effective number of 6.9 (Table 3).\n\nFIGURE 2 Manhattan plots for association test of 346 946 SNPs on (A) crude and (B) adjusted model\n\nTABLE 3 Frequency and P‐values using crude and adjusted logistic regression model for candidate SNPs (P‐value < 1.E−05)\n\n\nGene name\tRS ID\tCHR\tPhysical. position\tGenotype\tFrequency\tCrude model\tAdjusted model\na\n\n\t\nControl\tCase\tOR1 (95% CI)\tOR2 (95% CI)\t\nP‐value\tOR1 (95% CI)\tOR2 (95% CI)\t\nP‐value\t\n\nBEND4/SHISA3/ATP8A1\n\trs17530621\t4\t42 227 497\tG/G\t170\t18\t1\t1\t3.81.E−06\t1\t1\t3.10.E−06\t\nG/T\t42\t23\t4.24 (2.23‐8.06)\t5.15 (2.57‐10.33)\t4.53 (2.33‐8.84)\t5.66 (2.73‐11.72)\t\nT/T\t2\t1\t17.97 (4.97‐64.93)\t5.15 (2.57‐10.33)\t20.56 (5.41‐78.09)\t5.66 (2.73‐11.72)\t\n\nMIR548AB\n\trs6804462\t3\t103 342 570\tG/G\t198\t27\t1\t1\t3.18.E−06\t1\t1\t4.26.E−06\t\nG/C\t15\t14\t5.60 (2.59‐12.11)\t6.87 (3.06‐15.47)\t6.24 (2.86‐13.61)\t7.33 (3.13‐17.16)\t\nC/C\t1\t1\t31.35 (6.70‐146.56)\t6.87 (3.06‐15.47)\t38.91 (8.17‐185.28)\t7.33 (3.13‐17.16)\t\n\nMPP4\n\trs11894115\t2\t202 512 449\tC/C\t76\t2\t1\t1\t1.13.E−05\t1\t1\t4.71.E−06\t\nC/T\t102\t22\t3.39 (1.97‐5.84)\t10.78 (2.53‐45.92)\t3.96 (2.20‐7.15)\t11.57 (2.69‐49.79)\t\nT/T\t32\t16\t11.49 (3.86‐34.16)\t10.78 (2.53‐45.92)\t15.72 (4.83‐51.13)\t11.57 (2.69‐49.79)\t\n\nRPL7/RDH10\n\trs58328254\t8\t74 203 722\tG/G\t135\t12\t1\t1\t1.49.E−05\t1\t1\t6.09.E−06\t\nG/A\t70\t23\t3.48 (1.98‐6.11)\t4.29 (2.07‐8.90)\t3.98 (2.19‐7.23)\t4.90 (2.30‐10.47)\t\nA/A\t6\t6\t12.09 (3.91‐37.37)\t4.29 (2.07‐8.90)\t15.81 (4.78‐52.28)\t4.90 (2.30‐10.47)\t\n\nCA10/C17orf112\n\trs2113374\t17\t50 508 719\tC/C\t186\t23\t1\t1\t1.38.E−06\t1\t1\t7.06.E−06\t\nC/T\t24\t18\t5.29 (2.62‐10.69)\t6.15 (2.94‐12.85)\t5.07 (2.48‐10.36)\t5.73 (2.68‐12.28)\t\nT/T\t1\t1\t27.96 (6.85‐114.23)\t6.15 (2.94‐12.85)\t25.71 (6.15‐107.42)\t5.73 (2.68‐12.28)\t\n\nPRUNE2\n\trs117299725\t9\t79 423 611\tG/G\t191\t24\t1\t1\t2.53.E−06\t1\t1\t8.53.E−06\t\nG/A\t24\t18\t5.97 (2.84‐12.56)\t5.97 (2.84‐12.56)\t5.69 (2.65‐12.24)\t5.69 (2.65‐12.24)\t\nA/A\t0\t0\t35.63 (8.04‐157.79)\t5.97 (2.84‐12.56)\t32.41 (7.01‐149.92)\t5.69 (2.65‐12.24)\t\n\nCDH13\n\trs147631684\t16\t83 632 820\tG/G\t202\t28\t1\t1\t4.50.E−06\t1\t1\t9.61.E−06\t\nG/A\t11\t13\t6.21 (2.64‐14.60)\t7.82 (3.25‐18.82)\t6.20 (2.51‐15.34)\t7.97 (3.18‐19.97)\t\nA/A\t1\t0\t38.57 (6.98‐213.15)\t7.82 (3.25‐18.82)\t38.50 (6.30‐235.26)\t7.97 (3.18‐19.97)\t\nAbbreviations:\nRS ID, reference SNP cluster ID; CHR, chromosome; OR1, odds ratio (OR) and 95% confidence interval (CI) in additive model; OR2, odds ratio (OR) and 95% confidence interval (CI) in dominant model.\n\na Adjusted for body mass index and trastuzumab use.\n\nJohn Wiley & Sons, LtdAll these 7 SNPs, except rs11894115, were found in non‐exonic regions (Table 3, Figures 3 and S2). rs17530621 on chromosome 4 had the smallest observed P‐value of 3.10E−06 and was located in an intergenic region between BEND4 and SHISA3; this region also included the 5′‐end of ATP8A1 (Figure 3A). Although the allele frequency of rs17530621 was known to be 0.60 for the reference allele (T) and 0.40 for an alternative allele (G) in European populations, the frequency was 0.14 for T and 0.86 for G in our study population. These frequencies were similar to those reported in the dbSNP database (https://www.ncbi.nlm.nih.gov/snp) for Asian populations, with T of 0.12 and G of 0.88. rs11894115 on chromosome 2 was a missense variant in the exonic region of the MPP4 gene with a P‐value of 4.71E−06. rs58328254 on chromosome 8 and rs117299725 on chromosome 9 were located in the introns of RPL7 and PRUNE2 genes, respectively and showed strong associations, with P‐values of 6.09E−06 and 8.53E−06, respectively. rs2113374 and rs147631684 were placed in the intron region of the long intervening non‐coding RNA (lincRNA) of C17orf112 and CDH13 genes, respectively. rs6804462 was located near MIR548AB. In all results, denoting the homozygote of the reference allele as A/A, heterozygous as A/B, and homozygote of the alternative (risk, minor) allele as B/B, the odds of having the cardiotoxicity significantly increased as the number of alternative alleles increased (Table 3).\n\nFIGURE 3 Regional association plots for (A) rs17530621, (B) rs11894115, (C) rs58328254, and (D) rs117299725\n\nOnly among the persistent ACT group, we identified 62 SNPs with a minimum P‐value < 1.0E−04 in the crude or adjusted model, corresponding to an effective number of 53.4 (Table S2). In the adjusted model, rs4336659, which had the smallest P‐value, was located near the GLIS3 and SLC1A1 genes (P = 3.03E−06). The WWOX gene, which had a P‐value of 7.24E−05 in the crude model of the entire study population data set (Table S1), had a higher association in the persistent ACT group (P = 7.28E−06, Table S2). The PRUNE2 gene was a common gene that was identified both in the entire study population data set and in the persistent ACT group. (Table S2, Figure S3).\n\n3.3 Expression analysis of the candidate SNPs\nTo identify the association between the genetic variants and expression of related genes, we conducted expression quantitative trait loci (eQTL) analysis using the Genotype‐Tissue Expression (GTEx) database.\n20\n As a result, 2 SNPs showed association with the expression of nearby genes (P < .05). rs17530621 was associated with the expression of the ATP8A1 gene in the tibial artery (P = 3.8E−03) and in the left ventricle of the heart (P = 2.0E−02) with normalized effect sizes (NES) of 0.084 and 0.113, respectively. rs58328254 was associated with expression of the RDH10‐AS1 (antisense 1) gene in the tibial artery (P = 2.7E−12) and aorta artery (P = 1.0E−06) with NESs of −0.393 and −0.310, respectively (Table S3).\n\n3.4 Overall survival\nDuring the follow‐up period, 26 (10.1%) patients died. The most common cause of death was breast cancer recurrence, which occurred in 3 (7.1%) patients in the case group and 19 (8.8%) patients in the control group (Table 1). There was no death from ACT in the case group. In addition, there was no significant difference in overall survival (P = .464) between the 2 groups (Figure S4).\n\n4 DISCUSSION\nCardiotoxicity is a major side effect of anthracycline treatment, with a higher incidence in patients who received a cumulative dose of more than 450 mg/m2, as well as those with cardiovascular comorbidities or those who receive combination treatment with other chemotherapeutic agents such as trastuzumab.\n3\n, \n5\n Cardiotoxicity is a serious lifelong problem for both children and adults and is associated with high morbidity and mortality. The extent and frequency of cardiotoxicity varies significantly across patients. Susceptible genetic factors, as well as various clinical risk factors, have been studied to identify high‐risk patients before anthracycline administration. Previous studies have revealed that genes related to the generation of excess reactive oxygen species (encoded by POR, NCF4, RAC2, and CYBA), intracellular accumulation of toxic metabolites (encoded by CBR3, SLC8A3 and UGT1A6), and interaction of anthracycline with topoisomerase‐2β (encoded by RARG) were significant in the development of ACT.\n21\n, \n22\n In particular, the RARG variant (rs2229774) was found in one discovery cohort (280 European population) and 2 validation cohorts (96 European and 80 non‐European) that collectively included more than 450 childhood cancer patients.\n11\n\nRARG is known to bind the topoisomerase IIβ promoter and in a mouse model was expressed in cardiomyocytes after injury.\n23\n, \n24\n However, the RARG variant was not found in a GWAS of more than 7800 breast cancer patients from 3 large randomized clinical trials who had received anthracycline treatment.\n13\n This discrepancy in findings may be due to differences in study populations, methodologies, and concurrent treatments used across studies. In addition, the impact of age and other environmental factors such as weight and other comorbidities may be more significant in adult patient populations compared with cohorts involving children.\n\nTo date, most studies have been conducted on Western populations and only a few large‐scale clinical studies involving Asian patient cohorts have been conducted. The current study only included Korean women who had been diagnosed with early breast cancer. Every patient in our cohort received 4‐6 cycles of doxorubicin sequentially with or without trastuzumab as a neoadjuvant/adjuvant treatment. Based on our results, higher BMI and trastuzumab use were important clinical factors that were strongly associated with ACT; these findings were consistent with the results of prior studies.\n25\n, \n26\n, \n27\n In our GWAS analysis, we found that 7 susceptible variants, including rs17530621, rs6804462, rs11894115, rs58328254, rs2113374, rs117299725, and rs147731684, were associated with ACT across the entire study population (minimum P‐value < 1.0E−05). However, the SNPs discovered in this study did not reach statistical significance when adjusting for clinical factors, higher BMI, and trastuzumab use.\n\nOur expression analysis found only 2 SNPs (rs17530621 and rs58328254) that were associated with expression of nearby genes, because most variants, except rs118941115, were located in non‐coding regions. Their biological significance in relation to ACT development was also unclear, however several previous studies have suggested that the genes we identified may be linked functionally to cardiotoxicity. In a model of heart failure, SHISA3, which was associated with rs17530621 and primarily expressed in the vascular cells of the fetal heart, was involved in pathological tissue remodeling via reduction of KLF15 and WNT signaling activation.\n28\n\nPRUNE2 is reported to be highly expressed in patients with idiopathic dilated heart failure, as well as in patients with ischemic heart failure and also is functionally related to myocardial muscle tension.\n29\n Genetic polymorphisms of CDH13 are associated with plasma adiponectin levels and are involved in the development of cardiometabolic disease.\n30\n, \n31\n These data suggest that it is necessary to further study the relationship between these genes and development of ACT.\n\nIn this study, SNPs in RARG, SLC8A3, UGT1A6, NCF4, and RAC2 did not emerge as significant, despite reports in previous studies that these genes were associated with susceptibility to ACT.\n11\n, \n19\n, \n20\n There may be several reasons for these discrepancies, including the relatively small size of our control group, differences in ethnicity, and differences in combined chemotherapeutic regimens. For example, the MAF of the RARG variant rs2229774 was 6.7% in Europeans, while this value was significantly lower (0.7%) in East Asians. The MAF of rs17530621 found in our study also showed a significant difference between European and Asian populations. Such differences may have caused the lack of identification of results between studies. One advantage of our study, however, is that we were able to adjust for possible clinical risk factors in patients with long‐term follow‐up. Our study, therefore, enabled us to infer that the effect of genetic variations in the development of ACT may be diluted by the effects of various clinical risk factors.\n\nIn conclusion, we found that clinical factors such as higher BMI and trastuzumab use were important factors in the development of ACT among patients with early breast cancer. Our GWAS identified candidate SNPs that were associated with the development of ACT in a Korean female population. Although none of these SNPs reached a significance threshold, these candidate SNPs warrant further study.\n\nDISCLOSURE\nThe authors have no conflicts of interest.\n\nSupporting information\nFigure S1\n\nClick here for additional data file.\n\n Figure S2\n\nClick here for additional data file.\n\n Figure S3\n\nClick here for additional data file.\n\n Figure S4\n\nClick here for additional data file.\n\n Tables S1‐S3\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nWe thank all the patients who participated in this study. This work was supported by NCCK grant number 1940520‐1.\n\nDATA AVAILABILITY STATEMENT\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n1 \n\nVolkova \nM \n, \nRussell \nR \n. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment\n. Curr Cardiol Rev . 2011 ;7 :214 ‐220\n.22758622 \n2 \n\nKremer \nL \n, \nvan der Pal \nH \n, \nOffringa \nM \n, \nvan Dalen \nEC \n, \nVoûte \nPA \n. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review\n. Ann Oncol . 2002 ;13 :819 ‐829\n.12123328 \n3 \n\nSingal \nPK \n, \nIliskovic \nN \n. Doxorubicin‐induced cardiomyopathy\n. N Engl J Med . 1998 ;339 :900 ‐905\n.9744975 \n4 \n\nCameron \nD \n, \nBrown \nJ \n, \nDent \nR \n, et al. Adjuvant bevacizumab‐containing therapy in triple‐negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial\n. Lancet Oncol . 2013 ;14 :933 ‐942\n.23932548 \n5 \n\nGianni \nL \n, \nSalvatorelli \nE \n, \nMinotti \nG \n. Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes\n. Cardiovasc Toxicol . 2007 ;7 :67 ‐71\n.17652806 \n6 \n\nKotamraju \nS \n, \nKonorev \nEA \n, \nJoseph \nJ \n, et al. Doxorubicin‐induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species\n. J Biol Chem . 2000 ;275 :33585 ‐33592\n.10899161 \n7 \n\nDowd \nNP \n, \nScully \nM \n, \nAdderley \nSR \n, \nCunningham \nAJ \n, \nFitzgerald \nDJ \n. Inhibition of cyclooxygenase‐2 aggravates doxorubicin‐mediated cardiac injury in vivo\n. J Clin Invest . 2001 ;108 :585 ‐590\n.11518732 \n8 \n\nBlanco \nJG \n, \nLeisenring \nWM \n, \nGonzalez‐Covarrubias \nVM \n, et al. Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline‐related congestive heart failure after childhood cancer\n. Cancer . 2008 ;112 :2789 ‐2795\n.18457324 \n9 \n\nWang \nX \n, \nLiu \nW \n, \nSun \nC‐L \n, et al. Hyaluronan synthase 3 variant and anthracycline‐related cardiomyopathy: a report from the children's oncology group\n. J Clin Oncol . 2014 ;32 :647 ‐653\n.24470002 \n10 \n\nArmenian \nSH \n, \nDing \nY \n, \nMills \nG \n, et al. Genetic susceptibility to anthracycline‐related congestive heart failure in survivors of haematopoietic cell transplantation\n. Br J Haematol . 2013 ;163 :205 ‐213\n.23927520 \n11 \n\nAminkeng \nF \n, \nBhavsar \nAP \n, \nVisscher \nH \n, et al. A coding variant in RARG confers susceptibility to anthracycline‐induced cardiotoxicity in childhood cancer\n. Nat Genet . 2015 ;47 :1079 ‐1084\n.26237429 \n12 \n\nVisscher \nH \n, \nRoss \nCJD \n, \nRassekh \nSR \n, et al. Pharmacogenomic prediction of anthracycline‐induced cardiotoxicity in children\n. J Clin Oncol . 2012 ;30 :1422 ‐1428\n.21900104 \n13 \n\nSchneider \nBP \n, \nShen \nF \n, \nGardner \nL \n, et al. Genome‐wide association study for anthracycline‐induced congestive heart failure\n. Clin Cancer Res . 2017 ;23 :43 ‐51\n.27993963 \n14 \n\nSparano \nJA \n, \nWang \nM \n, \nMartino \nS \n, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer\n. N Engl J Med . 2008 ;358 :1663 ‐1671\n.18420499 \n15 \n\nZamorano \nJL \n, \nLancellotti \nP \n, \nRodriguez Muñoz \nD \n, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)\n. Eur Heart J . 2016 ;37 :2768 ‐2801\n.27567406 \n16 \n\nMoon \nS \n, \nKim \nYJ \n, \nHan \nS \n, et al. The Korea Biobank Array: design and identification of coding variants associated with blood biochemical traits\n. Sci Rep . 2019 ;9 :1382 .30718733 \n17 \nSNPolisher User Guide (Version 1.5.2.) . Affymetrix Inc ; 2015 \nhttp://tools.thermofisher.com/content/sfs/manuals/SNPolisher_User_Guide.pdf. Accessed December 20, 2018.\n18 \n\nJoo \nJ \n, \nKwak \nM \n, \nChen \nZ \n, et al. Efficiency robust statistics for genetic linkage and association studies under genetic model uncertainty\n. Stat Med . 2010 ;29 :158 ‐180\n.19918942 \n19 \n\nCheverud \nJM \n. A simple correction for multiple comparisons in interval mapping genome scans\n. Heredity . 2001 ;87 :52 ‐58\n.11678987 \n20 \nGTEx Consortium \n. The Genotype‐Tissue Expression (GTEx) project\n. Nat Genet . 2013 ;45 :580 ‐585\n.23715323 \n21 \n\nChang \nVY \n, \nWang \nJJ \n. Pharmacogenetics of chemotherapy‐induced cardiotoxicity\n. Curr Oncol Rep . 2018 ;20 :52 .29713898 \n22 \n\nLinschoten \nM \n, \nTeske \nAJ \n, \nCramer \nMJ \n, et al. Chemotherapy‐related cardiac dysfunction: a systematic review of genetic variants modulating individual risk\n. Circ Genom Precis Med . 2018 ;11 :e001753.29557343 \n23 \n\nDelacroix \nL \n, \nMoutier \nE \n, \nAltobelli \nG \n, et al. Cell‐specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells\n. Mol Cell Biol . 2010 ;30 :231 ‐244\n.19884340 \n24 \n\nBilbija \nD \n, \nHaugen \nF \n, \nSagave \nJ \n, et al. Retinoic acid signalling is activated in the postischemic heart and may influence remodelling\n. PLoS ONE . 2012 ;7 :e44740.23028599 \n25 \n\nPerez \nEA \n, \nSuman \nVJ \n, \nDavidson \nNE \n, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial\n. J Clin Oncol . 2008 ;26 :1231 ‐1238\n.18250349 \n26 \n\nSlamon \nD \n, \nEiermann \nW \n, \nRobert \nN \n, et al. Adjuvant trastuzumab in HER2‐positive breast cancer\n. N Engl J Med . 2011 ;365 :1273 ‐1283\n.21991949 \n27 \n\nGuenancia \nC \n, \nLefebvre \nA \n, \nCardinale \nD \n, et al. Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta‐analysis\n. J Clin Oncol . 2016 ;34 :3157 ‐3165\n.27458291 \n28 \n\nNoack \nC \n, \nIyer \nLM \n, \nLiaw \nNY \n, et al. KLF15‐Wnt‐dependent cardiac reprogramming up‐regulates SHISA3 in the mammalian heart\n. J Am Coll Cardiol . 2019 ;74 :1804 ‐1819\n.31582141 \n29 \n\nSong \nY \n, \nAhn \nJ \n, \nSuh \nY \n, et al. Identification of novel tissue‐specific genes by analysis of microarray databases: a human and mouse model\n. PLoS ONE . 2013 ;8 :e64483.23741331 \n30 \n\nChung \nC‐M \n, \nLin \nT‐H \n, \nChen \nJ‐W \n, et al. A genome‐wide association study reveals a quantitative trait locus of adiponectin on CDH13 that predicts cardiometabolic outcomes\n. Diabetes . 2011 ;60 :2417 ‐2423\n.21771975 \n31 \n\nMorisaki \nH \n, \nYamanaka \nI \n, \nIwai \nN \n, et al. CDH13 gene coding T‐cadherin influences variations in plasma adiponectin levels in the Japanese population\n. Hum Mutat . 2012 ;33 :402 ‐410\n.22065538\n\n",
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"title": "Genome-wide association study of genetic variants related to anthracycline-induced cardiotoxicity in early breast cancer.",
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"abstract": "In patients with COVID-19, even small radial aneurysm may suddenly rupture.",
"affiliations": "Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Plastic Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Plastic Surgery IRCCS Policlinico San Donato Milan Italy.;Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy.",
"authors": "Mazzaccaro|Daniela|D|https://orcid.org/0000-0002-7414-642X;Giannetta|Matteo|M|;Malacrida|Giovanni|G|;Zilio|Dino|D|;Modafferi|Alfredo|A|;Righini|Paolo|P|;Marrocco-Trischitta|Massimiliano M|MM|;Vaienti|Luca|L|;Nano|Giovanni|G|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4285\nCCR34285\nCase Report\nCase Reports\nSudden rupture of small aneurysm of the radial artery in a patient with COVID‐19 pneumonia\nMAZZACCARO et al.\nMazzaccaro Daniela https://orcid.org/0000-0002-7414-642X\n1 danymazzak83@libero.it\ndaniela.mazzaccaro@gmail.com\n\nGiannetta Matteo 1\nMalacrida Giovanni 1\nZilio Dino 2\nModafferi Alfredo 1\nRighini Paolo 1\nMarrocco‐Trischitta Massimiliano M. 1\nVaienti Luca 2\nNano Giovanni 1 3\n1 Operative Unit of Vascular Surgery IRCCS Policlinico San Donato Milan Italy\n2 Operative Unit of Plastic Surgery IRCCS Policlinico San Donato Milan Italy\n3 Department of Biomedical Sciences for Health University of Milan Milan Italy\n* Correspondence\nDaniela Mazzaccaro, Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, Piazza Malan, 1, 20097 San Donato Milanese, Milan, Italy.\nEmails: danymazzak83@libero.it; daniela.mazzaccaro@gmail.com\n\n23 6 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0428517 4 2021\n31 12 2020\n27 4 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nIn patients with COVID‐19, even small radial aneurysm may suddenly rupture.\n\nIn patients with COVID‐19, even small radial aneurysm may suddenly rupture.\n\naneurysm\narterial rupture\nCOVID‐19\nradial artery\nradial catheter\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.06.2021\nMazzaccaro D , Giannetta M , Malacrida G , et al. Sudden rupture of small aneurysm of the radial artery in a patient with COVID‐19 pneumonia. Clin Case Rep. 2021;9 :e04285. 10.1002/ccr3.4285\n==== Body\n1 INTRODUCTION\n\nWe report the case of sudden rupture of a radial artery small aneurysm occurring in a 63‐year‐old patient who had been hospitalized for COVID‐19 pneumonia.\n\nThere is increasing evidence of vascular complications related to COVID‐19, including arterial and venous thrombotic events. 1\n\nHowever, reports about the occurrence of arterial rupture in patients hospitalized for COVID‐19 pneumonia are lacking.\n\nThese patients frequently require percutaneous arterial procedures, such as radial/brachial catheterization for invasive blood pressure monitoring or blood sampling for gas analysis. Therefore, they are at increased risk of developing vascular complications of the access site.\n\nWe report the case of a 63‐year‐old patient hospitalized for COVID‐19 pneumonia requiring noninvasive mechanical ventilation, who developed arterial rupture of a small aneurysm following arterial catheterization.\n\n2 CASE DESCRIPTION\n\nPatient's consent was obtained to the anonymous use of his clinical data for research purposes.\n\nA 63‐year‐old man with a medical history of myocardial surgical revascularization was admitted to our hospital for a COVID‐19 pneumonia, which required ventilatory support until the need to wear a continuous positive airways pressure (c‐PAP) mask up to 60% FiO2 at day 4. Therapy with hydroxychloroquine 400 mg twice a day, lopinavir/ritonavir 400/100 mg twice a day and antibiotic coverage with ceftriaxone 2 g daily and azithromycin 500 mg daily was set up, according to the internal protocol. Moreover, a 4 French catheter (BD Medical™) was placed in his right radial artery for the arterial blood gas analyses, without any troubles. Then, he received a single dose of tocilizumab 640 mg and started methylprednisolone (40 mg twice a day). The respiratory function progressively improved until a complete weaning from the c‐PAP in day 10. The radial artery catheter was removed after 8 days in day 12 without any complications, and local compression was applied to the wrist. However, on day 14 a painful tumefaction in his right wrist, which extended to the forearm was found. The upper limb was warm, motility and sensitivity of the hand were preserved, and both radial and ulnar pulses were palpable. Doppler ultrasonography showed the presence of edema of the forearm extending to the arm, and the regular patency of the arterial and venous axis of the right upper limb, with regular flows and without any hematoma surrounding the artery, which had a regular caliber. A slight compression of the upper limb was then applied with a bandage.\n\nHowever, on day 16 the clinical picture worsened (Figure 1) and the patient complained of continuous pain of his forearm with initial impairment of the sensitivity and the motility of his right hand. Doppler ultrasonography was repeated, showing the presence of a small aneurysm of the radial artery at the wrist. The patient then underwent a right upper limb computed tomography angiography (CTA), which confirmed the presence of a focal ectasia of the radial artery of 6 mm (reference diameter of the artery above the ectasia was 4.5 mm), with edematous infiltration of the surrounding tissue and inflammation of the flexor muscles of the forearm (Figure 2). Blood cultures were negative; nevertheless, antibiotic therapy with daptomycin 10 mg/kg/day was set according to the infectivologist's suggestion, but 2 days later active bleeding from the right wrist suddenly occurred. Manual compression was unsuccessful; therefore, emergent surgery was performed. In the operating room, while keeping manual compression in the radial position at the distal third of the forearm, a right longitudinal incision was performed laterally at the wrist. A wide hematoma with active bleeding from the radial artery was found. The artery was completely lacerated (Figure 3A). Due to the impossibility of proceeding with arterial reconstruction, surgical ligation was performed with 5/0 polypropylene suture. Fasciotomies of the flexor muscles' lodge were also performed, in order to decompress the underlying median nerve which appeared to be edematous (Figure 3B). Adjunctive intermetacarpal fasciotomies on the back of the hand were performed at I, II, and III space, with immediate decongestion of the edematous component and good refill on all the fingers (Figure 3C). Intraoperative culture of both the endothelium and the surrounding tissue was negative for the presence of any bacterial agent.\n\nFIGURE 1 Pictures of the clinical presentation of the patient's right wrist (image on the left side). Note the edema extending to the forearm (image on the right side)\n\nFIGURE 2 Right upper limb CTA showing a focal ectasia of the radial artery of 6 mm (red arrow), with edematous infiltration of the surrounding tissue and inflammation of the flexor muscles of the forearm\n\nFIGURE 3 Intraoperative finding of laceration of the radial artery A. Note in figure B the fasciotomies of the flexor muscles' lodge at the level of the third middle‐distal of the forearm, and at the transverse ligament of the carpus. Figure C shows intermetacarpal fasciotomies on the back of the hand at I, II, and III space, with immediate decongestion of the edematous component\n\nThe postoperative course was uneventful, with complete recover of sensitivity and motility of the hand. A duplex ultrasound was performed in the first postoperative day, showing adequate vascularization of the interdigital arteries, supplied by a regularly patent ulnar artery.\n\nThe patient was then discharged in good clinical conditions on day 28.\n\n3 DISCUSSION\n\nRadial artery catheterization is a common maneuver, which is usually performed for invasive arterial pressure monitoring, 2 for endovascular and cardiac percutaneous procedures 3 or when there is the need for frequent arterial blood gas determination, such as in COVID‐19 patients.\n\nIndwelling radial artery catheters are generally safe, with an overall rate of associated vascular complications lower than 0.5%, being radial thrombosis the most reported. 4\n\nFurthermore, aneurysmal degeneration after radial artery catheterization has been reported in less than 0.1% of the cases, 5 and radial artery rupture after arterial catheterization has been occasionally described. 6\n\nIn our case report, the patient had a small radial aneurysm, which was, however, complicated by sudden rupture, despite antibiotic treatment and the not excessive size of the lesion. Some pathogenic mechanisms hypothetically could have contributed together to the development of such a complication.\n\nFirst, the reduced local immune defenses following the administration of immunosuppressive drugs, such as hydroxychloroquine, tocilizumab, and corticosteroids, needed for the COVID‐19 pneumonia, may have contributed to a possible local infection, even if the intraoperative cultures of the endothelium were negative.\n\nAs a second issue, the SARS‐CoV‐2 infection itself may have played a role in the impairment of the arterial wall. Recently published papers have described a significant increase in vascular disorders in COVID‐19 patients. 1 Furthermore, recent studies have shown direct viral infection of the endothelial cells through the angiotensin‐converting enzyme 2 receptor, and diffuse endothelial inflammation that can result in widespread endothelial dysfunction. 7\n\nMoreover, the so‐called “cytokine storm” that is typical of severe COVID‐19 infection also can cause arterial wall weakening and fragility which further cause arterial rupture or aneurysm formation. 8\n\nTherefore, vascular surgeons should be alert in patients with COVID‐19, bearing in mind that arterial complications may occur not only in the form of ischemic diseases but also as hemorrhagic complications following even small aneurysm.\n\n4 CONCLUSION\n\nSmall radial aneurysms following arterial catheterization may be complicated by sudden rupture in patients with COVID‐19. Vascular surgeons should, therefore, be aware of such complication to prevent potentially serious consequences.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nDM: involved in study design, data collection, writing, critical revision, and final approval. MG: involved in data collection, writing, critical revision, and final approval. GM: involved in data collection, critical revision, and final approval. AM, LV, PR, MMT, and GN: involved in critical revision and final approval. All authors read and approved the final version of the manuscript.\n\nCONSENT FOR PUBLICATION\n\nPatient's consent was obtained to the anonymous use of his clinical data for research purposes.\n\nACKNOWLEDGMENTS\n\nThis paper can be found online as a preprint publication at https://www.authorea.com/users/390127/articles/504563‐sudden‐rupture‐of‐small‐pseudoaneurysm‐of‐the‐radial‐artery‐in‐a‐patient‐with‐covid‐19‐pneumonia\n==== Refs\nREFERENCES\n\n1 Siddiqi HK , Libby P , Ridker PM . COVID‐19 ‐ A vascular disease. Trends Cardiovasc Med. 2021;31 (1 ):1‐5.33068723\n2 Kaufmann T , Cox EGM , Wiersema R , et al. Non‐invasive oscillometric versus invasive arterial blood pressure measurements in critically ill patients: a post hoc analysis of a prospective observational study. J Crit Care. 2020;57 :118‐123.32109843\n3 Bhat T , Teli S , Bhat H , et al. Access‐site complications and their management during transradial cardiac catheterization. Expert Rev Cardiovasc Ther. 2012;10 :627‐634.22651838\n4 Nuttall G , Bruckhardt J , Hadley A , et al. Surgical and patient risk factors for severe arterial line complications in adults. Anesthesiology. 2016;124 :590‐597.26640979\n5 Garg K , Howell BW , Saltzberg SS , et al. Open surgical management of complications from indwelling radial artery catheters. J Vasc Surg. 2013;58 :1325‐1330.23810262\n6 Ganchi PA , Wilhelmi BJ , Fujita K , Lee WP . Ruptured pseudoaneurysm complicating an infected radial artery catheter: case report and review of the literature. Ann Plast Surg. 2001;46 :647‐650.11405368\n7 Varga Z , Flammer AJ , Steiger P , et al. Endothelial cell infection and endothelitis in COVID‐19. Lancet. 2020;395 :1417‐1418.32325026\n8 Savić D , Alsheikh TM , Kh AA , et al. Ruptured cerebral pseudoaneurysm in an adolescent as an early onset of COVID‐19 infection: case report. Acta Neurochir. 2020;162 (11 ):2725‐2729.32720013\n\n",
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"title": "Sudden rupture of small aneurysm of the radial artery in a patient with COVID-19 pneumonia.",
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"abstract": "Dialepsis is defined as a predominant alteration of consciousness with preservation of motor tone and the ability to perform movements. While dialepsis is a common feature of both focal and generalized epilepsies, its precise symptomatogenic zone and pathogenesis remain undefined. This case report describes a patient who underwent intracarotid amobarbital procedures before and after dominant hemisphere multiple hippocampal transections. From our observations, we propose a possible pathogenesis for the generation of dialeptic seizures.",
"affiliations": "University Hospitals, Case Medical Center, Department of Neurology, Epilepsy Division, 11100 Euclid Avenue, Lakeside 3200, Cleveland, OH, USA ; University of Kansas Medical Center, Department of Neurology, 3599 Rainbow Blvd, Kansas City, KS 66103, USA.;University Hospitals, Case Medical Center, Department of Neurosurgery, 11100 Euclid Avenue, Lakeside 3200, Cleveland, OH 44106, USA.;University Hospitals, Case Medical Center, Department of Neurology, Epilepsy Division, 11100 Euclid Avenue, Lakeside 3200, Cleveland, OH, USA.",
"authors": "Landazuri|Patrick|P|;Miller|Jonathan|J|;Lüders|Hans|H|",
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"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(14)00029-210.1016/j.ebcr.2014.05.003Case ReportA case report of a Wada test after dominant hemisphere multiple hippocampal transections: Pathophysiology of confusion after amobarbital injection Landazuri Patrick plandazuri@kumc.eduac⁎Miller Jonathan jonathan.miller@uhhospitals.orgbLüders Hans hans.luders@uhhospitals.orgaa University Hospitals, Case Medical Center, Department of Neurology, Epilepsy Division, 11100 Euclid Avenue, Lakeside 3200, Cleveland, OH, USAb University Hospitals, Case Medical Center, Department of Neurosurgery, 11100 Euclid Avenue, Lakeside 3200, Cleveland, OH 44106, USAc University of Kansas Medical Center, Department of Neurology, 3599 Rainbow Blvd, Kansas City, KS 66103, USA⁎ Corresponding author at: 3599 Rainbow Blvd, Kansas City, KS 66103, USA. Tel.: + 1 913 588 6970. plandazuri@kumc.edu14 6 2014 2014 14 6 2014 2 130 132 15 5 2014 16 5 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Dialepsis is defined as a predominant alteration of consciousness with preservation of motor tone and the ability to perform movements. While dialepsis is a common feature of both focal and generalized epilepsies, its precise symptomatogenic zone and pathogenesis remain undefined. This case report describes a patient who underwent intracarotid amobarbital procedures before and after dominant hemisphere multiple hippocampal transections. From our observations, we propose a possible pathogenesis for the generation of dialeptic seizures.\n\nKeywords\nSemiologySymptomatogenic zoneDialepsisWadaMultiple hippocampal transections\n==== Body\n1 Introduction\nThe dominant temporal lobe houses two important functions for human behavior: language and memory. Patients with left temporal epilepsy, nonatrophic hippocampi, and normal verbal memory have been shown frequently to experience a postoperative worsening of their verbal memories compared with patients with atrophic hippocampi and impaired verbal memories [1].\n\nBecause of possible deleterious consequences associated with surgery on this region, localization of language and memory is of paramount importance before temporal resection or multiple hippocampal transections (MHTs) are performed. The intracarotid amobarbital procedure (IAP, Wada test) was developed in 1949 by Juhn Wada to determine language lateralization and was later expanded to assess verbal memory lateralization [2]. It has previously been observed that amobarbital injections into the dominant hemisphere tend to produce a more significant alteration of consciousness (confusion) compared with injections into the nondominant hemisphere [3], [4], [5], although one study asserted the side of injection does not influence the level of consciousness [6]. It was further observed that if the dominant hemisphere was injected second, arousal could be additionally decreased as compared with injection of the dominant lobe first. This was thought to be due to a residual sedative effect within the contralateral hemisphere, thus eliciting some simultaneous functional disruption of both hemispheres [6].\n\nIn conclusion, there seems to be disagreement within the literature if loss of awareness (confusion) that can occur during IAP is due to selective inactivation of the dominant hippocampus or is due to bilateral inactivation of both hippocampi. In that context, we report a patient who had MHT of the left temporal lobe without alteration of consciousness or memory during presurgical IAP but had marked impairment of consciousness, perseverations, and no memory of events during amobarbital injection of the intact right hemisphere during post-MHT IAP. This observation strongly suggests that IAP-induced confusion is due to bilateral hippocampal inactivation.\n\n2 Case study\nA 45-year-old ambidextrous male presented with paroxysmal episodes. The episodes began abruptly with 10–20 s of déjà vu followed by an occipital, throbbing headache that sometimes spread throughout the head. Consciousness was lost if the pain was severe. His wife then described generalized body shaking lasting approximately 1 min followed by 1 min of complete unresponsiveness. Upon awakening, he was confused and had slurred speech. It took 30–60 min to return to his baseline. He has taken both topiramate and lamotrigine in the past. Topiramate was stopped because of cognitive side effects and lack of seizure control. At presentation, he was taking lamotrigine 600 mg daily but continued to have two episodes monthly.\n\nHe was admitted to our epilepsy monitoring unit for further work-up. He had one seizure that began with déjà vu, followed by slurred speech and difficulty following commands, and concluded with secondary generalization. Analysis of the EEG seizure pattern showed a rhythmic delta activity that began in the temporal leads (F7, T7, and P7). An MRI done during that admission suggested but was not definitive for left mesial temporal sclerosis (Fig. 1). He was diagnosed with left mesial temporal lobe epilepsy and was felt to be a good surgical candidate.\n\nHe underwent a preoperative IAP to characterize language and memory localizations. One hundred twenty-five milligrams of sodium amobarbital was injected in each carotid artery, the left carotid artery being injected first. Angiograms done to ensure proper placement of the catheter revealed no contralateral blood flow during dye injection. Approximately 30 min elapsed between amobarbital injections. Language was assessed by testing fluency and naming during the anesthetized state. Memory was assessed by testing spontaneous recall and cued object recognition of the words and pictures shown during and after the anesthetized state. It took 181 s for him to regain language capabilities after left carotid artery injection, but he maintained language capabilities throughout injection of the right carotid artery. He recognized 8/12 pictures and words shown after the amobarbital injection of both the right and left carotid arteries (Table 1). Therefore, he was determined to have left language lateralization and bilateral memory representation. Importantly, he maintained attention and had no perseverations or roving eye movements during the pre-MHT IAP.\n\nThe patient proceeded to invasive monitoring with depth electrodes. Invasive monitoring demonstrated an epileptogenic zone in the left hippocampus. In an attempt to minimize postsurgical memory deficits, left MHT along with a left anterior temporal lobectomy including amygdala resection was performed. Postoperative pathology did not demonstrate hippocampal sclerosis.\n\nAfter surgery, the patient initially did well but, unfortunately, relapsed and continued to have seizures, although at a decreased frequency as compared his presurgical state. Additional surgery was considered in order to provide higher probability of seizure freedom. Postoperative EEG demonstrated only focal left temporal slowing. Repeat MRI showed an absence of the left temporal pole and amygdala with significant atrophy of the transected left hippocampus (Fig. 1).\n\nA repeat IAP was done using the same protocol as used in the first procedure, including initial injection of the left carotid artery, except that a different set of pictures and words were used to minimize practice effect. Approximately 30 min again elapsed between amobarbital injections. It took 200 s for him to regain language capabilities after left carotid artery injection. He maintained language capabilities throughout injection of the right carotid artery. He recognized 5/12 and 8/12 pictures and words shown after amobarbital injection of the right carotid artery and the left carotid artery, respectively (Table 1). After right carotid injection, however, he became extremely drowsy and required continuous stimulation to maintain his attention to the IAP protocol words and pictures shown to him. His eyelids were physically held open, as he continuously tried to close them. His eyes moved in a roving fashion after right carotid injection. His verbal language capabilities were demonstrated as part of a striking perseveration, manifesting as continued counting in addition to the maintenance of his right arm up despite continued instruction to stop counting and lower his arm. The patient fully recovered in approximately 20 min after the injection and reported no memory of the speaking or motor perseveration.\n\nLastly, the patient described both word finding and memory difficulties postoperatively. Pre-MHT neuropsychology testing revealed that auditory memory scores were in the 42nd–50th percentile range, but post-MHT neuropsychology testing showed that auditory memory scores had now dropped to the 6th–23rd percentile range (Table 2).\n\n3 Discussion\nThis case report supports the hypothesis that alteration of awareness after amobarbital injection is the consequence of bilateral hippocampal dysfunction. Prior to surgical intervention, there was no decreased awareness after injection of either hemisphere. After surgical intervention that resulted in disrupted left hippocampal function, amobarbital injection into the dominant left hemisphere predictably produced no confusion. However, a striking loss of awareness with motor and language perseverations was observed after amobarbital injection of the nondominant right hemisphere. We hypothesize that the decrease in consciousness was caused by acute bilateral inactivation of both hippocampi: the intact, nondominant hippocampus temporarily anesthetized by amobarbital and the dominant hippocampus permanently lesioned with MHT. As he experienced no alteration in consciousness during pre-MHT IAP, we conclude that his epileptic, although nontransected, hippocampus was able to independently support maintenance of attention. After MHT, the iatrogenically dysfunctional left hippocampus was unable to support maintenance of attention independently, and the previously described confusion and perseveration occurred.\n\nDuring his acute confusion, our patient had no loss of muscle tone and retained the capacity for voluntary movement ipsilateral to the amobarbital injection. This state has similarity to dialepsis. Dialepsis is defined as a state where the predominant change is an alteration of consciousness with no or very limited motor manifestations [7]. There has not been a description for the dialepsis symptomatogenic zone in the literature. We hypothesize here that rather than one discrete area being responsible for dialepsis, dysfunction of multiple discrete areas (i.e., both hippocampi) is required to produce this clinical state. Our patient had significant difficulty in maintaining attention during amobarbital injection of his healthy right hippocampus. Even more tellingly, he had no memory of the considerable verbal perseveration or attention difficulties. The loss of short-term memory in our patient is reminiscent of patient H.M. and his well-known anterograde amnesia following bilateral temporal lobe resection [8].\n\nMultiple hippocampal transection has been reported as a procedure that possibly spares verbal memory [9]. However, the significant drop in memory seen after MHT, concordant with left hippocampus atrophy on post-MHT MRI, suggests that MHT produced significant hippocampal damage, at least in this case. Therefore, the transected hippocampus appears unable to maintain awareness or a normal level of consciousness independently after the right carotid amobarbital injection. Indeed, Rosadini and Rossi made a similar observation on a subset of patients on whom they performed the IAP. In their study subset, 12 patients in whom there was either contralateral brain damage or large collateral arterial circulation supplying both hemispheres had decreased level of consciousness during IAP [10].\n\n4 Conclusions\nIn summary, this case shows that acute bilateral hippocampus inactivation can produce dialepsis with relative unresponsiveness to external stimuli, perseverations, and amnesia for the events. This finding suggests that the symptomatogenic zone responsible for dialepsis is the bilateral inactivation of the hippocampi.\n\nFig. 1 Subpanel A is a representative preoperative coronal T2 section. Subpanel B is a representative postoperative coronal T2 section. Note should be made of the absence of the left temporal pole and hippocampal atrophy after patient's multiple hippocampal resections with accompanying temporal resection.\n\nTable 1 IAP results.\n\n\tLanguage lateralization\tLeft carotid artery spontaneous recall\tLeft carotid artery recognition\tRight carotid artery spontaneous recall\tRight carotid artery recognition\t\nPre-MHT IAP\tLeft\t1/12\t8/12\t0/12\t8/12\t\nPost-MHT IAP\tLeft\t1/12\t8/12\t0/12\t5/12\t\nTable 2 Auditory memory test results.\n\n\tAuditory immediate memory (%)\tAuditory delay memory (%)\tAuditory recognition delay (%)\t\nPre-MHT\t42%\t47%\t15%\t\nPost-MHT\t6%\t23%\t16%\n==== Refs\nReferences\n1 Trenerry M. Jack C.J. Ivnik R. Sharborough F.W. Cascino G.D. Hirschorn K.A. MRI hippocampal volumes and memory function before and after temporal lobectomy Neurology 43 1993 1800 1805 8414035 \n2 Sharan A. Ooi Y.C. Langfitt J. Sperling M.R. Intracarotid amobarbital procedure for epilepsy surgery Epilepsy Behav 20 2 Feb 2011 214 222 20850386 \n3 Meador K.J. Loring D.W. Lee G.P. Nichols M.E. Moore E.E. Figueroa R.E. Level of consciousness and memory during the intracarotid sodium amobarbital procedure Brain Cogn 33 2 Mar 1997 178 188 9073372 \n4 Glosser G. Cole L.C. Deutsch G.K. Donofrio N. Bagley L. Baltuch G. Hemispheric asymmetries in arousal affect outcome of the intracarotid amobarbital test Neurology 52 8 May 12 1999 1583 1590 10331682 \n5 Serafetinides E.A. Hoare R.D. Drive M.V. Intracarotid sodium amylobarbitone and cerebral dominance for consciousness Brain 88 1965 107 130 14282892 \n6 Malmgren K. Bilting M. Hagberg I. Hedström A. Silfvenius H. Starmark J.E. A compound score for estimating the influence of inattention and somnolence during the intracarotid amobarbital test Epilepsy Res 12 3 Sep 1992 253 259 1396550 \n7 Lüders H. Acharya J. Baumgartner C. Benbadis S. Bleasel A. Burgess R. Semiological seizure classification Epilepsia 39 9 Sep 1998 1006 1013 9738682 \n8 Scoville W.B. Milner B. Loss of recent memory after bilateral hippocampal lesions J Neurol Neurosurg Psychiatry 20 1 Feb 1957 11 21 13406589 \n9 Shimizu H. Kawai K. Sunaga S. Sugano H. Yamada T. Hippocampal transaction for treatment of left temporal lobe epilepsy with preservation of verbal memory J Clin Neurosci 13 3 Apr 2006 322 328 16517167 \n10 Rosadini G. Rossi G.F. On the suggested cerebral dominance for consciousness Brain 90 1 Mar 1967 101 112 6023069\n\n",
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"affiliations": "aDepartment of Internal Medicine bSection of Hematology and Oncology cSection of Cardiovascular Diseases, University of Oklahoma, Oklahoma City, Oklahoma, USA.",
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"abstract": "Liver transplant recipients are at risk for complications of vascular thrombosis. The reconstructed hepatic artery and portal vein thrombosis potentially result in hepatic failure and graft loss. Renal infarction is a rare clinical condition, but in severe cases, it may lead to renal failure. We herein report a case of renal infarction after living donor liver transplantation (LDLT) during anticoagulant therapy.\nA 60-year-old woman with end-stage liver disease due to primary biliary cholangitis underwent LDLT with splenectomy. Postoperatively, tacrolimus, mycophenolate mofetil, and steroid were used for initial immunosuppression therapy. On postoperative day (POD) 5, enhanced computed tomography (CT) revealed splenic vein thrombosis, and anticoagulant therapy with heparin followed by warfarin was given. Follow-up enhanced CT on POD 20 incidentally demonstrated right renal infarction. The patient's renal function was unchanged and the arterial flow was good, and the splenic vein thrombosis resolved. At 4 months postoperatively, warfarin was discontinued, but she developed recurrent splenic vein thrombosis 11 months later, and warfarin was resumed. As of 40 months after transplantation, she discontinued warfarin and remains well without recurrence of splenic vein thrombosis or renal infarction.\nRenal infarction is a rare complication of LDLT. In this case, renal infarction was incidentally diagnosed during anticoagulant therapy and was successfully treated.",
"affiliations": "Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.;Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.;Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.;Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.;Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.;Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Onda|Shinji|S|;Shiba|Hiroaki|H|;Takano|Yuki|Y|;Furukawa|Kenei|K|;Hata|Taigo|T|;Yanaga|Katsuhiko|K|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000488526crg-0012-0165Single CaseRenal Infarction during Anticoagulant Therapy after Living Donor Liver Transplantation Onda Shinji *Shiba Hiroaki Takano Yuki Furukawa Kenei Hata Taigo Yanaga Katsuhiko Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan*Shinji Onda, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishishimbashi, Minato-ku, Tokyo 105-8461 (Japan), E-Mail s-onda@jikei.ac.jpJan-Apr 2018 24 4 2018 24 4 2018 12 1 165 169 12 2 2018 14 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Introduction\nLiver transplant recipients are at risk for complications of vascular thrombosis. The reconstructed hepatic artery and portal vein thrombosis potentially result in hepatic failure and graft loss. Renal infarction is a rare clinical condition, but in severe cases, it may lead to renal failure. We herein report a case of renal infarction after living donor liver transplantation (LDLT) during anticoagulant therapy.\n\nCase Presentation\nA 60-year-old woman with end-stage liver disease due to primary biliary cholangitis underwent LDLT with splenectomy. Postoperatively, tacrolimus, mycophenolate mofetil, and steroid were used for initial immunosuppression therapy. On postoperative day (POD) 5, enhanced computed tomography (CT) revealed splenic vein thrombosis, and anticoagulant therapy with heparin followed by warfarin was given. Follow-up enhanced CT on POD 20 incidentally demonstrated right renal infarction. The patient's renal function was unchanged and the arterial flow was good, and the splenic vein thrombosis resolved. At 4 months postoperatively, warfarin was discontinued, but she developed recurrent splenic vein thrombosis 11 months later, and warfarin was resumed. As of 40 months after transplantation, she discontinued warfarin and remains well without recurrence of splenic vein thrombosis or renal infarction.\n\nConclusion\nRenal infarction is a rare complication of LDLT. In this case, renal infarction was incidentally diagnosed during anticoagulant therapy and was successfully treated.\n\nKeywords\nRenal infarctionLiving donor liver transplantationAnticoagulant therapy\n==== Body\nIntroduction\nLiver transplant recipients are at risk for various postoperative complications. One of the most important complications is vascular thrombosis of the reconstructed hepatic artery and portal vein, which potentially results in hepatic failure and graft loss [1, 2, 3]. Several other thromboembolic complications may occur, such as pulmonary emboli, intracardiac thrombosis, and peripheral arterial thrombosis [4, 5]. Renal infarction is a rare clinical condition most commonly occurring in patients with predisposing risk factors. In severe cases, it may lead to renal failure, but small infarction is often asymptomatic and is incidentally detected by computed tomography (CT). The recent development of imaging modalities has increased the detection rate of renal infarction and several cases have been reported in the English literature [6, 7]. However, to our knowledge, renal infarction after liver transplantation has not been reported. We herein report a case of acute renal infarction incidentally detected on CT in a patient on anticoagulant for splenic vein thrombosis after living donor liver transplantation (LDLT) with concomitant splenectomy.\n\nCase Presentation\nA 60-year-old woman with end-stage liver disease due to primary biliary cholangitis was admitted to our hospital to undergo LDLT. The patient was diagnosed with primary biliary cholangitis by liver biopsy at 50 years of age and started on treatment with ursodeoxycholic acid 900 mg/day. Two years before transplantation, she suffered from rupture of esophageal varices and underwent endoscopic variceal ligation. After treatment of esophageal varices, she developed massive ascites refractory to diuretics with furosemide, spironolactone, and trichlormethiazide. Prior to transplantation, she had chronic kidney disease of unknown cause but without a history of diabetes, thromboembolic diseases, or cardiovascular diseases including hypertension, arrhythmia, coronary artery disease, and aortic aneurysm/dissection. Preoperative hemoglobin was 8.8 g/dL, platelet count was 75,000/μL, prothrombin time-international normalized ratio (PT-INR) was 1.1, and serum creatinine was 1.26 mg/dL. Child-Pugh score was 8 and Model for End-Stage Liver Disease score was 11. She underwent LDLT and splenectomy using a left lobe graft of her ABO-compatible husband. The resected liver and spleen weights were 1,000 and 420 g, respectively. The actual graft weight was 456 g, which accounted for 45.7% of the standard liver volume of the recipient. The operation time was 705 min. Intraoperative blood loss was 1,750 mL, and 4 units of red blood cells and 5 units of fresh frozen plasm were transfused. Postoperatively, tacrolimus, mycophenolate mofetil, and steroids were used as initial immunosuppression therapy. Continuous intravenous prostaglandin E1 and nafamostat mesilate were administered for 5 and 2 days after transplantation, respectively. Antithrombin III (AT-III) concentrate was administered in order to maintain the AT-III level over 70%. On postoperative day (POD) 5, enhanced CT revealed splenic vein thrombosis (Fig. 1a), for which anticoagulation therapy with intravenous heparin was started with a target APTT of 40–60 s. Follow-up enhanced CT on POD 11 showed hemorrhage in the right renal cyst, but no evidence of renal infarction. On POD 16, warfarin was started to maintain PT-INR between 1.5 and 2.5, and intravenous heparin was discontinued once PT-INR had become therapeutic (Fig. 2). However, enhanced CT on POD 20 incidentally demonstrated right renal infarction (Fig. 1b). She denied any abdominal pain, nausea, or vomiting. Her urinalysis showed no proteinuria or hematuria, and renal function was unchanged. The serum levels of AST, LDH, and CPK were not elevated, and PT-INR, APTT, and AT-III were 1.2, 44 s, and 79%, respectively. Echocardiography showed no vegetation. Doppler ultrasound on POD 27 demonstrated a normal flow pattern of the renal artery. She remained asymptomatic with no serious complications and was discharged on POD 36. Renal scintigraphy on POD 50 demonstrated normal flow and function of kidneys. Warfarin was continued for 4 months and then discontinued. However, at 11 months after transplantation, she developed recurrent splenic vein thrombosis and then warfarin was resumed, which was continued for another 12 months and the thrombus resolved, and it was then discontinued thereafter. As of 36 months after transplant, she remains well without recurrence of splenic vein thrombosis or renal infarction.\n\nDiscussion\nRenal infarction is a rare condition, with an estimated incidence of 0.007% [6]. The two major causes of renal infarction are thromboemboli, which usually originate from thrombi in the heart or aorta, and in situ thrombosis, which may cause complete occlusion of the main renal artery or a segmental branch artery [8, 9]. The risk factors for renal infarction include atrial fibrillation, valvular or ischemic heart disease, endocarditis, hypercoagulable state, hematologic disease, and spontaneous renal artery dissection [6, 7, 10].\n\nThromboembolism during and after liver transplantation has a complex etiology and the initiation of a procoagulative process may be triggered by abnormal thrombin generation and platelet function, along with a lack of efficacy of the profibrinolytic system. Secondary to cirrhosis, pro- and anticoagulants make up an unstable balance, and several factors inherent to the procedure of transplantation can promote a hypercoagulable state [11]. Various transplantation-related triggers, such as surgical damage, the release of activators from the donor liver, stagnation of blood, and systemic inflammatory responses can activate coagulation or induce platelet activation. When a hemostatic balance is disturbed, thrombus may form at the anastomotic site, such as the hepatic artery and portal vein, or systemic thrombosis may develop. Peripheral arterial thrombosis is rare, and renal infarction after liver transplantation has not been reported in the English literature.\n\nIn the presented case, small asymptomatic renal infarction was diagnosed by CT on POD 20 during anticoagulant therapy in therapeutic range, and there was no other peripheral arterial thrombosis. The cause of renal infarction in this case was unclear.\n\nSince the postoperative anticoagulant and/or antiplatelet prophylaxis may reduce the risk of reconstructed vascular thrombosis [12, 13, 14], several liver transplant centers provide prophylactic pharmacological therapy during the early period after liver transplantation. However, because of the lack of studies and guidelines on anticoagulant and antiplatelet prophylaxis and risk of post-transplant hemorrhage, prophylactic anticoagulant and antiplatelet therapy after liver transplantation in adults are not routinely performed, provided that follow-up of hepatic blood flow using Doppler ultrasonography and blood profile is performed.\n\nIn conclusion, renal infarction is a rare complication of LDLT, but potentially severe condition. In the case, renal infarction was incidentally diagnosed during anticoagulant therapy and was successfully treated.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors declare that they have no conflicts of interest.\n\nFig. 1. Enhanced computed tomography revealed splenic vein thrombosis on postoperative day 5 (a; arrow). Right renal infarction was identified on postoperative day 20 (b; arrowhead).\n\nFig. 2. The clinical course of the patient after liver transplantation. Anticoagulant therapy with heparin was started on postoperative day 5 and warfarin was started on postoperative day 16 to maintain a therapeutic prothrombin time-international normalized ratio (PT-INR) between 1.5 and 2.5. NM, nafamostat mesilate.\n==== Refs\nReferences\n1 Feltracco P Barbieri S Cillo U Zanus G Senzolo M Ori C Perioperative thrombotic complications in liver transplantation. World J Gastroenterol. 2015 7 21 (26) 8004 8013 26185371 \n2 Algarni AA Mourad MM Bramhall SR Anticoagulation and antiplatelets as prophylaxis for hepatic artery thrombosis after liver transplantation. World J Hepatol. 2015 5 7 (9) 1238 1243 26019738 \n3 Duffy JP Hong JC Farmer DG Ghobrial RM Yersiz H Hiatt JR Vascular complications of orthotopic liver transplantation: experience in more than 4,200 patients. J Am Coll Surg. 2009 5 208 (5) 896 903 19476857 \n4 Emuakhagbon V Philips P Agopian V Kaldas FM Jones CM Incidence and risk factors for deep venous thrombosis and pulmonary embolus after liver transplantation. Am J Surg. 2016 4 211 (4) 768 771 26852631 \n5 Sakai T Matsusaki T Dai F Tanaka KA Donaldson JB Hilmi IA Pulmonary thromboembolism during adult liver transplantation: incidence, clinical presentation, outcome, risk factors, and diagnostic predictors. Br J Anaesth. 2012 3 108 (3) 469 477 22174347 \n6 Korzets Z Plotkin E Bernheim J Zissin R The clinical spectrum of acute renal infarction. Isr Med Assoc J. 2002 10 4 (10) 781 784 12389340 \n7 Hazanov N Somin M Attali M Beilinson N Thaler M Mouallem M Acute renal embolism. Forty-four cases of renal infarction in patients with atrial fibrillation. Medicine (Baltimore). 2004 9 83 (5) 292 299 15342973 \n8 Bourgault M Grimbert P Verret C Pourrat J Herody M Halimi JM Acute renal infarction: a case series. Clin J Am Soc Nephrol. 2013 3 8 (3) 392 398 23204242 \n9 Paris B Bobrie G Rossignol P Le Coz S Chedid A Plouin PF Blood pressure and renal outcomes in patients with kidney infarction and hypertension. J Hypertens. 2006 8 24 (8) 1649 1654 16877969 \n10 Oh YK Yang CW Kim YL Kang SW Park CW Kim YS Clinical characteristics and outcomes of renal infarction. Am J Kidney Dis. 2016 2 67 (2) 243 250 26545635 \n11 Lisman T Caldwell SH Burroughs AK Northup PG Senzolo M Stravitz RT Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol. 2010 8 53 2 362 371 20546962 \n12 Vivarelli M La Barba G Cucchetti A Lauro A Del Gaudio M Ravaioli M Can antiplatelet prophylaxis reduce the incidence of hepatic artery thrombosis after liver transplantation? Liver Transpl. 2007 5 13 (5) 651 654 17457885 \n13 Shay R Taber D Pilch N Meadows H Tischer S McGillicuddy J Early aspirin therapy may reduce hepatic artery thrombosis in liver transplantation. Transplant Proc. 2013 Jan-Feb 45 (1) 330 334 23267805 \n14 Kaneko J Sugawara Y Tamura S Togashi J Matsui Y Akamatsu N Coagulation and fibrinolytic profiles and appropriate use of heparin after living-donor liver transplantation. Clin Transplant. 2005 12 19 (6) 804 809 16313329\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "12(1)",
"journal": "Case reports in gastroenterology",
"keywords": "Anticoagulant therapy; Living donor liver transplantation; Renal infarction",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "165-169",
"pmc": null,
"pmid": "29805361",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26852631;26545635;23204242;26019738;16313329;12389340;15342973;16877969;23267805;26185371;20546962;19476857;17457885;22174347",
"title": "Renal Infarction during Anticoagulant Therapy after Living Donor Liver Transplantation.",
"title_normalized": "renal infarction during anticoagulant therapy after living donor liver transplantation"
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"abstract": "Disseminated histoplasmosis is a life-threatening disease usually seen in immunocompromised patients living in endemic areas. We present an apparently immunocompetent patient with gastrointestinal histoplasmosis who was initially diagnosed with biopsy-proven Crohn's disease. Following discontinuation of anti-inflammatory drugs and institution of antifungal therapy, his gastrointestinal illness completely improved. Specific fungal staining should be routinely included in histopathologic assessment of tissue specimens diagnosed as Crohn's disease.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.;Department of Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada.;Department of Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada.;Division of Gastroenterology, Department of Medicine, Schulich School of Medicine & Dentistry, London Health Sciences Centre, Western University, London, Ontario, Canada.;Division of Infectious Diseases, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.;Division of Infectious Diseases, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.",
"authors": "Shojaei|Esfandiar|E|https://orcid.org/0000-0002-4640-2561;Walsh|Joanna C|JC|;Sangle|Nikhil|N|;Yan|Brian|B|;Silverman|Michael S|MS|;Hosseini-Moghaddam|Seyed M|SM|https://orcid.org/0000-0001-7979-2458",
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"doi": "10.1093/ofid/ofab249",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957\nOxford University Press US\n\n10.1093/ofid/ofab249\nofab249\nID Teaching Cases\nAcademicSubjects/MED00290\nGastrointestinal Histoplasmosis Mimicking Crohn’s Disease\nhttps://orcid.org/0000-0002-4640-2561\nShojaei Esfandiar 1\nWalsh Joanna C 2\nSangle Nikhil 2\nYan Brian 3\nSilverman Michael S 14\nhttps://orcid.org/0000-0001-7979-2458\nHosseini-Moghaddam Seyed M 15\n1 Division of Infectious Diseases, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada\n2 Department of Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada\n3 Division of Gastroenterology, Department of Medicine, Schulich School of Medicine & Dentistry, London Health Sciences Centre, Western University, London, Ontario, Canada\n4 Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada\n5 Division of Infectious Diseases, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada\nCorrespondence: Seyed M. Hosseini-Moghaddam, MD, MPH, MSc, Toronto General Hospital, University Health Network, University of Toronto 200 Elizabeth St., Toronto ON Canada, M5G 2C4 (sasan.hosseini@uhn.ca).\n7 2021\n16 5 2021\n16 5 2021\n8 7 ofab24910 3 2021\n11 5 2021\n13 5 2021\n12 7 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nDisseminated histoplasmosis is a life-threatening disease usually seen in immunocompromised patients living in endemic areas. We present an apparently immunocompetent patient with gastrointestinal histoplasmosis who was initially diagnosed with biopsy-proven Crohn’s disease. Following discontinuation of anti-inflammatory drugs and institution of antifungal therapy, his gastrointestinal illness completely improved. Specific fungal staining should be routinely included in histopathologic assessment of tissue specimens diagnosed as Crohn’s disease.\n\nalcoholism\ngastrointestinal histoplasmosis\ninflammatory bowel disease\n==== Body\nHistoplasmosis is a mycotic infection caused by Histoplasma capsulatum. Immunocompetent patients usually remain asymptomatic or develop mild illness. In such patients, histoplasmosis is rarely diagnosed as a disseminated fungal infection [1]. Clinical manifestations of disseminated histoplasmosis (DH) vary depending on the host’s immune status and severity of exposure. Autopsy series showed gastrointestinal (GI) involvement in 70% of patients with DH, while only 3%–12% of patients were symptomatic [2]. GI lesions range from patchy and superficial ulcerations to deep and mass-like lesions similar to inflammatory bowel disease (IBD), mycobacterial infection, or intestinal neoplasia [3]. In patients with DH, the terminal ileum and colon are commonly involved, and patients may present with fever, diarrhea, gastrointestinal bleeding, or abdominal pain [4].\n\nWe report a patient with DH presenting with a tonsillar mass. He was on anti-inflammatory therapy due to underlying biopsy-proven Crohn’s disease. Following discontinuation of immunosuppressive agents and appropriate antifungal treatment, his GI illness improved. Histopathologic reevaluation of initial GI specimens using specific fungal staining (ie, GMS and PAS-D) revealed GI histoplasmosis (GIH) associated with gastric involvement. This report from a low-prevalence area shows that clinical manifestations, endoscopic features, and even histopathologic findings of GIH can masquerade as Crohn’s disease. Careful exclusion of infectious etiologies is required even in patients with “biopsy-proven” Crohn’s disease before immunosuppressive therapy.\n\nCASE PRESENTATION\n\nA 78-year-old male patient was referred to Internal Medicine due to dysphagia. He also complained of severe constipation and 9-kg weight loss over the past 3 months. He denied fever, chills, or night sweats. He was born in Scotland and moved to London, Ontario, Canada, at age 14. He had no travel history to hyperendemic areas. He was a retired butcher with a history of drinking 3–4 beers per day for >40 years and had a 60-pack-year smoking history. He had no history of alcoholic liver disease or other medical illnesses.\n\nHis physical examination was unremarkable. Abdominal computed tomography (CT) scan did not reveal any significant abnormality. He underwent a colonoscopy that demonstrated aphthous ulcerations involving the terminal ileum, cecum, and ascending colon (Figure 1A, B). Histopathologic findings included patchy lesions, chronic active proctocolitis with scattered histiocytic aggregates, and occasional non-necrotizing granulomas (Figure 2A–C). Upper GI endoscopy also showed multiple shallow aphthous ulcers involving the gastric antrum and body. Histopathologic features of gastric biopsies included diffuse, chronic active gastritis with granulomatous inflammation consistent with Crohn’s disease involving the upper GI tract.\n\nFigure 1. Endoscopy of the ascending colon (A) and cecum (B) demonstrating erosion and ulceration.\n\nFigure 2. A, Hematoxylin and eosin–stained section of the colonic biopsy reveals diffuse cellular infiltrate within the lamina propria (×100). B, Higher magnification of the biopsy (×200) shows an ill-defined noncaseating epithelioid cell granuloma (yellow circle). C, In other areas of the same section (×200), there were few multinucleated giant cells (yellow arrow). D, Special stain, Grocott-Gomori’s Methenamine Silver–Fungal, highlights several yeast forms of histoplasmosis scattered throughout the lamina propria (×400; yellow arrow).\n\nThe patient was diagnosed with Crohn’s disease based on clinical presentation, endoscopic features, and histopathology. Initial treatment included corticosteroids followed by methotrexate (25 mg per week). During treatment, his symptoms improved, and he gained weight. Two months later, he was readmitted with persistent sore throat, dry cough, dysphagia, and odynophagia associated with progressive right-sided otalgia radiating to the mandibular angle. On chest examination, bilateral coarse crackles were present. Nasopharyngeal endoscopy revealed a tonsillar mass that extended to the glossal fold. A neck CT scan showed a significant tonsillar enhancement. A chest CT scan also demonstrated a diffuse parenchymal tree-in-bud nodularity, prominently in the upper lobes.\n\nHis laboratory data were as follows: white blood cells = 6400 (per mm3), hemoglobin = 11.1 g/dL, platelets = 248 000/µL, mean corpuscular volume = 98.7 FL, alanine transaminase = 11 U/L, aspartate transaminase = 23 U/L, alkaline phosphatase = 92 U/L, gamma-glutamyl transferase = 40 U/L, C-reactive protein = 55.4 mg/L, and serum ferritin = 977 ng/mL. The tonsillar mass biopsy revealed prominent submucosal ulcers, mixed acute and chronic histiocytic granulomatous inflammation associated with multiple small, oval budding yeasts. Tonsillar tissue (formalin-fixed paraffin-embedded [FFPE] specimen) polymerase chain reaction (PCR; end-point PCR using pan-fungus primers targeting ribosomal RNA genes and internal transcribed spacer [ITS] sequence) confirmed Histoplasma capsulatum. In serologic assays at Public Health Laboratory-Toronto, a complement fixation (CF) test was nonreactive (titer < 1:2), while immunodiffusion (ID) assay was reactive including H and M precipitin bands. A Histoplasma antigen assay was ordered by the Infectious Diseases service; however, this test was canceled at the Microbiology Lab due to the cost associated with this assay. Grocott-Gomori’s Methenamine Silver (GMS) staining of endobronchial non-necrotizing histiocytic granulomas showed intracellular budding yeasts. H. capsulatum was isolated from bronchoalveolar lavage (BAL) culture.\n\nWe discontinued his immunosuppressive therapy including prednisone and methotrexate. He received a 2-week course of treatment with liposomal amphotericin B (250 mg intravenously q24h), which was subsequently transitioned to oral itraconazole (200 mg orally twice a day). He continued antifungal therapy for a total of 1 year and remained under close clinical follow-up. His gastrointestinal illness gradually improved while he was off immunosuppressive therapy. He again underwent upper and lower GI endoscopies following a complete course of antifungal treatment, which demonstrated mucosal healing associated with no evidence of inflammatory bowel disease in histopathologic assessment of biopsy specimens.\n\nDue to complete resolution of his GI symptoms with antifungal therapy, we requested reassessment of the original GI biopsy specimens using standard histological stains for fungi. Re-examination of initial gastric and colonic tissue samples using GMS staining demonstrated yeast morphologically compatible with H. capsulatum (Figure 2 D).\n\nFigure 3 provides the timeline of different diagnostic tests.\n\nFigure 3. The timeline of different diagnostic tests. Abbreviations: BAL, bronchoalveolar lavage; GI, gastrointestinal; GIH, GI histoplasmosis; PCR, polymerase chain reaction.\n\nDISCUSSION AND CONCLUSIONS\n\nIn this study, we presented an apparently immunocompetent patient who was diagnosed with Crohn’s disease based on clinical presentation, endoscopic features, and histopathologic findings. Following immunosuppressive therapy, he developed a tonsillar mass and subsequently progressive pneumonia. H. capsulatum was isolated from his BAL culture. The diagnosis of histoplasmosis was subsequently supported by tissue PCR and Histoplasma serologic tests. Re-evaluation of his initial GI specimens with specific fungal staining revealed GI histoplasmosis. After a complete course of antifungal treatment, his GI symptoms resolved. The findings of this Teaching Case show that GIH can mimic all clinical, laboratory, endoscopic, and even histopathologic features of Crohn’s disease.\n\nIn patients with GIH, any part of the GI system from mouth to anus may be involved [2]. The most commonly involved sites are the colon and ileum [5]. GIH symptoms such as diarrhea, abdominal pain, and weight loss are nonspecific. Presence of fever is variable [4]. Thus, infectious etiologies may not be considered in differential diagnosis.\n\nThis patient initially presented with a rare manifestation of disseminated histoplasmosis. The gastric involvement that was confirmed in this Teaching Case has only been reported in 4% of autopsy series [2]. A high index of suspicion is required to diagnose GIH in patients with GI ulceration associated with a variable symptom complex of undetermined etiology. A delayed diagnosis is likely associated with fatal outcome due to progressive and invasive fungal infection [6].\n\nInterestingly, this patient did not initially present with fever or symptoms suggesting pneumonia. Following immunosuppressive therapy for the management of Crohn’s disease, he developed respiratory symptoms, and H. capsulatum was isolated from his BAL specimens. Although his GI symptoms improved with corticosteroid therapy, he experienced progressive illness associated with a tonsillar mass and pneumonia. Thus, a transient improvement of symptoms during immunosuppressive therapy does not rule out infectious etiologies.\n\nThis patient did not have a history of travel to hyperendemic areas. The province of Ontario, Canada, can be considered an endemic region (ie, 7.5 cases per year) [7]. The geographic range of infection with Histoplasma spp. has been shown to be extended in recent epidemiological and genomic data from Canada [8, 9]. The area that appears to be at geographical risk for histoplasmosis includes the river valleys of the central and eastern United States, extending to the southern regions of Ontario and Quebec in Canada [9, 10]. Thus, histoplasmosis should be considered in the differential diagnosis of inflammatory bowel disease in patients residing in Ontario [10–12]. Lack of travel history to hyperendemic areas might be misleading. Over 270 000 Canadians currently live with IBD, and forecasting models predict an increasing trend of IBD in Canada [13]. Although specific fungal staining is not routine in histopathologic assessment of tissue specimens diagnosed as IBD, fungal staining seems to be required to prevent misdiagnosis.\n\nCareful exclusion of infectious etiologies is required even in patients with “biopsy-proven” Crohn’s disease before immunosuppressive therapy. Lack of diagnosis and treatment with immunosuppressive agents may cause life-threatening complications. A relatively short course of immunosuppressive therapy in this patient caused a progressive illness associated with invasive multiorgan involvement. Table 1 provides a list of infectious diseases that should be excluded in patients diagnosed as IBD.\n\nTable 1. Infectious Etiologies That May Mimic Crohn’s Disease\n\nInfectious Etiologiesa\tGastrointestinal Involvement Site\tRoutine Staining\t\nBacterial\t\tHematoxylin and eosin\t\n E. coli, O157-H7 [27]\tColon\t\t\n Shigella spp. [28]\tColon\t\t\n Salmonella spp. [29]\tColon, terminal ileum\t\t\n Campylobacter spp. [30]\tColon, terminal ileum\t\t\n Yersinia enterocolitica [31]\tColon, terminal ileum\t\t\n Clostridioides difficile [32]\tColon\t\t\n Neisseria gonorrhoeae [33]\tColorectal\t\t\n Treponema pallidum [34]\tColorectal\t\t\n Chlamydia trachomatis [35]\tColorectal\t\t\n Aeromonas spp. [36]\tColon\t\t\n Mycobacterium tuberculosis [37]\tAny part of GI tract, mostly terminal ileum\t\t\nFungal\t\t\t\n Cryptococcus spp. [38]\tTerminal ileum\t\t\n Histoplasma capsulatum [39]\tTerminal ileum\t\t\n Coccidioides spp. [40]\tColon\t\t\n Paracoccidioides spp. [41]\tColorectal\t\t\nViral\t\t\t\n Cytomegalovirus [42]\tJejunoileal\t\t\n Herpes simplex [43]\tColorectal\t\t\nParasite\t\t\t\n Entamoeba histolytica [44]\tColon\t\t\n Enterobius vermicularis [45]\tColorectal\t\t\n Taenia saginata [46]\tIleum\t\t\n Strongyloides stercoralis [47]\tColon\t\t\n Anisakis spp. [48]\tIleum\t\t\n Hookworm (Ancylostoma duodenale and Necator americanus) [49]\tJejunoileal\t\t\nAbbreviations: GI, gastrointestinal; H&E, hematoxylin and eosin; IHC, immunohistochemistry.\n\naDifferent staining methods are typically used for diagnosis of infectious etiologies:\n\n•Bacterial: hematoxylin and eosin, gram stains [50].\n\n•Fungal: Grocott-Gomori’s Methenamine Silver or periodic acid-Schiff stains. The addition of the enzyme diastase reduces the potential of confounding findings caused by the presence of glycogen [51]. Fungal pathogens can be also detected by H&E.\n\n•Viral: immunohistochemical staining.\n\n•Parasites: Giemsa, H&E, IHC. The diagnosis of many parasitic infections is typically made by serology and stool examination [52].