article dict | reports listlengths 1 3.97k |
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{
"abstract": "Gemcitabine is a nucleoside analogue used widely across haemato-oncology. Side effects are generally predictable, and typically consist of cytopenia, nausea, and infection. As the present case clearly demonstrates, gemcitabine is in rare cases associated with life-threatening large vessel vasculitis, which can involve the aorta. It is important to consider gemcitabine-induced vasculitis in non-specifically unwell patients with raised inflammatory markers and fever of unknown origin, with or without signs of vascular compromise. Early recognition, cessation of gemcitabine therapy, and high-dose steroids are critical for a good outcome. PET CT is valuable to diagnose large vessel vasculitis and monitor treatment response.",
"affiliations": "Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, OX3 7EJ, UK, toby.eyre@ouh.nhs.uk.",
"authors": "Eyre|Toby A|TA|;Gooding|Sarah|S|;Patel|Ishita|I|;Moore|Niall|N|;Hatton|Chris|C|;Collins|Graham P|GP|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D019788:Fluorodeoxyglucose F18; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1555-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "99(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001013:Aorta, Thoracic; D003841:Deoxycytidine; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007083:Iliac Artery; D008875:Middle Aged; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D014657:Vasculitis",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "798-800",
"pmc": null,
"pmid": "24584910",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14597878;10815173;20213928;11955656;15728007;14766271;14745551;20407388;19076809;21411201;39515",
"title": "Gemcitabine-induced large vessel vasculitis demonstrated by PET CT: a rare, important side effect.",
"title_normalized": "gemcitabine induced large vessel vasculitis demonstrated by pet ct a rare important side effect"
} | [
{
"companynumb": "GB-DRREDDYS-USA/UKI/15/0054045",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine whether granulocyte colony-stimulating factor (G-CSF) prophylaxis after consolidation with high- or intermediate-dose cytarabine (H/IDAC) for treatment of acute myeloid leukemia (AML) reduces the frequency of neutropenia-associated complications.\n\n\nMETHODS\nRetrospective medical record review.\n\n\nMETHODS\nAcademic medical center.\n\n\nMETHODS\nSeventy-eight patients aged 18 years or older in whom H/IDAC consolidation chemotherapy was initiated for consolidation of AML between November 2004 and November 2010.\n\n\nRESULTS\nPatient demographic data, information on the hospitalization for consolidation, data on G-CSF use after H/IDAC chemotherapy, and details on any readmissions were collected. Patients were deemed to have received G-CSF prophylaxis if there was documentation of the intent for use of either filgrastim or pegfilgrastim. Outcome data also were collected, including dates of relapse or second induction treatment course, and death or last follow-up visit. We compared data based on patient receipt of G-CSF (G-CSF vs no G-CSF) after each chemotherapy cycle. We assessed differences in the duration of hospitalization, fever, intravenous antibiotic use, and neutropenia, as well as rate of documented infections, time to disease recurrence, and overall survival. Compared with no G-CSF, use of G-CSF after cycle 1 of H/IDAC significantly reduced the rate of hospitalization for febrile neutropenia (p=0.039); however, no significant differences were noted for subsequent cycles. No significant differences were seen in duration of hospitalization, rate of documented infections, or time to treatment failure between groups. Overall survival was longer for patients who received G-CSF during their first cycle (p=0.018) and for those who received G-CSF during any of their cycles (p=0.04).\n\n\nCONCLUSIONS\nUse of G-CSF prophylaxis after cycle 1 of H/IDAC consolidation for AML appears to reduce the frequency of hospitalization for febrile neutropenia and to increase overall survival compared with no G-CSF use. Prospective, controlled studies are needed to support our findings.",
"affiliations": "Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA 30912, USA. abradley@georgiahealth.edu",
"authors": "Bradley|Amber M|AM|;Deal|Allison M|AM|;Buie|Larry W|LW|;van Deventer|Hendrik|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "32(12)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006760:Hospitalization; D006801:Humans; D007902:Length of Stay; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1070-7",
"pmc": null,
"pmid": "23208834",
"pubdate": "2012-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Neutropenia-associated outcomes in adults with acute myeloid leukemia receiving cytarabine consolidation chemotherapy with or without granulocyte colony-stimulating factor.",
"title_normalized": "neutropenia associated outcomes in adults with acute myeloid leukemia receiving cytarabine consolidation chemotherapy with or without granulocyte colony stimulating factor"
} | [
{
"companynumb": "US-AMGEN-USASP2019182398",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy and safety of CAPOX plus bevacizumab as second-line chemotherapy for metastatic colorectal cancer.\n\n\nMETHODS\nIn this multicenter phase Ⅱ study, the planned number of patients was 48, but owing to poor case accumulation, registration was discontinued for 20 patients. The primary endpoint was the response rate(RR). Secondary endpoints were progression-free survival(PFS), overall survival(OS), disease control rate(DCR), and safety.\n\n\nRESULTS\nFirst-line treatment was combined with irinotecan in 14 cases and bevacizumab in 12 cases. The median number of second- line treatment courses was 7, and the median treatment period was 203 days. The reason for discontinuation of treatment was disease progression in 13 cases, adverse events in 4 cases, and other reasons in 3 cases. The best response was PR in 5 cases, SD in 8 cases, and NE in 4 cases. The RR was 25%, and the DCR was 65%. The median PFS was 7.2 months, and the median OS was 18.6 months. Grade≥3 adverse events were neutropenia in 3 cases and diarrhea and peripheral neuropathy in 2 cases each. There were no treatment-related deaths.\n\n\nCONCLUSIONS\nCAPOX plus bevacizumab was a safe and effective second-line treatment option for metastatic colorectal cancer.",
"affiliations": "Clinical Study Group of Osaka University, Colorectal Group.",
"authors": "Komori|Takamichi|T|;Fukunaga|Mutsumi|M|;Miyoshi|Norikatsu|N|;Paku|Masakatsu|M|;Murata|Kohei|K|;Kim|Ho Min|HM|;Takahashi|Hidekazu|H|;Uemura|Mamoru|M|;Matsuda|Chu|C|;Mizushima|Tsunekazu|T|;Doki|Yuichiro|Y|;Eguchi|Hidetoshi|H|",
"chemical_list": "D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005472:Fluorouracil; D006801:Humans; D000077150:Oxaliplatin; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "357-361",
"pmc": null,
"pmid": "33790157",
"pubdate": "2021-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Capecitabine and Oxaliplatin(CAPOX)plus Bevacizumab as Second-Line Chemotherapy for Metastatic Colorectal Cancer.",
"title_normalized": "capecitabine and oxaliplatin capox plus bevacizumab as second line chemotherapy for metastatic colorectal cancer"
} | [
{
"companynumb": "JP-ROCHE-2806300",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "In recent years, the number of patients undergoing liver transplant has increased. Successful transplant has resulted in better quality of life and improved fertility in younger women. This is a case study a 31-year-old woman, who had history of Budd-Chiari syndrome and underwent liver transplantation in 2014 with uneventful postoperative course. She was clinically stable on tablet tacrolimus and coumarin with no episode of allograft rejection since transplantation. The patient conceived spontaneously, after 4 years of transplant and during pregnancy, she was managed by multidisciplinary team. During the initial period, the graft and pregnancy continued without complications. However, at 33 weeks, the patient presented with sluggish fetal movements, amniotic fluid index of 3.4 and SD ratio of 3.31 for which she underwent caesarean section. She delivered a healthy female baby of 1.4 kg. This case study concludes that vigilant monitoring of fetal growth is pivotal for optimal fetal outcome.",
"affiliations": "Obstetrics & Gyunaecology, Services Institute of Medical Sciences, Lahore, Punjab, Pakistan rubina95@gmail.com.;Obstetrics & Gynaecology, Hameed Latif Hospital, Lahore, Punjab, Pakistan.;Obstetrics & Gynaecology, Hameed Latif Hospital, Lahore, Punjab, Pakistan.;Obstetrics & Gynaecology, Services Hospital, Lahore, Punjab, Pakistan.",
"authors": "Sohail|Rubina|R|;Bashir|Alia|A|;Safdar|Zara|Z|;Noreen|Asifa|A|",
"chemical_list": "D003374:Coumarins; C030123:coumarin; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229315",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(2)",
"journal": "BMJ case reports",
"keywords": "pregnancy; transplantation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D006502:Budd-Chiari Syndrome; D002585:Cesarean Section; D003374:Coumarins; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D016559:Tacrolimus",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32041753",
"pubdate": "2020-02-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful pregnancy in a liver transplant patient of Budd-Chiari syndrome.",
"title_normalized": "successful pregnancy in a liver transplant patient of budd chiari syndrome"
} | [
{
"companynumb": "PK-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-244321",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "BACKGROUND\nMetformin is commonly used for the treatment of type 2 diabetes mellitus. Renal insufficiency is one of the contraindications for its use. Inadvertent prescription in patients with renal insufficiency may lead to metformin-associated lactic acidosis (MALA), which is associated with a high risk of mortality. Consequently, the early recognition and management of MALA is essential.\n\n\nMETHODS\nWe present the case of a 68-year-old man who had reversible blindness resulting from severe lactic acidosis. On presentation, he was alert, oriented, and had no complaints except mild abdominal discomfort and blindness. He denied any history of trauma or drug abuse. The results of the laboratory studies showed severe metabolic acidosis with a high anion gap and increased levels of serum creatinine. There were no predisposing ocular or neurologic lesions that could have induced the blindness. Although the blood levels of methanol, ethanol, and metformin were not estimated, correction of acidosis and hemodialysis led to a complete recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Rarely, transient blindness may occur in patients with fatal severe metabolic acidosis. Evaluation for the presence of metabolic acidosis and a detailed medical history are essential in the management of acute blindness in such patients.",
"affiliations": "Department of Emergency Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.;Department of Emergency Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.;Department of Emergency Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.;Department of Emergency Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.;Department of Emergency Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.;Department of Nephrology, Chungnam National University Hospital, Daejeon, Republic of Korea.",
"authors": "Ryu|Seung|S|;Oh|Se-Kwang|SK|;Son|Seung-Ha|SH|;Jeong|Won-Joon|WJ|;You|Yeon-Ho|YH|;Ham|Young-Rok|YR|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2019.06.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "57(5)",
"journal": "The Journal of emergency medicine",
"keywords": "blindness; lactic acidosis; metformin",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D001766:Blindness; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e153-e156",
"pmc": null,
"pmid": "31591073",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible Acute Blindness in Suspected Metformin-Associated Lactic Acidosis.",
"title_normalized": "reversible acute blindness in suspected metformin associated lactic acidosis"
} | [
{
"companynumb": "KR-BEXIMCO-2019BEX00045",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nDoxorubicin and ifosfamide (AI) is standard therapy for high-risk soft tissue sarcoma (STS) but often causes severe toxicities resulting in hospitalisation. Gemcitabine and docetaxel (GD) has efficacy in metastatic STS and may be better tolerated. We conducted a study to compare toxicities and efficacies of these regimens.\n\n\nMETHODS\nThis open-label, phase II, single institution trial randomised 80 patients with localised, resectable, high grade STS ⩾ 5 cm to either neo/adjuvant AI or GD. AI was doxorubicin (75 mg/m(2)) and ifosfamide (2.5 g/m(2)/d) on days 1-3 with mesna 500 mg/m(2)/dose. GD was gemcitabine 900 mg/m(2) on days 1, 8 and docetaxel 100mg/m(2) day 8. Both arms included filgrastim. The primary end-point was hospitalisation rate. Secondary end-points included disease-free survival (DFS) and overall survival (OS).\n\n\nRESULTS\nBetween November 2004 and August 2012, 80 evaluable patients were randomised, 37 to AI and 43 to GT. In the AI arm, 13/37 (35%) patients were hospitalised versus 11/43 (26%) in the GD arm (p=0.25). Hospitalisation rates were not significantly different after adjusting for age, gender, location, chemotherapy and number of cycles (p=0.17). The 2-year and median DFS in the AI arm were 57% and 37 months, respectively, and 74% and not yet reached, respectively, in the GD arm. The most common serious adverse events with AI were haematologic. Metabolic derangements and constitutional symptoms were most common with GD.\n\n\nCONCLUSIONS\nHospitalisation rate was less with GD but not statistically significant. There was a trend towards longer DFS with GD, and the regimen was tolerable, suggesting GD merits further study.",
"affiliations": "Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States.;Department of Pathology, University of Michigan, Ann Arbor, MI, United States.;Department of Surgery, University of Michigan, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States.;Department of Surgery, University of Michigan, Ann Arbor, MI, United States.;Department of Radiology, University of Michigan, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Clinical Trials Office, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States.;Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States. Electronic address: scotschu@med.umich.edu.",
"authors": "Davis|Elizabeth J|EJ|;Chugh|Rashmi|R|;Zhao|Lili|L|;Lucas|David R|DR|;Biermann|J Sybil|JS|;Zalupski|Mark M|MM|;Feng|Mary|M|;Wong|Sandra L|SL|;Jacobson|Jon|J|;Zyczynski|Laurie|L|;Reinke|Denise|D|;Metko|Gino|G|;Baker|Laurence H|LH|;Schuetze|Scott M|SM|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; C056507:gemcitabine; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "51(13)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Docetaxel; Doxorubicin; Gemcitabine; Ifosfamide; Neo(adjuvant) chemotherapy; Soft tissue sarcoma",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D006760:Hospitalization; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008297:Male; D008824:Michigan; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D043823:Taxoids; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "1794-802",
"pmc": null,
"pmid": "26066736",
"pubdate": "2015-09",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomised, open-label, phase II study of neo/adjuvant doxorubicin and ifosfamide versus gemcitabine and docetaxel in patients with localised, high-risk, soft tissue sarcoma.",
"title_normalized": "a randomised open label phase ii study of neo adjuvant doxorubicin and ifosfamide versus gemcitabine and docetaxel in patients with localised high risk soft tissue sarcoma"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US07418",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "BACKGROUND\nRecent years have witnessed a marked improvement in the safety and accuracy of nerve blocks with the help of ultrasound and other visualization technologies. This study reports a challenging case of a severe complication during the ultrasound-guided stellate ganglion block.\nA 28-year-old male patient with refractory migraine complained episodic pulsatile pain with photophobia, haphalgesia of the scalp for 3 years.\n\n\nMETHODS\nUltrasound-guided stellate ganglion block with 4 ml of 1% lidocaine was administrated.\n\n\nRESULTS\nA sudden loss of consciousness and tonic-clonic seizure was occurred after negative aspiration and test dose. Further sonographic examination revealed a variation in the left vertebral artery, which remained unrecognized during the needle insertion because of its sliding ability under the differential pressure applied by the probe.\n\n\nCONCLUSIONS\nInadvertent intra-arterial injection of a local anesthetic agent could be minimized under the ultrasound guidance with various protective strategies, including the determination of any prior variation, optimizing the block route, maintaining a constant probe pressure, and using saline for the test dosage. This case resulted in the implementation of new protocols of the ultrasound-guided stellate ganglion block in our department.",