\n\nTests for Histoplasma antigen in urine or serum are routinely performed in patients with disseminated histoplasmosis [14]. Histoplasma antigen was detected in the urine of ~95% of immunocompromised patients with disseminated histoplasmosis [15]. However, antigen testing is not widely available outside the United States [16]. Lack of antigen assay was a limitation in this Teaching Case; however, the diagnosis of histoplasmosis was proven by culture. This diagnosis was also supported by tissue PCR and serology. Although Histoplasma antigen assay was ordered by the Infectious Diseases service, it was canceled at the Microbiology Lab due to the cost associated with the test. Histoplasma antigen assay is not routinely done at London Health Sciences Centre, and all specimens are regularly shipped to the United States. Recent enzyme immunoassay (EIA) methods using analyte-specific reagents (ASRs) for detection of Histoplasma galactomannan, quantitative EIA, and lateral flow assay are reliable rapid tests that could be considered for timely diagnosis of histoplasmosis in endemic areas [17, 18].\n\nAntibodies to H. capsulatum become detectable 4 to 8 weeks after acute infection; therefore, serologic tests are important diagnostic tools for patients with chronic pulmonary or disseminated histoplasmosis [14]. There are currently 3 methods to detect H. capsulatum–specific antibodies: complement fixation (CF), immunodiffusion (ID), and EIA. The standard serologic tests for histoplasmosis include CF and ID assay [19]. The ID assay is more sensitive than CF testing. Expectedly, this patient had a positive ID assay including both the M and H bands. The M band develops with acute infection and may persist for years after clinical improvement. However, the H band is seen most often in patients with chronic, disseminated, and progressive histoplasmosis [19]. CF, using yeast antigen, is the most sensitive serologic assay, while ID assay is a more specific test. CF testing was nonreactive in this Teaching Case [15, 17]. Immunosupressive therapy following diangosis of Crohn’s disease may explain the nonreactive CF test result [14, 20]. Other factors such as the type of antigen used for fixation of complement, blocking effects of rheumatoid factor, and cold agglutinins that may develop during histoplasmosis can affect CF performance [20, 21].\n\nOur patient was not receiving immunosuppressive medications at the time of initial presentation; however, he had a history of chronic alcoholism. Different aspects of the immune system may be affected by alcoholism, causing susceptibility to infection with fungal pathogens [22–25]. Underlying alcoholism could be a contributing factor to disseminated histoplasmosis in an apparently healthy individual [26]. Thus, the patient we present in this study seems to have been at an increased risk of histoplasmosis.\n\nIn summary, this Teaching Case highlights the similarities between IBD and GIH in terms of clinical presentation, endoscopic features, and histopathologic findings. Fungal staining of tissue specimens when evaluating patients for Crohn’s disease even in areas where histoplasmosis is not considered endemic will prevent misdiagnosis. Communication between clinicians and pathologists is crucially important before initiating immunosuppression.\n\nAcknowledgments\n\nFinancial support. No funding was received for this case report.\n\nPotential conflicts of interest. There are no conflicts of interest. 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\nAuthor contributions. S.M., E.S., J.C.W., B.Y., M.S., and N.S. collected the patient data and participated in the treatment. S.M. and E.S. wrote the manuscript. S.M., E.S., J.C.W., N.S., B.Y., and M.S. revised and edited the manuscript. B.Y. performed the gastrointestinal endoscopy. All authors read and approved the final manuscript.\n\nPatient consent. The patient’s written consent was obtained. The design of the work conforms to standards currently applied in Canada. Ethics approval is not needed for Case Reports according to our local Research Ethics Board.\n\nAvailability of data. All data generated during this study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n1. Assi MA , SandidMS, BaddourLM, et al. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007; 86 :162–9.17505255\n2. Kahi CJ , WheatLJ, AllenSD, SarosiGA. Gastrointestinal histoplasmosis. Am J Gastroenterol 2005; 100 :220–31.15654803\n3. Romano RC , SoapeMM, ThirumalaS, GhandourE. Disseminated histoplasmosis mimicking metastatic disease of the colon and omentum: report of a case and literature review. Arab J Gastroenterol 2015; 16 :66–8.26210870\n4. Psarros G , KauffmanCA. Colonic histoplasmosis: a difficult diagnostic problem. Gastroenterol Hepatol (N Y) 2007; 3 :461–3.23329906\n5. Ai XB , WangZJ, DongQC, et al. Ileum histoplasmosis mimicking intestinal tuberculosis and Crohn’s disease. Case Rep Gastroenterol 2018; 12 :63–8.29515346\n6. Hage CA , BowyerS, TarvinSE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis 2010; 50 :85–92.19951231\n7. Ashraf N , KubatRC, PoplinV, et al. Re-drawing the maps for endemic mycoses. Mycopathologia 2020; 185:843–65.\n8. Dingle TC , CroxenMA, FathimaS, et al. Histoplasmosis acquired in Alberta, Canada: an epidemiological and genomic study. Lancet Microbe 2021; 2:E191–7 .\n9. Dufresne SF , ColeDC, DenningDW, SheppardDC. Serious fungal infections in Canada. Eur J Clin Microbiol Infect Dis 2017; 36 :987–92.28161745\n10. Brown EM , McTaggartLR, DunnD, et al. Epidemiology and geographic distribution of blastomycosis, histoplasmosis, and coccidioidomycosis, Ontario, Canada, 1990–2015. Emerg Infect Dis 2018; 24 :1257–66.29912691\n11. Hosseini‐Moghaddam SM , OuédraogoA, NaylorKL, et al. Incidence and outcomes of invasive fungal infection among solid organ transplant recipients: a population‐based cohort study. Transpl Infect Dis 2020; 22 :e13250. 31981389\n12. Jansson-Knodell C , MoorsC, LoftusEVJr, WalkerR, EnzlerM, VirkA. Histoplasmosis in inflammatory bowel disease patients on tumor necrosis factor-a medications. Am J Gastroenterol 2018; 113 :S379.\n13. Rocchi A , BenchimolEI, BernsteinCN, et al. Inflammatory bowel disease: a Canadian burden of illness review. Can J Gastroenterol 2012; 26 :811–7.23166905\n14. Guimarães AJ , NosanchukJD, Zancopé-OliveiraRM. Diagnosis of histoplasmosis. Braz J Microbiol 2006; 37 :1–13.20445761\n15. Hage CA , RibesJA, WengenackNL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011; 53 :448–54.21810734\n16. Zhang X , GibsonBJr, DalyTM. Evaluation of commercially available reagents for diagnosis of histoplasmosis infection in immunocompromised patients. J Clin Microbiol 2013; 51 :4095–101.24088857\n17. Theel ES , HarringJA, DababnehAS, et al. Reevaluation of commercial reagents for detection of Histoplasma capsulatum antigen in urine. J Clin Microbiol 2015; 53 :1198–203.25631806\n18. Cáceres DH , GómezBL, TobónAM, ChillerTM, LindsleyMD. Evaluation of a Histoplasma antigen lateral flow assay for the rapid diagnosis of progressive disseminated histoplasmosis in Colombian patients with AIDS. Mycoses 2020; 63 :139–44.31625627\n19. Azar MM , LoydJL, RelichRF, WheatLJ, HageCA. Current concepts in the epidemiology, diagnosis, and management of histoplasmosis syndromes. Semin Respir Crit Care Med 2020; 41 :13–30.32000281\n20. Richer SM , SmedemaML, DurkinMM, et al. Improved diagnosis of acute pulmonary histoplasmosis by combining antigen and antibody detection. Clin Infect Dis 2016; 62 :896–902.26797210\n21. Arango-Bustamante K , RestrepoA, CanoLE, et al. Diagnostic value of culture and serological tests in the diagnosis of histoplasmosis in HIV and non-HIV Colombian patients. Am J Trop Med Hyg 2013; 89 :937–42.24043688\n22. Molina PE , HappelKI, ZhangP, KollsJK, NelsonS. Focus on: alcohol and the immune system. Alcohol Res Heal 2010; 33 :97–108.\n23. De la Rosa DN , NakandakariMD, Gutiérrez-GutiérrezJ, Bryson-MalcaW. Disseminated pulmonary histoplasmosis with multiple cutaneous lesions: case report and literature review. Rev Médica del Hosp Gen México 2017; 80 :170–3.\n24. García-Marrón M , García-GarcíaJM, Pajín-ColladaM, Alvarez-NavascuésF, Martínez-MuñizMA, Sanchez-AntunaAA. Chronic pulmonary histoplasmosis diagnosed in a nonimmunosuppressed patient 10 years after returning from an endemic area. Arch Bronconeumol 2008; 44 :567–70. 19006637\n25. Capone D , WankeB, MonteiroPC, et al. Chronic pulmonary histoplasmosis in the State of Rio de Janeiro, Brazil. Mycopathologia 1999; 145 :75–79. 10598067\n26. Turashvili G , CunninghamKS. Bilateral adrenal histoplasmosis in a man with chronic alcoholism. J Microbiol Immunol Infect 2016; 49 :797–8.25908247\n27. Ilnyckyj A , GreenbergH, BernsteinCN. Escherichia coli O157:H7 infection mimicking Crohn’s disease. Gastroenterology 1997; 112 :995–9.9041263\n28. Lin WC , ChangCW, ChenMJ, et al. Challenges in the diagnosis of ulcerative colitis with concomitant bacterial infections and chronic infectious colitis. PLoS One 2017; 12 :e0189377.29211811\n29. Friesen C , HillI, WoodsC. Salmonella gastroenteritis mimicking onset of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 2008; 46 :84–6.18162839\n30. Cohen GS , PrasadM. Campylobacter pouchitis mimicking the appearance of Crohn’s disease. Case Rep Gastrointest Med 2016; 2016 :5254914.27555972\n31. Naddei R , MartinelliM, StrisciuglioC, et al. Yersinia enterocolitica ileitis mimicking pediatric Crohn’s disease. Inflamm Bowel Dis 2017; 23 :E15–6.28230560\n32. Issa M , AnanthakrishnanAN, BinionDG. Clostridium difficile and inflammatory bowel disease. Inflamm Bowel Dis 2008; 14 :1432–42.18484669\n33. Arnold CA , RothR, ArsenescuR, et al. Sexually transmitted infectious colitis vs inflammatory bowel disease: distinguishing features from a case-controlled study. Am J Clin Pathol 2015; 144 :771–81.26486742\n34. Yilmaz M , MemisogluR, AydinS, et al. Anorectal syphilis mimicking Crohn’s disease. J Infect Chemother 2011; 17 :713–5.21437679\n35. Gallegos M , BradlyD, JakateS, KeshavarzianA. Lymphogranuloma venereum proctosigmoiditis is a mimicker of inflammatory bowel disease. World J Gastroenterol 2012; 18 :3317–21.22783058\n36. van Vliet MJ , de BontES. Aeromonas caviae infection mimicking inflammatory bowel disease in a child [in Dutch]. Ned Tijdschr Geneeskd 2005; 149 :1365–6.\n37. Rafael MA , Martins FigueiredoL, OliveiraAM, et al. Gastrointestinal tuberculosis mimicking Crohn’s disease. GE Port J Gastroenterol 2020; 27 :278–82.32775550\n38. Chavapradit N , AngkasekwinaiN. Disseminated cryptococcosis in Crohn’s disease: a case report. BMC Infect Dis 2018; 18 :620.30514241\n39. Ahmed A , HomsiN, KapilaR. Crohn’s disease or histoplasmosis? A case of severe disseminated histoplasmosis mimicking Crohn’s disease and literature review. Med Mycol Case Rep 2020; 30 :8–11.32953428\n40. Mitter SS , DerhovanessianA, HillmanJD, UslanDZ. Disseminated coccidioidomycosis in a patient managed with adalimumab for Crohn’s disease. Nat Rev Gastroenterol Hepatol 2010; 7 :231–5.20376095\n41. Lomazi EA , de NegreirosLMV, MagalhãesPVVS, et al. Intestinal paracoccidioidomycosis resembling Crohn’s disease in a teenager: a case report. J Med Case Rep 2018; 12 :108.29706133\n42. Khan FN , PrasadV, KleinMD. Cytomegalovirus enteritis mimicking Crohn’s disease in a lupus nephritis patient: a case report. World J Gastroenterol 2009; 15 :4327–30.19750578\n43. Sandgren KE , PriceNB, BishopWP, McCarthyPJ. Herpes simplex proctitis mimicking inflammatory bowel disease in a teenaged male. Case Rep Pediatr 2017; 2017 :3547230.28473937\n44. Cheng CW , FengCM, ChuaCS. Cecal amebiasis mimicking inflammatory bowel disease. J Int Med Res 2020; 48 :300060520922379.32475192\n45. Johansson J , IgnatovaS, EkstedtM. Pinworm infestation mimicking Crohns’ disease. Case Rep Gastrointest Med 2013; 2013 :706197.23555063\n46. Nussinson E , Yair-SabagS, ShibliF. Detection of Taenia saginata infection mimicking Crohn’s disease using video capsule endoscopy. Clin Case Rep 2018; 6 :741–4.29636951\n47. Yoon J , KaurM. Strongyloides stercoralis infection mimicking Crohn’s disease. Am J Gastroenterol 2013; 108 :S429–30.\n48. Montalto M , MieleL, MarcheggianoA, et al. Anisakis infestation: a case of acute abdomen mimicking Crohn’s disease and eosinophilic gastroenteritis. Dig Liver Dis 2005; 37 :62–4.15702862\n49. Aktay AN . Hookworm infection mimicking Crohn’s disease: diagnosed with wireless capsule endoscopy. Vol 3. 2015. Available at: http://www.jscimedcentral.com/Pediatrics/pediatrics-3-1083.pdf. Accessed 28 February 2021.\n50. Becerra SC , RoyDC, SanchezCJ, et al. An optimized staining technique for the detection of gram positive and gram negative bacteria within tissue. BMC Res Notes 2016; 9 :216.27071769\n51. Murphy JK , O’DonohueL. The diagnostic value and cost effectiveness of routine fungal stains in a dermatopathology service of a district general hospital. J Clin Pathol 2004; 57 :139–40.14747436\n52. Garcia LS , ArrowoodM, KokoskinE, et al. Practical guidance for clinical microbiology laboratories: laboratory diagnosis of parasites from the gastrointestinal tract. Clin Microbiol Rev 2018; 31:e00025-17 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "8(7)",
"journal": "Open forum infectious diseases",
"keywords": "alcoholism; gastrointestinal histoplasmosis; inflammatory bowel disease",
"medline_ta": "Open Forum Infect Dis",
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"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofab249",
"pmc": null,
"pmid": "34262987",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "15702862;26210870;32040709;21810734;29515346;28230560;15654803;17505255;32775550;20376095;21437679;29912691;27071769;19750578;32000281;23166905;19006637;31625627;29211811;20445761;28161745;24088857;10598067;27555972;32475192;28473937;16008045;29636951;26797210;24043688;25631806;18162839;30514241;31981389;26486742;19951231;29142079;25908247;23555063;22783058;18484669;23329906;29706133;14747436;23579940;9041263;32953428",
"title": "Gastrointestinal Histoplasmosis Mimicking Crohn's Disease.",
"title_normalized": "gastrointestinal histoplasmosis mimicking crohn s disease"
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"abstract": "BACKGROUND\nColorectal cancer (CRC) is the third leading cause of cancer-related death in males and females in the United States. Approximately, 20%-22% of patients have metastatic disease at the time of presentation, and 50%-60% will develop metastasis over the course of their disease. Despite advances in systemic therapies, there remains a paucity of effective third- and later-line therapies for patients with ongoing disease progression. However, rechallenging chemo-resistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer (mCRC).\n\n\nMETHODS\nA 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness. Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease. He underwent a colectomy with anastomosis. Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma (T4bN1bM1a). He received adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), but therapy was discontinued due to the development of atrial fibrillation. Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL, and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type. He was started on irinotecan with oxaliplatin (IROX), and bevacizumab (14 cycles), developed disease progression, was transitioned to FOLFOX and cetuximab, and then eventually three cycles of pembrolizumab. Following disease progression, he was rechallenged with IROX therapy, as he previously responded well to oxaliplatin-based therapy. The IROX rechallenge provided this patient with a ten-month survival benefit, decreased metastatic burden, and marked improvement in his clinical condition.\n\n\nCONCLUSIONS\nRechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.",
"affiliations": "College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, United States.;Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States.;Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States.",
"authors": "Reddy|Tejaswini Parlapalle|TP|;Khan|Usman|U|;Burns|Ethan Alexander|EA|;Abdelrahim|Maen|M|",
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"doi": "10.5306/wjco.v11.i11.959",
"fulltext": "\n==== Front\nWorld J Clin Oncol\nWJCO\nWorld Journal of Clinical Oncology\n2218-4333 Baishideng Publishing Group Inc \n\n33312889\njWJCO.v11.i11.pg959\n10.5306/wjco.v11.i11.959\nCase Report\nChemotherapy rechallenge in metastatic colon cancer: A case report and literature review \nReddy Tejaswini Parlapalle College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, United States\n Khan Usman Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States\n Burns Ethan Alexander Abdelrahim Maen Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States\nSection of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center. Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute and Weill Cornell Medical College, Houston, TX 77030, United States. mabdelrahim@houstonmethodist.org\n Author contributions: Reddy TP reviewed the literature; Reddy TP, Burns EA, Khan U, Abdelrahim M contributed to the design of the manuscript and manuscript drafting, and revision of the manuscript for intellectual content; Khan U imaged analysis and interpretation; Abdelrahim M was the patient’s oncologist and was responsible for the critical revision of the manuscript for intellectual content; and all authors issued final approval for the version to be submitted.\n\nCorresponding author: Maen Abdelrahim, BPharm, MD, PhD, Associate Professor, Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center. Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute and Weill Cornell Medical College, 6445 Main ST Fl 24, Houston, TX 77030, United States. mabdelrahim@houstonmethodist.org\n\n\n24 11 2020 \n24 11 2020 \n11 11 959 967\n5 8 2020 1 10 2020 19 10 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nColorectal cancer (CRC) is the third leading cause of cancer-related death in males and females in the United States. Approximately, 20%-22% of patients have metastatic disease at the time of presentation, and 50%-60% will develop metastasis over the course of their disease. Despite advances in systemic therapies, there remains a paucity of effective third- and later-line therapies for patients with ongoing disease progression. However, rechallenging chemo-resistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer (mCRC).\n\nCASE SUMMARY\nA 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness. Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease. He underwent a colectomy with anastomosis. Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma (T4bN1bM1a). He received adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), but therapy was discontinued due to the development of atrial fibrillation. Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL, and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type. He was started on irinotecan with oxaliplatin (IROX), and bevacizumab (14 cycles), developed disease progression, was transitioned to FOLFOX and cetuximab, and then eventually three cycles of pembrolizumab. Following disease progression, he was rechallenged with IROX therapy, as he previously responded well to oxaliplatin-based therapy. The IROX rechallenge provided this patient with a ten-month survival benefit, decreased metastatic burden, and marked improvement in his clinical condition.\n\nCONCLUSION\nRechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.\n\nMetastatic colorectal cancerRechallenge therapyTreatment holidayOxaliplatinIrinotecanCase reportChemoresistancePalliative option\n==== Body\nCore Tip: Despite advances in therapeutic strategies, colorectal cancer (CRC) remains a deadly disease. There are limited options for patients with chemo-refractory mCRC. We present a case of a patient with heavily treated metastatic colorectal cancer (mCRC) that was responsive to oxaliplatin-based rechallenge therapy. Oxaliplatin rechallenge therapy provided this patient with a ten-month survival benefit, marked improvement in his clinical condition, performance status, and quality of life. This case highlights the importance of considering rechallenge therapy in patients with chemo-refractory mCRC. Monitoring for oxaliplatin-associated peripheral sensory neuropathy should be considered for patients who are candidates for oxaliplatin rechallenge therapy.\n\nINTRODUCTION\nColorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in the United States[1]. An estimated 147950 new CRC cases and 53200 deaths are expected to occur in 2020[1]. Approximately 20%-22% of CRC patients present with metastatic disease at initial diagnosis and 50%-60% will develop metastasis throughout their disease[1]. Metastatic colorectal cancer (mCRC) carries a poor prognosis, with a 5-year overall survival (OS) rate of 14%[1]. The current recommended first-line systemic chemotherapy regimens include 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), capecitabine plus oxaliplatin (XELOX), and 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)[2-5]. Biologic agents such as the vascular endothelial growth factor inhibitor bevacizumab and epidermal growth factor receptor (EGFR) inhibitor cetuximab may be used as adjuncts to systemic chemotherapy in mCRC[6,7].\n\nDespite advances in cytotoxic and targeted therapy, treatment resistance remains a significant barrier to the management of mCRC. Resistance can be primary (poor initial response) or secondary (loss of initial response). Many patients exhibit rapid disease progression with third- and fourth-lines therapies. The therapeutic options for these patients remain limited and typically consist of regorafenib or trifluridine-tipiracil (FTD/TPI)[8,9]. The role of rechallenge therapy with chemotherapy, biologic agents, or combination therapy in patients who have developed secondary resistance, particularly previously responding patients, is not clear. We present a case that challenges the dogma of irreversible secondary resistance and supports the potential of rechallenge chemotherapy as a life-prolonging treatment option in heavily-treated mCRC.\n\nCASE PRESENTATION\nChief complaints\nA 41-year-old man presented for a second opinion regarding his worsening abdominal pain.\n\nHistory of present illness\nThe patient initially presented to a hospital in Qatar with an 8-mo history of diffuse abdominal pain. A computed tomography (CT) scan and colonoscopy revealed a splenic flexure mass and diffuse hepatic lesions concerning for metastatic disease. The patient then received another opinion at a hospital in Bangkok, Thailand, where a repeat CT scan and colonoscopy confirmed the initial diagnosis. The patient had a 17 pack-year cigarette smoking history. He denies alcohol consumption or a family history of cancer. During his clinical visits in Qatar and Thailand, his physical exam was unremarkable, and he denied weight loss, constipation, diarrhea, hematochezia, or melena. In Qatar, he underwent a colectomy with anastomosis. The pathologic diagnosis was moderate to well-differentiated colonic adenocarcinoma, stage T4bN1bM1a. He then received adjuvant treatment with FOLFOX chemotherapy, however after the first cycle, he developed atrial fibrillation, and treatment was discontinued. Afterward, he presented to our hospital for further workup and recommendations.\n\nHistory of past illness\nThe patient has no past medical history.\n\nPersonal and family history\nThe patient has no personal or family history.\n\nPhysical examination\nThe vitals on admission was within normal reference range and his physical examination was unremarkable.\n\nLaboratory examinations\nLabs indicated a normocytic anemia, and an elevated carcinoembryonic antigen (CEA) level (508.2 ng/mL). Blood chemistries, urinalysis, urine cultures, coagulation times including international normalized ratio, prothrombin, and partial thromboplastin times were within normal limits. Electrocardiogram was within normal limits.\n\nImaging examinations\nAn initial imaging evaluation with CT of the abdomen and pelvis revealed two hypoattenuating masses in the liver. One 6.1 cm superior mass was in the right lateral lobe of the liver and a 6.9 cm inferior mass was in the lower tip of the right lobe (Figure 1). These masses were most compatible with liver metastasis from invasive CRC. The portal vein was patient, bile ducts were not dilated, and the gallbladder was normal.\n\nFigure 1 \nInitial computed tomography images of abdomen and pelvis displaying two hypoattenuating liver masses, which are most consistent with liver metastases from invasive colorectal carcinoma. Images were captured on 7/25/2016.\n\nFurther diagnostic workup, diagnosis, disease management, and treatment\nPathology slides of tumor tissue samples were obtained from the patient’s hospitalization in Bangkok and reviewed. The pathology report indicated invasive colonic adenocarcinoma, moderately differentiated (low-grade). The mutational analysis found that the patient had high microsatellite instability and wildtype (WT) KRAS and BRAF mutations. Given his history of atrial fibrillation on FOLFOX, he was started on irinotecan and oxaliplatin (IROX) plus bevacizumab. The patient had a partial response to IROX plus bevacizumab therapy but after 14 cycles of treatment, he developed disease progression and was transitioned to FOLFOX plus cetuximab. His disease progressed on FOLFOX and cetuximab, and thereafter the patient was lost to follow up for one year. During that time, he received three cycles of pembrolizumab from an outside hospital. Unfortunately, staging workup after 3 cycles of pembrolizumab indicated enhanced disease progression, particularly increased enlargement of metastatic liver lesions. In early 2018, we discussed with the patient about three potential chemotherapy options: (1) FTD/TPI; (2) Regorafenib; and (3) Rechallenge with IROX. The decision was made to rechallenge with IROX therapy based on the patient’s previous response to this regimen. Therefore, the patient received rechallenge therapy with IROX plus cetuximab every two weeks (11 cycles total). He tolerated the treatment well and showed a marked improvement in his clinical condition, performance status, and quality of life. Furthermore, a substantial reduction in the CEA level from 4493 ng/mL to 2250 ng/mL was observed after four months of treatment (Figure 2). Follow-up CT scans showed a decrease in liver metastasis size shown in the scans obtained at five and six months after rechallenge therapy (Figure 3). The diagnostic workup, disease management, and treatment are also summarized in Figure 4.\n\nFigure 2 \nTrend in carcinoembryonic antigen levels during irinotecan with oxaliplatin rechallenge therapy. CEA: Carcinoembryonic antigen; IROX: Irinotecan with oxaliplatin.\n\nFigure 3 \nComputed tomography abdomen images showed interval response with decrease in liver metastasis size. These images show size of the metastatic lesion at 4- and 5-mo post initiation of irinotecan with oxaliplatin rechallenge therapy. CT: Computed tomography.\n\nFigure 4 \nTimeline summary of events. CT: Computed tomography; FOLFOX: Folinic acid, 5-fluorouracil, and oxaliplatin; CEA: Carcinoembryonic antigen; IROX: Irinotecan and oxaliplatin; KRAS: Kirsten rat sarcoma viral oncogene; BRAF: B-Raf oncogene.\n\nFINAL DIAGNOSIS\nThe final diagnosis was chemo-resistant metastatic KRAS/BRAF WT, microsatellite instability-high colorectal carcinoma (T4bN1bM1a).\n\nTREATMENT\nThe patient continued to receive IROX plus cetuximab rechallenge chemotherapy for a total of nine months. The treatment was eventually withheld due to hospital admission for pneumonia and respiratory failure.\n\nOUTCOME AND FOLLOW-UP\nAfter noting treatment complications, the patient and his family chose to transition to palliative care and hospice. He passed away 27 mo after his initial presentation to our hospital. The oxaliplatin rechallenge therapy provided this patient with a ten-month survival benefit.\n\nDISCUSSION\nLimited cytotoxic agents are available for the treatment of mCRC. Unfortunately, there are a significant number of patients that still progress past the third and fourth line of therapy, who may respond to other therapeutic options. Rechallenge therapy with either chemotherapy/biologic therapy alone or combination therapy has not been fully investigated as a viable option for patients with disease progression. In this case, oxaliplatin-based chemotherapy rechallenge demonstrated a viable alternative for this patient with heavily-pretreated mCRC. Despite progression on multiple lines of chemotherapy, immunotherapy, and investigational therapy, IROX rechallenge provided this patient with an additional ten-month survival benefit. The rationale of reattempting a previous line of systemic chemotherapy stems from the possibility that subsequent therapies following the development of chemoresistance may sensitize patients to the primary therapy by promoting the growth of sensitive clones[10]. Another possibility is epigenetic alterations may result in tumor resistance, which may reverse following a “drug holiday”[10]. While mechanisms that result in chemoresistance are well known, the cellular mechanisms and predictive factors associated with response to rechallenge therapy need to further elucidated.\n\nFindings from this case are consistent with previous studies demonstrating the promise of oxaliplatin-based chemotherapy rechallenge in the third- or fourth-line setting for mCRC. These previous studies are summarized in Table 1. Suenaga et al[11] performed a single-arm, open-label, phase II clinical trial (RE-OPEN) to examine the safety and efficacy of reintroducing oxaliplatin in patients with mCRC refractory to standard chemotherapy. The eligible patients in this study had previously received oxaliplatin and irinotecan and achieved stable disease or response, followed by disease progression ≥ 6 mo during the first oxaliplatin-based therapy. The primary endpoint was disease control rate (DCR) after 12 wk of re-challenge therapy and the secondary endpoints were safety, overall response rate, and progression-free survival (PFS). Oxaliplatin was reintroduced by treating patients with the FOLFOX6 regimen. The study found that the DCR after 12 wk of rechallenge therapy was 39.4% (95%CI 21.8-57.0) and the response rate (complete and partial response) was 6.1%. The median PFS and OS were 3.2 and 9.8 mo, respectively. A concern with rechallenging patients with oxaliplatin is the risk of developing peripheral sensory neuropathy (PSN) during the oxaliplatin rechallenge. However, in this study, the incidence of grade 1 and 3 PSN events was 53.1% and 0%, respectively[11].\n\nTable 1 Summary of studies assessing the efficacy of oxaliplatin-based rechallenge therapy against metastatic colorectal cancer\n\n\nRef.\n\n\t\nPrior lines of chemotherapy\n\n\t\nPatient cohort\n\n\t\nTreatment regimen\n\n\t\nPFS (months)\n\n\t\nOS (months)\n\n\t\nSuenaga et al[11]\tOxaliplatin-based therapy: First-line: 26 (78.8%); Second-line 7 (21.2%). Molecular-targeted therapy: None: 1 (3.0%); Bevacizumab: 27 (81.8%); Cetuximab or Panitumumab: 19 (57.6%)\t33 patients, previously received oxaliplatin and irinotecan, had stable disease, and disease progression ≥ 6 mo\tFOLFOX6: 33 (100%)\t3.2 \t9.8\t\nYang et al[13]\tOxaliplatin-based therapy: First-line: 76 (80.0%); Second-line 19 (20.0%). Oxaliplatin rechallenge therapy: Third-line: 78 (82.1%); Fourth-line: 13 (13.7%); Fifth or more: 4 (4.2%). Control arm: Anti-EGFR + irinotecan: 29 (100%)\tRechallenge arm: 95 patients received who received oxaliplatin in the first/second-line and were rechallenged as a third or later line of therapy\tmFOLFOX6: 70 (73.7%); XELOX: 19 (20%); Other: 6 (6.3)\t1.7a\t12.2\t\nControl arm: 29 patients received anti-EGFR and irinotecan therapy\tAnti-EGFR + irinotecan: 29 (100%)\t\t11.4\t\nKöstek et al[14]\tAll patients received two lines of chemotherapy of any of the following combinations: (FOLFIRI, FOLRFIRI/XELIRI, FOLFOX/XELOX, capecitabine, FUFA/capecitabine) monotherapy or combined with biologic agents bevacizumab/cetuximab/panitumab\tRegorafenib arm: 73\tRegorafenib\t3.4\t6.6\t\nRechallenge arm: 31; rechallenge therapy was identified as re-using a regimen that was previously administered to patients and had obtained disease control\tFOLFOX + cetuximab: 8, FOLFOX + bevacizumab: 6, FOLFOX: 4, FOLFIRI: 2, FOLFIRI + cetuximab: 3, capecitabine: 2, FOLFOX + panitumab: 1, FOLFIRI + bevacizumab: 1, FUFA + bevacizumab: 1, capecitabine + bevacizumab: 1, XELOX + bevacizumab: 1, FOLFIRINOX: 1\t9.2\t12.0\t\nFernandes et al[16]\tPatients with documented progression to regimens containing oxaliplatin, irinotecan, and 5-FU (most patients received at least three regimens)\tRechallenge arm: 21 patients who were rechallenged with either FOLFIRINOX or FOLFOXIRI\tFOLFIRINOX: 13 (61.9%); FOLFOXIRI: 8 (38.1%)\t4.0\t8.6\t\nTownsend et al[17]\tPatients identified to received oxaliplatin previously. Prior lines of chemotherapy before oxaliplatin rechallenge (information on prior regimen was not provided): 4 lines for 2 patients, 3 lines for 6 patients, 2 lines for 8 patients, 1 line for 4 patients\tRechallenge arm: 20 patients who were rechallenged with FOX therapy\tFOX: 20\t3.7\t7.8\t\nSgouros et al[18]\tPatients previously treated with IROX with refractory disease (median prior lines of chemotherapy: 3)\tRechallenge arm: 25 patients who were rechallenged with IROX therapy\tIrinotecan (180 mg/m2/135 mg/m2) and oxaliplatin (85 mg/m2/65 mg/m2) every two weeks\t3.0\t7.0\t\na Best PFS for all oxaliplatin based rechallenge regimens evaluated.\n\nFOLFOX: Folinic acid, 5-fluorouracil, and Oxaliplatin; EGFR: Epidermal growth factor receptor; XELOX: Capecitabine and oxaliplatin; FOLFIRI: Folinic acid, 5-fluorouracil, and irinotecan; XELIRI: Capecitabine and irinotecan; FUFA: Folinic acid and 5-fluorouracil; FOX: Oxaliplatin and fluoropyrimidine; 5-FU: 5-Fluorouracil; IROX: Irinotecan with oxaliplatin; FOLFOXIRI: 5-Fluorouracil, leucovorin, oxaliplatin, and irinotecan; FOLFIRINOX: Oxaliplatin, irinotecan, fluorouracil, and leucovorin. PFS: Progression free survival; OS: Overall survival; NR: Not reported.\n\nA follow-up to the RE-OPEN trial was a phase I clinical trial (LUPIN study), in which the study examined the safety of rechallenging oxaliplatin with FTD/TPI[12]. The patient cohort of interest in this study were patients with mCRC, whose tumors acquired resistance to prior chemotherapy with oxaliplatin and irinotecan[12]. The study concluded that a safe rechallenge regimen would be oxaliplatin 85 mg/m2 on days 1 and 15 every four weeks and FTD/TPI 35 mg/m2 bid on days 1-5 and 15-19. The LUPIN study concluded that FTD/TPI could potentially replace 5-fluorouracil in combination with oxaliplatin. The efficacy of this novel combinatorial approach of FTD/TPI with oxaliplatin for mCRC needs to be further evaluated.\n\nComparable results were found in a retrospective study performed by Yang et al[13] in 2018. In this study, patients with mCRC, who progressed from oxaliplatin, fluoropyrimidine, and irinotecan as first and second-line chemotherapy, were re-challenged with an oxaliplatin-based therapy. The control arm in this study was mCRC patients treated with anti-EGFR biologic therapy and irinotecan. The OS for oxaliplatin rechallenge arm and control arm was 12.2 and 11.4 mo, respectively (no significant difference between both treatment arms, P > 0.05). Multivariate analysis found that patients who obtained disease control with oxaliplatin rechallenge had a better time to treatment failure (6.1 vs 1.7 mo, P < 0.001) and OS (15.7 vs 6.3 mo, P < 0.001) compared to patients with progressive disease. This study showed that rechallenge with oxaliplatin-containing chemotherapy yielded equivalent tumor control and survival benefit to that of anti-EGFR antibodies with irinotecan in the third- or later-line setting in mCRC[13].\n\nKöstek et al[14] found that chemotherapy rechallenge (FOLFOX alone, FOLFOX with either cetuximab or bevacizumab, FOLFIRI alone or with cetuximab or bevacizumab, capecitabine plus bevacizumab, FOLFIRINOX, XELOX plus bevacizumab, or folinic acid and 5-fluorouracil plus bevacizumab) was more effective than regorafenib in the third-line treatment of mCRC patients. The PFS and OS with rechallenge therapy were 9.2 mo and 12 mo vs 3.4 mo and 6.6 mo with regorafenib, respectively. Another supporting study was a retrospective analysis that investigated the feasibility and efficacy of oxaliplatin rechallenge in mCRC patients previously treated with adjuvant or palliative oxaliplatin-based chemotherapy, who had remained disease-free or progression-free for at least 6 mo after the last dose of oxaliplatin-based therapy[15]. Sixty-five patients were rechallenged with FOLFOX and 45 patients were rechallenged with XELOX. The median PFS and OS in this study with oxaliplatin rechallenge were 5.9 mo and 18.5 mo, respectively[15].\n\nFernandes et al[16] conducted a retrospective study to evaluate the benefit of rechallenging patients with mCRC to 5-fluorouracil, irinotecan, and oxaliplatin therapy (FOLFIRINOX or FOLFOXIRI). Twenty-one patients were retrospectively analyzed, with a response rate was 38% and 24% of patients had stable disease after rechallenge therapy. The median OS was 8.6 mo and only one patient had experienced grade 5 neutropenic sepsis. Another retrospective study had examined a South Australian mCRC database for patients who were rechallenged with FOX therapy (oxaliplatin and fluoropyrimidine)[17]. The study included 20 patients and discovered that for this patient cohort, the response rate was 18% and 48% of patients had stable disease after oxaliplatin rechallenge. The median PFS and OS were 3.7 and 7.8 mo, respectively[17]. Another study reported a comparable OS to rechallenge therapy, a 7-mo median OS, and 32% DCR[18]. This particular study investigated oxaliplatin-based chemotherapy rechallenge in mCRC patients previously treated with oxaliplatin, irinotecan, bevacizumab, cetuximab, or panitumumab therapies (if wild-type KRAS)[18]. Though these retrospective studies support the rationale of oxaliplatin rechallenge as another third/fourth-line option for mCRC, the concern with such studies is that there is no formal assessment as to whether oxaliplatin rechallenge leads to worsening PSN in this patient cohort.\n\nIf considering chemotherapy rechallenge with an oxaliplatin-based regimen, clinicians should be wary of the development of PSN, which may lead to dose reduction of therapy, premature cessation of treatment, and significantly impair quality of life. To investigate whether oxaliplatin rechallenge results in new or worsening PSN, Besora et al[19] conducted a retrospective clinical study of 106 patients who were rechallenged with FOLFOX4/6, XELOX, or TOMOX. PSN was graded according to the National Cancer Institute-Common Toxicity Criteria for Adverse Events[20]. The study found that before oxaliplatin rechallenge, the frequencies of oxaliplatin-associated grade 1 and 2 PSN were 23.8% and 8.5%, respectively. After oxaliplatin rechallenge, 39.6% and 22.6% of patients developed grade 1 and 2 PSN, respectively; No patients developed grade 3 PSN. About 31% of all patients in this study experienced worsening PSN symptoms, whereas 68.9% of patients had the same PSN grade as before rechallenge therapy. This study sheds light on how oxaliplatin rechallenge may be a safe option, albeit neurological monitoring using scales such as the total neuropathy score, should be considered for mCRC patients who may undergo rechallenge therapy. Furthermore, a balance between rechallenge therapy to improve survival vs its impact on worsening PSN on quality of life for patients is crucial.\n\nCONCLUSION\nThere are limited therapeutic options for mCRC that has progressed past the third and fourth lines of therapy. Rechallenging a chemo-resistant tumor with a previous well-tolerated and responsive line of chemotherapy may be a life-prolonging therapeutic approach for mCRC. This case demonstrates that rechallenge with IROX may offer a valid treatment option for mCRC patients with chemo-resistant disease, particularly in select patients with previous favorable response to oxaliplatin-based chemotherapy. IROX may serve as a viable option for rechallenge therapy, as seen in this case. However, neurological monitoring should be considered for mCRC patients who may undergo oxaliplatin-based rechallenge therapy. Further studies to elucidate the cellular mechanisms and predictive factors associated with enhanced response to rechallenge therapy in mCRC are warranted.\n\nInformed consent statement: Verbal consent was obtained from the patient for publication of this report and any accompanying radiographic images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: August 5, 2020\n\nFirst decision: September 17, 2020\n\nArticle in press: October 19, 2020\n\nSpecialty type: Oncology \n\nCountry/Territory of origin: United States\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Guo XZ S-Editor: Huang P L-Editor: A P-Editor: Wang LL\n==== Refs\n1 Noone AM Howlader N Krapcho M Miller D Brest A Yu M Ruhl J Tatalovich Z Mariotto A Lewis DR Chen HS Feuer EJ Cronin KA (eds) SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD. 2018; Available from: https://seer.cancer.gov/archive/csr/1975_2015/ \n2 de Gramont A Figer A Seymour M Homerin M Hmissi A Cassidy J Boni C Cortes-Funes H Cervantes A Freyer G Papamichael D Le Bail N Louvet C Hendler D de Braud F Wilson C Morvan F Bonetti A Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer J Clin Oncol 2000 18 2938 2947 10944126 \n3 Goldberg RM Sargent DJ Morton RF Fuchs CS Ramanathan RK Williamson SK Findlay BP Pitot HC Alberts SR A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer J Clin Oncol 2004 22 23 30 14665611 \n4 Cassidy J Clarke S Díaz-Rubio E Scheithauer W Figer A Wong R Koski S Lichinitser M Yang TS Rivera F Couture F Sirzén F Saltz L Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer J Clin Oncol 2008 26 2006 2012 18421053 \n5 Falcone A Ricci S Brunetti I Pfanner E Allegrini G Barbara C Crinò L Benedetti G Evangelista W Fanchini L Cortesi E Picone V Vitello S Chiara S Granetto C Porcile G Fioretto L Orlandini C Andreuccetti M Masi G Gruppo Oncologico Nord Ovest Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest J Clin Oncol 2007 25 1670 1676 17470860 \n6 Fakih MG Metastatic colorectal cancer: current state and future directions J Clin Oncol 2015 33 1809 1824 25918280 \n7 Edwards MS Chadda SD Zhao Z Barber BL Sykes DP A systematic review of treatment guidelines for metastatic colorectal cancer Colorectal Dis 2012 14 e31 e47 21848897 \n8 Grothey A Van Cutsem E Sobrero A Siena S Falcone A Ychou M Humblet Y Bouché O Mineur L Barone C Adenis A Tabernero J Yoshino T Lenz HJ Goldberg RM Sargent DJ Cihon F Cupit L Wagner A Laurent D CORRECT Study Group Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 303 312 23177514 \n9 Mayer RJ Van Cutsem E Falcone A Yoshino T Garcia-Carbonero R Mizunuma N Yamazaki K Shimada Y Tabernero J Komatsu Y Sobrero A Boucher E Peeters M Tran B Lenz HJ Zaniboni A Hochster H Cleary JM Prenen H Benedetti F Mizuguchi H Makris L Ito M Ohtsu A RECOURSE Study Group Randomized trial of TAS-102 for refractory metastatic colorectal cancer N Engl J Med 2015 372 1909 1919 25970050 \n10 Ioannou P Talesnik J Platelet antiaggregatory substances inhibit arachidonic acid induced coronary constriction Can J Physiol Pharmacol 1986 64 398 405 2425912 \n11 Suenaga M Mizunuma N Matsusaka S Shinozaki E Ozaka M Ogura M Yamaguchi T Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study Drug Des Devel Ther 2015 9 3099 3108 \n12 Suenaga M Wakatsuki T Mashima T Ogura M Ichimura T Shinozaki E Nakayama I Osumi H Ota Y Takahari D Chin K Seimiya H Yamaguchi K A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study Invest New Drugs 2020 38 111 119 30838483 \n13 Yang Q Huang Y Jiang Z Wang H Li W Zhang B Xie D Rechallenge of oxaliplatin-containing regimens in the third- or later-line therapy for patients with heavily treated metastatic colorectal cancer Onco Targets Ther 2018 11 2467 2473 29760556 \n14 Köstek O Hacıoğlu MB Sakin A Demir T Sarı M Ozkul O Araz M Doğan AF Demircan NC Uzunoğlu S Çiçin İ Erdoğan B Regorafenib or rechallenge chemotherapy: which is more effective in the third-line treatment of metastatic colorectal cancer? Cancer Chemother Pharmacol 2019 83 115 122 30374523 \n15 Kim JJ Kang J Hong YS Kim KP Kim SY Kim TW Kim JE Oxaliplatin rechallenge in metastatic colorectal cancer patients after prior oxaliplatin treatment Med Oncol 2018 35 65 29623500 \n16 Fernandes GDS Braghiroli MI Artioli M Paterlini ACCR Teixeira MC Gumz BP Girardi DDM Braghiroli OFM Costa FP Hoff PM Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients J Gastrointest Cancer 2018 49 470 475 28884286 \n17 Townsend AR Bishnoi S Broadbridge V Beeke C Karapetis CS Jain K Luke C Padbury R Price TJ Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy Am J Clin Oncol 2013 36 49 52 22270106 \n18 Sgouros J Aravantinos G Dragasis S Koutsounas K Antoniou G Belechri M Antonopoulos M Visvikis A Res H Samantas E Reintroduction of irinotecan and oxaliplatin as a combination (IROX regimen) in heavily pretreated colorectal cancer patients - A single-center experience FCO 2013 4 13 18 \n19 Besora S Santos C Izquierdo C Martinez-Villacampa MM Bruna J Velasco R Rechallenge with oxaliplatin and peripheral neuropathy in colorectal cancer patients J Cancer Res Clin Oncol 2018 144 1793 1801 29955956 \n20 Velasco R Bruna J Briani C Argyriou AA Cavaletti G Alberti P Frigeni B Cacciavillani M Lonardi S Cortinovis D Cazzaniga M Santos C Kalofonos HP Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients J Neurol Neurosurg Psychiatry 2014 85 392 398 23813745\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2218-4333",
"issue": "11(11)",
"journal": "World journal of clinical oncology",
"keywords": "Case report; Chemoresistance; Irinotecan; Metastatic colorectal cancer; Oxaliplatin; Palliative option; Rechallenge therapy; Treatment holiday",
"medline_ta": "World J Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101549149",
"other_id": null,
"pages": "959-967",
"pmc": null,
"pmid": "33312889",
"pubdate": "2020-11-24",
"publication_types": "D002363:Case Reports",
"references": "28884286;10944126;25918280;18421053;23813745;29760556;22270106;30838483;29955956;25970050;26124634;17470860;21848897;14665611;23177514;2425912;29623500;30374523",
"title": "Chemotherapy rechallenge in metastatic colon cancer: A case report and literature review.",
"title_normalized": "chemotherapy rechallenge in metastatic colon cancer a case report and literature review"
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"abstract": "Vancomycin-resistant enterococcal bacteremia (VRE-B) is a common nosocomial infection associated with significant morbidity and mortality. Daptomycin and linezolid are primary treatment options although definitive clinical data to assess comparative therapeutic effectiveness are lacking. This study assessed the outcomes of patients with VRE-B treated with linezolid or daptomycin. This was a single-center, retrospective cohort study evaluating adult patients with VRE-B treated with either daptomycin or linezolid admitted between January 2012 and August 2016 at a tertiary care, academic medical center. The primary outcome was clinical failure, a composite outcome defined as 14-day in-hospital mortality, microbiologic failure, or relapse of VRE-B. Secondary outcomes included 14-day in-hospital mortality, microbiologic failure, relapse of VRE-B, duration of VRE-B, and antibiotic failure. A multivariate logistic regression model was performed to adjust for potential confounding variables. A total of 93 patients were included (n = 62 for linezolid and n = 31 for daptomycin). All blood isolates were Enterococcus faecium. Overall clinical failure was 55.9% and 14-day in-hospital mortality was 21.5%. There was a significantly higher rate of clinical failure in the daptomycin group as compared with the linezolid-treated patients (74.2% versus 46.8%; p = 0.01; respectively). In multivariate logistic regression analysis, there was a significantly higher odds of clinical failure for patients treated with daptomycin as compared with linezolid (adjusted odds ratio 2.89; 95% confidence interval 1.08-7.75) after adjusting for confounders. Secondary outcomes were not statistically significantly different between study groups. Standard-dose (6 mg/kg) daptomycin treatment was associated with a higher rate of clinical failure as compared with linezolid treatment.",
"affiliations": "Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.;Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.;Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.;Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.;Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.;Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.",
"authors": "Narayanan|Navaneeth|N|https://orcid.org/0000-0001-5071-9193;Rai|Rena|R|;Vaidya|Parth|P|;Desai|Avani|A|;Bhowmick|Tanaya|T|;Weinstein|Melvin P|MP|",
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"doi": "10.1177/2049936119828964",
"fulltext": "\n==== Front\nTher Adv Infect DisTher Adv Infect DisTAIsptaiTherapeutic Advances in Infectious Disease2049-93612049-937XSAGE Publications Sage UK: London, England 10.1177/204993611982896410.1177_2049936119828964Original ResearchComparison of linezolid and daptomycin for the treatment of vancomycin-resistant enterococcal bacteremia https://orcid.org/0000-0001-5071-9193Narayanan Navaneeth Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Road, Piscataway, NJ 08854, USARai Rena Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ, USAVaidya Parth Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ, USADesai Avani Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USABhowmick Tanaya Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USAWeinstein Melvin P. Division of Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USAnavan12@pharmacy.rutgers.edu13 2 2019 Jan-Dec 2019 6 20499361198289646 8 2018 18 12 2018 © The Author(s), 20192019SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Vancomycin-resistant enterococcal bacteremia (VRE-B) is a common nosocomial infection associated with significant morbidity and mortality. Daptomycin and linezolid are primary treatment options although definitive clinical data to assess comparative therapeutic effectiveness are lacking. This study assessed the outcomes of patients with VRE-B treated with linezolid or daptomycin. This was a single-center, retrospective cohort study evaluating adult patients with VRE-B treated with either daptomycin or linezolid admitted between January 2012 and August 2016 at a tertiary care, academic medical center. The primary outcome was clinical failure, a composite outcome defined as 14-day in-hospital mortality, microbiologic failure, or relapse of VRE-B. Secondary outcomes included 14-day in-hospital mortality, microbiologic failure, relapse of VRE-B, duration of VRE-B, and antibiotic failure. A multivariate logistic regression model was performed to adjust for potential confounding variables. A total of 93 patients were included (n = 62 for linezolid and n = 31 for daptomycin). All blood isolates were Enterococcus faecium. Overall clinical failure was 55.9% and 14-day in-hospital mortality was 21.5%. There was a significantly higher rate of clinical failure in the daptomycin group as compared with the linezolid-treated patients (74.2% versus 46.8%; p = 0.01; respectively). In multivariate logistic regression analysis, there was a significantly higher odds of clinical failure for patients treated with daptomycin as compared with linezolid (adjusted odds ratio 2.89; 95% confidence interval 1.08–7.75) after adjusting for confounders. Secondary outcomes were not statistically significantly different between study groups. Standard-dose (6 mg/kg) daptomycin treatment was associated with a higher rate of clinical failure as compared with linezolid treatment.\n\ndaptomycinminimum inhibitory concentrationlinezolidVRE bacteremiacover-dateJanuary-December 2019\n==== Body\nIntroduction\nVancomycin-resistant enterococcal (VRE) bacteremia (VRE-B) is an increasingly prevalent nosocomial infection worldwide with limited treatment options. It is associated with significant mortality, excess length of hospitalization, and rising healthcare costs.1–3 VRE is a leading cause of bacteremia among hospitalized patients especially in those at increased risk of infection which include immunocompromised hosts (e.g. stem cell transplants) and critically ill patients.2,4\n\nCurrently, there are limited effective agents available to treat VRE-B; these include linezolid and daptomycin as the two most commonly used agents.5 Guidelines published by the Infectious Diseases Society of America (IDSA) specifically recommend treatment with daptomycin or linezolid for VRE intravascular catheter-related bacteremia.6 Although the IDSA guidelines are from 2009, these two agents remain the mainstay of therapy today with no clear evidence regarding comparative therapeutic effectiveness.\n\nLinezolid is an oxazolidinone antibiotic with broad Gram-positive bacterial activity including VRE. It is the only antibiotic with a United States Food and Drug Administration (US FDA) approval for treatment of VRE infections, including cases with bacteremia.7 Early data demonstrated the effectiveness of linezolid for VRE-B with clinical and microbiologic cure rates of 78% and 85%, respectively.8 Linezolid is bacteriostatic in vitro which raises concern for its use for deep-seated infections such as infective endocarditis. Despite these theoretical concerns, some data exist for treatment of VRE infective endocarditis and it is currently recommended as a first-line treatment option, along with daptomycin.9 Other concerns regarding the use of linezolid include toxicities such as myelosuppression or peripheral neuropathy with long-term therapy, as well as potentially severe drug interactions.7\n\nDaptomycin is a lipopeptide antibiotic with potent in vitro activity against Gram-positive organisms including bactericidal activity against enterococci. Despite a lack of US FDA approval for VRE, daptomycin is considered a first-line agent for VRE-B.6,9 Given its in vitro activity, clinical data, and its favorable safety profile, daptomycin is frequently used in clinical practice. As with linezolid, there are aspects of daptomycin that warrant consideration for VRE-B including emerging resistance, elevated daptomycin minimum inhibitory concentrations (MICs) that may hinder optimal pharmacodynamic target attainment, and lack of standard dosing for VRE infections.10 A recent national retrospective cohort study observed that high-dose (⩾10 mg/kg total body weight) daptomycin was associated with improved survival and microbiologic clearance in VRE-B as compared with lower dosing regimens including ‘standard’ dosing (6 mg/kg).11 Other studies assessing mortality have found similar results in which higher doses of daptomycin are associated with lower mortality for patients with VRE-B.12,13 The MIC breakpoint for daptomycin (susceptible: MIC ⩽ 4 mg/l) has also come into question as being too high with a recent multicenter cohort study concluding that daptomycin MICs of 3–4 mg/l are predictive of microbiologic failure.14\n\nIn several meta-analyses published prior to 2015, the results indicate that linezolid may have improved survival as compared with daptomycin for treatment of VRE-B.15–17 Many of the studies had significant limitations and a variety of outcome measures. In 2015, a large multicenter observational study was published assessing treatment failure of daptomycin versus linezolid among Veterans Affairs patients.18 Results from this study were contrary to previous meta-analyses and indicated that daptomycin was associated with lower rates of treatment failure, lower mortality and lower microbiologic failure as compared with linezolid. Despite previous published literature, the optimal antibiotic treatment for VRE-B remains undefined. The absence of prospective randomized controlled trials requires further observational studies in vulnerable populations. The aim of our study was to assess the outcomes of patients with VRE-B treated with linezolid or daptomycin.\n\nMethods\nStudy design and population\nWe performed a single-center, retrospective cohort study of adult inpatients with VRE-B treated with either linezolid or daptomycin between January 2012 to August 2016 at an academic medical center in New Brunswick, New Jersey, USA. VRE-B was defined as the presence of VRE growth in at least one blood culture and treated with antibiotics accordingly as true infection. Patients were identified by consecutive sampling through the microbiology laboratory database. Demographic, microbiologic and clinical data were abstracted from the hospital electronic medical record. At our institution, MICs were determined by broth microdilution via automated susceptibility testing methods [MicroScan (BeckmanCoulter, West Sacramento, CA, USA) January 2012 to July 2015 and BD Phoenix (BD, Sparks, MD, USA) August 2015 to August 2016] as per Clinical and Laboratory Standards Institute standards. Only the first VRE-B episode per patient during the study period was included for analysis. All patients were treated with daptomycin or linezolid for at least 48 h. We excluded patients with polymicrobial blood cultures, treated with antibiotics agents other than linezolid or daptomycin, and treated with combination antibiotic therapy for VRE-B. This study was approved by the Rutgers University Institutional Review Board.\n\nPredictor and outcome measures\nThe primary predictor of interest was treatment with daptomycin compared with linezolid. Multiple covariates were recorded to adequately describe the study population at our institution as well as to control for potential confounding variables by logistic regression modeling. Covariates included age, sex, weight, hospital onset of bacteremia (at least 48 hours after hospital admission), intensive care unit admission day 1 of index blood culture (ICU day 1), presumed source of infection, presence of central line, hematologic malignancy, neutropenia (absolute neutrophil count <500 cell/mm3), presence of infective endocarditis, on dialysis, comorbidities (measured by the Charlson comorbidity index), severity of illness (measured by Pitt bacteremia score), infectious diseases consultation, use of corticosteroids (prednisone equivalent of 20 mg for at least 14 days). Additional variables were recorded for exploratory analysis assessing outcomes in daptomycin-treated patients: daptomycin dose (measured as mg/kg) and daptomycin MIC.\n\nThe primary outcome measure was clinical failure, defined as a composite of 14-day in-hospital mortality, microbiologic failure (positive blood cultures for ⩾4 days following index blood culture with at least 72 h of effective antibiotic therapy or died with persistently positive blood cultures), or VRE-B relapse (positive blood culture with VRE within 30 days of index blood culture after documented clearance). Secondary outcomes included 14-day in-hospital mortality, microbiologic failure, VRE-B relapse, duration of VRE-B (time from index blood culture to first negative blood culture), and antibiotic failure (addition or change in antibiotic therapy by treating physician not due to simplification of regimen for discharge planning).\n\nStatistical analysis\nDescriptive statistics were performed for all variables. Continuous variables were compared using a Mann–Whitney U test (for nonparametric distributions) or Student’s t test. Categorical variables were compared using a Chi-square test. The significance level was set at p < 0.05 (two-sided). We performed a logistic regression analysis to estimate the crude odds ratio (OR) and 95% confidence interval (CI). Multivariate logistic regression modeling was done to assess for the presence and magnitude of the association of daptomycin treatment and clinical failure while adjusting for potential confounding variables (reported as an adjusted OR). Any variable in the initial bivariate analysis with a modest association (p < 0.2) with both the outcome (clinical failure) and the primary predictor (daptomycin treatment) and theoretical clinical plausibility was entered into the multivariable logistic regression model as a potential confounding variable. Only covariates with a priori knowledge of potential confounding was assessed for inclusion in the final regression model. Data analysis was performed using Stata, version 15.0 (StataCorp, College Station, TX, USA).\n\nResults\nA total of 93 patients were included in the final analysis. Of these patients, 62 patients were treated with linezolid and 31 patients were treated with daptomycin. All blood isolates were identified as Enterococcus faecium. Most patients in both groups were male, ICU day 1 occurred in 22.6% in the linezolid group and 38.7% in the daptomycin group (p = 0.10). A large portion of patients in both groups had an underlying hematologic malignancy (linezolid 61.3% versus daptomycin 38.7%; p = 0.07) and were neutropenic (linezolid 50% versus daptomycin 41.9%; p = 0.46). An infectious diseases consult was noted for a majority of patients in the linezolid and daptomycin group (95.2% versus 87.1%; p = 0.17; respectively). Particularly for the daptomycin group, the median dose was 6.1 mg/kg [interquartile range (IQR), 5.9–6.7] and 67.7% of patients had a blood isolate with a daptomycin MIC of 4 mg/l. Summary of baseline demographic and clinical characteristics stratified by treatment groups are shown in Table 1.\n\nTable 1. Baseline demographic and clinical characteristics.\n\nCharacteristic\tLinezolid\n(n = 62)\tDaptomycin\n(n = 31)\tp value\t\nAge, years, mean (SD)\t61.5 (15.7)\t65.2 (16.8)\t0.29\t\nMale, n (%)\t36 (58.1)\t21 (67.7)\t0.37\t\nWeight, kg, mean (SD)\t80.3 (24.4)\t87.1 (19.8)\t0.18\t\nHospital onset bacteremia, n (%)\t55 (88.7)\t23 (74.2)\t0.07\t\nICU day 1, n (%)\t14 (22.6)\t12 (38.7)\t0.10\t\nInfection source, n (%)\t0.16\t\n Not identified\t23 (37.1)\t19 (61.3)\t\t\n Gastrointestinal\t12 (19.4)\t4 (12.9)\t\t\n Catheter-related\t20 (32.3)\t5 (16.1)\t\t\n Other\t7 (11.3)\t3 (9.7)\t\t\nPresence of central line, n (%)\t37 (59.7)\t18 (58.1)\t0.88\t\nHematologic malignancy, n (%)\t38 (61.3)\t12 (38.7)\t0.07\t\nNeutropenia, n (%)\t31 (50)\t13 (41.9)\t0.46\t\nPresence of infective endocarditis, n (%)\t3 (4.8)\t2 (6.5)\t0.75\t\nDialysis, n (%)\t10 (16.1)\t11 (35.5)\t0.04\t\nCharlson comorbidity index, median (IQR)\t6 (5-9)\t8 (5–9)\t0.15\t\nPitt bacteremia score, median (IQR)\t2 (0–4)\t2 (0–4)\t0.48\t\nInfectious diseases consultation, n (%)\t59 (95.2)\t27 (87.1)\t0.17\t\nCorticosteroids, n (%)\t22 (35.5)\t14 (45.2)\t0.37\t\nDaptomycin dose, mg/kg, median (IQR)\t–\t6.1 (5.9–6.7)\t–\t\nDaptomycin MIC, mg/l, median (IQR)\t–\t4 (2–4)\t–\t\nDaptomycin MIC of 4 mg/l, n (%)\t–\t21 (67.7)\t–\t\nANC, absolute neutrophil count; ICU, intensive care unit; IQR, interquartile range; MIC, minimum inhibitory concentration; SD, standard deviation.\n\nOverall clinical failure was 55.9% and 14-day in-hospital mortality was 21.5% in the total study population. There was a significantly higher rate of clinical failure in the daptomycin group as compared with the linezolid-treated patients (74.2% versus 46.8%; p = 0.01; respectively). Although not statistically significant, 14-day in-hospital mortality, microbiologic failure, and VRE-B relapse were all worse in the daptomycin patients (Table 2). The duration of VRE-B was slightly longer in the daptomycin group versus linezolid, but the difference was not statistically significant (3.7 days versus 3.0 days; p = 0.78; respectively). In the multivariate logistic regression analysis (Table 3), there was a significantly higher odds of clinical failure for patients treated with daptomycin as compared with linezolid (adjusted OR 2.89; 95% CI 1.08–7.75) after adjusting for ICU day 1.\n\nTable 2. Primary and secondary outcomes stratified by treatment group.\n\nOutcome measures\tLinezolid\n(n = 62)\tDaptomycin\n(n = 31)\tp value\t\nClinical failure, n (%)\t29 (46.8)\t23 (74.2)\t0.01\t\n14-day in-hospital mortality, n (%)\t11 (17.7)\t9 (29)\t0.21\t\nMicrobiologic failure, n (%)\t23 (39.7)\t15 (55.6)\t0.17\t\nVRE-B relapse, n (%)\t7 (11.3)\t5 (16.1)\t0.51\t\nDuration of VRE-B, days, median (IQR)\t3.0 (1.8–4.9)\t3.7 (2.1–4.9)\t0.78\t\nAntibiotic failure, n (%)\t11 (17.7)\t4 (12.9)\t0.55\t\nIQR, interquartile range; VRE-B, vancomycin-resistant enterococcal bacteremia.\n\nTable 3. Logistic regression model assessing association of daptomycin treatment and clinical failure.\n\nCharacteristic\tCrude OR (95% CI)\tAdjusteda OR (95% CI)\t\nDaptomycin\t3.27 (1.27–8.43)\t2.89 (1.08–7.75)\t\nLinezolid\tReference\tReference\t\nCI, confidence interval; OR, odds ratio.\n\na Adjusted for ICU day 1.\n\nA post hoc exploratory analysis was conducted to assess the association of daptomycin MIC with study outcomes as stratified by daptomycin MIC of 4 mg/l (n = 21) versus MIC ⩽2 mg/l (n = 10). There were no statistically significant differences between the two daptomycin MIC groups when assessing rate of clinical failure (p = 0.61), 14-day in-hospital mortality (p = 0.35), and microbiologic failure (p = 0.64).\n\nDiscussion\nWe sought to assess the clinical and microbiologic outcomes of patients with VRE-B treated with either daptomycin or linezolid. The overall high rate of clinical failure was similar to previously published data but, in contrast our findings suggest daptomycin at standard doses is associated with a higher rate of clinical failure relative to linezolid for VRE-B after adjusting for confounding variables. This differs from previous publications that concluded daptomycin is either similar in effectiveness or superior as compared with linezolid.18,19 Most notably, Britt and colleagues conducted a large observational study among Veterans Affairs (VA) patients that concluded that daptomycin had a significantly lower rate of treatment failure compared with linezolid. Differences in our conclusion could be related to the different study populations including underlying comorbidities. For example, approximately 15% of the VA patients in the Britt and colleagues study had a hematologic malignancy in contrast with 54% of our sample which may be a more vulnerable population affected by likely suboptimal daptomycin dosing.18 The secondary endpoints that composed the primary outcome, 14-day in-hospital mortality, microbiologic failure and VRE-B relapse, were all numerically higher in the daptomycin group but not statistically significant. Additionally, the duration of VRE-B was slightly higher in the daptomycin group, but the difference was not statistically significant. This suggests that clinically, daptomycin as given at our institution with standard dosing (~6 mg/kg) but possibly suboptimal, is associated with worse clinical outcomes as compared with linezolid. Our findings are in contrast to the traditional thought that bactericidal agents (i.e. daptomycin) are superior to bacteriostatic agents (i.e. linezolid) for severe invasive infections such as bacteremia although this is a belief with a significant lack of supporting clinical evidence.18,20 A recent systematic review evaluating clinical effectiveness of bactericidal versus bacteriostatic antibiotics demonstrated no intrinsic superiority of bactericidal agents, a finding consistent with our study results and supports the notion to not simply select antibiotics based on the type of in vitro activity.21\n\nOur observational study was conducted at a tertiary care academic medical center with a large hematology/oncology population including bone marrow transplant patients. A significant portion in both treatment groups had a hematologic malignancy or were neutropenic. Despite concern of side effects of bone marrow suppression, linezolid-treated patients had a relatively low mortality rate even with a majority of patients possessing an underlying immunocompromising condition. Among Gram-positive bacterial infections, VRE-B is one of the most common in neutropenic cancer patients.22 Therefore, our results can offer much needed clinical data on treatment approaches and clinical outcomes for this vulnerable group of patients given over 40% of our study population was neutropenic.\n\nGiven the daptomycin dose was relatively fixed (~6 mg/kg) in our study, we were able to evaluate the daptomycin MIC as an independent/predictor variable among daptomycin-treated patients. Our post hoc exploratory analysis of the daptomycin group demonstrated no significant association of daptomycin MIC and study outcomes. This was not consistent with a previous publication evaluating the impact of daptomycin MIC although our null findings may be due to the limited sample size in the daptomycin group.14 A lack of association could also be due to the potential unreliability of obtaining an accurate daptomycin MIC (e.g. 2 mg/l versus 4 mg/l) with automated susceptibility test systems.23 This could result in a nondifferential misclassification of the exposure (daptomycin MIC ⩽2 mg/l versus 4 mg/l) which would bias the outcome measures towards a null finding. Our goal in providing this analysis was to begin to present evidence assessing the causal pathway of daptomycin treatment for VRE-B and mortality or clinical failure. We hypothesize that higher but ‘susceptible’ daptomycin MIC, suboptimal daptomycin dosing, and resulting microbiologic failure are mediating factors leading to attributable mortality due to VRE-B. Further studies evaluating high-dose daptomycin versus linezolid are necessary to better understand the role of daptomycin dose as well as studies assessing the influence of daptomycin MIC on outcomes for daptomycin-treated cases.\n\nLimitations to our study should be considered to appropriately interpret these findings. First, given the retrospective observational nature of this study, we could not assure that all patients had daily blood cultures that would allow for more accurate determination of duration of bacteremia for research purposes. The timing of follow-up blood cultures was dependent on the treating physician at the time of occurrence. Despite this intrinsic limitation, the high rate of infectious diseases consultation likely provided best practice of drawing follow-up blood cultures as clinically indicated. Second, mortality and relapse of VRE-B were only assessed through inpatient hospitalization at our institution. Lastly, our study had a limited sample size and may have been underpowered to detect differences in study outcomes including our post hoc analysis evaluating impact of daptomycin MIC for daptomycin-treated patients. This is not necessarily a concern for finding significance of the primary outcome given that limited power poses the risk of a false-negative conclusion.\n\nDespite these limitations, our study has multiple notable strengths. First, the high rate of infectious diseases consultation ensured that standards of care for VRE-B patients were met. This helps to limit the influence of factors on outcome measures difficult to evaluate retrospectively, such as proper source control for all patients. Second, susceptibility and MIC data were recorded and evaluated for all daptomycin-treated patients which has not been readily assessed in previous studies.18 Although the strength of our analysis is limited (post hoc exploratory analysis with limited sample size), the daptomycin MIC is a key feature for research consideration given the emerging data that it may be associated with clinical outcomes.14 Third, although we acknowledge the emerging evidence that higher doses of daptomycin appear to have a survival advantage, the standard dose of daptomycin (6 mg/kg) utilized in our study reflects dosing practices in many clinical settings despite this being likely suboptimal. This dosing is also similar to previous cohort studies which improves consistency to compare and interpret outcomes between studies.18 Therefore, our results may provide value in its external validity and extrapolation to real-world clinical practice where daptomycin 6 mg/kg is used. Clinicians may consider linezolid over daptomycin at standard doses, given that the effectiveness of daptomycin in our study may be underestimated compared with high-dose daptomycin. Fourth, our population included a large portion of hematologic malignancy patients and many with neutropenia, a high risk, vulnerable population of interest for VRE-B. Lastly, we were able to measure clinical and microbiologic outcomes that may better elucidate mediators of mortality such as microbiologic failure and duration of bacteremia.\n\nIn summary, standard-dose (6 mg/kg) daptomycin treatment was associated with a higher rate of clinical failure as compared with linezolid treatment after adjusting for confounding variables. Linezolid treatment may provide clinical benefit for treatment of VRE-B over daptomycin although further studies inclusive of high-dose daptomycin are needed to draw more definitive conclusions for clinical practice.\n\nRena Rai and Parth Vaidya contributed equally to this work.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nORCID iD: Navaneeth Narayanan \nhttps://orcid.org/0000-0001-5071-9193\n==== Refs\nReferences\n1 \nRamsey AM Zilberberg MD. \nSecular trends of hospitalization with vancomycin-resistant enterococcus infection in the United States, 2000–2006 . Infect Control Hosp Epidemiol \n2009 ; 30 : 184 –186 .19125679 \n2 \nO’Driscoll T Crank CW. \nVancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management . Infect Drug Resist \n2015 ; 8 : 217 –230 .26244026 \n3 \nSong X Srinivasan A Plaut D et al \nEffect of nosocomial vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and costs . Infect Control Hosp Epidemiol \n2003 ; 24 : 251 –256 .12725353 \n4 \nKamboj M Chung D Seo SK et al \nThe changing epidemiology of vancomycin-resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplants (HSCT) recipients . Biol Blood Marrow Transplant \n2010 ; 16 : 1576 –1581 .20685257 \n5 \nPatel R Gallagher JC. \nVancomycin-resistant enterococcal bacteremia pharmacotherapy . Ann Pharmacother \n2015 ; 49 : 69 –85 .25352037 \n6 \nMemel LA Allon M Bouza E et al \nClinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America . Clin Infect Dis \n2009 ; 49 : 1 –45 .19489710 \n7 \nZyvox® (linezolid) . Product information: Zyvox® (linezolid) . New York, NY : Pfizer Inc , 2007 .\n8 \nBrimingham MC Rayner CR Meagher AK et al \nLinezolid for the treatment of multidrug-resistant, Gram-positive infections: experience from a compassionate-use program . Clin Infect Dis \n2003 ; 36 : 159 –168 .12522747 \n9 \nBaddour LM Wilson WR Bayer AS et al \nInfective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications . Circulation \n2015 ; 132 : 1435 –1486 .26373316 \n10 \nMcKinnell JA Arias CA. \nLinezolid vs daptomycin for vancomycin-resistant enterococci: the evidence gap between trials and clinical experience . Clin Infect Dis \n2015 ; 61 : 879 –882 .26063714 \n11 \nBritt NS Potter EM Patel N et al \nComparative effectiveness and safety of standard-, medium-, and high-dose daptomycin strategies for the treatment of vancomycin-resistant enterococcal bacteremia among Veterans Affairs patients . Clin Infect Dis \n2017 ; 64 : 605 –613 .28011602 \n12 \nChuang YC Lin HY Chen PY et al \nEffect of daptomycin dose on the outcome of vancomycin-resistant, daptomycin-susceptible Enterococcus faecium bacteremia . Clin Infect Dis \n2017 ; 64 : 1026 –1034 .28329222 \n13 \nChuang YC Lin HY Chen PY et al \nDaptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteremia: implication of daptomycin dose . Clin Microbiol Infect \n2016 ; 22 : 890.e1–890 e7 26408277 \n14 \nShukla BS Shelburne S Reyes K et al \nInfluence of minimum inhibitory concentration in clinical outcomes of Enterococcus faecium bacteremia treated with daptomycin: is it time to change the breakpoint? \nClin Infect Dis \n2016 ; 62 : 1514 –1520 .27045126 \n15 \nWhang DW Miller LG Partain NM et al \nSystematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections . Antimicrob Agents Chemother \n2013 ; 57 : 5013 –5018 .23896468 \n16 \nBalli EP Benetis CA Miyakis S. \nSystematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia . Antimicrob Agents Chemother \n2014 ; 58 : 734 –739 .24247127 \n17 \nChuang YC Wang JT Lin HY et al \nDaptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis . BMC Infect Dis \n2014 ; 14 : 687 .25495779 \n18 \nBritt NS Potter EM Patel N et al \nComparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: a national cohort study of Veterans Affairs patients . Clin Infect Dis \n2015 ; 61 : 871 –878 .26063715 \n19 \nMave V Garcia-Diaz J Islam T et al \nVancomycin-resistant enterococcal bacteremia: is daptomycin as effective as linezolid? \nJ Antimicrob Chemother \n2009 ; 64 : 175 –180 .19423543 \n20 \nArias CA Contreras GA Murray BE. \nManagement of multidrug-resistant enterococcal infections . Clin Micro Infect \n2010 ; 16 : 555 –562 .\n21 \nWald-Dickler N Holtorn P Spellberg B \nBusting the myth of static vs. cidal: a systemic literature review . Clin Infect Dis \n2018 ; 66 : 1470 –1474 .29293890 \n22 \nSmith PF Birmingham MC Noskin GA et al \nSafety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia . Ann Oncol \n2003 ; 14 : 795 –801 .12702536 \n23 \nHumphries RM Pollett S Sakoulas G. \nA current perspective on daptomycin for the clinical microbiologist . Clin Microbiol Rev \n2013 ; 26 : 759 –780 .24092854\n\n",
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"journal": "Therapeutic advances in infectious disease",
"keywords": "VRE bacteremia; daptomycin; linezolid; minimum inhibitory concentration",
"medline_ta": "Ther Adv Infect Dis",
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"nlm_unique_id": "101606715",
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"pmid": "30792858",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "12522747;12702536;12725353;19125679;19423543;19489710;20569266;20685257;23896468;24092854;24247127;25352037;25495779;26063714;26063715;26244026;26373316;27045126;27475738;28011602;28329222;29293890",
"title": "Comparison of linezolid and daptomycin for the treatment of vancomycin-resistant enterococcal bacteremia.",
"title_normalized": "comparison of linezolid and daptomycin for the treatment of vancomycin resistant enterococcal bacteremia"
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"abstract": "We present a case of a young healthy female who developed recurrent cranial wound infections after a traumatic injury, the etiologic organism finally identified as Mycoplasma hominis, an uncommon and difficult to isolate bacterium.",
"affiliations": "Division of Infectious Diseases, Thomas Jefferson University Hospital, United States.;Department of Neurosurgery, Thomas Jefferson University Hospital, United States.;Department of Clinical Microbiology, Thomas Jefferson University Hospital, United States.;Division of Infectious Diseases, Thomas Jefferson University Hospital, United States.;Division of Infectious Diseases, Thomas Jefferson University Hospital, United States.",
"authors": "Qamar|Zahra|Z|;Tjoumakaris|Stavropoula|S|;Pattengill|Matthew A|MA|;Ahmed|Maliha|M|;Hess|Bryan|B|",
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"doi": "10.1016/j.idcr.2021.e01175",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00131-1\n10.1016/j.idcr.2021.e01175\ne01175\nCase Report\nIntracranial Mycoplasma hominis infection following emergent craniectomy\nQamar Zahra Zahra.qamar@jefferson.edu\na⁎\nTjoumakaris Stavropoula b\nPattengill Matthew A. c\nAhmed Maliha maliha.ahmed2@jefferson.edu\na⁎\nHess Bryan a\na Division of Infectious Diseases, Thomas Jefferson University Hospital, United States\nb Department of Neurosurgery, Thomas Jefferson University Hospital, United States\nc Department of Clinical Microbiology, Thomas Jefferson University Hospital, United States\n⁎ Corresponding authors at: 1015 Chestnut Street, Suite 1020, Philadelphia, PA, 19107, United States. Zahra.qamar@jefferson.edumaliha.ahmed2@jefferson.edu\n08 6 2021\n2021\n08 6 2021\n25 e011757 4 2021\n7 6 2021\n7 6 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nWe present a case of a young healthy female who developed recurrent cranial wound infections after a traumatic injury, the etiologic organism finally identified as Mycoplasma hominis, an uncommon and difficult to isolate bacterium.\n\nKeywords\n\nMycoplasma hominis\nCranial infection\nNeurosurgery\n==== Body\nCase\n\nA 25-year old woman with no pertinent past medical history presented intoxicated after a mechanical fall down a flight of 15 stairs, and was found to have fractures of the left temporo-parietal bone, with extension into the sinuses and acute epidural hematoma with midline shift. She emergently underwent left decompressive hemicraniectomy with duroplasty. Her initial post-surgical course was uncomplicated and she was discharged home after 5 days.\n\nShe returned 1 month later with acute onset expressive aphasia. At that time, she denied any fevers, chills, or night sweats, however she reported clear fluid drainage from her operative site. MRI with and without contrast of the brain revealed a collection concerning for subdural empyema at the site of the recent craniectomy. She underwent a cranial wound washout and purulence was noted in the subdural plane. Intraoperative specimens were negative on Gram stain and grew low quantities (single or few colonies) of normal skin flora including Staphylococcus capitis, Cutibacterium acnes (formerly Propionibacterium acnes) and Staphylococcus epidermidis. Initially she was treated empirically with IV vancomycin, however she was transitioned to daptomycin after failure to achieve therapeutic vancomycin troughs. Her aphasia resolved, and following her clinical improvement she was discharged on post-operative day 4 with a plan to complete a 6-week course of daptomycin.\n\nTwo days after her discharge, she was readmitted with fever, weakness, recurrent aphasia, and edema at her recent surgical site. MRI brain showed focal dehiscence along the temporal bone, leptomeningeal enhancement along the left cerebral hemisphere and a complex extra-axial fluid collection along the left cerebral convexity. There was no clinical or radiographic concern for osteomyelitis in several CT and MRI images enhanced with gadolinium. She was taken to the operating room urgently, and a large amount of purulent drainage was noted in the epidural, subdural, and subarachnoid spaces, without any adjacent bony involvement. These findings were consistent with a complex recurrent empyema and associated cerebritis. Daptomycin, cefepime and metronidazole were started empirically, however she failed to improve and developed worsening aphasia and right-hand weakness. Repeat MRI brain on post-operative day 4 demonstrated extensive leptomeningeal enhancement in the left cerebral hemisphere consistent with meningitis as well as swelling in the left frontoparietal region favoring cerebritis {Fig. 1}. Continuous EEG monitoring was consistent with subclinical seizures. Therefore, the patient was initiated on a short steroid taper and anticonvulsant medications.Fig. 1 MRI Brain with and without contrast T2/FLAIR: Hyperintensity involving left frontal gyrus concerning for focal cerebritis of the left anterior frontal lobe.\n\nFig. 1\n\nGram stains from the intra operative specimens on this readmission revealed white blood cells (WBC) but no organisms and cultures showed no growth for the first 3 days. On day 4, possible pinpoint colonies were noted on anaerobic cultures (CDC anaerobic agar), however Gram staining of the possible colonies was negative. Colonies on CDC anaerobic agar from approximately day 6 of culture are shown in Fig. 2. Upon further review of cultures from the previous admission (collected 1 week prior), these pinpoint colonies were also identified. These findings of fastidious growth and inability to stain organisms with Gram stain raised suspicions for Mycoplasma or Ureaplasma infection and she was started on levofloxacin and doxycycline. Culture growth morphologically consistent with Mycoplasma species was recovered from all 9 intraoperative specimens (brain tissue, scalp, fluid aspiration) submitted for culture on readmission, and Mycoplasma hominis was eventually identified using 16 s ribosomal DNA sequencing. Susceptibility testing was requested, but unable to be obtained.Fig. 2 Pinpoint colonies visible on CDC anaerobic agar.\n\nFig. 2\n\nHer aphasia improved significantly 2 days after starting appropriate therapy. She was ultimately sent home to complete an 8-week course of levofloxacin 750 mg daily and doxycycline 100 mg every 12 h, and a 6 week course of daptomycin 10 mg/kg IV via PICC line. A follow-up MRI brain 1 month after completion of antibiotics revealed improvement in left cerebral edema and leptomeningeal enhancement. Her symptoms completely resolved and she completed her antibiotic regimen without complication. She did well, and 11 months later (delay due to COVID-19 pandemic) she underwent left autologous cranioplasty. She was seen 6 weeks post-operatively, and was doing well.\n\nDiscussion\n\nThis case highlights an otherwise healthy young woman who presented on multiple occasions to the hospital with complications from a neurosurgery with an uncommon organism. Surgical site infections are not uncommon, and typical organisms are usually treated empirically until offending organisms are identified. Appropriate antimicrobial therapy also takes into account antibiotics penetration into abscesses in the cranial nervous system (CNS). Studies have suggested that the blood-brain barrier is different than the blood-CSF barrier and antimicrobial levels in the abscess cavities do not always correlate with the CSF levels [1]. Most common bacteria associated with post-operative cranial infections include S.aureus, followed by coagulase-negative staphylococci, C.acnes, other gram negative bacteria, while no organisms are identified in up to 8% of cases [2,3]. In the case of this patient, empiric therapies, followed by pathogen-directed antibiotics after the first infection resulted in recurrent hospitalization.\n\nThe diagnostic conundrum was caused by the unique characteristics of Mycoplasma spp. These organisms are distinctive among prokaryotes in that they do not have a cell wall (along with other Mollicutes genera such as Ureaplasma). Not only does this make them difficult to treat (most empiric antibiotic regimens target cell walls), it makes identification by Gram staining impossible [4].\n\nThe presence of colonies which could not be observed with Gram stain is what led the infectious disease and clinical microbiology team to suspect Mycoplasma species as a likely pathogen. Careful examination of microbiological cultures revealed pinpoint growth on culture media which could have been missed owing to their small size.\n\nPrior to very recent phylogenetic updates [5] the genus Mycoplasma included 118 species, of which M. genitalium (now Mycoplasmoides genitalium), M. hominis (now Metamycoplasma hominis) and M. pneumoniae (now Mycoplasmoides pneumoniae) are clinically significant. These bacteria have trilayered cell membranes instead of a cell wall. They have the smallest genome of known self-replicating organisms in the bacterial kingdom, with limited biosynthetic capabilities which explains their parasitic or saprophytic existence and fastidious growth requirements which can complicate culture detection. Most mollicutes grow poorly or not at all on standard microbiologic media, however, M. hominis can grow on standard media (such as sheep’s blood trypticase soy agar) and may be detected as early as 2–5 days [4]. These bacteria can also be identified using polymerase chain reaction (PCR) and DNA sequencing when routine cultures identify no growth, or to confirm the identification of suspicious colonies as in our case.\n\nMycoplasmas are mucosally associated, rarely penetrating the submucosa, except in cases of immunosuppression or instrumentation when they can enter the bloodstream and disseminate. The natural habitat of M. hominis is the lower genital tracts of healthy sexually active adults and usually does not cause disease while M. genitalium is associated with non-gonococcal urethritis. M. hominis has been associated with bacterial vaginosis, pelvic inflammatory disease, and post-partum fever [6]. Infants can be colonized with genital mycoplasmas during delivery, and cases of neonatal meningitis, pneumonia and adverse pregnancy outcomes due to M. hominis have been reported due to vertical transmission [7,8].\n\nExtrapulmonary and extragenital infections caused by mycoplasmas are infrequently encountered, and M. hominis is the most common culprit. There has been a recent rise in reported infections due to mycoplasma, likely as a result of more widespread use of PCR and DNA sequencing when routines cultures show no bacterial growth [4]. There are several case reports of cranial infections due to mycoplasmas. A healthy 29 year old male was found to have a brain abscess 3 weeks after craniotomy for a subdural hematoma due to a motor vehicle accident [9]. Brain empyema caused by M. hominis was identified in another 43 year old alcoholic male after sustaining a fall, when he developed signs of infection on day 5 of his admission [10]. Delayed intracranial surgical site infections are hypothesized to be disseminated possibly from iatrogenic genitourinary trauma, while infections presenting early on are potentially inoculated at the time of head trauma [11,12]. Meningitis as a delayed presentation after neurosurgical intervention for intracerebral hemorrhage has also been reported [13]. There are well documented cases of post-operative wound infections after open heart surgeries, causing sternal wound infections, mediastinitis and pericarditis. Other cases include sepsis syndromes, endocarditis and rarely abscesses [14]. These systemic infections are often linked to immunosuppression related to impaired cell-mediated immunity or hypogammaglobulinemia [15].\n\nThere have been no comparative studies to establish optimal therapeutic strategies for treatment of genital mycoplasmas. Standardized methods with defined MIC ranges have been published by the Clinical and Laboratory Standards Institute (CLSI) [16]. Mycoplasmas are intrinsically resistant to all beta-lactams, sulfonamides, trimethoprim and rifampin, with variable resistance of macrolides and lincosamides. M. hominis is intrinsically resistant to erythromycin and azithromycin owing to mutations in 23srRNA. Oral tetracyclines have been the drugs of choice for urogenital infections due to M. hominis, but resistance now occurs in 20–40 % of isolates and varies geographically. Fluoroquinolones are usually active against all mycoplasmas, however resistance in M. hominis has also been reported [[17], [18], [19]]. This has led to recommendations of obtaining in vitro susceptibility testing when M. hominis is recovered from normally sterile sites, from immunocompromised hosts, and/or from persons who have not responded to an initial treatment [17].\n\nConclusion\n\nThis case illustrates the importance of considering M. hominis infection in all well-documented systemic and local infections in which properly collected specimens do not reveal a pathogen, while in the absence of prior antibiotic treatment. In this example, due to growth of skin flora that could be potentially pathogenic, an atypical infection was not initially suspected. On her second presentation, failure to grow bacteria despite copious purulence heightened the suspicion of an atypical infection and careful examination by an experienced pathologist ultimately led to the diagnosis. Review of literature also reveals a potential association of M. hominis infections with head trauma as illustrated in this case report, and has often caused delay in appropriate antimicrobials due to difficulty in identification of these bacteria.\n\nCRediT authorship contribution statement\n\nZahra Qamar: Writing - original draft, Writing - review & editing, Investigation. Stavropoula Tjoumakaris: Writing - review & editing. Matthew A. Pattengill: Writing - review & editing. Maliha Ahmed: Writing - original draft, Writing - review & editing. Bryan Hess: Writing - review & editing, Conceptualization.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n\nAcknowledgements\n\nChristine Slovic, clinical microbiology technologist (ASCP) who helped in isolation of M.hominis from our patient’s cultures\n==== Refs\nReferences\n\n1 Kramer P.W. Griffith R.S. Campbell R.L. Antibiotic penetration of the brain. A comparative study J Neurosurg 31 3 1969 295 302 10.3171/jns.1969.31.3.0295 4390285\n2 Whitson W.J. Ball P.A. Lollis S.S. Balkman J.D. Bauer D.F. Postoperative Mycoplasma hominis infections after neurosurgical intervention J Neurosurg Pediatr 14 2 2014 212 218 10.3171/2014.4.PEDS13547 24856879\n3 Dashti S.R. Baharvahdat H. Spetzler R.F. Operative intracranial infection following craniotomy Neurosurg Focus 24 6 2008 E10 10.3171/FOC/2008/24/6/E10\n4 Dumler J.S. General approaches to identification of mycoplasma, ureaplasma, and obligate intracellular bacteria Jorgensen J.H. Carroll K.C. Funke G. Manual of Clinical Microbiology 2015 ASM Press Washington, DC, USA 1082 1087 10.1128/9781555817381 ch61\n5 Munson E. Carroll K.C. Summary of novel bacterial isolates derived from human clinical specimens and nomenclature revisions published in 2018 and 2019 J Clin Microbiol 59 2 2021 10.1128/JCM.01309-20\n6 Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases | R2 Digital Library 2021 ch0092s0003. Accessed February 25 https://www-r2library-com.proxy1.lib.tju.edu/resource/detail/0323482554/\n7 Capoccia R. Greub G. Baud D. Ureaplasma urealyticum, Mycoplasma hominis and adverse pregnancy outcomes Curr Opin Infect Dis 26 3 2013 231 240 10.1097/QCO.0b013e328360db58 23587772\n8 Taylor-Robinson D. Infections due to species of Mycoplasma and Ureaplasma: an update Clin Infect Dis 23 4 1996 671 682 10.1093/clinids/23.4.671 quiz 683 8909826\n9 Payan D., Seigal N., Madoff S. Infection of a Brain Abscess by Mycoplasma h.\n10 Pailhoriès H. Rabier V. Eveillard M. A case report of Mycoplasma hominis brain abscess identified by MALDI-TOF mass spectrometry Int J Infect Dis 29 2014 166 168 10.1016/j.ijid.2014.08.004 25449252\n11 Henao-Martínez A.F. Young H. Nardi-Korver J.J.L. Burman W. Mycoplasma hominis brain abscess presenting after a head trauma: a case report J Med Case Reports 6 2012 253 10.1186/1752-1947-6-253\n12 Kupila L. Rantakokko-Jalava K. Jalava J. Brain abscess caused by Mycoplasma hominis: a clinically recognizable entity? Eur J Neurol 13 5 2006 550 551 10.1111/j.1468-1331.2006.01209.x 16722987\n13 Zhou M. Wang P. Chen S. Meningitis in a Chinese adult patient caused by Mycoplasma hominis: a rare infection and literature review BMC Infect Dis 16 1 2016 557 10.1186/s12879-016-1885-4 27729031\n14 Mattila P.S. Carlson P. Sivonen A. Life-threatening Mycoplasma hominis mediastinitis Clin Infect Dis 29 6 1999 1529 1537 10.1086/313529 10585808\n15 Meyer R.D. Clough W. Extragenital Mycoplasma hominis infections in adults: emphasis on immunosuppression Clin Infect Dis 17 Suppl 1 1993 S243 9 10.1093/clinids/17.supplement_1.s243 8399923\n16 Waites K.B. Bade D.J. Bébéar C. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline 2011 Clinical and Laboratory Standards Institute Wayne (PA)\n17 Clinical Infectious Disease 2008 Cambridge University Press Cambridge; New York\n18 Kong Y. Qiao Y. Song J. Comparative analysis of male and female populations on prevalence and antibiotic resistance of Mycoplasma hominis in China, 2005-2014 J Glob Antimicrob Resist 6 2016 69 72 10.1016/j.jgar.2016.03.004 27530842\n19 Kasprzykowska U. Sobieszczańska B. Duda-Madej A. Secewicz A. Nowicka J. Gościniak G. A twelve-year retrospective analysis of prevalence and antimicrobial susceptibility patterns of Ureaplasma spp. and Mycoplasma hominis in the province of lower Silesia in Poland Eur J Obstet Gynecol Reprod Biol 220 2018 44 49 10.1016/j.ejogrb.2017.11.010 29154180\n\n",
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"title": "Intracranial Mycoplasma hominis infection following emergent craniectomy.",
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"abstract": "There was a major outbreak of severe acute respiratory syndrome (SARS) affecting more than 300 patients occurring in a private housing estate in Hong Kong, in which an infected renal patient was suspected to be the primary source. It is unknown whether renal patients would represent a distinct group of patients who share some characteristics that could predispose them to have higher infectivity. In this context, we have encountered 4 dialysis patients contracting SARS in a minor outbreak, which involved 11 patients and 4 health care workers, in a medical ward of a regional hospital. Of these 4 dialysis patients, 1 patient was receiving hemodialysis while the other 3 patients were on continuous ambulatory peritoneal dialysis. Fever and radiological changes were their dominant presenting features. All were having positive results for SARS-associated coronavirus ribonucleic acid by reverse transcriptase-polymerase chain reaction performed on their nasopharyngeal aspirates or stool samples. It appeared that treatment with high-dose intravenous ribavirin and corticosteroids could only resolve the fever, but it could not stop the disease progression. All 4 patients developed respiratory failure requiring mechanical ventilation on days 9 through 12. At the end, all of the patients died from sudden cardiac arrest, which was associated with acute myocardial infarction in 2 cases. From this small case series, it appeared that dialysis patients might have an aggressive clinical course and poor outcome after contracting SARS. However, a large-scale study is required to further examine this issue, and further investigation into the immunologic abnormalities associated with the uremic state in this group of patients is also warranted.",
"affiliations": "Department of Medicine and Geriatrics and Intensive Care Unit, Kwong Wah Hospital, Kowloon, Hong Kong SAR, China. apnwong@yahoo.com",
"authors": "Wong|Ping-Nam|PN|;Mak|Siu-Ka|SK|;Lo|Kin-Yee|KY|;Tong|Gensy M W|GM|;Wong|Yuk|Y|;Watt|Chi-Leung|CL|;Wong|Andrew K M|AK|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003428:Cross Infection; D004196:Disease Outbreaks; D005260:Female; D006723:Hong Kong; D006801:Humans; D017053:Infection Control; D017758:Infectious Disease Transmission, Patient-to-Professional; D007676:Kidney Failure, Chronic; D008297:Male; D008506:Medical Waste; D008875:Middle Aged; D010356:Patient Isolation; D010531:Peritoneal Dialysis, Continuous Ambulatory; D006435:Renal Dialysis; D012128:Respiratory Distress Syndrome",
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"title": "Clinical presentation and outcome of severe acute respiratory syndrome in dialysis patients.",
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"abstract": "A 66-year-old woman with a history of stage IA mixed endometrioid and serous endometrial cancer presented to our centre with 2 weeks of worsening headaches nearly 4 years after her initial surgery. At admission, she manifested bitemporal hemianopsia, difficulty walking and clinical and laboratory findings of panhypopituitarism, including diabetes insipidus. Magnetic resonance imaging of the brain revealed a 2.7 cm sellar/suprasellar mass compressing the optic chiasm and infiltrating the pituitary stalk. Computerised tomography documented mediastinal, lung, adrenal and liver involvement, including a 2.5 cm palpable left supraclavicular node that on excisional biopsy demonstrated metastatic endometrial adenocarcinoma. Due to the advanced stage of her cancer as well as the presence of multiple metastases, including lung and hepatic metastases causing post-obstructive pneumonia and coagulopathy, the sellar/suprasellar mass was treated with fractionated radiosurgery rather than surgical excision.",
"affiliations": "Department of Internal Medicine, NYU Langone Health, New York, NY 10016, USA.;Department of Gynecologic Oncology, NYU Langone Health, New York, NY 10016, USA.;Department of Neurosurgery, NYU Langone Health, New York, NY 10016, USA.;Department of Radiation Oncology, NYU Langone Health, New York, NY 10016, USA.;Department of Pathology, NYU Langone Health, New York, NY 10016, USA.;Department of Neurosurgery, NYU Langone Health, New York, NY 10016, USA.;Department of Medical Oncology, NYU Langone Health, New York, NY 10016, USA.",
"authors": "Granina|Evgenia|E|;Fehniger|Julia|J|;Kondziolka|Douglas|D|;Silverman|Joshua|J|;Downey|Andrea|A|;Placantonakis|Dimitris|D|;Muggia|Franco|F|",
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"fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605 Cancer Intelligence \n\n10.3332/ecancer.2020.1083\ncan-14-1083\nCase Report\nEndometrial adenocarcinoma presenting as a suprasellar mass: lessons to be learned\nGranina Evgenia 1 Fehniger Julia 2 Kondziolka Douglas 3 Silverman Joshua 4 Downey Andrea 5 Placantonakis Dimitris 6 Muggia Franco 7 \n1 Department of Internal Medicine, NYU Langone Health, New York, NY 10016, USA\n\n2 Department of Gynecologic Oncology, NYU Langone Health, New York, NY 10016, USA\n\n3 Department of Neurosurgery, NYU Langone Health, New York, NY 10016, USA\n\n4 Department of Radiation Oncology, NYU Langone Health, New York, NY 10016, USA\n\n5 Department of Pathology, NYU Langone Health, New York, NY 10016, USA\n\n6 Department of Neurosurgery, NYU Langone Health, New York, NY 10016, USA\n\n7 Department of Medical Oncology, NYU Langone Health, New York, NY 10016, USA\nCorrespondence to: Evgenia Granina Evgenia.Granina@nyulangone.org\n2020 \n31 7 2020 \n14 108315 5 2020 © the authors; licensee ecancermedicalscience.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 66-year-old woman with a history of stage IA mixed endometrioid and serous endometrial cancer presented to our centre with 2 weeks of worsening headaches nearly 4 years after her initial surgery. At admission, she manifested bitemporal hemianopsia, difficulty walking and clinical and laboratory findings of panhypopituitarism, including diabetes insipidus. Magnetic resonance imaging of the brain revealed a 2.7 cm sellar/suprasellar mass compressing the optic chiasm and infiltrating the pituitary stalk. Computerised tomography documented mediastinal, lung, adrenal and liver involvement, including a 2.5 cm palpable left supraclavicular node that on excisional biopsy demonstrated metastatic endometrial adenocarcinoma. Due to the advanced stage of her cancer as well as the presence of multiple metastases, including lung and hepatic metastases causing post-obstructive pneumonia and coagulopathy, the sellar/suprasellar mass was treated with fractionated radiosurgery rather than surgical excision.\n\nstage IA cancerpanhypopituitarismadenocarcinomaradiosurgeryHER2/neumetastases\n==== Body\nIntroduction\nThe occurrence of metastatic carcinoma to the sella turcica and the pituitary gland has been previously reported, including one instance in a patient with a history of endometrial cancer [1]. We report another instance that highlights clinico-pathologic aspects of interest, including substantial improvement following stereotactic radiotherapy and a gratifying initial response to carboplatin-based chemotherapy. This benefit was followed by rapid disease progression and underscores therapeutic issues that are central to the management of this all too common cancer in women: recognising which patients benefit most from adjuvant therapy, and the development of systemic regiments upon resistance to platinum-based chemotherapy.\n\nCase presentation\nA 62-year-old non-obese computer scientist, originally born in Azerbaijan, presented to an outside institution in 2014 with postmenopausal bleeding. In September 2014, she underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy and pelvic and para-aortic lymph node dissection. Surgical pathology was consistent with a stage IA (23% myometrial invasion), grade 3, mixed endometrioid and serous endometrial adenocarcinoma (Figure 1). No adjuvant treatment was recommended and she underwent twice yearly routine surveillance physical exams by her gynaecologic oncologist.\n\nIn May 2018, she manifested increasingly severe headaches later associated with dizziness, fatigue and weight loss. In August 2018, she was admitted to our centre with findings of right lid ptosis, right ophthalmoplegia, bitemporal visual field deficits and gait unsteadiness. Endocrine testing revealed low TSH (<0.02), fT4 (<0.5), LH (<0.2) and cortisol (2.2), as well as hypernatremia, suggesting panhypopituitarism and diabetes insipidus. The endocrine deficiencies prompted initiation of replacement therapy. Further inpatient work up included a brain MRI, showing a sellar/suprasellar mass with invasion into the sphenoid and cavernous sinuses, and mass effect on the optic chiasm and hypothalamus (Figure 2). Endoscopic transphenoidal resection was initially planned, but pre-operative chest X-ray and CT (Figures 3 and 4) showed extensive tumour in the right upper and right middle lobes with obliteration of the right upper lobe bronchus as well as hilar, mediastinal and left supraclavicular node involvement. CT abdomen pelvis demonstrated multiple bilobar hepatic metastases measuring up to 3.2 cm and bilateral adrenal metastases (Figure 5). The patient’s clinical course was further complicated by post-obstructive pneumonia and coagulopathy. We, therefore, opted to not resect the suprasellar mass. Excisional biopsy of a supraclavicular node showed metastatic adenocarcinoma of Mullerian origin. Immunohistochemistry demonstrated over-expression of PAX8, TP53, P16, ER and Her-2/Neu (3+). We presumed that the sellar/suprasellar mass also represented endometrial adenocarcinoma metastasis and treated it with three fractions of stereotactic radiotherapy (Gamma Knife) at a fairly low total dose (6Gy × 3). The total tumour volume was 16cc. For hypofractionated radiosurgery, a margin dose of 18Gy was used at the 50% isodose line. Fortunately, this led to an impressive tumour regression for the patient. She maintained visual function and oculomotor function improved.\n\nFollowing discharge, the patient began systemic therapy in September 2018 with carboplatin and trastuzumab every 3 weeks. Paclitaxel was initially omitted to avoid impeding the recovery of her improving right ophthalmoplegia. Indeed, while on this regimen, the patient’s right ophthalmoplegia, diplopia and visual field deficits (Figure 6A) totally resolved. Consistent with the clinical improvement, repeat MRI demonstrated a dramatic response of the suprasellar metastasis to the radiotherapy within a few months (Figure 6B and C). We achieved outstanding control of her endocrine deficiencies and water/electrolyte balance throughout her therapy. Repeat CT imaging after five cycles of carboplatin/trastuzumab showed decreased size of metastatic lesions in the lung, liver and adrenal glands. Anticolagulation with apixaban was given after documentation of venous thrombosis in the right femoral vein.\n\nIn January 2019, on her sixth cycle of carboplatin (fourth cycle of paclitaxel), the patient experienced an allergic reaction to the carboplatin. Paclitaxel and double antibody treatment with trastuzumab and pertuzumab were initiated. Subsequently, the patient’s CA125 began to rise and she developed hoarseness, cough and left laryngeal nerve paralysis. Imaging subsequently showed a marked regression of the sellar mass and symptoms were attributed to drug side effects. The treatment was initiated with oxaliplatin and pegylated liposomal doxorubicin (Doxil). Unfortunately following four cycles, she manifested progression not only in lung and liver, but also new scattered small brain metastases in the cerebellum, midbrain, left occipital lobe and left frontal lobe. The patient underwent radiosurgery for nine new brain lesions in June, followed by oxaliplatin in July 2019, this time in combination with capecitabine. In August, hoarseness, relentless non-productive cough and eventually haemoptysis prompted withholding anticoagulation. After documenting right major bronchus invasion by tumour, surgical debulking was performed, followed by radiation confined to the bronchus and adjacent mediastinum. Cisplatin 30 mg/m2 was also given twice weekly as a radiosensitiser. Surgical tissue was sent for Next Generation Sequencing with Foundation Medicine to check for targetable mutations. The tumour was found to be microsatellite stable and no other targetable mutations than HER2 were found (Figure 7). The initial plan was for the patient to start on Pembrolizumab with Lenvatinib in October 2019 [2]. After receiving one dose of Pembrolizumab, she was found to be too weak to tolerate Lenvatinib. The patient then expressed her desire to stop all therapy. She died at home one week later in November 2019.\n\nDiscussion\nEndometrial cancer is the seventh most common malignancy world-wide. In North America, it is the eighth most common cause of cancer death among women [3]. Risk factors include increasing age, unopposed oestrogen exposure, tamoxifen use and obesity. Postmenopausal vaginal bleeding is the usual presenting symptom leading to early detection by sampling the endometrium. Diagnosis and staging include surgical removal and pathologic evaluation of the uterus, cervix, bilateral fallopian tubes and ovaries and regional (e.g., sentinel) lymph nodes. Currently, staging is most often accomplished by minimally invasive robotic surgery that facilitates sentinel node mapping of draining lymph nodes. Outcomes from minimally invasive procedures are similar to those from open, staging procedures and nodal dissection, even in patients with more aggressive histologic subtypes [4, 5].\n\nAtypical sites of metastasis include extra-abdominal lymph nodes, liver, adrenals, brain, bones and soft tissue [6]. Central nervous system (CNS) metastases are generally rare, but in a recent series from University of North Carolina from 2004–2018, 24 cases were identified and 83% of these including ‘high grade’ (i.e., type 2 histologies) [7]. A preceding Mayo Clinic review of 1,632 endometrial cancer included 18 referred for treatment of brain metastases – those with single site of disease had best prognosis [8]. In a Gynaecologic Oncology Group, phase II study investigating the use of pegylated liposomal doxorubicin in 42 patients with recurrent previously treated metastatic endometrial cancer, four patients manifested new brain metastases (two in the cerebellum). Individual case reports describe one case with metastases to cerebellum and one to the pituitary gland [9].\n\nBrain metastases are a significant cause of morbidity and mortality for cancer patients. Without treatment, median survival rates are exceedingly low [10]. Stereotactic radiosurgery (SRS), which involves the administration of targeted high dose radiation to affected areas, has emerged as an effective way to manage systemic disease and improve local control [11]. Prior to the widespread use of SRS, whole brain radiotherapy (WBRT) and surgery were the mainstays of treatment. Both approaches often result in somewhat profound neurotoxicity and a decline in functional status. Although SRS offers the benefit of precision, lower toxicity and shorter treatment course, there has been some debate regarding whether SRS should be offered alone or in combination with WBRT. Our patient initially received SRS alone for a solitary sellar mass with profound results. Subsequently, upon progression of disease, SRS was offered again due to the small volume of lesions despite their significant number (nine lesions in total). WBRT was not offered due to evidence suggesting that there is no difference in overall survival or neurocognitive function when WBRT is given in conjunction with SRS [12]. Due to the number and distribution of brain mets, excisional surgery was not an option, although it should be mentioned that thus far there have been no trials directly comparing surgery to SRS.\n\nIn high risk stage I (grade 3 with deep invasion), Stage II, III endometrioid cancers, as well as Stage I–III serous or clear cell histology cancers, randomised clinical trial evidence that the addition of chemotherapy to radiotherapy in the adjuvant setting results in improved outcomes was lacking until PORTEC III. Generally, endometrial cancer carries a favourable prognosis, except in the case of high grade features (such as in our patient). Although the PORTEC III showed an improvement in survival with adjuvant chemoradiation versus radiotherapy alone, patients with Stage III and serous cancers had a higher rate of recurrence than those with Stage I/II cancers or those with other histologic types [13, 14]. It is unclear whether using PORTEC III to guide treatment would have resulted in a different outcome for our patient at the time of her initial diagnosis as this evidence was not yet available. For patients presenting in advanced stages and with evidence of recurrence more than 6 months after adjuvant therapy, treatment with carboplatin and paclitaxel is favoured [15]. After progression from first-line platinum and taxane-based treatment a wide range of options including targeted therapies and best supportive care should be considered [16].\n\nPossible new targeted therapies include HER2 directed therapies, anti-angiogenic drugs, immune check point inhibitors and antibody-drug conjugates. HER2/NEU over-expression is found in 10%–20% of endometrial carcinomas [17] and is associated with late progression and poor survival. Additionally, HER2/NEU overexpression is common in high grade, especially serous tumours [18]. Fleming et al [19] did not demonstrate a benefit for single agent trastuzumab in HER2 overexpressed or amplified endometrial cancers. In contrast, Fader et al [20] found that the addition of trastuzumab to carboplatin and paclitaxel in patients with metastatic or recurrent uterine serous cancer with HER2/neu overexpression led to improved progression free survival. Interestingly, Teplinsky and Muggia [21] discussed a partial response to single agent lapatinib in persistent or recurrent endometrial cancer. Nevertheless, the routine incorporation of HER2/NEU testing is increasingly being incorporated into the pathologic evaluation of uterine serous cancers to identify patients who may benefit from targeted therapy with trastuzumab. In our patient, however, an initial response to carboplatin and radiation was followed by resistance to other therapies, including those directed against HER2/neu.\n\nConclusion\nRecurrent endometrial cancer with central nervous system metastasis is a rare presentation of recurrent disease. Of note, stereotactic radiation provided excellent control of the patient’s intraparenchymal cerebral disease. An initial response to platinum-based chemotherapy provided the patient an extended period of well-being. Ultimately however, drug resistance ensued and the patient succumbed to rapid disease progression in pre-existing pulmonary and hepatic metastases. In addition, to the key importance of incorporating new knowledge in tumour biology to our increasingly more precise surgical staging, this case serves as a reminder for clinical trials exploring initial treatments beyond surgery and earlier detection of recurrences during follow-up, including enhanced clinical suspicion of CNS metastases, especially following an initial diagnosis of high grade and serous histologic subtypes regardless of stage.\n\nDisclosures\nNone to report.\n\nConflicts of interest\nThere are no conflicts of interest, including financial, non-financial to report.\n\nFunding statement\nThe authors received no specific funding for this work.\n\nAcknowledgment\nThose of us directly involved in treating this patient during the 15 months following diagnosis and treatment of her CNS and other metastatic disease remember her vividly as a most courageous individual questioning us – but always assisting us – in making difficult decisions.\n\nFigure 1. Surgical pathology report (4/23/14).\nFigure 2. Large sellar/suprasellar mass on MRI. Views of the tumour (red arrows) on coronal T2 (A), coronal T1 with gadolinium (B) and sagittal T1 with gadolinium (C). As pointed out in (A), the tumour invades the right cavernous sinus and extends into the sphenoid sinus. The tumour also compresses the optic chiasm and both optic nerves appear oedematous.\nFigure 3. Right hilar mass/opacity with atypical right upper lung zone opacity representing mass or atelectasis. There are multiple smaller nodules in the left chest. Findings suspicious for neoplasia. CT scan of the chest with IV contrast is recommended for further evaluation.\nFigure 4. Extensive tumour in the right upper and right middle lobes. Obliteration of the right upper lobe bronchus. There may be some superimposed atelectasis and/or pneumonia. Tumour is contiguous with the right hilum and there is significant adenopathy in the mediastinum and left supraclavicular region. Numerous subcentimetre pulmonary nodules bilaterally, compatible with metastatic disease. T1 sclerotic lesion, worrisome for metastatic disease.\nFigure 5. Multiple bilobar hepatic metastases measuring up to 3.2 cm. Bilateral adrenal metastases.\nFigure 6. Visual field and radiographic response to radiotherapy. (A) Comparison of Humphreys visual fields for the right (OD) and left (OS) eye at presentation and 3 months after stereotactic radiotherapy. (B) and (C) MRI images obtained 3 months after stereotactic radiotherapy show dramatic regression of the sellar/suprasellar tumour.\nFigure 7. Foundation Medicine molecular analysis. Microsatellite stable. No targetable mutations discovered.\n==== Refs\nReferences\n1. Salvatore B D’Amico D Fonti R Metastasis to the sellar/suprasellar region in a patient with endometrial carcinoma detected by 18F-FDG PET/CT Clin Nucl Med 2018 43 5 363 364 10.1097/RLU.0000000000002037 29485436 \n2. Makker V Rasco D Vogelzang N Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial Lancet Oncol 2019 20 5 711 718 10.1016/S1470-2045(19)30020-8 30922731 \n3. Leslie K Thiel K Goodheart M Endometrial cancer Obstetr Gynecol Clin North Am 2012 39 2 255 268 10.1016/j.ogc.2012.04.001 \n4. Walker J Piedmonte M Spirtos N Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 study J Clin Oncol 2012 30 7 695 700 10.1200/JCO.2011.38.8645 22291074 \n5. Fader AN Java J Tenney M Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: an nrg oncology/gynecologic oncology group ancillary analysis Gynecol Oncol 2016 143 3 460 465 10.1016/j.ygyno.2016.10.016 27743738 \n6. Kurra V Krajewski K Jagannathan J Typical and atypical metastatic sites of recurrent endometrial carcinoma Cancer Imaging 2013 13 1 113 122 10.1102/1470-7330.2013.0011 23545091 \n7. Zhang Y Grant MS Stepp WH Clinical characteristics of CNS metastases from primary gynecologic cancers Gynecol Oncol Rep 2019 30 100518 10.1016/j.gore.2019.100518 31867433 \n8. Uccella S Morris J Multinu F Primary brain metastases of endometrial cancer: A report of 18 cases and review of the literature Gynecol Oncol 2016 142 1 70 75 10.1016/j.ygyno.2016.04.013 27095189 \n9. Sewak S Muggia F Zagzag D Endometrial carcinoma with cerebellar metastasis: a case report and review of the literature J Neuro-Oncol 2002 58 2 137 140 10.1023/A:1016039024196 \n10. Halasz LM Rockhill JK Stereotactic radiosurgery and stereotactic radiotherapy for brain metastases Surg Neurol Int 2013 4 S185 S191 10.4103/2152-7806.111295 23717789 \n11. O’Beirn M Benghiat H Meade S The expanding role of radiosurgery for brain metastases Medicines (Basel) 2018 5 3 90 10.3390/medicines5030090 \n12. Aoyama H Shirato H Tago M Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial JAMA 2006 295 21 2483 2491 10.1001/jama.295.21.2483 16757720 \n13. deBoer S Powell M Mileshkin L Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial Lancet Oncol 2019 20 9 1273 1285 10.1016/S1470-2045(19)30395-X 31345626 \n14. deBoer S Powell M Mileshkin L Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial Lancet Oncol 2018 19 3 295 309 10.1016/S1470-2045(18)30079-2 29449189 \n15. Bestvina CM Fleming GF Chemotherapy for endometrial cancer in adjuvant and advanced disease settings Oncologist 2016 21 10 1250 1259 10.1634/theoncologist.2016-0062 27412393 \n16. Fleming G Second-line therapy for endometrial cancer: the need for better options J Clin Oncol 2015 33 31 3535 3540 10.1200/JCO.2015.61.7225 26195695 \n17. Żyła M Wilczyński J Kostrzewa M The significance of markers in the diagnosis of endometrial cancer Menopausal Rev 2016 15 3 176 185 10.5114/pm.2016.63500 \n18. Grushko T Filiaci V Mundt A An exploratory analysis of her-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group Study Gynecol Oncol 2018 108 1 3 9 10.1016/j.ygyno.2007.09.007 \n19. Fleming G Sill M Darcy K Phase II trial of trastuzumab in women with advanced or recurrent, her2-positive endometrial carcinoma: a Gynecologic Oncology Group Study Gynecol Oncol 2010 116 1 15 20 10.1016/j.ygyno.2009.09.025 19840887 \n20. Fader A Roque D Siegel E Randomized phase ii trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu J Clin Oncol 2018 36 10 2044 2051 10.1200/JCO.2017.76.5966 29584549 \n21. Teplinsky E Muggia F Targeting HER2 in ovarian and uterine cancers: challenges and future directions Gynecol Oncol 2014 135 2 364 370 10.1016/j.ygyno.2014.09.003 25220628\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "14()",
"journal": "Ecancermedicalscience",
"keywords": "HER2/neu; adenocarcinoma; metastases; panhypopituitarism; radiosurgery; stage IA cancer",
"medline_ta": "Ecancermedicalscience",
"mesh_terms": null,
"nlm_unique_id": "101392236",
"other_id": null,
"pages": "1083",
"pmc": null,
"pmid": "32863877",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23545091;29449189;27095189;17945336;22640714;25220628;30922731;23717789;22291074;19840887;31345626;16757720;27980530;27743738;29485436;12164685;30110927;26195695;31867433;27412393;29584549",
"title": "Endometrial adenocarcinoma presenting as a suprasellar mass: lessons to be learned.",
"title_normalized": "endometrial adenocarcinoma presenting as a suprasellar mass lessons to be learned"
} | [
{
"companynumb": "US-TEVA-2020-US-1851390",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "A 70-year-old white man presented to the internal medicine outpatient clinic with symptoms of significant hyperhidrosis. He had been started on antiretroviral therapy (ART) with tenofovir, lamivudine and nevirapine. The patient complained of excessive sweating following severe asthenia after taking nevirapine. Based on these findings, we suspected that the causative agent was nevirapine and a diagnosis of hyperhidrosis due to nevirapine was made. Nevirapine treatment was stopped and was substituted with efavirenz: the patient continued on therapy with tenofovir and lamivudine. The hyperhidrosis symptoms resolved in 2-3 days. No relapse was observed with the new ART regimen. Drugs that induce hyperhidrosis can cause patient discomfort and embarrassment. In our patient, this adverse drug reaction also caused severe asthenia that decreased the patient's physical and emotional quality of life. There was a temporal relationship between the developments of symptoms and starting nevirapine therapy. Once nevirapine was suspended and switched to efavirenz, excessive sweating resolved. An objective causality assessment revealed that the adverse effect was probable. Until further data are available, clinicians should consider discontinuation of nevirapine therapy in patients who develop severe hyperhidrosis.",
"affiliations": "Internal Medicine Service, Hospital de Sagunto, Valencia, Spain.",
"authors": "Belda|A|A|;Borrás-Blasco|J|J|;Rosique-Robles|D|D|;Jiménez|I|I|;López-Montes|L|L|;Casterá|E|E|",
"chemical_list": "D019380:Anti-HIV Agents; D063065:Organophosphonates; D019259:Lamivudine; D019829:Nevirapine; D000068698:Tenofovir; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1258/ijsa.2009.009080",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "23(1)",
"journal": "International journal of STD & AIDS",
"keywords": null,
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000225:Adenine; D000368:Aged; D019380:Anti-HIV Agents; D003875:Drug Eruptions; D006679:HIV Seropositivity; D006801:Humans; D006945:Hyperhidrosis; D019259:Lamivudine; D008297:Male; D019829:Nevirapine; D063065:Organophosphonates; D000068698:Tenofovir",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "61-3",
"pmc": null,
"pmid": "22362694",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyperhidrosis related to nevirapine therapy.",
"title_normalized": "hyperhidrosis related to nevirapine therapy"
} | [
{
"companynumb": "ES-ACTAVIS-2013-26240",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": "1",
"... |
{
"abstract": "An elderly person died of uncontrolled bradycardia in a hospital. The doctor had prescribed 1.35 mg of bisoprolol fumarate orally, but a nurse mistakenly gave the patient 10 mg of the drug 9 hours prior to her death. Bisoprolol was detected in her blood by liquid chromatography-mass spectrometry at a concentration of 176 ng/mL. Even if the patient had chronic heart failure, this concentration is double the expected value. This patient was found to have a mutation within cytochrome P2D6, with thymidine substituted for cytosine at position 100 and cytosine for guanine at position 4180, causing proline to serine and threonine to serine amino acid substitutions. This mutation in the intermediate metabolizer allele reportedly reduces enzyme activity by half. However, in addition to the type of cytochrome P450 allelic variant, the amount of enzyme product influences metabolism of this drug. In this case, the high blood concentration of bisoprolol was only partly attributable to an error in prescription; its concentration was inexplicably high.",
"affiliations": "Division of Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. hashiyad@forensic.med.tohoku.ac.jp",
"authors": "Hashiyada|Masaki|M|;Usui|Kiyotaka|K|;Hayashizaki|Yoshie|Y|;Hosoya|Tadashi|T|;Igari|Yui|Y|;Sakai|Jun|J|;Funayama|Masato|M|",
"chemical_list": "D058671:Adrenergic beta-1 Receptor Antagonists; D003577:Cytochrome P-450 Enzyme System; D017298:Bisoprolol",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "15(2)",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D058671:Adrenergic beta-1 Receptor Antagonists; D000368:Aged; D017298:Bisoprolol; D001919:Bradycardia; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System; D062787:Drug Overdose; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D013058:Mass Spectrometry; D008508:Medication Errors; D009154:Mutation; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "103-5",
"pmc": null,
"pmid": "23219584",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unexpectedly high blood concentration of bisoprolol after an incorrect prescription: A case report.",
"title_normalized": "unexpectedly high blood concentration of bisoprolol after an incorrect prescription a case report"
} | [
{
"companynumb": "PHHY2013JP072237",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the consequences of lamivudine withdrawal in kidney transplant recipients, under immunosuppression, with inactive hepatitis B virus (HBV) infection.\n\n\nBACKGROUND\nHBV infection is more frequent in kidney transplant recipients than in the general population mainly due to the high risk of acquisition during dialysis, before kidney transplantation.\n\n\nMETHODS\nThe records of hepatitis B surface antigen (HBsAg)-positive, immunosuppressed kidney transplant recipients, where lamivudine was withdrawn after transplantation along with reduction in immunosuppressant dose, admitted to our hospital between 2005 and 2012, were retrospectively evaluated.\n\n\nCONCLUSIONS\nThree patients aged 33, 42 and 33, experienced hepatitis flares 2-3 months after lamivudine withdrawal. Serum HBV DNA levels were 2.5×107, 3.4×104 and 4×103 IU/ml in cases 1, 2, and 3, respectively. Lamivudine was re-initiated in all cases which led to rapid viral suppression. However, liver function continued to deteriorate leading to severe jaundice, coagulopathy and encephalopathy. All patients died of acute liver failure within six months after the onset of withdrawal hepatitis.\n\n\nCONCLUSIONS\nLamivudine should be continued as long as immunosuppressive therapy lasts.",
"affiliations": "Department of Organ Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Hepatobilliary Disorders, Cancer Center Sun Yat-sen University, Guangzhou, China.;Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.",
"authors": "Miao|Bin|B|;Lao|Xiang-Ming|XM|;Lin|Guo-Li|GL|",
"chemical_list": "D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D019259:Lamivudine",
"country": "Uganda",
"delete": false,
"doi": "10.4314/ahs.v16i4.27",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1680-6905",
"issue": "16(4)",
"journal": "African health sciences",
"keywords": "Hepatitis B virus; kidney transplantation; lamivudine",
"medline_ta": "Afr Health Sci",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D019259:Lamivudine; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "101149451",
"other_id": null,
"pages": "1094-1100",
"pmc": null,
"pmid": "28479903",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "19729084;12395336;19451024;3006059;19845597;16269182;22414762;21530218;12135009;19217993;19187868;20216412;26038757;17062306;21241754;15518771;22436845;15077027",
"title": "Post-transplant withdrawal of lamivudine results in fatal hepatitis flares in kidney transplant recipients, under immune suppression, with inactive hepatitis B infection.",
"title_normalized": "post transplant withdrawal of lamivudine results in fatal hepatitis flares in kidney transplant recipients under immune suppression with inactive hepatitis b infection"
} | [
{
"companynumb": "CN-STRIDES ARCOLAB LIMITED-2017SP008999",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "To evaluate the efficacy and safety of plasma rich in growth factors (PRGF) eye drops in patients with glaucoma with secondary ocular surface disorders (OSDs) due to surgeries and topical hypotensive drugs use.\nA retrospective case-series study design was used including six patients (eight eyes) diagnosed with glaucoma who received surgical (nonpenetrating deep sclerectomy and/or trabeculectomy) and medical treatments (hypotensive eye drops) to control intraocular pressure (IOP) and who developed secondary OSDs, unresponsive to conventional treatments. Patients were treated with PRGF eye drops (four times a day). Outcome measures were ocular surface disease index (OSDI), best-corrected visual acuity (BCVA, in logarithm of the minimum angle of resolution), visual analog scale (VAS), frequency and severity of symptoms, and IOP. The safety of the treatment was also evaluated.\nSix patients (seven eyes with open-angle glaucoma and one eye with uveitic glaucoma) treated with PRGF eye drops were evaluated. Mean age was 71 years (SD=7.2, range 58-79 years). Five were female and one was male. The mean treatment time was 21.8 weeks (SD=9.0, range 12-36 weeks). The mean time to reach closure of the corneal ulcer was 14.5 (SD=5.5) weeks. A statistical significant reduction in OSDI scale (50.6%), VAS frequency (53.1%), VAS severity (42.0%), and a 41.8% improvement in BCVA were observed (p<0.05). IOP also decreased by 16.6% (p=0.010). Only one of the six patients reported itching in both eyes as an adverse event (AE); however, the patient continued with the PRGF eye drops until the end of therapy; the remaining patients did not report any AEs during the follow-up period.\nIn patients with glaucoma and secondary OSDs refractive to conventional treatments, the treatment with PRGF eye drops could be considered a possible therapeutic option, because it demonstrates an improvement in the signs and symptoms of the ocular surface, as well as a better control of the IOP. This is an initial research work that can open doors for future research to confirm these findings.",
"affiliations": "University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain.;University Institute for Regenerative Medicine and Oral Implantology (UIRMI), University of the Basque Country, Eduardo Anitua Foundation, Vitoria, Spain.;University Institute for Regenerative Medicine and Oral Implantology (UIRMI), University of the Basque Country, Eduardo Anitua Foundation, Vitoria, Spain.;University Institute for Regenerative Medicine and Oral Implantology (UIRMI), University of the Basque Country, Eduardo Anitua Foundation, Vitoria, Spain.",
"authors": "Sánchez-Avila|Ronald M|RM|;Merayo-Lloves|Jesus|J|;Fernández|Maria Laura|ML|;Rodríguez-Gutiérrez|Luis Alberto|LA|;Rodríguez-Calvo|Pedro Pablo|PP|;Fernández-Vega Cueto|Andres|A|;Muruzabal|Francisco|F|;Orive|Gorka|G|;Anitua|Eduardo|E|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S153918",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S153918imcrj-11-097Case SeriesPlasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma Sánchez-Avila Ronald M 1Merayo-Lloves Jesus 1Fernández Maria Laura 12Rodríguez-Gutiérrez Luis Alberto 1Rodríguez-Calvo Pedro Pablo 1Fernández-Vega Cueto Andres 1Muruzabal Francisco 34Orive Gorka 3456Anitua Eduardo 34\n1 University Institute Fernández-Vega, Ophthalmological Research Foundation, University of Oviedo, Oviedo, Spain\n2 Quilmes Eye Center, Buenos Aires, Argentina\n3 University Institute for Regenerative Medicine and Oral Implantology (UIRMI), University of the Basque Country, Eduardo Anitua Foundation, Vitoria, Spain\n4 Biotechnology Institute (BTI), Vitoria, Spain\n5 Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria, Spain\n6 Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria, SpainCorrespondence: Ronald M Sánchez-Avila, Fernández-Vega University Institute, Ophthalmological Research Foundation, Avda Dres Fernández-Vega num 34, Oviedo PC-33012, Spain, Tel +34 98 524 0141, Fax +34 98 523 3288, Email ronald.sanchezavila@gmail.com2018 01 5 2018 11 97 103 © 2018 Sánchez-Avila et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Purpose\nTo evaluate the efficacy and safety of plasma rich in growth factors (PRGF) eye drops in patients with glaucoma with secondary ocular surface disorders (OSDs) due to surgeries and topical hypotensive drugs use.\n\nMaterials and methods\nA retrospective case-series study design was used including six patients (eight eyes) diagnosed with glaucoma who received surgical (nonpenetrating deep sclerectomy and/or trabeculectomy) and medical treatments (hypotensive eye drops) to control intraocular pressure (IOP) and who developed secondary OSDs, unresponsive to conventional treatments. Patients were treated with PRGF eye drops (four times a day). Outcome measures were ocular surface disease index (OSDI), best-corrected visual acuity (BCVA, in logarithm of the minimum angle of resolution), visual analog scale (VAS), frequency and severity of symptoms, and IOP. The safety of the treatment was also evaluated.\n\nResults\nSix patients (seven eyes with open-angle glaucoma and one eye with uveitic glaucoma) treated with PRGF eye drops were evaluated. Mean age was 71 years (SD=7.2, range 58–79 years). Five were female and one was male. The mean treatment time was 21.8 weeks (SD=9.0, range 12–36 weeks). The mean time to reach closure of the corneal ulcer was 14.5 (SD=5.5) weeks. A statistical significant reduction in OSDI scale (50.6%), VAS frequency (53.1%), VAS severity (42.0%), and a 41.8% improvement in BCVA were observed (p<0.05). IOP also decreased by 16.6% (p=0.010). Only one of the six patients reported itching in both eyes as an adverse event (AE); however, the patient continued with the PRGF eye drops until the end of therapy; the remaining patients did not report any AEs during the follow-up period.\n\nConclusions\nIn patients with glaucoma and secondary OSDs refractive to conventional treatments, the treatment with PRGF eye drops could be considered a possible therapeutic option, because it demonstrates an improvement in the signs and symptoms of the ocular surface, as well as a better control of the IOP. This is an initial research work that can open doors for future research to confirm these findings.\n\nKeywords\nglaucomaocular surface disordersplasma rich in growth factorsPRGFplatelet-rich plasmaPRP\n==== Body\nIntroduction\nGlaucoma is the second leading cause of blindness in the world, according to the World Health Organization.1 In Spain, the prevalence of primary open-angle glaucoma (POAG) has been estimated to be 2.1%.2 There are wide arrays of medical and surgical treatments for POAG including nonpenetrant deep sclerectomy (NPDS) and trabeculectomy.3–5 NPDS surgery is indicated in patients diagnosed with glaucoma with elevated intraocular pressure (IOP) after management with maximal topical therapy.5 The most common complications in patients after these surgeries for glaucoma include bleb leakage, hyphema, flat anterior chamber, inflammation in the anterior chamber, bleb encapsulation, and cataract-related surgery.6,7\n\nThe first lines of glaucoma therapeutic treatment include topical eye drops, including several groups of drugs: prostaglandin (PG) analogs, alpha agonists, betablockers, carbonic anhydrase inhibitor, cholinergic, or combined. PG analogs are the most potent topical ocular hypotensors currently in the market.5 The maximum IOP reduction in the daylight curve was obtained by latanoprost (31%), followed by travoprost (28%), bimatoprost (26%), and timolol (23%), which all obtained similar results in the daylight curve valley. According to the 2007 International Dry Eye Workshop report, topical glaucoma medications and their preservatives are responsible for a form of extrinsic evaporative dry eye induced by their pathologic side effects on the ocular surface.8\n\nThe benzalkonium chloride (BAK) preservative associated with the long-term use of topical drugs for glaucoma may induce ocular surface disorders (OSDs), causing a number of symptoms and signs including discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, and corneal surface impairment.9 The mechanisms by which BAK is involved in the induction of OSDs are still being debated, but may potentially result from an especially proinflammatory, toxic, or, more rarely, an allergic etiology. In the treatment of ocular surface pathologies, the so-called PRP (platelet-rich plasma) has been used; clinical efficacy and safety depend on the manufacturing process of each of them; the preparation systems (closed or open), the method of obtaining the blood, the type of anticoagulant, the centrifugation, the activation process, the heating, storage, stability, and dispensing are involved in the manufacturing process.10,11 A particular type of PRP is eye drop PRGF (plasma rich in growth factor) manufactured with the Endoret system (BTI Biotechnology Institute, S.L., Miñano, Álava, Spain). This eye drop has approval as a human use product,12 and it is manufactured with a closed technique that makes its manufacture safer and more reproducible. It has a standardized manufacturing protocol; calcium chloride is used as a platelet activator, which initiates a greater release of growth factors,13,14 and when the PRGF is heated at 56°C for 1 hour, the immunoglobulin E content and complement activity are reduced, and its stability can be maintained up to 6 months.15 All these technical advantages have not been demonstrated by other PRP. Additionally, there is ample evidence of the efficacy and safety of the use of PRGF eye drops in pathologies of the ocular surface and cornea16.\n\nIn the present case-series study report, we evaluate the safety and efficacy of PRGF eye drops, a new blood-based autologous eye drop with significant advantages compared to autologous serum (AS).16 The PRGF eye drops consist of a 100% autologous PRP with no proinflammatory cytokines in their composition.16,17 Basic and clinical studies support the use of PRGF eye drops in several disorders of the ocular surface.16–20 We show for the first time treatment with PRGF eye drops and clinical evaluation of patients with glaucoma who developed diverse OSDs secondary to the inflammatory mechanism of this pathology and to the use of topical hypotensive drugs.\n\nMaterials and methods\nThis retrospective case-series study included patients diagnosed with glaucoma who received surgical (non-penetrating deep sclerectomy and or trabeculectomy) and medical treatments (hypotensive eye drops) to control IOP and who developed secondary OSDs unresponsive to conventional treatments.\n\nThese patients were treated with PRGF eye drops and were evaluated at the Fernandez-Vega University Institute (Oviedo-Spain) by ophthalmologists between January 2010 and September 2013. All patients included in this study signed informed consent for the use of PRGF eye drops and to have their data used in this study. The Clinical Research Committee of Fernandez-Vega University Institute approved this study. The principles of the Declaration of Helsinki were fulfilled to perform this study.\n\nIncluded patients had the following conditions: POAG, any secondary glaucoma, age >18 years, had previous glaucoma surgeries (NPDS, trabeculectomy), and had developed diverse severe OSDs (dry eye disease [DED], corneal ulcers, and so on) after glaucoma surgery that did not respond (with poor or no response) to conventional treatments (artificial tears, topical antibiotics and steroids, oral antibiotics or antiviral drugs, therapeutic contact lenses, and lacrimal plugs), or AS and/or cyclosporine.\n\nFor the diagnosis of DED, patients must meet all the following criteria: 1) Schirmer I-test <5 mm (the measurement of tear secretion requires about 5 min, allowing for natural blinking); 2) Tear film breakup time <5 seconds; 3) Subjective symptoms of dry eye in the level of severe (as defined in EDE Workshop Committee in 2007).8 4) Lesion on the ocular surface (dry eye syndrome, blepharitis, corneal ulcer, keratitis, and so on).\n\nPRGF preparation and patients’ treatment\nBlood from patients was collected into 9 mL tubes, after informed consent. Samples were centrifuged at 580× g for 8 min at room temperature in an Endoret System centrifuge (BTI Biotechnology Institute, S.L., Miñano, Álava, Spain). The whole column of PRGF was collected after centrifugation, avoiding the buffy coat that contains the leukocytes, using an Endoret ophthalmology kit (BTI Biotechnology Institute, S.L., Miñano, Álava, Spain). The obtained supernatant was incubated at 37°C for 1 h, and then heat treated at 56°C for 60 min. The plasma supernatants were filtered, aliquoted, and stored at −20°C until use. All procedures were performed under highly sterile conditions, operating inside a laminar flow hood. The eye drops were then heated to 57°C to inactivate the complement (immuno-safe). Before initiating the treatment, the patients were instructed to keep the PRGF eye-drop dispensers at −20°C for a maximum of 3 months; each dispenser was used for 3 consecutive days (the eye drops could be at 8°C or ambient temperature).\n\nPRGF eye drops were applied topically (in the conjunctival sac) four times daily for 6 weeks in the affected eye. In case of poor or no initial response, an additional 6 weeks of treatment was administered, up to a maximum of 36 weeks. The treatment with PRGF eye drops did not exclude the use of other concomitant treatments (antibiotic agents, anti-inflammatory, artificial tears, and so on) when considered necessary by clinicians.\n\nOutcome measures\nBoth the demographic (gender, age) and clinical variables of patients (systemic diseases, type of glaucoma, hypotensive eye drops, eye diseases, eye surgery, associated treatment, and use of topical corticosteroids) were collected. All necessary data were obtained from patient clinical records.\n\nTreatment response was determined by a combination of clinical examination (slit lamp) and evaluation of ocular surface symptoms using diverse outcome measures: Ocular surface disease index (OSDI), the best-corrected visual acuity (BCVA) using Snellen optotype (conversion to logarithmic scale of the minimum angle of resolution [LogMAR]), visual analog scale (VAS, frequency and severity of symptoms), and IOP were also determined. All measures were taken before starting (baseline), and after finishing treatment with PRGF eye drops. The following times were recorded: duration of treatment with PRGF eye drops, follow-up after treatment, and time to reach closure of the corneal ulcer.\n\nThe evaluation of ocular surface symptoms was performed using the Spanish version of the OSDI scale that includes 12 questions,21 and estimates the severity of dry-eye symptoms in a range from 0 to 100, and with the VAS, which is a 100-point scale in which 0=no discomfort and 100=maximal discomfort (dryness, burning/stinging, photophobia, foreign body sensation, blurred vision, itching, and pain), both in the frequency and severity of symptoms. IOP was determined with the Perkins tonometer, based on the same principles as the Goldmann applanation tonometry. A safety assessment was also performed recording and evaluating any adverse event (AE) or complication that occurred during the patient’s follow-up period.\n\nStatistical analysis\nData were analyzed using absolute and relative frequency distributions for qualitative variables, and mean values and SDs for quantitative variables. Patients’ treatment response was analyzed comparing outcomes measures’ mean values between baseline and after PRGF treatment using the nonparametric Wilcoxon statistical test. The level of statistical significance was set at p<0.05. The statistical software package SPSS v19.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.\n\nResults\nData from six patients (seven eyes with open-angle glaucoma and one eye with uveitic glaucoma) treated with PRGF eye drops were recorded and evaluated. Mean age of patients was 71 years (SD=7.2, range 58–79 years). Five were female and one patient was male. Patients had different previous associated eye diseases, and received diverse surgery types and topical hypotensive drugs therapy for glaucoma. Table 1 summarizes the clinical situation of the patients. Patients received between 12 and 36 weeks of treatment with PRGF eye drops. Mean treatment time was 21.8 weeks (SD=9.0). The mean time of follow-up after treatment was 12.3 weeks (SD=4.5). The mean time to reach closure of the corneal ulcer was 14.5 (SD=5.5) weeks.\n\nResults of primary outcome measures before and after PRGF eye-drop treatment are summarized in Figures 1 and 2. A significant reduction in the OSDI scale was observed from a baseline value of 50.6 (SD=37.6) to a final post-treatment value of 21.0 (SD=11.5). The latter represents a total reduction of 50.6 %, which was statistically significant (p=0.027; Figure 1A). The BCVA was reduced from a baseline value of 0.59 (SD=0.43) to a final post-treatment value of 0.33 (SD=0.31), showing an improvement of 41.84% in BCVA (p≤0.0326; Figure 1B).\n\nRegarding the ocular symptoms (discomfort, dryness, burning/stinging, photophobia, foreign body sensation, blurred vision, itching, and pain) measured by the VAS score in frequency of symptoms, a significant decrease was measured ranging from a baseline value of 82.5 (SD=25.3) to a final post-treatment value of 38.3 (SD=12.9). This represented a reduction of 53.1% which was statistically significant (p=0.026; Figure 1C). Finally, the VAS score of severity of symptoms resulted in a relevant and significant decrease of 42.0%, going from a baseline value of 69.2 (SD=22.5) to a final post-treatment value of 38.3 (SD=12.9), which was statistically significant (p=0.027; Figure 1D). Regarding IOP, a reduction of 16.6% was observed after treatment, going from a baseline value of 15.13 (SD=3.0) to a final post-treatment value of 12.6 (SD=2.8), which was statistically significant (p=0.010). Figures 1 and 2 show mean values before and after PRGF eye-drop treatment.\n\nRegarding safety assessment, only one of the six patients reported itching in both eyes as an AE but continued with PRGF treatment. The remaining patients did not report any AEs during the follow-up period. The use of corticosteroids, antibiotics, or other additional treatments was not necessary during follow-up in patients treated with PRGF eye drops.\n\nFigures 3–5 show eye examination with slit lamp of three of the included patients with glaucoma and associated OSDs, where the clinical improvement after treatment with PRGF eye drops was clinically significant.\n\nDiscussion\nThis retrospective clinical study involved six patients with glaucoma and secondary OSDs treated with PRGF eye drops. To our knowledge, this is the first study in the literature that evaluates a blood-derived treatment based on plasma and platelets in patients with glaucoma, used to treat secondary OSDs.\n\nPatients suffering from glaucoma usually have ocular surface alterations associated with the use of topical eye drops. Most of these topical drugs have preservatives that stimulate the inflammatory mechanisms that exacerbate glaucoma, leading to ocular surface disease. Topical agents and in particular preservatives such as BAK, which induce the expression of inflammatory cell markers at the ocular surface, may provoke epithelial cell damage, cell death by apoptosis, and a decrease in goblet cell density.22 Recently, it was reported that the use of preservatives was associated with a lower expression of MUC5AC and the lowest MUC5AC levels were associated with the highest ICAM-1 and HLA-DR levels.23 This negative correlation suggested inflammation as a possible basis for the decreased mucin expression, in addition to any direct effect of BAK on goblet cells themselves.8,22 Pisella et al, in an unmasked study of 4,107 glaucoma patients, found that the frequency of ocular surface changes was twice as high in those receiving preserved drops as in those receiving unpreserved drops, and the frequency of signs and symptoms was dose-related.24\n\nResults reported herein support that in glaucoma patients with secondary OSDs, treatment with PRGF eye drops could be considered a possible therapeutic option to improve associated signs and symptoms and to reduce IOP. There are several potential explanations for these effects. Firstly, PRGF eye drops contain a cocktail of trophic agents. For example, they contain large amounts of epidermal growth factor, which may be responsible for the increased proliferation and migration activity, promoting accelerated wound healing time in corneal injuries.25–27 In addition, PRGF eye drops also contain fibroblast growth factor, insulin-like growth factor-1, and platelet-derived growth factor (PDGF), with critical roles in promoting proliferation and migration of stromal fibroblasts in ocular surface tissues; the PRGF eye drops also have nerve growth factor with its neurotrophic properties in the cornea.17 Secondly, several studies have supported that PRGF eye drops reduce scar formation because of the balance of PDGF/transforming growth factor-β1 (TGF-β1) in their composition.16 Thirdly, PRGF eye drops exert potent anti-inflammatory effects.17 A better control on inflammation could contribute to a higher treatment adherence in patients with glaucoma. Last but not least, PRGF eye drops have shown clinical efficacy in patients with moderate-to-severe dry eye, diverse epithelial defects, and corneal ulcers;18,19,10,28–30 the efficacy and safety of PRGF eye drops in the treatment of neurotrophic keratitis have also been demonstrated.31\n\nTGF-β because of its pleiotropic properties contributes to normal cellular physiologic processes, and also to the development of ophthalmologic pathologies such as glaucoma or corneal scars.27,32 It is known that the increased activity of TGF-β leads to the increase of deposits in the extracellular matrix of the trabecular tissue, with increase in the outflow resistance of the aqueous humor, and the consequent elevation of intraocular pressure; anti-TGF-β drugs are being developed as possible therapeutic options for glaucoma.32,33 In vitro and in vivo studies have shown that PRGF eye drops can modulate the activity of TGF-β, decreasing tissue fibrosis and favoring cell regeneration,16,15 these mechanisms could explain the decrease in intraocular pressure.\n\nWhen interpreting the results from the present study, some limitations should be considered. One important issue is that results come from a retrospective study and in a small number of patients. This type of study has less validity than prospective clinical studies, because of the issues of selection bias and confounding factors. Further prospective and controlled clinical studies should be performed to corroborate the therapeutic potential efficacy of PRGF eye drops in glaucoma patients with secondary OSDs.\n\nConclusion\nIn this study, patients with glaucoma and secondary OSDs refractive to conventional treatments showed a significant global clinical improvement after treatment with PRGF eye drops, in signs and symptoms. Although more clinical studies are needed, treatment with PRGF eye drops could be considered a possible therapeutic option in glaucoma patients with secondary OSDs, to improve both clinical signs and symptoms of associated pathology and also for reducing IOP.\n\nAcknowledgments\nThe authors would like to thank Virginia Cuadrado for her support with English grammar. This study received funding from the Ministry of Economy and Competitiveness of the Spanish Government, within the project denominated SURFEYE (reference RTC-2014-2375-1).\n\nDisclosure\n\nThe authors declare the following competing financial interest(s): EA is the Scientific Director of BTI Biotechnology Institute, GO and FM are scientists at BTI Biotechnology Institute, a dental implant company that investigates in the fields of oral implantology and PRGF-Endoret technology. The authors report no other conflicts of interest in this work.\n\nFigure 1 Bar graphs showing the different outcome measures before and after treatment with PRGF (OSDI [A], BCVA [B], and VAS severity–frequency of symptoms [C–D]).\n\nNote: *p<0.05.\n\nAbbreviations: BCVA, best-corrected visual acuity; OSDI, ocular surface disease index; PRGF, plasma rich in growth factors; VAS, visual analog scale.\n\nFigure 2 Bar graph showing IOP before and after PRGF treatment.\n\nNote: *p<0.05.\n\nAbbreviations: IOP, intraocular pressure; PRGF, plasma rich in growth factors.\n\nFigure 3 Photographs showing one of the cases (patient #3) with an epithelial and stromal ulcer defect in the left eye.\n\nNotes: (A) Baseline situation before treatment with PRGF eye drops showing the corneal ulcer that reaches deep stroma, with consequent risk of corneal perforation. (B) During PRGF treatment, with a therapeutic contact lens 2 weeks after a second amniotic membrane transplant. (C) Final clinical situation 1 month after finishing PRGF treatment observing corneal defect closure and corneal regeneration in process.\n\nAbbreviation: PRGF, plasma rich in growth factors.\n\nFigure 4 A sequence of three photographs showing one of the treated cases (patient #4) with an epithelial and stromal defect in the left eye with new vessels, and an additional limbic insufficiency.\n\nNotes: (A, B) Baseline situation before initiating PRGF treatment with an important stromal defect and ocular surface inflammation and associated neovascularization. (C) Final clinical situation after PRGF treatment showing the favorable closure of the epithelial and stromal defect, inflammation reduction, and less vascularization.\n\nAbbreviation: PRGF, plasma rich in growth factors.\n\nFigure 5 Photographs (patient # 5) with deep corneal ulcer, associated neovessels and risk of corneal perforation.\n\nNotes: (A) Basal situation: deep corneal ulcer, thick neovessels, and risk of perforation. (B) Four weeks of PRGF treatment: closure of corneal ulcer, minor inflammation, and decrease of neovessels. Corneal regeneration continues to progress.\n\nAbbreviation: PRGF, plasma rich in growth factors.\n\nTable 1 Demographic and clinical data of six included patients with glaucoma\n\nPatient number\tAge\tGender\tGlaucoma type\tPrevious hypotensive drugs\tPrevious ophthalmic surgeries\tOther ocular pathologies\tSecondary OSDs\tPRGF weeks\t\n1\t76\tFemale\tOpen angle\tApraclonidine (BE)\tCataract surgery (BE)\tAMD (BE)\nPosterior blephatritis (BE)\tDED/corneal ulcer (BE)\t18\t\n2\t79\tFemale\tOpen angle\tTimolol/bimatoprost/dorzolamide/pilocarpine (LE)\tAhmed valve (LE)\tRetinal detachment (LE)\nCorneal dystrophy aphakia (RE)\tCorneal ulcer (LE)\t30\t\n3\t66\tFemale\tOpen angle\tTimolol/latanoprost/travoprost/brinzolamide (LE)\tCataract (BE)\nVitrectomy with silicon oil Amniotic membrane (LE)\tAmblyopia (LE)\nRetinal detachment (LE)\tCorneal ulcer (LE)\t18\t\n4\t65\tFemale\tOpen angle\tTimolol/bimatoprost/dorzolamide/brinzolamide (LE)\tVitrectomy and scleral buckling (RE)\nCataract surgery (BE)\tMacular hole (LE)\nAmblyopia (LE)\nAMD (BE)\tCorneal ulcer (LE)\t36\t\n5\t58\tFemale\tUveitic\tTimolol/travoprost/brinzolamide/brimonidine (RE)\tAhmed valve (RE)\nConjunctival flap (RE)\nCataract surgery (RE)\tNecrotizing scleritis and uveitis (RE)\nCentral trophic ulcer (RE)\tCorneal ulcer (RE)\t30\t\n6\t74\tMale\tOpen angle\tTravaprost/brinzolamide (BE)\tNonpenetrating deep sclerectomy (BE)\tAMD (BE)\tDED/corneal ulcer (BE)\t12\t\nAbbreviations: AMD, age-related macular degeneration; BE, both eyes; DED, dry eye disease; LE, left eye; OSD, ocular surface disorders; PRGF, plasma rich in growth factors; RE, right eye.\n==== Refs\nReferences\n1 Pascolini D Mariotti SP Global estimates of visual impairment: 2010 Br J Ophthalmol 2012 96 5 614 618 22133988 \n2 Anton A Andrada MT Mujica V Calle MA Portela J Mayo A Prevalence of primary open-angle glaucoma in a Spanish population: the Segovia study J Glaucoma 2004 13 5 371 376 15354074 \n3 Chiselita D Non-penetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma surgery Eye (Lond) 2001 15 Pt 2 197 201 11339590 \n4 Mermoud A Schnyder CC Nonpenetrating filtering surgery in glaucoma Curr Opin Ophthalmol 2000 11 2 151 157 10848223 \n5 Lachkar Y Hamard P Nonpenetrating filtering surgery Curr Opin Ophthalmol 2002 13 2 110 115 11880725 \n6 Lachkar Y Neverauskiene J Jeanteur-Lunel MN Nonpenetrating deep sclerectomy: a 6-year retrospective study Eur J Ophthalmol 2004 14 1 26 36 15005582 \n7 Baudouin C Labbe A Liang H Pauly A Brignole-Baudouin F Preservatives in eyedrops: the good, the bad and the ugly Prog Retin Eye Res 2010 29 4 312 334 20302969 \n8 Michael AL Christophe B Jules B The definition and classification of dry eye disease: report of the definition and classification subcommittee of the International Dry Eye WorkShop (2007) Ocul Surf 2007 5 2 75 92 17508116 \n9 Monaco G Cacioppo V Consonni D Troiano P Effects of osmoprotection on symptoms, ocular surface damage, and tear film modifications caused by glaucoma therapy Eur J Ophthalmol 2011 21 37 243 250 20872359 \n10 Alio JL Colecha JR Pastor S Rodriguez A Artola A Symptomatic dry eye treatment with autologous platelet-rich plasma Ophthalmic Res 2007 39 3 124 129 17374962 \n11 Alio JL Rodriguez AE Martinez LM Rio AL Autologous fibrin membrane combined with solid platelet-rich plasma in the management of perforated corneal ulcers: a pilot study JAMA Ophthalmol 2013 131 6 745 751 23559361 \n12 Anitua E Prado R Orive G Closing regulatory gaps : new ground rules for platelet-rich plasma Trends Biotechnol 2015 33 9 492 495 26319248 \n13 Freire V Andollo N Etxebarria J Duran JA Morales MC In vitro effects of three blood derivatives on human corneal epithelial cells Invest Ophthalmol Vis Sci 2012 53 9 5571 5578 22786903 \n14 Freire V Andollo N Etxebarria J Hernaez-Moya R Duran JA Morales MC Corneal wound healing promoted by 3 blood derivatives: an in vitro and in vivo comparative study Cornea 2014 33 6 614 620 24727633 \n15 Riestra AC Alonso-Herreros JM Merayo-Lloves J Plasma rico en plaquetas en superficie ocular Arch Soc Esp Oftalmol 2016 91 10 475 490 Spanish 27062018 \n16 Anitua E Muruzabal F Tayebba A Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies Acta Ophthalmol 2015 93 8 e605 e614 25832910 \n17 Anitua E Muruzabal F de la Fuente M Merayo J Duran J Orive G Plasma rich in growth factors for the treatment of ocular surface diseases Curr Eye Res 2016 41 7 875 882 26828610 \n18 Merayo-Lloves J Sanchez-Avila RM Riestra AC Safety and efficacy of autologous plasma rich in growth factors eye drops for the treatment of evaporative dry eye Ophthalmic Res 2016 56 2 68 73 27229893 \n19 Merayo-Lloves J Sanchez RM Riestra AC Autologous plasma rich in growth factors eyedrops in refractory cases of ocular surface disorders Ophthalmic Res 2015 55 2 53 61 26569104 \n20 Anitua E Alonso R Girbau C Aguirre JJ Muruzabal F Orive G Antibacterial effect of plasma rich in growth factors (PRGF® -Endoret® ) against Staphylococcus aureus and Staphylococcus epidermidis strains Clin Exp Dermatol 2012 37 6 652 657 22329713 \n21 Schiffman RM Christianson MD Jacobsen G Hirsch JD Reis BL Reliability and validity of the Ocular Surface Disease Index Arch Ophthalmol 2000 118 5 615 621 10815152 \n22 Onizuka N Uematsu M Kusano M Sasaki H Suzuma K Kitaoka T Influence of different additives and their concentrations on corneal toxicity and antimicrobial effect of benzalkonium chloride Cornea 2014 33 5 521 526 24619166 \n23 Baudouin C Pisella PJ Fillacier K Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies Ophthalmology 1999 106 3 556 563 10080214 \n24 Pisella PJ Pouliquen P Baudouin C Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication Br J Ophthalmol 2002 86 4 418 423 11914211 \n25 Freire V Andollo N Etxebarria J Durán JA Morales MC In vitro effects of three blood derivatives on human corneal epithelial cells Invest Ophthalmol Vis Sci 2012 53 9 5571 5578 22786903 \n26 Freire V Andollo N Etxebarria J Hernáez-Moya R Durán JA Morales MC Corneal wound healing promoted by 3 blood derivatives: an in vitro and in vivo comparative study Cornea 2014 33 6 614 620 24727633 \n27 Anitua E Muruzabal F Alcalde I Merayo-Lloves J Orive G Plasma rich in growth factors (PRGF-Endoret) stimulates corneal wound healing and reduces haze formation after PRK surgery Exp Eye Res 2013 115 153 161 23872360 \n28 Lopez-Plandolit S Morales MC Freire V Etxebarria J Duran JA Plasma rich in growth factors as a therapeutic agent for persistent corneal epithelial defects Cornea 2010 29 8 843 848 20508516 \n29 Lopez-Plandolit S Morales MC Freire V Grau AE Duran JA Efficacy of plasma rich in growth factors for the treatment of dry eye Cornea 2011 30 12 1312 1317 22012030 \n30 Alio JL Pastor S Ruiz-Colecha J Rodriguez A Artola A Treatment of ocular surface syndrome after LASIK with autologous platelet-rich plasma J Refract Surg 2007 23 6 617 619 17598582 \n31 Sanchez-Avila RM Merayo-Lloves J Riestra AC Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops Int Ophthalmol Epub 2017 6 15 \n32 Agarwal R Agarwal P Future target molecules in antiglaucoma therapy: tgf-Beta may have a role to play Ophthalmic Res 2010 43 1 1 10 19829006 \n33 Wang J Harris A Prendes MA Targeting transforming growth factor-beta signaling in primary open-angle glaucoma J Glaucoma 2017 26 4 390 395 28169917\n\n",