"affiliations": "Department of Anesthesiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.",
"authors": "Lu|Fan|F|;Tian|Jie|J|;Dong|Jifu|J|;Zhang|Kexian|K|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018168",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31770265MD-D-19-0231910.1097/MD.0000000000018168181683300Research ArticleClinical Case ReportTonic–clonic seizure during the ultrasound-guided stellate ganglion block because of an injection into an unrecognized variant vertebral artery A case reportLu Fan MDTian Jie MDDong Jifu MD, PhDZhang Kexian MD, PhD∗NA. Department of Anesthesiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.∗ Correspondence: Kexian Zhan, Sichuan Cancer Hospital & Institute, #55 Ren Min Road South, Chengdu 610000, Sichuan Province, China (e-mail: zhangkx3@sina.com).11 2019 27 11 2019 98 48 e1816825 3 2019 17 10 2019 30 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This 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:\nRecent years have witnessed a marked improvement in the safety and accuracy of nerve blocks with the help of ultrasound and other visualization technologies. This study reports a challenging case of a severe complication during the ultrasound-guided stellate ganglion block.\n\nPatient concerns:\nA 28-year-old male patient with refractory migraine complained episodic pulsatile pain with photophobia, haphalgesia of the scalp for 3 years.\n\nInterventions:\nUltrasound-guided stellate ganglion block with 4 ml of 1% lidocaine was administrated.\n\nOutcomes:\nA sudden loss of consciousness and tonic–clonic seizure was occurred after negative aspiration and test dose. Further sonographic examination revealed a variation in the left vertebral artery, which remained unrecognized during the needle insertion because of its sliding ability under the differential pressure applied by the probe.\n\nLessons:\nInadvertent intra-arterial injection of a local anesthetic agent could be minimized under the ultrasound guidance with various protective strategies, including the determination of any prior variation, optimizing the block route, maintaining a constant probe pressure, and using saline for the test dosage. This case resulted in the implementation of new protocols of the ultrasound-guided stellate ganglion block in our department.\n\nKeywords\nseizurestellate ganglion blockultrasound-guidedOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA stellate ganglion block is a standard diagnostic and treatment modality for reflex sympathetic dystrophy and Meniere disease. It also demonstrates a good effect on sympathetically maintained headaches, including migraines.[1–3] Compared with a blind procedure, the ultrasound guidance is a reliable method to decrease complications arising from an intravascular injection and nerve injury because of its advantages in the direct visualization of the trachea, blood vessels, thyroid, and bony surfaces.[4] However, a successful ultrasound-guided stellate ganglion block warrants proficiency in anatomy, pre-procedural planning, and inserting technologies to evade any possible injury of the proximity structures.[5] In addition, intravascular injections could cause mild to severe complications, from tinnitus to even cardiac arrest.[6,7] Here, we report the case of a patient who demonstrated symptoms of sudden loss of consciousness and tonic–clonic seizure during the ultrasound-guided stellate ganglion block, despite us taking several preventive measures such as test dose, negative aspiration, and good cooperation of the patient.\n\n2 Case presentation\nA 28-year-old Asian male patient was admitted to our hospital for a refractory migraine of 3 years. He complained hours of pulsatile pain with photophobia, haphalgesia of the scalp, and fatigue during each attack. His medical history was unremarkable, and his magnetic resonance imaging and computed tomography angiography revealed no imaging anomaly. Accordingly, he was treated with naproxen (0.5 g qd) and flunarizine hydrochloride (10 mg qd) with poor improvement. Thus, treatment with an ultrasound-guided stellate ganglion block on each side a time was planned as a complementary therapy.\n\nWith the patient's informed consent, the first block was successfully performed on the right side with temporary Horner syndrome, decreasing attacks on the first day. Thus, the next block for the other side was administrated the day after. During the practice, the patient laid in the supine position with a thin pillow under his shoulder to ensure the extension of the anterior neck. Before the procedure, the patient was instructed to raise his hand if he felt any discomfort but was not allowed to speak or swallow. He was monitored by pulse oximetry and noninvasive blood pressure. We adopted the in-plane approach because of the clear ultrasonography at the level of the 6th cervical vertebra (C6) transverse process and prepared 4 ml of 1% lidocaine with a 22-gauge needle and 12-MHz linear probe. During the procedure, the needle was supposed to be inserted between the carotid artery and thyroid toward the prevertebral fascia anterior to the longus colli muscle (Fig. 1). However, we lost track of the tip when the inserting the needle, which passed the fascia of the artery and thyroid. Hence, the operator cautiously jiggled the needle to detect the tip. After the tip was confirmed by the concomitant jitter of the target tissue (the surface of the longus colli muscle), 0.5 ml of 1% lidocaine was injected; however, the injectate could not be clearly visualized, prompting the operator to slowly withdraw the needle and decide using the in-plane approach instead. The patient suddenly raised his hand and lost consciousness followed by approximately 2-minute tonic–clonic seizure. The patient was immediately ventilated manually with 100% oxygen by a facemask, and an intravenous line was set up followed by an injection of 2-mg midazolam. The patient quickly returned to calm and natural breathing state, and, after 10 minutes of somnolence, regained complete consciousness but could not recall the previous experience.\n\nFigure 1 The planned puncture path route at the sixth cervical vertebral level. AT = anterior tubercle, C = carotid artery, LC = longus colli muscle, SCM = sternocleidomastoid muscle, TP = transverse process. Puncture path (dotted arrow).\n\nLater, we used ultrasound to re-examine the patient, but found no hematoma. However, further examination revealed that a 6-mm-diameter artery at the C6 level was in the posteromedial of the carotid artery, which went completely unrecognized at the initial scanning, and could easily slide to the lateral side when the operator pressurizes the probe (Fig. 2). Then, we traced cranially to determine the entry of the artery into the transverse foramen of the 5th cervical vertebra (C5) (Fig. 3), which was preliminarily determined as a variant vertebral artery. The patient was discharged after 2-hour of observation and was followed up for 2 months. No complaints of dizziness, tinnitus, and dysphagia were reported.\n\nFigure 2 The change in the position of the left vertebral artery under the differential pressure of ultrasound probe. (a) The ultrasound image at the C6 level with higher pressure on the probe; (b) The ultrasound image at the C6 level with less pressure on the probe. AT = anterior tubercle, C = carotid artery, IJ = internal jugular vein, LC = longus colli muscle, SCM = sternocleidomastoid muscle, TP = transverse process. ∗Vertebral artery (white dotted circle).\n\nFigure 3 The color Doppler ultrasound image of the vertebral artery. (a) The M-mode ultrasound image of the vertebral artery at C6 level; (b) The color Doppler ultrasound image showed the left vertebral artery entered the transverse foramen at C5.\n\n3 Discussion\nThis case reports the rare occurrence of a severe complication during the ultrasound-guided stellate ganglion block. Although ultrasound remarkably enhances the safety of nerve blocks, avoidable negligence can be encountered even by senior operators when there is a lack of complete protocols. In our case, an intra-arterial injection was confirmed by intoxicated reactions of a local anesthetic agent and ultrasonography of the unrecognized left vertebral artery.\n\nIntra-arterial injection, intravenous injection, and regional absorption could cause the systemic local anesthetic toxicity. The onset and severity of complications highly depend on the injection routes and dosage of the local anesthetic agent. The lowest dose of lidocaine-associated seizure during intravenous regional anesthesia was 1.4 mg/kg,[8] and only large volumes (5–10 ml) of a local anesthetic agent could cause systemic toxicity within 5 minutes during an inadvertent intravenous injection.[9,10] However, central nervous system symptoms might occur very rapidly after a bolus of an intra-arterial injection. The minimum toxic dose of lidocaine injected into the vertebral artery is approximately 16.8 mg for adults with a body weight of 70 kg.[11] In our case, the tonic–clonic seizure occurred only after the 5-mg lidocaine injection, which was lower than any other reports.[11,12] The rapid injection might be accountable for the toxic central plasma concentration of local anesthetic agents. Mechanism research revealed that the central toxicity of lidocaine originates in areas of thalamocortical neurons and could result from evoked high-threshold Ca2+ currents.[13]\n\nIn this case, intra-arterial injections occurred despite the absence of the blood reflux. Some studies have reported complications followed by negative aspiration,[11,14,15] suggesting that the single aspiration is not entirely reliable to determine the location of the needle tip. The best method is always to ensure good visualization of the entire needle, especially the tip, under the ultrasound guidance, and re-confirm the tip position by the spread of the liquid sonolucent in real-time.\n\nThe stellate ganglion block is considered to be safer at the C6 level to avoid the proximity of the vertebral artery, inferior thyroid artery, and pleura. However, the risk of this procedure could be profoundly exacerbated with the absence of the transverse foramen, as in the case of a vertebral artery variation. Approximately 2% to 10% of the vertebral artery entered into the transverse foramen at a level other than C6, with the most common variation entrance at C5.[16–18] In our procedure, the anatomical variation was undetected at the C6 level during the pre-scanning because the high pressure conducted by the probe pressed the vertebral artery to the lateral side of the carotid artery. However, during the out-of-plane puncture, this uncovered vertebral artery slid to the needle path because of pressure variations. In addition, the muscular neck of the patient made it even harder to detect the tip in the out-of-plane approach, eventually resulting in the intra-arterial injection. Thus, maintaining the constant pressure of the ultrasound probe is imperative to retain an optimal insertion path under the ultrasound guidance. Moreover, it is not recommended to inject a local anesthetic agent to verify the location of the unvisualized tip even if it is possibly near the target areas. Instead, normal saline can work as a good alternative injectate to visualize the needle tip with no occurrence of local anesthetic intoxication.[19]\n\nA new protocol for ultrasound-guided stellate ganglion block was implemented in our department (Fig. 4). The out-of-plane technique is primarily applied to the superficial nerve block, especially when the repeated blocks to the same target are required. This approach shortens the puncture path route and time but is only recommended for experienced operators and in the absence of any anatomical variation of the target areas. The vertebral artery is not the only cause for the intra-arterial injection in the neck during the stellate ganglion block, the presence of the ascending cervical artery, deep cervical artery, and inferior thyroid artery is recorded in the proximity of puncture levels.[20] Thus, the in-plane technique or semi-in-plane technique is essential for patients with high risks of puncture-related complications. Meticulous pre-scanning plays a vital role in the block strategy decision, and it is necessary to move the probe cranially and caudally from the target level, assisted by tilting and pressure variation to eliminate the possibility of variations. For patients with known variations, it is preferable to comprehensively assess the benefits of this invasive procedure in the first place, educate patients to prove good cooperation, put an intravenous line beforehand, and ensure visualizing the whole needle during the block. If the tip of needle and the test injectate were not confirmed after 2 attempts, the alternative procedures should be considered.\n\nFigure 4 The new protocol for ultrasound-guided stellate ganglion block.\n\nAcknowledgments\nThe authors acknowledge the patient presented case report, and thank Dr. He Huang for editorial assistance for this manuscript.\n\nAuthor contributions\nConceptualization: Kexian Zhang.\n\nMethodology: Kexian Zhang.\n\nSupervision: Kexian Zhang.\n\nValidation: Jifu Dong.\n\nWriting – original draft: Jie Tian, Fan Lu.\n\nWriting – review & editing: Jie Tian, Fan Lu.\n\nAbbreviations: C5 = 5th cervical vertebra, C6 = 6th cervical vertebra.\n\nHow to cite this article: Lu F, Tian J, Dong J, Zhang K. Tonic–clonic seizure during the ultrasound-guided stellate ganglion block because of an injection into an unrecognized variant vertebral artery: a case report. Medicine. 2019;98:48(e18168).\n\nFL and JT contributed to the work equally and should be regarded as co-first authors.\n\nThe authors have no sources of funding to declare for this manuscript.\n\nThe patients have provided written informed consents for publication of the cases and the related images.\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n[1] Chan CW Chalkiadis GA \nA case of sympathetically mediated headache treated with stellate ganglion blockade . Pain Med \n2010 ;11 :1294 –8 .20456082 \n[2] Lehmann LJ Warfield CA Bajwa ZH \nMigraine headache following stellate ganglion block for reflex sympathetic dystrophy . Headache \n1996 ;36 :335 –7 .8682679 \n[3] Noma N Kamo H Nakaya Y \nStellate ganglion block as an early intervention in sympathetically maintained headache and orofacial pain caused by temporal arteritis . Pain Med \n2013 ;14 :392 –7 .23332006 \n[4] Narouze S \nUltrasound-guided stellate ganglion block: safety and efficacy . Curr Pain Headache Rep \n2014 ;18 :424 .24760493 \n[5] Manickam BP Perlas A Chan VW \nThe role of a preprocedure systematic sonographic survey in ultrasound-guided regional anesthesia . Reg Anesth Pain Med \n2008 ;33 :566 –70 .19258972 \n[6] Shankar H Simhan S \nTransient neuronal injury followed by intravascular injection during an ultrasound guided stellate ganglion block . Anesth Pain Med \n2013 ;2 :134 –7 .24244924 \n[7] Rastogi S Tripathi S \nCardiac arrest following stellate ganglion block performed under ultrasound guidance . Anaesthesia \n2010 ;65 :1042 .\n[8] Guay J \nAdverse events associated with intravenous regional anesthesia (Bier block): a systematic review of complications . J Clin Anesth \n2009 ;21 :585 –94 .20122591 \n[9] El-Boghdadly K Chin KJ \nLocal anesthetic systemic toxicity: continuing professional development . Can J Anaesth \n2016 ;63 :330 –49 .26830640 \n[10] Di Gregorio G Neal JM Rosenquist RW \nClinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009 . Reg Anesth Pain Med \n2010 ;35 :181 –7 .20301824 \n[11] Mahli A Coskun D Akcali DT \nAetiology of convulsions due to stellate ganglion block: a review and report of two cases . Eur J Anaesthesiol \n2002 ;19 :376 –80 .12095020 \n[12] Chaturvedi A Dash H \nLocked-in syndrome during stellate ganglion block . Indian J Anaesth \n2010 ;54 :324 –6 .20882175 \n[13] Putrenko I Ghavanini AA Meyer Schoniger KS \nCentral nervous system-toxic lidocaine concentrations unmask L-type Ca(2)(+) current-mediated action potentials in rat thalamocortical neurons: an in vitro mechanism of action study . Anesth Analg \n2016 ;122 :1360 –9 .26771269 \n[14] Aldrete JA Romo-Salas F Arora S \nReverse arterial blood flow as a pathway for central nervous system toxic responses following injection of local anesthetics . Anesth Analg \n1978 ;57 :428 –33 .101097 \n[15] Ellis JS JrRamamurthy S \nSeizure following stellate ganglion block after negative aspiration and test dose . Anesthesiology \n1986 ;64 :533 –4 .\n[16] Gitkind AI Olson TR Downie SA \nVertebral artery anatomical variations as they relate to cervical transforaminal epidural steroid injections . Pain Med \n2014 ;15 :1109 –14 .25202774 \n[17] Shin HY Park JK Park SK \nVariations in entrance of vertebral artery in Korean cervical spine: MDCT-based analysis . Korean J Pain \n2014 ;27 :266 –70 .25031813 \n[18] Vujmilovic S Spasojevic G Vujnovic S \nVariability of the vertebral artery origin and transverse foramen entrance level - CT angiographic study . Folia Morphol (Warsz) \n2018 ;77 :687 –92 .29651795 \n[19] Bloc S Ecoffey C Dhonneur G \nControlling needle tip progression during ultrasound-guided regional anesthesia using the hydrolocalization technique . Reg Anesth Pain Med \n2008 ;33 :382 –3 .18675754 \n[20] Huntoon MA \nThe vertebral artery is unlikely to be the sole source of vascular complications occurring during stellate ganglion block . Pain Pract \n2010 ;10 :25 –30 .19761512\n\n",