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"keywords": "PRGF; PRP; glaucoma; ocular surface disorders; plasma rich in growth factors; platelet-rich plasma",
"medline_ta": "Int Med Case Rep J",
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"title": "Plasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma.",
"title_normalized": "plasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma"
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"abstract": "Leprosy is rare in Australia, particularly in the southern states. We report two cases of leprosy in southern Australia that presented to the dermatology outpatients' department within a 4-month period. The presentation of the first case was complex, making the correct diagnosis difficult. Both cases involved immigrants from South-East Asia, were classified as multi-bacillary leprosy as defined by the World Health Organization, and were commenced on the recommended multiple drug therapy. The ensuing clinical course was complicated, with both cases developing Type 1 leprosy reactions. The first case also developed the rare but serious dapsone-induced delayed hypersensitivity reaction.",
"affiliations": "Department of Dermatology, Flinders Medical Centre, South Australia, Australia. rmanifol@bigpond.net.au",
"authors": "Manifold|Rachel|R|;Marshman|Gillian|G|",
"chemical_list": "D005938:Glucocorticoids; D007917:Leprostatic Agents; D003622:Dapsone; D002991:Clofazimine; D012293:Rifampin",
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"journal": "The Australasian journal of dermatology",
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"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D001132:Arm; D001415:Back; D002991:Clofazimine; D003622:Dapsone; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D005145:Face; D005260:Female; D005542:Forearm; D005938:Glucocorticoids; D006801:Humans; D007917:Leprostatic Agents; D015439:Leprosy, Borderline; D008297:Male; D009166:Mycobacterium leprae; D012293:Rifampin; D016896:Treatment Outcome",
"nlm_unique_id": "0135232",
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"pages": "36-40",
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"pmid": "19178490",
"pubdate": "2009-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leprosy: not always an easy diagnosis and often a management challenge.",
"title_normalized": "leprosy not always an easy diagnosis and often a management challenge"
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"abstract": "A 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.",
"affiliations": "Department of Neurology, Rajagiri Hospital, Kochi, India.;Department of Neurology, Rajagiri Hospital, Kochi, India.;Department of Neurology, Rajagiri Hospital, Kochi, India.;Department of Neurology, Rabindranath International Institute of Cardiac Sciences, Kolkata, India.",
"authors": "Alapatt|Paul J|PJ|;Panwar|Ajay|A|;Kuruttukulam|Gigy Varkey|GV|;Sundar|Kaushik|K|",
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"country": "Korea (South)",
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"doi": "10.5469/neuroint.2020.00416",
"fulltext": "\n==== Front\nNeurointervention\nNeurointervention\nNI\nNeurointervention\n2093-9043\n2233-6273\nKorean Society of Interventional Neuroradiology\n\n33460536\n10.5469/neuroint.2020.00416\nneuroint-2020-00416\nCase Report\nLessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility\nhttp://orcid.org/0000-0002-2051-5664\nAlapatt Paul J MD DM 1\nhttp://orcid.org/0000-0002-8938-9168\nPanwar Ajay MD DM 1\nhttp://orcid.org/0000-0003-1614-5434\nKuruttukulam Gigy Varkey MD DM 1\nhttp://orcid.org/0000-0003-0108-1810\nSundar Kaushik MD DM 2\n1 Department of Neurology, Rajagiri Hospital, Kochi, India\n2 Department of Neurology, Rabindranath International Institute of Cardiac Sciences, Kolkata, India\nCorrespondence to: Ajay Panwar, MD, DM Department of Neurology, Rajagiri Hospital, Chunangamvely, Aluva, Kochi 683112, Kerala, India Tel: +91-8948800337 Fax: +91-40-27154758 E-mail: ajay19panwar@gmail.com\n3 2021\n19 1 2021\n16 1 7882\n18 11 2020\n12 12 2020\n14 12 2020\nCopyright © 2021 Korean Society of Interventional Neuroradiology\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nA 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.\n\nReversible cerebral vasoconstriction syndrome\nMilrinone\nDiagnostic cerebral angiography\nVasculitis\n==== Body\nINTRODUCTION\n\nThe diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) often may be misleading and delayed because of the dynamic evolution of clinico-radiological features. RCVS is known to have an initial week of a hemorrhagic phase, which is later followed by ischemic complications. The angiographic features of RCVS are often best demonstrable only in the ischemic phase. Here, we present an unusual case of large basal ganglia hemorrhage in which the diagnosis was initially considered vasculitis. The diagnosis of RCVS was subsequently established by excellent angiographic reversibility to intra-arterial milrinone.\n\nCASE REPORT\n\nA 34-year-old pregnant female (gravida 4, para 2, abortion 1, intrauterine death 1) at 32 weeks of gestation presented with preterm premature rupture of membranes. The patient had a background history of dermatomyositis with interstitial lung disease in remission for the last 4 years. She was initially optimized on steroids and mycophenolate mofetil and subsequently switched to tacrolimus after detection of pregnancy. She underwent an uneventful emergency cesarean section under regional anesthesia. During the next day, she developed a moderately severe headache, which was holocranial and continuous. She had no features of raised intracranial tension. Her headache was not relieved with analgesics, and on the second postoperative day, she developed a generalized seizure during sleep. She continued to be in a comatose state following the seizure with a Glasgow Coma Scale score of eye opening (E)1, verbal response (V)2, best motor response (M)5. Serial blood pressure readings were normal in the post-partum period. Examination revealed bilateral pupils 1.5 mm in size and a sluggish reaction to light, along with a paucity of movements in the right extremities. Magnetic resonance imaging of the brain showed a large intra-parenchymal hematoma involving the left ganglio-capsular and frontotemporal regions causing a midline shift of 16 mm with intra-ventricular extension and uncal herniation (Fig. 1A). She underwent emergency craniotomy and hematoma evacuation. A postoperative computed tomography (CT) scan of the brain showed good evacuation of the hematoma and correction of midline shift (Fig. 1B). Computed tomography angiography (CTA) showed mild focal narrowing and irregularities in distal branches of bilateral middle cerebral arteries, anterior cerebral arteries, and posterior cerebral arteries (Fig. 1C). In the background of dermatomyositis and radiological findings, the possibility of vasculitis was considered. Erythrocyte sedimentation rate was 25 mm/h and C-reactive protein was 6 mg/L. Autoimmune workup for vasculitis including antinuclear antibody, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antiphospholipid antibodies were negative. Viral serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Intravenous pulse methylprednisolone was given for 3 days; however, she continued to be in a deep coma. Serial follow-up CT scans of the brain did not show any hydrocephalus or bleed. Electroencephalogram did not show any epileptiform abnormalities. On the twelfth postoperative day, an examination revealed the patient to be in a quadriparetic state because of a newly developed left-sided weakness. A consequent CT brain showed multiple infarcts in the territories of the right anterior and middle cerebral arteries (Fig. 1D). Digital subtraction angiography (DSA) done on the same day showed severe narrowing and irregularity of bilateral anterior, middle, and posterior cerebral arteries, which showed excellent reversibility to intra-arterial milrinone infusion over 15 minutes (Fig. 1E, F). She was continued on intravenous milrinone infusion for 7 days. The diagnosis of RCVS was made secondary to her post-partum status, along with a possible etiological implication of tacrolimus therapy. Despite an RCVS2 score of only 4, which implies a low diagnostic sensitivity for the syndrome, the diagnosis of RCVS as opposed to vasculitis, was supported by excellent reversibility of angiographic abnormalities to milrinone [1]. Subsequently, the patient gradually recovered from her comatose state and started moving her right upper and lower limbs. CTA done before the discharge from the hospital in the sixth postoperative week showed no significant abnormalities. She was conscious and alert at the time of discharge with a power of grade 3/5 and 2/5 in her right and left extremities, respectively. Her neurological recovery is expected to be delayed due to bihemispheric dysfunction and multiple infarcts in the right cerebral hemisphere before milrinone therapy.\n\nDISCUSSION\n\nRCVS is a clinical and radiological syndrome characterized by sudden severe headache and reversible multifocal narrowing of cerebral arteries [2]. This syndrome is often considered to have a benign outcome; however, major strokes resulting in severe disability and death have been reported [3]. A recent systematic review has observed intracerebral hemorrhage (ICH) as the most common presentation (42%) in fatal RCVS cases, followed by encephalopathy and/or headaches in 25%, and ischemic stroke and posterior reversible encephalopathy syndrome in 16.5% each [4]. The same review noted that half of these fatal cases initially presented with a non-specific headache (NSH). Our patient also had NSH as the initial manifestation. Diagnosis of RCVS can often be delayed due to the dynamic natural history and radiological features of the disease. Stroke may occur after a few days of the initial normal brain imaging. Further, angiographic vasoconstriction may show up the best only after 2–3 weeks of the clinical onset [3].\n\nIn the present case, we were deceived initially by the mild distal focal narrowings on CTA, which steered our diagnosis towards cerebral vasculitis especially against the backdrop of dermatomyositis. Central nervous system vasculitis is known to be associated with ICH [5]. Consequently, we started pulse therapy of intravenous methylprednisolone; the patient, however, continued to be in a comatose state. She instead developed new cerebral infarcts, and hence underwent DSA, which revealed severe multi-focal narrowings that demonstrated a striking reversal on the administration of intra-arterial milrinone. So, a probable diagnosis of RCVS was established, which was further supported by the normal CTA in the sixth postoperative week. In the retrospect, however, we understand that corticosteroid use may result in a poor outcome in RCVS and should be avoided, although, in our case, it was used considering the possibility of vasculitis before the diagnosis got confirmed [6,7].\n\nThis case of fulminant RCVS was unusual and left us with several learning lessons. First, the diagnosis was delayed because of the characteristically dynamic natural history of the disease. Clinically, our patient presented with a non-specific headache initially, as against a thunderclap headache which is classically seen in RCVS. Furthermore, this disease is described as having an initial hemorrhagic phase followed by an ischemic phase in the second week [8-10]. It is also characterized by minimal angiographic findings in the initial hemorrhagic phase when the vasospasm is in the distal vessels, which is followed by proximal migration of vasospasm causing ischemic strokes in the second phase [8]. Although the evolution of radiological changes with time has been described in the literature, this case highlights how this may cause confusion in the diagnosis and require caution in evaluating such cases. Normal angiography in the first week may not rule out the disease and a repeat angiography may be warranted if the clinical suspicion of the RCVS is high. Further, our patient had a massive ganglio-capsular regional bleed, which has rarely been mentioned in the medical literature. RCVS commonly presents in the hemorrhagic phase as SAH and cortical bleeds [3]. It may be noted that the presence of a large basal ganglia hemorrhage should not preclude one from considering RCVS as a diagnosis, especially in an appropriate clinical setting such as a post-partum state. The exposure of our patient to tacrolimus further strengthened the associated risk.\n\nLastly, the high diagnostic utility of intra-arterial milrinone for RCVS has a mere anecdotal mention in the literature [11]. We, however, observed it to have a dramatic role in reversing the vasoconstriction; and thus, it has a remarkable potential for differentiating RCVS from vasculitis. In the medical literature though, angiographic response to intra-arterial vasodilators is varied and there is a lack of strong evidence for the therapeutic role of the same in RCVS [11-14]. Randomized studies conducted on the role of Nimodipine for the same have not shown any significant benefit [15,16]. Thus, our case may be considered as a potential source for conducting further randomized studies in this regard. It would be worthwhile to see if the diagnostic utility of milrinone as observed in our case can be established further with well-designed prospective studies. In conclusion, intra-arterial milrinone appears to have a significant diagnostic utility for RCVS.\n\nFig. 1. (A) Magnetic resonance imaging of brain showing large intra-parenchymal hematoma involving left ganglio-capsular and frontotemporal regions with significant midline shift. (B) Post-operative computed tomography (CT) scan of brain showing hematoma evacuation. (C) CT angiography demonstrating multifocal luminal irregularities and narrowing (white arrowheads) of distal branches of bilateral middle and posterior cerebral arteries. (D) CT brain on twelfth postoperative day showing multiple acute infarcts (white arrows) in right middle cerebral arteries (MCA) territory. (E) Digital subtraction angiography performed in the second week showing severe proximal narrowing of left MCA (black thick arrow) and the anterior cerebral arteries (ACA) (black thin arrow). (F) Post intra-arterial milrinone injection of left internal carotid artery showing excellent reversibility of MCA and ACA abnormalities.\n\nFund\n\nNone.\n\nEthics Statement\n\nThis study was a case report, ethical approval was not required; however, informed consent was taken from the patient’s close relatives for presenting the patient’s data as a report.\n\nConflicts of Interest\n\nThe authors have no conflicts to disclose.\n\nAuthor Contribution\n\nConcept and design: PJA, AP, GVK, and KS. Analysis and interpretation: PJA, AP, and GVK. Data collection: PJA and AP. Writing the article: PJA, AP, and KS. Critical revision of the article: PJA, AP, GVK, and KS. Final approval of the article: PJA, AP, GVK, and KS. Overall responsibility: AP.\n==== Refs\nREFERENCES\n\n1 Rocha EA Topcuoglu MA Silva GS Singhal AB RCVS2 score and diagnostic approach for reversible cerebral vasoconstriction syndrome Neurology 2019 92 e639 e647 30635475\n2 Saini M Jeerakathil T Butcher K Reversible cerebral vasoconstriction syndrome Neurol India 2009 57 63 65 19305081\n3 Ducros A Reversible cerebral vasoconstriction syndrome Lancet Neurol 2012 11 906 917 22995694\n4 Valencia-Mendoza M Ramírez-Rodríguez N Vargas-Avila N Peña-Ortiz A Corzo-Villamizar M Serna-Ramírez L Fatal reversible cerebral vasoconstriction syndrome: a systematic review of case series and case reports J Clin Neurosci 2019 70 183 188 31416730\n5 Salvarani C Brown RD Jr Calamia KT Christianson TJ Huston J 3rd Meschia JF Primary central nervous system vasculitis presenting with intracranial hemorrhage Arthritis Rheum 2011 63 3598 3606 22038406\n6 Singhal AB Hajj-Ali RA Topcuoglu MA Fok J Bena J Yang D Reversible cerebral vasoconstriction syndromes: analysis of 139 cases Arch Neurol 2011 68 1005 1012 21482916\n7 Singhal AB Topcuoglu MA Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome Neurology 2017 88 228 236 27940651\n8 Xing B Lenck S Krings T Hengwei J Jaigobin CS Schaafsma JD Angiographic characteristics of hemorrhagic and ischemic phases of reversible cerebral vasoconstriction syndrome Clin Neuroradiol 2020 30 85 89 30390096\n9 Ducros A Fiedler U Porcher R Boukobza M Stapf C Bousser MG Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors Stroke 2010 41 2505 2511 20884871\n10 Mrozek S Lonjaret L Jaffre A Januel AC Raposo N Boetto S Reversible cerebral vasoconstriction syndrome with intracranial hypertension: should decompressive craniectomy be considered? Case Rep Neurol 2017 9 6 11 28203185\n11 Bouchard M Verreault S Gariépy JL Dupré N Intra-arterial milrinone for reversible cerebral vasoconstriction syndrome Headache 2009 49 142 145 18647181\n12 Nowak DA Rodiek SO Henneken S Zinner J Schreiner R Fuchs HH Reversible segmental cerebral vasoconstriction (Call-Fleming syndrome): are calcium channel inhibitors a potential treatment option? Cephalalgia 2003 23 218 222 12662190\n13 Mijalski C Dakay K Miller-Patterson C Saad A Silver B Khan M Magnesium for treatment of reversible cerebral vasoconstriction syndrome: case series Neurohospitalist 2016 6 111 113 27366294\n14 Linn J Fesl G Ottomeyer C Straube A Dichgans M Bruckmann H Intra-arterial application of nimodipine in reversible cerebral vasoconstriction syndrome: a diagnostic tool in select cases? Cephalalgia 2011 31 1074 1081 21220377\n15 Ducros A Boukobza M Porcher R Sarov M Valade D Bousser MG The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients Brain 2007 130 Pt 12 3091 3101 18025032\n16 Chen SP Fuh JL Chang FC Lirng JF Shia BC Wang SJ Transcranial color doppler study for reversible cerebral vasoconstriction syndromes Ann Neurol 2008 63 751 757 18496847\n\n",
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"title": "Lessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility.",
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"abstract": "BACKGROUND\nInformation regarding the clinical features and outcomes of pneumonia due to an infection with human coronavirus (HCoV)-OC43 in children with cancer is rare. This report presents the clinical features in terms of chest CT scan images which may be used to identify cases of HCoV-OC43 infection induced pneumonia in immunocompromised children.\nWe report here a girl with acute lymphoblastic leukemia who developed respiratory symptoms during febrile neutropenia. Rapid clinical progression and nodular lesions on her chest X-ray and computed tomography scans were suggestive of a pulmonary fungal infection.\n\n\nMETHODS\nA series of tests eventually confirmed the exclusive presence of HCoV-OC43 by the FilmArray Respiratory Panel from a throat swab sample.\n\n\nMETHODS\nAfter the diagnosis was confirmed, the antimicrobial agents initially administered were discontinued.\n\n\nRESULTS\nAlthough the chest CT scan images looked severe, the clinical course of the infection induced pneumonia was benign. The respiratory status of the patient was completely resolved in 2 weeks.\n\n\nCONCLUSIONS\nThis report highlights the importance of early identification of respiratory viruses, via the realization of their clinical characteristics, which helps reduce the duration of administration of antimicrobial agents in this setting.",
"affiliations": "Division of Pediatric Hematology-Oncology.;Division of Pediatric General Medicine.;Department of Medical Imaging and Intervention.;Division of Pediatric Hematology-Oncology.;Division of Pediatric Infectious Diseases.;Division of Pediatric Pulmonology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Division of Pediatric Infectious Diseases.",
"authors": "Chang|Tsung-Yen|TY|;Du|Chia-Jui|CJ|;Chang|Chih-Chen|CC|;Chen|Shih-Hsiang|SH|0000-0003-2588-2735;Chen|Chih-Jung|CJ|;Chiu|Chih-Yung|CY|;Chiu|Cheng-Hsun|CH|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-04694\n10.1097/MD.0000000000021520\n21520\n6200\nResearch Article\nClinical Case Report\nHuman coronavirus OC43 infection associated pneumonia in a girl with acute lymphoblastic leukemia\nA case reportChang Tsung-Yen MDa Du Chia-Jui MDb Chang Chih-Chen MDc http://orcid.org/0000-0003-2588-2735Chen Shih-Hsiang MDa∗ Chen Chih-Jung MD, PhDd Chiu Chih-Yung MD, PhDe Chiu Cheng-Hsun MD, PhDd Saranathan. Maya a Division of Pediatric Hematology-Oncology\nb Division of Pediatric General Medicine\nc Department of Medical Imaging and Intervention\nd Division of Pediatric Infectious Diseases\ne Division of Pediatric Pulmonology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.\n∗ Correspondence: Shih-Hsiang Chen, Division of Pediatric Hematology-Oncology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 5 Fu-Shin Street, Kwei-Shan 333, Taoyuan, Taiwan (e-mail: samechen@cgmh.org.tw).\n14 8 2020 \n14 8 2020 \n99 33 e2152019 5 2020 5 6 2020 1 7 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nInformation regarding the clinical features and outcomes of pneumonia due to an infection with human coronavirus (HCoV)-OC43 in children with cancer is rare. This report presents the clinical features in terms of chest CT scan images which may be used to identify cases of HCoV-OC43 infection induced pneumonia in immunocompromised children.\n\nPatient concerns:\nWe report here a girl with acute lymphoblastic leukemia who developed respiratory symptoms during febrile neutropenia. Rapid clinical progression and nodular lesions on her chest X-ray and computed tomography scans were suggestive of a pulmonary fungal infection.\n\nDiagnosis:\nA series of tests eventually confirmed the exclusive presence of HCoV-OC43 by the FilmArray Respiratory Panel from a throat swab sample.\n\nInterventions:\nAfter the diagnosis was confirmed, the antimicrobial agents initially administered were discontinued.\n\nOutcomes:\nAlthough the chest CT scan images looked severe, the clinical course of the infection induced pneumonia was benign. The respiratory status of the patient was completely resolved in 2 weeks.\n\nLessons:\nThis report highlights the importance of early identification of respiratory viruses, via the realization of their clinical characteristics, which helps reduce the duration of administration of antimicrobial agents in this setting.\n\nKeywords\nacute lymphoblastic leukemiachildrenfebrile neutropeniahuman coronavirus OC43pneumoniaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe human coronavirus (HCoV)-OC43 is one of the common coronaviruses to cause an infection in healthy children, and usually induces only mild upper respiratory diseases. Approximately 30% to 33% of children with HCoV-OC43 infection have been diagnosed with lower respiratory tract infection.[1,2] Despite this, information regarding the clinical features and outcomes of an HCoV-OC43 infection in children with cancer is limited. In this report, we present a young girl with acute lymphoblastic leukemia (ALL) who developed pneumonia resulting from an HCoV-OC43 infection, which was characterized by severe chest CT scan images but a benign clinical course.\n\n1.1 Patient presentation\nAn 8-year-old girl presented with fever and an abnormal hemogram (leukocyte count 29.7 × 109 cells/L with 49% blasts, hemoglobin 7.9 g/dl, and platelet count 231 × 109 cells/L). She had been diagnosed with B cell precursor ALL on December 24th, 2019. Cytogenetic analysis disclosed the presence of the karyotype 46,XX,del(9)(q34),t(12;22)(p13;q11.2), while molecular analysis was negative for ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1. The girl received chemotherapy according to the Taiwan Pediatric Oncology Group (TPOG) 2013-ALL-SR protocol, and spinal tap and triple intrathecal therapy was performed 7 to 10 days after chemotherapy.[3] No leukemic cells were found in the cerebral spinal fluid and the patient commenced prophylactic antibiotic and antifungal therapies with levofloxacin and micafungin on January 14th, when her leukocyte count was less than 1 × 109 cells/μl. She later developed febrile neutropenia on January 20th, and was administered teicoplanin and meropenem post collection of her blood for culture. Her blood culture yielded Streptococcus mitis which is sensitive to teicoplanin. However, she gradually developed a cough in parallel with a respiratory tract infection from her mother who was taking care of her in the hospital. A chest X-ray on January 22nd showed increased infiltration in the right lower lobe (Fig. 1A). In the meantime, the optical density index (ODI) of serum galactomannan was 0.07. She was then administered with azithromycin for 3 days as atypical pneumonia resulting from a bacterial infection was suspected. Despite this, the patients fever was not resolved and her cough further worsened even after her leukocyte count increased (1.6 × 109 cells/μl with granulocytes 0.08 × 109 cells /μl and lymphocytes 0.85 × 109 cells /μl on January 25). She had increased difficulty in breathing requiring low-flow nasal cannula support and auscultation yielded a coarse breathing sound without wheezing or rales. A second chest X-ray revealed patchy nodular opacities in the right middle lobe and bilateral lower lobes (Fig. 1B). Further, computed tomography (CT) of the chest showed multiple ill-defined nodular and wedge-shape opacities predominantly in the bilateral lower lobes (Fig. 2). Since pulmonary fungal infection was initially suspected, liposomal amphotericin-B was substituted for micafungin. Concurrently, the ODI of serum galactomannan increased to 0.15. Finally, a throat swab sample was collected and tested using the FilmArray Respiratory Panel, a multiplex polymerase chain reaction (PCR) assay that can detect up to 16 viruses and the 3 bacterial targets, Mycoplasma pneumoniae, Bordetella pertussis, and Chlamydia pneumoniae. The result of this assay confirmed the exclusive presence of HCoV-OC43. Although the cough gradually improved, the parents agreed to let the patient undergo bronchoscopy with collection of bronchoalveolar lavage (BAL) fluid 1 week later. The BAL samples were subjected to multiple staining and culture, including Gram staining and special stains in cytology, which later revealed the samples to be negative for fungi, acid-fast bacilli, and viruses. Thus, antimicrobial agents were discontinued. Her respiratory status became asymptomatic in the following week, and a chest X-ray 1 month later showed complete resolution of the pulmonary infiltrates.\n\nFigure 1 A: Increased infiltration in right lower lobe. B: Patchy nodular opacities in right middle lobe and bilateral lower lobes.\n\nFigure 2 Multiple ill-defined nodular and wedge-shape opacities in bilateral lung fields (A & B), predominantly in bilateral lower lobes (C).\n\nInformed written consent was obtained from the mother of the patient for publication of this case report and any accompanying images.\n\n2 Discussion\nBefore the outbreak of the coronavirus disease of 2019 (COVID-19), 6 types of human coronaviruse (HCoV) have been known to cause infections, namely HCoV-OC43, HCoV-299E, HCoV-HKU1, HCoV-NL63, severe acute respiratory syndrome (SARS)-CoV, and middle east respiratory syndrome (MERS)-CoV. It has been reported that the HCoV-OC43 infection occurs frequently in early childhood and largely presents symptoms of upper respiratory tract infection.[4] Pneumonia caused by HCoV-OC43 infection is seldom discussed, especially in children with cancer.\n\nAlthough HCoV-OC43 is predominantly associated with upper respiratory tract infections, there have been cases where it has been associated with a serious infection in immunocompromised children. Simon et al reported a 5-year-old boy with ALL who presented with febrile neutropenia and pneumonia.[5] Real-time polymerase chain reaction assay of the nasopharyngeal aspirate sample confirmed an HCoV-OC43 infection, and after the leukocyte count increased, the respiratory condition of the young boy reportedly improved. In another study, Morfopoulou et al reported an 11-month-old boy with severe combined immunodeficiency who contracted HCoV-OC43-associated encephalitis after he underwent cord blood transplantation and died 1.5 months after the transplantation.[6] In yet another study, Nilsson et al reported a 9-month-old infant with ALL who had persistent HCoV-OC43-associated respiratory infection and developed fatal encephalitis.[7] Therefore, it is of paramount importance that physicians be aware of the risk of the serious complications associated with the HCoV-OC43 infection during the treatment of immunocompromised children.\n\nExtensive or multifocal ground glass opacification with consolidations is a common sign in chest radiography, which is suggestive of pneumonia caused by the highly pathogenic coronaviruses, SARS-CoV, MERS-CoV, or COVID-19.[8,9] However, little is known about the radiographic findings of pneumonia caused by the other coronaviruses, which generally cause self-limited upper respiratory tract infections in immunocompetent patients. Pene et al reported 2 immunocompromised patients with pneumonia caused by HCoV-299E infection, of whom one had chest CT images that showed multiple micronodular opacities.[10] In this report, our patients chest CT scan revealed multiple nodular and wedge-shape opacities, predominantly in the bilateral lower lobes and the right upper lobe, which were similar to those reported by Pene et al To the best of our knowledge, our report is the first to describe the specific features of a chest CT scan in pediatric cancer patients with HCoV-OC43 pneumonia.\n\nFebrile neutropenia is a common complication of cancer treatment in children. Because of the decreased inflammatory response, bacterial and fungal infections in neutropenic patients are the major causes of morbidity and mortality. As a result, there is an updated guideline, which focuses on strategies for antibacterial and antifungal therapies for the management of febrile neutropenia in children with cancer or hematopoietic stem cell transplantation.[11] Recently, there has been a growing emphasis on the identification of viral infections to enable the application of individualized treatments and reduce the antibiotic burden in children with cancer and febrile neutropenia.[12–14] Although we identified HCoV-OC43 from the throat swab sample, we modified and continued the administration of antimicrobial agents to our patient due to the severe chest images we obtained that were mimicking serious pulmonary infections. Nonetheless, rapid improvement of the respiratory status and negative microbiological results on the BAL fluid sample were suggestive of a benign course of the HCoV-OC43 infection-associated pneumonia. Therefore, it is important for physicians to recognize the clinical characteristics of such an infection so that the duration of the antimicrobial therapy may be reduced.\n\nIn conclusion, our report describes the case of pneumonia caused due to an HCoV-OC43 infection during the induction therapy of a girl with ALL. Although HCoV-OC43 infection occasionally causes serious lower respiratory infection in immunocompromised children, as presented by severe chest images, its clinical course may be benign as is the case with our patient.\n\nAuthor contributions\nConceptualization: Shih-Hsiang Chen, Tsung-Yen Chang, Chia-Jui Du.\n\nData curation: Shih-Hsiang Chen, Tsung-Yen Chang, Chia-Jui Du.\n\nFormal analysis: Shih-Hsiang Chen.\n\nInvestigation: Chih-Chen Chang, Chih-Jung Chen, Chih-Yung Chiu.\n\nSupervision: Cheng-Hsun Chiu.\n\nValidation: Chih-Chen Chang, Chih-Jung Chen, Chih-Yung Chiu.\n\nVisualization: Chih-Chen Chang, Chih-Jung Chen, Chih-Yung Chiu.\n\nWriting – original draft: Tsung-Yen Chang, Chia-Jui Du, Shih-Hsiang Chen\n\nWriting – review & editing: Shih-Hsiang Chen, Cheng-Hsun Chiu.\n\nAbbreviations: ALL = acute lymphoblastic leukemia, BAL = bronchoalveolar lavage, COVID-19 = coronavirus disease 2019, CT = computer tomography, HCoV = human coronavirus, MERS = Middle East respiratory syndrome, ODI = optical density index, PCR = polymerase chain reaction, SARS = severe acute respiratory syndrome, TPOG = Taiwan Pediatric Oncology Group.\n\nHow to cite this article: Chang TY, Du CJ, Chang CC, Chen SH, Chen CJ, Chiu CY, Chiu CH. Human coronavirus OC43 infection associated pneumonia in a girl with acute lymphoblastic leukemia: a case report. Medicine. 2020;99:33(e21520).\n\nThis study was supported by grants from National Science Council, Taiwan (105-2314-B-182A-116 & 106-2314-B-182A-143-MY2).\n\nTsung-Yen Chang and Chia-Jui Du, Contributed equally as co-first authors.\n\nThe authors report no conflicts of interest.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Jean A Quach C Yung A \nSeverity and outcome associated with human coronavirus OC43 infections among children\n. Pediatr Infect Dis J \n2013 ;32 :325 –9\n.23337903 \n[2] Lee J Storch GA \nCharacterization of human coronavirus OC43 and human coronavirus NL63 infections among hospitalized children <5 years of age\n. Pediatr Infect Dis J \n2014 ;33 :814 –20\n.24577040 \n[3] Yeh TC Liang DC Hou JY \nTreatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: results of the TPOG-ALL-2002 study\n. Cancer \n2018 ;124 :4538 –47\n.30303520 \n[4] Dijkman R Jebbink MF Gaunt E \nThe dominance of human coronavirus OC43 and NL63 infections in infants\n. J Clin Virol \n2012 ;53 :135 –9\n.22188723 \n[5] Simon A Volz S Fleischhack G \nHuman coronavirus OC43 pneumonia in a pediatric cancer patient with down syndrome and acute lymphoblastic leukemia\n. J Pediatr Hematol Oncol \n2007 ;29 :432 –4\n.17551411 \n[6] Morfopoulou S Brown JR Davies EG \nHuman coronavirus OC43 associated with fatal encephalitis\n. N Engl J Med \n2016 ;375 :497 –8\n.27518687 \n[7] Nilsson A Edner N Albert J \nFatal encephalitis associated with coronavirus OC43 in an immunocompromised child\n. Infect Dis (Lond) \n2020 ;52 :419 –22\n.32067542 \n[8] Koo HJ Lim S Choe J \nRadiographic and CT features of viral pneumonia\n. Radiographics \n2018 ;38 :719 –39\n.29757717 \n[9] Kanne JP \nChest CT findings in 2019 novel coronavirus nCoV) infections from Wuhan, China: key points for the radiologist\n. Radiology \n2020 ;295 :16 –7\n.32017662 \n[10] Pene F Merlat A Vabret A \nCoronavirus 229E-related pneumonia in immunocompromised patients\n. Clin Infect Dis \n2003 ;37 :929 –32\n.13130404 \n[11] Lehrnbecher T Robinson P Fisher B \nGuideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update\n. J Clin Oncol \n2017 ;35 :2082 –94\n.28459614 \n[12] Torres JP De la Maza V Kors L \nRespiratory viral infections and coinfections in children with cancer, fever and neutropenia: clinical outcome of infections caused by different respiratory viruses\n. Pediatr Infect Dis J \n2016 ;35 :949 –54\n.27518750 \n[13] Aldemir-Kocabas B Karbuz A Pekpak E \nEffects of respiratory viruses on febrile neutropenia attacks in children\n. Turk J Pediatr \n2017 ;59 :511 –9\n.29745111 \n[14] Soderman M Rhedin S Tolfvenstam T \nFrequent respiratory viral infections in children with febrile neutropenia - a prospective follow-up study\n. PLoS One \n2016 ;11 :e0157398 .27309354\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(33)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D002648:Child; D018352:Coronavirus Infections; D028962:Coronavirus OC43, Human; D064147:Febrile Neutropenia; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D011024:Pneumonia, Viral; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e21520",
"pmc": null,
"pmid": "32871999",
"pubdate": "2020-08-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Human coronavirus OC43 infection associated pneumonia in a girl with acute lymphoblastic leukemia: A case report.",
"title_normalized": "human coronavirus oc43 infection associated pneumonia in a girl with acute lymphoblastic leukemia a case report"
} | [
{
"companynumb": "TW-STRIDES ARCOLAB LIMITED-2020SP012443",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo prospectively trial ertapenem prophylaxis in patients with known risk factors of sepsis undergoing transrectal biopsy of the prostate.\n\n\nMETHODS\nIn this prospective audit, patients were identified as having a low- or high-risk of sepsis based on a questionnaire about established risk factors: previous biopsy; recurrent urine infections; receiving ciprofloxacin in the 12 months prior; travel to South-East Asia or South America in the previous 6 months; or diabetes, immune system impairment or receipt of immunosuppressant drugs. All received ciprofloxacin and amoxicillin-clavulanate and high-risk patients additionally received ertapenem. Sepsis requiring hospital admission was recorded. Data was analysed using a two-tailed Fisher's exact test.\n\n\nRESULTS\nIn all, 80 men were identified as high risk of sepsis and 90 as low risk during the audit period. Six patients in the low-risk group (6.7%, 95% confidence interval 2.1-11.3) and none in the high-risk group developed sepsis (P = 0.03). Of the six developing sepsis, two grew ciprofloxacin-resistant organisms, two had no growth and two grew a ciprofloxacin-sensitive organism, although one of these grew extended-spectrum β-lactamase-producing Escherichia coli.\n\n\nCONCLUSIONS\nThe addition of ertapenem to standard prophylaxis is effective at reducing sepsis after prostate biopsy. Risk stratification is not effective at identifying those men at low risk of sepsis, as these men still have a high sepsis rate. Ertapenem prophylaxis for all patients undergoing prostate biopsy is likely to be the most effective strategy in our population group.",
"affiliations": "Department of Urology, Wellington Regional Hospital, Wellington, New Zealand.",
"authors": "Losco|Giovanni|G|;Studd|Rod|R|;Blackmore|Timothy|T|",
"chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D002939:Ciprofloxacin; D019980:Amoxicillin-Potassium Clavulanate Combination; D000077727:Ertapenem",
"country": "England",
"delete": false,
"doi": "10.1111/bju.12590",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-4096",
"issue": "113 Suppl 2()",
"journal": "BJU international",
"keywords": "antibiotic prophylaxis; biopsy; carbapenems; prostatic neoplasms; sepsis",
"medline_ta": "BJU Int",
"mesh_terms": "D000368:Aged; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D001706:Biopsy; D002939:Ciprofloxacin; D004359:Drug Therapy, Combination; D000077727:Ertapenem; D004927:Escherichia coli Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011446:Prospective Studies; D011471:Prostatic Neoplasms; D012007:Rectum; D018570:Risk Assessment; D012307:Risk Factors; D018805:Sepsis; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional; D047090:beta-Lactams",
"nlm_unique_id": "100886721",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "24894854",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ertapenem prophylaxis reduces sepsis after transrectal biopsy of the prostate.",
"title_normalized": "ertapenem prophylaxis reduces sepsis after transrectal biopsy of the prostate"
} | [
{
"companynumb": "NZ-BAYER-2014-093125",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
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... |
{
"abstract": "We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.",
"affiliations": "Department of Oncology and Hematology, University Hospitals of Strasbourg, Strasbourg University.;Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospitals of Strasbourg, Strasbourg University, Strasbourg.",
"authors": "Imperiale|Alessio|A|;Latgé|Adrien|A|;Schaff-Wendling|Frédérique|F|;Goichot|Bernard|B|;Kurtz|Jean-Emmanuel|JE|;Malouf|Gabriel G|GG|",
"chemical_list": "D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000002231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "43(9)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000140:Acidosis, Lactic; D018278:Carcinoma, Neuroendocrine; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007093:Imidazoles; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases; D058990:Molecular Targeted Therapy; D009154:Mutation; D010091:Oximes; D000072078:Positron Emission Tomography Computed Tomography; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D016896:Treatment Outcome",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "701-702",
"pmc": null,
"pmid": "30036245",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metabolic Response to BRAF-MEK Combination Therapy in Cecal Neuroendocrine Carcinoma With BRAFV600E Mutation and Refractory Lactic Acidosis.",
"title_normalized": "metabolic response to braf mek combination therapy in cecal neuroendocrine carcinoma with brafv600e mutation and refractory lactic acidosis"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1026681",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In Crohn's disease, it is essential to distinguish between persistent damage and abnormalities that can heal with anti-inflammatory therapy.\n\n\n\nTo assess magnetic resonance enterography (MRE) lesions that persist in patients in long-standing endoscopic remission, analyse their relationship with baseline characteristics, and determine their prognostic implications.\n\n\n\nWe systematically reviewed pre- and post-treatment MRE findings in patients with Crohn's disease and severe inflammation (segmental CDEIS ≥ 7 or ulcers in at least one segment) who achieved endoscopic remission (CDEIS < 2) after 1 year of treatment with TNF-inhibitors or autologous haematopoietic stem-cell transplantation. Logistic regression analysis was used to identify predictors of persistent abnormalities.\n\n\n\nEndoscopic remission was achieved in 73 intestinal segments in 28 patients (69% females; 9.95 years disease duration, 67.9% inflammatory phenotype; 39.3% ileal location). Creeping fat and intestinal wall fat deposits were unchanged on pre- and post-treatment MRE despite the endoscopic remission. Luminal strictures persisted in 6 out of the 8 segments with baseline strictures, and wall thickening in 23 out of the 72 of segments with thickening at baseline. Predictors of persistent mural thickening were pre-treatment wall thickness > 5.9 mm (OR = 4.38, P = 0.027) and refractory disease prior to baseline (OR = 2.35, P = 0.001). Creeping fat was the only predictor for persistence of creeping fat (OR = 36.43, P < 0.001). Persistence of strictures at MRE is associated with earlier recurrence (P = 0.014).\n\n\n\nPersistent MRE abnormalities are frequent in patients with Crohn's disease despite achieving endoscopic remission. Significant wall thickening, intestinal fat deposition, strictures, and creeping fat at baseline MRE are signs of established damage.",
"affiliations": "IBD unit, Radiology Department, Hospital Clínic of Barcelona, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Radiology Department, Hospital Clínic of Barcelona, Barcelona, Spain.;IBD unit, Radiology Department, Hospital Clínic of Barcelona, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.;IBD unit, Gastroenterology Department, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.",
"authors": "Rimola|Jordi|J|0000-0002-1814-4198;Alfaro|Ignacio|I|;Fernández-Clotet|Agnès|A|;Castro-Poceiro|Jesús|J|;Vas|Daniel|D|;Rodríguez|Sonia|S|;Masamunt|Maria Carme|MC|;Ordás|Ingrid|I|;Ricart|Elena|E|;Panés|Julián|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/apt.15013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "48(11-12)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003251:Constriction, Pathologic; D003424:Crohn Disease; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012074:Remission Induction; D055815:Young Adult",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "1232-1241",
"pmc": null,
"pmid": "30345577",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Persistent damage on magnetic resonance enterography in patients with Crohn's disease in endoscopic remission.",
"title_normalized": "persistent damage on magnetic resonance enterography in patients with crohn s disease in endoscopic remission"
} | [
{
"companynumb": "ES-SAMSUNG BIOEPIS-SB-2019-14126",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Spontaneous spinal epidural hematoma (SSEH) is considered to be a relatively rare disease that can result in serious neurological sequelae. The pathogenesis and risk factors of SSEH are still unknown, and its differential diagnosis varies widely. Misdiagnosis with more common conditions such as stroke or aortic syndromes can occur. We report the case of a 27-year-old man who developed sudden upper back pain with no specific precipitant. Five days later, he visited our emergency department complaining of weakness in both lower limbs and dysuria. He had a history of intracardiac repair and a Blalock-Park procedure for an interrupted aortic arch and ventricular septal defect in infancy. Additionally, he had undergone an aortic root dilatation and aortic valve replacement at the age of 10 because of progression of aortic and supra-aortic stenosis and had received chronic anticoagulation and antiplatelet therapy with warfarin and aspirin, respectively. An emergency spine magnetic resonance imaging scan indicated a mass at the Th3-Th5 level with severe compression of the dural sac and the spinal cord. Emergency excision showed a spinal epidural hematoma. Mild postoperative gait disturbance and dysuria persisted, requiring rehabilitation and intermittent self-urethral catheterization. As patients with adult congenital heart disease have an increased risk of bleeding, they may be at risk of developing SSEH. However, this is the first report to describe such an association.",
"affiliations": "Department of Pediatrics, Miyazaki Prefectural Miyazaki Hospital.;Department of Pediatrics, Miyazaki Prefectural Miyazaki Hospital.",
"authors": "Ifuku|Toshinobu|T|;Nishiguchi|Toshihiro|T|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.20-721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "62(4)",
"journal": "International heart journal",
"keywords": "Anticoagulant; Antiplatelet; Aortic valve replacement; Aortic valve stenosis; Interrupted aortic arch",
"medline_ta": "Int Heart J",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001024:Aortic Valve Stenosis; D001241:Aspirin; D006330:Heart Defects, Congenital; D006345:Heart Septal Defects, Ventricular; D019918:Heart Valve Prosthesis Implantation; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011183:Postoperative Complications; D014859:Warfarin",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "935-937",
"pmc": null,
"pmid": "34234072",
"pubdate": "2021-07-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous Spinal Epidural Hematoma in an Adult Patient with Complex Congenital Heart Disease.",
"title_normalized": "spontaneous spinal epidural hematoma in an adult patient with complex congenital heart disease"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-309919",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "We discuss two cases of abdominal candidiasis in critically ill patients with multiple organ failure and sepsis. Microbiological and clinical courses remained unresponsive to apparently appropriate antifungal therapy with azole or polyene derivatives. Both microbiological and clinical outcomes dramatically improved after starting caspofungin therapy. Lack of cross-resistance, lack of toxicity and potent fungicidal activity make caspofungin a very attractive drug in life threatening abdominal candidiasis. The optimal treatment of life threatening candidiasis remains a controversial issue. Because of recent advances in the field, we propose a critical review of the problem of refractory candidiasis.",
"affiliations": "Service de Soins Intensifs Généraux, Centre Hospitalier Universitaire Domaine universitaire du Sart-Tilman, B-4000 Liège. Jean-Luc.Canivet@chu.ulg.ac.be",
"authors": "Canivet|J L|JL|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000077336:Caspofungin",
"country": "England",
"delete": false,
"doi": "10.1179/acb.2004.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "59(1)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000005:Abdomen; D000368:Aged; D000935:Antifungal Agents; D002177:Candidiasis; D000077336:Caspofungin; D016638:Critical Illness; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D054714:Echinocandins; D005260:Female; D006801:Humans; D055666:Lipopeptides; D009102:Multiple Organ Failure; D010455:Peptides; D010456:Peptides, Cyclic; D018805:Sepsis; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "24-9",
"pmc": null,
"pmid": "15065693",
"pubdate": "2004",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical impact of the fungicidal activity of caspofungin administered alone or in combination in critically ill patients with severe abdominal candidiasis refractory to conventional antifungal drugs: case studies and critical review of the problem.",
"title_normalized": "clinical impact of the fungicidal activity of caspofungin administered alone or in combination in critically ill patients with severe abdominal candidiasis refractory to conventional antifungal drugs case studies and critical review of the problem"
} | [
{
"companynumb": "BE-MYLANLABS-2021M1065929",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "Immunosuppressants have been the mainstay of treatment for certain inflammatory joint conditions for many years. Developments in this field, namely biological treatments, have led to a change in the classical presentation of acute bone, joint and soft tissue infections. The normal findings of severe pain and tenderness on examination may be absent or simply mimic a typical exacerbation of the chronic joint condition. A minimally raised white cell count and elevated C-reactive protein in the absence of systemic signs of infection may be interpreted as further evidence for the diagnosis of an exacerbation of inflammatory arthritis. We present a unique case of recurrent polyarticular septic arthritis in a patient treated with immunosuppression for refractory rheumatoid arthritis. We hope this article will enable doctors to appreciate and recognise the changing face of septic arthritis in the modern era of immunosuppressant treatments.",
"affiliations": "Nottingham University Hospitals NHS Trust, UK.",
"authors": "Salar|O|O|;Baker|B|B|;Kurien|T|T|;Taylor|A|A|;Moran|C|C|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1308/003588414X13814021678196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-8843",
"issue": "96(2)",
"journal": "Annals of the Royal College of Surgeons of England",
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"abstract": "•Three patients with cytology positive pericardial effusions from high grade serous carcinoma.•Patients' conditions amenable to treatment with chemotherapy after effusion symptom improvement.•Patient with pericardial effusion from high grade serous ovarian cancer post a poly ADP ribose polymerase inhibitor.",
"affiliations": "Tom Baker Cancer Center, Calgary, Alberta, Canada.;Tom Baker Cancer Center, Calgary, Alberta, Canada.;Tom Baker Cancer Center, Calgary, Alberta, Canada.;Tom Baker Cancer Center, Calgary, Alberta, Canada.",
"authors": "Kooy|Joni|J|;Findley|Rachelle|R|;Nelson|Gregg|G|;Chu|Pamela|P|",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30087-4\n10.1016/j.gore.2020.100621\n100621\nCase Report\nCytology positive pericardial effusion causing tamponade in patients with high grade serous carcinoma of the ovary\nKooy Joni joni.kooy@albertahealthservices.ca⁎ Findley Rachelle 1 Nelson Gregg Chu Pamela Tom Baker Cancer Center, Calgary, Alberta, Canada\n⁎ Corresponding author at: cc110D – 1331 29 Street NW, Calgary, Alberta T2N 4N2, Canada. joni.kooy@albertahealthservices.ca1 Co-first author.\n\n\n07 8 2020 \n8 2020 \n07 8 2020 \n33 10062123 6 2020 30 7 2020 3 8 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Three patients with cytology positive pericardial effusions from high grade serous carcinoma.\n\n• Patients’ conditions amenable to treatment with chemotherapy after effusion symptom improvement.\n\n• Patient with pericardial effusion from high grade serous ovarian cancer post a poly ADP ribose polymerase inhibitor.\n\n\n\nKeywords\nPericardial effusionHigh grade serous ovarian carcinoma\n==== Body\n1 Introduction\nHigh grade serous carcinoma (HGSC) of the ovary is known to cause malignant fluid accumulation in the peritoneal and pleural space. Reported but rare is malignant pericardial effusion with tamponade (Dracham et al., 2019). Urgent recognition and treatment of this rare condition is essential to lifesaving management. We present 3 cases of malignant pericardial effusion with features of cardiac tamponade caused by HGSC. Written informed consent was obtained from all patients presented in this report.\n\n2 Case reports\n2.1 Patient A\nA previously healthy 41-year-old presented with an enlarged supraclavicular lymph node associated with non-specific abdominal symptoms. PET-CT demonstrated diffuse lymphadenopathy including supraclavicular, mediastinal, and carotid lymph nodes with a complex ovarian mass. Pathology of the biopsied supraclavicular lymph node demonstrated adenocarcinoma of ovarian primary. After an excellent response to 3 cycles of neoadjuvant carboplatin/paclitaxel, she was microscopically debulked. She received 6 cycles of adjuvant carboplatin/docetaxel due to a paclitaxel reaction. She is BRCA negative.\n\nDisease recurred 6 months after chemotherapy with involved pelvic and paraaortic lymph nodes. A complete response was achieved with 6 cycles of liposomal doxorubicin but a second recurrence with abdominopelvic nodal disease was diagnosed 6 months later. She responded to 3 cycles of cisplatin/gemcitabine and then enrolled in a trial receiving rucaparib. After 32 cycles, she progressed and received 4 cycles of cisplatin/gemcitabine with one cycle of bevacizumab.\n\nNine months later, and 85 months after her original cancer diagnosis, she presented to emergency services with bloating, weakness, a change in bowel movements, and orthopnea. She was tachycardic at 128 beats/minute and hypotensive at 94/69 mmHg with remaining vital signs normal. A chest x-ray noted mildly enlarged cardiac silhouette and small bilateral pleural effusions (Fig. 1A). An electrocardiogram showed tachycardia, decreased QRS voltage, and non-specific T-wave changes. An echocardiogram showed a large pericardial effusion with features of tamponade. Pericardiocentesis was performed for 1 L and a pericardial drain remained in situ for 3 days (Fig. 1B). The pericardial and pleural fluid was positive for metastatic HGSC. On further imaging, she was noted to have a new pulmonary embolus, thrombi in the inferior vena cava, renal and portal vein, increased adenopathy, hepatic metastases, and peritoneal nodularity.Fig. 1 Patient A – chest x-ray prior to pericardial drain (A) and chest x-ray after drain (B) Patient B – CT of pericardial effusion (C) and echocardiogram of pericardial effusion (D) Patient C – chest x-ray image prior to drain (E) and echocardiogram of pericardial effusion (F).\n\n\n\nShe was well following her 5-day hospital admission and 2 months on, is still without recurrence of her pericardial effusion and tolerating palliative single agent carboplatin.\n\n2.2 Patient B\nA 67-year-old with a history of type 2 diabetes, thalassemia minor, and breast ductal carcinoma in-situ presented with shortness of breath. She had a large pulmonary embolus, pleural effusions, peritoneal carcinomatosis, and ascites. Peritoneal and pleural cytology as well as omental biopsy were consistent with HGSC. She received 3 cycles of neoadjuvant carboplatin/paclitaxel. After a good response, she was microscopically debulked. She then received 6 cycles of adjuvant carboplatin/paclitaxel followed by 12 cycles of maintenance bevacizumab when she was noted to have recurred with omental nodularity and a pleural effusion. She is BRCA negative.\n\nBack on chemotherapy and 17 months after her initial cancer diagnosis, she developed increasing shortness of breath and O2 saturation of 75% on room air with otherwise normal vital signs. A CT showed both pulmonary embolism and pericardial effusion (Fig. 1C and D). Echocardiogram confirmed a large pericardial effusion with findings of tamponade. Pericardiocentesis was performed, a drain inserted, and a total of 930 cc of malignant fluid was drained. She received 3 cycles of cisplatin/gemcitabine with resolution of the effusion.\n\nAfter a 4-month treatment break, she had progressive disease with pericardial thickening, new liver metastases, peritoneal carcinomatosis, mesenteric deposits, lymphadenopathy, and increasing pleural effusion. This improved with 4 cycles of cisplatin/gemcitabine. During treatment, she developed a repeat pulmonary embolism and small pericardial effusion not requiring drainage. Ten months after the malignant pericardial effusion, she is alive and on niraparib.\n\n2.3 Patient C\nA 56-year-old patient with osteoarthritis presented with abdominal pain and weight loss over 2 years. On CT scan, extensive enlarged paraaortic and prominent inguinal lymph nodes were seen. A retroperitoneal biopsy confirmed metastatic HGSC. She is BRCA negative. She underwent 3 cycles of neoadjuvant carboplatin/paclitaxel. After the first, she developed a right internal jugular vein clot from the brachiocephalic vein extending to the sigmoid sinus. She was microscopically debulked with intraoperative findings of a complete response. Three adjuvant cycles of carboplatin/paclitaxel were completed and a post-treatment PET-CT demonstrated no active disease. She recurred 17 months later in her inguinal lymph nodes and mesentery. After 3 cycles of carboplatin/paclitaxel followed by 2 cycles of carboplatin, she had a complete response. She recurred 7 months later with pelvic and inguinal adenopathy. She declined chemotherapy at that time as she was relatively asymptomatic.\n\nTwo months later, and 37 months after her cancer diagnosis, she presented to hospital with increasing dyspnea leading to presyncope and orthopnea. A chest x-ray noted mild cardiac enlargement and an echocardiogram showed a large pericardial effusion with features of cardiac tamponade (Fig. 1E and F). A pericardial drain was left in situ for 24 h, draining a total of 1450 cc of bloody fluid, positive for HGSC.\n\nShe was started on palliative carboplatin within 2 weeks of her cardiac tamponade, and then transitioned to niraparib. Three months following pericardial tamponade, she is alive, tolerating treatment, and follow up imaging has shown no evidence of further pericardial effusion.\n\n3 Discussion\nPericardial effusion develops most commonly due to iatrogenic, idiopathic, malignant, or infectious causes (Strobbe et al., 2017). If the fluid is of low volume or accumulates slowly, the effusion can be asymptomatic and found incidentally (Donato et al., 1986). Symptoms of effusion associated with tamponade include shortness of breath, chest pain and orthopnea. Physical exam findings include an elevated jugular venous pressure, quiet heart sounds, decreased blood pressure, narrow pulse pressure, and tachycardia. Investigations will often reveal an ECG with low QRS amplitude, an enlarged cardiac silhouette on chest x-ray, and an increase in pericardial fluid on CT chest or echocardiogram (Dracham et al., 2019, Donato et al., 1986). Among ovarian cancer patients who present with the above symptoms, more common diagnoses include pulmonary embolism, pleural effusion, or pneumonia. However, given the mortality risk with pericardial tamponade, it is an essential diagnosis to consider.\n\nMalignancy is a major cause of pericardial effusion leading to tamponade (Strobbe et al., 2017). HGSC of the ovary is a very uncommon cause of cytology positive pericardial effusion. A retrospective study found that 1.2% of 255 patients reviewed developed a malignant pericardial effusion causing tamponade (Dauplat et al., 1987). Pericardial effusions are more common in lung and breast cancers (Dracham et al., 2019) and their pathophysiology includes lymphangitic, hematogenous, or local spread. Pericardial fluid drains through the subepicardial plexus to the mediastinal nodes. It is thought that metastasis to mediastinal lymph nodes spread via this lymphatic plexus to the heart, leading to malignant pericardial effusions (Donato et al., 1986).\n\nA literature review of cytology confirmed pericardial effusions from recurrent HGSC of the ovary with descriptions of cancer treatment is presented in Table 1. Many published cases dating back to the 1980s and 1990s describe women who passed away within weeks to months of developing a pericardial effusion but significant changes in treatment protocols have occurred since that time. Limited literature is available on pericardial effusion associated with HGSC and its effects on treatment options and survival.Table 1 Case reports of cytology positive high grade serous pericardial effusions with descriptions of patient cancer treatment and course.\n\nAuthor\tAge\tInitial Stage\tTime from Initial Diagnosis\tPrior Lines of Therapy\tTreatment for Effusion\tOutcome\t\nDracham et al. (2019)\t51\tIIIC\t7 years\tCarboplatin/paclitaxel\tPericardiocentesis & pericardial window followed by carboplatin/paclitaxel then olaparib\tAlive at time of publication 12 months post therapy\t\nFeferkorn et al. (2014)\t72\tIIIC\t6 years\tUnspecified neoadjuvant and adjuvant chemotherapy, olaparib\tPericardiocentesis, patient refused chemo & recurred 6 weeks later & received a pericardiocentesis\tDeceased after 6 weeks\t\nPetersen et al. (2009)\tNot reported\tIV\tNot reported\tTopotecan/carboplatin, carboplatin/paclitaxel, bortezomib, temozolomide, liposomal doxorubicin\tPericardiocentesis & placement of a drain, recurred in 9 days & treated with repeat drain & sclerosis\tDeceased after 12 months\t\nBlich et al. (2007)\t74\tNot reported\tNot reported\tDoxorubicin/5FU/cyclophosphamide, liposomal doxorubicin\tPericardiocentesis & recurred 1 month later followed by another pericardiocentesis\tDeceased after 1 week\t\nLevitan et al. (1990)\t46\tIIIC\t3 years\tCyclophosphamide/Adriamycin/Cisplatin\tPericardiocentesis & drain, tetracycline sclerosis followed by radiation to pericardium, cyclophosphamide/cisplatin\tDeceased after 2.5 years\t\nMäenpää et al. (1988)\t67\tIIB\t2 years\tCyclophosphamide/doxorubicin/tegafur\tPericardiocentesis followed by cyclophosphamide/doxorubicin/cisplatin\tDeceased after 7 months\t\nLund (1985)\t53 & 60 (2 patients)\tIII & IV\t2 years\tDoxorubicin/5FU /cyclophosphamide, cisplatin/hexamethylmelamine, & doxorubicin /5FU /cyclophosphamide,cisplatin/hexamethylmelamine\tPericardiocentesis, tetracycline sclerosis twice, recurred 2 weeks later. Repeat pericardiocentesis & drain. Effusion recurred in 1 week\tDeceased after 1 week & Deceased after 3 months\t\n\n\nWe report 3 additional cases of cytology positive pericardial effusions with tamponade presenting during the course of HGSC of the ovary. Our cases are unique for several reasons. Two of three patients initially presented with diffuse lymphadenopathy including one involving a supraclavicular node. This is an unusual initial presentation of HGSC of the ovary and the likely route of access to the pericardial space. The third patient had a more typical presentation of ovarian cancer with ascites, peritoneal disease, and pleural effusions. Each patient had a venous thromboembolism prior to or concurrently with the diagnosis of their pericardial effusion. Of the patients presenting with unusual lymphatic presentations, they also had unusual thromboembolism sites: renal and portal vein as well as involving the internal jugular vein.\n\nTo our knowledge, we report the second malignant pericardial effusion with tamponade in a patient previously treated with a poly ADP ribose polymerase (PARP) inhibitor. For this patient, without the benefit of the PARP inhibitor, it is likely her disease would have progressed more rapidly, perhaps never presenting with cardiac tamponade. Instead she had 85 months between diagnosis of cancer and pericardial tamponade.\n\nAll patients had pericardial drains inserted but none required sclerotherapy. None have had clinically significant re-accumulation of their effusion. Perhaps reflecting their younger ages, all patients had a performance status that allowed provision of palliative chemotherapy to reduce the likelihood of further fluid accumulation.\n\n4 Conclusion\nCytology positive pericardial effusion and tamponade in HGSC of the ovary remains rare. We postulate that this presentation may become more common with advances in treatment such as PARP-inhibitors and hyperthermic intraperitoneal chemotherapy (HIPEC) that better control abdominal disease, permitting cancer growth in cavities not typically seen before. These cases add to the literature in their unique initial disease presentation and provide further prognostic information that pericardial effusions are not necessarily a perimortem event; and with prompt diagnosis and treatment, patients can have a prolonged life expectancy and improved quality of life.\n\n5 Contributions\nAll authors reviewed the article for its content and editing. JK formulated the idea for the case report and contributed to the literature review, data collection, preparation, and editing of the article as well as care for the patients. RF refined the report direction and contributed to the literature review, data collection, preparation, and editing of the article as well as care for the patients. GN is responsible for one patient’s management and contributed to the review and editing of this article. PC is responsible for two patients’ management and contributed to the review and editing of this article.\n\nDeclaration of Competing Interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\nBlich M. Malkin L. Kapeliovich M. Malignant pericardial tamponade secondary to papillary serous adenocarcinoma of the ovary Israel Med. Assoc. J.: IMAJ 9 4 2007 337 338 \nDauplat J. Hacker N.F. Nieberg R.K. Berek J.S. Rose T.P. Sagae S. Distant metastases in epithelial ovarian carcinoma Cancer 60 7 1987 1561 1566 3621129 \nDonato D.M. Sevin B.U. Averette H.E. Neoplastic pericarditis and gynecologic malignancies–a review of the literature Obstet. Gynecol. Surv. 41 8 1986 473 479 3526214 \nDracham C.B. Gupta S. Das C.K. Elangovan A. Platinum sensitive carcinoma of ovary relapsed as pericardial effusion with cardiac tamponade BMJ Case Rep. 12 3 2019 e228268 \nFeferkorn I. Shai A. Gemer O. Auslender R. Lavie O. The natural history of pericardial tamponade secondary to recurrent ovarian carcinoma—A case report and review of the literature Gynecol. Oncol. Rep. 10 2014 53 55 26082940 \nLevitan L.Z. Kaplan N.A. Gordon N.A. Survival after malignant pericardial effusion and cardiac tamponade in advanced ovarian cancer Southern Med. J. 83 2 1990 241 242 2305307 \nLund B. Pericardial effusion in advanced ovarian carcinoma a literature review and report of two cases Acta Obstet. Gynecol. Scand. 64 5 1985 443 445 4061062 \nMäenpää J. Taina E. Erkkola R. Malignant pericardial effusion in ovarian carcinoma cured by systemic chemotherapy Gynecol. Oncol. 30 2 1988 298 301 3371750 \nPetersen E.E. Shamshirsaz A.A. Brennan T.M. Demetroulis E.M. Goodheart M.J. Malignant pericardial effusion with cardiac tamponade in ovarian adenocarcinoma Arch. Gynecol. Obstet. 280 4 2009 675 678 19225795 \nStrobbe A. Adriaenssens T. Bennett J. Dubois C. Desmet W. McCutcheon K. Etiology and long‐term outcome of patients undergoing pericardiocentesis J. Am. Heart Assoc. 6 12 2017 n/a–n/a\n\n",
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"title": "Cytology positive pericardial effusion causing tamponade in patients with high grade serous carcinoma of the ovary.",
"title_normalized": "cytology positive pericardial effusion causing tamponade in patients with high grade serous carcinoma of the ovary"
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"abstract": "Inherited disorders of interferon gamma (IFN) γ, also known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD), have been classified as Primary Immuno Deficiency 6, ie, defect in intrinsic and innate immunity. As IFN-γ plays an important role in conferring immunity to mycobacterial infections, its disorders have been increasingly reported in association with disseminated BCG/Non Tubercular Mycobacterial infections. So far germline mutations in 16 genes have been reported, most common being IL12RB1 followed by IFNGR1 and IFNGR2. There is limited published data on MSMD from India and here we report 4 unrelated children with proven mutations in IL12RB1 in 2 children and IFNGR1 and IFNGR2 in one each with disseminated opportunistic mycobacterial infections from a tertiary care centre in India.",
"affiliations": "Department of Paediatrics, St John's Medical College Hospital, Bengaluru, Karnataka, India. Electronic address: ckindumathi@gmail.com.;University of Paris, Imagine Institute, Laboratory of Human Genetics of Infectious Diseases, Institut National de La Santé et de La Recherche Médicale U1163 and Study Center of Immunodeficiencies, Necker Hospital for Sick Children, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, the Rockefeller University, New York, NY, USA.",
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"abstract": "OBJECTIVE\nEffects of methadone misuse have been rarely described. The purpose of this case report is to increase the knowledge of methadone-related leukoencephalopathy.\n\n\nMETHODS\nWe report the long-term follow-up by brain magnetic resonance imaging including isotropic diffusion-weighted imaging and mean apparent diffusion coefficient values of a 49-year-old patient who attempted suicide by intravenous methadone.\n\n\nCONCLUSIONS\nLesion pattern included subtle cerebellar involvement, mainly reversible extensive bilateral and symmetric brain involvement, cystic degeneration in the periventricular regions, sparing of corpus callosum and subcortical U-fibers, development of diffuse brain atrophy, and clear-cut clinical improvement.",
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"title": "Methadone-induced toxic leukoencephalopathy: diagnosis and follow-up by magnetic resonance imaging including diffusion-weighted imaging and apparent diffusion coefficient maps.",
"title_normalized": "methadone induced toxic leukoencephalopathy diagnosis and follow up by magnetic resonance imaging including diffusion weighted imaging and apparent diffusion coefficient maps"
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"abstract": "At an intermediate or advanced stage, i.e. stage B or C, based on the Barcelona Clinic Liver Cancer classification of hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) may be offered as a treatment of palliative intent. We report the case of a patient suffering from acute respiratory distress syndrome after TACE with drug-eluting beads loaded with doxorubicin for HCC. To our knowledge, this is the first case described where a bronchoalveolar lavage was performed, and where significant levels of alveolar eosinophilia and neutrophilia were evident, attributed to a pulmonary toxicity of doxorubicin following liver chemoembolization.",
"affiliations": "Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.",
"authors": "Alifakioti|Dimitra|D|;Daccord|Cécile|C|;Lachenal|Yann|Y|;Fitting|Jean-William|JW|",
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"title": "Acute eosinophilic and neutrophilic pneumonia following transarterial chemoembolization with drug-eluting beads loaded with doxorubicin for hepatocellular carcinoma: a case report.",
"title_normalized": "acute eosinophilic and neutrophilic pneumonia following transarterial chemoembolization with drug eluting beads loaded with doxorubicin for hepatocellular carcinoma a case report"
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"abstract": "BACKGROUND\nA dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy.\n\n\nMETHODS\nPatients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis.\n\n\nRESULTS\nIn March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%).\n\n\nCONCLUSIONS\nSequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.",