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"mesh_terms": "D000328:Adult; D000779:Anesthetics, Local; D001340:Autonomic Nerve Block; D006801:Humans; D007431:Intraoperative Complications; D008012:Lidocaine; D008297:Male; D019300:Medical Errors; D008881:Migraine Disorders; D005791:Patient Care; D012640:Seizures; D013233:Stellate Ganglion; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional; D014474:Unconsciousness; D014711:Vertebral Artery",
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"title": "Tonic-clonic seizure during the ultrasound-guided stellate ganglion block because of an injection into an unrecognized variant vertebral artery: A case report.",
"title_normalized": "tonic clonic seizure during the ultrasound guided stellate ganglion block because of an injection into an unrecognized variant vertebral artery a case report"
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"abstract": "Chronic liver disease and liver transplantation (LT) can delay both timing and ability of women to conceive. With increased awareness and availability of in vitro fertilisation (IVF), the need for accurate counselling is paramount. To date, minimal data exist on outcomes of IVF in patients with chronic liver disease, cirrhosis, or post-LT. We report the largest experience of IVF in women with liver-related subfertility (LRSF).\n\n\n\nA retrospective analysis was performed on 42 women with LRSF who had undergone 57 IVF cycles between 1990 and 2019.\n\n\n\nForty-two women with LRSF received IVF; 9 cycles in 6 women with cirrhosis, 14 cycles in 11 women post-LT, and 34 cycles in 25 women without cirrhosis. The main aetiologies of liver disease included HBV, HCV, and autoimmune hepatitis (AIH). Of 57 IVF cycles evaluated, 43 (75%) resulted in successful implantation. Eight (2 post-LT, 3 with cirrhosis, 4 without cirrhosis) resulted in miscarriage. The live birth rate (LBR) was 74% (32/43). Two of 9 (22%) patients with cirrhosis, 4/14 (29%) patients who were post-LT, and 6/34 (18%) patients without cirrhosis had unsuccessful IVF attempts. Nine of 57 (16%) IVF cycles resulted in new liver enzyme derangement during therapy, which improved after treatment completion. Six pregnancies (2 in patients who were post-LT, 4 without cirrhosis) were complicated by obstetric cholestasis (OC). Ovarian hyperstimulation syndrome (OHSS) was rare (n = 3, 7%). One patient with AIH-related cirrhosis decompensated after initiating IVF, warranting discontinuation of therapy. There were no maternal deaths. Three women developed a hypertensive disorder of pregnancy. Half the pregnancies resulted in premature deliveries (range 27-36 weeks).\n\n\n\nIn selected cases, IVF in women with LRSF can be successful. However, patients should be counselled on the potential increased risks of OHSS, OC, and prematurity.\n\n\n\nWomen with liver disease or those who have had a liver transplant can experience difficulties getting pregnant. In this study, we look at whether alternative approaches to achieve pregnancy are harmful in these women. Overall, there were no significant issues with the use of in vitro fertilisation in women with liver disease, but they need to be aware of potential risks, such as early delivery of the baby.",
"affiliations": "Institute of Liver Studies, King's College Hospital, London, UK; King's Liver Pregnancy Research Group, King's College Hospital, London, UK.;Institute of Liver Studies, King's College Hospital, London, UK.;King's Liver Pregnancy Research Group, King's College Hospital, London, UK; Foetal Medicine Research Unit, King's College Hospital, London, UK.;Institute of Liver Studies, King's College Hospital, London, UK; King's Liver Pregnancy Research Group, King's College Hospital, London, UK.;Institute of Liver Studies, King's College Hospital, London, UK.;King's Liver Pregnancy Research Group, King's College Hospital, London, UK; Foetal Medicine Research Unit, King's College Hospital, London, UK.;Institute of Liver Studies, King's College Hospital, London, UK; King's Liver Pregnancy Research Group, King's College Hospital, London, UK.;Institute of Liver Studies, King's College Hospital, London, UK; King's Liver Pregnancy Research Group, King's College Hospital, London, UK; EASL European Registry for Liver Diseases in Pregnancy, Geneva, Switzerland; European Reference Network - Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany. Electronic address: michael.heneghan@nhs.net.",
"authors": "Rahim|Mussarat N|MN|;Theocharidou|Eleni|E|;Yen Lau|Katherine Gar|KG|;Ahmed|Refah|R|;Marattukalam|Flevin|F|;Long|Lisa|L|;Cannon|Mary D|MD|;Heneghan|Michael A|MA|",
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"keywords": "Cirrhosis; Foetal outcomes; In vitro fertilisation; Liver transplantation; Maternal outcomes; Pregnancy",
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"references": null,
"title": "Safety and efficacy of in vitro fertilisation in patients with chronic liver disease and liver transplantation recipients.",
"title_normalized": "safety and efficacy of in vitro fertilisation in patients with chronic liver disease and liver transplantation recipients"
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"abstract": "We report the case of a man in his early 70s with idiopathic acquired haemophilia A and persistent high-titre type II inhibitors on immunosuppressive treatment to eradicate the inhibitor. As complications, he had a nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused severe pneumonia and an explosive inflammatory reaction that required tocilizumab and remdesivir treatment, and a high-risk retroperitoneal haematoma. Recombinant porcine factor VIII, susoctocog alfa, was requested from the Pharmacy Service in view of the extreme risk of thromboembolism resulting from the concomitant inflammatory storm caused by SARS-CoV-2. Improvement in the SARS-CoV-2 infection made it possible to complete the immunosuppressive treatment with rituximab. The patient was discharged with mycophenolate mofetil as immunosuppressive treatment after 89 days in hospital and 22 days of treatment with susoctocog alfa. His SARS-CoV-2 infection resolved and the haematoma evolved favourably.",
"affiliations": "Pharmacy, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain.;Pharmacy, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain sandra.rotea.salvo@sergas.es.;Hematology, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain.;Pharmacy, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain.;Pharmacy, Complexo Hospitalario Universitario A Coruna, A Coruna, Spain.",
"authors": "Fernández-Oliveira|Carla|C|;Rotea-Salvo|Sandra|S|http://orcid.org/0000-0002-7860-4029;Fernández-Docampo|Marta|M|;González-Piñeiro|Sara|S|;Martín-Herranz|Isabel|I|",
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"pmid": "34011555",
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"title": "Treatment of high-risk bleeding with susoctocog alfa in a patient with acquired haemophilia A and a nosocomial severe acute respiratory syndrome coronavirus 2 infection.",
"title_normalized": "treatment of high risk bleeding with susoctocog alfa in a patient with acquired haemophilia a and a nosocomial severe acute respiratory syndrome coronavirus 2 infection"
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"abstract": "OBJECTIVE\nIn the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment of PM/DM.\n\n\nMETHODS\nWe retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1 mg/kg/day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8 mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected.\n\n\nRESULTS\nThere were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination Group was significantly lower than that in the Conventional Monotherapy Group during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients, except one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate was comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy.\n\n\nCONCLUSIONS\nThis study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.",
"affiliations": "a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.;a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.;a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.;a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.;a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.",
"authors": "Yokoyama|Yusuke|Y|;Furuta|Shunsuke|S|;Ikeda|Kei|K|;Hirose|Koichi|K|;Nakajima|Hiroshi|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D011239:Prednisolone; D016559:Tacrolimus",
"country": "England",
"delete": false,
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"issue": "25(6)",
"journal": "Modern rheumatology",
"keywords": "Corticosteroid; Dermatomyositis; Polymyositis; Tacrolimus",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D003882:Dermatomyositis; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009220:Myositis; D017285:Polymyositis; D011239:Prednisolone; D012189:Retrospective Studies; D016559:Tacrolimus",
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"title": "Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis.",
"title_normalized": "corticosteroid sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis"
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"abstract": "A 59-year-old woman who underwent an uncomplicated exploratory laparotomy, adhesiolysis, small bowel resection and anterolateral thigh flap had a complicated postoperative period characterised by wound dehiscence and poor nutritional intake. 29 days postoperatively, a tremor developed in her upper limbs associated with weakness. Her Glasgow Coma Scale (GCS) fell to 4 and she was transferred to the intensive care unit. The patient was reviewed by multiple specialists and multiple differentials were considered and eliminated. Eventually, investigations revealed hyperammonaemic encephalopathy, being a result of low arginine and potentially small intestinal bacterial overgrowth. Following treatment with sodium benzoate, sodium phenylbutyrate and arginine along with haemodialysis and rifaximin, GCS and hyperammonaemia rapidly improved. She was stepped down to surgical high-dependency unit, continued arginine therapy with total parenteral nutrition and percutaneous endoscopic gastrostomy feeds. She was discharged with regular follow-up from surgeons and biochemistry and continues oral arginine therapy.",
"affiliations": "Plastic Surgery Department, NHS Grampian, Aberdeen, UK.;Plastic Surgery Department, NHS Grampian, Aberdeen, UK.;Department of Biochemistry, NHS Grampian, Aberdeen, UK.;Plastic Surgery Department, NHS Grampian, Aberdeen, UK.",
"authors": "McIntosh|Stuart|S|;Medjoub|Karima|K|;Deans|Kevin|K|;Sexton|Sara|S|",
"chemical_list": "D001120:Arginine",
"country": "England",
"delete": false,
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"keywords": "adult intensive care; medical management; neurology; nutritional support; parenteral / enteral feeding",
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"mesh_terms": "D001120:Arginine; D001927:Brain Diseases; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D010535:Laparoscopy; D008875:Middle Aged; D010289:Parenteral Nutrition, Total; D011183:Postoperative Complications",
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"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28814581",
"pubdate": "2017-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11677282;17006913;17934124;21960820;25387900;25908985;26041954;27269953",
"title": "Hyperammonaemic encephalopathy following an uncomplicated surgery.",
"title_normalized": "hyperammonaemic encephalopathy following an uncomplicated surgery"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201806823",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "3",
... |
{
"abstract": "Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.",
"affiliations": "Division of Medical Oncology and Developmental Oncology Research, Cancer Center Statistics Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. buckner.jan@mayo.edu",
"authors": "Buckner|Jan C|JC|;Reid|Joel M|JM|;Wright|Keith|K|;Kaufmann|Scott H|SH|;Erlichman|Charles|C|;Ames|Matthew|M|;Cha|Steve|S|;O'Fallon|Judith R|JR|;Schaaf|Lawrence J|LJ|;Miller|Langdon L|LL|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.11304",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "97(9 Suppl)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D001932:Brain Neoplasms; D002166:Camptothecin; D002986:Clinical Trials as Topic; D005909:Glioblastoma; D005910:Glioma; D006801:Humans; D000077146:Irinotecan",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2352-8",
"pmc": null,
"pmid": "12712456",
"pubdate": "2003-05-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.",
"title_normalized": "irinotecan in the treatment of glioma patients current and future studies of the north central cancer treatment group"
} | [
{
"companynumb": "US-PFIZER INC-2021456379",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "PCR assay cannot always detect the SARS-CoV2 virus, which might be due to differences in the sensitivities of each sampling site. Under these circumstances, immunochromatography may serve as an alternative method to detect anti-SARS-CoV-2 IgG antibodies that can demonstrate a history of infection. In patients with severe COVID-19 infection, 14 of 19 serum samples were shown to be positive, whereas 6 of 10 samples from patients with asymptomatic or mild cases were negative for IgG antibodies. Two patients with immune thrombocytopenia, who were treated with prednisolone, experienced aggressive behavior of COVID-19-related respiratory failure and eventually died. Patients who were before an achievement of remission and those who received steroid-based chemotherapy possessed a higher risk of death, and more deaths were observed in patients with lymphoid malignancies including lymphoma and myeloma compared with those with myeloid malignancies. As for daily medical care in hematological department, a stricter cohorting strategy using repeat PCR tests or isolation to a private room should be adopted in order to prevent viral spread to the environment.",
"affiliations": "Eiju General Hospital.;Eiju General Hospital.;Eiju General Hospital.;Eiju General Hospital.",
"authors": "Hagihara|Masao|M|;Ohara|Shin|S|;Uchida|Tomoyuki|T|;Inoue|Morihiro|M|",
"chemical_list": "D000914:Antibodies, Viral; D012367:RNA, Viral",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.115",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Anti-SARS-CoV2 IgG; COVID-19; Nosocomial infection; Survival",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000914:Antibodies, Viral; D000086382:COVID-19; D006402:Hematologic Diseases; D006801:Humans; D007564:Japan; D058873:Pandemics; D012367:RNA, Viral; D000086402:SARS-CoV-2",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "115-124",
"pmc": null,
"pmid": "33678770",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Practical management of the patients with hematological diseases during the COVID-19 pandemic in Japan.",
"title_normalized": "practical management of the patients with hematological diseases during the covid 19 pandemic in japan"
} | [
{
"companynumb": "JP-ROCHE-2805144",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "There is no consensus about the best treatment option for patients with HP-negative gastric MALT lymphomas or persistent disease after HP eradication.We have investigated fludarabine and mitoxantrone with rituximab (R-FM) as first-line treatment. A cohort of 13 patients was analyzed. Induction treatment consisted of fludarabine (25 mg/m2 i.v. on days 2 to 4), mitoxantrone (10 mg/m2 i.v. on day 2), and rituximab (375 mg/m2 i.v. on day 1), for up to six cycles every 28 days. All patients achieved a complete remission, a median of four cycles was given. Treatment-related toxicities were mainly hematologic, with grade 3-4 neutropenia observed in 11/13 patients (84.6%). One patient had grade 3 febrile neutropenia, two patients developed prolonged pancytopenia (15%), and one patient experienced CMV reactivation at 2 months. After a median follow-up of 84 months, 1/13 had disease relapse and received total gastrectomy; estimated 10-year progression-free survival and overall survival were 92.4 and 100%, respectively. Our study suggests R-FM regimen has a high long-term efficacy for untreated HP-negative gastric MALT lymphoma patients and HP-positive patients who failed HP eradication. The elevated incidence of grade 3-4 hematological toxicity, yet manageable, makes this treatment less safe compared to rituximab in combination with chlorambucil or bendamustine.",
"affiliations": "Haematology Unit, Azienda Ospedaliera Universitaria Senese, Viale Bracci, 16, 53100, Siena, Italy. cencioema@libero.it.;Haematology Unit, Azienda Ospedaliera Universitaria Senese, Viale Bracci, 16, 53100, Siena, Italy.;University of Siena, Siena, Italy.;Haematology Unit, Azienda Ospedaliera Universitaria Senese, Viale Bracci, 16, 53100, Siena, Italy.",
"authors": "Cencini|Emanuele|E|http://orcid.org/0000-0002-0432-9706;Fabbri|Alberto|A|;Lauria|Francesco|F|;Bocchia|Monica|M|",
"chemical_list": "D000069283:Rituximab; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-018-3243-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "97(5)",
"journal": "Annals of hematology",
"keywords": "Indolent B-NHL; Low-grade lymphoma; Rituximab; Toxicity",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D012189:Retrospective Studies; D000069283:Rituximab; D013274:Stomach Neoplasms; D013997:Time Factors; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "821-829",
"pmc": null,
"pmid": "29340761",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Long-term efficacy and toxicity of rituximab plus fludarabine and mitoxantrone (R-FM) for gastric marginal zone lymphoma: a single-center experience and literature review.",
"title_normalized": "long term efficacy and toxicity of rituximab plus fludarabine and mitoxantrone r fm for gastric marginal zone lymphoma a single center experience and literature review"
} | [
{
"companynumb": "PHHY2018IT057687",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nTo determine the risk of postoperative hemorrhage associated with the use of analgesic drugs including paracetamol, metamizole sodium and ibuprofen after pediatric tonsillectomy.\n\n\nMETHODS\nThree hundred and forty consecutive children with recurrent tonsillitis and/or obstructive symptoms were included in the study. Children were divided into three groups based on the drugs used for postoperative pain relief. Each group received paracetamol, metamizole sodium and ibuprofen following the surgery. The study of population was compared respect to postoperative bleeding. Chi-square test was used for statistical analysis.\n\n\nRESULTS\nA total of 115 patients received ibuprofen, 115 patients were given metamizole sodium and 110 patients were given paracetamol. Posttonsillectomy hemorrhage occurred in fourteen (4.11%) children, consisting of primary hemorrhage in two patients and secondary hemorrhage in twelve patients. While 6 of 115 children (5.21%) who were given ibuprofen had postoperative hemorrhage, 4 of 115 children (3.47%) in metamizole sodium group and 4 of 110 patients (3.63%) in paracetamol group had hemorrhage. There was no significant difference with respect to hemorrhage rates between these three groups (p<0.05).\n\n\nCONCLUSIONS\nIn our study we could not show significant risk of hemorrhage after using of ibuprofen, metamizole sodium and paracetamol administration and they can be used safely for posttonsillectomy pain.",
"affiliations": "Department of Otolaryngology, Head and Neck Surgery, Bozok University Medical Faculty, Yozgat, Turkey. mozkiris@yahoo.com",
"authors": "Özkiriş|Mahmut|M|;Kapusuz|Zeliha|Z|;Yildirim|Yavuz Selim|YS|;Saydam|Levent|L|",
"chemical_list": "D000700:Analgesics; D000082:Acetaminophen; D004177:Dipyrone; D007052:Ibuprofen",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ijporl.2012.03.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5876",
"issue": "76(7)",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": null,
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000082:Acetaminophen; D000700:Analgesics; D002648:Child; D002675:Child, Preschool; D004177:Dipyrone; D005260:Female; D006801:Humans; D007052:Ibuprofen; D008297:Male; D010149:Pain, Postoperative; D019106:Postoperative Hemorrhage; D014068:Tonsillectomy; D014069:Tonsillitis",
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "1027-9",
"pmc": null,
"pmid": "22595462",
"pubdate": "2012-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "The effect of paracetamol, metamizole sodium and ibuprofen on postoperative hemorrhage following pediatric tonsillectomy.",
"title_normalized": "the effect of paracetamol metamizole sodium and ibuprofen on postoperative hemorrhage following pediatric tonsillectomy"
} | [
{
"companynumb": "TR-PFIZER INC-2015297407",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThis phase IB, open-label, dose-escalation study evaluated the safety, tolerability, and optimally tolerated regimen (OTR) of lapatinib in combination with docetaxel and trastuzumab in patients with previously untreated stage IV metastatic breast cancer (MBC) tumors overexpressing human epidermal growth factor receptor 2 (HER2).\n\n\nMETHODS\nEvaluated dose regimens included lapatinib (500-1500 mg/day), docetaxel (triweekly; 60-100 mg/m²), and trastuzumab (weekly; 2 mg/kg fixed dose); prophylactic granulocyte colony-stimulating factor was included with regimens with ≥750 mg/day lapatinib. End points included OTR and safety/tolerability (primary), overall response rate (ORR), and pharmacokinetics (secondary).\n\n\nRESULTS\nNone of the patients (N = 53) experienced dose-limiting toxic effects (DLTs) at the highest dose level; thus, the OTR of lapatinib with 100 mg/m(2) docetaxel was not determined. Common adverse events included diarrhea, nausea, alopecia, fatigue, and rash; grade 3/4 (≥2 patients) were neutropenia, diarrhea, leukopenia, peripheral neuropathy, and rash. Seven patients had DLTs (cycle 1). In 45 patients with measurable disease confirmed by bone scan, investigator-assessed ORR was 31%; without bone scan, confirmation was 64%; 8 patients without measurable disease were evaluated as stable. Lapatinib/docetaxel plasma concentrations were positively associated with complete response.\n\n\nCONCLUSIONS\nLapatinib/docetaxel/trastuzumab is a feasible and well-tolerated treatment of untreated HER2-positive stage IV MBC. Two lapatinib/docetaxel OTR doses were recommended (1250 mg/75 mg/m²; 1000 mg/100 mg/m²).\n\n\nBACKGROUND\nNCT00251433.",
"affiliations": "All Ireland Cooperative Oncology Research Group, Dublin, Ireland. john.crown@icorg.ie",
"authors": "Crown|J|J|;Kennedy|M J|MJ|;Tresca|P|P|;Marty|M|M|;Espie|M|M|;Burris|H A|HA|;DeSilvio|M|M|;Lau|M R|MR|;Kothari|D|D|;Koch|K M|KM|;Diéras|V|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D011994:Recombinant Proteins; D043823:Taxoids; D000077341:Lapatinib; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; C455861:pegfilgrastim; D011092:Polyethylene Glycols; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdt222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "24(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "HER2/ERBB2; docetaxel; lapatinib; metastatic breast cancer; trastuzumab; tyrosine kinase inhibitor",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000077143:Docetaxel; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011092:Polyethylene Glycols; D011799:Quinazolines; D018719:Receptor, ErbB-2; D011994:Recombinant Proteins; D043823:Taxoids; D000068878:Trastuzumab; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "2005-11",
"pmc": null,
"pmid": "23878115",
"pubdate": "2013-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2-positive metastatic breast cancer.",
"title_normalized": "optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first line treatment of her2 positive metastatic breast cancer"
} | [
{
"companynumb": "IE-AMGEN-IRLSP2020025124",
"fulfillexpeditecriteria": "2",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": null,
... |
{
"abstract": "To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus.\n\n\n\nParticipants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol.\n\n\n\nNon-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug.\n\n\n\nThe combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial.",
"affiliations": "Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.;Clinical Statistics, GlaxoSmithKline, Stevenage, UK.;Alternative Discovery and Development, GlaxoSmithKline, Brentford, UK.;Alternative Discovery and Development, GlaxoSmithKline, Brentford, UK.;Alternative Discovery and Development, GlaxoSmithKline, Brentford, UK.;Alternative Discovery and Development, GlaxoSmithKline, Brentford, UK.;Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Research Triangle Park, NC, USA.;Diabetes Centre, Eulji Hospital, Eulji University School of Medicine, Seoul, Republic of Korea.",
"authors": "Ambery|P|P|;Stylianou|A|A|;Atkinson|G|G|;Dott|C|C|;Baylor Curtis|L|L|;Haque|N|N|;LaCroix|K|K|;Min|K W|KW|;|||",
"chemical_list": "D008078:Cholesterol, LDL; D004338:Drug Combinations; D006442:Glycated Hemoglobin A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human; C057619:glimepiride; D008687:Metformin; D000069059:Atorvastatin",
"country": "England",
"delete": false,
"doi": "10.1111/dme.13003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "33(8)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000368:Aged; D000069059:Atorvastatin; D008078:Cholesterol, LDL; D003924:Diabetes Mellitus, Type 2; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D000074099:Equivalence Trials as Topic; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D013453:Sulfonylurea Compounds",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "1084-93",
"pmc": null,
"pmid": "26484794",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin.",
"title_normalized": "open label randomized non inferiority trial of a fixed dose combination of glimepiride and atorvastatin for the treatment of people whose type 2 diabetes is uncontrolled on metformin"
} | [
{
"companynumb": "KR-SA-2019SA151544",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "Anti-PD-1 monoclonal antibody is approved as an option for third-line treatment of advanced gastric and gastroesophageal junction (G/GEJ) cancer in several countries, but no anti-PD-1 monoclonal antibody treatment is yet approved for first-line treatment of advanced G/GEJ cancer. We report a phase Ib trial of HX008, a highly selective, humanized anti-programmed death-1 monoclonal antibody, plus oxaliplatin and capecitabine as first-line treatment for advanced G/GEJ cancer. Patients with previously untreated, locally advanced or metastatic G/GEJ cancer were enrolled. All patients received HX008 3 mg/kg intravenously every 3 weeks, oxaliplatin 130 mg/m2 intravenously on day 1 every 3 weeks (up to 6 cycles), and capecitabine 1000 mg/m2 orally twice daily for 14 days continuous dosing followed by a 7-day break. The primary end point was the incidence of adverse events and serious adverse events. In total, 35 patients were enrolled. Median follow-up was 12.7 months. Most frequent (>10%) grade ≥3 treatment-related adverse events were anemia (27.5%), neutropenia (20%), thrombocytopenia (17.1%), leukopenia (17.1%) and fatigue (17.3%). Objective response rate was 60.0% (95% confidence interval [CI] 42.1-76.1%). Disease control rate was 77.1% (95% CI 59.9-89.6). Median time to response and duration of response were 1.4 months (range 1.3-2.9) and 12.3 months (range 1.4-17.9+), respectively. Median PFS was 9.2 months (95% CI 5.4-not reached). These results demonstrated that HX008 combined with oxaliplatin plus capecitabine was well tolerated and demonstrated encouraging efficacy as first-line treatment for advanced G/GEJ cancer. This study was registered in china, register number was CTR20181270.",
"affiliations": "Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.;Department of Medical Oncology, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China.;Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.;Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.;Department of Medical Oncology, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China.;Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.;Taizhou Hanzhong Biomedical Co., Ltd., Jiangsu, China.;Taizhou Hanzhong Biomedical Co., Ltd., Jiangsu, China.;Taizhou Hanzhong Biomedical Co., Ltd., Jiangsu, China.",
"authors": "Xu|Jianming|J|;Xu|Nong|N|;Bai|Yuxian|Y|;Liu|Rongrui|R|;Mao|Chenyu|C|;Sui|Hong|H|;Wang|Xiaofei|X|;Jiang|Qian|Q|;Dou|Yiwei|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000077150:Oxaliplatin; D000069287:Capecitabine",
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2020.1864908",
"fulltext": "\n==== Front\nOncoimmunology\nOncoimmunology\nOncoimmunology\n2162-4011\n2162-402X\nTaylor & Francis\n\n33457083\n10.1080/2162402X.2020.1864908\n1864908\nVersion of Record\nResearch Article\nOriginal Research\nAnti-PD-1 antibody HX008 combined with oxaliplatin plus capecitabine for advanced gastric or esophagogastric junction cancer: a multicenter, single-arm, open-label, phase Ib trial\nJ. XU ET AL.\nONCOIMMUNOLOGY\nXu Jianming a\nXu Nong b\nBai Yuxian c\nLiu Rongrui a\nMao Chenyu b\nSui Hong c\nWang Xiaofei d\nJiang Qian d\nDou Yiwei d\na Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital , Beijing, China\nb Department of Medical Oncology, Zhejiang University School of Medicine First Affiliated Hospital , Hangzhou, China\nc Department of Medical Oncology, Harbin Medical University Cancer Hospital , Harbin, China\nd Taizhou Hanzhong Biomedical Co., Ltd ., Jiangsu, China\nCONTACT Jianming Xu jmxu2003@yahoo.com Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital . 8 East Street, Fengtai District, Beijing100071, China.\nJianming Xu, Nong Xu, and Yuxian Bai contributed equally to this work.\n\n31 12 2020\n2021\n31 12 2020\n10 1 1864908© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.\n2020\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.\n\nABSTRACT\n\nAnti-PD-1 monoclonal antibody is approved as an option for third-line treatment of advanced gastric and gastroesophageal junction (G/GEJ) cancer in several countries, but no anti-PD-1 monoclonal antibody treatment is yet approved for first-line treatment of advanced G/GEJ cancer. We report a phase Ib trial of HX008, a highly selective, humanized anti-programmed death-1 monoclonal antibody, plus oxaliplatin and capecitabine as first-line treatment for advanced G/GEJ cancer. Patients with previously untreated, locally advanced or metastatic G/GEJ cancer were enrolled. All patients received HX008 3 mg/kg intravenously every 3 weeks, oxaliplatin 130 mg/m2 intravenously on day 1 every 3 weeks (up to 6 cycles), and capecitabine 1000 mg/m2 orally twice daily for 14 days continuous dosing followed by a 7-day break. The primary end point was the incidence of adverse events and serious adverse events. In total, 35 patients were enrolled. Median follow-up was 12.7 months. Most frequent (>10%) grade ≥3 treatment-related adverse events were anemia (27.5%), neutropenia (20%), thrombocytopenia (17.1%), leukopenia (17.1%) and fatigue (17.3%). Objective response rate was 60.0% (95% confidence interval [CI] 42.1–76.1%). Disease control rate was 77.1% (95% CI 59.9–89.6). Median time to response and duration of response were 1.4 months (range 1.3–2.9) and 12.3 months (range 1.4–17.9+), respectively. Median PFS was 9.2 months (95% CI 5.4-not reached). These results demonstrated that HX008 combined with oxaliplatin plus capecitabine was well tolerated and demonstrated encouraging efficacy as first-line treatment for advanced G/GEJ cancer. This study was registered in china, register number was CTR20181270.\n\nKEYWORDS\n\nHX008\noxaliplatin\ncapecitabine\ngastric cancer\nPD-1\nTaizhou Hanzhong Biomedical Co., Ltd This study was funded completely by a company of limited liability, which named Taizhou Hanzhong Biomedical Co., Ltd.