"affiliations": "Department of Medical Oncology, Institut Curie - Hôpital René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France. etienne.brain@curie.net",
"authors": "Brain|E|E|;Levy|C|C|;Serin|D|D|;Roché|H|H|;Spielmann|M|M|;Delva|R|R|;Veyret|C|C|;Mauriac|L|L|;Rios|M|M|;Martin|A L|AL|;Jimenez|M|M|;Asselain|B|B|;Gauthier|M|M|;Bonnetain|F|F|;Fumoleau|P|P|",
"chemical_list": "D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2011.414",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\nbjc2011414\n10.1038/bjc.2011.414\n22009030\nClinical Study\nHigh rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer\nDose dense chemotherapy for breast cancer\nBrain E 1*\nLevy C 2\nSerin D 3\nRoché H 4\nSpielmann M 5\nDelva R 6\nVeyret C 7\nMauriac L 8\nRios M 9\nMartin A L 10\nJimenez M 10\nAsselain B 11\nGauthier M 12\nBonnetain F 12\nFumoleau P 12\n1 Department of Medical Oncology, Institut Curie – Hôpital René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France\n2 Breast Oncology Unit, Centre de Lutte Contre le Cancer – Centre François Baclesse 3, Avenue Général Harris, 14076 CAEN cedex 05, France\n3 Breast Oncology Unit, Institut Sainte-Catherine, 1750 Chemin du Lavarin, 84000 Avignon, France\n4 Department of Medical Oncology, Institut Claudius Regaud, 20-24, rue du Pont-Saint-Pierre, 31052 Toulouse cedex, France\n5 Department of Medical Oncology, Institut de Cancérologie Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France\n6 Breast Oncology Unit, Centre Paul Papin, 2 rue Moll, 49000 Angers, France\n7 Department of Medical Oncology, Centre Henri Becquerel, rue d’Amiens, 76038 Rouen cedex 1, France\n8 Department of Medical Oncology, Centre Régional de Lutte Contre le Cancer – Institut Bergonié, 229 cours de l’Argonne, 33076 Bordeaux cedex, France\n9 Department of Medical Oncology, Centre Alexis Vautrin, avenue de Bourgogne, 54511 Vandoeuvre-les-Nancy, France\n10 UNICANCER – Fédération Nationale des Centres de Lutte Contre le Cancer, 101, rue de Tolbiac, 75654 Paris, France\n11 Department of Bioinformatics – Institut Curie, 26 rue d’Ulm, 75248 Paris, France\n12 Centre Georges François Leclerc, 1 rue Professeur Marion, 21000 Dijon, France\n* E-mail: etienne.brain@curie.net\n08 11 2011\n18 10 2011\n105 10 14801486\n15 07 2011\n12 09 2011\n13 09 2011\nCopyright © 2011 Cancer Research UK\n2011\nCancer Research UK\nhttps://creativecommons.org/licenses/by/4.0/ 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 license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license 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 license, visit https://creativecommons.org/licenses/by/4.0/.\nBackground:\n\nA dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy.\n\nMethods:\n\nPatients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m−2, epirubicin 100 mg m−2, cyclophosphamide 500 mg m−2 (FEC 100) followed by three cycles of docetaxel 100 mg m−2 delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis.\n\nResults:\n\nIn March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%).\n\nConclusion:\n\nSequential dose-dense FEC 100 followed by docetaxel 100 mg m−2 is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.\n\nadjuvant treatment\ndocetaxel\ndose-dense regimen\nearly breast cancer\nskin toxicity\ntaxanes\n==== Body\npmcOver the last three decades, adjuvant systemic chemotherapy for early breast cancer has delivered steadily improving outcomes, as a result of the introduction of new cytotoxic agents such as anthracyclines and taxanes, the optimisation of standard regimens administration, and more recently, better patient selection using elaborate prognostic algorithms (Dang and Hudis, 2006; Levine and Whelan, 2006). Polychemotherapy regimens based on an anthracycline and taxane backbone have emerged as the international standard in high-risk breast cancer including node positive (pN+) cases (Goldhirsch et al, 2009). Further attempts to improve the outcomes with standard chemotherapy have focused on either dose intense (higher dose) or dose-dense (more frequent administration) strategies, both being made possible with highly effective granulocyte colony-stimulating factors (G-CSF). For the dose-dense strategy, models of tumour growth and response based on the Norton–Simon hypothesis (Norton et al, 1976) were translated into regimens, which aimed to increase tumour cell kill by decreasing the time intervals between treatments, preventing cancer cell repopulation, particularly in tumours with high proliferation rates. This strategy was fully evaluated in the Cancer and Leukemia Group B 9741 adjuvant trial, which demonstrated significant benefits compared with the conventionally scheduled four cycles of standard doxorubicin and cyclophosphamide (AC) followed by four cycles of paclitaxel (Citron et al, 2003). However trans-Atlantic differences in the preferred anthracycline regimen hampered the further application of this approach to Europe where fluorouracil 500 mg m−2, epirubicin 100 mg m−2 and cyclophosphamide 500 mg m−2 regimen (FEC 100) (French Adjuvant Study Group, 2001) or the Canadian cyclophosphamide, epirubicin and flurouracil regimen (Levine et al, 1998) are more widely used than AC. Uncertainties also persist regarding the optimal choice of taxane and the best way to deliver it: docetaxel might be more active than paclitaxel based on results obtained in the metastatic setting, and concomitant schedules (Brain et al, 2005) might be responsible for more side effects than the genuinely sequential ones (Bear et al, 2003). In order to resolve these differences, we chose to investigate the feasibility of two dose-dense versions of the standard FEC-D sequential chemotherapy regimen consisting of three cycles of FEC 100 followed by three cycles of docetaxel 100 mg m−2 (D), as used on a 3-weekly basis in the PACS 01 adjuvant trial run by the Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER) (Roché et al, 2006). The phase II study was designed to identify the optimal 2-weekly version of FEC-D, which could then be taken into a phase III trial against standard 3-weekly FEC-D.\n\nMaterials and methods\n\nPatient population\n\nEligible patients were recruited from 14 French cancer centres. They were women, aged between 18 and 65 years with unilateral pT1–pT3-operated breast cancer, clear surgical margins and axillary node clearance including at least five lymph nodes. Main eligibility criterion was a ‘high-risk’ pN+ disease defined as either one, two or three positive nodes and negative oestrogen and progesterone receptors status (ER-negative and PgR-negative) or more than three positive nodes irrespective of the hormone receptor status. Main inclusion criteria included the following: WHO performance status <2; interval period between first surgery and start of adjuvant chemotherapy of less than 60 days; normal left ventricular ejection fraction; normal haematological, renal and liver functions. Patients were excluded in the case of any evidence of distant metastasis, documented history of previous cancer (except treated basal cell of the skin and uterine cervix cancer), cardiac disease, any chronic digestive disease, B or C hepatitis, and serious underlying medical or psychiatric illness. Pregnant or breast-feeding women were ineligible, and contraception was mandatory for those of child-bearing age.\n\nPotentially eligible patients underwent bone scan, chest radiograph, abdominal ultrasound or computed tomography, and ultrasound or radionuclide cardiac scan before being randomly assigned to treatment after giving written informed consent.\n\nTreatment regimens\n\nPatients were assigned to one of the two regimens by the central office of the UNICANCER Bureau des Etudes Cliniques et Thérapeutiques (Paris, France), which guaranteed allocation concealment. Randomisation was stratified according to the participating centre only, using a 1 : 1 computerised randomisation.\n\nBoth arms consisted of three cycles of FEC 100 followed by three cycles of docetaxel 100 mg m−2, given intravenously (1-h infusion) either every 2 weeks without interruption (arm A), or with a 2-week additional period of rest between the third cycle of FEC 100 and first cycle of docetaxel (arm B).\n\nDaily G-CSF (filgrastim) support was mandatory (5 μg kg−1 per day subcutaneously from day 3 to day 10) for each cycle, as well as standard docetaxel steroids-based premedication.\n\nToxicity evaluations using the National Cancer Institute Common Toxicity Criteria Version 3.0 were performed on day 1 of each cycle of chemotherapy.\n\nIn case of grade 2 neutropenia or grade 1 thrombocytopenia, the next cycle of chemotherapy was to be postponed by 1 or 2 weeks to allow patient recovery. The same guideline was applied in case of extra-haematological toxicity (excluding alopecia, nausea and vomiting) to allow recovery to a grade ⩽1. In both cases, treatment was to be stopped if recovery did not occur after a 2-week delay.\n\nDose reduction by 25% was to be applied in the event of febrile neutropenia (defined as a grade 4 neutropenia with temperature above 38.5°C having required antibiotics and/or having lasted more than 24 h), thrombocytopenia grade 4 or extra-haematological toxicity grade ⩾3 (excepting alopecia, nausea and vomiting). In the event of toxicity recurrence despite dose reduction, treatment was to be stopped.\n\nExternal beam radiotherapy and endocrine treatment were to follow the last cycle of chemotherapy according to standard guidelines.\n\nStatistical design\n\nThe primary endpoint of this study was the rate of success of chemotherapy delivery in both arms, without dose reduction or treatment delay. A total of 120 patients were necessary to give 97% power according to a two-stage Fleming design with a two-sided type I error of 3%, allowing 30% (H0) of dose reduction compared with 11% (H1) in the q3w experimental arm (three FEC 100, three docetaxel) of the PACS 01 trial (Roché et al, 2006).\n\nAn intermediate analysis was to be performed after inclusion of 30 patients into each arm, without temporary stop of enrolment, before extending to a full recruitment of 60 patients into each arm only if less than eight patients per arm had required a dose reduction or cycle postponement for reasons of toxicity. At the final analysis, the observation in an arm of 12 or more patients requiring dose reduction or cycle delay would lead to the conclusion that such a dose-dense schedule was not feasible.\n\nSecondary endpoints included safety profile, dose intensity (mg m−2 per week), relapse-free survival and overall survival.\n\nQualitative data were reported by frequency and 95% confidence interval, and compared using Pearson's χ2-test or Fisher's exact test. Quantitative data were summarised by mean, s.d., median and range values, and compared as appropriate with Student's t-test or the Mann–Withney or Wilcoxon tests. All the analyses were based on the intention-to treat principle and performed with the R software (version 2.0.1, http://cran.univ-lyon1.fr/, Lyon, France). All the tests were bilateral and a threshold of 5% or less was to be considered significant.\n\nA steering committee was in charge of supervising the study and monitoring patient accrual, treatment compliance and safety. The protocol of this study (EudraCT No 2004-002031-11) was approved by the institutional review board of each participating centre and by the study ethics review committee. It was conducted according the Declaration of Helsinki and the Good Clinical Practice guidelines.\n\nResults\n\nConduct of the study\n\nEnrolment started in October 2004. According to the statistical design, an interim analysis was to be conducted after enrolment of the sixtieth patient. However, before that, the identification of nine cases of grade ⩾3 skin toxicity occurring after the first cycle of docetaxel in arm A (leading to withdrawal from treatment in five patients) resulted in suspension of recruitment in March 2005 in both arms, pending full interim safety analysis. All patients in arm A were switched to a classical 3-week interval for the remaining cycles (FEC 100 or docetaxel). As no extra-haematological toxicity, grade ⩾3, had yet been reported in arm B, recruitment to arm B was allowed to resume, but in fact no further enrolment occurred, reflecting perhaps investigators’ concern as to the feasibility of this regimen as well. In September 2005, after completion of the interim analysis, the steering committee decided to terminate the study with 37 patients enrolled in each arm, because of the unexpectedly high rate of skin toxicity (grade ⩾3) in both arms (32.4% and 18.9% of patients in arm A and B, respectively, Figure 1).\n\nPatient population\n\nApart from a slight imbalance for age, type of surgery and nodal status favouring arm A, the patients’ characteristics were relatively well balanced between the two groups (Table 1). More than 50% of tumours were Scarf Bloom and Richardson grade III. The status of both ER and PgR was negative in 30% of cases whereas 27% of tumours showed HER2 overexpression.\n\nTolerance\n\nTable 2 summarises the distribution of main side effects according to arm and regimen component. For reasons of clarity, the data shown combine all events recorded in each arm until the trial closure of the trial (September 2005), including also those occurring in arm A after the shift to a 3-weekly schedule in that arm in March 2005.\n\nHaematological toxicity did not differ between both arms, neutropenia occurring in one third of patients during FEC (cycle 1–3) with less than 6% of patients developing one or more febrile event during either sequential regimen. Neither grade 4 thrombocytopenia nor any grade 5 event was reported.\n\nExtra-haematological toxicity peaked from cycle 4 (first cycle with docetaxel) in both arms, including skin and nail toxicity, arthralgia/myalgia and fluid retention.\n\nGrade 3–4 skin toxicity occurred in 32.4% and 18.9% of patients in arm A and B respectively, all during the docetaxel component of therapy, with lower rates of grade 1–2 nail toxicity events, arthralgia/myalgia and grade 1–2 oedemas being seen in arm A. Of note, no grade 3–4 skin toxicity was observed in arm A after the intercycle interval was set to 3 weeks in March 2005 (data not shown).\n\nSkin toxicity included dermatitis, erythematous diffuse or peripheral eruptions, pruritus, labial and peripheral oedema, culminating in grade 4 palmo-plantar erythrodysesthesia (Figure 2). Most resolved, some with long delays exceeding 3 to 6 months, but some patients were left with persisting skin problems and head alopecia.\n\nTreatment delays and dose reductions\n\nA total of 54 cycles were given on a 3-weekly basis following discontinuation of enrolment in arm A whereas 390 cycles were administered according to the allocated treatment schedule. When considering all cycles in each arm, significant delays (⩾5 days), dose reductions and cycle cancellations occurred in 66 (30%), 11 (5%) and 15 (7%) of cycles vs 15 (7%), 7 (3%) and 6 (3%) in arm A and arm B, respectively. Excluding the 54 cycles deliberately given on a 3-weekly schedule, the rate of significant delays in arm A lowered to 7% (12 out of 168 cycles) (see detail in Table 3). Except one cycle cancelled in arm B, one cycle with a 25% dose reduction in each arm and four delays at cycle 2 in arm A, there was no dose density alteration of FEC 100 administration in either arm. Most of the treatment modifications occurred from cycle 5 onwards, after the first cycle of docetaxel, and mostly due to toxicity. In total, nine patients stopped docetaxel in arm A compared with three in arm B.\n\nDiscussion\n\nIn this study, administration of adjuvant, dose-dense FEC 100 therapy with G-CSF followed by dose-dense docetaxel with G-CSF proved to be not feasible in women with high-risk node-positive early-stage breast cancer. Whatever schedule chosen, with (arm B) or without (arm A) an extra 2-week interval between both sequences, dose-dense chemotherapy yielded an unacceptable high rate of grade 3–4 skin toxicity (32.4% and 18.9% in arm A and B, respectively). This led to the termination of the trial in two steps: (i) following the interim analysis (at 6 months of enrolment), early closure and shift from a continuous bi-weekly regimen to a continuous tri-weekly schedule for arm A; (ii) final closure of the trial after an additional 6-month careful monitoring, which showed a similar unacceptable toxicity profile in arm B.\n\nAlthough the advent of neutrophil-stimulating growth factors has permitted exploration of the benefits of administering chemotherapy at shortened intervals (so-called ‘dose-density’) with manageable or even decreased haematological toxicity (Citron et al, 2003; Jones et al, 2009), it also revealed extra-haematological side effects unusual with the use of standard scheduling. In our trial, febrile neutropenia rates were low and we did not observe any other significant grade 3–4 haematological toxicity. Conversely, extra-haematological toxicity of grade 2 or even 1 was noted, which may prove to be significant. Thus not only was grade 3–4 skin toxicity increased but also grade 1–2 nail toxicity, fluid retention, and arthralgia/myalgia, some occurring in up to one third of patients. Of note, the incidence of all these extra-haematological side effects peaked during the docetaxel component right from cycle 4, and the lower global rates favouring arm A likely reflect the conservative measure to increase by 1 week the interval between each remaining cycle of chemotherapy in this group after March 2005 (Table 2).\n\nNevertheless, dose-dense chemotherapy for early-stage breast cancer remains an important strategy as it is predicted to maximise the impact of individual cytotoxic agents (Norton et al, 1976; Norton and Simon, 1977; Budman et al, 1998), with encouraging results on long-term outcome (Citron et al, 2003; Moebus et al, 2010), especially in ER-negative and PgR-negative tumours (Berry et al, 2006). However, benefits of dose-dense approach must be seen in the context of greater non-haematological toxic effects, myelosuppression being no longer the limiting toxicity. For this approach to be successful, it cannot jeopardise the quality of life by early acute and persistent toxicity, and feasibility still depends largely on several factors including the choice of agents, and dose and sequence (anthracyclines or taxanes first?).\n\nMore dose-dense trials have used paclitaxel (standard or new formulations) with less reported complications than with docetaxel (Citron et al, 2003; Lambert-Falls and Modugno, 2007; Yardley et al, 2008; Wildiers et al, 2009; Burnell et al, 2010; Jacot et al, 2010; Moebus et al, 2010; Robert et al, 2011). In the Arbeitsgemeinschaft Gynäkologische Onkologie phase III study, the rate of grade 3–4 skin toxicity observed in the intense sequential dose-dense arm (epirubicin, paclitaxel, followed by cyclophosphamide) was less than 5%, though the rates of grade 1 and 2 events reported as high as 31 and 15% cannot be ignored (Moebus et al, 2010).\n\nThe optimal sequence of component parts of a sequential regimen remains unclear, as published results often mix strategies (e.g., dose, length of intervals). In one study, a reverse sequence to ours was stated as feasible at least in neoadjuvant setting, yielding a high relative dose intensity and a 25% complete pathological rate; however, anthracyclines (FEC 100) were given every 3 weeks after dose-dense docetaxel at 100 mg m−2, and grade 3 skin toxicity was reported in one quarter of patients, questioning the real feasibility of such regimen given that the pathological complete response rate is not very different from what would be expected with conventional 3-weekly chemotherapy (Jacot et al, 2010). Another trial investigated a similar dose-dense reverse sequence: docetaxel followed by AC every 2 weeks. Recruitment was stopped for toxicity reasons after enrolment of 36 women, based on significant toxicity being observed in more than 50% of cases, despite systematic dose reduction applied to docetaxel from 100 to 75 mg m−2 (Lambert-Falls and Modugno, 2007). Of note, grade 3–4 palmar-plantar erythrodysesthesia occurred in 25% of patients during docetaxel medication vs none during AC, and 25% dose reduction of docetaxel did not solve the skin toxicity, grade 3 still occurring in 11% patients at the lower dosage (Lambert-Falls and Modugno, 2007), stressing that dose and sequence are not exclusive issues and may affect delivery of planned doses and toxicity (Yardley et al, 2008; Wildiers et al, 2009).\n\nIn conclusion, this phase study adds to the body of evidence that dose-dense FEC 100 followed by docetaxel 100 mg m−2 (FEC-D) is not feasible. Indeed the feasibility of dose-dense chemotherapy incorporating a taxane within an anthracycline-based polychemotherapy backbone remains unclear and depends on careful regimen design and a justified therapeutic ratio. Use of the reverse sequence (taxane preceding anthracycline) should be restricted to clinical studies until there is more evidence of its benefit, and any such research should also focus on defining which tumours would derive the most therapeutic benefit of using such a strategy in the place of standard scheduling.\n\nWe thank Valère Lounnas for his assistance with the manuscript. This work was supported by the Ligue Nationale Contre le Cancer and by Sanofi-Aventis (France).\n\nFigure 1 Study flow chart.\n\nFigure 2 Photographs of grade 4 palmo-plantar erythrodysesthesia.\n\nTable 1 Baseline characteristics\n\n \tArm A N (%)\tArm B N (%)\t\nN\t37 (100)\t37 (100)\t\nAge, median (range), year\t47 (29–64)\t56 (34–67)\t\nConservative surgery\t21 (57)\t16 (43)\t\nMastectomy\t16 (43)\t21 (57)\t\n \t \t \t\nPathology\t\n Invasive lobular carcinoma\t4 (11)\t3 (8)\t\n Invasive ductal carcinoma\t33 (89)\t33 (89)\t\n Other\t0 (0)\t1 (3)\t\n \t \t \t\npT, mean (range), mm\t24.0 (6–50)\t28.3 (9–90)\t\n \t \t \t\npN+\t\n 1–3 pN+\t8 (22)\t4 (11)\t\n >3 pN+\t29 (78)\t33 (89)\t\n \t \t \t\nSBR grade\t\n I\t4 (11)\t4 (11)\t\n II\t11 (30)\t14 (38)\t\n III\t22 (59)\t19 (51)\t\n \t \t \t\nER and PgR status\t\n ER-negative\t12 (32)\t12 (32)\t\n PgR-negative\t17 (46)\t17 (46)\t\n ER- and PgR-negative\t11 (30)\t11 (30)\t\n ER- and/or PgR-positive\t26 (70)\t26 (70)\t\n \t \t \t\nHER2\t\n Positive (IHC+++ or FISH+)\t11 (30)\t9 (24)\t\n Negative\t12 (32)\t16 (43)\t\n ND\t14 (38)\t13 (35)\t\nAbbreviations: ER=estrogen receptor; FISH=fluorescence in situ hybridization; IHC=immunohistochemistry; N=number of patients; ND=not determined; PgR=progesterone receptor; pN=pathologic lymph nodes; pT=pathological size; SBR=Scarff–Bloom–Richardson.\n\nTable 2 Toxicity per patient\n\n \tArm A (N=37)\tArm B (N=37)\t\n \tTotal\tCycle 1–3\tCycle 4–6\tTotal\tCycle 1–3\tCycle 4–6\t\nEvent\tN (%)\tN (%)\tN (%)\tN (%)\tN (%)\tN (%)\t\nNeutropenia\t \t \t \t \t \t \t\n Grade 3–4\t18 (48.6)\t12 (32.4)\t10 (27.0)\t14 (37.8)\t11 (29.7)\t6 (16.2)\t\n \t \t \t \t \t \t \t\nFebrile neutropenia\t2 (5.4)\t0\t2 (5.4)\t1 (2.7)\t1 (2.7)\t0\t\n \t \t \t \t \t \t \t\nThrombocytopenia\t\nGrade 3–4\t0\t0\t0\t1 (2.7)\t1 (2.7)\t0\t\n \t \t \t \t \t \t \t\nSkin toxicity\t\n Grade 1–2\t10 (27.0)\t7 (18.9)\t10 (27.0)\t20 (54.1)\t4 (10.8)\t19 (51.4)\t\n Grade 3–4\t12 (32.4)\t0\t12 (32.4)\t7 (18.9)\t0\t7 (18.9)\t\n \t \t \t \t \t \t \t\nMucositis\t\n Grade 3–4\t2 (5.4)\t1 (2.7)\t1 (2.7)\t1 (2.7)\t0\t1 (2.7)\t\n \t \t \t \t \t \t \t\nNail toxicity\t\n Grade 1–2\t7 (18.9)\t0\t7 (18.9)\t9 (24.3)\t1 (2.7)\t9 (24.3)\t\n Grade 3–4\t1(2.7)\t0\t1 (2.7)\t1 (2.7)\t0\t1 (2.7)\t\n \t \t \t \t \t \t \t\nArthralgia myalgia\t\n Grade 1–2\t10 (27.0)\t3 (8.1)\t7 (18.9)\t13 (35.1)\t2 (5.4)\t13 (35.1)\t\n Grade 3–4\t1 (2.7)\t0\t1 (2.7)\t1 (2.7)\t0\t1 (2.7)\t\n \t \t \t \t \t \t \t\nOedema\t\n Grade 1–2\t4 (10.8)\t1 (2.7)\t3 (8.1)\t6 (16.2)\t1 (2.7)\t6 (16.2)\t\n Grade 3–4\t1 (2.7)\t0\t1 (2.7)\t0\t0\t0\t\n\nTable 3 Dose reductions and treatment delays (⩾5days)\n\nCycle\tAdministration\tArm A (N=37), N\tArm B (N=37), N\t\nCycle 1\tQ2w cycles administered\t37\t37\t\n \t As planned\t37\t37\t\n \t \t \t \t\nCycle 2\tQ2w cycles administered\t35\t37\t\n \t As planned\t31\t36\t\n \t With dose reduction\t0\t1\t\n \t Delayed\t4\t0\t\n \t Cancelled\t0\t0\t\n \tQ3w cyclesa\t2\tNA\t\n \t \t \t \t\nCycle 3\tQ2w cycles administered\t31\t37\t\n \t As planned\t30\t36\t\n \t With dose reduction\t1\t0\t\n \t Delayed\t0\t0\t\n \t Cancelled\t0\t1\t\n \tQ3w cyclesa\t6\tNA\t\n \t \t \t \t\nCycle 4\tQ2w cycles administered\t23\t37\t\n \t As planned\t23\t33\t\n \t With dose reduction\t0\t0\t\n \t Delayed\t0\t3\t\n \t Cancelled\t0\t1\t\n \tQ3w cyclesa\t14\tNA\t\n \t \t \t \t\nCycle 5\tQ2w cycles administered\t22\t37\t\n \t As planned\t6\t26\t\n \t With dose reduction\t6\t3\t\n \t Delayed\t4\t7\t\n \t Cancelled\t6\t1\t\n \tQ3w cyclesa\t15\tNA\t\n \t \t \t \t\nCycle 6\tQ2w cycles administered\t20\t37\t\n \t As planned\t3\t26\t\n \t With dose reduction\t4\t3\t\n \t Delayed\t4\t5\t\n \t Cancelled\t9\t3\t\n \tQ3w cyclesa\t17\tNA\t\nAbbreviation: NA=not applicable.\n\na Shift to a 3-week interval in remaining cycles in March 2005 and discontinuation of inclusions in arm A is seen (not applicable in arm B).\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nThe data were presented in part at the 28th San Antonio Breast Cancer Symposium held in 2005.\n==== Refs\nBear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 22 : 4165–4174\nBerry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, MArtino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295 : 1658–166716609087\nBrain EGC, Bachelot T, Serin D, Kirscher S, Graic Y, Eymard JC, Extra JM, Combe M, Fourme E, Nogues C, Rouesse J (2005) Life-threatening sepsis associated with adjuvant adriamycin plus docetaxel for intermediate-risk breast cancer. J Am Med Assoc 293 : 2367–2371\nBudman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Muss HB, Green MR, Norton L, Frei III E (1998) Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90 : 1205–12119719081\nBurnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O’Brien P, Shepherd LE (2010) Cyclophosphamide, epirubicin, and Fluorouracil vs dose-dense epirubicin and cyclophosphamide followed by Paclitaxel vs Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol 28 : 77–8219901117\nCitron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, MArtino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L (2003) Randomized trial of dose-dense vs conventionally scheduled and sequential vs concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21 : 1431–143912668651\nDang C, Hudis C (2006) Adjuvant taxanes in the treatment of breast cancer: no longer at the tip of the iceberg. Clin Breast Cancer 7 : 51–5816764744\nFrench Adjuvant Study Group (2001) Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19 : 602–61111157009\nGoldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2009) Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer. Ann Oncol 20 : 1319–132919535820\nJacot W, Bibeau F, Gourgou-Bourgade S, Gutowski M, Colombo PE, Bleuse JP, Kramar A, Romieu G (2010) Phase II trial of dose dense docetaxel followed by FEC100 as neoadjuvant chemotherapy in patients with operable breast cancer. Am J Clin Oncol 33 : 544–54920042972\nJones RL, Walsh G, Ashley S, Chua S, Agarwal R, O’Brien M, Johnston S, Smith IE (2009) A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer. Br J Cancer 100 : 305–31019165198\nLambert-Falls R, Modugno S (2007) Toxicity of dose-dense docetaxel followed by doxorubicin with cyclophosphamide as adjuvant therapy for breast cancer in a phase II study. Clin Breast Cancer 7 : 697–70417919350\nLevine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D (1998) Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16 : 2651–26589704715\nLevine MN, Whelan T (2006) Adjuvant chemotherapy for breast cancer – 30 years later. N Engl J Med 355 : 1920–192217079767\nMoebus V, Jackisch C, Lueck HJ, Du BA, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M (2010) Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 28 : 2874–288020458045\nNorton L, Simon R (1977) Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61 : 1307–1317589597\nNorton L, Simon R, Brereton HD, Bogden AE (1976) Predicting the course of Gompertzian growth. Nature 264 : 542–5451004590\nRobert N, Krekow L, Stokoe C, Clawson A, Iglesias J, O’Shaughnessy J (2011) Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab-paclitaxel is safe in women with early-stage breast cancer: a pilot study. Breast Cancer Res Treat 125 : 115–12020945091\nRoché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulie P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Geneve J, Asselain B (2006) Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 trial. J Clin Oncol 24 : 5664–567117116941\nWildiers H, Dirix L, Neven P, Prove A, Clement P, Squifflet P, Amant F, Skacel T, Paridaens R (2009) Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence. Breast Cancer Res Treat 114 : 103–11218344024\nYardley DA, Burris III HA, Farley CP, Barton JH, Peacock NW, Spigel DR, Greco FA, Hainsworth JD (2008) A phase II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide as adjuvant or neoadjuvant treatment for women with node-positive or high-risk node-negative breast cancer. Clin Breast Cancer 8 : 242–24818650154\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0007-0920",
"issue": "105(10)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1480-6",
"pmc": null,
"pmid": "22009030",
"pubdate": "2011-11-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "20458045;12668651;9704715;20042972;589597;15900007;17079767;1004590;19165198;14559892;19535820;11157009;18344024;17919350;19901117;18650154;17116941;16764744;16609087;20945091;9719081",
"title": "High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.",
"title_normalized": "high rate of extra haematological toxicity compromises dose dense sequential adjuvant chemotherapy for breast cancer"
} | [
{
"companynumb": "FR-AMGEN-FRASP2021172007",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder that usually develops before 20 years of age and is characterized by periodic fever with serositis and arthritis. Both FMF and rheumatoid arthritis (RA) involve arthritis; however, their coexistence is rare. We describe two RA patients with an MEFV mutation in exon 2, who were diagnosed with FMF at an age of over 50 years. We also discuss the possibility that MEFV mutations could modulate RA disease activity.",
"affiliations": "Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan.;Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan.;Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan.;Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan.;Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan.;Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Rheumatology, Clinical Research Center, NHO National Nagasaki Medical Center, Omura, Japan.",
"authors": "Matsuoka|Naoki|N|;Iwanaga|Junko|J|;Ichinose|Yasufumi|Y|;Fujiyama|Kaoru|K|;Tsuboi|Masahiko|M|;Kawakami|Atsushi|A|;Migita|Kiyoshi|K|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; C000604192:MEFV protein, human; D000071198:Pyrin",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.12354",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "21(10)",
"journal": "International journal of rheumatic diseases",
"keywords": "MEFV gene; familial Mediterranean fever; rheumatoid arthritis",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D017668:Age of Onset; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005091:Exons; D010505:Familial Mediterranean Fever; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000071198:Pyrin; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "1873-1877",
"pmc": null,
"pmid": "24661635",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two elderly cases of familial mediterranean fever with rheumatoid arthritis.",
"title_normalized": "two elderly cases of familial mediterranean fever with rheumatoid arthritis"
} | [
{
"companynumb": "JP-ASTELLAS-2013JP009444",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS"
},
"drugaddi... |
{
"abstract": "Cerebral vasculitis is a very rare complication after brain tumour surgery. We herein report a case and discuss the origins of this complication. A 52-year-old female was admitted because of motor aphasia due to a left frontal lobe brain tumour. The magnetic resonance imaging (MRI) study revealed a non-enhanced tumour. A partial resection of the tumour and the placement of an Ommaya's reservoir were performed. The pathological diagnosis was an oligoastrocytoma. The patient recovered well without any neurological deficits. Post-operative radiotherapy and the intravenous injection of interferon beta were performed. During these treatments, the patient showed a continued high fever. An MRI scan revealed multiple enhanced lesions in the residual tumour, thus raising suspicions about a post-operative infection. We therefore performed a tumour biopsy and the removal of the exogenous materials. The histopathological diagnosis was vasculitis in the residual tumour. The patient's consciousness and neurological symptoms recovered quickly with the steroid treatment. Following the radiotherapy (50 Gy total), complete remission of the tumour was rapidly obtained and no recurrence was observed. Cerebral vasculitis confined to the tumour bed is an unusual complication; however, this special condition was of critical importance for a successful tumour regression in this patient.",
"affiliations": "Department of Neurosurgery, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan. abet@med.oita-u.ac.jp",
"authors": "Abe|Tatsuya|T|;Sugita|Kenji|K|;Morishige|Masaki|M|;Ohnishi|Kouhei|K|;Ishii|Keisuke|K|;Kamida|Tohru|T|;Hikawa|Takamitsu|T|;Fujiki|Minoru|M|;Kobayashi|Hidenori|H|;Kashima|Kenji|K|;Yokoyama|Shigeo|S|",
"chemical_list": "D000970:Antineoplastic Agents; D016899:Interferon-beta",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10143-008-0149-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5607",
"issue": "31(4)",
"journal": "Neurosurgical review",
"keywords": null,
"medline_ta": "Neurosurg Rev",
"mesh_terms": "D000970:Antineoplastic Agents; D001254:Astrocytoma; D001932:Brain Neoplasms; D005260:Female; D006801:Humans; D016899:Interferon-beta; D008875:Middle Aged; D018365:Neoplasm, Residual; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "7908181",
"other_id": null,
"pages": "447-50; discussion 450",
"pmc": null,
"pmid": "18618157",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9863504;9719249;16193843;11314698;16961130;10408566;3729312;9570663;15546596;10647954;16040668;16674611;16038117",
"title": "Possible involvement of interferon beta in post-operative vasculitis restricted to the tumour bed: a case report.",
"title_normalized": "possible involvement of interferon beta in post operative vasculitis restricted to the tumour bed a case report"
} | [
{
"companynumb": "JP-EMD SERONO-230001L08JPN",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INTERFERON BETA"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nFew case reports exist that link lactulose use with pneumatosis intestinalis in cirrhotics. This study investigates the relationship between lactulose use and idiopathic pneumatosis intestinalis in a cohort of cirrhotic patients.\n\n\nMETHODS\nThis case series considers several notable cases of patients with idiopathic pneumatosis intestinalis and concurrent lactulose use. Idiopathic pneumatosis intestinalis was defined as pneumatosis intestinalis with no identifiable etiology. A cohort of 119 patients with cirrhosis and pneumatosis intestinalis were identified in a tertiary care setting, via chart review by a multidisciplinary team. Eleven of these patients were found to have idiopathic pneumatosis intestinalis. Nine of these patients were being treated with lactulose.\n\n\nRESULTS\nSix out of 9 patients with idiopathic pneumatosis intestinalis that were being treated with lactulose saw resolution of pneumatosis intestinalis following discontinuation of treatment.\n\n\nCONCLUSIONS\nThe etiology of idiopathic pneumatosis intestinalis is likely multifactorial, but lactulose might play a preventable role in its formation.",
"affiliations": "Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine.;Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.",
"authors": "Varelas|Lee J|LJ|https://orcid.org/0000-0002-2579-4092;Klinge|Matthew J|MJ|;Malik|Shahid M|SM|;Borhani|Amir A|AA|;Neal|Matthew|M|",
"chemical_list": "D005765:Gastrointestinal Agents; D007792:Lactulose",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14920",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "35(6)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "hepatic encephalopathy; lactulose; liver cirrhosis; liver imaging; pneumatosis intestinalis",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000368:Aged; D015331:Cohort Studies; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007792:Lactulose; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1065-1068",
"pmc": null,
"pmid": "31692099",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Idiopathic pneumatosis intestinalis secondary to lactulose use in patients with cirrhosis.",
"title_normalized": "idiopathic pneumatosis intestinalis secondary to lactulose use in patients with cirrhosis"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201913346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACTULOSE"
},
"drugadditional": "1",
... |
{
"abstract": "A 48-year-old woman with advanced gastric cancer with peritoneal dissemination was treated with weekly paclitaxel from October 2015 and was then administered the CapeOX regimen. Although she had no adverse event during the 2-hour administration of the first oxaliplatin(L-OHP), sudden wheezing, subsequent decrease in blood pressure, and vomiting occurred after completing the administration. After intravenous injection of epinephrine(1mg)and drip infusion of methylprednisolone( 500mg), she received continuous administration of norepinephrine for 5 days. Hypersensitivity reaction to LOHP typically occurs after several cycles and within 30 minutes of starting the administration. However, we have to recognize that the hypersensitivity can also occur after the first cycle and at a later onset.",
"affiliations": "Dept. of Surgery·Gastroenterological Surgery, Kobe City Nishi-Kobe Medical Center.",
"authors": "Shiota|Tetsuya|T|;Okamura|Ryuji|R|;Nakayama|Hiroyuki|H|;Kato|Tatsushi|T|;Kito|Yoshinori|Y|;Sata|Ritsuko|R|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000707:Anaphylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1433-1435",
"pmc": null,
"pmid": "31530784",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Anaphylactic Shock after First Administration of Oxaliplatin.",
"title_normalized": "a case of anaphylactic shock after first administration of oxaliplatin"
} | [
{
"companynumb": "NVSC2019JP010159",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
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"abstract": "Minimal residual disease (MRD) is a standard measurement for response assessment in multiple myeloma (MM). Despite new treatments, high-risk MM patients continue to have poor prognosis. We evaluated the effect of MRD negativity in high-risk versus standard-risk patients.\n\n\n\nWe retrospectively evaluated all consecutive MM patients who underwent routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10-5 at our center from 2015 to 2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups.\n\n\n\nOne hundred thirty-six patients with MRD testing after initial therapy or autologous stem-cell transplantation were identified. At a median follow-up of 14 months (range, 1-36 months), progression-free survival and overall survival were significantly worse in high-risk versus standard-risk patients. During the study period, 50% of high-risk group had experienced disease progression (relapse and/or death) versus 20% in the standard-risk group (P = .0006). No patients with standard-risk died, but 4 (14%) in the high-risk group did (P = .0007). Regardless of MRD status, high-risk patients had statistically significant worse progression-free survival than standard-risk patients. At median follow-up, those with disease 10% standard-risk/MRD negative; 20% standard-risk/MRD positive; 40% high-risk/MRD negative; and 45% high-risk/MRD positive had either experienced relapse or died (P = .0041). MRD status did not significantly affect overall survival in either group (P = .0914); however, longer follow-up is needed to assess survival.\n\n\n\nGenetic abnormalities remain a powerful prognostic indicator for MM, regardless of MRD status. For newly diagnosed MM patients treated with novel triple-drug initial therapy and frontline autologous stem-cell transplantation, MRD-negative status did not mitigate the poor-prognosis outcomes of high-risk MM patients.",
"affiliations": "Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Statistics, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: eemanasanch@mdanderson.org.",
"authors": "Kunacheewa|Chutima|C|;Lee|Hans C|HC|;Patel|Krina|K|;Thomas|Sheeba|S|;Amini|Behrang|B|;Srour|Samer|S|;Bashir|Qaiser|Q|;Nieto|Yago|Y|;Qazilbash|Muzzaffar H|MH|;Weber|Donna M|DM|;Feng|Lei|L|;Orlowski|Robert Z|RZ|;Lin|Pei|P|;Manasanch|Elisabet E|EE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(5)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Genetic risk; High-risk myeloma; Minimal residual disease; Newly diagnosed myeloma; Prognosis",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D018365:Neoplasm, Residual; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e221-e238",
"pmc": null,
"pmid": "32037287",
"pubdate": "2020-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25943786;17975015;18268286;30142420;29128071;25619868;30032678;29759152;18024376;22128143;16855634;28379796;29728700;25303369;30249784;27658735;27779105;27595280;29296716;23733781;27118453;26834489;24646471;23860448;25184863;25907102;28945825;28061990;28498784;28104919;26181891;26100534;18669875;21228328;16219573;27511158;17024118;10190948;25381128;30778767;27632282;27402608",
"title": "Minimal Residual Disease Negativity Does Not Overcome Poor Prognosis in High-Risk Multiple Myeloma: A Single-Center Retrospective Study.",
"title_normalized": "minimal residual disease negativity does not overcome poor prognosis in high risk multiple myeloma a single center retrospective study"
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"abstract": "Serious infection is a concern for patients with inflammatory joint diseases treated with biological drugs (bDMARDs). The objectives were to compare risk of serious infection, defined as infection leading to hospitalization, in patients initiating bDMARD treatment with that in the general population and, second, to develop a simple clinical prediction model and to obtain risk estimates for individual patients.\n\n\n\nThis was a matched-cohort study based on nationwide registries in Denmark. Patients with RA, axial SpA and PsA initiating first bDMARD monitored in the DANBIO registry were matched 1:10 by age, gender and postal code with controls from the general population. The risk of serious infection during 12 months' follow-up was assessed with Cox regression. Prediction models were developed using logistic regression and compared using area under the receiver operating characteristic curve (AUC).\n\n\n\nWe included 11 372 patients and 113 715 controls. During follow-up, 522 patients (4.6%) and 1434 controls (1.3%) developed a serious infection (hazard ratio 3.7, 95% CI 3.4, 4.1). Age-stratified risk was largely similar across diagnoses. A simple prediction model, the 'DANBIO infection risk score', based on age and a count of six clinical risk factors had moderate discriminative power (internal validation: AUC 0.69) that was comparable to that of the existing RABBIT (Rheumatoide Arthritis Beobachtung der BIologika-Therapie) Risk Score (external validation: AUC 0.68).\n\n\n\nPatients with inflammatory joint diseases initiating bDMARD treatment had a four times increased risk of serious infection compared with the general population. A simple prediction model, feasible for shared decision-making, was developed to obtain risk estimates for individual patients.",
"affiliations": "Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.;Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.;Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark.;Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.",
"authors": "Krabbe|Simon|S|0000-0002-2877-1582;Grøn|Kathrine L|KL|;Glintborg|Bente|B|;Nørgaard|Mette|M|;Mehnert|Frank|F|;Jarbøl|Dorte E|DE|;Østergaard|Mikkel|M|;Hetland|Merete L|ML|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D000079424:Tumor Necrosis Factor Inhibitors; D000069283:Rituximab; D000069549:Ustekinumab; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keaa876",
"fulltext": null,
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"issn_linking": "1462-0324",
"issue": "60(8)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "biologicals; epidemiology; infection",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D019540:Area Under Curve; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D016022:Case-Control Studies; D000081415:Clinical Decision Rules; D015331:Cohort Studies; D005260:Female; D006760:Hospitalization; D006801:Humans; D007239:Infections; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012372:ROC Curve; D000069283:Rituximab; D012720:Severity of Illness Index; D025242:Spondylarthropathies; D000079424:Tumor Necrosis Factor Inhibitors; D000069549:Ustekinumab",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "3834-3844",
"pmc": null,
"pmid": "33493342",
"pubdate": "2021-08-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of serious infections in arthritis patients treated with biological drugs: a matched cohort study and development of prediction model.",
"title_normalized": "risk of serious infections in arthritis patients treated with biological drugs a matched cohort study and development of prediction model"
} | [
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"companynumb": "DK-ROCHE-2993737",
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{
"abstract": "We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21-53 years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence.",
"affiliations": "Joint Authority for Päijät-Häme Social and Health Care, Lahti, Finland.;Department of Child Neurology, Turku University Hospital, Turku, Finland.;Joint Authority for Päijät-Häme Social and Health Care, Lahti, Finland.;Tampere University Hospital, Tampere, Finland.",
"authors": "Arvio|Maria|M|;Sauna-Aho|Oili|O|;Nyrke|Timo|T|;Bjelogrlic-Laakso|Nina|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X18777951",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1877795110.1177_2050313X18777951Case ReportIntellectual disability in patients with epilepsy with eyelid myoclonias Arvio Maria 123Sauna-aho Oili 24Nyrke Timo 1Bjelogrlic-Laakso Nina 51 Joint Authority for Päijät-Häme Social and Health Care, Lahti, Finland2 Department of Child Neurology, Turku University Hospital, Turku, Finland3 PEDEGO, Oulu University Hospital, Oulu, Finland4 Southwest Special Care Municipal Authority, Paimio, Finland5 Tampere University Hospital, Tampere, FinlandMaria Arvio, Joint Authority for Päijät-Häme Social and Health Care, Arvi Kariston katu 4b10, Hämeenlinna 13100, Finland. Email: maria.arvio@phhyky.fi21 5 2018 2018 6 2050313X1877795116 11 2017 25 4 2018 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21–53 years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence.\n\nEpilepsy with eyelid myocloniasJeavons syndromeeyelid myoclonia with absencesintellectual disabilitycover-dateJanuary-December 2018\n==== Body\nIntroduction\nEpilepsy with eyelid myoclonias (EEM; Jeavons syndrome) was first described as a separate form of photosensitive epilepsy in 1977.1 EEM is a genetically determined syndrome with a female predominance and it is characterized by eyelid myoclonia, eye closure–induced electroencephalogram (EEG) paroxysms or absence seizures and photosensitivity. The seizure onset usually occurs between ages 2 and 14. Many patients have a positive family history with epilepsy. The patients’ early history, as well as appearance and neurological examination, is usually normal.2,3\n\nChildhood-onset epilepsy syndromes, in general, show highly variable clinical outcome with regard to seizure remission and patient’s cognitive development and adaptive skills.4 Neurocognition in EEM patients is considered normal but is in fact poorly known. To our knowledge, there are only two cognition-related studies. Fournier-Goodnight et al.5 have defined neurocognitive functioning in a detailed manner in six young patients, whose global IQ ranged from low-average to borderline impaired. Capovilla et al.6 have suggested that there may be an EEM subtype that is associated with an impaired cognition.\n\nHere, we describe the clinical outcome of four women with EEM. All patients were followed by the first author (M.A.) and occasionally by other specialists in an epilepsy clinic at a public central hospital.\n\nEach study subject had a decisional capacity to provide an informed consent.\n\nCases\nAll four women had an uneventful early history, normal physical growth and appearance, but no motor or sensory disability. Brain magnetic resonance imaging (MRI) showed normal finding in patients 2, 3 and 4; the oldest woman, patient 1, had a slight cortical atrophy. EEM was identified in adulthood on all four women. By reviewing their medical records and numerous EEG recordings retrospectively, we found that the diagnostic criteria for EEM had been reached already at the onset of seizures. Women had similar interictal EEG findings, that is, normal background but generalized 3–6 Hz spike/polyspike waves. Eye closure (fixation off sensitivity) and intermittent photic stimulation activated the EEG and often elicited eyelid myoclonias with or without absences. A typical EEG abnormality was facilitated also by hyperventilation in all but patient 4, who did not hyperventilate during registration. Gene panel of epilepsy including CHD2 epileptic encephalopathy was not done to any of the study subjects.\n\nClinical data including family history with epilepsy, onset age of epilepsy, earlier and present epilepsy drug medication and comorbidities of the study subjects are presented in the table.\n\nPatient 1\nThe initial diagnosis of patient 1 (a 54-year-old woman) was childhood absence epilepsy and later on epilepsy with myoclonic astatic seizures (Doose syndrome). During childhood and adolescence, she was treated with phenytoin and carbamazepine. She suffered one or two generalized seizures on a monthly basis but since the initiation of lamotrigine and identification of EEM at the age of 45, she has had only a single absence seizure per year (apart from daily eyelid myoclonias). Her intelligence test results done during childhood and adolescence were not available. At the age of 25, she showed subnormal intelligence (Wechsler Adult Intelligence Scale (WAIS), 7), and at the age of 53, a mild intellectual disability (ID; WAIS-III, 8) (Figure 1). In adulthood, she has suffered from somatic comorbidities (Table 1) but has good social skills and she lives with a spouse and works as an assistant in kindergarten.\n\nFigure 1. The full-scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ) of the study patients. Patients 1, 2 and 4 were assessed twice and patient 3 once with Wechsler tests.7–12\n\nTable 1. Clinical data of four women with EEM.\n\nPatient number/year of birth\t1/1964\t2/1971\t3/1996\t4/1983\t\nLevel of intellectual disability\tMild\tModerate\tLow-average intelligence\tModerate\t\nFamily history with epilepsy\tNo\tNo\tMother, sister, grandmother\tNo\t\nOnset age of epileptic seizures\t2 years\t7 years (febrile seizures < 2 years)\t5 years\t2 years\t\nEarlier antiepileptic drug treatment\tPhenytoin, carbamazepine, ethosuximide\tCarbamazepine, valproate\t\tCarbamazepine, valproate, clonazepam, vigabatrin, acetazolamide, ethosuximide, nitrazepam, ketogenic diet\t\nPresent antiepileptic drug treatment\tLamotrigine, valproate\tLamotrigine\tValproate, ethosuximide\tTopiramate, levetiracetam, lamotrigine\t\nPresent psychotrophic drug treatment\tNo\tNo\tNo\tOlanzapine\t\nComorbid disorder\tBreast cancer, sleep apnea\tMeningioma\tMood disorder, compliance difficulties with authorities\tPsychotic periods\t\nAccommodation\tWith a spouse\tGroup home\tIndependently alone\tNursing home\t\nDaily activity\tAssistant in kindergarten\tShelter work\tRehabilitative workshop\tDay care center\t\nPatient 2\nPatient 2 (a 46-year-old woman) had experienced febrile seizures before epilepsy diagnosis was made at the age of 7. Her initial diagnosis, before identifying EEM at the age of 43, was childhood absence epilepsy. During childhood and adolescence, she was treated with carbamazepine with poor response. After the initiation of valproate and later of lamotrigine (because of obesity caused by valproate), at the age of 35 she had only eyelid myoclonias until she reached the age of 45 and experienced a prolonged generalized seizure. Soon after this, a brain scanning revealed a meningioma necessitating a brain surgery. Mild ID (Wechsler Intelligence Scale for Children (WISC), 9) was diagnosed at the age of 14, and at the age of 46, she acted on a level of moderate ID (WAIS-III, 8) (Figure 1). She lives quite independently in a group facility and attends shelter work.\n\nPatient 3\nPatient 3 (a 21-year-old woman) has a positive family history of epilepsy (Table 1). Her initial diagnosis was childhood absence epilepsy before EEM was recognized at the age of 19. She has been on valproate and ethosuximide medication since the epilepsy diagnosis, but she suffers from daily eyelid myoclonias and occasionally from prolonged epileptic seizures due to an irregular use of antiepileptic medication. She has repeatedly refused a psychiatric assessment. At the age of 6, she showed a low-average intelligence (Wechsler Preschool and Primary Scale of Intelligence—Revised (WPPSI-R), 10) (Figure 1). She has passed the normal curriculum at comprehensive school. She lives alone and attends a rehabilitative workshop.\n\nPatient 4\nThe initial diagnosis for patient 4 (a 34-year-old woman) was epilepsy with myoclonic astatic seizures (Doose syndrome). She has been unresponsive to ketogenic diet and to several antiepileptic drugs (Table 1) except to topiramate, after initiation of which (from the age of 19) she has been seizure free (except daily eyelid myoclonias). At the ages of 12 and 22, she showed moderate ID (WPPSI-R, 10; Wechsler Adult Intelligence Scale—Revised (WAIS-R), 11). She is in psychiatric follow-up because of her aggressive behavior and intermittent psychic symptoms and she lives in a 24-h nursing home. The clinical geneticist has examined her and ordered wide metabolic and molecular genetic analyses which did not reveal any specific etiology.\n\nGlobal intellectual ability\nThe figure presents the full-scale, verbal and performance IQs of the four patients. In patients 1, 2 and 4, the performance IQ was somewhat better than the verbal IQ. They all had difficulties at precise understanding and naming and in higher order verbal reasoning. All had quite good perception of visual details but difficulties in visuomotor and/or visuoconstructive functions. The same three patients (1, 2 and 4) had problems in executive functions which have most likely affected their memory and their auditive working memory which turned out to be narrow. On the other hand, all three showed slow verbal and nonverbal learning but quite good long-term recalling. Patients 2 and 4 were found to have prominent problems in attention, especially in flexibility.\n\nDiscussion\nTo our knowledge, this is the only long-term study in which cognitive function has been followed in EEM patients. The intelligence is generally thought to be normal., ID was diagnosed in as many as three out of the four patients. The observed frequency seems high but the possibility of recruitment bias cannot be totally excluded as these four cases may not necessarily represent all EEM patients living in the district (with a population of 202,000).\n\nTwo groups have earlier evaluated retrospectively the cognition in patients with EEM. Fournier-Goodnight et al.5 defined neurocognitive functioning using the same Wechsler test (as we) in six young patients but none of them can be considered intellectually disabled based on their performance on higher order tasks including nonverbal reasoning. The IQ figure of our youngest patient 3 (i.e. the only one without a confirmed ID diagnosis), who was assessed at the age of 6 was in line with the study patients of Fournier-Goodnight et al. In another retrospective study by Capovilla et al.,6 no details are given either of the used test methods or the age at which the diagnosis of ID was established, which makes a reliable comparison of the cognitive status between their 14 intellectually disabled cases and our patients impossible.\n\nThe underlying cause for an impaired cognition in our three oldest patients may have been their poor epilepsy control or unidentified CHD2 epileptic encephalopathy12 apart from possible genetic susceptibility. These patients had been treated with narrow-spectrum antiepileptic medicines and one with vigabatrin in their childhood. The prescribed medication can also have contributed to the impaired cognition taking into account that carbamazepine and phenytoin are contraindicated in photosensitive epilepsies because they may aggravate various types of seizures and because vigabatrin is known to provoke absence and myoclonic seizures.13,14 Interestingly, patient 3 with the best cognition had been treated only with valproate and ethosuximide, that is, broad-spectrum anticonvulsants that are nowadays generally recommended for EEM. In this particular case, however, the problem was a poor adherence to the antiepileptic medication. Thus, it might be too speculative to claim that her better cognitive capacity compared to the three other cases could have been due to the right medication prescribed at the time when her epilepsy was initially diagnosed. In addition, the differential diagnostics may have been insufficient because gene panel of epilepsy was not carried out.\n\nPharmacotherapy should and is ideally based on an as accurate epilepsy diagnosis as possible, but the identification of epilepsy or epilepsy syndrome in a clinical realm is often time-consuming15,16 as also in these four cases. This leaves us with an open question: Would the cognitive outcome have been any better if the EEM diagnosis had not been delayed and if the patients had been treated according to the current guidelines from the beginning of their epilepsy diagnosis?\n\nConclusion\nEEM does not belong to a group of epileptic encephalopathies in which epileptogenesis forms a causative or contributing factor for ID. Consequently, this epilepsy syndrome is not usually associated with ID. However, the three out of our four EEM patients turned out to be intellectually disabled. The right diagnosis was delayed in all cases and the initially prescribed narrow-spectrum antiepileptic drugs or vigabatrin could have impaired their epilepsy control (provided that none of the patients had CHD2 epileptic encephalopathy). All this may have had a negative impact on their cognition. These clinical observations emphasize the importance of the right epilepsy diagnosis and the initiation of an appropriate medication at as early stage as possible. Epilepsy gene panel that was unfortunately not available for our cases can be expected to help in choosing the right antiepileptic medicine in the future.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed consent: Written informed consent was obtained from the patients for their anonymized information to be published in this article.\n==== Refs\nReferences\n1 \nJeavons PM. \nNosological problems of myoclonic epilepsies in childhood and adolescence . Dev Med Child Neurol \n1977 ; 19 : 3 –8 .403103 \n2 \nCovanis A. \nEyelid myoclonia and absences . In: Delgado-Escueta AV (ed.) Myoclonic epilepsies: advances in neurology , vol. 95 \nPhiladelphia, PA : Lippincott Williams & Wilkins , 2005 , pp. 183 –194 .\n3 \nStriano S Capovilla G Sofia V et al \nEyelid myoclonia with absences (Jeavons syndrome): a well-defined idiopathic generalized epilepsy syndrome or a spectrum of photosensitive conditions? \nEpilepsia \n2009 ; 50 : 15 –19 .19469840 \n4 \nPanayiotopoulos CP. \nChapter 7: epileptic encephalopathies in infancy and early childhood in which the epileptiform abnormalities may contribute to progressive dysfunction . In: Panayiotopoulos CP (ed.) The epilepsies: seizures, syndromes and management . London : Bladon Medical Publishing , 2005 , pp. 137 –193 .\n5 \nFournier-Goodnight AS Gabriel M Perry MS. \nPreliminary neurocognitive outcomes in Jeavons syndrome . Epilepsy Behav \n2015 ; 52 : 260 –263 .26492104 \n6 \nCapovilla G Striano P Gambardella A et al \nEyelid fluttering, typical EEG pattern, and impaired intellectual function: a homogeneous epileptic condition among the patients presenting with eyelid myoclonia . Epilepsia \n2009 ; 50 : 1536 –1541 .19490056 \n7 \nWechler D. \nWAIS: Wechslerin aikuisten älykkyysasteikko . Helsinki : Psykologien Kustannus Oy , 1971 .\n8 \nWechler D. \nWAIS-III: The Wechsler Adult Intelligence Scale III . Helsinki : Psykologien Kustannus Oy , 2005 .\n9 \nWechler D. \nWISC: Wechslerin kouluikäisten älykkyysasteikko . Helsinki : Psykologien Kustannus Oy , 1974 .\n10 \nWechsler D. \nWPPSI-R: Preschool and Primary Scale of Intelligence—Revised . Helsinki : Psykologien Kustannus Oy , 1995 .\n11 \nWechsler D. \nWAIS-R: Wechslerin aikuisten älykkyysasteikko, toinen painos . Helsinki : Psykologien Kustannus Oy , 1992 .\n12 \nBernardo P Galletta D Iasevoli F et al \nCHD2 mutations: only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation . Seizure \n2017 ; 51 : 186 –189 .28910737 \n13 \nShorvon S. \nHandbook of epilepsy treatment . Malden, MA : Blackwell Science Ltd , 2000 .\n14 \nPanayiotopoulos CP. \nTreatment of typical absence seizures and related epileptic syndromes . Paediatr Drugs \n2001 ; 3 : 379 –403 .11393330 \n15 \nArvio M Nyrke T Sauna-Aho O et al \nContinuous Spike-Wave in Slow Wave Sleep (CSWS) mimicking dementia in a 55-year old man with intellectual disability . Neuropsychiatry \n2017 ; 7 (6 ): 640 –652 .\n16 \nArvio M Nyrke T Muller M et al \nEpileptiform discharges in a patient with Angelman syndrome . J Autism Epilepsy \n2017 ; 2 (1 ): 1013 .\n\n",
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"issn_linking": "2050-313X",
"issue": "6()",
"journal": "SAGE open medical case reports",
"keywords": "Epilepsy with eyelid myoclonias; Jeavons syndrome; eyelid myoclonia with absences; intellectual disability",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
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"pages": "2050313X18777951",
"pmc": null,
"pmid": "29844915",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "Intellectual disability in patients with epilepsy with eyelid myoclonias.",
"title_normalized": "intellectual disability in patients with epilepsy with eyelid myoclonias"
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"abstract": "Rivaroxaban, enoxaparin, and aspirin are commonly used medications for thromboprophylaxis following lower extremity joint arthroplasty or revision. Previous research has demonstrated efficacy in preventing venous thromboembolism with each medication, however, the comparative risk of bleeding between them remains poorly understood. The aim of this study was to compare the odds of bleeding between rivaroxaban, enoxaparin, and aspirin following lower extremity joint arthroplasty or revision.\n\n\n\nThis is a 3-year retrospective cohort study.\n\n\n\nData were obtained from 148 facilities across 55 states and territories of the United States.\n\n\n\nThis study included 85,938 patients who underwent hip or knee arthroplasty or revision.\n\n\n\nPatients received enoxaparin, rivaroxaban, or aspirin as monotherapy for thromboprophylaxis.\n\n\n\nThe primary outcome was all bleeding, classified as major or minor bleeding, occurring in the 40 days following surgery. The secondary outcome was venous thromboembolism.\n\n\n\nAmong 85,938 patients, 10,465 received rivaroxaban, 14,047 received enoxaparin, and 61,426 received aspirin. Bleeding occurred in 126 (1.20%) patients with rivaroxaban, 253 (1.80%) with enoxaparin, and 611 (0.99%) with aspirin. There was a significant increase in odds of bleeding in the enoxaparin compared to aspirin group odds ratio (OR) 1.18, 95% confidence interval (CI) 1.01-1.38, p = 0.042), and a trend toward increased odds of bleeding in rivaroxaban compared to aspirin group (OR 1.21, 95% CI 0.99-1.47, p = 0.058) and rivaroxaban compared to enoxaparin (OR 1.03, 95% CI 0.82-1.28, p = 0.827). Odds of venous thromboembolism were not statistically significant between all three study medications.\n\n\n\nAmong rivaroxaban, enoxaparin, and aspirin used for thromboprophylaxis in knee and hip arthroplasty or revision, aspirin had significantly decreased odds of bleeding complications compared to enoxaparin. Although not statistically significant, aspirin also had a trend toward decreased odds of bleeding complications compared to rivaroxaban. Our study results suggest that aspirin is a safer alternative for use in postoperative thromboprophylaxis following lower extremity joint arthroplasty or revision.",
"affiliations": "Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.;Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.;Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.;HCA Healthcare, Denver, Colorado, USA.;HCA Healthcare, Denver, Colorado, USA.;Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.;Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.;Graduate Medical Education, HCA HealthONE - Sky Ridge Medical Center, Lone Tree, Colorado, USA.",
"authors": "Watts|Paula J|PJ|0000-0002-0017-7565;Kopstein|Michael|M|;Harkness|Weston|W|;Cornett|Brendon|B|;Dziadkowiec|Oliwier|O|;Hicks|M Elizabeth|ME|;Hassan|Shakib|S|;Scherbak|Dmitriy|D|",
"chemical_list": null,
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"doi": "10.1002/phar.2599",
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"issn_linking": "0277-0008",
"issue": "41(7)",
"journal": "Pharmacotherapy",
"keywords": "arthroplasty; aspirin; bleed; enoxaparin; revision; rivaroxaban; thromboprophylaxis",
"medline_ta": "Pharmacotherapy",
"mesh_terms": null,
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "608-615",
"pmc": null,
"pmid": "34050956",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective analysis of bleeding risk with rivaroxaban, enoxaparin, and aspirin following total joint arthroplasty or revision.",
"title_normalized": "a retrospective analysis of bleeding risk with rivaroxaban enoxaparin and aspirin following total joint arthroplasty or revision"
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"abstract": "OBJECTIVE\nTo assess utility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist device (VAD).\n\n\nMETHODS\nRetrospective study of pediatric patients supported with a Berlin EXCOR VAD at a single pediatric tertiary care center during a single year.\n\n\nRESULTS\nWe demonstrated associations between activated thromboplastin time (aPTT) and R-thromboelastography (R-TEG) values (rs = 0.65, P < 0.001) and between anti-Xa assay and R-TEG values (rs = 0.54, P < 0.001). The strongest correlation was seen between aPTT and anti-Xa assays (rs = 0.71, P < 0.001). There was also a statistically significant correlation between platelet counts and the maximum amplitude of TEG (rs = 0.71, P < 0.001). Importantly, there was no association between dose of unfractionated heparin and either measure of anticoagulation (aPTT, anti-Xa or R-TEG value).\n\n\nCONCLUSIONS\nThis study suggests that while there is strong correlation between aPTT, anti-Xa assay and R-TEG values for patients requiring VAD support, there is a lack of relevant correlation between heparin dose and degree of effect. This raises concern as various guidelines continue to recommend using these parameters to titrate heparin therapy.",
"affiliations": "Division of Pediatric Cardiology, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.;Division of Pediatric Cardiology, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.;Mechanical Circulatory Support Program, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.;Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States.;Department of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, GA 30322, United States.;Division of Pediatric Cardiology, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States.;Division of Pediatric Cardiology, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA 30322, United States. deshpandes@kidsheart.com.",
"authors": "Bhatia|Ajay K|AK|;Yabrodi|Mouhammad|M|;Carroll|Mallory|M|;Bunting|Silvia|S|;Kanter|Kirk|K|;Maher|Kevin O|KO|;Deshpande|Shriprasad R|SR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4330/wjc.v9.i9.749",