\n==== Body\nIntroduction\n\nGastric or gastroesophageal junction (G/GEJ) cancer is the fifth most common cancer and the third leading cause of cancer death worldwide. In 2018, nearly 1,000,000 new cases and 783,000 deaths were estimated to have occurred.1 Notably, almost half of the total case of G/GEJ cancer occurs in East Asian, with the age-standardized incidence rate of 32.1 per 100,000 and a mortality rate of 13.2 per 100,000.1 Although the incidence rate has declined and survival has improved in recent years, G/GEJ cancer remains the second most common cancer and the second leading cause of cancer death in China, with a poor prognosis.2\n\nThe standard therapy of first-line treatment for advanced G/GEJ adenocarcinoma remains to be fluoropyrimidine- and platinum-based therapy. A doublet regimen of cisplatin or oxaliplatin in combination with 5-fluorouracil or capecitabine or S-1 is preferred in Asia. In previously untreated gastric cancer, the doublet regimen demonstrated an objective response rate (ORR) of 28.8–54%, a progression-free survival (PFS) of 4.9–6.0 months, and an overall survival (OS) of 8.5–13.0 months, respectively.3–5 Although several clinical trials have investigated the efficacy of targeted agents plus chemotherapy as first-line treatment, including trastuzumab,6 lapatinib,7 bevacizumab,8 rilotumumab9 and ramucirumab,10 only trastuzumab significantly improved overall survival of up to 13.8 months in human epidermal growth factor receptor 2 (HER 2)-positive advanced G/GEJ cancer. Thus, the first-line treatment of advanced G/GEJ cancer is clearly unsatisfied, and potential novel agent that will improve survival in these patients is urgently needed.\n\nImmune-checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) have shown promising efficacy in multiple malignant diseases. PD-L1 is frequently upregulated in gastric cancer, with 12%-65% detected in tumor tissues; notably, a poorer prognosis was observed in patients with PD-L1 positive tumors.11–13 Preliminary clinical data of single-agent PD-1 inhibitors in metastatic G/GEJ cancer have demonstrated anti-tumor efficacy, with response rates of 22–27% for patients with PD-L1 positive tumors and 10–17% for unselected patients.14 Nivolumab and pembrolizumab have been approved as third-line treatment of advanced gastric cancer.15,16\n\nCombination with immune check point inhibitors and standard chemotherapy exerts synergistic anti-tumor activity through modulation of the immune system or reshaping the tumor microenvironments (TME),17–19 which has proved to improve survival in several cancer types.20–24 Promising antitumor activity of combination treatment was also initially presented in advanced GC in KEYNOTE-059 study25 and ATTRACTION-4 trial,26 with differential efficacy results. But the results of phase III trial KEYNOTE-062 failed to demonstrate superior efficacy of pembrolizumab plus chemotherapy in either combined positive score (CPS) ≥1 or CPS ≥10 subgroups.27 However, hardly any results of combination with anti-PD-1 antibody and chemotherapy for first-line treatment in Chinese patients with advanced G/GEJ cancer has been reported.\n\nHX008 is a highly selected, humanized, IgG4 anti-PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligand.28 Results from a phase I trial of HX008 in advanced solid tumors suggested 3 mg/kg or 200 mg every 3 weeks as the recommended dose (data not published). Here, we report the safety and efficacy of HX008 with oxaliplatin plus capecitabine as first-line therapy in Chinese patients with advanced G/GEJ cancer.\n\nMaterials and methods\n\nEligibility criteria\n\nPatients were ≥18 and ≤75 years of age with histologically or cytologically confirmed diagnosis of unresectable locally advanced or metastatic G/GEJ cancer, and with no exposure to previous systemic treatment for advanced or metastatic disease. Additional key eligibility criteria included: at least one measurable lesion at baseline, assessed by Response Evaluation Criteria in Advanced Solid Tumors version 1.1 (RECIST v1.1); Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; a life expectancy ≥3 months and adequate organ function. The main exclusion criteria included: active or history of autoimmune disease; active central nervous system metastases; history or current interstitial lung disease or pulmonary fibrosis; prior treatment with an agent directed against PD-1/PD-L1, CTLA-4 or another co-inhibitory T-cell receptor; history of allogeneic hematopoietic stem cell transplantation; adverse events (AEs) from previous therapy that had not recovered to grade ≤1. Patients with active gastrointestinal ulcer, intestinal obstruction, active gastrointestinal bleeding and perforation were also excluded. The full criteria are available in supplementary materials.\n\nStudy design and treatment\n\nThis study was an ongoing open-label, multi-center, single-arm randomized, phase Ib, exploratory clinical study of HX008 combined with oxaliplatin plus capecitabine as first-line therapy for patients with advanced G/GEJ cancer. Eligible patients received HX008 3 mg/kg by intravenous infusion over 60 min on day 1, oxaliplatin 130 mg/m2 by intravenous infusion over 2 hours on day 1 (for up to 6 cycles), and capecitabine 1000 mg/m2 orally twice daily for 14 days continuous dosing followed by a 7-day break of each 21-day cycle. Treatment was continued for up to one year, or until disease progression, unacceptable toxicity, or patient or investigator decision to withdraw. Patients with a durable response may receive HX008 for another year following the completion of one-year treatment. Clinically stable patients with the first radiographic progressive disease (PD) might continue treatment at the investigator’s discretion until confirmed PD. Treatment interruptions were permitted for the management of treatment-related AEs. All patients were examined at discontinuation of the protocol treatment and on day 28 post-treatment, and were followed up.\n\nThe study protocol and all amendments were approved by the Ethics Committee of each study site and conducted in accordance with the Declaration of Helsinki guidelines and applicable local laws and regulations. All patients provided written informed consent before enrollment. The study was registered in china, register number was CTR20181270.\n\nEnd points and assessments\n\nThe primary endpoint was incidence of adverse events (AEs) and serious adverse events (SAEs). The secondary endpoint endpoints included ORR, duration of response (DOR) and PFS, assessed by the site investigator per RECIST v1.1, and pharmacokinetics parameters (not addressed in this article). Endpoint definitions are available in the supplementary materials.\n\nAll AEs were recorded during the study period from the initiation of treatment to 30 days after the last dose or the start date of subsequent anti-tumor therapy followed the last dose, whichever came first. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). The correlation between adverse events and study drugs was evaluated.\n\nTumor response was assessed with chest, abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) every 6 weeks until week 24, then every 12 weeks until discontinuation. For patients with available tumor samples, PD-L1 tumor expression and mismatch repair (MMR) status were determined by immunohistochemistry at a central laboratory, using anti-human PD-L1 monoclonal antibody 28–8 (Abcam, UK) and anti-MLH1, MSH2, MSH6 and PMS2 monoclonal antibodies (MXB, China), respectively. PD-L1 expression was measured using CPS, defined as the number of PD-L1-positive cells (tumor cells, lymphocytes, macrophages) as a proportion of the total number of tumor cells multiplied by 100.\n\nStatistical analysis\n\nThis study was designed to enroll at least 15 evaluable patients, more patient could be considered if the toxicity and efficacy are acceptable. The full analysis set (FAS) consisted of patients who successfully entered the group and received at least one treatment. Safety and efficacy will be statistically analyzed based on FAS. Safety was analyzed using descriptive statistics. ORR and disease control rate (DCR) with 95% CI were calculated using the Clopper–Pearson exact method based on binomial distribution. Patients without tumor assessment data were considered nonresponders. Kaplan–Meier method was used to estimate median DOR and PFS, and their 95% CIs were estimated by Brookmeyer-Crowley method. Data analyses were conducted using SAS statistical software version 9.4.\n\nResults\n\nDemographics and baseline characteristics\n\nFrom August 09, 2018 to June 24, 2019, 35 patients with advanced G/EGJ cancer were enrolled at 3 sites (Supplementary Table 1) in China. All patients had received ≥1 dose of HX008 combined with oxaliplatin plus capecitabine and thus were included in the FAS. Baseline characteristics are listed in Table 1. The median age was 63 (range 21–71) years and 77.1% were male. Sixty percent of patients had ECOG PS 1, and 31.4% had received prior surgery. At baseline, PD-L1 expression and MMR status detection were performed in 21 and 22 patients with available tumor samples, respectively. Among those, 12 patients (57.1%) had PD-L1 positive (CPS ≥ 1) tumors; mismatch repair deficient (dMMR) was confirmed in 2 patients (9.1%), the others were determined as mismatch repair proficient (pMMR).Table 1. Demographics and baseline characteristics\n\nDemographic or characteristic\tEvaluable patients (N = 35)\t\nMedian age, years (range)\t63 (21–71)\t\nSex\t \t\nMales\t27 (77.1)\t\nFemales\t9 (22.9)\t\nECOG PS\t \t\n0\t14 (40.0)\t\n1\t21 (60.0)\t\nHistological subtype\t \t\nIntestinal\t19 (54.3)\t\nDiffuse\t4 (11.4)\t\nMixed\t7 (20.0)\t\nUnknown\t5 (14.3)\t\nG/GEJ cancer\t \t\nAdvanced\t23 (65.7)\t\nRecurrent\t12 (34.3)\t\nPrimary location\t \t\nGastric\t28 (80.0)\t\nGastroesophageal junction\t7 (20.0)\t\nMetastatic stage\t \t\nM0\t5 (14.3)\t\nM1\t30 (85.7)\t\nPrior surgery\t10 (28.6)\t\nPrior adjuvant chemotherapy\t7 (20.0)\t\nMetastatic disease sites\t \t\nLymph nodes\t33 (94.3)\t\nLiver\t15 (42.9)\t\nLung\t4 (11.4)\t\nOthers\t9 (25.7)\t\nTumor PD-L1 quantifiable\t \t\nCPS < 1\t9 (25.7)\t\nCPS ≥ 1\t12 (34.3)\t\nNE\t14 (40.0)\t\nMMR status\t \t\ndMMR\t2 (5.7)\t\npMMR\t20 (57.1)\t\nNE\t13 (37.1)\t\nUnless otherwise indicated, all data are n (%); CPS, combined positive score; dMMR, mismatch repair deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; G/GEJ cancer, gastric cancer/gastroesophageal junction cancer; NE, not evaluated; PD-L1, programmed death-ligand 1; pMMR, mismatch repair proficient.\n\nAt data cutoff (June 16, 2020), the median follow-up duration was 12.7 months (range 0.3–21.2), with a median duration of treatment of 5.7 months (range 0.3–21.2). The median number of HX008 dose administrated was 8 (range 1–26). The median cycle number of oxaliplatin and capecitabine was 6 (range 1–6) and 8 (range 1–26), respectively. A total of 26 patients (74.3%) discontinued study treatment mainly due to disease progression, and 9 patients (25.7%) were still on treatment (Supplementary Figure 1).\n\nSafety\n\nMost of the patients (34/35) experienced treatment-related adverse events. The most common treatment-related AEs (TRAEs) were neutropenia (65.7%), thrombocytopenia (62.9%), anemia (60.0%), leukopenia (54.3%), aspartate aminotransferase increased (42.9%) and blood bilirubin increased (40.0%) (Table 2). Grade ≥3 TRAEs occurred in 25 patients (71.4%). The most frequent (>10%) grade ≥3 TRAEs were anemia (27.5%), neutropenia (20%), thrombocytopenia (17.1%), leukopenia (17.1%) and fatigue (17.1%). Serious TRAEs including anorexia (5.7%), thrombocytopenia (5.7%), fatigue (2.9%) and small intestinal obstruction (2.9) occurred in 6 (17.1%) patients, and recovered with appropriate supportive care. Immune-related TRAEs included fatigue (22.9%), proteinuria (20.0%), hypothyroidism (14.3%), rash (11.4), hyperthyroidism (11.4), diarrhea (8.6%), arthralgia (5.7%) and pruritus (2.9%), most of which were grade 1 or 2 (Table 3). Immune-related treatment emergent AEs are listed in Supplementary Table 2.Table 2. TRAEs of any grade occurring in ≥10% of patients\n\nTreatment-related AEsa n (%)\tTotal\nN = 35\t\n \tAny grade\tGrade 3\tGrade 4\tGrade 5\t\nAny TRAE\t34 (97.1)\t25 (71.4)\t2 (5.7)\t1 (2.9)\t\nTreatment-related SAEs\t6 (17.1)\t3 (14.3)\t1 (2.9)\t1 (2.9)\t\nTRAEs leading to discontinuation\t4 (11.4)\t1 (2.9)\t1 (2.9)\t1 (2.9)\t\nTRAE leading to dose delay or reduction\t17 (48.6%)\t12 (34.3)\t0\t0\t\nHematologic\t \t \t \t \t\nNeutropenia\t23 (65.7)\t6 (17.1)\t1 (2.9)\t0\t\nThrombocytopenia\t22 (62.9)\t5 (14.3)\t1 (2.9)\t0\t\nAnemia\t21 (60.0)\t9 (25.7)\t0\t0\t\nLeukopenia\t19 (54.3)\t6 (17.1)\t0\t0\t\nNon-hematologic\t \t \t \t \t\nAspartate aminotransferase increased\t15 (42.9)\t0\t0\t0\t\nBlood bilirubin increased\t14 (40.0)\t0\t0\t0\t\nFatigue\t11 (31.4)\t6 (17.1)\t0\t0\t\nAnorexia\t9 (25.7)\t0\t0\t1 (2.9)\t\nVomiting\t9 (25.7)\t0\t0\t0\t\nHypoalbuminemia\t9 (25.7)\t0\t0\t0\t\nAlanine aminotransferase increased\t8 (22.9)\t0\t0\t0\t\nProteinuria\t8 (22.9)\t0\t0\t0\t\nNausea\t7 (20.0)\t1 (2.9)\t0\t0\t\nPalmar-plantar erythrodysesthesia syndrome\t7 (20.0)\t4 (11.4)\t0\t0\t\nHypertriglyceridemia\t6 (17.1)\t0\t0\t0\t\nHyperuricemia\t5 (14.3)\t0\t0\t0\t\nCreatinine increased\t5 (14.3)\t1 (2.9)\t0\t0\t\nHypothyroidism\t5 (14.3)\t0\t0\t0\t\nWeight loss\t5 (14.3)\t2 (5.7)\t0\t0\t\nRash\t4 (11.4)\t1 (2.9)\t0\t0\t\nFever\t4 (11.4)\t0\t0\t0\t\nHyperthyroidism\t4 (11.4)\t0\t0\t0\t\naAttribution of AEs to study treatment was determined by the investigator.\n\nTable 3. Immune-related TRAEs\n\nImmune-related AEsa n (%)\tTotal\nN = 35\t\n \tAny grade\tGrade 3\t\nFatigue\t8 (22.9)\t5 (14.3)\t\nProteinuria\t7 (20.0)\t0\t\nHypothyroidism\t5 (14.3)\t0\t\nRash\t4 (11.4)\t1 (2.9)\t\nHyperthyroidism\t4 (11.4)\t0\t\nDiarrhea\t3 (8.6)\t1 (2.9)\t\nArthralgia\t2 (5.7)\t0\t\nPruritus\t1 (2.9)\t0\t\naAttribution of AEs to study treatment was determined by the investigator. TRAEs, treatment-related adverse events.\n\nTRAEs leading to discontinuation of the protocol treatment including anorexia (2.9%), thrombocytopenia (2.9%), palmar-plantar erythrodysesthesia syndrome (2.9%), and fatigue (2.9) occurred in 4 (11.4%) patients, three of which were caused by SAEs as anorexia, thrombocytopenia and fatigue, respectively. Nearly half of patients had TRAEs leading to reduced or delayed dosing of chemotherapy and/or HX008, the most frequent (>5%) TRAEs were thrombocytopenia (17.1%), vomiting (14.3%), fatigue (11.4%), leukopenia (8.6%), nausea (8.6%), anemia (5.7%), abdominal pain (5.7%) and palmar-plantar erythrodysesthesia syndrome (5.7%). The most frequent (>5%) Grade 3 TRAEs leading to dose delay or reduction were fatigue (8.6%), thrombocytopenia (5.7%), anemia (5.7%) and palmar-plantar erythrodysesthesia syndrome (5.7%).\n\nThere was one (2.9%) patient who experienced treatment-related fatal AEs, that died from thrombocytopenia leading to upper gastrointestinal hemorrhage which was considered affirmably related to oxaliplatin and capecitabine, and unlikely related to HX008.\n\nEfficacy\n\nThirty-two of 35 patients were evaluable by RECIST v1.1 criteria. Tumor evaluations by site investigators are listed in Table 4. ORR was 60.0% (95% CI 42.1–76.1), with complete response (CR) in 1 patients and partial response in 20 patients. DCR was 77.1% (95% CI 59.9–89.6). ORR and DCR in evaluable patients were 65.6% (95% CI 46.8–81.4) and 84.4% (95% CI 67.2–94.7), respectively. Most patients (28/32) with measurable disease at baseline and ≥1 evaluable postbaseline assessment experienced a reduction in target lesion size and maintained over several assessments (Figure 1). Notably, tumors of two patients shrunk to be operable and received radical surgery after combination treatment. At data cutoff, nine patients remained on treatment with ongoing responses.Table 4. Summary of response and survival data (FAS population)\n\nCategory\tTotal\t\nN = 35\t\nORR, n (%) (95% CI)a\t21 (60.0) (42.1–76.1)\t\nBOR, n (%)\t \t\nCR, n (%)\t1 (2.9)\t\nPR, n (%)\t20 (57.1)\t\nSD, n (%)\t6 (17.1)\t\nPD, n (%)\t5 (14.3)\t\nNot evaluable, n (%)\t3(8.6)\t\nDCR, n (%) (95% CI)a\t27 (77.1) (59.9–89.6)\t\nPFSb, median (95% CI), months\t9.2 (5.4-NR)\t\n6-month rate (95% CI)\t59.3 (40.1–74.1)\t\nMedian (range) time to response (months)\t1.4 (1.3–2.9)\t\nMedian (range) duration of response (months)\t12.3 (1.4–17.9+)\t\naBased on the Clopper-Pearson exact method.\n\nbEstimated using the Kaplan–Meier method.\n\nBOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; FAS, full analysis set; NR, not reached; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease\n\nFigure 1. Overall tumor responses of HX008 with oxaliplatin plus capecitabine as assessed by site investigators in patients with ≥ 1 assessable postbaseline image assessment (N = 32). (A) Best change from baseline in the size of target tumor lesion. Color code defines the best of response of target tumor lesion. (B) Percent change in the size of target tumor lesion from baseline in each patient\n\nMedian time to response (TTR) was 1.4 months (range 1.3–2.9). Median duration of response was 12.3 months (range 1.4–17.9+) (Supplementary figure 2). Median PFS was 9.2 months (95% CI 5.4-NR), and the 6-month PFS rate was 59.3% (95% CI 40.1–74.1). Median OS was NR (95% CI 10.7-NR), and the 12-month OS rate was 62.2% (95% CI 42.6–76.8) (Figure 2).Figure 2. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B)\n\nIn patients with PD-L1-positive tumors, ORR and DCR were 75% (9/12) and 83.3% (10/12), respectively, whereas in patients with PD-L1-negative tumors, ORR and DCR were 66.7% (6/9) and 100% (9/9), respectively. Nevertheless, no PFS difference (P = .19) was observed in PD-L1-positive and PD-L1-negative patients (Supplementary figure 3). Durable partial response was confirmed in two dMMR patients, both were still on treatment at the last follow-up of 12.7 and 19.9 months, respectively.\n\nDiscussion\n\nIn this single-arm, phase Ib study, HX008 combined with oxaliplatin plus capecitabine demonstrated a manageable safety profile and durable antitumor efficacy as first-line treatment in Chinese patients with advanced G/GEJ adenocarcinoma.\n\nThe incidences and severity of TRAEs with HX008 plus chemotherapy were generally consistent with those of known side effects of oxaliplatin plus capecitabine29,30 and anti-PD-1 antibody in combination with oxaliplatin plus capecitabine.26 Most AEs were grade 1/2. Hematotoxicity, such as neutropenia and thrombocytopenia, was some of the most frequently reported, which are expected AEs associated with oxaliplatin and/or capecitabine. However, the incidences of any grade and grade ≥3 anemia and leukopenia were somewhat higher than those in ATTRACTION-4 study. Although consistent with the reported AEs of oxaliplatin or capecitabine,31,32 the severity might be enhanced by HX008. Furthermore, the incidences of diarrhea and nausea were relatively lower than those in ATTRACTION-4 study. Immune-related toxicities were comparable to reports with anti-PD-1 monotherapy and parallel combination therapies in similar patient populations.25,26,33 The addition of HX008 to chemotherapy was well tolerated and did not significantly aggregate the side effect of patients with advanced G/GEJ cancer. Treatment discontinuation due to TRAEs occurred in 14.3% patients, due to fatigue (5.7%), anorexia (2.9%), thrombocytopenia (2.9%) and palmar-plantar erythrodysesthesia syndrome (2.9%), respectively.\n\nEfficacy results of this study were generally consistent with that of ATTRACTION-4 study and KEYNOTE-059 cohort 2, which suggest that HX008 plus chemotherapy showed preliminary promising anti-tumor efficacy. In ATTRACTION-4 study, ORR evaluated by central assessment was 65.8%, median PFS was 9.7 months (95% CI 6.8–12.5), and median OS was not reached with in a median follow-up time of 13.2 months. In KEYNOTE-059 cohort 2, ORR was 60.0%, median PFS was 6.6 months (95% CI 5.9–10.6), and median OS was 13.8 months (95% CI 8.6-NR). However, in the phase III KEYNOTE-062 study, median PFS of pembrolizumab plus chemotherapy in CPS ≥ 1 patients was 6.9 months (95% CI 5.7–7.3), and median OS was 12.3 months (95% CI 9.5–14.8), which demonstrated to be noninferior to chemotherapy alone. There might be several reasons that could partially explain the different therapeutic efficacy observed in studies on advanced G/GEJ cancer. Oxaliplatin was used in our study and ATTRACTION-4 study, while cisplatin was used in KEYNOTE-059 and KEYNOTE-062 trials. It has been reported that oxaliplatin-based chemotherapy might be more efficacious and more tolerant than cisplatin-based chemotherapy in patients with advanced G/GEJ cancer.34 Compared with cisplatin plus S-1, oxaliplatin plus S-1 presented significantly improved PFS (5.7 vs 4.9 months) and OS (13.0 vs 11.8 months). Indeed, compared with oxaliplatin, cisplatin possesses less activity by turning “cold” into “hot” tumors, due to its inability to trigger translocation of calreticulin to the outer leaflet of the plasma membrane of dying cells.35 Furthermore, the cycle of chemotherapy administrated varied among studies, oxaliplatin was limited for up to six cycles, while capecitabine was used until progressive decrease or intolerable toxicity in our study. Lymphopenia and neutropenia, caused by long-term chemotherapy intervention especially platinum might interfere with the mechanism of the effect of anti-PD-1 antibodies by impairing clonal expansion of effector lymphocytes. On the other hand, anti-tumor efficacy of the same therapy may vary among distinct molecular subtypes. The Cancer Genome Atlas proposed molecular classification of patients with GC into four subtypes: Epstein-Barr virus (EBV), chromosomal instability (CIN), microsatellite instable (MSI) and genomically stable (GS),36 while CIN and MSI subgroups had better overall survival than GS, but worse than EBV subtypes.37 MSI and EBV subgroups tend to be more common in Asia than in non-Asia patients,38 which has been associated with a superior response to ICIs.39,40 Intriguingly, immunity signature analysis between Asian and non-Asian gastric adenocarcinomas supposed an enrichment of tumor-infiltrating T-cells in non-Asian patients.41 Whereas better clinical efficacy of ICIs combined with chemotherapy was affirmed in Asian patients with advanced G/GEJ cancer, which manifests the need of further mechanism development.\n\nAlthough studies in several types of carcinoma have demonstrated that PD-L1 expression can be a reliable biomarker for the prediction of anti-tumor efficacy, and pembrolizumab has been approved for third-line treatment of PD-L1 positive (combined positive score ≥1) advanced G/GEJ cancer. However, no apparent association between efficacy and PD-L1 expression was determined in our exploratory analysis, which is generally unanimous with results of ATTRACTION-4 and KEYNOTE-062 studies. This result implied that PD-L1 expression might not be a robust predictive factor for anti-PD-1 antibodies combined with chemotherapy in patients with advanced G/GEJ cancer.\n\nThere are several limitations to the study. It was a single-arm study without a standard of care comparator arm, results interpreting and comparisons across trial must be cautious. The ORR was assessed by the investigators, rather than by an independent reviewer, systematic bias could be found among different investigators. The sample size was relatively small and biomarker analysis was not feasible for all patients, which made it difficult to correlate each biomarker with clinical efficacy.\n\nIn conclusion, HX008 in combination with oxaliplatin and capecitabine demonstrated an acceptable safety profile and promising anti-tumor activity as first-line treatment in Chinese patients with advanced G/GEJ cancer. Additional large-scale clinical trials are needed to further confirm the efficacy and safety of the combination treatment.\n\nSupplementary Material\n\nSupplemental Material\n\nClick here for additional data file.\n\nAcknowledgments\n\nWe would like to thank the patients who participated in the trial and their families. We would also like to thank the physicians, nurses, research coordinators, and other staff at each site who assisted with the study.\n\nDisclosure of potential conflicts of interest\n\nXF. Wang, Q. Jiang and YW. Dou are employees of Taizhou Hanzhong Biomedical Co., Ltd. All remaining authors declare that they have no conflict of interest.\n\nAuthor contributions\n\nStudy design and conception: Jianming Xu, Nong Xu, Yuxian Bai. Clinical investigators: Jianming Xu, Nong Xu, Yuxian Bai, Rongrui Liu, Chenyu Mao, Hong Sui. Data analysis and interpretation: Jianming Xu, Xiaofei Wang, Qian Jiang, Yiwei Dou. Jianming Xu and Xiaofei Wang drafted the initial version of this manuscript. All authors participated in review and revision of the manuscript. All authors read and approved the final manuscript.\n\nSupplementary materials\n\nSupplemental data for this article can be accessed Publisher’swebsite.\n==== Refs\nReferences\n\n1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68 (6 ):394–8. doi:10.3322/caac.21492.30207593\n2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66 (2 ):115–132. doi:10.3322/caac.21338.26808342\n3. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9 (3 ):215–221. doi:10.1016/S1470-2045(08)70035-4.18282805\n4. Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, et al. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016;19 (1 ):234–244. doi:10.1007/s10120-015-0457-4.25604851\n5. Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, et al. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018;21 (5 ):782–791. doi:10.1007/s10120-018-0809-y.29488121\n6. Bang Y-J, Van Cutsem E, Feyereislova A, HC C, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376 (9742 ):687–697. doi:10.1016/S0140-6736(10)61121-X.20728210\n7. Hecht JR, Bang Y-J, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–A randomized phase III trial. J Clin Oncol. 2016;34 (5 ):443–451. doi:10.1200/JCO.2015.62.6598.26628478\n8. Ohtsu A, Shah MA, Van Cutsem E, SY R, Sawaki A, SR P, HY L, Yamada Y, Wu J, Langer B, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29 (30 ):3968–3976. doi:10.1200/JCO.2011.36.2236.21844504\n9. Catenacci DVT, Tebbutt NC, Davidenko I, AM M, SE A-B, DH I, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 11;18 (11 ):1467–1482. doi:10.1016/S1470-2045(17)30566-1.28958504\n10. Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran S-E, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20 (3 ):420–435. doi:10.1016/S1470-2045(18)30791-5.30718072\n11. Wu C, Zhu Y, Jiang J, Zhao J, Zhang X-G, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108 (1 ):19–24. doi:10.1016/j.acthis.2006.01.003.16530813\n12. Hou J, Yu Z, Xiang R, Li C, Wang L, Chen S, Li Q, Chen M, Wang L. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Mol Pathol. 2014;96 (3 ):284–291. doi:10.1016/j.yexmp.2014.03.005.24657498\n13. Geng Y, Wang H, Lu C, Li Q, Xu B, Jiang J, Wu C. Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance. Int J Clin Oncol. 2015;20 (2 ):273–281. doi:10.1007/s10147-014-0701-7.24804867\n14. Kelly RJ. Immunotherapy for esophageal and gastric cancer. Am Soc Clin Oncol Educ Book. 2017;37 :292–300. doi:10.14694/EDBK_175231.28561677\n15. Kang Y-K, Boku N, Satoh T, Ryu M-H, Chao Y, Kato K, Chung HC, Chen J-S, Muro K, Kang WK, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538–12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390 (10111 ):2461–2471. doi:10.1016/S0140-6736(17)31827-5.28993052\n16. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges J-P, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4 (5 ):e180013. doi:10.1001/jamaoncol.2018.0013.29543932\n17. Hato SV, Khong A, de Vries IJM, Lesterhuis WJ. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res. 2014;20 (11 ):2831–2837. doi:10.1158/1078-0432.CCR-13-3141.24879823\n18. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39 (1 ):74–88. doi:10.1016/j.immuni.2013.06.014.23890065\n19. Kon E, Benhar I. Immune checkpoint inhibitor combinations: current efforts and important aspects for success. Drug Resist Updat. 2019;45 :13–29. doi:10.1016/j.drup.2019.07.004.31382144\n20. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 12 6;379 (23 ):2220–2229. doi:10.1056/NEJMoa1809064.30280641\n21. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379 (21 ):2040–2051. doi:10.1056/NEJMoa1810865.30280635\n22. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, CA T, Barlesi F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378 (24 ):2288–2301. doi:10.1056/NEJMoa1716948.29863955\n23. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, Psyrri A, Basté N, Neupane P, Bratland Å, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394 (10212 ):1915–1928. doi:10.1016/S0140-6736(19)32591-7.31679945\n24. Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382 (9 ):810–821. doi:10.1056/NEJMoa1910549.32101663\n25. Bang Y-J, Kang Y-K, Catenacci DV, Muro K, Fuchs CS, Geva R, Hara H, Golan T, Garrido M, Jalal SI, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019;22 (4 ):828–837. doi:10.1007/s10120-018-00909-5.30911859\n26. Boku N, Ryu MH, Kato K, Chung HC, Minashi K, Lee K-W, Cho H, Kang WK, Komatsu Y, Tsuda M, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol. 2019;30 (2 ):250–258. doi:10.1093/annonc/mdy540.30566590\n27. Tabernero J, Cutsem EV, Bang Y-J, CS F, Wyrwicz L, KW L, Kudaba I, Garrido M, HC C, Castro Salguero HR, et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study. J Clin Oncol. 2019;37 (18_suppl ):LBA4007–LBA4007.\n28. Zhang J, Huang Y, Xi G, Zhang F. HX008: a humanized PD-1 blocking antibody with potent antitumor activity and superior pharmacologic properties. MAbs. 2020;12 (1 ):1724751. doi:10.1080/19420862.2020.1724751.32106752\n29. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20 (4 ):666–673. doi:10.1093/annonc/mdn717.19153121\n30. Kim GM, Jeung H-C, Rha SY, Kim HS, Jung I, Nam BH, Lee KH, Chung HC. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012;48 (4 ):518–526. doi:10.1016/j.ejca.2011.12.017.22243774\n31. Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, Takeda Y, Moriwaki T, Amagai K, Sekikawa T, et al. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014 5;50 (8 ):1437–1445. doi:10.1016/j.ejca.2014.01.020.24560487\n32. Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, Yasui H, Kim T-Y, Yamaguchi K, Fuse N, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2015 10;18 (4 ):824–832. doi:10.1007/s10120-014-0420-9.25185971\n33. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16 (9 ):563–580. doi:10.1038/s41571-019-0218-0.31092901\n34. Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, et al. Anti-PD-1 antibody shr-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019 1 15;25 (2 ):515–523. doi:10.1158/1078-0432.CCR-18-2484.30348638\n35. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17 (2 ):97-111. doi:10.1038/nri.2016.107.\n36. Chia NY, Tan P. Molecular classification of gastric cancer. Ann Oncol. 2016;27 (5 ):763–769. doi:10.1093/annonc/mdw040.26861606\n37. Park C, Cho J, Lee J, Kang SY, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, et al. Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity. Oncoimmunology. 2017;6 (11 ):e1356150. doi:10.1080/2162402X.2017.1356150.29147610\n38. Liao P, Jia F, Teer JK, Knepper TC, Zhou H-H, He Y-J, McLeod HL. Geographic variation in molecular subtype for gastric adenocarcinoma. Gut. 2019;68 (7 ):1340–1341. doi:10.1136/gutjnl-2018-316605.29960981\n39. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 6 25;372 (26 ):2509–2520. doi:10.1056/NEJMoa1500596.26028255\n40. Kim ST, Cristescu R, Bass AJ, Kim K-M, Odegaard JI, Kim K, Liu XQ, Sher X, Jung H, Lee M, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018 9;24 (9 ):1449–1458. doi:10.1038/s41591-018-0101-z.30013197\n41. Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K, Ylstra B, van Grieken N, Rha SY, Chung HC, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut. 2015;64 (11 ):1721–1731. doi:10.1136/gutjnl-2014-308252.25385008\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2162-4011",
"issue": "10(1)",
"journal": "Oncoimmunology",
"keywords": "HX008; PD-1; capecitabine; gastric cancer; oxaliplatin",
"medline_ta": "Oncoimmunology",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002681:China; D004943:Esophagogastric Junction; D006801:Humans; D000077150:Oxaliplatin; D013274:Stomach Neoplasms",
"nlm_unique_id": "101570526",
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"pmid": "33457083",
"pubdate": "2020-12-31",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Anti-PD-1 antibody HX008 combined with oxaliplatin plus capecitabine for advanced gastric or esophagogastric junction cancer: a multicenter, single-arm, open-label, phase Ib trial.",
"title_normalized": "anti pd 1 antibody hx008 combined with oxaliplatin plus capecitabine for advanced gastric or esophagogastric junction cancer a multicenter single arm open label phase ib trial"
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"abstract": "Spontaneous gallbladder hemorrhage (SGBH) is a rare diagnosis related to trauma, malignancy or vascular abnormalities, associated with significant morbidity and mortality. We present a case of SGBH in a 55-year-old patient with right upper quadrant (RUQ) pain following initiation of apixaban for deep vein thrombosis post recent kidney transplant. Multiple imaging studies revealed a distended gallbladder with heterogeneous hyperdense material in the lumen and cystic duct obstruction. Surgery revealed a gallbladder with chronic cholecystitis, hemorrhage and hematoma. This case highlights a rare adverse event of anticoagulation, and SGBH should be considered when acute RUQ pain occurs in this setting.",
"affiliations": "Department of Medicine, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Department of Radiology, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Division of Gastroenterology and Hepatology, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Division of Gastroenterology and Hepatology, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Department of Pathology, Augusta University-Medical College of Georgia, Augusta, GA, USA.;Division of Gastroenterology and Hepatology, Augusta University-Medical College of Georgia, Augusta, GA, USA. Electronic address: kvega@augusta.edu.",
"authors": "Azam|Mohammad Umair|MU|;Ibrahim|Muaz A|MA|;Perry|Isaac|I|;Ellison|Steven B|SB|;Barrett|Amanda|A|;Vega|Kenneth J|KJ|",