"fulltext": "\n==== Front\nWorld J CardiolWJCWorld Journal of Cardiology1949-8462Baishideng Publishing Group Inc jWJC.v9.i9.pg74910.4330/wjc.v9.i9.749Retrospective StudyUtility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist devices Bhatia Ajay K Division of Pediatric Cardiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United StatesYabrodi Mouhammad Division of Pediatric Cardiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United StatesCarroll Mallory Mechanical Circulatory Support Program, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United StatesBunting Silvia Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United StatesKanter Kirk Department of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, GA 30322, United StatesMaher Kevin O Division of Pediatric Cardiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United StatesDeshpande Shriprasad R Division of Pediatric Cardiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United States. deshpandes@kidsheart.comAuthor contributions: Bhatia AK and Yabrodi M contributed to data collection, writing manuscript; Carroll M contributed to clinical care and data, oversight; Bunting S contributed to laboratory oversight, technical writing and oversight; Kanter K contributed to surgical care, overnight and critical review; Maher KO contributed to critical care, study oversight and critical review; Deshpande SR contributed to study design and concept, oversight and manuscript writing and final edits.\n\nCorrespondence to: Shriprasad R Deshpande, MBBS, MS, Division of Pediatric Cardiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, 1405, Clifton Rd NE, Atlanta, GA 30322, United States. deshpandes@kidsheart.com\n\nTelephone: +1-404-6947739 Fax: +1-770-4889480\n\n26 9 2017 26 9 2017 9 9 749 756 12 1 2017 20 7 2017 2 8 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/AIM\nTo assess utility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist device (VAD).\n\nMETHODS\nRetrospective study of pediatric patients supported with a Berlin EXCOR VAD at a single pediatric tertiary care center during a single year.\n\nRESULTS\nWe demonstrated associations between activated thromboplastin time (aPTT) and R-thromboelastography (R-TEG) values (rs = 0.65, P < 0.001) and between anti-Xa assay and R-TEG values (rs = 0.54, P < 0.001). The strongest correlation was seen between aPTT and anti-Xa assays (rs = 0.71, P < 0.001). There was also a statistically significant correlation between platelet counts and the maximum amplitude of TEG (rs = 0.71, P < 0.001). Importantly, there was no association between dose of unfractionated heparin and either measure of anticoagulation (aPTT, anti-Xa or R-TEG value).\n\nCONCLUSION\nThis study suggests that while there is strong correlation between aPTT, anti-Xa assay and R-TEG values for patients requiring VAD support, there is a lack of relevant correlation between heparin dose and degree of effect. This raises concern as various guidelines continue to recommend using these parameters to titrate heparin therapy.\n\nVentricular assist deviceAnticoagulationBERLIN-EXCORPediatricThromboelastography\n==== Body\nCore tip: This study suggests that while there is strong correlation between activated thromboplastin time, anti-Xa assay and R-thromboelastography values for patients requiring ventricular assist device support, there is a lack of relevant correlation between heparin dose and degree of effect. This raises concern as various guidelines continue to recommend using these parameters to titrate heparin therapy. A comprehensive strategy for appropriate anticoagulation may therefore warrant a combination of parameter monitoring and warrants further study.\n\nINTRODUCTION\nAppropriate anticoagulation continues to be a significant challenge in pediatric patients supported with ventricular assist devices (VADs). VAD implantation leads to dysregulation of hemostasis through contact of blood with foreign materials and introduction of shear forces that activate vascular endothelium, platelets, leukocytes and the coagulation cascade. This constellation of events increases the generation of thrombin and thus greatly increases the risk of thrombosis. Clinicians attempt to address the resultant imbalance between the pro- and anti-thrombotic states through the administration of anticoagulation and antiplatelet therapy. However, appropriate titration of these therapies in the pediatric population is challenging and resulting in various complications related to either a pro-thrombotic state leading to embolic complications or an overly anti-thrombotic state presenting as post-operative bleeding, gastrointestinal bleeding or hemorrhagic stroke.\n\nDespite technological advances in VAD design and development of new methods of anticoagulation, complication rates remain significant. Adults on VAD support have bleeding rate of 15%-50% while the risk of stroke has been reported at 5%[1,2]. Unfortunately the overall incidence of these complications in children with VAD appears to be higher[3-5]. While the VAD technology and anticoagulation agents are the same as those for adult patients, there are marked differences in dosing of medications, device performance characteristics in children and intrinsic differences in the maturity of the hemostatic system in children as they develop[6-9]. One retrospective study of 28 pediatric patients with various types of VAD demonstrated major bleeding in 29% and stroke in 25%. Given that there are several types of VAD that can be used in the pediatric population, and technology is constantly evolving, interpretation of older studies is challenging. The Berlin Heart EXCOR Pediatric VAD, a pulsatile extracorporeal device, is currently the most commonly used in pediatrics as it can accommodate a wide range of patient sizes and can support both the right and left heart as necessary. A prospective study comparing the Berlin Heart Pediatric EXCOR device to extracorporeal membrane oxygenation (ECMO) as bridge-to-transplantation demonstrated bleeding in 50% of patients and stroke in 29%[3] in the setting of a prescribed anticoagulation protocol with high degree of adherence.\n\nThe major obstacle to achieving adequate anticoagulation while minimizing the risk of hemorrhagic complications revolves around ineffective monitoring strategies and the lack of evidence-based pediatric guidelines to assist clinicians in modifying therapy. Various laboratory tests exist that measure specific components of the hemostatic system, including anti-Xa, activated thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR), but none of these gives a complete picture of hemostasis[7,10-12]. Thromboelastography (TEG) has been proposed to more accurately demonstrate the in vivo state of hemostasis[13,14]. Specifically the R-value is thought to reflect the anticoagulant effect of heparin. Current VAD anticoagulation guidelines, including those adopted for clinical trials, lack standardization to guide heparin therapy[15]. In addition, there is very limited data on coagulation parameters in pediatric patients supported on VADs. This disconnect may explain why, in many cases, using target lab values to indicate degree of anticoagulation does not prevent poor clinical outcomes. This study attempts to assess the utility and correlation between various measures of anti-coagulation, including the value of TEG, in a cohort of patients who received the Berlin Heart Pediatric EXCOR VAD.\n\nMATERIALS AND METHODS\nAnticoagulation parameters from four patients supported with a Berlin Heart EXCOR VAD at a single center during 2013 were studied retrospectively. The study was approved by the institutional review board. Standard anticoagulation therapy was initiated for all of these patients after the implantation of the Berlin EXCOR VAD in accordance with the published guidelines[15]. All management decisions for anticoagulation and anti-platelet therapy were made by the VAD team, again with target levels for various parameters consistent with the published protocol. Briefly, our standard regimen included unfractionated heparin initiated typically about 12 h post-operative, followed by initiation of anti-platelet therapy with aspirin and dipyridamole typically, 48 h post-operative in the setting of good surgical hemostasis. This was followed by dose adjustments as needed based on monitoring parameters. Patients were monitored closely by assessing various anticoagulation parameters such as PT, aPTT, anti-Xa assay, complete blood count, fibrinogen level daily. TEG was performed using a TEG® 5000 Thrombelastograph® Hemostasis Analyzer system (Haemonetics Corporation, MA, United States). Kaolin TEG as well as heparinase TEG were both performed as part of a standard approach to assess whole blood anticoagulation related to heparin as well as the health of coagulation system without the heparin effect. Additionally, TEG was also used to perform platelet-mapping studies using the platelet agonists arachidonic acid (AA) and adenosine diphosphate (ADP) to study platelet inhibition achieved by aspirin and dipyridamole. We tabulated all laboratory tests that were ordered to both assess their coagulation system and to direct their anticoagulation therapy. Additionally, we tabulated incidental heparin dose at time of laboratory collection, as well as clinical data reflecting outcomes, adverse events, morbidities and mortality. Statistical analysis was performed using SPSS 21 software (SPSS Inc., Chicago, IL, United States). Continuous data are reported as mean ± SD, categorical data are reported as frequency (%). Continuous data was compared using student t-test while χ2 test was used for categorical variables. Spearman’s Correlation was used to assess correlation between various tests. Statistical significance was defined as P < 0.05.\n\nRESULTS\nChart review of anticoagulation parameters from a total of four patients who were supported with the Berlin EXCOR Pediatric VAD during a single year yielded nearly 100 data points for every test. Three of the four patients had the primary diagnosis of dilated cardiomyopathy while the fourth patient carried a diagnosis of congenital heart block and developed pacemaker induced cardiomyopathy (Table 1). No other significant comorbidities, genetic syndrome or coagulation disorders noted prior to the implants. Indications for VAD placement were heart failure non-responsive to standard inotropic therapy with milrinone and need for a second agent (dobutamine), along with evidence of end-organ injury. The later was extremely poor tolerance of enteral feeds in 3 patients while it was increased need for respiratory support (including intubation) in one patient. Berlin EXCOR VAD implantation was performed in the standard fashion per manufacturer’s detailed instructions. There were no intraoperative complications.\n\nTable 1 Patient demographics\n\n\tPatient 1 K\tPatient 2 S\tPatient 3 P\tPatient 4 N\t\nDiagnosis\tDCM\tDCM\tCHB, DCM\tDCM\t\nAge\t13 mo\t5 mo\t8 mo\t10 yr\t\nWeight\t8.4 kg\t7.2 kg\t8.1 kg\t24.5 kg\t\nGender\tF\tM\tM\tF\t\nType of VAD\tLVAD\tLVAD\tLVAD\tLVAD\t\nDays on VAD\t141\t69\t13\t54\t\nOutcome\tOHT\tOHT\tOHT\tOHT\t\nRelevant clinical data from the four patients studied including diagnosis prior to receiving VAD, type of ventricular support (LVAD), absolute number of days on VAD support and eventual patient outcome. All patients received Berlin EXCOR devices as bridge to successful transplantation. DCM: Dilated cardiomyopathy; CHB: Congenital heart block; OHT: Orthotopic heart transplantation; LVAD: Left ventricular assist device.\n\nMeasures of anticoagulation and correlations\nThe results for the various tests are shown in Table 2. As noted, there was wide variation in the degree of anticoagulation achieved. We performed Spearman correlation testing to assess the relationship between individual tests measuring degree of anticoagulation, namely, aPTT, anti-Xa assay and R value on TEG. There was a strong and statistically significant correlation between all of these three parameters, with the strongest correlation existing between the aPTT value and anti-Xa assays (R2 = 0.55, Spearman correlation coefficient of 0.71, P < 0.001). R-TEG had correlation coefficients of 0.54 and 0.65 with anti-Xa and aPTT, respectively. These correlations are summarized in Table 3 and demonstrated in Figure 1.\n\nTable 2 Distribution of values for various measures of coagulation status\n\nTest\tn\tMinimum\tMaximum\tmean\tSD\t\nProthrombin time\t97\t12.5\t30.8\t14.542\t2.34\t\nActivated partial thromboplastin time (s)\t98\t26.1\t200\t79.779\t44.62\t\nINR\t98\t0.9\t3\t1.132\t0.25\t\nAnti-Xa levels (U/mL)\t97\t0.05\t1.2\t0.4381\t0.24\t\nTEG-R (min)\t102\t5.2\t82.8\t32.464\t19.77\t\nTEG-alpha angle\t99\t5.9\t71.8\t28.83\t18\t\nTEG-MA\t98\t10\t75\t46.002\t18.08\t\nTEG R (heparinase) (min)\t102\t5.1\t34.5\t8.455\t3.2\t\nTEG-K (heparinase)\t102\t0.8\t12\t2.029\t1.12\t\nTEG-α angle (heparinase)\t102\t17.8\t74.4\t63.306\t7.3\t\nTEG-MA (heparinase)\t102\t45.1\t73\t59.696\t6.03\t\nTEG-G (heparinase)\t100\t4.1\t13.5\t7.712\t2.01\t\nPlatelet inhibition-ADP (%)\t90\t0\t100\t41.113\t33.73\t\nPlatelet inhibition-AA (%)\t91\t0\t100\t43.69\t37.05\t\nPlatelet count (k/μL)\t131\t77\t451\t267.05\t89.6\t\nPlatelet volume\t121\t6.8\t10.1\t8.46\t0.69\t\nHeparin dose (units/kg per hour)\t131\t15\t46\t33.66\t7.15\t\nSummary of data are presented as number of individual data points (n) with value ranges, mean value and standard deviation given. TEG values without heparinase are represented by R (reaction time), ANGLE (alpha-angle), MA (mean amplitude). TEG values with heparinase are noted as RHEP, KHEP (K = coagulation time), ANGLEHEP, MAHEP and GAHEP (GA = overall clot strength). Percent of platelet inhibition via the AA and ADP pathways are shown. The range of administered heparin dose at the time of laboratory value collection is also presented. AA: Arachidonic acid; ADP: Adenosine phosphate; PT: Prothrombin time; aPTT: Activated thromboplastin time; INR: International normalized ratio.\n\nTable 3 Correlation matrix between tests\n\n\taPTT\ncorrelation\ncoefficient\tP\tAnti-Xa\ncorrelation\ncoefficient\tP\tR-TEG\ncorrelation\ncoefficient\tP\t\naPTT\t1\t\t0.71\t< 0.001\t0.65\t< 0.001\t\nAnti Xa\t0.71\t< 0.001\t1\t\t0.54\t< 0.001\t\nR-TEG\t0.65\t< 0.001\t0.54\t< 0.001\t1\t\t\nSpearman correlation analyses were used to determine the degree of correlation between aPTT, anti-Xa and R values (R-TEG). aPTT: Activated thromboplastin time; TEG: Thromboelastogram.\n\nFigure 1 Scatterplots demonstrating correlation between standard measures of anticoagulation for patients on left ventricular assist device support. The estimated linear regression line (line of best fit) is shown along with 95%CI for individual value predictions for (A) anti-Xa and TEG-R levels, (B) aPTT and TEG-R levels, and (C) aPTT and anti-Xa levels. The R2 values are shown alongside each panel (all P < 0.001). aPTT: Activated thromboplastin time; TEG: Thromboelastogram.\n\nRole of platelets\nWe also assessed the correlation between platelet count (PLT) and the maximum amplitude (MA) on TEG with heparinase added to nullify the heparin effect. We demonstrated that there was a strong and statistically significant correlation between the two values (Spearman correlation coefficient of 0.71, P < 0.001) (Figure 2).\n\nFigure 2 Correlation between platelet count and maximum amplitude after treatment with heparinase. The estimated linear regression line (line of best fit along with 95%CI) is shown for platelet counts and TEG-MA (heparinase). Correlation coefficient of 0.541 (P < 0.001). TEG: Thromboelastogram.\n\nHeparin dose and effect\nSimilar to previous studies, we found no clinically relevant association between heparin dose and the degree of anticoagulation measured by the tests. There was no relationship between aPTT and Heparin dose (Figure 3A) giving a Spearman’s rho correlation coefficient of 0.152 and a P value of 0.168. Similarly, there was no correlation between the heparin dose and anti-Xa levels (Spearman’s rho of -0.004, P = 0.971). There was weak correlation between heparin dose and TEG-R values (Spearman’s rho of 0.24, P = 0.015). To account for patient variation in response to heparin as well as inherent differences in the coagulation system in pediatric patients, we also performed a correlation analyses by patient. In this case, there was a large variation in correlation between heparin dosing and aPTT or anti-Xa levels for a given patient. The R2 value ranged from 0.0318 to 0.108 with a P value between 0.01 to 0.18 giving a statistically unstable model.\n\nFigure 3 Scatterplots demonstrating correlation between unfractionated heparin dose and (A) activated thromboplastin time (B) Anti-Xa levels and (C) thromboelastogram-R value. The estimated linear regression line (line of best fit) is shown along with 95%CI for individual value predictions. aPTT: Activated thromboplastin time; TEG: Thromboelastogram.\n\nVAD associated coagulopathy\nIt has been widely hypothesized that the circulatory support devices themselves induce a coagulopathic state beyond that induced by anti-coagulant therapy[7,16]. The degree and nature of coagulopathy was assessed using heparinase-TEG to neutralize the heparin effect. Figure 4 shows dot-density plots of the distribution of individual values for individual parameters such as R, K, Angle, Maximum Amplitude value obtained on heparinase TEG. As demonstrated in the panel, we found a wide variation in the health of the underlying coagulation system with variable demonstration of factor deficiencies as well as clot strength. Four point nine to 13.72% of all values for individual parameters were out of the normal range (represented by solid grey circles in the plots) suggesting significant coagulopathy or factor deficiencies. These findings were used to guide therapy for correcting the coagulopathy by administering appropriate factors in the form of cryoprecipitate or fresh frozen plasma.\n\nFigure 4 Dot-density plots of thromboelastogram (heparinase) parameters R (panel A), K (panel B), angle (panel C) and maximum amplitude (panel D) showing distribution of individual values. Abnormal values are represented by solid grey circles. TEG: Thromboelastogram.\n\nOutcomes\nThe mean duration of VAD support was 69.25 d (range 13 to 141 d). Two patients suffered stroke. One patient suffered an ischemic stroke with hemorrhagic conversion, a second patient suffered an ischemic stroke diagnosed by computed tomography (CT). Although the exact timing of the strokes could not be ascertained, the degree of anticoagulation was within prescribed ranges for the 12 h before the CT scan and or clinical detection of the event. Both these patients made complete clinical recovery. A secondary endpoint was need for VAD pump change-out. A total of 8 pump exchanges were performed. The indications for pump change were made by the VAD team based on rate of clot growth, visualization of a dark clot measuring greater than 4 mm and subjective mobility of the clots. White clots and fibrin deposits in the blood chamber did not initiate pump exchanges, per manufacturer guidelines. Pump exchanges were well tolerated and did not result in any procedural complication. We were unable to identify predictors, such as degree of anticoagulation, fibrinogen levels, heparin dosing and the occurrence of either stroke or need for pump change. There were no mortalities in the cohort. All four patients underwent successful heart transplantation and at follow-up are alive and well.\n\nDISCUSSION\nManaging anticoagulation in the pediatric VAD patient remains a challenging task. Failure to provide adequate anticoagulation results in thromboembolic events. Unfortunately, if the balance is tipped too far, devastating hemorrhagic complications may ensue. Clinicians are further stymied by the lack of evidence-based guidelines to direct therapy based on available laboratory data. The current study provides a direct comparison of these laboratory tests to determine their degree of correlation with one another as well as with anticoagulant effect. In a robust comparison sample of greater than 100 individual data points from four patients, our study showed very strong correlations between aPTT, anti-Xa assay and R-TEG (Figure 1). This is not unexpected, but demonstrates that these tests segregate together and may be substituted for one another, especially in the clinically relevant ranges.\n\nThe role of TEG in routine monitoring remains controversial[17]. While TEG has limitations, including difficulty with reproducibility, the utilization of TEG may be beneficial when employed routinely by experienced practitioners within a single center. Interestingly, we found a significant and clinically important correlation between platelet count and MA-TEG (Figure 2). This supports the importance of maintaining a normal platelet count and need for increased anti-platelet agents in the setting of thrombocytosis to manage the strength of clot formation. Additionally, TEG with- and without heparinase is important for diagnosing coagulopathy on VAD and guiding therapy. Furthermore, the presence of a wide range of values suggests a significant underlying coagulopathy that would otherwise be under-appreciated. This may be secondary to multiple factor deficiencies, prothrombotic microparticles or activation of coagulation factors. TEG may enable clinicians to monitor underlying VAD-induced coagulopathy and thereby explain how complications of anticoagulation therapy arise despite achievement of target levels for other coagulation parameters. We are currently validating this hypothesis using a larger cohort of patients that includes those dependent upon mechanical circulatory support devices as well as those requiring extracorporeal membrane oxygenation support.\n\nOne important observation from our investigation is the lack of relevant correlation between unfractionated heparin (UNFH) dose and degree of effect as measured by aPTT, anti-Xa or R value (Figure 3). This potentially reflects a significant variation in response to heparin by patient as well as by the coagulation milieu at any given time. These results differ somewhat from data that suggests good correlation between aPTT and UNFH levels in adults on extracorporeal life support (ECLS)[18] as well as a recent study in a small cohort of pediatric patients on ECLS[19]. These discrepancies may reflect variations in heparin response amongst patients due to developmental differences in hemostasis and genetic variability[20,21]. Lastly, none of these tests are specific in their assessment of the effect of unfractionated heparin in vivo. A lack of correlation between heparin dose and PTT or anti-Xa assay has also been noted in other settings, including a cohort of critically ill children[10]. This is extremely relevant as various guidelines continue to recommend use of these monitoring parameters to titrate heparin therapy.\n\nWe also noted timing and significance of thrombotic or hemorrhagic events in our patient cohort. Three patients experienced significant morbidities. Two had an ischemic stroke and one had a hemorrhagic stroke. The older patient had an uneventful course. All patients eventually underwent successful bridge to transplantation and were discharged to home. At follow-up, all of them are alive. The patients with ischemic strokes have made a complete functional recovery, albeit after extensive rehabilitation. The patient who had hemorrhagic stroke still has speech delay and motor delay, but no deficits. Unfortunately, due to a small number of events, predictive modeling could not be performed to analyze further risk factors. Correlation of TEG and anticoagulation values with thromboembolic or hemorrhagic events in a larger patient cohort will provide valuable data as to the predictive ability of these tests. This study was also limited only to a single type of VAD. Future studies will include non-pulsatile and implantable devices such as Heartmate II or HeartWare HVAD in an effort to not only provide device-specific information, but also to determine if standards can be applied across all devices.\n\nThis study provides valuable data regarding the utility of common laboratories to monitor the state of hemostasis in VAD patients, as suggested by existing guidelines. It also highlights the imprecise nature of current means of monitoring and demonstrates that multiple targets in the hemostatic pathway need to be targeted in order to achieve the desired balance between prevention of device thrombosis and hemorrhagic consequences.\n\nCOMMENTS\nBackground\nAppropriate anticoagulation continues to be a significant challenge in pediatric patients supported with ventricular assist devices (VADs) resulting in high rate of complications related to bleeding or clotting related complications. Clinicians attempt to address the imbalance between the pro- and anti-thrombotic states through the administration of anticoagulation and antiplatelet therapy. However, the data regarding monitoring parameters is largely an extension of adult experience with very little data to support any pediatric monitoring strategies.\n\nResearch frontiers\nThere is therefore an immediate need for improving our understanding of coagulation and anticoagulation parameters in pediatric patients on VAD as well as for studies that validated anticoagulation strategies.\n\nInnovations and breakthroughs\nThe current study provides a direct comparison of various laboratory tests to determine their degree of correlation with one another as well as with anticoagulant effect. In a robust comparison sample, this study showed very strong correlations between activated thromboplastin time (aPTT), anti-Xa assay and R-thromboelastography (R-TEG). Additionally, the authors show that the dose-response relationship between heparin and these monitoring parameters in very weak, underscoring the authors’ presumption that current guidelines for dose-titration based on anti-Xa levels may not be appropriate. Lastly, for the first time, the authors show the degree of underlying coagulopathy that can be assessed using TEG and underline the utility of the same.\n\nApplications\nThe study underscores the need for continued research in pediatric coagulation system especially within hitherto unexplored world of pediatric VAD and hopefully improves understanding of monitoring and management parameters to improve the morbidity and mortality associated with VADs.\n\nTerminology\nVAD: Ventricular assist device, mechanical support as a circulatory assist; TEG: Thromboelastogram - a whole blood test for assessing the coagulation system in real time.\n\nPeer-review\nThis is an interesting manuscript about the utility and correlation of anticoagulation parameters such as aPTT, anti-Xa, and R-TEG in the management of pediatric VADs.\n\nInstitutional review board statement: Study was reviewed and approved by the Institutional Review Board at Children’s Healthcare of Atlanta.\n\nInformed consent statement: Not applicable, retrospective study. Institutional review board waived need for consent for retrospective study.\n\nConflict-of-interest statement: The authors have no conflicts of interest or financial disclosures. No funding source to disclose.\n\nData sharing statement: Not applicable.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Cardiac and cardiovascular systems\n\nCountry of origin: United States\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nPeer-review started: January 16, 2017\n\nFirst decision: May 11, 2017\n\nArticle in press: August 2, 2017\n\nP- Reviewer: Ueda H S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ\n==== Refs\n1 Slaughter MS Hematologic effects of continuous flow left ventricular assist devices J Cardiovasc Transl Res 2010 3 618 624 20835786 \n2 Adzic A Patel SR Maybaum S Impact of adverse events on ventricular assist device outcomes Curr Heart Fail Rep 2013 10 89 100 23314865 \n3 Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE, Blackstone EH, Naftel DC, Ichord RN, Bomgaars L, Tweddell JS, Massicotte MP, Turrentine MW, Cohen GA, Devaney EJ, Pearce FB, Carberry KE, Kroslowitz R, Almond CS; Berlin Heart Study Investigators Prospective trial of a pediatric ventricular assist device N Engl J Med 2012 367 532 541 22873533 \n4 Almond CS Morales DL Blackstone EH Turrentine MW Imamura M Massicotte MP Jordan LC Devaney EJ Ravishankar C Kanter KR Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children Circulation 2013 127 1702 1711 23538380 \n5 Adachi I, Fraser CD Jr Berlin Heart EXCOR Food and Drug Administration Investigational Device Exemption Trial Semin Thorac Cardiovasc Surg 2013 25 100 106 24216526 \n6 Monagle P Anticoagulation in the young Heart 2004 90 808 812 15201260 \n7 Annich G Adachi I Anticoagulation for pediatric mechanical circulatory support Pediatr Crit Care Med 2013 14 S37 S42 23735984 \n8 Bembea MM Annich G Rycus P Oldenburg G Berkowitz I Pronovost P Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey Pediatr Crit Care Med 2013 14 e77 e84 23287906 \n9 Monagle P Chan AKC Goldenberg NA Ichord RN Journeycake JM Nowak-Göttl U Vesely SK Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 e737S e801S 22315277 \n10 Kuhle S Eulmesekian P Kavanagh B Massicotte P Vegh P Lau A Mitchell LG Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children Haematologica 2007 92 554 557 17488668 \n11 Miller BE Bailey JM Mancuso TJ Weinstein MS Holbrook GW Silvey EM Tosone SR Levy JH Functional maturity of the coagulation system in children: an evaluation using thrombelastography Anesth Analg 1997 84 745 748 9085950 \n12 Alexander DC Butt WW Best JD Donath SM Monagle PT Shekerdemian LS Correlation of thromboelastography with standard tests of anticoagulation in paediatric patients receiving extracorporeal life support Thromb Res 2010 125 387 392 19674773 \n13 Spiess BD Tuman KJ McCarthy RJ DeLaria GA Schillo R Ivankovich AD Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies J Clin Monit 1987 3 25 30 3819793 \n14 Miller BE Guzzetta NA Tosone SR Levy JH Rapid evaluation of coagulopathies after cardiopulmonary bypass in children using modified thromboelastography Anesth Analg 2000 90 1324 1330 10825314 \n15 Almond CS Buchholz H Massicotte P Ichord R Rosenthal DN Uzark K Jaquiss RD Kroslowitz R Kepler MB Lobbestael A Berlin Heart EXCOR Pediatric ventricular assist device Investigational Device Exemption study: study design and rationale Am Heart J 2011 162 425 435.e6 21884857 \n16 Achneck HE Sileshi B Parikh A Milano CA Welsby IJ Lawson JH Pathophysiology of bleeding and clotting in the cardiac surgery patient: from vascular endothelium to circulatory assist device surface Circulation 2010 122 2068 2077 21098468 \n17 Chitlur M Lusher J Standardization of thromboelastography: values and challenges Semin Thromb Hemost 2010 36 707 711 20978991 \n18 Brill-Edwards P Ginsberg JS Johnston M Hirsh J Establishing a therapeutic range for heparin therapy Ann Intern Med 1993 119 104 109 8512158 \n19 Liveris A Bello RA Friedmann P Duffy MA Manwani D Killinger JS Rodriquez D Weinstein S Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation* Pediatr Crit Care Med 2014 15 e72 e79 24335992 \n20 Chan KL Summerhayes RG Ignjatovic V Horton SB Monagle PT Reference values for kaolin-activated thromboelastography in healthy children Anesth Analg 2007 105 1610 1613, table of contents 18042858 \n21 Newall F Johnston L Ignjatovic V Monagle P Unfractionated heparin therapy in infants and children Pediatrics 2009 123 e510 e518 19221154\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "9(9)",
"journal": "World journal of cardiology",
"keywords": "Anticoagulation; BERLIN-EXCOR; Pediatric; Thromboelastography; Ventricular assist device",
"medline_ta": "World J Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101537090",
"other_id": null,
"pages": "749-756",
"pmc": null,
"pmid": "29081908",
"pubdate": "2017-09-26",
"publication_types": "D016428:Journal Article",
"references": "18042858;24335992;19221154;23538380;21884857;19674773;22315277;20835786;21098468;3819793;9085950;8512158;23314865;20978991;22873533;15201260;24216526;23735984;23287906;17488668;10825314",
"title": "Utility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist devices.",
"title_normalized": "utility and correlation of known anticoagulation parameters in the management of pediatric ventricular assist devices"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-054956",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"dr... |
{
"abstract": "BACKGROUND\nManagement of anxiety, delirium, and agitation cannot be neglected in coronavirus disease (COVID-19). Antipsychotics are usually used for the pharmacological management of delirium, and confusion and behavioral disturbances. The concurrent use of treatments for COVID-19 and antipsychotics should consider eventual drug-drug interactions OBJECTIVE: To systematically review evidence-based available on drug-drug interactions between COVID-19 treatments and antipsychotics.\n\n\nMETHODS\nThree databases were consulted: Lexicomp® Drug Interactions, Micromedex® Solutions Drugs Interactions, and Liverpool© Drug Interaction Group for COVID-19 therapies. To acquire more information on QT prolongation and Torsade de Pointes (TdP), the CredibleMeds® QTDrugs List was searched. The authors made a recommendation agreed to by consensus. Additionally, a systematic review of drug-drug interactions between antipsychotics and COVID-19 treatment was conducted.\n\n\nRESULTS\nThe main interactions between COVID-19 drugs and antipsychotics are the risk of QT-prolongation and TdP, and cytochromes P450 interactions. Remdesivir, baricinitib, and anakinra can be used concomitantly with antipsychotics without risk of drug-drug interaction (except for hematological risk with clozapine and baricinitib). Favipiravir only needs caution with chlorpromazine and quetiapine. Tocilizumab is rather safe to use in combination with antipsychotics. The most demanding COVID-19 treatments for coadministration with antipsychotics are chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir because of the risk of QT prolongation and TdP and cytochromes interactions. The systematic review provides highly probable drug interaction between lopinavir/ritonavir plus quetiapine and ritonavir/indinavir plus risperidone.\n\n\nCONCLUSIONS\nClinicians prescribing antipsychotics should be aware of the likely risk of drug-drug interaction with COVID-19 medication and may benefit from taking into account present recommendations of use to preserve patient safety.",
"affiliations": "Department of Psychiatry, University Hospital Virgen del Rocio, Av Manuel Siurot, Seville, S/n 41013, Spain.;Department of Psychiatry, University Hospital Virgen del Rocio, Av Manuel Siurot, Seville, S/n 41013, Spain.;Department of Psychiatry, University Hospital Virgen del Rocio, Av Manuel Siurot, Seville, S/n 41013, Spain.;Department of Psychiatry, University Hospital Virgen del Rocio, Av Manuel Siurot, Seville, S/n 41013, Spain.;Department of Clinical Pharmacology, University Hospital Virgen del Rocio, Av Manuel Siurot, Sevilla, S/n 41013, Spain.;Department of Psychiatry, University Hospital Virgen del Rocio, IBIS, CIBERSAM, University of Sevilla, Av Manuel Siurot, S/n 41013, Sevilla, Spain. benedicto.crespo.sspa@juntadeandalucia.es.",
"authors": "Plasencia-García|Beatriz Oda|BO|;Rodríguez-Menéndez|Gonzalo|G|;Rico-Rangel|María Isabel|MI|;Rubio-García|Ana|A|;Torelló-Iserte|Jaime|J|;Crespo-Facorro|Benedicto|B|http://orcid.org/0000-0003-0033-7132",
"chemical_list": "D014150:Antipsychotic Agents; D000998:Antiviral Agents; D003577:Cytochrome P-450 Enzyme System",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00213-020-05716-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-3158",
"issue": "238(2)",
"journal": "Psychopharmacology",
"keywords": "COVID-19; Drug-drug interaction; Psychopharmacotherapy; Side effects",
"medline_ta": "Psychopharmacology (Berl)",
"mesh_terms": "D014150:Antipsychotic Agents; D000998:Antiviral Agents; D000086382:COVID-19; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D006801:Humans; D008133:Long QT Syndrome; D000086402:SARS-CoV-2; D016171:Torsades de Pointes",
"nlm_unique_id": "7608025",
"other_id": null,
"pages": "329-340",
"pmc": null,
"pmid": "33410987",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": "28071178;17576808;20978219;32330277;15799682;17285099;11797025;15082703;15523003;29473523;32330276;18577765;24158020;20606815;32352535;30400791;17389673;30666436;12410055;11978161;24170642;11996011;15080763;29882581;11015640;21954480;19621072;31003063;27919275;12172335;19857154;24278396;19144938;30181002;14999113;19712597;26272741;15544470;24677112;30179988;19929028;17166171;24801071;30524704;17646028;23333322",
"title": "Drug-drug interactions between COVID-19 treatments and antipsychotics drugs: integrated evidence from 4 databases and a systematic review.",
"title_normalized": "drug drug interactions between covid 19 treatments and antipsychotics drugs integrated evidence from 4 databases and a systematic review"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-10940",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATAZANAVIR\\RITONAVIR"
},
... |
{
"abstract": "BACKGROUND\nCarcinoma of the cervix is the most common malignancy associated with pregnancy. In the first and second trimesters patients should receive the same treatment as is used in nonpregnant women and termination is advised. In selected cases neoadjuvant chemotherapy (NACT) could be proposed but only a few cases have been reported.\n\n\nMETHODS\nA 27-year-old woman, gravida 1 para 0, at 15 weeks' gestation, was diagnosed with FIGO stage IB2 squamous cervical cancer. After refusing to terminate pregnancy, she was treated with neoadjuvant chemotherapy (cisplatin) starting at 18 weeks. A cesarean section with radical surgery was performed at 32 weeks and a healthy baby delivered. Four weeks later the patient started chemoradiation therapy. She relapsed 1 year after surgery and died when her child was 2 years old.\n\n\nCONCLUSIONS\nNACT followed by radical surgery was an unsuccessful treatment in our patient; platinum-based chemotherapy was harmless to the child up to the last follow-up.",
"affiliations": "Obstetrics and Gynecology Department, IRCCS Ospedale San Raffaele, Milan, Italy.",
"authors": "Rabaiotti|Emanuela|E|;Sigismondi|Cristina|C|;Montoli|Serena|S|;Mangili|Giorgia|G|;Candiani|Massimo|M|;Viganò|Riccardo|R|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "96(4)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D002585:Cesarean Section; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D005260:Female; D006801:Humans; D007044:Hysterectomy; D020360:Neoadjuvant Therapy; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D018714:Radiotherapy, Adjuvant; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "623-6",
"pmc": null,
"pmid": "20968145",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of locally advanced cervical cancer in pregnancy: a case report.",
"title_normalized": "management of locally advanced cervical cancer in pregnancy a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1011400",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Intravenous haloperidol is the agent of choice for controlling severe agitated delirium in seriously ill cardiac patients in many institutions. Prior reports have proposed that high-dose intravenous haloperidol may be without untoward effects in these patients. Recently, however, a few reports of significant QTc prolongation and torsade de pointes as complications of high-dose intravenous haloperidol therapy have appeared. The present report describes three patients with definite haloperidol-induced QTc prolongation and torsade. In each case, QTc prolongation preceded the arrhythmia and disappeared following the discontinuation of haloperidol. Neither electrolyte imbalance, therapy with other cardiac drugs, bradycardia, ischemia, left ventricular dysfunction, nor other known cause of torsade was present in these patients. It is hypothesized that QTc prolongation and torsade likely are idiosyncratic, unpredictable reactions to high-dose haloperidol in select patients. Careful serial electrocardiographic monitoring and prompt discontinuation of the drug should suffice to prevent this relatively uncommon, life-threatening complication of high-dose intravenous haloperidol.",
"affiliations": "Cardiac Unit, Massachusetts General Hospital, Boston 02114, USA.",
"authors": "Di Salvo|T G|TG|;O'Gara|P T|PT|",
"chemical_list": "D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1002/clc.4960180512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-9289",
"issue": "18(5)",
"journal": "Clinical cardiology",
"keywords": null,
"medline_ta": "Clin Cardiol",
"mesh_terms": "D000368:Aged; D003693:Delirium; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006220:Haloperidol; D006331:Heart Diseases; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D016171:Torsades de Pointes",
"nlm_unique_id": "7903272",
"other_id": null,
"pages": "285-90",
"pmc": null,
"pmid": "7628136",
"pubdate": "1995-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Torsade de pointes caused by high-dose intravenous haloperidol in cardiac patients.",
"title_normalized": "torsade de pointes caused by high dose intravenous haloperidol in cardiac patients"
} | [
{
"companynumb": "US-PFIZER INC-202200641063",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Animal studies suggest that receptor for advanced glycation end products (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE), high-mobility group box 1 (HMGB1), and Nε-(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health-sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN-RAGE, CML, and sRAGE were detected by enzyme-linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN-RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN-RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3-73; P < 0.001). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.",
"affiliations": "Institute of Clinical Physiology, National Research Council, Pisa, Italy.;Institute of Clinical Physiology, National Research Council, Pisa, Italy.;Institute of Clinical Physiology, National Research Council, Pisa, Italy.;Division of Digestive and Liver Diseases, Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX.",
"authors": "Basta|Giuseppina|G|;Del Turco|Serena|S|;Navarra|Teresa|T|;Lee|William M|WM|;|||",
"chemical_list": "C000593871:AGER protein, human; D015415:Biomarkers; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D000067759:Receptor for Advanced Glycation End Products; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D000082:Acetaminophen; C048496:N(6)-carboxymethyllysine; D008239:Lysine",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.24129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "21(6)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D015415:Biomarkers; D016022:Case-Control Studies; D005260:Female; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D006801:Humans; D017114:Liver Failure, Acute; D008239:Lysine; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products; D000067616:S100A12 Protein; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "847-54",
"pmc": null,
"pmid": "25825217",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "19114209;18328438;14523675;14767995;16317692;21450080;23846410;12530947;16677153;16490618;18952609;15734480;18607166;17763397;22790970;16737880;16237684;11460223;9037225;19414536;10393704;16926247;19783637;20539169;25671828;17826783;21438128;21745283;16980512;22511153;12484709;15795240;19931603;10398600;17370333;17981300;15841455;17901832;10628605;20630612;19125949;22846388;19845566",
"title": "Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure.",
"title_normalized": "circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure"
} | [
{
"companynumb": "IT-JNJFOC-20150701691",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of colostomy-free, long-term survival following 5-FU/CDDP for the local recurrence of anal cancer after chemoradiation therapy(CRT). The patient was a 48-year-old woman who was diagnosed with cStage ⅢA anal cancer. She was treated with CRT(5-FU/MMC plus 59 Gy)and achieved a complete response upon treatment completion. A local recurrence was detected on the left-side wall of her rectum after 6 months. We recommended abdominoperineal resection but the patient refused operation. The patient was treated with chemotherapy consisting of 5-FU(1,000mg/m / 2/day)on days 1-5 and CDDP(100mg/m / 2/day)on day 2. Grade 3 peripheral neuropathy appeared following the completion of 5 courses. Therefore, the dose was reduced to 60%. Twenty-five courses of this treatment were continued and chemotherapy was completed. The patient has been alive with no sign of recurrence for 6 years and 8 months from the initial treatment. CRT for anal cancer is becoming a standard therapy but local recurrence is possible. In these cases, abdominoperineal resection is required. Chemotherapy with 5-FU/CDDP in cases of recurrence can be a colostomy-free option.",
"affiliations": "Dept. of Surgery, Toyokawa City Hospital.",
"authors": "Aoyama|Yoshinaga|Y|;Katada|Takeyasu|T|;Saito|Masaki|M|;Tsuchiya|Tomonori|T|;Nishido|Toru|T|;Kato|Akira|A|;Shibata|Takahiro|T|;Shibata|Tadashi|T|;Teranishi|Futoshi|F|;Sakamoto|Shoko|S|;Mita|Keiko|K|;Karamatsu|Shoji|S|;Hikosaka|Yu|Y|;Nishida|Tsutomu|T|",
"chemical_list": "D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D059248:Chemoradiotherapy; D003125:Colostomy; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "523-525",
"pmc": null,
"pmid": "30914602",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Colostomy-Free and Long-Term Survival with 5-FU/CDDP for Local Recurrence of Anal Cancer after Chemoradiation Therapy.",
"title_normalized": "a case of colostomy free and long term survival with 5 fu cddp for local recurrence of anal cancer after chemoradiation therapy"
} | [
{
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"abstract": "Coronavirus disease (COVID-19) is a contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents a patient who had difficulty eradicating the corona virus due to being treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies. The combined use of external anti-viral agents like convalescent plasma, IVIG and Remdesivir successfully helped the patient's immune system to eradicate the virus without B-cell population recovery. In vitro studies showed that convalescent plasma is the main agent that helped in eradicating the virus.",
"affiliations": "Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel.;Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel.;Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7404905, Israel.;Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7404905, Israel.;The Clinical Microbiology Laboratory, Galilee Medical Center, Nahariya 2210001, Israel.;The Clinical Microbiology Laboratory, Galilee Medical Center, Nahariya 2210001, Israel.;Azrieli Bar-Ilan Faculty of Medicine, Safad 2210001, Israel.;Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel.",
"authors": "Basheer|Maamoun|M|;Saad|Elias|E|;Laskar|Orly|O|0000-0003-3109-6554;Schuster|Ofir|O|;Rechnitzer|Hagai|H|0000-0002-7438-5252;Zisman-Rozen|Simona|S|;Azoulay|David|D|0000-0002-3451-5737;Assy|Nimer|N|",
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"fulltext": "\n==== Front\nInt J Mol Sci\nInt J Mol Sci\nijms\nInternational Journal of Molecular Sciences\n1422-0067\nMDPI\n\n10.3390/ijms22168902\nijms-22-08902\nCase Report\nClearance of the SARS-CoV-2 Virus in an Immunocompromised Patient Mediated by Convalescent Plasma without B-Cell Recovery\nBasheer Maamoun 1*\nSaad Elias 12\nhttps://orcid.org/0000-0003-3109-6554\nLaskar Orly 3\nSchuster Ofir 3\nhttps://orcid.org/0000-0002-7438-5252\nRechnitzer Hagai 4\nZisman-Rozen Simona 4\nhttps://orcid.org/0000-0002-3451-5737\nAzoulay David 25\nAssy Nimer 12*\nLeeansyah Edwin Academic Editor\n1 Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel; EliasS@gmc.gov.il\n2 Azrieli Bar-Ilan Faculty of Medicine, Safad 2210001, Israel; DavidA@gmc.gov.il\n3 Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 7404905, Israel; orlyl@iibr.gov.il (O.L.); schustero@gmc.gov.il (O.S.)\n4 The Clinical Microbiology Laboratory, Galilee Medical Center, Nahariya 2210001, Israel; HagaiR@gmc.gov.il (H.R.); Zisman-Rozen@gmc.gov.il (S.Z.-R.)\n5 Hematology Unit and Clinical Laboratory, Galilee Medical Center, Nahariya 2210001, Israel\n* Correspondence: maamon.basheer@mail.huji.ac.il (M.B.); nimera@gmc.gov.il (N.A.)\n18 8 2021\n8 2021\n22 16 890227 6 2021\n17 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nCoronavirus disease (COVID-19) is a contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents a patient who had difficulty eradicating the corona virus due to being treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies. The combined use of external anti-viral agents like convalescent plasma, IVIG and Remdesivir successfully helped the patient’s immune system to eradicate the virus without B-cell population recovery. In vitro studies showed that convalescent plasma is the main agent that helped in eradicating the virus.\n\nimmunocompromised\nSARS-COV-2\npneumonia\nT lymphocytes\n==== Body\n1. Introduction\n\nCoronavirus disease (COVID-19) is contagious and is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Rituximab, an anti-CD20 monoclonal antibody, is one of the main treatments for B-cell malignancies and auto-immune diseases [2]. It acts by depleting normal cells (as well as pathogenic B cells) while sparing other plasma cells and hematopoietic stem cells [2,3]. This medication prolongs B-cell depletion, which impairs the adaptive immune response and the ability to produce neutralizing antibodies. Patients treated with Rituximab are at a higher risk for prolong severe forms of COVID-19 [4,5,6,7].\n\nThis case report presents a patient treated with Rituximab, and discusses the specific interventions conducted to eradicate the virus.\n\n2. Material and Methods\n\n2.1. Convalescent Plasma\n\nConvalescent plasma donations were tested for the presence of anti-SARS-CoV-2 IgG using an ELISA assay with the spike protein as an antigen. The titer of anti-SARS -CoV-2 IgG was more than 1:1000. The protocol of the Israeli ministry of health is two units of convalescent plasma for COVID-19 patients [8].\n\n2.2. Flow Cytometry Analysis of Leucocyte Differentials and Lymphocytic Subsets\n\nFor measuring lymphocyte sub-set proportions, 50 µL of whole blood was incubated with an antibody mixture containing: Pacific-Blue conjugated anti-human CD7 (Beckman Coulter Inc., Carlsbad, CA, USA), PE-Cy7 conjugated anti-human CD45 (Beckman Coulter Inc., Carlsbad, CA, USA), PE-Cy5, conjugated anti-human CD56 (Beckman Coulter Inc., Carlsbad, CA, USA), ECD conjugated anti-human CD3 (Beckman Coulter Inc., Carlsbad, CA, USA), PE conjugated anti-human CD8 (Beckman Coulter Inc., Carlsbad, CA, USA) and FITC conjugated anti-human CD4 and CD19 (Beckman Coulter Inc., Carlsbad, CA, USA). The samples were incubated for 10 min at room temperature, and underwent red blood cell lysis via VersaLyse solution (Beckman Coulter Inc., Carlsbad, CA, USA)for an additional 10 min. The total lymphocytes count of the patients were determined by the system XN-1000 hematology analyzer (Sysmex Corporation, Kobe, Japan) and recorded. The results were read by a Beckman Coulter Navios flow cytometer. The total leucocytes were recorded, and the percentages of the lymphocyte subsets from the total gated lymphocytes were also recorded.\n\n2.3. COVID-19 Infection Status as Detected by the Nasopharyngeal RT-PCR Test and the Cytopathic Effect\n\nFollowing nasal and throat sampling, viral swabs were inserted into refrigerated transfer buffer containing tubes (Copan). Tubes containing the swabs were vortexed for 1 min. Two ml of the buffer were transferred to a new 15mL tube and centrifuged (5000× g, 5 min, 4 °C), and the supernatant was transferred through a 0.22 µm filter. Vero E6 (ATCC CRL-1586TM), were cultured in DMEM supplemented with 10% fetal bovine serum (FBS), MEM non-essential amino acids, 2mM L-Glutamine, 100 Units/mL Penicillin, 0.1 mg/mL streptomycin, 12.5 Units/mL Nystatin (Biological Industries, Beit Haemek, Israel). Each supernatant sample was added in duplicates to cells monolayers in 12-well plates (Costar; 0.2 mL/well) for 1 h, followed by the addition of 2 mL MEM containing 2% FBS, MEM non-essential amino acids, 2 mM L-Glutamine, 100 Units/mL Penicillin, 0.1 mg/mL streptomycin, 12.5 Units/mL Nystatin and 0.15% sodium bicarbonate (Biological Industries, Beit Haemek, Israel). Plates were further incubated at 37 °C, 5% CO2 for 5 days. SARS-CoV-2 (GISAID accession EPI_ISL_406862), kindly provided by Bundeswehr Institute of Microbiology, Munich, Germany, was used as positive control at a concentration of 60 pfu/mL. Cytopathic effect (CPE) was microscopically determined [9]. To confirm that the cytopathic effect was due to SARS-Cov-2, a RT-real time PCR for the virus was performed on cell supernatant. The assay was conducted on days 41, 54 and 95 after the first positive corona test.\n\nRT-PCR and PCR were used for SARS-CoV-2 detection. Viral RNA was extracted from nasopharyngeal samples using the QIAamp Viral RNA Mini Kit (Qiagen) according to the manufacturer’s instructions. RT-PCR and PCR were performed subsequently with a one-step real time RT-PCR kit containing primers and probes targeting the ORF1b and a positive internal reference gene. Reaction system and amplification conditions were performed according to the manufacturer’s specifications (Wuhan BGI Biotechnology Co. Ltd., Wuhan, China). The result was considered valid only when the cycle threshold (Ct) value of the reference gene was ≤32. The result was considered positive for 2019-nCoV when the Ct value of the ORF1b target gene was ≤36 (borderline result was determined when the Ct value of the ORF1b target gene was >36 but ≤40 and negative when ORF1b Ct was above 40 or not detected).\n\n2.4. In Vitro Studies of the Efficiency of Different Agents to Eradicate the SARS-CoV-2 Virus\n\nSARS-CoV-2 viruses (60 PFU/well) were treated with different materials (Remdesivir 100 µg/mL, Ivermectin 3 µg/mL, IVIG 20 mg/mL or convalescent plasma 50 µL/well). The blood of the patient was drained to an EDTA tube. The wells were then incubated with 50 µL buffy coat, the fraction of an anti-coagulated blood sample that contained most of the white blood cells of the patient. Each mixture was transferred to Vero E6 cells, followed by 5 days of incubation. The cytopathogenic effect of the intact virus was measured in all study groups.\n\n2.5. Ethics\n\nThis work was done according to the instructions of the local committee of Helsinki for human Studies. The patient signed a form concern confirming the publication of this work.\n\n3. Results\n\n3.1. Clinical and Labortory Monitoing of the Pateint\n\nThe patient was infected with the SARS-CoV-2 virus on day 1. On day 25, he came to the emergency room with general weakness, cough and dyspnea. The RT-PCR from a nasopharyngeal sample was positive for corona virus. While hospitalized in a designated COVID-19 ward, the patient was treated with two units of convalescent plasma, systemic steroids, anticoagulants and vitamin D, a known COVID-19 treatment protocol, with a good response. Throughout the hospitalization, the patient was hemodynamically stable with normal saturation levels on room air (Figure 1A). Radiographic imaging showed about 50% of lung injury Figure 1B). He was discharged on day 41 with no need for supplementary oxygen.\n\nOn day 61, the patient returned to the hospital with a fever. Laboratory tests showed signs of inflammation. Repeated SARS-CoV-2 RT-PCR were positive, causing concern for a continuous persistent COVID-19 infection. The patient was therefore, readmitted to the COVID-19 ward. To achieve virus eradication, the patient underwent a second regiment of Remdesivir (10-day course), four units of convalescent plasma, 120 g of intravenous immunoglobulin and one dose of ivermectin (15 mg). The patient improved and was discharged within 10 days.\n\nThe complete blood count of the patient showed thrombocytopenia and severe lymphopenia (Figure 1C). Biochemical analysis showed stable plasma electrolyte concentrations. Inflammatory parameters (C-reactive protein, ferritin, D-dimer and fibrinogen) were increased upon admission. A decrease in these parameters was noted once treatment was presented (Figure 1C).\n\n3.2. Analysis of Leucocytes Differential and Lymphocyte Subsets Proportion by Flow Cytometry\n\nAnalysis of the leucocyte differential and lymphocyte subset proportion via flow cytometry showed a depletion of B-cells (<1%) upon admission with no recovery after the intervention. However, T-cells were increased after intervention from 73% to 83.5%. The CD4, CD8 and NK cell (CD3-/CD56+) populations also increased after the treatment. The CD4+/CD8+ ratio was low before the intervention, with no further changes (Figure 2).\n\n3.3. COVID-19 Infection and Immunity Status as Detected by a Nasopharynx COVID-19 PCR Test and Viral Culture\n\nCOVID-19 infection and immunity status were tested. RT-PCRs were performed on nasal and throat samples on days 1, 25, 41, 54, 60, 75, 95 and 136, after the first positive corona test was done. To confirm that the virus was alive and intact, the viral cytotoxic effect was tested on a VERO cell culture.\n\nThe results showed that the patient was positive for the Corona virus (days 1, 25, 41, 54 and 60) until intervention as shown also by the cytotoxic culture assay in days 41 and 54. Negative SARS-CoV-2 RT PCR results were initially achieved after the intervention (days 75, 95 and 136). A cytotoxic culture assay confirmed the eradication of the virus after intervention (day 95). No SARS-CoV-2 antibodies were found (Figure 3). Viral genetic sequencing showed that it was probably a wild strain and less suitable for variant sequencing.\n\n3.4. In Vitro Studies: Different Agents’ Effects on SARS-CoV2 Cytotoxic Effect Using Vero E6 Cells\n\nIn vitro studies confirmed that convalescent plasma and Remdesivir successfully eradicated the virus. Convalescent sera or Remdesivir were shown to confer protection against the cytopathic effect, while CPE was observed in all other treatments (Figure 4). The PCR results showed low or absent viral loads in convalescent plasma or Remdesivir samples. These data support the CPE observations, and demonstrates that CPE formation was due to SARS-CoV-2 presence (Figure 4).\n\nAll substances (Remdesivir, Ivermectin, IVIG and convalescent plasma) without patient blood cells were added to Vero E6 cells with or without SARS-CoV-2, and their effect on the cells was tested. It was found that in the absence of the virus, no CPE was observed using any of the substances. In the presence of SARS-CoV-2 and without patient blood cells, CPE observed in the Ivermectin and IVIG samples, whereas in the Remdesivir and convalescent plasma samples, minimal CPE was observed. The RT-PCR results for these samples showed that there was a significant eradication of the virus; however, at slightly lower CT levels (33 and 35, respectively) compared to these samples in the presence of white blood cells from the patient. This suggests that the patient immune system with convalescent plasma synergically eradicate the virus.\n\n4. Discussion\n\nThis case report presents a patient treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies, creating difficulties in eradicating the corona virus.\n\nOn day one, the infected patient was asymptomatic. He presented to the ER on day 25 with general weakness. His first hospitalization period extended to 16 days. The patient was treated with two units of convalescent plasma, systemic steroids, anti-coagulants and vitamin D, a known COVID-19 treatment protocol (as recommended by the Israeli ministry of health) with good response. He was discharged on day 41 with no need for supplementary oxygen. The RT-PCR assay from a nasopharyngeal sample was still positive, while anti–SARS specific- coV-2 IgG were negative.\n\nDue to the fact that the patient was treated with Rituximab, he was immunocompromised, and due to the positive cell culture test, the patient was still contagious and was indicated for quarantine. From day 41 through day 61, the patient was quarantined alone at home. During this period, the patient felt good, with no need for supplementary oxygen. Another RT-PCR test taken on day 54, with positive results, with no SARS-CoV-2 antibodies. A cell culture test also showed that the patient still had live intact virus particles within the cells.\n\nAt day 61, the patient returned to the hospital with a fever. Repeated RT-PCR assays were positive, causing concern for a continuous persistent COVID-19 infection. During this hospitalization stay, the patient received a second course of Remdesivir (10-day course), four units of convalescent plasma, 120 g of intravenous immunoglobulin, as recommended by some studies [10,11,12] and one dose of Ivermectin (15 mg) [13]. He improved under this treatment. On discharge day (day 77), an RT-PCR assay from a nasopharyngeal swab was negative and no Coronavirus antibodies were found. Furthermore, a cell culture test was repeated laterally on day 95, with no presence of live intact viruses. It should be noted that analysis of whole blood samples taken both on admission and discharge, showed a limited B lymphocyte population (about 1%).\n\nThe patient was positive for COVID-19 for 75 days, confirmed by a special cell culture test that showed evidence of intact live virulent viruses with cytotoxic abilities. No anti-SARS-CoV-2 IgG antibodies were identified. A specific intervention, which included convalescent plasma and another extended course of Remdesivir, eventually eradicated the virus. Remdesivir and convalescent plasma are anti-viral agents, but each works through different mechanisms. Remdesivir is known to inhibit the replication of the virus. It works as a nucleoside analog and inhibits the RNA-dependent RNA polymerase. On the other hand, convalescent plasma contains SARS-CoV-2 antibodies, which work synergically with the patient immune system in order to eradicate the virus.\n\nRituximab treated patients need passive immunotherapy to eradicate viruses. The supply of these antibodies by convalescent plasma is critical for the good function of the immune system mediating viral clearance. The immune system, with B cell depletion, could eradicate the SARS-CoV-2 virus. These results were also previously presented by Thomas Hueso et al. [10]. This case study suggests that T cells and other cells in the innate system work synergistically with exogenous antibodies in eradicating the SARS-CoV-2 virus.\n\nIn conclusion, this case report presents a patient treated with Rituximab, which depletes B lymphocyte population and, therefore, disables the production of neutralizing antibodies. The combined use of external anti-viral agents such as convalescent plasma and Remdesivir, helped the patient’s immune system in eradicating the virus, with no need for B-cell population recovery.\n\nAuthor Contributions\n\nAll authors contribute equally in this paper. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board.\n\nInformed Consent Statement\n\nInformed consent was established and signed.\n\nData Availability Statement\n\nAll data from patient file.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (A) O2 saturation, body temperature, systolic and diastolic blood pressure. The upper and lower panels relate to the first and the second hospitalization, respectively. (B) Upper panel: Posterior anterior chest radiograph showing bilateral patchy lung consolidation in a peripheral distribution pattern on days 25, 30 and 64 after the first positive corona test. Lower panel: Unenhanced, thin-section CT performed on day 26 after the first positive corona test showing bilateral ground–glass attenuations with subsequent deterioration in the second hospitalization on day 58. (C) Complete blood count and bio-chemical results of the patient during the first and the second hospitalizations upon admittance and discharge.\n\nFigure 2 Analysis of leucocytes differential and lymphocyte subsets proportion by flow cytometry.\n\nFigure 3 COVID-19 infection and immunity status as detected by nasopharynx COVID-19 PCR tests and viral culture. A PCR test of nasal and throat samples showed positive test on days 1, 25, 41, 54 and 60 with a low cycle threshold (CT). Negative results were visible on days 75, 95 and 136. Cell cultures showed intact viruses on days 41 and 54. Negative cell culture for the corona virus was verified on day 95 after the completed course of the treatment.\n\nFigure 4 In vitro studies confirming that convalescent plasma and Remdesivir successfully eradicated the virus. (A): SARS-CoV-2 viruses (60 PFU/well) were treated with different agents in the presence of white blood cells from the immunodeficient patient. Each mixture was transferred to Vero E6 cells, followed by five days incubation to the formation of CPE. Representative images for each treatment are presented. (B): PCR results of SARS-CoV-2 identification from each treatment are presented (averages of three triplicates with their SD). P.C: positive control. N.C.: negative control. (C): Summary of CPE and PCR results for each treatment. +/− presence/absence of CPE.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Richardson S. Hirsch J.S. Narasimhan M. Crawford J.M. McGinn T. Davidson K.W. Northwell COVID-19 Research Consortium Presenting characteristics, comorbidities and outcomes among 5,700 patients hospitalized with COVID-19 in the New York City area JAMA 2020 323 2052 2059 10.1001/jama.2020.6775 32320003\n2. Salles G. Barrett M. Foà R. Maurer J. O’Brien S. Valente N. Maloney D.G. Rituximab in B-cell hematologic malignancies: A review of 20 years of clinical experience Adv. Ther. 2017 34 2232 2273 10.1007/s12325-017-0612-x 28983798\n3. Hawker K. O’Connor P. Freedman M.S. Calabresi P.A. Antel J. Simon J. Hauser S. Waubant E. Vollmer T. Panitch H. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo controlled multicenter trial Ann. Neurol. 2009 66 460 471 10.1002/ana.21867 19847908\n4. Tepasse P.R. Hafezi W. Lutz M. Kühn J. Wilms C. Wiewrodt R. Sackarnd J. Keller M. Schmidt H.H. Vollenberg R. Persisting SARS-CoV-2 viraemia after rituximab therapy: Two cases with fatal outcome and a review of the literature Br. J. Haematol. 2020 190 185 188 10.1111/bjh.16896 32557623\n5. Schulze-Koops H. Krueger K. Vallbracht I. Hasseli R. Skapenko A. Increased risk for severe COVID-19 in patients with inflammatory rheumatic diseases treated with rituximab Ann. Rheum. Dis. 2021 80 e67 10.1136/annrheumdis-2020-218075 32591357\n6. Avouac J. Airó P. Carlier N. Matucci-Cerinic M. Allanore Y. Severe COVID-19-associated pneumonia in 3 patients with systemic sclerosis treated with rituximab Ann. Rheum. Dis. 2021 80 e37 10.1136/annrheumdis-2020-217864 32503849\n7. Monti S. Balduzzi S. Delvino P. Bellis E. Quadrelli V.S. Montecucco C. Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies Ann. Rheum. Dis. 2020 79 667 668 10.1136/annrheumdis-2020-217424 32241793\n8. Yan K. Rawle D.J. Le T.T. Suhrbier A. Simple rapid in vitro screening method for SARS-CoV-2 anti-virals that identifies potential cytomorbidity-associated false positives Virol. J. 2021 18 123 10.1186/s12985-021-01587-z 34107996\n9. The Israeli Ministry of Health: The Protocol of Convalscent Plasma in COVID-19 Patient Available online: https://www.health.gov.il/English/Topics/Diseases/corona/Pages/press-release.aspx (accessed on 25 June 2021)\n10. Hueso T. Pouderoux C. Péré H. Beaumont A.-L. Raillon L.-A. Ader F. Chatenoud L. Eshagh D. Szwebel T.-A. Martinot M. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19 Blood 2020 136 2290 2295 10.1182/blood.2020008423 32959052\n11. Cao W. Liu X. Bai T. Fan H. Hong K. Song H. Han Y. Lin L. Ruan L. Li T. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019 Open Forum Infectious Diseases Oxford University Press Oxford, UK 2020 Volume 7 ofaa102\n12. Dufort E.M. Koumans E.H. Chow E.J. Rosenthal E.M. Muse A. Rowlands J. Maxted A.M. Rosenberg E.S. Easton D. Udo D. Multisystem inflammatory syndrome in children in New York State N. Engl. J. Med. 2020 383 347 358 10.1056/NEJMoa2021756 32598830\n13. Heidary F. Gharebaghi R. Ivermectin: A systematic review from antiviral effects to COVID-19 complementary regimen J. Antibiot. 2020 73 1 10 10.1038/s41429-020-0336-z 32533071\n\n",
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"mesh_terms": "D000249:Adenosine Monophosphate; D000409:Alanine; D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D001402:B-Lymphocytes; D000086382:COVID-19; D002522:Chlorocebus aethiops; D006801:Humans; D007116:Immunization, Passive; D016867:Immunocompromised Host; D000069283:Rituximab; D000086402:SARS-CoV-2; D013601:T-Lymphocytes; D014709:Vero Cells",
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"title": "Clearance of the SARS-CoV-2 Virus in an Immunocompromised Patient Mediated by Convalescent Plasma without B-Cell Recovery.",
"title_normalized": "clearance of the sars cov 2 virus in an immunocompromised patient mediated by convalescent plasma without b cell recovery"
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"abstract": "BACKGROUND\nLong-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules.\n\n\nOBJECTIVE\nTo evaluate the incidence of cancers in uninfected children born to HIV-infected mothers.\n\n\nMETHODS\nCancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population.\n\n\nRESULTS\nTen cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990-1999 or 2000-2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3-1.5) and 1.0 (0.5-1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0-7.2] P = 0.05 and 2.4 [0.8-5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine-lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5-73.9)].\n\n\nCONCLUSIONS\nThis study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.",
"affiliations": "Inserm, U822, Le Kremlin-Bicêtre, France.",
"authors": "Benhammou|Valérie|V|;Warszawski|Josiane|J|;Bellec|Stéphanie|S|;Doz|François|F|;André|Nicolas|N|;Lacour|Brigitte|B|;Levine|Martine|M|;Bavoux|Françoise|F|;Tubiana|Roland|R|;Mandelbrot|Laurent|L|;Clavel|Jacqueline|J|;Blanche|Stéphane|S|;|||",
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"mesh_terms": "D019380:Anti-HIV Agents; D002648:Child; D002675:Child, Preschool; D004812:Epidemiologic Methods; D005260:Female; D005602:France; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D009369:Neoplasms; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011297:Prenatal Exposure Delayed Effects; D018894:Reverse Transcriptase Inhibitors",
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"title": "Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors.",
"title_normalized": "incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors"
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"abstract": "Acute limb compartment syndrome is a surgical emergency associated with significant morbidity if not diagnosed promptly and treated effectively. We describe a case of severe and eventually lethal acute limb compartment syndrome, which complicated veno-arterial extracorporeal membrane oxygenation in a previously well young woman who had suffered an unexplained cardiac arrest. We recommend that intensive care units develop clinical practice guidelines for the use of extracorporeal membrane oxygenation therapy in order to minimise the risk of similar adverse events in the future.",
"affiliations": "Intensive Care Unit, St. Vincent's Hospital, Melbourne, Victoria, Australia. wallcj@gmail.com",
"authors": "Wall|C J|CJ|;Santamaria|J|J|",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D003161:Compartment Syndromes; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D007866:Leg; D011247:Pregnancy; D011248:Pregnancy Complications",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Extracorporeal membrane oxygenation: an unusual cause of acute limb compartment syndrome.",
"title_normalized": "extracorporeal membrane oxygenation an unusual cause of acute limb compartment syndrome"
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"abstract": "A 67-year-old previously healthy woman presented with progressive visual impairment including bitemporal hemianopsia. A brain magnetic resonance imaging revealed a contrast-enhancing mass in the optic chiasm, spreading along the left optic tract. The patient underwent a transcranial biopsy of the left optical tract that yielded a diagnosis of diffuse large B-cell lymphoma. CT scans of the chest, abdomen, and pelvis, PET-CT, and bone marrow biopsy revealed no evidence of systemic lymphoma. Thus, the final diagnosis was of primary central nervous system lymphoma of the optic chiasm. Systemic treatment was initiated with full response. Six months after the end of the treatment, recurrence at cerebellum parenchyma and left tentorium was recorded. A new systemic treatment achieved full response. A second recurrence was noted in an optical coherence tomography of the right eye, 2 years after the initial diagnosis. The patient was treated with intravitreal methotrexate with initial success, but eventual failure after 10 months. Intravitreal rituximab was used with no effect. The patient was then referred to radiotherapy and underwent external beam radiotherapy with VMAT. There were no acute toxicities to report. After the radiotherapy treatment, at 1-year follow-up, the patient has no evidence of disease. Long-term toxicities were recorded and are considered manageable. The present case emphasizes the role of ocular irradiation as an option in the management of intraocular lymphoma patients, including in the salvage setting, with an acceptable ocular toxicity profile.",
"affiliations": "Radiotherapy Department, Instituto Português de Oncologia Francisco Gentil E.P.E, Lisbon, Portugal.;Ophthalmology Department, Hospital de Egas Moniz Centro Hospitalar Lisboa Ocidental E.P.E, Lisbon, Portugal.;Neurology Department, Instituto Português de Oncologia Francisco Gentil E.P.E, Lisbon, Portugal.;Ophthalmology Department, Hospital de Egas Moniz Centro Hospitalar Lisboa Ocidental E.P.E, Lisbon, Portugal.;Radiotherapy Department, Instituto Português de Oncologia Francisco Gentil E.P.E, Lisbon, Portugal.",
"authors": "Colaço|Raul|R|;Portela|Mariana|M|;Costa|Ilda|I|;Guedes|Marta|M|;Mota|António|A|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000512216\ncro-0014-0184\nCase Report\nRadiotherapy as Salvage Treatment in Intraocular Lymphoma: A Case Report\nColaço Raul a*\nPortela Mariana b\nCosta Ilda c\nGuedes Marta b\nMota António a\naRadiotherapy Department, Instituto Português de Oncologia Francisco Gentil E.P.E, Lisbon, Portugal\nbOphthalmology Department, Hospital de Egas Moniz Centro Hospitalar Lisboa Ocidental E.P.E, Lisbon, Portugal\ncNeurology Department, Instituto Português de Oncologia Francisco Gentil E.P.E, Lisbon, Portugal\n*Raul Colaço, Radiotherapy Department, Instituto Português de Oncologia Francisco Gentil E.P.E., Rua Professor Lima Basto, PT–1099-023 Lisbon (Portugal), rcolaco@ipolisboa.min-saude.pt\nJan-Apr 2021\n1 3 2021\n1 3 2021\n14 1 184189\n6 10 2020\n12 10 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nA 67-year-old previously healthy woman presented with progressive visual impairment including bitemporal hemianopsia. A brain magnetic resonance imaging revealed a contrast-enhancing mass in the optic chiasm, spreading along the left optic tract. The patient underwent a transcranial biopsy of the left optical tract that yielded a diagnosis of diffuse large B-cell lymphoma. CT scans of the chest, abdomen, and pelvis, PET-CT, and bone marrow biopsy revealed no evidence of systemic lymphoma. Thus, the final diagnosis was of primary central nervous system lymphoma of the optic chiasm. Systemic treatment was initiated with full response. Six months after the end of the treatment, recurrence at cerebellum parenchyma and left tentorium was recorded. A new systemic treatment achieved full response. A second recurrence was noted in an optical coherence tomography of the right eye, 2 years after the initial diagnosis. The patient was treated with intravitreal methotrexate with initial success, but eventual failure after 10 months. Intravitreal rituximab was used with no effect. The patient was then referred to radiotherapy and underwent external beam radiotherapy with VMAT. There were no acute toxicities to report. After the radiotherapy treatment, at 1-year follow-up, the patient has no evidence of disease. Long-term toxicities were recorded and are considered manageable. The present case emphasizes the role of ocular irradiation as an option in the management of intraocular lymphoma patients, including in the salvage setting, with an acceptable ocular toxicity profile.\n\nKeywords\n\nIntraocular lymphoma\nPrimary central nervous system lymphoma\nRadiotherapy\n==== Body\nIntroduction\n\nAnterior visual pathway lymphoma can occur as a primary intraocular lymphoma (PIOL), as an intraocular lymphoma (IOL) associated with a primary central nervous system lymphoma (PCNSL) or as a secondary IOL which derives from a systemic lymphoma [1]. PIOL may present independently, prior or subsequent to central nervous system (CNS) involvement [2].\n\nThe incidence of PCNSL is 0.28% per 100,000 persons per year in immunocompetent patients [3, 4]. In these patients, ocular involvement occurs in 15–25% of cases, and 80% of these have bilateral involvement [5, 6].\n\nThe prognosis of IOL patients depends on the institution of dedicated ocular therapy in addition to PCNSL therapy; median progression-free survival (PFS) and overall survival (OS) are about 18 and 31 months, respectively. Median PFS was prolonged in patients who received dedicated ocular therapy at 19 months as compared to 15 months in those who did not receive dedicated ocular therapy. However, the addition of dedicated ocular therapy had no impact on OS [7].\n\nThe optimal treatment of PIOL has yet to be defined, mainly due to treatment data being limited to small studies and case reports.\n\nHere, we report a case of IOL derived from a PCNSL in an immunocompetent patient, resistant to treatment with intravitreal therapy methotrexate (MTX) and rituximab (RTX) that was successfully salvaged with radiation therapy.\n\nCase Report\n\nA 67-year-old woman presented with decreased vision in both eyes (greater loss in the left eye [LE]), bitemporal hemianopsia and fatigue, with no other symptoms or findings in February 2015. Her past medical history was unremarkable. A brain magnetic resonance imaging (MRI) revealed a mass in the optic chiasm, spreading along the left optic tract with homogenous contrast enhancement. Blood tests and cerebrospinal fluid (CSF) analysis were normal, and CSF cytology was negative for malignancy. Symptomatic therapy with corticosteroids was initiated achieving clinical resolution of the bitemporal hemianopsia and improving the LE best corrected visual acuity (BCVA) from 6/30 to 20/40. The patient underwent a transcranial biopsy of the left optical tract, and microscopic examination revealed a lymphoid cell infiltrate composed of predominantly medium to large cells with irregular hyperchromatic nuclei and scant cytoplasm in the background of smaller more monomorphic populations of lymphoid cells. Large cells were CD20+, small cells were CD3+. The malignant B-lymphocytes were MUM1+, BCL2+, CD10–, and BCL6–. The findings were compatible with diffuse large B-cell lymphoma of the CNS. CT scans of the chest, abdomen, and pelvis, PET-CT and bone marrow biopsy revealed no evidence of systemic lymphoma. Thus, the final diagnosis was of PCNSL of the optic chiasm.\n\nTreatment with R-MVP (five cycles), RTX (500 mg/m2), MTX (3,5 g/m2), procarbazine (100 mg/m2/day), and vincristine (1.4 mg/m2) was initiated in March 2015. After three cycles, the patient developed Pneumocystis pneumonia with the need of ventilatory support, and the treatment was stopped. A brain MRI showed full resolution of the chiasm lesion, and the patient was maintained in vigilance. In August 2015, a follow-up brain MRI showed an occipital periventricular lesion with contrast enhancement, and no signs of disease at the optic chiasm. No other evidence of disease was found. Treatment with R-MVP was re-initiated to a total of 5 cycles. In November 2015, a brain MRI showed imaging complete response and consolidation treatment (two cycles) with citarabine (3 g/m2/day) was initiated. The patient maintained imaging follow-up with no evidence of disease.\n\nIn July 2016, the patient presented with meningeal signs and headache; CSF analysis revealed a monoclonal B lymphocyte population (CD20+, CD5-) in 0.35% of the sample, and a brain MRI showed contrast enhancement compatible with active disease in the cerebellum parenchyma and left tentorium; no systemic disease was found.\n\nTherapy was initiated (5 cycles) with RTX (500 mg/m2), MTX (3.5 g/m2), and alternate weekly intra-CSF MTX (7.5 mg/m2). Complete remission was achieved in CSF and Brain MRI. RTX (500 mg/m2) was continued, and in January 2018, after the 10th cycle, there was no macroscopic evidence of disease (CSF, MRI, and PET scan).\n\nIn March 2018, the patient complained of photophobia and pain in the right eye (RE). The ophthalmologic examination revealed an anterior chamber cellular reaction (+2 Tyndall), vitritis, and a temporal yellow subretinal plaque on fundoscopy. An optical coherence tomography (OCT) was performed revealing retinal pigment epithelium (RPE) undulation, suggestive of subretinal cellular infiltration (shown in Fig. 1). RE panuveitis was diagnosed, and a vitreous biopsy was performed, revealing NHL B cells. No macroscopic disease was found on a brain and optic tract MRI. The patient continued RTX (500 mg/m2) until completion of 12 cycles and initiated intravitreal treatment with MTX (400 μg/0.1 mL) bi-weekly (8 cycles), then weekly (4 cycles), and then monthly.\n\nAfter the first two intravitreal injections, opthalmologic examination was negative for cellular inflammation in both anterior chamber and vitreous, and although the patient developed macular edema, evidence of subretinal infiltration was no longer visible in consecutive OCTs. In January 2019, after 10 monthly cycles of intravitreal therapy, a worsening in the control OCT with RPE undulation, indicated probable disease progression (with no macroscopic evidence on MRI), and the patient was proposed to receive 4 weekly cycles of intraocular RTX (1 mg/0.1 mL).\n\nIn April of 2019, patient's BCVA of the RE was 20/50 and LE 20/30 with no cellular anterior chamber reaction but with central vitritis (2+) at fundoscopy and RPE undulation showing no signs of improvement at the follow-up OCT. Because there was no evidence of clinical improvement after intravitreal treatment with RTX, the patient returned to weekly MTX intravitreal injections and was referred to radiotherapy. A new evaluation revealed no macroscopic evidence of disease (CSF and MRI). The patient underwent external beam radiotherapy with VMAT, a total of 24 Gy in 12 fractions was given to both eyes and the optic tract, a subsequent boost up to 36 Gy in 18 fractions was given to the RE, right optic nerve, chiasm, and right optic tract. There were no acute toxicities related to the treatment.\n\nAt 12 months of follow-up, there is no evidence of ocular recurrence (Fig. 2) and a brain MRI also showed no signs of disease. At the last ophthalmologic examination, as a probable consequence of radiotherapy, the patient presented with an RE diffuse superficial punctate keratitis that was managed with ocular lubricant. Her current RE BCVA is 20/100 and LE 20/25. Due to presence of a RE nuclear cataract and refractory macular edema, the patient is scheduled to have RE phacoemulsification surgery with a simultaneous injection of a sustained-release dexamethasone intravitreal implant (Ozurdex®).\n\nDiscussion\n\nGiven the rarity of IOL, there is a lack of prospective randomized trials that establish a standard therapy. Currently treatment is influenced by disease degree, CNS involvement, and the general performance status of patients [8]. Radiotherapy, chemotherapy, and intravitreal chemotherapy are all available, either used alone or in combination. Retrospective data seems to indicate that treatment of IOL, regardless of CNS involvement should include some form of local therapy, such as intraocular chemotherapy or ocular radiation as this increases disease-free survival in these patients [7].\n\nSome authors have recommended high-dose intravenous MTX, but doubts remain around the concentration of MTX in the anterior chamber due to the limited penetration of systemic chemotherapy into the eye due to the existence of blood-ocular barriers [9]. As an alternative, intravitreal chemotherapy with MTX is nowadays widely used with most reports and case series showing prolonged remission with maintenance of visual function and minimal complications from the injections [1, 10, 11]. MTX can also be used in combination with other medications, such as thiotepa and dexamethasone [1]. Recent reports indicate that the combination of systemic high-dose MTX with intravitreal MTX is associated with a CNS disease-free survival at 2 years of 58.3%, although polychemotherapy is also associated with higher drug toxicity [1, 11]. Intravitreal chemotherapy with 0.4 mg MTX in 0.1 mL, has thus been used in persistent IOL [12]. But drug resistance can arise with prolonged use, as it has probably happened in this case. As an alternative to intravitreous MTX, intravitreal RTX has been used, either to decrease the frequency of treatments with MTX or in MTX-resistant patients [13].\n\nOcular irradiation has been widely used in IOL, with or without concomitant prophylactic CNS treatment, and doses ranging from 30 to 50 Gy have been reported with rapid improvement of patient's symptoms [1, 9]. Exclusive ocular irradiation toxicities include radiation retinopathy, vitreous hemorrhage, dry eye syndrome, conjunctivitis, neovascular glaucoma, optic atrophy, punctate epithelial erosions, and cataract [1].\n\nIn this case, the patient had PCNSL with multiple relapses, treated with systemic chemotherapy. The last relapse was an IOL with no other evidence of disease. Given the favorable toxicities profile, intravitreous MTX therapy was initiated with initial success, but eventual failure. RTX was used as the ocular disease appeared to be MTX resistant, but with no evidence of clinical improvement. The patient was then referred to radiotherapy, with good results in local control, no evidence of disease present in the follow-up examinations and manageable toxicities. The dose used in this patient, up to 36 Gy, is well below the Quantec limits of 55 Gy (<3% of probability of optic neuropathy) for the optical pathways and chiasma, and well below the limits for brain parenchyma of 60 Gy (<3% of probability of radionecrosis) [14].\n\nAlthough other systemic and intravitreal therapies are associated with less toxicity and should be considered as a first line of treatment, ocular irradiation should be regarded as an option in the management of IOL patients, including in the salvage setting, with an acceptable ocular toxicity profile.\n\nStatement of Ethics\n\nThe patient in question has given written informed consent for the publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNo funding was solicited for this case report.\n\nAuthor Contributions\n\nRaul Colaço − intern that followed the case during the radiotherapy treatment, drafting of the case report. Mariana Portela − intern that followed the case during the ophthalmological treatment, drafting of the case report. Marta Guedes − medical consultant in ophthalmology who followed the case in ophthalmology, revised the case report. António Mota − medical consultant in radiotherapy who followed the case in radiotherapy, revised the case report.\n\nFig. 1 Ocular OCT after failure with MTX intravitreal injections. Arrowheads point to nodular hyperreflective signals that may indicate lymphomatous infiltrates. RPE disruption has developed into small pigment epithelial detachments.\n\nFig. 2 Ocular OCT after radiotherapy. No subretinal infiltration is present.\n==== Refs\nReferences\n\n1 Tang LJ Gu CL Zhang P Intraocular lymphoma Int J Ophthalmol Aug 2017 10 (8) 1301 28861359\n2 Coupland SE Heimann H Bechrakis NE Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features Graefes Arch Clin Exp Ophthalmol 2004 242 (11) 901 13 15565454\n3 Behin A Hoang-Xuan K Carpentier AF Delattre JY Primary brain tumours in adults Lancet 2003 361 (9354) 323 31 12559880\n4 Cote TR Manns A Hardy CR Yellin FJ Hartge P Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome AIDS/Cancer Study Group J Natl Cancer Inst May 15 1996 88 (10) 675 9 8627644\n5 Levy-Clarke GA Chan CC Nussenblatt RB Diagnosis and management of primary intraocular lymphoma Hematol Oncol Clin North Am 2005 19 (4) 739 viii 16083834\n6 Freeman LN Schachat AP Knox DL Michels RG Green WR Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma Ophthalmology 1987 94 (12) 1631 9 3323986\n7 Grimm SA McCannel CA Omuro AM Ferreri AJ Blay JY Neuwelt EA Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report Neurology 2008 71 (17) 1355 60 18936428\n8 Sagoo MS Mehta H Swampillai AJ Cohen VM Amin SZ Plowman PN Primary intraocular lymphoma Surv Ophthalmol 2014 59 (5) 503 16 24560125\n9 Isobe K Ejima Y Tokumaru S Treatment of primary intraocular lymphoma with radiation therapy: a multi-institutional survey in Japan. Leuk Lymphoma Sep 2006 47 (9) 1800 5\n10 Fishburne BC Wilson DJ Rosenbaum JT Neuwelt EA Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma Arch Ophthalmol 1997 115 (9) 1152 6 9298056\n11 Akiyama H Takase H Kubo F Miki T Yamamoto M Tomita M High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma Cancer Sci 2016 107 (10) 1458 64 27412324\n12 Wang JK Yang CM Lin CP Shan YD Lo AY Tien HF An Asian patient with intraocular lymphoma treated by intravitreal methotrexate Jpn J Ophthalmol 2006 Sep 50 (5) 474 8 17013703\n13 Fu BD Alexandruy D Curticiu D Kong XT Bota DA The use of intravitreal rituximab in conjunction with systemic temozolomide and intravenous rituximab for the treatment of primary intraocular lymphoma Hematol Leuk 2013 1 1\n14 Mayo C Martel MK Marks LB Flickinger J Nam J Kirkpatrick J Radiation dose-volume effects of optic nerves and chiasm Int J Radiat Oncol Biol Phys 2010 76 (3 Suppl l) S28 35 20171514\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "14(1)",
"journal": "Case reports in oncology",
"keywords": "Intraocular lymphoma; Primary central nervous system lymphoma; Radiotherapy",
"medline_ta": "Case Rep Oncol",
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"pages": "184-189",
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"title": "Radiotherapy as Salvage Treatment in Intraocular Lymphoma: A Case Report.",
"title_normalized": "radiotherapy as salvage treatment in intraocular lymphoma a case report"
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"abstract": "Gram-positive cocci species, notably Staphylococcus, Streptococcus, and Enterococcus account for 80 to 90% of infective endocarditis cases. HACEK microorganisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) account for approximately 3% of cases and Candida species account for 1-2% of cases. Micrococcus luteus is a rare cause of endocarditis. To our knowledge, only 17 cases of prosthetic valve endocarditis have been described due to M. luteus and a single case of native aortic valve endocarditis has been described. The following case is the only documented case of native mitral valve endocarditis. A review of the literature pertaining to Micrococcus endocarditis was performed to further characterize the entity.",
"affiliations": "State University of New York Upstate University Hospital, USA.;State University of New York Upstate University Hospital, USA.;State University of New York Upstate University Hospital, USA.",
"authors": "Khan|Alisha|A|https://orcid.org/0000-0001-5379-6645;Aung|Thu Thu|TT|;Chaudhuri|Debanik|D|",
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"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2019/5907319Case ReportThe First Case of Native Mitral Valve Endocarditis due to Micrococcus luteus and Review of the Literature https://orcid.org/0000-0001-5379-6645Khan Alisha khanali@upstate.eduAung Thu Thu Chaudhuri Debanik State University of New York Upstate University Hospital, USAAcademic Editor: Expedito E. Ribeiro\n\n2019 4 12 2019 2019 590731913 7 2019 16 9 2019 16 11 2019 Copyright © 2019 Alisha Khan et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Gram-positive cocci species, notably Staphylococcus, Streptococcus, and Enterococcus account for 80 to 90% of infective endocarditis cases. HACEK microorganisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) account for approximately 3% of cases and Candida species account for 1-2% of cases. Micrococcus luteus is a rare cause of endocarditis. To our knowledge, only 17 cases of prosthetic valve endocarditis have been described due to M. luteus and a single case of native aortic valve endocarditis has been described. The following case is the only documented case of native mitral valve endocarditis. A review of the literature pertaining to Micrococcus endocarditis was performed to further characterize the entity.\n==== Body\n1. Case Presentation\nA 67-year-old gentleman presented to our hospital with complaints of dyspnea and orthopnea. His past medical history included diabetes, hypertension, three cerebrovascular accidents, peripheral vascular disease status post right below knee amputation (BKA), and moderate-to-severe mitral valve insufficiency. He was admitted with acute on chronic diastolic heart failure and was started on a bumetanide infusion. Of note, the patient's BKA was three months prior to admission and was complicated by bacteremia and sepsis.\n\nOn admission, his vital signs were stable and within normal limits. He was intermittently noted to be tachypneic with his respiratory rate reaching 26 breaths per minute. Physical examination was remarkable for jugular venous distention, grade 4/6 systolic murmur best heard at the mitral position, decreased lung breath sounds at the bases, and trace pedal edema. Complete blood count and comprehensive metabolic panel laboratory values were within normal limits. Pro b-type natriuretic peptide level was elevated at 5309 pg/mL. Two sets of blood cultures showed no growth at 5 days. Chest radiograph revealed large bilateral pleural effusions. Transthoracic echocardiogram revealed prolapse of the anterior mitral leaflet with moderate-to-severe mitral regurgitation, hyperdynamic left ventricular (LV) systolic function with an ejection fraction between 65 and 70%, no evidence of vegetation, and an estimated pulmonary artery systolic pressure of 71 mmHg with moderate-to-severe tricuspid regurgitation. Preoperative left heart catheterization showed 80-90% stenosis of the diagonal artery and elevated left ventricular diastolic pressure. Snapshot hemodynamic recordings of the aortic pressure revealed 109/70 mmHg (mean 86 mmHg), whereas the left ventricle measured 110/11 mmHg (mean 27 mmHg).\n\nThe patient was diuresed over several days with partial relief of his respiratory symptoms. Cardiac catheterization showed occlusion of one of the diagonal branches that was not amenable to endovascular intervention. The cardiothoracic surgery team evaluated the patient for replacement of his mitral valve. He was brought to the operating room where he underwent cardiopulmonary bypass and had his native mitral valve replaced with a 29-Medtronic Mosaic porcine bioprosthetic valve. Upon visual inspection, the native mitral valve was found to have fibrinopurulent exudate on the anterior and posterior leaflets. Surgical tissue cultures of the excised mitral valve grew Micrococcus luteus. Surgical pathology of the excised valve showed acute endocarditis with focal necrosis. Antibiotic susceptibility testing revealed that the Micrococcus luteus was sensitive to vancomycin, clindamycin, erythromycin, and penicillin. Replacement of his mitral valve and concurrent diuresis resulted in significant symptomatic and echocardiographic findings. Transthoracic echocardiogram performed approximately one week following valve replacement showed resolution of the mitral and tricuspid regurgitation as well as normalization of the pulmonary artery systolic pressure, indicating that the initial derangements noted on the echocardiogram were likely dynamic changes resulting from the mitral regurgitation. Ejection fraction at this time was noted to be 60-65%.\n\nThe patient was initially treated with empiric antibiotics including vancomycin, gentamicin, and rifampin. However, the patient developed acute kidney injury due to acute tubular necrosis from vancomycin and gentamicin and was subsequently transitioned to rifampin 300 mg by mouth every 12 hours and daptomycin 8 mg/kg intravenously every 48 hours at 100 mL/hour over 30 minutes to complete his treatment course for a total of six weeks of antibiotics. The patient was subsequently discharged to cardiac rehabilitation while receiving a total of six weeks of intravenous antibiotics to treat for endocarditis from the date of his mitral valve replacement.\n\nSince treatment for his infective endocarditis, the patient's bioprosthetic valve appeared to have been functioning well for several months. However, approximately nine months after replacement, he was diagnosed with end-stage renal disease. Due to the associated fluid overload, his most recent echocardiogram shows that he has recurrent moderate mitral valve regurgitation; however, the prosthetic valve is well seated and does not rock. He is currently undergoing preparation for hemodialysis.\n\n2. Discussion\n\nMicrococcus species are Gram-positive, catalase-positive, oxidase-positive, nonmotile, and nonspore-forming cocci that comprise oropharyngeal and skin flora and rarely cause disease [1]. In fact, M. luteus used to be considered a nonpathogenic saprophyte or pure contaminant.\n\n\nMicrococcus species, along with coagulase negative-staphylococci, viridans group streptococci, Propionibacterium acnes, Corynebacterium spp., and Bacillus spp., are the microorganisms the College of American Pathologists considers to be the most common blood culture contaminants when isolated from one out of two or three blood sets [2, 3]. However, in rare circumstances, Micrococcus spp. may be the causative organism for infectious diseases such as endocarditis. The first documented disease due to the organism was septic shock in 1978, when it was simultaneously recovered from a patient's blood cultures and gallbladder isolate [4]. In our case, the patient's diagnosis of infective endocarditis was confirmed by histology of the surgical specimen and the presence of new valvular regurgitation, according to the Modified Duke Infective Endocarditis Criteria.\n\nThe five species in the Micrococcus genus include M. luteus, M. lylae, M. antarcticus, M. endophyticus, and M. flavus. Micrococcus luteus is an obligate aerobe and has one of the smallest genomes of free-living actinobacteria sequenced to date, comprised of a single circular chromosome of 2,501,097 base pairs encoding 2,403 proteins [5].\n\n\nM. luteus is a rare cause of endocarditis. Although low in virulence and usually sensitive to penicillin, it may colonize the surface of heart valves in immunosuppressed patients [1]. It has now been proposed as the pathogenic organism responsible for bacteremia, ventriculitis, peritonitis, pneumonia, endophthalmitis, keratolysis, and septic arthritis in isolated case reports [6].\n\nIn November 2018, a case of bacteremia due to Micrococcus luteus was described in an immunocompromised patient with a central venous catheter [7]. In December 2018, M. luteus was found to be the cause of a brain abscess in an immunocompromised patient with systemic lupus erythematosus who was being treated with immunosuppressive therapy for lupus nephritis [8]. Our patient's uncontrolled diabetes mellitus, with an HbA1c level of 7.4% on admission appears to have been his only known predisposing factor for immunosuppression, which would make him more susceptible to infection with a low virulence organism such as M. luteus.\n\nIn a review of the literature published by Miltiadous and Elisaf in 2011, only 17 cases of native valve endocarditis secondary to M. luteus had been reported and all involved prosthetic valves. A single case of native aortic valve endocarditis due to M. luteus has been described in an immunosuppressed patient [9]. To our knowledge, there are no case reports describing isolated native mitral valve endocarditis due to M. luteus.\n\nWe suspect that our patient became bacteremic with M. luteus during his BKA surgery three months prior to admission. Interestingly, in the case of native aortic valve endocarditis described by Miltiadous and Elisaf, the authors presumed that orthopedic surgery (total knee replacement) three weeks prior to admission was the source of bacteremia [9]. This supports the theory that in order for low virulence organisms such as M. luteus to become pathogenic and cause serious and invasive infections such as endocarditis, a significant bacterial load is required.\n\nDue to the rarity of this microorganism as a cause for infective endocarditis, the optimal therapeutic regimen remains undefined. Of note, in the case of native aortic valve endocarditis secondary to M. luteus mentioned above, a treatment regimen consisting of vancomycin, gentamicin, and rifampicin for four weeks was not successful and the patient ultimately required aortic valve replacement [9]. Our patient who was treated with rifampin and daptomycin in addition to mitral valve replacement appears to have been successfully treated thus far.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\n1 Durst U. N. Bruder E. Egloff L. Wust J. Schneider J. Hirzel H. O. Micrococcus luteus: a rare pathogen of valve prosthesis endocarditis Zeitschrift fur Kardiologie 1991 80 4 294 298 1862670 \n2 Dargere S. Cormier H. Verdon R. Contaminants in blood cultures: importance, implications, interpretation and prevention Clinical Microbiology and Infection 2018 24 9 964 969 10.1016/j.cmi.2018.03.030 2-s2.0-85046731875 29621616 \n3 Alcorn K. Meier F. Schifman R. Blood Culture Contamination. Q-Tracks 2013 Monitor Instructions 2013 Northfield, IL College of American Pathologists \n4 Albertson D. Natsios G. A. Gleckman R. Septic shock with Micrococcus luteus Archives of Internal Medicine 1978 138 3 487 488 629642 \n5 Young M. Artsatbanov V. Beller H. R. Genome sequence of the Fleming strain of Micrococcus luteus, a simple free-living actinobacterium Journal of bacteriology 2010 192 3 841 860 10.1128/JB.01254-09 2-s2.0-75149189598 19948807 \n6 von Eiff C. Kuhn N. Herrmann M. Weber S. Peters G. Micrococcus luteus as a cause of recurrent bacteremia The Pediatric Infectious Disease Journal 1996 15 8 711 713 10.1097/00006454-199608000-00019 2-s2.0-0029829069 8858680 \n7 Guerra J. M. M. Asenjo M. M. Martín C. R. Bacteriemia por Microccocus luteus en un paciente inmunodeprimido Medicina Clínica 2019 152 11 469 470 10.1016/j.medcli.2018.09.011 30502303 \n8 Erbasan F. Brain abscess caused by Micrococcus luteus in a patient with systemic lupus erythematosus: case-based review Rheumatology International 2018 38 12 2323 2328 10.1007/s00296-018-4182-2 2-s2.0-85055987233 30374688 \n9 Miltiadous G. Elisaf M. Native valve endocarditis due to Micrococcus luteus: a case report and review of the literature Journal of Medical Case Reports 2011 5 1, article 1611 p. 251 10.1186/1752-1947-5-251 2-s2.0-79959643069\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2019()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "5907319",
"pmc": null,
"pmid": "31885931",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "629642;21714882;19948807;8858680;30374688;29621616;1862670;30502303",
"title": "The First Case of Native Mitral Valve Endocarditis due to Micrococcus luteus and Review of the Literature.",
"title_normalized": "the first case of native mitral valve endocarditis due to micrococcus luteus and review of the literature"
} | [
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"companynumb": "US-BAUSCH-BL-2020-002221",
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... |
{
"abstract": "BACKGROUND\nThe aim of this study was to establish the feasibility of using computed tomography (CT) in a multicenter setting to assess structural airway changes.\n\n\nMETHODS\nThis was a 12-week, randomized, double-blind, placebo-controlled, Phase IIb trial using CT to investigate the effect of a novel, oral, reversible neutrophil elastase inhibitor, AZD9668 60 mg twice daily (BID), on structural airway changes in patients aged 50-80 years with chronic obstructive pulmonary disease (COPD) (ex-smokers).\n\n\nMETHODS\nairway wall thickness at an extrapolated interior perimeter of 10 mm (AWT-Pi10). Secondary outcome variables: fifth-generation wall area %; air trapping index; pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1); morning and evening peak expiratory flow and FEV1; body plethysmography; EXAcerbations of Chronic pulmonary disease Tool (EXACT); Breathlessness, Cough, and Sputum Scale (BCSS); St George's Respiratory Questionnaire for COPD; and proportion of reliever-medication-free trial days. Safety variables were also assessed.\n\n\nRESULTS\nThere was no difference between placebo (n = 19) and AZD9668 (n = 17) for AWT-Pi10 at treatment end. This was consistent with results for most secondary variables. However, patients randomized to AZD9668 experienced an improvement versus placebo for morning and evening FEV1, and EXACT and BCSS cough and sputum scores. AZD9668 60 mg BID was well tolerated and no new safety concerns were identified.\n\n\nCONCLUSIONS\nThis study confirmed the feasibility of using CT to assess structural airway changes in COPD. However, there was no evidence of improvements in CT structural measures following 12 weeks' treatment with AZD9668 60 mg BID.\n\n\nBACKGROUND\nAstraZeneca.",
"affiliations": "AstraZeneca R&D, Mölndal, Sweden, Lars.Nordenmark@astrazeneca.com.",
"authors": "Nordenmark|Lars H|LH|;Taylor|Rosemary|R|;Jorup|Carin|C|",
"chemical_list": "D001993:Bronchodilator Agents; D011728:Pyridones; D013450:Sulfones; C568080:N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-015-0215-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "32(6)",
"journal": "Advances in therapy",
"keywords": null,
"medline_ta": "Adv Ther",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling; D001993:Bronchodilator Agents; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D011728:Pyridones; D035845:Research Embryo Creation; D013450:Sulfones; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "548-66",
"pmc": null,
"pmid": "26043724",
"pubdate": "2015-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Feasibility of Computed Tomography in a Multicenter COPD Trial: A Study of the Effect of AZD9668 on Structural Airway Changes.",
"title_normalized": "feasibility of computed tomography in a multicenter copd trial a study of the effect of azd9668 on structural airway changes"
} | [
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"companynumb": "SE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-46176GD",
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"activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE"
... |
{
"abstract": "The FDA-approved schedule and dose of bevacizumab (BVZ) for recurrent glioblastoma (rGB) (10 mg/kg q 2 weeks) were adopted from systemic cancer protocols. No dose-defining studies have been performed for glioblastoma. We began using BVZ for the treatment of rGB in 2005 at the dose of 5 mg/kg every 2 weeks combined with irinotecan, and later as single agent. Our previous report of 20 patients treated with BVZ 5 mg/kg every 2 weeks showed similar response rates and overall survival (OS) compared to other BVZ treatment protocols, with less adverse effects. In this study we retrospectively reviewed our 7 year experience with BVZ in 162 rGB patients. Treatment outcomes were analyzed from 87 patients who received BVZ at 5 mg/kg and 75 patients at 10 mg/kg. While median age was similar in both groups, the median KPS was significantly higher in the group treated with 10 mg/kg BVZ (85 versus 60). There was no significant difference in OS or progression free survival (PFS) between the groups treated with BVZ 5 versus 10 mg/kg. Overall survival was significantly improved in the subgroup treated with cytotoxic therapy in addition to BVZ 10 mg/kg. There were more adverse events seen with BVZ 10 mg/kg. There is no significant difference in OS for rGB treated with BVZ 5 mg/kg versus 10 mg/kg when given as monotherapy. The smaller dose was slightly less toxic. Addition of cytotoxic therapy resulted in prolongation of OS in a small subgroup of BVZ 10 mg/kg.",
"affiliations": "Neuro-Oncology Service, Division of Oncology, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., 64239, Tel-Aviv, Israel. deborahblumenthal@gmail.com.;Omnistat Statistical Consulting, Tel-Aviv, Israel.;Neuro-Oncology Service, Division of Oncology, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., 64239, Tel-Aviv, Israel.",
"authors": "Blumenthal|D T|DT|;Mendel|L|L|;Bokstein|F|F|",
"chemical_list": "D000068258:Bevacizumab; D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-015-2025-5",
"fulltext": null,
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"issn_linking": "0167-594X",
"issue": "127(3)",
"journal": "Journal of neuro-oncology",
"keywords": "Bevacizumab; Chemotherapy; Dose; Glioblastoma; Recurrent; Regimen; Standard; Toxicity",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D002166:Camptothecin; D016190:Carboplatin; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "493-502",
"pmc": null,
"pmid": "26721244",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "21865314;22586694;25943888;25557543;18421054;19114704;20061402;17602060;18205003;15169807;24637997;25575937;19720927;25035291;18156031;19406901;12890841;22722713;17405901;12506171;18327820;21464145;21789143;20159801;15758009",
"title": "The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter?",
"title_normalized": "the optimal regimen of bevacizumab for recurrent glioblastoma does dose matter"
} | [
{
"companynumb": "IL-ROCHE-1692936",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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{
"abstract": "Hepatitis C virus (HCV) infection is associated with a variety of glomerular diseases, most notably cryoglobulin associated membranoproliferative glomerulonephritis Type I. Focal segmental glomerulosclerosis has only rarely been reported in association with HCV. More striking are multiple reports of de novo collapsing focal segmental glomerulosclerosis (cFSGS) developing during administration of interferon for treatment of HCV. Herein is presented a case of HCV associated cFSGS stabilized with combination therapy of interferon α-2a and ribavirin in a patient with advanced kidney disease.",
"affiliations": null,
"authors": "Sperati|C John|CJ|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN107337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "80(3)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000998:Antiviral Agents; D001706:Biopsy; D004359:Drug Therapy, Combination; D005923:Glomerulosclerosis, Focal Segmental; D006526:Hepatitis C; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "231-4",
"pmc": null,
"pmid": "22541681",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stabilization of hepatitis C associated collapsing focal segmental glomerulosclerosis with interferon alpha-2a and ribavirin.",
"title_normalized": "stabilization of hepatitis c associated collapsing focal segmental glomerulosclerosis with interferon alpha 2a and ribavirin"
} | [
{
"companynumb": "PHHY2013US125203",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "2",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
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"drugadditional": null,
"druga... |
{
"abstract": "We measured the serial changes in N-terminal probrain natriuretic peptide (NT-proBNP) levels in a 6-month-old male infant with chronic lung disease (CLD) complicated by pulmonary arterial hypertension (PAH). The patient was born at the 24th week of gestation weighing 695 g. At 1 month after birth, an echocardiogram confirmed the diagnosis of CLD with PAH. He was treated with inhaled nitric oxide (iNO) and oral sildenafil and discharged from the hospital. At 190 days of age, the patient was readmitted to our department because of a viral upper respiratory infection. At 195 days of age, his respiratory condition worsened with pulmonary edema and his NT-proBNP level was determined to be 10,117 pg/mL. The patient was immediately administered iNO, and his respiratory condition improved, and NT-proBNP levels decreased. However, he experienced repeated severe cyanosis attacks. Before the attacks, his NT-proBNP level was > 1,000 pg/mL. Therefore, we continuously administered iNO until his NT-proBNP level decreased to < 1,000 pg/mL. We safely discontinued iNO administration at 473 days of age. In conclusion, serial change in NT-proBNP is a surrogate marker with prognostic value in patients with PAH associated with CLD.",
"affiliations": "Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.",
"authors": "Seki|Keigo|K|;Iwashima|Satoru|S|;Uchiyama|Hiroki|H|;Ohishi|Akira|A|;Ishikawa|Takamichi|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0039-1684026",
"fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0039-1684026180062Case ReportSuccessful Management of Pulmonary Arterial Hypertension by Monitoring N-Terminal Pro-B-Type Natriuretic Peptide Serum Levels in a Preterm Infant with Chronic Lung Disease: A Case Report Seki Keigo MD1Iwashima Satoru PhD1Uchiyama Hiroki MD1Ohishi Akira PhD1Ishikawa Takamichi PhD11 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, JapanAddress for correspondence Satoru Iwashima, MD Department of Pediatrics, Chutoen General Medical CenterSyoubugauraike 1-1, Kakegawa City, 436-8555Japaniwashima3617@gmail.com4 2019 09 4 2019 9 2 e133 e137 05 11 2018 24 2 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.We measured the serial changes in N-terminal probrain natriuretic peptide (NT-proBNP) levels in a 6-month-old male infant with chronic lung disease (CLD) complicated by pulmonary arterial hypertension (PAH). The patient was born at the 24th week of gestation weighing 695 g. At 1 month after birth, an echocardiogram confirmed the diagnosis of CLD with PAH. He was treated with inhaled nitric oxide (iNO) and oral sildenafil and discharged from the hospital. At 190 days of age, the patient was readmitted to our department because of a viral upper respiratory infection. At 195 days of age, his respiratory condition worsened with pulmonary edema and his NT-proBNP level was determined to be 10,117 pg/mL. The patient was immediately administered iNO, and his respiratory condition improved, and NT-proBNP levels decreased. However, he experienced repeated severe cyanosis attacks. Before the attacks, his NT-proBNP level was > 1,000 pg/mL. Therefore, we continuously administered iNO until his NT-proBNP level decreased to < 1,000 pg/mL. We safely discontinued iNO administration at 473 days of age. In conclusion, serial change in NT-proBNP is a surrogate marker with prognostic value in patients with PAH associated with CLD.\n\nKeywords\nNT-proBNPbronchopulmonary dysplasiachronic lung diseasepulmonary arterial hypertensiontracheobronchomalaciaFunding\nEquipment provided by the Hamamatsu University School of Medicine was used. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. If the article is accepted for publication, the disclosure statement may be published. This study has no sponsor. This is a case report. The decision to submit the manuscript for publication was made by Satoru Iwashima. The author who wrote the first draft of the manuscript is Satoru Iwashima. There was no honorarium, grant, or other form of payment made to produce this manuscript.\n==== Body\nPulmonary arterial hypertension (PAH) complicates the course of chronic lung disease (CLD) in newborns and contributes to later morbidity and mortality during infancy, especially in the context of bronchopulmonary dysplasia (BPD). Earlier studies showed that patients with CLD and later-onset PAH represent a very high-risk population that exhibits increased morbidity and mortality.\n1\nAmong infants with BPD, 20 to 40% develop PAH at some point during their initial hospital course, and PAH is an important risk factor for mortality in this population.\n2\n3\nEchocardiography is often used both to screen for and monitor the progression of PAH in infants with BPD. However, it has been reported that echocardiographic screening at 28 days of life fails to identify many late-developing cases of PAH in extremely low–birth-weight infants.\n4\nThere are many causes for failed or late diagnosis of PAH in CLD, such as poor imaging due to over-inflation caused by CLD, the complexities of evaluating PAH by echocardiography, and dramatic changes in the hemodynamic status of PAH in CLD due to the patient's unstable respiratory condition. Recently, N-terminal probrain natriuretic peptide (NT-proBNP) levels and BNP levels have been useful in screening for PAH in preterm infants with CLD who are at risk for death.\n5\n6\nHowever, few studies have elucidated the changes in NT-proBNP levels over time in CLD complicated by PAH. In this report, we determined the serial changes in NT-proBNP levels in a 6-month-old male infant with CLD complicated by PAH.\n\n\nPatient Report\n\nThe patient's mother was referred to our department for premature rupture of the membranes at the 24th week of gestation. An emergency cesarean section was required because of oligohydramnios and indications of fetal distress. The patient's birth weight was 695 g and his Apgar's scores were 3 and 7 at 1 and 5 minutes, respectively. The patient was immediately intubated with surfactant and admitted to our newborn intensive care unit. His respiratory condition was poor and he could not be weaned from mechanical ventilator support. One month after birth, an X-ray examination was performed, and the patient was diagnosed with CLD. His oxygenation level was poor. An echocardiogram revealed no congenital heart disease, but PAH was observed with right atrial enlargement, right ventricular dilation, and septal flattening (\nFig. 1\n). He was treated with inhaled nitric oxide (iNO), oral sildenafil, diuretics, and intravenous and inhaled steroids. Progressive improvement in his respiratory condition led to subsequent extubation and, at 169 days of age, his weight had increased to 2,568 g. At this time, the patient was discharged and prescribed supplemental oxygen (1.0 L/min by nasal cannula). At 190 days of age, he was readmitted to our department due to a viral upper respiratory infection. At 195 days of age, his respiratory condition and oxygenation level worsened and he developed pulmonary edema. His peripheral capillary oxygen saturation (SpO\n2\n) was 67% and he developed cardiopulmonary arrest. We immediately performed successful cardiopulmonary resuscitation. His clinical course is shown in\nFig. 2\n. His laboratory findings were: white blood cells, 10,070/µL; C-reactive protein level, 0.03 mg/dL; and NT-proBNP level, 10,117 pg/mL, as indicated by an Elecsys 2010 analyzer with a chemiluminescent immunoassay kit (Roche Diagnostics, Mannheim, Germany). The protocol for this assay has been previously described.\n7\nWe could not determine the NT-proBNP levels during his stay in the neonatal intensive care unit because echocardiography performed after he was treated with iNO, oral sildenafil, and diuretics showed improvement of the characteristic PAH signs (right atrial enlargement, right ventricular dilation, and septal flattening). After his condition stabilized, we continued the administration of iNO, catecholamines, and epoprostenol and measured his NT-proBNP levels two to three times per week. His SpO\n2\nlevel increased and his respiratory condition improved after treatment, with the levels of NT-proBNP decreasing to 1,201 pg/mL at 197 days of age. However, echocardiography indicated that his PAH did not improve; therefore, we added oral bosentan and tadalafil to his treatment regimen and, at 201 days of age, we were able to discontinue the iNO. We were not able to wean the patient from mechanical ventilator support and we transported him to another institution to perform a tracheotomy while maintaining oral bosentan and tadalafil. During his stay at the other institution, there were no episodes of pulmonary hypertension. After the tracheotomy was performed, we performed a bronchoscopy and confirmed a diagnosis of tracheobronchomalacia. High positive-end expiratory pressure (PEEP) therapy was started for the tracheobronchomalacia and the patient's respiratory condition was improved. We then started to wean him from mechanical ventilator support. At the age of approximately 300 days, when the PEEP setting was decreased from 7 to 6 mm Hg, the patient's NT-proBNP level slightly increased to 1,171 pg/mL at 308 days of age.\n\n\nFig. 1 \nEchocardiography (aortic valve short axis image). Observation of flattening of the ventricular septum.\n\n\nFig. 2 \nSerial change in NT-proBNP level and the patient's clinical course. Over the course of treatment, there were six instances during which the NT-proBNP levels increased, of which three instances were associated with severe cyanosis attacks. iNO, inhaled nitric oxide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SpO\n2\n, oxygen saturation of peripheral artery.\n\n\nHowever, at 323 days of age, he suddenly experienced a severe cyanosis attack (after crying), and the suspected cause was PAH or uncontrolled tracheobronchomalacia. Cardiopulmonary resuscitation was initiated and iNO, catecholamines, and epoprostenol were administered. High PEEP therapy was performed for tracheobronchomalacia which was difficult to control. Furthermore, the patient experienced repeated severe cyanosis attacks at 427 days of age after ending iNO therapy. His NT-proBNP levels were slightly increased and were always > 1,000 pg/mL when tracheobronchomalacia was hard to manage and he exhibited unstable respiratory conditions. We continued to administer iNO even when the NT-proBNP values were < 1,000 pg/mL. At 454 days of age, the patient's NT-proBNP value had slightly increased and we suspected the re-emergence of an unstable respiratory condition due to tracheobronchomalacia. After we maintained 10 mm Hg PEEP, his NT-proBNP level decreased. He was subsequently weaned from iNO therapy and his medication was changed from bosentan to ambrisentan. Subsequently, his NT-proBNP values decreased to < 1,000 pg/mL and iNO therapy was stopped at 473 days of age. His respiratory condition, which was caused by tracheobronchomalacia, gradually stabilized and high PEEP therapy was reduced. When the patient was 2 years and 2 months of age, we performed cardiac catheterization. His mean pulmonary arterial pressure was 24 mm Hg and, under treatment with tadalafil and ambrisentan, there was no evidence of PAH. Furthermore, at 2 years and 4 months of age, his NT-proBNP value was 350 pg/mL. He was discharged with a home respiratory machine, supplemental oxygen, and ongoing treatment with tadalafil and ambrisentan. After discharge, these therapies will be carefully tapered since infants with CLD have increased risks of mortality due to respiratory failure, unremitting pulmonary hypertension with cor pulmonale, or acquired infection (pneumonia or sepsis).\n\nDiscussion\nWe determined the serial changes in NT-proBNP levels in a 6-month-old male infant with CLD complicated by PAH retrospectively. Our patient experienced five cyanotic attacks, including two requiring CPA. Before his severe cyanotic attacks developed, the NT-proBNP levels were nearly always slightly increased to > 1,000 pg/mL. The elevated NT-proBNP was a cause of one CPA, while the others might have been due to the PAH. When we failed to wean him off the iNO therapy for PAH twice, his NT-proBNP levels were unstable and exceeded 1,000 pg/mL. Hence, we decided to maintain the iNO therapy until the NT-proBNP dropped to less than 1000 pg/mL after which the iNO was successfully stopped.\n\n\nNT-proBNP is the precursor of brain natriuretic peptide. This peptide is released from the myocardial tissue of the right and left ventricles when stretched. NT-proBNP is helpful in diagnosing heart failure; however, it does not distinguish between left or right ventricular failure. In the present case, NT-proBNP levels increased with hemodynamic changes associated with PAH and respiratory instability. NT-proBNP and BNP are two different types of peptides but, as reported previously, there is a strong correlation between NT-proBNP and BNP levels during childhood.\n8\nIt is also possible that the measurement results of these peptides reflect the time lag between the time of specimen collection and measurement. Since NT-proBNP has a longer half-life (70 minutes) than atrial NP (12 minutes) or BNP (15 minutes),\n9\nit is likely less influenced by stress on the heart just prior to blood collection. In adults, NT-proBNP correlates with right ventricle function in PAH and has been shown to be of prognostic value in PAH.\n10\n11\nIn the present case, the serial changes in NT-proBNP levels were observed to correlate with the patient's respiratory condition and the hemodynamic changes associated with PAH. While no optimal cut-off value of NT-proBNP, such as 1,000 pg/mL, has been determined, Cuna et al previously reported that a BNP value of > 220 pg/mL might serve as a prognostic marker of all-cause mortality in extremely low-birth-weight infants with BPD-associated PAH.\n12\nSugimoto et al\n8\nreported a strong correlation between BNP and NT-proBNP levels, where NT-proBNP = 9.080 × BNP\n0.923\n. We speculated that at a threshold of approximately 2000 pg/mL, NT-proBNP might serve as a prognostic indicator, and that our patient̀s level (< 1000 pg/dL) might be a safe level at which to control the CLD complicated by PAH. We speculated that the serial changes in NT-proBNP levels observed in this case were associated with the patient's PAH with CLD. Furthermore, high levels of NT-proBNP might be useful in predicting the risk of severe cyanotic attacks.\n\n\n\nEchocardiography is often used both to screen for and to monitor the progression of PAH in infants with CLD. Right ventricular structural or functional abnormalities, as determined by an echocardiogram, are used as indirect indicators of PAH, including septal flattening, right atrial enlargement, right ventricular hypertrophy, dilation, and decreased function. Certain quantitative echocardiographic parameters used to screen for PAH, such as tricuspid annular plane systolic excursion, tricuspid regurgitant jet velocity, and/or pulmonary systolic time intervals, are supported by the 2015 guidelines from the American Heart Association.\n13\nHowever, these parameters have not been validated in preterm infants. There are several causes for failed or late diagnosis of PH in CLD, such as poor electrocardiogram quality due to CLD-induced over-inflation, as in the present case. While an echocardiogram obtained upon admission revealed severe PAH, as indicated by right atrial enlargement, right ventricular dilation, and septal flattening, we were unable to confirm PAH using echocardiography due to the unstable respiratory conditions and high PEEP therapy. Recently, consensus recommendations for the care of children with bronchopulmonary dysplasia-PAH\n14\nwere published. Serial NT-proBNP levels may be useful in monitoring disease progression/regression and response to therapy and in modulating decision making, but these biomarkers should be used in conjunction with echocardiography rather than in isolation. We suggest that NT-proBNP level may be a useful biochemical marker in predicting the presence of PAH in CLD infants.\n\n\n\nTracheobronchomalacia is an acquired complication of BPD and is more common in infants and children with classic BPD who are treated with prolonged positive pressure ventilation. Tracheobronchomalacia is characterized by abnormally compliant, collapsible central airways and may be associated with barotrauma, chronic or recurrent infection, chronic aspiration, and endotracheal intubation. Tracheobronchomalacia can improve with age, as the tracheal cartilage matures and becomes less compliant.\n15\nOur patient was diagnosed with tracheobronchomalacia after undergoing a tracheotomy. After this diagnosis, he experienced at least two severe cyanotic attacks induced by PAH. Interestingly, tracheobronchomalacia is easily inducible by PAH, which requires long-term control by a respiratory machine that in turn, sometimes induces unstable respiratory conditions, such as desaturation, hypercapnia, and apneic attack.\n\n\nConclusion\nIn conclusion, serial changes in NT-proBNP levels can serve as a surrogate marker in place of an electrocardiogram. These changes have been shown to have good prognostic value in patients with PAH associated with CLD. Patients who exhibit higher and unstable levels of NT-proBNP might be developing a serious respiratory and hemodynamic condition. As a result, PAH with CLD should be evaluated carefully and the therapeutic strategy used should be mindful of potential complications, such as tracheobronchomalacia.\n\nAcknowledgments\nThe authors thank Shigeo Iijima and for their valuable assistance in the treatment of the patients admitted to the Maternal–Fetal and Neonatal Care Center or the Department of Pediatrics at Hamamatsu University School of Medicine.\n\nConflicts of Interest The authors of this manuscript do not have any potential, perceived, or real conflicts of interest, including any financial arrangement to disclose.\n==== Refs\nReferences\n1 Khemani E McElhinney D B Rhein L Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era Pediatrics 2007 120 06 1260 1269 18055675 \n2 Slaughter J L Pakrashi T Jones D E South A P Shah T A Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation J Perinatol 2011 31 10 635 640 21311503 \n3 Check J Gotteiner N Liu X Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia J Perinatol 2013 33 07 553 557 23328924 \n4 Bhat R Salas A A Foster C Carlo W A Ambalavanan N Prospective analysis of pulmonary hypertension in extremely low birth weight infants Pediatrics 2012 129 03 e682 e689 22311993 \n5 Kalra V K Aggarwal S Arora P Natarajan G B-type natriuretic peptide levels in preterm neonates with bronchopulmonary dysplasia: a marker of severity? Pediatr Pulmonol 2014 49 11 1106 1111 24214578 \n6 Joseph L Nir A Hammerman C Goldberg S Ben Shalom E Picard E N-terminal pro-B-type natriuretic peptide as a marker of bronchopulmonary dysplasia in premature infants Am J Perinatol 2010 27 05 381 386 20013606 \n7 Collinson P O Barnes S C Gaze D C Galasko G Lahiri A Senior R Analytical performance of the N terminal pro B type natriuretic peptide (NT-proBNP) assay on the Elecsys 1010 and 2010 analysers Eur J Heart Fail 2004 6 03 365 368 14987590 \n8 Sugimoto M Manabe H Nakau K The role of N-terminal pro-B-type natriuretic peptide in the diagnosis of congestive heart failure in children. - Correlation with the heart failure score and comparison with B-type natriuretic peptide - Circ J 2010 74 05 998 1005 20378998 \n9 Pemberton C J Johnson M L Yandle T G Espiner E A Deconvolution analysis of cardiac natriuretic peptides during acute volume overload Hypertension 2000 36 03 355 359 10988264 \n10 Leuchte H H Baumgartner R A Nounou M E Brain natriuretic peptide is a prognostic parameter in chronic lung disease Am J Respir Crit Care Med 2006 173 07 744 750 16415273 \n11 Fijalkowska A Kurzyna M Torbicki A Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension Chest 2006 129 05 1313 1321 16685024 \n12 Cuna A Kandasamy J Sims B B-type natriuretic peptide and mortality in extremely low birth weight infants with pulmonary hypertension: a retrospective cohort analysis BMC Pediatr 2014 14 68 24612708 \n13 Abman S H Hansmann G Archer S L Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society Circulation 2015 132 21 2037 2099 26534956 \n14 Krishnan U Feinstein J A Adatia I Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia J Pediatr 2017 188 24 340 28645441 \n15 Shaffer T H Bhutani V K Wolfson M R Penn R B Tran N N In vivo mechanical properties of the developing airway Pediatr Res 1989 25 02 143 146 2919128\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2157-7005",
"issue": "9(2)",
"journal": "AJP reports",
"keywords": "NT-proBNP; bronchopulmonary dysplasia; chronic lung disease; pulmonary arterial hypertension; tracheobronchomalacia",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "e133-e137",
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"pmid": "30972228",
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"title": "Successful Management of Pulmonary Arterial Hypertension by Monitoring N-Terminal Pro-B-Type Natriuretic Peptide Serum Levels in a Preterm Infant with Chronic Lung Disease: A Case Report.",
"title_normalized": "successful management of pulmonary arterial hypertension by monitoring n terminal pro b type natriuretic peptide serum levels in a preterm infant with chronic lung disease a case report"
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"abstract": "Genetic variants of the neuronal nicotinic acetylcholine receptor (nAChR) cause autosomal dominant sleep-related hypermotor epilepsy. Approximately 30% of autosomal dominant sleep-related hypermotor epilepsy patients are medically intractable. In preclinical models, pathogenic nAChR variants cause a gain of function mutation with sensitivity to acetylcholine antagonists and agonists. Nicotine modifies the activity of nAChRs and can be used as targeted therapy.\n\n\n\nWe reviewed next-generation sequencing epilepsy panels from a single laboratory (GeneDx) from patients at Children's Medical Center Dallas between 2011 and 2015 and identified patients with nAChR variants. Retrospective review of records included variant details, medical history, neuroimaging findings, and treatment history.\n\n\n\nTwenty-one patients were identified. Four patients were prescribed nicotine patches for intractable seizures. Three of 4 patients had a clinical response, with >50% seizure reduction.\n\n\n\nTreatment with a nicotine patch can be an effective therapy in epilepsy patients with nAChR gene variants. We propose consideration of transdermal nicotine treatment in intractable epilepsy with known nAChR variants as an experimental therapy. Further clinical trials are needed to fully define therapeutic effects.",
"affiliations": "Barrow Neurological Institute at 14524Phoenix Children's Hospital, Phoenix, AZ, USA.;14480Driscoll Children's Hospital, Corpus Christi, TX, USA.;196285University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.",
"authors": "Fox|Jordana|J|0000-0003-4113-3814;Thodeson|Drew M|DM|;Dolce|Alison M|AM|",
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"journal": "Journal of child neurology",
"keywords": "acetylcholine nicotinic receptors; autosomal dominant nocturnal frontal lobe epilepsy; autosomal dominant sleep-related hypermotor epilepsy; genetic; nicotine",
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"publication_types": "D016428:Journal Article",
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"title": "Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants.",
"title_normalized": "nicotine a targeted therapy for epilepsy due to nachr gene variants"
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"abstract": "Background and study aims For early esophageal adenocarcinoma, endoscopic resection is an accepted curative treatment with an excellent long-term prognosis. Case series from Japan have reported endoscopic resection of residual esophageal squamous cell carcinoma after chemoradiotherapy. This is the first report describing endoscopic resection of residual esophageal adenocarcinoma after chemoradiotherapy. Two patients with advanced esophageal adenocarcinoma had been treated with chemoradiotherapy because comorbidity precluded esophageal resection. When residual tumor was observed endoscopically, complete remission was achieved by salvage endoscopic therapy alone or in combination with argon plasma coagulation (APC). Both patients achieved long-term sustained remission and died of non-tumor-related causes.",
"affiliations": "Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands.;Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands.;PAMM (laboratory of Pathology and Medical Microbiology), Eindhoven, the Netherlands.;Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands.;Department of Oncology, Catharina Hospital, Eindhoven, the Netherlands.;Department of Radiation Oncology, Catharina Hospital, Eindhoven, the Netherlands.;Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands.",
"authors": "Noordzij|Irma C|IC|;Curvers|Wouter L|WL|;Huysentruyt|Clément J|CJ|;Nieuwenhuijzen|Grard A P|GAP|;Creemers|Geert-Jan|GJ|;van der Sangen|Maurice J C|MJC|;Schoon|Erik J|EJ|",
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"fulltext": "\n==== Front\nEndosc Int OpenEndosc Int Open10.1055/s-00025476Endoscopy International Open2364-37222196-9736© Georg Thieme Verlag KG Stuttgart · New York 10.1055/a-0599-6008Case reportSalvage endoscopic resection in patients with esophageal adenocarcinoma after chemoradiotherapy Noordzij Irma C. 1Curvers Wouter L. 1Huysentruyt Clément J. 2Nieuwenhuijzen Grard A.P. 3Creemers Geert-Jan 4van der Sangen Maurice J.C. 5Schoon Erik J. 11 Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands2 PAMM (laboratory of Pathology and Medical Microbiology), Eindhoven, the Netherlands3 Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands4 Department of Oncology, Catharina Hospital, Eindhoven, the Netherlands5 Department of Radiation Oncology, Catharina Hospital, Eindhoven, the NetherlandsCorresponding author E.J. Schoon, MD, PhD, Gastroenterologist Department of Gastroenterology and HepatologyCatharina HospitalMichelangelolaan 2, 5623 EJEindhovenThe Netherlands+3140-239 97 51erik.schoon@catharinaziekenhuis.nl9 2018 11 9 2018 6 9 E1126 E1129 19 9 2017 \naccepted after revision\n02 2 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground and study aims\n For early esophageal adenocarcinoma, endoscopic resection is an accepted curative treatment with an excellent long-term prognosis. Case series from Japan have reported endoscopic resection of residual esophageal squamous cell carcinoma after chemoradiotherapy. This is the first report describing endoscopic resection of residual esophageal adenocarcinoma after chemoradiotherapy. Two patients with advanced esophageal adenocarcinoma had been treated with chemoradiotherapy because comorbidity precluded esophageal resection. When residual tumor was observed endoscopically, complete remission was achieved by salvage endoscopic therapy alone or in combination with argon plasma coagulation (APC). Both patients achieved long-term sustained remission and died of non-tumor-related causes.\n==== Body\nIntroduction\n\nEsophageal adenocarcinoma is the fastest increasing type of cancer in the western world\n1\n. Endoscopic resection is an effective treatment for early esophageal adenocarcinoma with an excellent long-term prognosis\n2\n. For advanced cases, the preferred curative treatment is neoadjuvant chemoradiotherapy (CRT) followed by esophageal resection. In patients who are unfit for surgery, definitive CRT is an alternative, but local failure after definitive CRT at the primary site remains a significant problem\n3\n.\n\n\n\nIn case series from Japan, salvage endoscopic resection of residual cancer after definitive CRT has been reported in esophageal squamous cell carcinoma\n3\n4\n5\n. Yano et al reported a local failure rate of 34 % in patients treated with definitive CRT after diagnosis of squamous cell carcinoma of the esophagus. Because of the high local recurrence rate for squamous cell carcinomas, curative local control is crucial and salvage endoscopic resection provides a therapeutic option with curative intent\n3\n5\n. Reports of curative treatment with salvage endoscopic resection of recurrent or residual squamous cell carcinoma after definitive CRT have been described, however to date, curative treatment with salvage endoscopic resection in cases of residual adenocarcinoma after CRT has not been reported. The only reported case of endoscopic resection after neoadjuvant chemotherapy was described with a submucosal invasive adenocarcinoma with concomitant distant metastases\n6\n.\n\n\nThis is the first report describing salvage endoscopic resection of esophageal adenocarcinoma after CRT in two patients with residual tumour.\n\nCase reports\nWe present two patients with an advanced esophageal adenocarcinoma who had been treated with CRT because they were considered “not fit for surgery” due to comorbidity and/or complications during treatment.\n\nPatient 1\n\nA 68-year-old male patient with obstructive pulmonary disease GOLD III (Global initiative for chronic obstructive lung disease, stage III [30 % ≤ FEV\n1\n < 50 % predicted]) presented with dysphagia. At endoscopy active reflux esophagitis was observed in the presence of a lesion suspicious for malignancy. Pathology showed a moderately differentiated adenocarcinoma. Endoscopic ultrasonography (EUS) revealed a tumor invading the muscularis propria with no signs of lymph node metastases. Subsequent computed tomography (CT) showed no distant metastases (cT2N0M0). Our multidisciplinary team proposed treating the patient with neoadjuvant CRT followed by esophageal resection and reconstruction. Chemoradiation consisted of radiotherapy with a total dose of 41.4 Gy in 23 fractions of 1.8 Gy, 5 fractions per week and concurrent chemotherapy of 5 weekly administrations of carboplatin (AUC [area under the curve] 2 and paclitaxel 50 mg/m\n2\n).\n\n\nShortly after finishing the neoadjuvant CRT, the patient developed massive pulmonary embolism and a pneumothorax. Due to these complications after neoadjuvant CRT and his preexisting comorbidity, he was no longer considered suitable for esophageal resection.\n\n\nFour months after the neoadjuvant CRT treatment, endoscopy revealed a minimal residual Paris type IIa lesion of about 5 mm in a short Barrett segment (\nFig. 1a\n). We did not perform EUS, but the tumor invasion and lateral margins were very well judged endoscopically, based on extensive clinical experience. Biopsies confirmed residual adenocarcinoma. Subsequently, the lesion was removed by salvage endoscopic resection in one single resection using the multi-band mucosectomy device (MBM, Cook, Ireland) (\nFig. 1b\n). The resected specimen showed a moderately differentiated adenocarcinoma invading the muscularis mucosa without lymphovascular invasion and a free vertical resection margin (R0 resection) (\nFig. 1c\n). During follow-up, a second endoscopic resection was performed on residual Barrett mucosa at the level of the Z-line containing high-grade dysplasia. During subsequent endoscopy, the residual Barrett mucosa was treated with radiofrequency ablation (Halo 90, Barrx, Sunnyvale, California, United States).\n\n\nFig. 1 \n Endoscopic images of salvage ER for residual adenocarcinoma after definitive CRT in a 68-year-old male.\na\nDelineation of the residual Paris type IIA lesion by coagulation markers.\nb\nWound resection after salvage ER.\nc\nHistopathological evaluation of the specimen showed a radically resected adenocarcinoma infiltrating the muscularis mucosae (ypT1m3), R0 resection.\nd\nAt long-term follow-up, the neosquamocolumnar junction in the same area looked normal 3 years after salvage ER.\n\n\n\nEndoscopic and radiologic follow-up by means of a CT scan was performed once every 3 months in the first year after endoscopic resection, once every 6 months in the second year, and once a year in the subsequent years. During this subsequent follow-up there were no signs of metastases, and complete remission of cancer and intestinal type dysplasia sustained for 35 months (\nFig. 1d\n).\n\n\nThe patient died 3 years and 10 months after achieving complete remission due to respiratory failure, which was unrelated to the primary esophageal carcinoma.\n\nPatient 2\n\nA 78-year-old male patient with a history of myocardial infarction presented with pain in the epigastric region and weight loss. Endoscopy showed a suspicious lesion with a length of 3 cm at the gastroesophageal junction (GEJ) (\nFig. 2\n), and subsequent biopsies revealed a moderately differentiated adenocarcinoma. EUS and CT scan demonstrated a tumor invading the muscularis propria with no signs of lymph node metastases or distant metastases (cT2N0M0).\n\n\nFig. 2 \n Endoscopic image of primary lesion before definitive CRT in a 78-year-old male.\n\n\nOur multidisciplinary team decided to treat the patient with definitive CRT because of frailty. In case of incomplete response to restaging, a subsequent esophageal resection could be considered.\n\n\nThe treatment consisted of a total radiation dose of 50.4 Gy in 28 fractions of 1.8 Gy, 5 fractions per week and concurrent chemotherapy with 6 weekly intravenous administrations of carboplatin (AUC and paclitaxel 50 mg/m\n2\n). Due to grade 3 thrombopenia, only four of six intended chemotherapy cycles were given. Furthermore, definitive CRT was complicated by post-irradiation pneumonitis. Five months after the end of definitive CRT, endoscopic response evaluation revealed a histologically proven residual adenocarcinoma Paris IIa type lesion at the GEJ without signs of distant metastases. The residual tumor was removed by means of salvage endoscopic resection using the multiband mucosectomy technique (MBM, Cook, Ireland) combined with argon plasma coagulation (APC) in the center of the lesion due to local non-lifting. Pathology showed a poorly differentiated adenocarcinoma invading the muscularis mucosa without lymphovascular invasion and doubtful vertical resection margins (R1). In three consecutive endoscopies, histological remnants of adenocarcinoma were found in biopsies of the scar and treated with APC, which eventually resulted in a complete endoscopic remission.\n\n\nSubsequently, the follow-up was similar to that in Patient 1. Complete endoscopic and histological remission of cancer sustained for 37 months. CT scan 1 year after endoscopic resection presented no signs of metastases. Three years and 8 months after achieving complete remission, the patient died of massive intracerebral hemorrhage, a non-tumor-related cause.\n\nDiscussion\nThis is the first report describing endoscopic resection salvage treatment of residual adenocarcinoma after CRT. Two patients with an initial cT2N0M0 adenocarcinoma of the distal esophagus were treated with CRT. After CRT, both patients were considered “unfit for surgery” due to comorbidity or persistent physical impairment after CRT. In both cases, complete remission could be achieved by means of salvage endoscopic resection of the residual tumor alone or in combination with APC. Sustained clinical remission was achieved in both patients. Endoscopic treatment was uncomplicated.\n\n\nState-of-the-art treatment in the Netherlands for surgically resectable locally advanced esophageal or GEJ carcinoma is neoadjuvant CRT followed by a subsequent esophagectomy\n7\n.\nDefinitive CRT is regarded as first-choice treatment with curative intent for unresectable esophageal cancer or for patients unfit for surgery. Although CRT has shown a high response rate, local failure with recurrence or residual tumor is common\n3\n8\n. Shapiro et al showed that 76 % (56/74) of patients with esophageal adenocarcinoma had residual tumor cells after neoadjuvant CRT\n8\n, however, definitive CRT is more intensive treatment.\n\n\n\nThis report demonstrates that curative treatment with salvage endoscopic resection after CRT in patients with esophageal carcinoma is feasible. Salvage endoscopic resection could be considered in patients with limited residual superficial cancer in the esophagus and no signs of systemic dissemination. Furthermore, the lesion should be suitable for endoscopic resection, and an R0 resection should be pursued. Esophageal adenocarcinomas are mostly associated with Barrett’s metaplasia or dysplasia. Neoadjuvant or definitive CRT, however, does not eradicate Barrett’s epithelium esophagus. In addition, patients with persisting (dysplastic) Barrett’s epithelium are at potential risk for developing metachronous neoplastic lesions. Therefore, most esophageal adenocarcinoma recurrences arise in the persisting (dysplastic) Barrett’s epithelium\n9\nand are not visible on CT scan. Additional endoscopic surveillance and treatment of residual Barrett’s dysplasia after CRT, therefore, should be considered.\n\n\n\nSystematic endoscopic follow-up after treatment with definitive CRT in patients unfit for surgery is unusual in the Netherlands. The ongoing preSANO (Surgery As Needed for Oesophageal cancer) study evaluates the accuracy of detecting the presence or absence of residual disease after neoadjuvant CRT\n10\n.\nShapiro et al. showed that neoadjuvant CRT induces non-random and concentric regression of esophageal cancer within the esophageal wall towards the lumen. In patients (63/71) with residual disease, the tumor lesions were most commonly present in the mucosa, the submucosa or both. This suggests a possible preferential persistence of malignant cells in the mucosa or submucosa after neoadjuvant CRT\n8\n, which could therefore potentially be suitable for endoscopic therapy.\n\n\n\nFor patients who are unfit for surgery but fit enough for systematic sedated endoscopy, long-term follow-up after CRT could be considered since local control could be achieved by means of salvage endoscopic resection of small remnant or recurrent tumours in the absence of lymph node metastases. However, salvage endoscopic resection may be hampered by development of submucosal fibrosis and destruction of the esophageal wall layers after CRT\n11\n. In the future, an alternative endoscopic treatment for residual or recurrent esophageal carcinoma could be endoscopic submucosal dissection (ESD). In addition, ESD could facilitate R0 resection in larger lesions.\n\n\nConclusion\nIn conclusion, this report suggests that salvage endoscopic resection after CRT could potentially be a curative treatment for residual adenocarcinoma after CRT in selected patients who are unfit for surgery.\n\nCompeting interests None\n==== Refs\nReferences\n1 Pohl H Sirovich B Welch H G Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer Epidemiol Biomarkers Prev 2010 19 1468 1470 20501776 \n2 Ell C May A Pech O Curative endoscopic resection of early esophageal adenocarcinomas (Barrett's cancer) Gastrointest Endosc 2007 65 3 10 17185072 \n3 Yano T Muto M Hattori S Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma Endoscopy 2008 40 717 721 18773340 \n4 Takeuchi M Kobayashi M Hashimoto S Salvage endoscopic submucosal dissection in patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma Scand J Gastroenterol 2013 48 1095 1101 23906093 \n5 Hatogai K Yano T Kojima T Local efficacy and survival outcome of salvage endoscopic therapy for local recurrent lesions after definitive chemoradiotherapy for esophageal cancer Radiat Oncol 2016 11 31 26922374 \n6 Nakatani K Tanabe S Koizumi W Successful treatment of S-1 + CDDP followed by salvage EMR for a case with metastatic Barrett's esophageal cancer Dis Esophagus 2007 20 173 177 17439603 \n7 Shapiro J van Lanschot J J Hulshof M C Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial Lancet Oncol 2015 16 1090 1098 26254683 \n8 Shapiro J ten Kate F J van Hagen P Residual esophageal cancer after neoadjuvant chemoradiotherapy frequently involves the mucosa and submucosa Ann Surg 2013 258 678 688 24096766 \n9 Theisen J Stein H J Dittler H J Preoperative chemotherapy unmasks underlying Barrett's mucosa in patients with adenocarcinoma of the distal esophagus Surg Endosc 2002 16 671 673 11972212 \n10 Noordman B J Shapiro J Spaander M C Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol JMIR Res Protoc 2015 4 e79 26121676 \n11 Shapiro J Wijnhoven B P van Lanschot J J Reply to Letter: \"Residual esophageal cancer after neoadjuvant chemoradiotherapy frequently involves the mucosa and submucosa\" Ann Surg 2015 262 e84 e85 24743617\n\n",
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"title": "Salvage endoscopic resection in patients with esophageal adenocarcinoma after chemoradiotherapy.",
"title_normalized": "salvage endoscopic resection in patients with esophageal adenocarcinoma after chemoradiotherapy"
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"abstract": "Spontaneous Bacterial Empyema (SBEM) denotes infection of the pleural fluid in the absence of pneumonia. Almost all cases of SBEM in literature are described in a background of ascites secondary to cirrhosis. Contiguous spread of the infected ascitic fluid through defects in the diaphragm is the most likely mechanism of SBEM. Most of these cases are transudative in nature and are managed with antibiotics. Literature on SBEM in the absence of cirrhosis or ascites is very limited so far. We describe a 59 year old female with ESRD status post renal transplant, on chronic immunosuppression for renal allograft rejection who was admitted with pleuritic chest pain that turned to be secondary to right sided pleural effusion. Further evaluation revealed Escherichia coli in both the blood and pleural fluid. There was no clinical or imaging evidence of pneumonia as well as cirrhosis or ascites. She was managed as a case of SBEM requiring drainage by chest tube. Management of SBEM in non-cirrhotic individuals usually requires drainage with chest tube as against patients with liver cirrhosis with hepatic hydro-thorax in whom chest tube drainage is contraindicated for risk of massive protein and electrolyte depletion and dehydration.",
"affiliations": "Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, 07740, USA.;Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, 07740, USA.;Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, 07740, USA.",
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"doi": "10.1016/j.rmcr.2016.06.008",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30052-110.1016/j.rmcr.2016.06.008Case ReportSpontaneous bacterial empyema in a non cirrhotic end stage renal disease patient with immunosuppression Lourdusamy Dennis drdennisdhilak@gmail.com∗Munshi Lubna B. Eltawansy Sherif Ali Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, 07740, USA∗ Corresponding author. drdennisdhilak@gmail.com27 6 2016 2016 27 6 2016 19 34 36 11 10 2015 19 6 2016 22 6 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Spontaneous Bacterial Empyema (SBEM) denotes infection of the pleural fluid in the absence of pneumonia. Almost all cases of SBEM in literature are described in a background of ascites secondary to cirrhosis. Contiguous spread of the infected ascitic fluid through defects in the diaphragm is the most likely mechanism of SBEM. Most of these cases are transudative in nature and are managed with antibiotics. Literature on SBEM in the absence of cirrhosis or ascites is very limited so far. We describe a 59 year old female with ESRD status post renal transplant, on chronic immunosuppression for renal allograft rejection who was admitted with pleuritic chest pain that turned to be secondary to right sided pleural effusion. Further evaluation revealed Escherichia coli in both the blood and pleural fluid. There was no clinical or imaging evidence of pneumonia as well as cirrhosis or ascites. She was managed as a case of SBEM requiring drainage by chest tube. Management of SBEM in non-cirrhotic individuals usually requires drainage with chest tube as against patients with liver cirrhosis with hepatic hydro-thorax in whom chest tube drainage is contraindicated for risk of massive protein and electrolyte depletion and dehydration.\n\nKeywords\nSBEMPleural fluidESRD\n==== Body\n1 Case presentation\nA 59 year old Caucasian female was admitted with complaints of sharp right sided chest pain aggravated with deep inspiration, and low grade fever of one day duration. There were no associated symptoms of cough, palpitations or shortness of breath.\n\nHer past medical history was significant for ESRD secondary to chronic glomerulonephritis, status post renal transplant (1995) with chronic allo-graft rejection on immunosuppression for several years with regular intake of mycophenolate mofetil, and prednisone. She has been dialysis independent post-transplant, except for one time emergency dialysis about 6 months prior to this admission when she presented with acute kidney injury secondary to dehydration from diarrhea. At that time she had a temporary dialysis catheter placed into the right internal jugular vein that was removed later. Patient had no history alcohol abuse. Vitals signs were normal apart tachypnea. Oxygen saturation was adequate in room air. Systemic examination revealed dullness over the right lung field from middle zone to base, with decreased breath sounds. Bilateral pitting pedal edema was also seen. Abdomen was soft and non-distended with no shifting dullness. There was no palpable Organomegaly. Chest x ray showed blunting of the Right costo-phrenic angle consistent with effusion. Initial laboratory work showed blood count with leukocyte count of 6900·9/L with 68% neutrophils and 30% lymphocytes. Blood chemistry showed normal electrolytes, BUN 32.85 mmol urea/L, Creatinine 540 μmol/L (baseline Creatinine 257.14–342.85 μmol/L). Liver function test showed AST 13Unit/L, ALT 7Unit/L, ALP 86 Unit/L, Total protein 55 g/L, albumin 29.14 g/L. Serum LDH was 210 Int Unit/L. ESR (Erythrocyte Sedimentation Rate and CRP (C-reactive Protein) levels, initially on admission were elevated at 107 mm/hr and 147.4 mg/dl respectively. Blood cultures were positive for gram negative rods from two different sites, later identified as Escherichia coli. Urine analysis and culture was negative for Urinary Tract Infection. The patient was initially started on intravenous meropenem for broad spectrum coverage (as she was allergic to penicillin/fluoro-quinolone), with renal dose adjustment, which was later changed to ertapenem as per microbiological sensitivity pattern of the culture. All immunosuppressive medications were stopped with the exception of prednisone.\n\nShe underwent right sided thoracentesis on the same day of admission and 500 cc of cloudy fluid was withdrawn. Pleural fluid analysis was consistent with exudative characteristics (Table 1), and the culture of the exudate was positive for Escherichia coli. ESR and CRP levels trended down on day 3 of admission after the initiation of intravenous antibiotics and thoracentesis. ESR decreased from 107 to 93 mm/hr and CRP from 147.4 to 79.6 mg/dl. However serial ESR/CRP measures were not done as the patient was already showing clinical improvement with appropriate management.\n\nCT scan of the Chest was done after thoracentesis (Fig. 1) for any source of infection, and to assess for chest tube drainage.\n\nCT scan showed bilateral moderate-sized pleural effusion, with right side more than left side. There was no parenchymal disease or features of consolidation on the CT chest. CT scan of the upper abdomen showed normal liver and spleen characteristics with bilateral atrophic kidneys. No ascites was noted on the CT scan of the abdomen. Echocardiogram done 5 months prior to the admission showed normal ejection fraction (>70%), with mild concentric left ventricular hypertrophy. There was no wall motion abnormality.\n\nThe patient ultimately had a chest tube drain placed on the right side of the chest to drain the empyema. Chest tube was removed after one week, and intravenous antibiotics were given for a total duration of 8 days. The patient showed clinical improvement, with negative repeat blood cultures. She was transitioned to oral trimethoprim-sulfamethoxazole upon discharge. A permanent catheter was inserted into the Left Internal Jugular Vein for the possible need for long term dialysis. She required 4 sessions of hemodialysis during this admission, and was referred for outpatient hemodialysis upon discharge as she had progressive renal failure.\n\n2 Discussion\nInfection of the pleural fluid in the absence of pneumonia is a rare event. It is usually denoted by the term Spontaneous bacterial Empyema (SBEM). SBEM criteria include transudative pleural fluid in the absence of pulmonary source of infection, with polymorphs> 500 cell/mm 3 or positive pleural fluid culture [1]. Several cases of spontaneous bacterial empyema have been described in the past. Almost all cases described in literature are seen in patients with ascites secondary to liver cirrhosis [1], [2], [3], [4], [5]. Lower levels of complement C3 (with resultant lower opsonic activity) in the pleural fluid of patients with hepatic hydrothorax and a higher Child-Pugh score are considered to be contributing factors for SBEM [3], [5], [6]. In a recently published article in CHEST (May, 2015) it was proposed that the term “secondary pleuritis of cirrhosis” be used instead of SBEM as it is not a spontaneous event and is usually due to migration of the infected peritoneal fluid through the defects in the diaphragm [3]. In our case report, we describe a case of spontaneous empyema which occurred in the absence of ascites or liver cirrhosis.\n\n2.1 SBEM in a background of liver cirrhosis\nOccurrence of SBEM in cirrhotic patients is well established in literature. In a large prospective study on SBEM which included 120 cirrhotic patients with hydrothorax, about 13% developed SBEM [4]. In majority of the cases (>50%), SBEM was associated with Spontaneous Bacterial Peritonitis (SBP) [1], [3], [4]. In a retrospective study involving 11 cases of SBEM in cirrhotic patients by Xiol et al., [1] in four out of the six cases with culture positive empyema, the same organism was grown in both ascitic and pleural culture. Most commonly isolated bacteria from SBEM in cirrhotic patients include Escherichia coli, enterococcus and klebsiella species, suggesting Gastro Intestinal source [1], [2], [4]. This again emphasizes the concept of migration of the infected ascitic fluid as a cause of the empyema. However literature on SBEM in non-cirrhotic/ascitic patients is very limited.\n\n2.2 Empyema in chronic kidney disease/end stage renal disease\nIn a retrospective analysis of empyema cases in 124 patients with either CKD Stage 4 or ESRD, an infective source was identified in over 82% of the cases, with pneumonia and catheter based infections occupying the top 2 causes [7]. In the same study, it was found that empyema culture in patients with ESRD showed a predominance of aerobic gram-positive organisms (54%), while in CKD stage 4 patients, aerobic gram-negative organisms (67%) were the predominant isolates. They described that the predominance of gram positive infection in ESRD patients was secondary to the dialysis catheter. We could not find any source of infection in our patient, and she did not have any dialysis catheter upon presentation to the hospital. The last time she had any central venous catheter was 6 months prior to this admission for emergency dialysis, and it was removed immediately after the dialysis.\n\nIncidence of SBEM in non-cirrhotic individuals is very rare. Upon review of literature, we found only few cases of spontaneous empyema reported in the absence of ascites or liver cirrhosis [8], [9] In the case report by Chen et al. [8]\nEscherichia coli and Aeromonas hydrophila were isolated in the pleural fluid, and blood. Hematogenous spread was coming from transient bacteremia from Gastrointestinal tract was thought to be the mechanism of the spontaneous empyema. Nguyen et al. [9] reported a case of spontaneous empyema from streptococcal pneumonia bacteremia in a patient with uncontrolled Diabetes Mellitus and Dialysis dependent renal disease [9]. In both these instances the patients were non cirrhotic and had no ascites. Immuno-compromised state is thought to be contributing factor in both these cases. Both of these patients required management by chest tube thoracostomy.\n\nIn our patient, there was no evidence of cirrhosis or ascites or pneumonia based on clinical findings and imaging. The pleural effusion was thought secondary to fluid overload status from ESRD. The pleural fluid was infected with Escherichia coli, and it was exudative in nature based on Light’s LDH criteria (pleural LDH: serum LDH (ratio was 2.07). The protein content in the pleural fluid was <2 g/dl and the pleural fluid protein: serum protein (ratio) was <0.36. Her risk factors for infection included immunosuppressive agents for the history of allograft transplantation. The most likely explanation for Escherichia coli bacteremia is translocation from Gastrointestinal tract, and the mechanism of infection of pleural fluid is through hematogenous spread. From the above explanation, our patient represents a unique case, where the infection of the pleural fluid is spontaneous (not contiguous with peritoneal fluid infection, absence of pneumonia). We therefore suggest that as stated in the recent article in CHEST [2], the term “secondary pleuritis of cirrhosis” could be used for those cases of non-pneumonia empyema associated with cirrhosis, while the term “spontaneous bacterial empyema” could be used to refer these rare cases of infected pleural fluid, in the absence of pneumonia or liver cirrhosis with ascites.\n\nManagement of SBEM has to be individualized on case to case basis. As most of the cases of SBEM associated with liver cirrhosis are transudative in nature [2], [4], [5], antibiotic treatment is the preferred approach. Also chest tube drainage is contraindicated in hepatic hydrothorax due to concerns of fluid and protein loss and electrolyte imbalance which can be life threatening [10], [11]. However, as in our case where SBEM is not secondary to liver cirrhosis with ascites and if consistent with Light’s exudative criteria, it has to be managed similar to empyema secondary to pneumonia and a chest tube thoracostomy is warranted.\n\n2.3 Conclusion\nWe report a case of empyema that occurred spontaneously with no preceding pneumonia or associated liver cirrhosis and ascites. That is considered to be of rare incidence. The presence of co-existent immune-suppression is usually expected in spontaneous bacterial empyema.\n\nDisclosure\nNo conflict of interest regarding that case report.\n\nFig. 1 CT Chest post thoracentesis showing bilateral pleural effusion, right more than left side.\n\nTable 1 Pleural fluid characteristics.\n\nAppearance\tYellow, hazy\t\nPH\t7.28\t\nGlucose\t4.54 mmol/L\t\nProtein\t<20 g/L\t\nWBC\t51,450·9/L\t\nNeutrophils\t95%\t\nLDHa\t436 Int Unit/L\t\nCulture\tEscherichia coli\t\nLDH-Lactate Dehydrogenase.\n\na Meets Light’s criteria for exudative pleural effusion (Pleural fluid LDH/Serum LDH-2.07).\n==== Refs\nReferences\n1 Xiol X. Castellote J. Baliellas C. Ariza J. Roca A. Gimenez Guardiola J. Casais L. Spontaneous bacterial empyema in cirrhotic patients: analysis of eleven cases Hepatology 11 3 1990 Mar 365 370 2179097 \n2 Nguyen T.A. Liendo C. Owens M.W. COUNTERPOINT: does spontaneous bacterial empyema occur? no Chest 147 5 2015 May 1 1208 1210 25940246 \n3 Chen T.A. Lo G.H. Lai K.H. Risk factors for spontaneous bacterial empyema in cirrhotic patients with hydrothorax J. Chin. Med. Assoc. 66 10 2003 Oct 579 586 14703274 \n4 Xiol X. Castellví J.M. Guardiola J. Sesé E. Castellote J. Perelló A. Cervantes X. Iborra M.J. Spontaneous bacterial empyema in cirrhotic patients: a prospective study Hepatology 23 4 1996 Apr 719 723 8666323 \n5 Mansour A. El-Rahman A. Besheer T. Prevalence and risk factors for spontaneous bacterial pleuritis in cirrhotic patients with hydrothorax Egyptial J. Chest Dis. Tuberc. 62 3 2013 435 438 \n6 Sese E. Xiol X. Castellote J. Rodríguez-Fariñas E. Tremosa G. Low complement levels and opsonic activity in hepatic hydrothorax: its relationship with spontaneous bacterial empyema J. Clin. Gastroenterol. 36 1 2003 Jan 75 77 12488714 \n7 Chen C.H. Hsu W.H. Chen H.J. Chen W. Shih C.M. Hsia T.C. Tu C.Y. Different bacteriology and prognosis of thoracic empyemas between patients with chronic and end-stage renal disease Chest 132 2 2007 Aug 532 539 17699132 \n8 Chen W.C. Huang J.W. Chen K.Y. Hsueh P.R. Yang P.C. Spontaneous bilateral bacterial empyema in a patient with nephrotic syndrome J. Infect. 53 3 2006 Sep e131 e134 Epub 2006 Feb 7 16457891 \n9 Nguyen H. Gupta S. Eiger G. Spontaneous bacterial empyema in a noncirrhotic patient: an unusual scenario Am. J. Med. Sci. 342 6 2011 Dec 521 523 21825962 \n10 Tu C.Y. Chen C.H. Spontaneous bacterial empyema Curr. Opin. Pulm. Med. 18 4 2012 Jul 355 358 22450302 \n11 Orman E.S. Lok A.S. Outcomes of patients with chest tube insertion for hepatic hydrothorax Hepatol. Int. 3 4 2009 Dec 582 586 Epub 2009 Aug 11 19669710\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "19()",