"chemical_list": "D015951:Factor Xa",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jnma.2020.12.008",
"fulltext": null,
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"issn_linking": "0027-9684",
"issue": "113(3)",
"journal": "Journal of the National Medical Association",
"keywords": "Anticoagulation; Gallbladder; Hemorrhage",
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D002764:Cholecystitis; D015951:Factor Xa; D006470:Hemorrhage; D006801:Humans; D008875:Middle Aged; D014463:Ultrasonography",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "252-254",
"pmc": null,
"pmid": "33454137",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "It's the Bloody Gallbladder! Spontaneous Gallbladder Hemorrhage Following Factor Xa Inhibition.",
"title_normalized": "it s the bloody gallbladder spontaneous gallbladder hemorrhage following factor xa inhibition"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-111673",
"fulfillexpeditecriteria": "2",
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"abstract": "OBJECTIVE\nSuicide attempts (SAs) in the paediatric age group represent an important cause of morbidity and mortality. Our aim was to examine the factors affecting the decision to hospitalize children with a diagnosis of non-fatal SA by pills.\n\n\nMETHODS\nChildren <18 years of age admitted with SA by pills during 2014 were evaluated retrospectively. Patients were divided into two groups: Group-I comprised hospitalised patients and Group-II included those who were discharged from the PED. These two groups were compared in terms of clinical and demographic characteristics recorded upon PED admission.\n\n\nRESULTS\nA total of 196 patients were included in the study. The number of pills taken for self-poisoning in Group-I (median: 20 pills) was higher than that in Group-II (median: 12 pills) (p < 0.001), and the rate of pathological findings during the first paediatric psychiatric consultation was higher in Group-I (91.1%) than in the Group-II (54.8%) (p < 0.001).\n\n\nCONCLUSIONS\nFactors affecting the disposition decision in cases of children who performed non-fatal SA via pills included the amount of medication taken for the suicide attempt and the presence of psychiatric disorders, as determined by a paediatric psychiatrist during the acute phase.",
"affiliations": "Gamze Gokalp, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.;Murat Anil, MD. Associate Professor, Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.;Alkan Bal, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.;Yuksel Bicilioglu, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.;Fulya Kamit Can, MD. Pediatric Intensive Care Clinic, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.;Ayse Berna Anil, MD. Associate Professor, Pediatric Intensive Care Unit, Pediatric Intensive Care Clinic of Izmir Katip Celebi University, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey.",
"authors": "Gokalp|Gamze|G|;Anil|Murat|M|;Bal|Alkan|A|;Bicilioglu|Yuksel|Y|;Kamit Can|Fulya|F|;Anil|Ayse Berna|AB|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.12669/pjms.323.9765",
"fulltext": "\n==== Front\nPak J Med SciPak J Med SciPakistan Journal of Medical Sciences1682-024X1681-715XProfessional Medical Publications Pakistan PJMS-32-73110.12669/pjms.323.9765Original ArticleFactors affecting the decision to hospitalise children admitted to the emergency department due to non-fatal suicide attempts by pills Gokalp Gamze 1Anil Murat 2Bal Alkan 3Bicilioglu Yuksel 4Kamit Can Fulya 5Anil Ayse Berna 61 Gamze Gokalp, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey2 Murat Anil, MD. Associate Professor, Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey3 Alkan Bal, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey4 Yuksel Bicilioglu, MD. Pediatric Emergency Department, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey5 Fulya Kamit Can, MD. Pediatric Intensive Care Clinic, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey6 Ayse Berna Anil, MD. Associate Professor, Pediatric Intensive Care Unit, Pediatric Intensive Care Clinic of Izmir Katip Celebi University, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey\nCorrespondence: Gamze Gokalp, MD. Pediatric Emergency Department, Izmir Tepecik Teaching & Research Hospital, Izmir, Turkey. E-mail: drgamzegokalp@mynet.comNote: All the authors declare that they conducted this research in accordance with the rules of ethics.\n\nMay-Jun 2016 32 3 731 735 13 1 2016 21 1 2016 12 5 2016 17 5 2016 Copyright: © Pakistan Journal of Medical Sciences2016This 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.Objective:\nSuicide attempts (SAs) in the paediatric age group represent an important cause of morbidity and mortality. Our aim was to examine the factors affecting the decision to hospitalize children with a diagnosis of non-fatal SA by pills.\n\nMethods:\nChildren <18 years of age admitted with SA by pills during 2014 were evaluated retrospectively. Patients were divided into two groups: Group-I comprised hospitalised patients and Group-II included those who were discharged from the PED. These two groups were compared in terms of clinical and demographic characteristics recorded upon PED admission.\n\nResults:\nA total of 196 patients were included in the study. The number of pills taken for self-poisoning in Group-I (median: 20 pills) was higher than that in Group-II (median: 12 pills) (p < 0.001), and the rate of pathological findings during the first paediatric psychiatric consultation was higher in Group-I (91.1%) than in the Group-II (54.8%) (p < 0.001).\n\nConclusion:\nFactors affecting the disposition decision in cases of children who performed non-fatal SA via pills included the amount of medication taken for the suicide attempt and the presence of psychiatric disorders, as determined by a paediatric psychiatrist during the acute phase.\n\nKEY WORDS\nHospitalisationPaediatricEmergencySelfPoisoning\n==== Body\nINTRODUCTION\nSuicide attempts (SAs) represent one of the most important causes of mortality among children and adolescents.1 In the United States, suicide has been identified as the third most important cause of death for those between the ages of 10 and 24 years. According to these data, approximately 4300 deaths per year were due to SA. Non-fatal SAs are much more common, comprising about 5% of emergency department visits.2\n\nA variety of means may be involved in SA. The most common means are firearms, stabbing, hanging, drowning, motor vehicle injuries, jumping from a high place, and poison ingestion.3–5 Approximately, 50% of SA cases are hospitalised.2 Most studies of SA have focused on psychiatric causes.2 Nonetheless, one of the most practical issues from the perspective of the paediatric emergency physician is the decision regarding whether a patient being treated for non-fatal SA should be hospitalised.\n\nOur objective was to determine which demographic, clinic, and laboratory risk factors upon admission to a paediatric emergency department (PED) were influential in the decision to hospitalise children being treated for non-fatal self-poisoning by pills. We chose to focus on self-poisoning by pill ingestion, because this is one of the most common means of SA in our patient.\n\nMETHODS\nA retrospective analysis of the records of paediatric patients admitted to the PED of Tepecik Teaching and Research Hospital, Izmir, Turkey, from 1st January to 31st December 2014 was performed. The local ethical committee granted permissions. The PED of Tepecik Teaching and Research Hospital, one of the most crowded PEDs in Turkey, is a paediatric emergency sub-specialty training clinic. The PED has a 14-bed observation unit to monitor and treat critical patients for up to 24 hour, after which the patients can be admitted to the hospital if necessary. The standard interventions (gastric lavage, activated charcoal treatments, and specific antidotes as appropriate) are performed in all patients admitted to the emergency department where they are observed. Consultations with the National Poison Control Centre are routine. A paediatric psychiatrist performs psychiatric consultations with the patients in the PED or the paediatric ward.\n\nCriteria for inclusion in our study were children <18 years of age who came to the PED following self-poisoning by pills. Self-poisoning was defined as intentional ingestion of a toxic substance or medication in excess of the prescribed dosage. Our hospital data system has a standard poisoning and suicide medical record page that must be filled out by the physician who provides medical care. This medical record page includes thorough demographic and medical data. For the present study, we reviewed the suicide-specific medical records in the hospital’s electronic data system to collect data on the patient’s age, gender, and medical history, including the amount of drugs (in this study, the number of pills) taken for self-poisoning, physical examination findings, results of all laboratory tests, results of the first psychiatric evaluation, disposition type, and final outcomes. Patients were divided into two groups according to the disposition type: Group-I included patients who were hospitalised and Group-II included patients who were discharged from the PED. These two groups were compared in terms of clinical and demographic characteristics. Patients who attempted suicide by other means (stabbing, firearms, intentional traffic accidents, intentional choking, jumping, or hanging) were excluded.\n\nCategorical data are expressed as number (n) and percentage (%) and were analysed using chi-square or Fischer’s exact tests, as appropriate. Continuous data are presented as mean±standard deviation (SD) and minimum–maximum values, or as median and interquartile range (25–75th percentile), according to the parametric condition. Student’s t-tests or Mann–Whitney U-tests were used for the analyses of continuous variables. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics 20.0 software (IBM, Armonk, NY, USA).\n\nRESULTS\nDuring the study period, 161,928 children were admitted to the PED of Tepecik Teaching and Research Hospital, Izmir, Turkey. Of these, 196 patients (mean age: 14.0±1.7, range: 6–17 years; 167 female, 29 male) were included in the study. According to their medical histories, 21 (10.7%) children had one or more previous SAs. Antidepressant drugs (52 patients, 26.5%) were the most commonly used drugs (Table-I), and 97 (49.5%) patients engaged in multi-drug self-poisoning. On admission, 10 patients (5.1%) exhibited abnormal physical examination findings, 44 patients (22.4%) had abnormal laboratory results (22 serum electrolyte abnormality, 27 liver function test abnormality, and four renal function test abnormality), and five patients (2.6%) had abnormal electrocardiogram (ECG) findings (4 sinus tachycardia and one ventricular tachycardia). Low Glasgow Coma Scale (GCS) scores were identified in 6 patients (3.2%) on admission (4 patients had scores of 14; 2 had scores of 13). Paediatric psychiatric consultations were performed for all patients in the PED or paediatrics ward. The first psychiatric consultations identified pathological conditions in 152 (77.6%) patients (Table-II). After observation in the PED, 123 (62.8%) patients were hospitalised (7 patients in the paediatric intensive care unit; no patient required mechanical ventilation). There was no patient who was hospitalized at pediatric psychiatry unit. The median length of stay was 2 days (25–75th percentile: 2–4 days; range: 1–10 days). No patient died. All patients were discharged from the hospital neurologically intact.\n\nTable-I Drugs used in self-poisoning and hospitalization rates in each drug type.\n\nType of drug\tNumber of patient (% of total patient)\tNumber of hospitalized patient (% of drug type)\t\nAntidepressant\t52 (26.5)\t28 (53.8)\t\nParacetamol\t45 (23)\t33 (73.3)\t\nAcetylsalicylic acid\t16 (8.2)\t11 (68.8)\t\nAntigripal drug\t47 (24)\t32 (68.1)\t\nNonsteroidal anti-inflammatory drug\t45 (23)\t33 (73.3)\t\nCardiovascular drug\t22 (11.2)\t17 (77.3)\t\nAnti-diabetic\t7 (3.6)\t6 (85.7)\t\nAntibiotic\t29 (14.8)\t19 (62.1)\t\nAnti-histaminic\t15 (7.7)\t10 (66.7)\t\nFerrous drugs\t8 (4.1)\t5 (62.5)\t\nH2 receptor blocker\t24 (12.2)\t18 (75)\t\nAntiepileptic\t15 (7.7)\t8 (53.3)\t\nColchicine\t1 (0.5)\t1 (100)\t\nOthers\t15 (7.7)\t10 (66.7)\t\nTable-II The results of pediatric psychiatric consultation.\n\nResult of pediatric psychiatric consultation\tn (%)\t\nMajor depression\t112 (57.1)\t\nAnxiety disorder\t22 (11.2)\t\nPervasive developmental disorder\t3 (1.5)\t\nPathological sadness\t4 (2)\t\nAdjustment disorder\t7 (3,6)\t\nMood disorders\t4 (2)\t\nNo clear pathology\t44 (22.4)\t\nWe compared the hospitalised patients (Group-I) and discharged patients (Group-II) according to demographic, clinical, and laboratory findings upon admission to the PED. There were no statistical differences between the groups in terms of age, gender, presence of multi-drug poisoning, presence of self-harm scarring, rate of first SA, GCS on admission, pathological findings on physical examination on admission, ECG abnormality on admission, or abnormal laboratory test results on admission (all p > 0.05). The number of pills taken for self-poisoning in Group-I was much higher than that in Group-II (median number of tablets: 20 vs. 12; p < 0.001). The rate of pathological findings during the first paediatric psychiatry consultation was significantly different between Group-I (112 patients, 91.1%) and Group-II (40 patients, 54.8%) (p < 0.001) (Table-III). Furthermore, we found no significant difference in the rate of hospitalisation based on the type of drug used in self-poisoning (p > 0.05). The highest hospitalisation rates were seen in children who ingested anti-diabetic medications (17 of 22 patients, 77.3%) and in children with self-poisoning via colchicine (1 patient, 100%) (Table-I).\n\nTable-III The differences between the cases with or without hospitalization according to demographic and clinical findings.\n\nParameters\tTotal n: 196\tGroup-I n: 123\tGroup-II n: 73\tp\t\nAge, mean±SD (minimum – maximum)\t14.0±1.7 (6-17)\t14.1±1.6 (9-17)\t13.8±1.9 (6-17)\t0,235\t\nGender, n (%)\t\n F\t167 (85,2)\t104 (84.6)\t63 (86.3)\t0,739\t\n M\t29 (14,8)\t19 (13.4)\t10 (13.7)\t\nNumber of pills taken for self-poisoning, median, (25-75 p)\t14 (10-30)\t20 (10-36)\t12(8-16)\t<0.001\t\n> 1 type drug, n (%)\t97 (49.5)\t63 (51.2)\t34 (46.6)\t0.530\t\nSelf-harm scarring (+), n (%)\t189 (96,4)\t117 (95,1)\t72 (98,6)\t0,261\t\nFirst suicide attempt (+), n (%)\t175 (89,3)\t109 (88.6)\t66 (90.4)\t0,695\t\nGlasgow Coma Score <15, n (%)\t6 (3.1)\t4 (3.3)\t2(2.7)\t>0.999\t\nPathological findings on physical examination, n (%)\t10 (5.1)\t6 (4.9)\t4 (5.5)\t>0.999\t\nCardiacarrhythmia on ECG, n (%)\t5 (2.6)\t2 (1.6)\t3 (4.1)\t0.363\t\nAbnormality in any laboratory result on admission, n (%)\t44 (22.4)\t32 (26)\t12 (16.4)\t0.120\t\nPathological findings on first pediatric psychological consultation, n (%)\t152 (77.6)\t112 (91.1)\t40 (54.8)\t<0.001\t\nDISCUSSION\nIn this retrospective analysis, we found that most SAs in the study population were performed by female children and adolescents. Antidepressants were most frequently chosen. Approximately half of the patients took multiple drugs. The number of pills taken and the incidence of pathological findings at the first paediatric psychiatric consultation were higher in hospitalised than in non-hospitalised patients. We found no significant difference between the patients discharged from the PED and the patients hospitalised in terms of clinical or laboratory parameters.\n\nWorldwide, approximately 200,000 adolescents lose their lives due to suicide every year,3 making suicide one of the most important causes of morbidity and mortality in this age group.³ SA is one of the most important problems in PEDs.8\n\nIn the literature on paediatric patients who attempt suicide, the ages considered range from 13 to 18 years.9-11 Most studies have reported higher numbers of female than male patients.3,9,10 However the proportion of females in our study (approximately 85%) was much higher than that reported in the literature. The reason for this difference may be that we included only children who attempted suicide by taking an overdose of pills.\n\nSome authors have reported that the rate of previous SA was high among children admitted to the emergency department.3,10,12 However, these results do not correspond with our data. In our study, the rate of previous SA was only 10%. This difference may arise from the fact that our study covered only one year. Additionally, most of the published studies were carried out in developed countries. Our country is a developing nation, and this may affect our findings.