"journal": "Respiratory medicine case reports",
"keywords": "ESRD; Pleural fluid; SBEM",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "34-6",
"pmc": null,
"pmid": "27419065",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "12488714;2179097;17699132;14703274;25940246;22450302;16457891;21825962;8666323;19669710",
"title": "Spontaneous bacterial empyema in a non cirrhotic end stage renal disease patient with immunosuppression.",
"title_normalized": "spontaneous bacterial empyema in a non cirrhotic end stage renal disease patient with immunosuppression"
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"abstract": "BACKGROUND\nThoracic epidurals are commonly recommended in enhanced recovery protocols, though they may cause hypotension and urinary retention. Peripheral nerve blocks using liposomal bupivacaine are a potential alternative, though they have not been extensively studied in major cancer operations with an epigastric incision.\n\n\nMETHODS\nWe conducted a retrospective review of prospectively collected data following the transition from thoracic epidural to liposomal peripheral nerve blocks in patients undergoing major oncologic surgery. Patients receiving peripheral nerve blocks were compared to those receiving thoracic epidural. Outcome variables included postoperative opioid use (milligram morphine equivalents [MME]), severe pain, and postoperative complications.\n\n\nRESULTS\nForty-seven of 102 patients studied (46%) received peripheral nerve blocks. Opioid use was higher in the peripheral nerve block group during the 0-24 h (116 vs. 94 MME, p = 0.04) and 24-48 h postoperative period (94 vs. 23 MME, p < 0.01). There was no significant difference in severe pain, hypotension, urinary retention, or ileus. Peripheral nerve blocks were associated with earlier ambulation (1 vs. 2 days, p = 0.04), though other milestones were similar.\n\n\nCONCLUSIONS\nLiposomal peripheral nerve blocks were associated with increased opioid use compared to thoracic epidural. On the basis of our results, thoracic epidural might be preferred in surgical oncology patients with an epigastric incision.",
"affiliations": "Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.;Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;Department of Anesthesiology, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.;Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA.",
"authors": "Aiken|Taylor J|TJ|http://orcid.org/0000-0003-1139-9822;Padilla|Elena|E|;Lemaster|Deborah|D|;Ronnekleiv-Kelly|Sean|S|;Weber|Sharon|S|;Minter|Rebecca M|RM|;Ethier|Steven|S|;Abbott|Daniel E|DE|http://orcid.org/0000-0002-5539-0734",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jso.26711",
"fulltext": null,
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"issn_linking": "0022-4790",
"issue": null,
"journal": "Journal of surgical oncology",
"keywords": "oncologic surgery; thoracic epidural; transversus abdominis plane block",
"medline_ta": "J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "0222643",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34617592",
"pubdate": "2021-10-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Peripheral nerve blocks with liposomal bupivacaine are associated with increased opioid use compared to thoracic epidural in patients with an epigastric incision.",
"title_normalized": "peripheral nerve blocks with liposomal bupivacaine are associated with increased opioid use compared to thoracic epidural in patients with an epigastric incision"
} | [
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"companynumb": "US-ORG100016242-2021000547",
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"abstract": "Occipital nerve blocks are commonly performed to treat a variety of headache syndromes and are generally believed to be safe and well tolerated. We report the case of an otherwise healthy 24-year-old woman with left side-locked occipital, parietal, and temporal pain who was diagnosed with probable occipital neuralgia. She developed complete left facial nerve palsy within minutes of blockade of the left greater and lesser occipital nerves with a solution of bupivicaine and triamcinolone. Magnetic resonance imaging of the brain with gadolinium contrast showed no abnormalities, and symptoms had completely resolved 4-5 hours later. Unintended spread of the anesthetic solution along tissue planes seems the most likely explanation for this adverse event. An aberrant course of the facial nerve or connections between the facial and occipital nerves also might have played a role, along with the patient's prone position and the use of a relatively large injection volume of a potent anesthetic. Clinicians should be aware that temporary facial nerve palsy is a possible complication of occipital nerve block.",
"affiliations": "Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Faulkner Hospital, Boston, MA, USA.",
"authors": "Strauss|Lauren|L|;Loder|Elizabeth|E|;Rizzoli|Paul|P|",
"chemical_list": "D000779:Anesthetics, Local; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1111/head.12403",
"fulltext": null,
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"issn_linking": "0017-8748",
"issue": "54(10)",
"journal": "Headache",
"keywords": "complication; facial nerve palsy; greater occipital nerve block; lesser occipital nerve block; scalp block",
"medline_ta": "Headache",
"mesh_terms": "D000779:Anesthetics, Local; D002045:Bupivacaine; D005155:Facial Nerve Diseases; D005260:Female; D006261:Headache; D006801:Humans; D009407:Nerve Block; D013127:Spinal Nerves; D055815:Young Adult",
"nlm_unique_id": "2985091R",
"other_id": null,
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"pmc": null,
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"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient facial nerve palsy after occipital nerve block: a case report.",
"title_normalized": "transient facial nerve palsy after occipital nerve block a case report"
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"abstract": "OBJECTIVE\nDermatological problems after chemotherapy are often neglected with gynecological oncologists. Since paclitaxel is one of most popular agents for gynecology organ-related cancers, dermatologic change after paclitaxel treatment is seldom reported before.\n\n\nMETHODS\nTwo patients with gynecological organ malignancy who underwent the postoperative dose-dense weekly schedule of paclitaxel 80 mg/m2 plus carboplatin (area of curve 5) every three weeks had repeat dermatological problems (skull, facial and upper trunk areas) during the treatment. They included dermatitis, eczema, and folliculitis. Topical use of anti-fungal cream and oral anti-histamine agents stopped the disease progression and all had completed their chemotherapy without interruption.\n\n\nCONCLUSIONS\nClinicians should be aware of paclitaxel-induced skin toxicities, especially on the skull, face and upper trunk areas to minimize the occurrence of severe morbidity and to provide the better quality of life when cure is our primary priority in the management of gynecological organs-related malignancies.",
"affiliations": "Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Female Cancer Foundation, Taipei, Taiwan. Electronic address: phwang@vghtpe.gov.tw.",
"authors": "Su|Ming-Hsuan|MH|;Chen|Guan-Yeu|GY|;Lin|Jun-Hung|JH|;Lee|Howard Hao|HH|;Chung|Kai-Cheng|KC|;Wang|Peng-Hui|PH|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2019.08.003",
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"issn_linking": "1028-4559",
"issue": "58(6)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Dermatological problems; Dose-dense chemotherapy; Folliculitis; Paclitaxel",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000505:Alopecia; D000972:Antineoplastic Agents, Phytogenic; D005260:Female; D005499:Folliculitis; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D012867:Skin; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101213819",
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"pmid": "31759547",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paclitaxel-related dermatological problems: Not only alopecia occurs.",
"title_normalized": "paclitaxel related dermatological problems not only alopecia occurs"
} | [
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"companynumb": "TW-ACCORD-164756",
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"activesubstancename": "PACLITAXEL"
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"abstract": "In 2012, Canadian pharmacies experienced a shortage of trimethoprim-sulfamethoxazole tablets. Drug shortages may result in unintended clinical consequences such as infection with pathogens against which the alternative medication is ineffective. This is highlighted in the present article, which describes a case of brain abscess due to Nocardia species that developed while receiving dapsone as an alternative for prophylaxis against Pneumocystis jirovecii pneumonia in a highly immune-suppressed patient. Clinicians should be cognizant of these issues when prescribing alternative agents.",
"affiliations": "Department of Internal Medicine, Section of Infectious Diseases, University of Manitoba, Winnipeg, Manitoba ; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba.;Department of Internal Medicine, Section of Infectious Diseases, University of Manitoba, Winnipeg, Manitoba ; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba ; Department of Internal Medicine, Section of Haematology/Oncology, University of Manitoba, Winnipeg, Manitoba.;Department of Internal Medicine, Section of Haematology/Oncology, University of Manitoba, Winnipeg, Manitoba.",
"authors": "Wuerz|Terry C|TC|;Bow|Eric J|EJ|;Seftel|Matthew D|MD|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2013/805797",
"fulltext": null,
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"issn_linking": "1712-9532",
"issue": "24(3)",
"journal": "The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale",
"keywords": "Drug shortage; Nocardia; PCP prophylaxis; Pneumocystis jirovecii; Trimethoprim-sulfamethoxazole",
"medline_ta": "Can J Infect Dis Med Microbiol",
"mesh_terms": null,
"nlm_unique_id": "101226876",
"other_id": null,
"pages": "159-61",
"pmc": null,
"pmid": "24421828",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "2118307;17803871;19747629;20636427;19847156;17443467;1351371;14532173;22908148",
"title": "Potential consequences of essential drug shortages in Canada: Brain abscess due to Nocardia farcinica associated with dapsone prophylaxis for Pneumocystis jirovecii pneumonia.",
"title_normalized": "potential consequences of essential drug shortages in canada brain abscess due to nocardia farcinica associated with dapsone prophylaxis for pneumocystis jirovecii pneumonia"
} | [
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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... |
{
"abstract": "Behçet's syndrome is a multisystemic vasculitis of unknown aetiology. Cardiac involvement is rare, with described prevalence between 1% and 46%, with pericarditis, valvular insufficiency, intracardiac thrombosis, and eventually sinus of Valsalva aneurysms being the most common findings. Although previously reported, myocarditis is a very rare complication of Behçet's syndrome.\nA 26-year-old man, smoker but otherwise healthy, was admitted to the emergency department with atypical chest pain, with no radiation, relation to efforts, position or deep inspiration, and dyspnoea, since the day before. His physical examination was unremarkable, including no fever, tachycardia, or pericardial friction rub. Electrocardiogram (ECG) revealed an early repolarization pattern, with no changes noted in subsequent exams. He had elevation of inflammatory parameters and an increased high-sensitivity troponin level of 3300 ng/L. Transthoracic echocardiography (TTE) was unremarkable. Coronary angiography showed no coronary stenosis. A presumed diagnosis of non-complicated viral myocarditis was established. The patient's condition improved with acetylsalicylic acid as needed and colchicine and he was discharged after 3 days. Cardiac magnetic resonance was performed, showing late epicardial enhancement in the apical segment of the lateral wall, supporting the diagnosis of myocarditis. Four months later, the patient returned with recurrence of chest pain. Additionally, he also complained of fever, odynophagia, and otalgia since the previous week. Oropharyngeal examination revealed tonsillar pillars aphthosis. The ECG was similar to the previous and TTE was normal. Bloodwork revealed once again elevation of inflammatory parameters and elevation of troponin. Recurrent myocarditis was diagnosed. Treatment with ibuprofen, colchicine, and antibiotic therapy was started with no significant improvement. After a more thorough physical examination, an ulcerated scrotal lesion, a left buttock folliculitis, and an axillary hidradenitis were found, which, according to the patient, were recurrent in the last year. Accordingly, the diagnosis of Behçet's syndrome with mucocutaneous and cardiac involvement was established. The patient was kept on colchicine and was also started on immunosuppressive therapy with corticosteroids and azathioprine, with resolution of the symptoms in the following day. A positron emission tomography (PET) was performed 2 days after discharge and showed a higher myocardial uptake in the left ventricular basal segments and both papillary muscles. Prednisolone tapering was started after 2 months, while maintaining azathioprine. At 1-year follow-up, the patient remained asymptomatic. A re-evaluation PET was performed, showing no images suggestive of metabolically active disease in the myocardium.\nThis case highlights the importance of awareness of this rare but potentially serious entity and reinforces the significance of aetiology investigation in cases of recurrent myocarditis. It also shows the success of immunosuppressive therapy in a context where the optimal management is still considerably uncertain.",
"affiliations": "Department of Cardiology, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal.;Department of Cardiology, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal.;Department of Internal Medicine, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal.;Department of Cardiology, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal.;Department of Cardiology, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal.",
"authors": "Moura|Ana|A|https://orcid.org/0000-0001-8010-8780;Saraiva|Mariana|M|https://orcid.org/0000-0003-4369-1940;Costa|João Matos|JM|https://orcid.org/0000-0002-7553-7465;Domingues|Kevin|K|https://orcid.org/0000-0002-0264-4112;Martins|Vítor|V|https://orcid.org/0000-0003-0880-4778",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab212",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab212\nytab212\nCase Report\nAcademicSubjects/MED00200\nRecurrent myocarditis in the context of Behçet’s disease: a case report\nhttps://orcid.org/0000-0001-8010-8780\nMoura Ana 1\nhttps://orcid.org/0000-0003-4369-1940\nSaraiva Mariana 1\nhttps://orcid.org/0000-0002-7553-7465\nCosta João Matos 2\nhttps://orcid.org/0000-0002-0264-4112\nDomingues Kevin 1\nhttps://orcid.org/0000-0003-0880-4778\nMartins Vítor 1\n1 Department of Cardiology, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal\n2 Department of Internal Medicine, Hospital Distrital de Santarém, Av. Bernardo Santareno, 2005-177 Santarém, Portugal\nPellicori Pierpaolo Handling Editor\nVelagapudi Poonam Editor\nRusso Domitilla Editor\nAmin Reshma Editor\nRanganathan Deepti Editor\nCorresponding author. Tel: +351 243 300 200, Email: an.rita5@gmail.com\n7 2021\n30 7 2021\n30 7 2021\n5 7 ytab21204 11 2020\n25 11 2020\n06 5 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.com\n\nAbstract\n\nBackground\n\nBehçet’s syndrome is a multisystemic vasculitis of unknown aetiology. Cardiac involvement is rare, with described prevalence between 1% and 46%, with pericarditis, valvular insufficiency, intracardiac thrombosis, and eventually sinus of Valsalva aneurysms being the most common findings. Although previously reported, myocarditis is a very rare complication of Behçet’s syndrome.\n\nCase summary\n\nA 26-year-old man, smoker but otherwise healthy, was admitted to the emergency department with atypical chest pain, with no radiation, relation to efforts, position or deep inspiration, and dyspnoea, since the day before. His physical examination was unremarkable, including no fever, tachycardia, or pericardial friction rub. Electrocardiogram (ECG) revealed an early repolarization pattern, with no changes noted in subsequent exams. He had elevation of inflammatory parameters and an increased high-sensitivity troponin level of 3300 ng/L. Transthoracic echocardiography (TTE) was unremarkable. Coronary angiography showed no coronary stenosis. A presumed diagnosis of non-complicated viral myocarditis was established. The patient’s condition improved with acetylsalicylic acid as needed and colchicine and he was discharged after 3 days. Cardiac magnetic resonance was performed, showing late epicardial enhancement in the apical segment of the lateral wall, supporting the diagnosis of myocarditis. Four months later, the patient returned with recurrence of chest pain. Additionally, he also complained of fever, odynophagia, and otalgia since the previous week. Oropharyngeal examination revealed tonsillar pillars aphthosis. The ECG was similar to the previous and TTE was normal. Bloodwork revealed once again elevation of inflammatory parameters and elevation of troponin. Recurrent myocarditis was diagnosed. Treatment with ibuprofen, colchicine, and antibiotic therapy was started with no significant improvement. After a more thorough physical examination, an ulcerated scrotal lesion, a left buttock folliculitis, and an axillary hidradenitis were found, which, according to the patient, were recurrent in the last year. Accordingly, the diagnosis of Behçet’s syndrome with mucocutaneous and cardiac involvement was established. The patient was kept on colchicine and was also started on immunosuppressive therapy with corticosteroids and azathioprine, with resolution of the symptoms in the following day. A positron emission tomography (PET) was performed 2 days after discharge and showed a higher myocardial uptake in the left ventricular basal segments and both papillary muscles. Prednisolone tapering was started after 2 months, while maintaining azathioprine. At 1-year follow-up, the patient remained asymptomatic. A re-evaluation PET was performed, showing no images suggestive of metabolically active disease in the myocardium.\n\nDiscussion\n\nThis case highlights the importance of awareness of this rare but potentially serious entity and reinforces the significance of aetiology investigation in cases of recurrent myocarditis. It also shows the success of immunosuppressive therapy in a context where the optimal management is still considerably uncertain.\n\nMyocarditis\nBehçet disease\nAuto immune disease\nCase report\n==== Body\nLearning points\n\nOur case:\n\nEmphasizes the importance of aetiology investigation in cases of recurrent myocarditis.\n\nRaises awareness for Behçet's syndrome as a possible rare aetiology underlying myocarditis.\n\nDemonstrates the relevance of aggressive immunosuppressive therapy with high-dose glucocorticoids and azathioprine in a field where the optimal therapy scheme is unknown.\n\nIntroduction\n\nBehçet’s syndrome is a multisystemic vasculitis of unknown aetiology.1 Cardiac involvement is rare, with described prevalence between 1% and 46%.2–4 Cardiac abnormalities reported in the literature include pericarditis, myocarditis, endocarditis, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with or without myocardial infarction, and coronary arteries or sinus of Valsalva aneurysms.4\n\nTimeline\n\nTime\tEvents\t\n1 Year prior to presentation\tRecurrent buttock folliculitis and axillary hidradenitis\t\nDay 0\tAdmission to the emergency department with chest pain and dyspnoea since the previous day\t\nDay 1\tCoronary angiography showed no coronary stenosis or aneurysms. Diagnosis of presumed myocarditis. Treatment with aspirin as needed and colchicine\t\nDay 3\tDischarged from hospital\t\n1 month after initial presentation\tCardiac magnetic resonance imaging showed late epicardial enhancement in the apical segment of the lateral wall, consistent with the diagnosis of myocarditis\t\n4 months after initial presentation\tReturn to the emergency department with recurrence of persistent chest pain with no pleuritic characteristics, fever, sore throat, odynophagia, and otalgia with a week of duration. Oropharyngeal examination revealed tonsillar pillars aphthosis with exudate. Recurrent myocarditis with possible bacterial tonsillitis was diagnosed, and the patient was hospitalized. Ibuprofen, colchicine, and antibiotic therapy was started\t\n4 months and 2 days after initial presentation\tPersistence of fever, chest pain, and elevation of inflammatory markers despite treatment. Thorough physical exam noting an ulcerated scrotal lesion, left buttock folliculitis, and axillary hidradenitis. Diagnosis of Behçet’s syndrome with mucocutaneous and cardiac involvement was established. The patient was kept on colchicine and was also started on immunosuppressive therapy with corticosteroids and azathioprine\t\n4 months and 13 days after initial presentation\tDischarge from hospital\t\n4 months and 15 days after initial presentation\tA positron emission tomography (PET) with fludeoxyglucose (FDG) showed a more intense myocardial uptake in the left ventricular basal segments, as well as in both papillary muscles\t\n6 months after presentation (2 months after initiation of immunosuppressant therapy)\tWeaned from steroids\t\n1 year after presentation (6 months after initiation of immunosuppressant therapy)\tFollow-up PET-FDG showed no images suggestive of metabolically active disease. The distribution of FDG in the myocardium presented as a diffuse pattern, without individualization of hypermetabolic foci\t\n\nCase presentation\n\nA 26-year-old man, smoker but otherwise healthy, was admitted to the emergency department with atypical chest pain with no radiation and no relation to efforts, position or deep inspiration; associated with dyspnoea, since the day before. There was no history of previous flu-like symptoms, fever, or gastrointestinal symptoms. On examination, the patient was haemodynamically stable, afebrile, and eupnoeic; no pericardial friction rub and no cardiac murmurs were noted. Electrocardiogram (ECG) revealed an early repolarization pattern with no changes noted in subsequent exams (Figure 1A). His blood test results showed neutrophilic leucocytosis (white blood cell count of 13.3 × 109/L—normal range 4–10.0 × 109/L), a normal C-reactive protein (0.68 mg/dL—normal value < 0.05 mg/dL), mild elevation of erythrocyte sedimentation rate (ESR) of 20 mm/h (normal value < 14 mm/h), and an increased initial high-sensitivity troponin level of 3300 ng/L (normal value < 34.2 ng/L). Transthoracic echocardiography (TTE) was unremarkable, with no pericardial effusion. Invasive coronary angiography showed no coronary stenosis or aneurysms (Figure 2). A presumed diagnosis of non-complicated viral myocarditis was established. The patient’s condition improved with aspirin as needed and colchicine, and he was discharged after a 3-day in-hospital stay with complete resolution of his symptoms. Cardiac magnetic resonance (Figure 3) was performed 1 month after presentation, with identification of an area of late epicardial enhancement, located in the apical segment of the lateral wall, supporting the diagnosis of myocarditis. Four months later, the patient returned to the emergency department with recurrence of chest pain. Additionally, he also complained of fever, sore throat, odynophagia, and otalgia since the previous week. Oropharyngeal examination revealed the tonsillar pillars aphthosis with exudate, while his otoscopy was normal. The ECG was similar to the one of the previous hospitalization (Figure 1B) and TTE was again normal. Bloodwork revealed once more elevation of inflammatory markers (white blood cell count of 14.0 × 109/L, C-reactive protein of 4.02 mg/dL, and ESR of 140 mm/h) and elevation of troponin (2828 ng/L). There was a normal platelet count (338 × 109/L—normal range 150–400 × 109/L) and coagulation parameters (INR: 1.07—normal range 0.88–1.12). Recurrent myocarditis was diagnosed, and the patient was hospitalized. Treatment with ibuprofen and colchicine was started and, given the possibility of concomitant bacterial tonsillitis, he was also initiated on antibiotic therapy. Despite treatment, there was no significant improvement, with persistence of fever and elevation of inflammatory markers. After a more thorough physical examination, an ulcerated scrotal lesion (Figure 4), a left buttock folliculitis, and axillary hidradenitis were found, which, according to the patient, were recurrent for the last year. Accordingly, the diagnosis of Behçet’s syndrome with mucocutaneous and cardiac involvement was established. The patient was kept on colchicine 1 mg per day, and was also started on immunosuppressive therapy with corticosteroids (initial 1 g 3-day pulse of methylprednisolone followed by prednisolone 1 mg/kg daily) and azathioprine (2.5 mg/kg daily) with resolution of the symptoms on the following day. A positron emission tomography (PET) with fludeoxyglucose (FDG) was performed 2 days after discharge (Figure 5) and showed a higher myocardial uptake in the left ventricular basal segments, as well as in both papillary muscles with no other foci of abnormal uptake. Prednisolone tapering was started after 2 months, while remaining on long-term azathioprine (100 mg daily) and colchicine (1 mg daily) therapy. At 1-year follow-up, the patient remained asymptomatic, with complete resolution of ulcerated and aphthous lesions and with no recurrence of chest pain. A re-evaluation PET was performed at that time, showing a uniform capture of FDG in the myocardium, with no images suggestive of metabolically active disease.\n\nDiscussion\n\nBehçet’s syndrome was first described in 1937 and it is classified as an inflammatory vascular systemic disease with an aetiopathogenesis that remains unknown.1 As there is a lack of a universally recognized pathognomonic test, Behçet’s syndrome diagnosis is primarily based on clinical criteria. Recurrent mucocutaneous lesions (oral aphthosis), skin lesions (papulopustular lesions, erythema nodosum, and skin ulcers), ocular findings (uveitis/retinitis/hypopyon-iritis), and reactivity to needle prick test are the most common clinical findings. Currently, the International Criteria for Behçet Disease (ICBD), reviewed in 2013,5 are recommended as a guide for diagnosis, with a score ≥4 being supportive of Behçet’s syndrome with estimated sensitivity of 93.9% and specificity of 92.1%. In this case, the patient had an ICBD score of 6.\n\nThe real prevalence of cardiac involvement in Behçet’s syndrome remains unknown as it can be asymptomatic. The reports in the literature are very discrepant, with prevalence between 1% and 46%.2,6 It is estimated to be the first manifestation of the disease in <2% of the cases.2,3 The mean age at diagnosis in this specific group is 29.7 ± 9.9 years7 and cardiac lesions are predominantly reported in men and in the first years of the disease's diagnosis, characteristics that are in conformity with our case.\n\nIn the largest review available, in 52 Behçet’s syndrome patients with cardiac involvement,7 pericarditis was the most common form (38.5%), followed by valvular insufficiency (26.9%), intracardiac thrombosis (19.2%), myocardial infarction (17.3%), and endomyocardial fibrosis (7.7%). In other series sinus of Valsalva aneurysms and aortitis were the most frequently reported cardiac complications.8 Myocarditis related to Behçet’s syndrome is very rare, with diagnosis in only 1.2% of the autopsies performed in a cohort of Japanese patients with Behçet’s syndrome9 and described in some series as isolated cases, with some developing heart failure in the context of dilated cardiomyopathy.4,6,8,10–12\n\nAlthough veins are more frequently affected by vasculitis in Behçet’s syndrome, arteries of any size can also be involved,12 which seems to be the most prevalent underlying mechanism of cardiovascular manifestations. Necrotizing leucocytoclastic or polymorphonuclear, obliterative perivasculitis, and lymphocytic cell infiltration of capillaries, arteries, and vasa vasorum are the main pathologic features in affected tissues during acute phases. In advanced stages, a significant fibrosis and scarring may develop.13\n\nLittle is known about the optimal treatment for the patients with Behçet’s syndrome. It is usually determined by the degree of systemic manifestations and involves a therapeutic combination of colchicine, corticosteroids, and/or other immunosuppressants.13 The level of uncertainty increases in the context of Behçet’s syndrome with myocarditis, with no guidelines established for this entity so far.14 In the cases of reported Behçet’s syndrome with cardiac involvement in a presumed context of vasculitis (Table 1) the majority of the authors report the use of a combination of colchicine,3,14 corticosteroids,2,3,14 and azathioprine.12 Although there is no data in the literature about the recurrence rate of myocarditis in Behçet’s syndrome, in the previously cited review article,7 relapse of symptoms is documented in 35% of the patients with pericarditis.\n\nTable 1 Cases of cardiac involvement in Behçet disease—review of the literature (1990–2019)\n\nFirst author, year\tType of cardiac involvement\tTreatment\tOutcome\t\nMarzban et al., 20081\tSevere aortic insufficiency\tCorticosteroids; surgery\tComplete remission\t\nKusuyama et al., 20022\tAortic insufficiency and aneurysm of sinus of Valsalva\tSurgery\tComplete remission\t\nVanhaleweyk et al., 19983\tIntracardiac thrombosis (right atrium and ventricle and left ventricle)\tAnticoagulant, corticosteroids, cyclophosphamide\tComplete remission\t\nBasaran et al., 20004\tIntracardiac thrombosis\tAnticoagulant; corticosteroids; surgery\tRelapse (surgical excision)\t\nYakut et al., 20075\tAnticoagulant, corticosteroids, cyclophosphamide\tComplete remission\t\nBaykan et al., 20016\tAnticoagulant, corticosteroids, cyclophosphamide\tComplete remission\t\nCevik et al., 20097\tAnticoagulant\tComplete remission\t\nNoureddine et al., 20048\tCorticosteroids\tComplete remission\t\nKirali et al., 19989\tSurgery\tComplete remission\t\nChiari et al., 200810\tAnticoagulant; corticosteroids; immunosuppressants\tComplete remission\t\nDogan et al., 200711\tAnticoagulant; corticosteroids; immunosuppressants\tComplete remission\t\nDarie et al., 200512\tRight ventricular thrombus and endomyocardial fibrosis\tSurgery\tComplete remission\t\nSoulami et al., 199613\t—\tDeath\t\nKosar et al., 200514\tAcute myocardial infarction\tColchicine\tPartial remission\t\nBeyranvand et al., 200915\tCorticosteroids\tPartial remission\t\nRolland et al., 199316\tLeft ventricular and coronary artery aneurysms\tSurgery\tComplete remission\t\nMarashi et al., 200517\tLeft ventricular pseudoaneurysm\tSurgery\tComplete remission\t\nNakata et al., 199518\tRight atrial vegetation\tCorticosteroids\tComplete remission\t\nKwon et al., 200619\tPericarditis and cardiac tamponade, coronary arteritis\tColchicine; corticosteroids; surgery\tComplete remission\t\nJagadeesh et al., 201420\tPericarditis\tCorticosteroids; methotrexate; pericardiocentesis. Patient intolerant to azathioprine, 6-mercaptopurine, mycophenolate, thalidomide\tComplete remission\t\nLewis et al., 196421\tMyopericarditis\tAspirin\tComplete remission\t\nSatoshi et al, 201422\tGiant-cell myocarditis\t—\tDeath\t\nFelix et al, 201623\tMyocarditis and dilated cardiomyopathy\tCorticosteroids; azathioprine; ICD\tPartial remission\t\nJagadeesh et al., 201420\tDilated cardiomyopathy\tColchicine, AINE’s; corticosteroids; azathioprine\n\nBeta-blocker, IECA and diuretics; CRT-D\n\n\tPartial remission\t\nScheuble et al., 200324\t—\t—\t\nMustafa et al., 201025\tCorticosteroids\tPartial remission\t\nKaatz et al., 199826\tCorticosteroids; azathioprine\tComplete remission\t\nReferences provided in the Supplementary material online.\n\nIn this case, anti-inflammatory therapy and colchicine only were clearly insufficient to control symptoms related to myocarditis, supporting an important role for stronger immunosuppressants in this kind of presentation.\n\nAnnual mortality in Behçet’s syndrome varies between 2% and 4%. Studies show that overall survival in the patients with cardiac involvement is significantly worse than in those without, with a documented 5-year survival rate of 83.6% vs. 95.8% (P = 0.03), respectively.3\n\nConclusions\n\nThis case highlights the importance of awareness of this rare but potentially serious entity and emphasizes the significance of aetiology investigation in cases of recurrent myocarditis. It also shows the success of immunosuppressive therapy in a context where the optimal management is still considerably uncertain.\n\nLead author biography\n\nAna Moura, MD, is currently a third year resident in Hospital Distrital de Santarém, Portugal. She received an MD degree from Instituto Ciências Biomédicas Abel Salazar—University of Porto in 2016.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nFigure 1 (A) Twelve-lead electrocardiogram at initial presentation with early repolarization pattern. (B) Twelve-lead electrocardiogram at the second hospital admission with no evolution noted when compared to the previous electrocardiogram.\n\nFigure 2 Invasive coronary angiography showing no coronary stenosis.\n\nFigure 3 Cardiac magnetic resonance with identification of an area of late epicardial enhancement, located in the apical segment of the lateral wall, reinforcing the diagnosis of myocarditis.\n\nFigure 4 Ulcerated scrotal lesion.\n\nFigure 5 A positron emission tomography with fludeoxyglucose performed 2 days after discharge of the second hospitalization. It shows a more intense myocardial uptake at the left ventricular basal segments, and in both papillary muscles, corresponding to the locations with active inflammation.\n\nSupplementary Material\n\nytab212_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 Kalayciyan A , ZouboulisC. An update on Behçet’s disease. J Eur Acad Dermatol Venereol 2007;21 :1–10.\n2 Bennis A , NoureddineM, AzzouziL, SoulamiS, BenamourS, ChraibiN. Cardiac manifestations of Behçet disease. Ann Med Interne (Paris) 1996;147 :126–129.8760696\n3 Godeau P , WechslerB, MaaouniA, FagardM, HerremanG. Cardiovascular involvement in Behçet’s disease. Ann Dermatol Venereol 1980;107 :741–747.7447254\n4 Satoshi M , AkiraT, HirofumiZ. Behçet’s disease complicated by giant-cell myocarditis. Intern Med 2014;53 :1721.25088896\n5 International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014;28 :338–347.23441863\n6 Bletry O , MohattaneA, WechslerB, BeaufilsP, ValèreP, PetitJ et al Cardiac manifestations of Behçet's disease 12 cases. Presse Med 1988;17 :2388–2391.2974981\n7 Geri G , WechslerB, Thi HuongDL, IsnardR, PietteJ-C, AmouraZ et al Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of the literature. Medicine 2012;91 :25–34.22198500\n8 Yoshikawa K , HoriH, FukunagaS, TayamaE, AoyagiS. Aortic root replacement in Behçet disease. Asian Cardiovasc Thorac Ann 2007;15 :521–523.18042781\n9 Lakhanpal S , TaniK, LieJT, KatohK, IshigatsuboY, OhokuboT. Pathologic features of Behçet's syndrome: a review of Japanese autopsy registry data. Hum Pathol 1985;16 :790–795.4018777\n10 Melek K , SanaS. Cardiac and vascular complications of Behçet disease in the Tunisian context: clinical characteristics and predictive factors. Adv Rheumatol 2018;58 :32.30657088\n11 Felix N , FabianC, RussellB, LouiseMB. A rare case of Behçet disease with generalised myositis, cardiomyositis and necrotising fasciitis. BMJ Case Rep 2016;2016 :bcr2015211983.\n12 Feridun K , IbrahimS, HakanG. Acute myocardial infarction with normal coronary arteries in a young man with the Behçet’s disease. Int J Cardiol 2005;355–357.\n13 Owlia M , MehrpoorG. Behcet's disease: new concepts in cardiovascular involvements and future direction for treatment. ISRN Pharmacol 2012;2012 :1.\n14 Gulen H , RobinC, DongsikB. 2018 Update of the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis 2018;77 :808–818.29625968\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(7)",
"journal": "European heart journal. Case reports",
"keywords": "Auto immune disease; Behçet disease; Case report; Myocarditis",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab212",
"pmc": null,
"pmid": "34345764",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "22530146;2974981;26740268;17207160;7447254;15749205;30657088;23441863;29625968;25088896;18042781;22198500;4018777;8760696",
"title": "Recurrent myocarditis in the context of Behçet's disease: a case report.",
"title_normalized": "recurrent myocarditis in the context of beh et s disease a case report"
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"activesubstancename": "COLCHICINE"
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"abstract": "Older individuals are susceptible to accident, such as falls, some of which are fatal. In such cases, autopsies and toxicological analysis may be deemed unnecessary, especially if the critical injuries and manner of death can be determined conclusively based on information at the scene and an external investigation. Here, we report the results of two autopsies performed on elderly individuals who died accidentally under the influence of chlorpheniramine. These autopsies revealed valuable additional information. Case 1: A woman in her 70s, who was living alone, was found dead under the stairs in her house. She had no history of a condition that could have led to sudden death. The autopsy revealed a neck fracture, multiple rib fractures, and a coccyx fracture. The histopathological findings showed fat embolisms in numerous small vessels of the interalveolar septum. Toxicological analysis of blood samples revealed the presence of chlorpheniramine (0.41μg/ml). Case 2: A woman in her 70s, who was living alone, was found dead in the bathtub in her house. There was no past medical history other than diabetes mellitus and vertigo. The autopsy revealed hyper-inflated lungs and brown-red fluids in the trachea, but there was no evidence of a pathology or injury that could have induced a loss of consciousness. Toxicological analysis of the fluids in the right thoracic cavity revealed the presence of chlorpheniramine (0.57μg/ml). In both cases, re-examination of the scene after the autopsy revealed the presence of common cold medicine containing chlorpheniramine. The victim may have accidentally overdosed on common cold medicine. This overdose would have been compounded by anti-histamine-induced drowsiness. The present cases suggest that forensic pathologists should always notify physicians/pharmacists of findings pertaining to unexpected drug side effects. Such intervention would prevent many accidental deaths. In addition, each autopsy must be performed in conjunction with a detailed postmortem investigation. Such efforts would also increase the accuracy of the public health record's mortality statistics.",
"affiliations": "Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Japan. hideto-@qk9.so-net.ne.jp",
"authors": "Suzuki|Hideto|H|;Shigeta|Akio|A|;Fukunaga|Tatsushige|T|",
"chemical_list": "D006634:Histamine H1 Antagonists; D002744:Chlorpheniramine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "15(5)",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Accidental deaths; Chlorpheniramine; Forensic autopsy; Side effect",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D001344:Autopsy; D002423:Cause of Death; D002744:Chlorpheniramine; D004332:Drowning; D062787:Drug Overdose; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D049429:Forensic Pathology; D006634:Histamine H1 Antagonists; D006801:Humans; D033181:Information Dissemination; D033183:Interdisciplinary Communication; D007564:Japan; D010595:Pharmacists; D010820:Physicians",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "253-5",
"pmc": null,
"pmid": "23747192",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Accidental death of elderly persons under the influence of chlorpheniramine.",
"title_normalized": "accidental death of elderly persons under the influence of chlorpheniramine"
} | [
{
"companynumb": "PHHY2013JP097269",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORPHENIRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone-sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab.",
"affiliations": "Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.;Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.;Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.;Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.;Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.",
"authors": "Rodriguez|Cesar A|CA|http://orcid.org/0000-0003-3484-4829;Martin|Teresa|T|;Lozano|Rebeca|R|;Gomez|Amalia|A|;Cruz|Juan J|JJ|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.12913",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-122X",
"issue": "23(6)",
"journal": "The breast journal",
"keywords": "bevacizumab; breast cancer; nasal septum perforation",
"medline_ta": "Breast J",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D061270:Nasal Septal Perforation; D009362:Neoplasm Metastasis; D017239:Paclitaxel",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "745-746",
"pmc": null,
"pmid": "28845572",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer.",
"title_normalized": "spontaneous nasal perforation in a bevacizumab treated patient with metastatic breast cancer"
} | [
{
"companynumb": "ES-PFIZER INC-2017395968",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nOnly few reports in literature have pointed out to the possibility of a cranial subdural haematoma formation associated with dural puncture during spinal or epidural analgesia. We herein describe such a rare case who was diagnosed to have acute subdural haematoma after combined spinal-epidural anaesthesia used in labour.\n\n\nMETHODS\nA 34-year-old, primigravid women with a gestation of 38 weeks underwent caesarean section under combined spinal-epidural anaesthesia and gave birth to a healthy boy. Thirty-two hours after delivery, her moderate headache progressed to a severe headache associated with nausea and vomiting and later was more complicated with a generalized tonic-clonic seizure and ensuing lethargy. Computed tomography of the brain demonstrated a right-sided fronto-temporo-parietal acute subdural haematoma with diffuse cerebral oedema. She underwent urgent FTP craniotomy and evacuation of the haematoma. Early postoperative cranial computed tomography showed a clean operative site. Eight days after subdural haematoma surgery, she became lethargic again, and this time cranial computed tomography disclosed an extradural haematoma under the bone flap for which she had to undergo surgery again. Two days later, she was discharged home with Karnofsky performance score of 90/100. At follow-up exam, she was neurologically intact and her cranial computed tomography and magnetic resonance were normal.\n\n\nCONCLUSIONS\nAs conclusion, with the use of this combined spinal-epidural anaesthesia, it should be kept in mind that headache does not always mean low pressure headache associated with spinal anaesthesia and that a catastrophic complication of subdural haematoma may also occur.",
"affiliations": "Department of Neurosurgery, Faculty of Medicine, Kirikkale University, Kirikkale, Turkey. Electronic address: bulentbanrs@yahoo.com.;Department of Anaesthesiology and Reanimation, TOBB-ETU Hospital, Ankara, Turkey.;Department of Neurosurgery, TOBB-ETU Hospital, Ankara, Turkey.",
"authors": "Bakar|Bulent|B|;Ozer|Esra|E|;Tekkok|Ismail Hakki|IH|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "65(5)",
"journal": "Brazilian journal of anesthesiology (Elsevier)",
"keywords": "Anestesia combinada raqui-peridural; Combined spinal–epidural anaesthesia; Hematoma subdural; Labour; Parto; Subdural haematoma",
"medline_ta": "Braz J Anesthesiol",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D005260:Female; D020199:Hematoma, Subdural, Acute; D006801:Humans; D011247:Pregnancy",
"nlm_unique_id": "101624623",
"other_id": null,
"pages": "417-20",
"pmc": null,
"pmid": "26323744",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening acute subdural haematoma after combined spinal-epidural anaesthesia in labour.",
"title_normalized": "life threatening acute subdural haematoma after combined spinal epidural anaesthesia in labour"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK201701265",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "The aims of this study were to evaluate whether treatment with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) affects the risk of developing severe extraarticular rheumatoid arthritis (ExRA) manifestations and to investigate potential predictors for developing ExRA.\n\n\n\nA dynamic community-based cohort of patients with RA was studied (n = 1977). Clinical records were reviewed and cases of severe ExRA were identified. Information on exposure to TNF inhibitors was obtained from a regional register. Exposure to TNF inhibitors was analyzed in a time-dependent fashion and the incidence of severe ExRA in exposed patients was compared with the incidence in unexposed patients. Cox regression models were used to assess potential predictors of severe ExRA.\n\n\n\nDuring treatment with TNF inhibitors, there were 17 patients with new onset of severe ExRA in 2400 person-years at risk (PY; 0.71/100 PY, 95% CI 0.41-1.13) compared with 104 in 15,599 PY (0.67/100 PY, 95% CI 0.54-0.81) in patients without TNF inhibitors. This corresponded to an incidence rate ratio of 1.06 (95% CI 0.60-1.78). The age- and sex-adjusted HR for ExRA in anti-TNF-treated patients was 1.21 (95% CI 1.02-1.43), with similar findings in models adjusted for time-dependent Health Assessment Questionnaire and propensity for anti-TNF treatment. Male sex, positive rheumatoid factor (RF), long disease duration, and greater disability were predictors for ExRA.\n\n\n\nThis study suggests that patients treated with TNF inhibitors are at a slightly increased risk of developing severe ExRA. RF-positive patients with disabling disease of long duration were more likely to develop severe ExRA.",
"affiliations": "From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.;From Rheumatology, Department of Clinical Sciences Malmö, Lund University; Department of Rheumatology, Skåne University Hospital, Malmö; Department of Rheumatology, Falun Hospital, Falun; Rheumatology, and Orthopedics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. Carl.Turesson@med.lu.se.",
"authors": "Theander|Lisa|L|;Nyhäll-Wåhlin|Britt-Marie|BM|;Nilsson|Jan-Åke|JÅ|;Willim|Minna|M|;Jacobsson|Lennart T H|LTH|;Petersson|Ingemar F|IF|;Turesson|Carl|C|",
"chemical_list": "D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.161103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "44(7)",
"journal": "The Journal of rheumatology",
"keywords": "EXTRAARTICULAR MANIFESTATIONS; INTERSTITIAL LUNG DISEASE; RHEUMATOID ARTHRITIS; TNF INHIBITORS; VASCULITIS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D005260:Female; D006801:Humans; D015994:Incidence; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D010493:Pericarditis; D010998:Pleurisy; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha; D014657:Vasculitis",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "981-987",
"pmc": null,
"pmid": "28461642",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe Extraarticular Manifestations in a Community-based Cohort of Patients with Rheumatoid Arthritis: Risk Factors and Incidence in Relation to Treatment with Tumor Necrosis Factor Inhibitors.",
"title_normalized": "severe extraarticular manifestations in a community based cohort of patients with rheumatoid arthritis risk factors and incidence in relation to treatment with tumor necrosis factor inhibitors"
} | [
{
"companynumb": "SE-JNJFOC-20170713837",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Advances in cancer biology research led to the identification of new molecular drivers in non-small cell lung cancer. These alterations should be searched especially in young and never-smoker patients, in order to ensure access to targeted therapies. In particular, RET mutations occur in 1-2% of lung adenocarcinomas and represent the molecular target of innovative treatments such as pralsetinib. The Next Generation Sequencing provides a comprehensive genomic profiling both on tissue and blood sampling. The liquid biopsy could be extremely advantageous, as it is a simple, non-invasive and repeatable test. We report the case of a non-smoker woman with metastatic lung adenocarcinoma unresponsive to chemotherapy and immunotherapy. RET mutation (RET-KIF5B fusion) was found by liquid biopsy. The patient started therapy with pralsetinib obtaining an early radiological response and a significant clinical benefit.",
"affiliations": "Oncologia Medica, Policlinico Universitario Campus Bio-Medico di Roma.",
"authors": "Russano|Marco|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1701/3525.35131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-1193",
"issue": "112(1)",
"journal": "Recenti progressi in medicina",
"keywords": null,
"medline_ta": "Recenti Prog Med",
"mesh_terms": null,
"nlm_unique_id": "0401271",
"other_id": null,
"pages": "5e-9e",
"pmc": null,
"pmid": "33512366",
"pubdate": "2021-01",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Detection of novel driver mutations in liquid biopsy: case report of a RET-positive lung adenocarcinoma treated with pralsetinib.",
"title_normalized": "detection of novel driver mutations in liquid biopsy case report of a ret positive lung adenocarcinoma treated with pralsetinib"
} | [
{
"companynumb": "IT-drreddys-LIT/ITL/21/0137986",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "1",
... |
{
"abstract": "Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development with an incidence of I in 40,000 to in 70,000 live births. It is characterized by abnormalities of the pinnae which are frequently associated with atresia of the external auditory canals and anomalies of the middle ear ossicles. Rarely congenital heart defects can be present. Prenatal paroxetine exposure may enhance the risks of major malformation, particularly cardiac defects. This article reports a newborn, whose mother used paroxetine during pregnancy, presenting with multiple congenital heart defects associated to typical physical characteristics of Treacher Collins syndrome.",
"affiliations": null,
"authors": "Dinlen|N|N|;Zenciroğlu|A|A|;Dilli|D|D|;Aydin|B|B|;Beken|S|S|;Okumuş|N|N|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D017374:Paroxetine",
"country": "Switzerland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-8146",
"issue": "25(1)",
"journal": "Genetic counseling (Geneva, Switzerland)",
"keywords": null,
"medline_ta": "Genet Couns",
"mesh_terms": "D000015:Abnormalities, Multiple; D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008342:Mandibulofacial Dysostosis; D017374:Paroxetine; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "9015261",
"other_id": null,
"pages": "7-11",
"pmc": null,
"pmid": "24783649",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treacher Collins syndrome with multiple congenital heart defects after paroxetine exposure: case report.",
"title_normalized": "treacher collins syndrome with multiple congenital heart defects after paroxetine exposure case report"
} | [
{
"companynumb": "US-MYLANLABS-2014S1014914",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PAROXETINE\\PAROXETINE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "A 70-year-old man presented to the emergency department with blood hypotension associated to a sudden paraplegia and thermalgesic analgesia. He had an history of colic and prostatic adenocarcinoma, hypertension and non-dialyzed Chronic Kidney Disease (CKD) related to an idiopathic membranous glomerulonephritis type 1 discovered 9 years ago. Magnetic resonance imaging confirmed a diagnosis of Spinal Cord Infarction (SCI). Few months later, he presented a blurred vision due to central Retinal Vein Occlusion (RVO), which was improved by Anti-VEGF therapy. This is the first reported case of a concomitance of retinal vascular event and SCI highlights the links between the central nervous system and retinal vascularization despite separate involvement of the two events in the arterial and venous systems. Additionally, CKD worsened the risk of cardiovascular incidents by induced oxidative stress, thrombophilia, chronic inflammation, and endothelial dysfunction. SCI occurrence indicates severe vascular dysfunction and elevates the risk of additional vascular disorders.",
"affiliations": "Ophthalmology Department.;Neurology Department.;Neurology Department.;Nephrology Department.;Physical Medicine and Rehabilitation Department, Centre hospitalier Argenteuil, Paris, France.;Ophthalmology Department.;Ophthalmology Department.",
"authors": "Ghezzaz|Amina|A|;Cristea|Cristina|C|;Ferradji|Amel|A|;Aboubekr|El Habib|EH|;Bouhanna-Hamitouche|Lynda|L|;Chahed|Sadri|S|;Mahdjoubi|Amir|A|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/ni.2020.8558",
"fulltext": "\n==== Front\nNeurol Int\nNI\nNeurology International\n2035-8385 2035-8377 PAGEPress Publications, Pavia, Italy \n\n10.4081/ni.2020.8558\nCase Report\nSpinal cord infarction associated to retinal vein occlusion in a patient with chronic kidney disease\nGhezzaz Amina 1 Cristea Cristina 2 Ferradji Amel 2 Aboubekr El Habib 3 Bouhanna-Hamitouche Lynda 4 Chahed Sadri 1 Mahdjoubi Amir 1 1 Ophthalmology Department\n2 Neurology Department\n3 Nephrology Department\n4 Physical Medicine and Rehabilitation Department, Centre hospitalier Argenteuil, Paris, France\nOphthalmology Department, Centre hospitalier Argenteuil, 69 Rue du Lieutenant-Colonel Prudhon, 95100 Argenteuil, France. 0033.134232749-0033.134232696. amir.mahdjoubi@gmail.comContributions: AG, AM, AF, CC, EB, LB data collecting and analysing; AG, AM Manuscript writing; SC manuscript reviewing.\n\nConflict of interest: The authors report no conflicts of interest.\n\nEthics approval and consent to participate: Informed consent: Informed consent was obtained from all individual participants included in the study.\n\n\n01 9 2020 \n18 8 2020 \n12 2 855828 3 2020 12 8 2020 ©Copyright: the Author(s)2019Licensee 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/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 70-year-old man presented to the emergency department with blood hypotension associated to a sudden paraplegia and thermalgesic analgesia. He had an history of colic and prostatic adenocarcinoma, hypertension and non-dialyzed Chronic Kidney Disease (CKD) related to an idiopathic membranous glomerulonephritis type 1 discovered 9 years ago. Magnetic resonance imaging confirmed a diagnosis of Spinal Cord Infarction (SCI). Few months later, he presented a blurred vision due to central Retinal Vein Occlusion (RVO), which was improved by Anti-VEGF therapy. This is the first reported case of a concomitance of retinal vascular event and SCI highlights the links between the central nervous system and retinal vascularization despite separate involvement of the two events in the arterial and venous systems. Additionally, CKD worsened the risk of cardiovascular incidents by induced oxidative stress, thrombophilia, chronic inflammation, and endothelial dysfunction. SCI occurrence indicates severe vascular dysfunction and elevates the risk of additional vascular disorders.\n\nKey words\nSpinal cord infarctionretinal vein occlusionchronic kidney failurestrokeMagnetic resonance imagingFunding: This work was not supported by any specific grant.\n==== Body\nIntroduction\nSpinal Cord Infarction (SCI), a rare disease that constricts the extensive anastomotic vascularization of the spinal cord, is difficult to diagnose.1 The occlusion of the anterior spinal artery, which vascularizes the anterior two-thirds of the spinal cord, is more frequent and manifests clinically as paraplegia and deficits in spinothalamic sensation, sparing the proprioceptive and vibrational senses, and autonomous dysfunction. 1\n\nRetinal Vein Occlusion (RVO) is a vascular disease caused by circulatory depression of the central or branch retinal vein.2 However, its pathological origin remains unclear despite the identification of multiple risk factors such as: hypertension, diabetes, sleep apnea syndrome, thrombophilia, hyperhomocysteinemia, and glaucoma.3 Interestingly, several studies have reported the association between RVO and cerebral stroke; both conditions shared a same vascular origins, have common anatomical/physiological characteristics, and risk factors.4,5 Furthermore, the mortality rate after stroke is high among patients with a history of RVO.6\n\nChronic Kidney Disease (CKD) has been identified as a risk factor for both RVO and cerebral stroke.7 Furthermore, although the presence of a retinopathy and relatively large venous diameters have been associated with an increased risk of cardiovascular disease and stroke in patients with CKD,8 the association between retinopathy/RVO and SCI has not been reported.\n\nThis case study reports for the first time an uncommon presentation of the sequential occurrence of an SCI and central RVO in a patient with decompensated CKD secondary to idiopathic membranous nephropathy. Such an association underlines the importance of correction of risk factors after SCI and highlights the necessity of an ophthalmological exam after all the forms of stroke.\n\nCase Report\nA 69-year-old man presented to the emergency department with lumbar pain and acute bilateral motor weakness of the legs started 12-hour ago associated to blood hypotension. No history of a recent surgery or traumatism was reported while the patient had a 9-year history of chronic kidney disease associated with idiopathic membranous glomerulonephritis type 1 (predialysis) that was complicated by hypertension. The patient also had also a history of cancer; he underwent surgery (15 years ago) and local radiotherapy (14 years ago) for colic adenocarcinoma and prostate cancer, respectively. The former was in complete remission and the latter was maintained in remission with hormonotherapy (leuprorelin acetate).\n\nNeurological exam, realized according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI),9 revealed an important proximal motor deficit in the patient’s lower limbs, which was graded at 1/5 for muscle strength of the quadriceps, iliopsoas, gluteus medius, and gluteus maximus; it was less severe in the distal muscles (grade 4/5). Deep tendon reflex was absent and plantar reflex was preserved in the right limb, and the left limb showed extensor plantar response. The sensory loss of limb was selective along with a bilateral loss of thermalgesic sensation till the L5 level in the right and L3 level in the left, with sparing of proprioception. The motricity and sensitivity of the superior members were well-preserved. The patient had a diminished rectal tonicity without anal dilation; however, no abnormality of the bladder or bowel function were noted. The patient was not able to walk.\n\nThe first Magnetic Resonance Imaging (MRI), performed 18 hours after the onset of symptoms, did not show any abnormalities. However, T2-weighted sagittal and axial images obtained 4 days later showed a hyperintensity in the form of an anteromedial spot at the T12-L1 level. No other lesions, tumors, abscesses, or herniated vertebral discs were observed (Figure 1). Cerebrospinal fluid (CSF) examination showed no abnormalities. Blood tests yielded the following results: perturbation of renal parameters (creatinine, 605 μmol/L; urea, 34 mmol/L), mixed metabolic acidosis (pH, 7.21), rhabdomyolysis parameters (CPK, 22,000 IU/L), severe anemia, (hemoglobin, 6.8 g/dl), protein S deficiency (36%), prothrombin level >120%, and negative C-reactive protein.\n\nThe diagnosis of non-traumatic spontaneous SCI was retained and an anti-platelet treatment targeting platelet aggregation was initiated. The anemia was corrected by two rounds of red blood cell transfusion, followed by darbepoetin alfa administration. The hemodialysis was started at two sessions per week. Hypertension was treated with calcium channel blockers and diuretics. The patient was provided a wheelchair for rehabilitation before leaving the neurology department after being hospitalized for a month. At the Physical Medicine and Rehabilitation department, motor kinesitherapy was started to strengthen the iliopsoas, gluteus medius, gluteus maximus, and hamstrings muscles. The twice-daily sessions involved progressive efforts aimed to facilitate the patient’s transition from bed to wheelchair. Subsequently, efforts were aimed to achieve a vertical posture, first, with walker-assisted gait recovery, and thereafter, with the use of parallel bars. Finally, the muscles were reinforced by staircase step-based workout. At the end of rehabilitation (5 months later), muscle strength of the right leg was graded at 4/5 for the iliopsoas, gluteus medius, and gluteus maximus muscles, and 3/5 for the quadriceps; for the left leg, it was graded 4/5 for the gluteus medius and gluteus maximus muscles, and at 3/5 for the iliopsoas and quadriceps. The patient was equipped with a knee-ankle-foot orthosis to prevent laxity of the legs during transition to vertical gait. The patient could perform daily activities autonomously using a walker. He was able to climb and descend stairs with the support of 2 grab bars and assistance from another person. However, the use of a wheelchair was maintained for external activities and for long-distance locomotion. For self-improvement and at-home improvement, the ergotherapist recommended the installation of technical aids, such as an electric stairlift, to preserve autonomy.\n\nUnfortunately, during the rehabilitation, the patient experienced blurred vision in the right eye, 5 months after the SCI. His visual acuity at presentation was 20/200. Slit lamp examination findings were normal, but fundus examination revealed multiple retinal hemorrhages associated with venous tortuosity, cotton-wool spots, and optic nerve edema. The presence of macular edema was confirmed with Optical Coherence Tomography (OCT) (Heidelberg Engineering, Heidelberg, Germany). These findings informed a diagnosis of central RVO complicated by macular edema (Figure 2). The patient was administered intravitreal anti-vascular endothelial growth factor (aflibercept 25 mg/mL) injections.\n\nThe last follow-up, six months after the onset of RVO and 11 months after SCI, revealed no new neurological sign or systemic symptoms. Muscle strength remained at 4/5 for the iliopsoas, gluteus medius, and gluteus maximus muscles, and at 3/5 for the quadriceps of both legs; however, hypoesthesia and associated paresthesia persisted. The patient could move autonomously with a walker. MRI examination did not reveal any new abnormalities in the spinal cord or brain. Although fundus examination showed partial regression of the central RVO signs, OCT showed complete resorption of the macular edema. Moreover, the patient’s renal function improved after hemodialysis.\n\nFigure 1. Magnetic resonance images acquired 4 days after the onset of paraplegia. T2- weighted sagittal (A) and axial (B) images show hyperintensity at the T12-L1 level in the form an anteromedial spot. No other spinal cord lesions were detected.\n\nFigure 2. Fundus photography acquired at the onset of blurred vision (A) show signs of central retinal venous occlusion, such as retinal hemorrhage, venous tortuosity, cottonwool spots, and optic nerve edema. Optical coherence tomography image shows a cystoid macular edema associated with serous retinal detachment (B). Six months later, the signs of central retinal venous occlusion show partial regression (C), with subtotal resorption of the macular edema after four intravitreal injections of anti-vascular endothelial growth factor drug (Aflibercept; D).\n\nDiscussion and Conclusions\nSCI, with an estimated prevalence of 1.2% among patients who have experienced stroke, remains an elimination diagnosis.10 Indeed, even in patients with signs suggestive of SCI—e.g., abrupt onset of bilateral motor deficiency, dissociative anesthesia with selective loss of thermalgesic sensitivity and involvement of the anterior artery— the MRI results can appear normal in the first few hours after the ischemic event, and even across all follow-up visits in up to 45% of SCI cases.11 In our case, the clinical presentation was typical of SCI, and T2- weighted MR images obtained 4 days after symptom onset confirmed the presumptive diagnosis of SCI. However, the ischemic site was situated in the lower level of the spinal cord, which accounts for the limited presentation of autonomic disorders. The fulfillment of three major criteria of SCI as proposed by Zalewski et al. (clinical presentation, MRI findings, and non-inflammatory CSF profile) supported the diagnosis of probable spontaneous SCI.12\n\nMultiple etiologies can result in SCI such as: atherosclerosis, systemic hypotension, infection, emboli, vasculitis, aortic dissection, decompression sickness, and iatrogenic causes during vascular or neurological surgery.13 Furthermore, previous case studies have reported that patients with thrombophilia, such as those with protein S deficiency or prothrombin mutation, experience episodes of SCI.14,15 In our case, beside a prolonged history of cancer treatment, the patient presented systemic hypotension at SCI onset, along with severe anemia and a thrombophilic profile (protein S, 36%; total protein, >120%), which by extension may be indicative of severe CKD. Indeed, CKD induces hypertension, endothelial dysfunction, chronic inflammation, oxidative stress, anemia, nitric oxide (NO) reduction, hyperhomocysteinemia, and other systemic dysfunctions that promote atherogenesis and arteriosclerosis.7 The coagulation abnormalities might also be due to CKD, which is generally accompanied by a thrombophilic state and protein S deficiency.16 Hence, these multiple factors, in conjunction with cancer treatmentinduced atherosclerosis, which observed at presentation and throughout his clinical history, yielded a favorable environment for thrombosis.17\n\nAn additional vascular accident in the retina that occurred only a few months after the first SCI event exacerbated the patient’s condition. The rates of stroke and all-cause mortality increases with RVO, even if the latter involves the venous retinal system.6 Moreover, venular widening observed in RVO has been identified as a risk factor for lacunar strokes, which are a consequence of small vessel occlusion.18 Interestingly, a large case series identified shared risk factors between RVO and stroke.3 RVO can thus be considered as an indirect sign of deteriorating vascular state, despite selective involvement of the veins. This may be explained by the narrow physical connections between arteries and veins in the optic nerve head and retina, wherein they share a common adventitial sheath; hence, a thickwalled, atherosclerotic central retinal artery can compresses the thin-walled ventral vein.3\n\nOn other hand, CKD exacerbates the frequency and severity of risk factors for cardiovascular diseases and increases the incidence of RVO and strokes.19,20 However, after adjustment of the aforementioned systemic disorder-induced confounding factors, several studies have reported that CKD in itself is a risk factor for cardiovascular diseases.6 Admittedly, in our case, the patient developed CKD after idiopathic membranous glomerulonephritis type 1, and previous case studies have reported the occurrence of RVO after development of membranous glomerulonephritis without uremia.18 This association was attributed to coagulation disorders and hypovolemia, consequent of nephrotic syndrome. Although our patient manifested hypotension with acute kidney dysfunction at the onset of SCI, CKD was observed 9 years ago, and moreover, he had severe uremia. Thus, the underlying mechanism for RVO development can be explained by a vascular disorder induced by pre-existing uremia in addition to hypovolemia and thrombophilia.\n\nThe most probable explanation for the association of SCI and RVO, in this case, is the presentation of several well-documented risk factors for cardiovascular diseases, such as blood hypertension, anemia, and cardiotoxicity induced by cancer treatment. The CKD facilitated a prothrombotic environment, which was exacerbated by oxidative stress, thrombophilia, chronic inflammation, hyperhomocysteinemia, endothelial dysfunction, and decreased synthesis of vitamin D and NO. We surmise that all these factors contributed to the development of severe atherosclerosis, which resulted in SCI due to thrombosis and occlusion of the anterior spinal artery. This SCI, despite anti-platelet treatment, resulted in central RVO a few months later; the latter incident was likely caused by the compression of the central retinal vein by a rigid retinal artery.\n\nIn conclusion, the present case illustrates that beyond being a rare, disabling disease, SCI can also predict a high risk of future cardiovascular events, such as ocular vascular disease, especially in patients with chronic kidney disease (CKD). This report thus highlights that mitigation of associated risk factors, including early management of CKD, is required to prevent vascular complications associated with stroke. Finally, further studies are required to evaluate the state of retinal vascularization in patients with SCI, especially since retinal vascularization abnormalities were noted in patients suffering from stroke. Such assessment would indicate a bad vascular state in patients with spontaneous SCI.\n\nAcknowledgements\nWe acknowledge the contribution of the centre de recherche Clinique (CRC) department of Centre hospitalier d’Argenteuil for supporting and providing facilities for the revision and edition of this work.\n==== Refs\nReferences\n1. Vuong SM Jeong WJ Morales H Abruzzo TA \nVascular Diseases of the Spinal Cord: Infarction, Hemorrhage, and Venous Congestive Myelopathy\n. Seminars in Ultrasound, CT and MRI \n2016 ;37 :466 –81\n.\n2. Ip M Hendrick A. \nRetinal Vein Occlusion Review\n. Asia Pac J Ophthalmol (Phila) \n2018 ;7 :40 –5\n.29280368 \n3. Risk factors for central retinal vein occlusion . The Eye Disease Case- Control Study Group\n. Arch Ophthalmol \n1996 ;114 :545 –54\n.8619763 \n4. Park SJ Choi NK Yang BR \nRisk of stroke in retinal vein occlusion\n. Neurology \n2015 ;85 :1578 –84\n.26453647 \n5. Zhong C You S Zhong X \nRetinal vein occlusion and risk of cerebrovascular disease and myocardial infarction: A meta-analysis of cohort studies\n. Atherosclerosis \n2016 ;247 :170 –6\n.26922716 \n6. Wu CY Riangwiwat T Limpruttidham N \nAssociation of retinal vein occlusion with cardiovascular events and mortality: a systematic review and meta-analysis\n. Retina (Philadelphia, Pa) \n2019 ;39 :1635 -45\n.\n7. Cherng YG Lin CS Shih CC \nStroke risk and outcomes in patients with chronic kidney disease or endstage renal disease: Two nationwide studies\n. PLoS ONE \n2018 ;13 :e0191155 .29329323 \n8. Grunwald JE Ying G-S Maguire M \nChronic Renal Insufficiency Cohort (CRIC) Study Group. Association between retinopathy and cardiovascular disease in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study)\n. Am J Cardiol \n2012 ;110 :246 –53\n.22516527 \n9. Kirshblum SC Burns SP Biering-Sorensen F \nInternational standards for neurological classification of spinal cord injury (revised 2011)\n. J Spinal Cord Med \n2011 ;34 :535 –46\n.22330108 \n10. Sandson TA Friedman JH \nSpinal cord infarction. Report of 8 cases and review of the literature\n. Med (Baltimore) \n1989 ;68 :282 –92\n.\n11. Yadav N Pendharkar H Kulkarni GB \nSpinal Cord Infarction: Clinical and Radiological Features\n. J Stroke Cerebrovasc Dis \n2018 ;27 :2810 -21\n.30093205 \n12. Zalewski NL Rabinstein AA Krecke KN \nCharacteristics of Spontaneous Spinal Cord Infarction and Proposed Diagnostic Criteria\n. JAMA Neurol \n2018 ;76 :56 -73\n.\n13. Nasr DM Rabinstein A. \nSpinal Cord Infarcts: Risk Factors, Management, and Prognosis\n. Curr Treat Options Neurol \n2017 ;19 :28 .28688063 \n14. Hakimi KN Massagli TL \nAnterior spinal artery syndrome in two children with genetic thrombotic disorders\n. J Spinal Cord Med \n2005 ;28 :69 –73\n.15832907 \n15. Ramelli GP Wyttenbach R von der Weid N Ozdoba C. \nAnterior spinal artery syndrome in an adolescent with protein S deficiency\n. J Child Neurol \n2001 ;16 :134 –5\n.11292220 \n16. Bauer A Limperger V Nowak-Göttl U. \nEnd-stage renal disease and thrombophilia\n. Hamostaseologie \n2016 ;36 :103 –7\n.25639843 \n17. Mukai M Komori K Oka T. \nMechanism and Management of Cancer Chemotherapy-Induced Atherosclerosis\n. J Atheroscler Thromb \n2018 ;25 :994 –1002\n.30224607 \n18. Masoodi I Wani IA Hussain S Najar MS Reshi AR Qurashi FA Khan S. \nSudden retinal vein thrombosis in a patient with nephrotic syndrome\n. BMJ Case Rep \n2011 ;2011 .\n19. Lindley RI Wang JJ Wong M-C \nMulti-Centre Retina and Stroke Study (MCRS) Collaborative Group. Retinal microvasculature in acute lacunar stroke: a cross-sectional study\n. Lancet Neurol \n2009 ;8 :628 –34\n.19481977 \n20. Masson P Webster AC Hong M \nChronic kidney disease and the risk of stroke: a systematic review and metaanalysis\n. Nephrol Dial Transplant \n2015 ;30 :1162 –9\n.25681099\n\n",
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"title": "Spinal cord infarction associated to retinal vein occlusion in a patient with chronic kidney disease.",
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"abstract": "The administration of furosemide to pre-term neonates has been associated with urolithiasis. We report 1 of 2 such cases that we have managed. The etiology of these stones appears to be related to furosemide-induced hypercalciuria. Nonsurgical management with thiazide diuretics can be successful in this high risk group of patients.",
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"authors": "Noe|H N|HN|;Bryant|J F|JF|;Roy|S|S|;Stapleton|F B|FB|",
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"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D002118:Calcium; D005665:Furosemide; D006801:Humans; D007231:Infant, Newborn; D007669:Kidney Calculi; D008297:Male; D011859:Radiography; D012306:Risk",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Urolithiasis in pre-term neonates associated with furosemide therapy.",
"title_normalized": "urolithiasis in pre term neonates associated with furosemide therapy"
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