\n\nAntidepressants, non-steroidal anti-inflammatory drugs, and analgesics are mainly chosen in self-poisoning attempts.13-15 Our results were similar to the literature in this regard. Additionally, flu medications were used by one our of every four patients in our study group. We found no significant difference in the hospitalization rate, based on the type of drug used in SAs.\n\nVarious drugs lead to different clinical results, and the most severe clinical outcomes are dose-related.16-18 The need for hospitalization varies according to the clinical situation and risk factors.9,10,19 Psychiatric problems are common in patients being treated for non-fatal SAs.20,21,22 In our study, the physical examination and laboratory tests revealed no abnormalities in most patients. However, abnormal psychiatric findings were seen in the majority of children in the acute phase, with major depression being the most common disorder. The number of pills used in SAs was much higher, and abnormal psychiatric findings in the acute phase were much more common in hospitalized patients compared with discharged patients, among children who performed non-fatal SA using pills. The abnormal clinical and laboratory findings did not differ between the groups. These results indicated that the amount of drugs consumed, as determined from the medical history, and the results of the paediatric psychiatry consultation during the acute phase of poisoning may be important parameters affecting the decision by PED physicians regarding whether to hospitalize. These findings were likely related to two important considerations. One of these was the features of our study group, which consisted of children with non-fatal, moderate to severe poisoning. Secondly, our PED is a training center; thus, most patients with moderate to severe clinical stages received appropriate medical care in our emergency department, as they would in other top-tier emergency departments around the world19; furthermore, we were able to follow them in the observation unit without hospitalization for the first 24 h. Hence, there was usually no need to hospitalize patients based on abnormal clinical findings at admission. The remaining factors affecting the hospitalization decision in the case of children who performed non-fatal SA via pills were the risks posed by a severe clinical situation (the number of pills used in SA) and the risk of SA recurrence (presence of psychiatric problems during the acute phase of poisoning).\n\nLimitations of the study\nFirst, the retrospective character of the study is an important limitation. Second, our results were from only one center; however, the number of patients included in the study was substantial. Finally, prospective multi-center studies will better illuminate the factors that affect the hospitalization decision in PED.\n\nIn conclusion, in a top-tier PED, the factors affecting the disposition decision for children who performed non-fatal SA via pill overdose were the amount of medication used for SA and psychiatric disorders as determined by a paediatric psychiatrist during the acute phase.\n\nDeclaration of interest: All the authors declare that there is no conflict of interest.\n\n\nAuthors’ Contributions\nGG, MA: Contributions to conception and design, or acquisition of data, analysis and interpretation of data.\n\nGG, MA: Drafting the article or revising it critically for important intellectual content.\n\nGG, MA, AB, YB, FKN, ABA: Final approval of the version to be published.\n\nGG, AB, YB, FKN, ABA: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n==== Refs\nREFERENCES\n1 Patton GC Coffey Sawyer SM Viner RM Haller DM Bose K Global patterns of mortality in young people:A systematic analysis of population health data Lancet 2009 374 881 892 doi:10.1016/S0140-6736(09)60741-8 19748397 \n2 Bridge JA Goldstein TR Brent DA Adolesent suicide & suicidal behavior J Child Psycol Psychiatry 2006 47 372 394 doi:10.1111/j.1469-7610.2006.01615.x \n3 Greydanus DE Bacopoulou F Tsalamanios E Suicide in adolescents:A worldwide preventable tragedy Keio J Med 2009 58 2 95 102 doi:10.2302/kjm.58.95 19597305 \n4 Maris RW Suicide Lancet 2002 360 319 326 doi:10.1016/S0140-6736(02)09556-9 12147388 \n5 Keith CR Adolescent suicide:Perspectives on a clinical quandary JAMA 2001 286 3126 3127 doi:10.1001/jama.286.24.3126 11754679 \n6 Greydanus DE Calles J Jr Suicide in children & adolescents Prim Care:Clin Off Pract 2007 34 259 273 doi:10.1016/j.pop.2007.04.013 \n7 Centers for Disease Control & Prevention. Methods of suicide among persons age 10-19 years- United States 1992-2001 MMWR 2004 53 471 474 15190241 \n8 De Tournemire R Teenagers’suicides & suicide attempts:Finding one’s way in epidemiologic data Arch Pediatr 2010 17 8 1202 1209 doi:10.1016/j.arcped.2010.05.011 20598866 \n9 Hysinger EB Callahan ST Caples TL Fuchs DC Shelton R Cooper WO Suicidal behavior differs among early & late adolescents treated with antidepressant agents Pediatrics 2011 128 3 447 454 doi:10.1542/peds.2010-3262 21824883 \n10 Mirkovic B Labelle R Guile JM Belloncle V Bodeau N Knafo A Skills among adolescent suicide attempters:results of a multisite study Can J Psychiatry 2015 60 2 Suppl 1 S37 45 25886670 \n11 Hauser M Galling B Correll CU Suicidal ideation & suicide attempts in children & adolescents with bipolar disorder:A systematic review of prevalence & incidence rates, correlates, & targeted interventions Bipolar Disord 2013 15 5 507 523 doi:10.1111/bdi.12094 23829436 \n12 Takara K Kondo T Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients:A case-control study Ann Gen Psychiatry 2014 13 1 33 doi:10.1111/bdi.12094 25328535 \n13 Kara H Bayir A Degirmenci S Kayis SA Akinci M Ak A Causes of poisoning in patients evaluated in a hospital emergency department in Konya, Turkey J Pak Med Assoc 2014 64 9 1042 1048 25823185 \n14 Avsarogullari L Senol V Akdur O Akin A Durukan P Ozkan S Characteristics of acute adult poisonings in a university hospital emergency department in central Turkey:a three-year analysis J Pak Med Assoc 2012 62 2 129 133 22755373 \n15 Olguin HJ Garduño LB Pérez JF Bastida MA Flores-Pérez C Frequency of suicide attempts by ingestion of drugs seen at a tertiary care pediatric hospital in Mexico J Popul Ther Clin Pharmacol 2011 18 e161 165 21471607 \n16 Atas B Caksen H Tuncer O Kirimi E Akgun C Odabaş D Four children with colchicine poisoning Hum Exp Toxicol 2004 23 7 353 356 15311853 \n17 Debnath CR Debnath MR Alam MM Moshwan MM A case of acute insulin poisoning with attempt to suicide Mymensingh Med J 2014 23 4 800 802 25481605 \n18 Avci D Çetinkaya A Karahan S Oğuzhan N Karagoz H Başak M Suicide commitment with metformin:our experience with five cases Ren Fail 2013 35 6 863 865 doi:10.3109/0886022X.2013.801299 23742066 \n19 Zohre E Ayrik C Bozkurt S Kose A Narci H Çevik I Retrospective analysis of poisoning cases admitted to the emergency medicine Arch Iran Med 2015 117 122 doi:015182/AIM.0011 25644801 \n20 Hawton K Saunders K Topiwala A Haw C Psychiatric disorders in patients presenting to hospital following self-harm:a systematic review J Affect Disord 2013 151 821 830 doi:10.1016/j.jad.2013.08.020 24091302 \n21 Evans E Hawton K Rodham K Factors associated with suicidal phenomena in adolescents:A systematic review of population-based studies Clin Psychol Rev 2004 24 957 979 doi:10.1016/j.cpr.2004.04.005 15533280 \n22 Mars B Heron J Crane C Hawton K Lewis G Macleod J Clinical & Social outcomes of adolescent self harm:Population based birth cohort study BMJ 2014 349 5954 doi:10.1136/bmj.g5954\n\n",
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"journal": "Pakistan journal of medical sciences",
"keywords": "Emergency; Hospitalisation; Paediatric; Poisoning; Self",
"medline_ta": "Pak J Med Sci",
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"title": "Factors affecting the decision to hospitalise children admitted to the emergency department due to non-fatal suicide attempts by pills.",
"title_normalized": "factors affecting the decision to hospitalise children admitted to the emergency department due to non fatal suicide attempts by pills"
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"abstract": "A 60-year-old man with advanced gastric cancer achieved good pain control on a stable dose of methadone for 10 days. However, he developed respiratory depression 2 days after intravenous fluconazole was administrated for refractory oral candidiasis. Intravenous naloxone effectively reversed the respiratory depression. This case illustrates a significant interaction between methadone and fluconazole, and highlights the need for awareness of potential interactions between drugs used in palliative care.",
"affiliations": "Palliative Care Program, Grey Nuns Community Hospital, Edmonton, Alberta, Canada.",
"authors": "Tarumi|Yoko|Y|;Pereira|Jose|J|;Watanabe|Sharon|S|",
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"title": "Methadone and fluconazole: respiratory depression by drug interaction.",
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"abstract": "We describe the successful treatment of a 24-week pregnant, 44-year-old woman with COVID-19. Management of this complex case required multidisciplinary collaboration and included prolonged invasive mechanical ventilation and prone positioning. Caesarean section delivery was delayed for 32 days, with no monitored fetal compromise, while stabilising the mother. To our knowledge, this is the longest reported duration of invasive ventilation while pregnant in a patient with COVID-19. COVID-19 has been shown to cause increased disease severity in pregnant women, and certain pregnancy-related physiological adaptations that occur could help explain this association. While COVID-19 has been shown to cause no increased adverse neonatal outcomes, clinicians should be aware that data show increased preterm birth in symptomatic pregnant women, thereby increasing the chance of prematurity-related complications. Further research on COVID-19 in pregnancy is crucial to facilitate better management, and full inclusion of pregnant women in therapeutic clinical trials will help achieve this.",
"affiliations": "Intensive Care Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK kaladerhan.agbontaen@nhs.net.;Intensive Care Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.;Intensive Care Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.",
"authors": "Agbontaen|Kaladerhan Osemwengie|KO|http://orcid.org/0000-0002-5571-230X;Somasundram|Khevan|K|;Baker|Matthew|M|",
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"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002585:Cesarean Section; D005260:Female; D005333:Fetus; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D037841:Pregnant Women; D047928:Premature Birth; D012121:Respiration, Artificial; D000086402:SARS-CoV-2",
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"title": "Critical COVID-19 in a 24-week pregnant woman with 32 days of invasive mechanical ventilation before delivery of fetus: a case of successful collaborative multidisciplinary care.",
"title_normalized": "critical covid 19 in a 24 week pregnant woman with 32 days of invasive mechanical ventilation before delivery of fetus a case of successful collaborative multidisciplinary care"
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"abstract": "Essentials Anticoagulation in patients with factor X deficiency is an evidence-poor area. A patient with factor X deficiency was anticoagulated with warfarin followed by rivaroxaban. Warfarin may be a safer anticoagulant option than rivaroxaban in hereditary factor X deficiency. A baseline coagulation screen should be performed prior to commencement of anticoagulation.\n\n\nCONCLUSIONS\nWe report a case of a previously undiagnosed factor X deficiency in an 83-year-old man who had no previous bleeding history despite multiple hemostatic challenges. He was anticoagulated with warfarin for atrial fibrillation without bleeding complications; however, major hemorrhage occurred soon after a switch to rivaroxaban.",
"affiliations": "Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.",
"authors": "Sayar|Z|Z|http://orcid.org/0000-0001-8838-9257;Speed|V|V|;Patel|J P|JP|http://orcid.org/0000-0003-4197-8294;Patel|R K|RK|;Arya|R|R|",
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"keywords": "coagulation; factor X; oral anticaogulants; pharmacotherapeutics; rivaroxaban",
"medline_ta": "J Thromb Haemost",
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"pmid": "29883037",
"pubdate": "2018-06-08",
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"title": "The perils of inhibiting deficient factors.",
"title_normalized": "the perils of inhibiting deficient factors"
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"abstract": "Ranitidine hydrochloride (Zantac) is a recently released H(2)-receptor antagonist that is stated not to cause significant increases in serum gastrin. The case described herein demonstrates that this is not always true. Zantac produced significant acute hypergastrinemia, which was sustained for several days after the discontinuation of the drug.",
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"authors": "Chisholm|J C|JC|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6129180;6105116",
"title": "Ranitidine hydrochloride-induced hypergastrinemia.",
"title_normalized": "ranitidine hydrochloride induced hypergastrinemia"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-03820BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANITIDINE HYDROCHLORIDE"
... |
{
"abstract": "This study sought to evaluate clinical features, treatment patterns, and outcomes of patients with idiopathic inflammatory myopathy (IIM) complicated by heart failure (HF). Thirty-two patients with IIM-HF admitted to the Peking Union Medical College Hospital between January 1999 and January 2018 were retrospectively reviewed, including 14 patients with polymyositis, 11 with dermatomyositis, and 7 with overlap syndrome. Survivors and no-survivors were compared on clinical characteristics and treatment. Although systemic symptoms were variable, all patients presented with elevated troponin I. Rapid atrial arrhythmia was the most frequent arrhythmia. Systolic dysfunction and restrictive diastolic dysfunction were typical presentations in echocardiography. Twenty-nine patients were followed up for a median of 2.8 years (0.1 month to 11 years). We recorded 13 deaths of cardiogenic cause, 1 of serious IIM, and 3 of infective complications. The median survival time from diagnosis of IIM-HF to all-cause mortality was 8.4 months (range from 1 month to 5 years). Both all-cause deaths and cardiogenic deaths were more reported in the methotrexate-alone group than in the combination therapy group (6/7 versus 3/10, P = 0.050; 5/6 versus 2/9, P = 0.041). Combination therapy including methotrexate (HR = 0.188, 95%CI 0.040-0.871, P = 0.033) and taking β-receptor blockers (HR = 0.249, 95%CI 0.086-0.719, P = 0.010) was associated with reduced risk of all-cause deaths. In conclusion, elevated troponin I, atrial arrhythmia, and systolic and restrictive diastolic dysfunction are typical characteristics of IIM-HF. Combined immunosuppression that includes methotrexate and β-receptor blockers seems to be important to improve survival.",
"affiliations": "Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.;Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.",
"authors": "Liu|Yingxian|Y|;Fang|Ligang|L|;Chen|Wei|W|;Lin|Xue|X|;Wang|Qian|Q|;Zhu|Yanlin|Y|;Pang|Haiyu|H|;Zhang|Shuyang|S|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008775:Methylprednisolone; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.19-568",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "61(5)",
"journal": "International heart journal",
"keywords": "Cardiac involvement; Clinical manifestation; Dermatomyositis; Immunosuppression; Myositis; Prognosis",
"medline_ta": "Int Heart J",
"mesh_terms": "D000293:Adolescent; D000319:Adrenergic beta-Antagonists; D000328:Adult; D000368:Aged; D002681:China; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006333:Heart Failure; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008775:Methylprednisolone; D008875:Middle Aged; D009220:Myositis; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "1005-1013",
"pmc": null,
"pmid": "32999188",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Characteristics, Treatment, and Outcomes in Patients with Idiopathic Inflammatory Myopathy Concomitant with Heart Failure.",
"title_normalized": "clinical characteristics treatment and outcomes in patients with idiopathic inflammatory myopathy concomitant with heart failure"
} | [
{
"companynumb": "CN-ACCORD-205245",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND Patients <60 years old with high-risk diffuse large B-cell lymphoma (DLBCL) receiving standard RCHOP(E) treatment display high relapse rates. Here, we compared this standard regimen to a high-intensity regimen in terms of recurrence and long-term survival. MATERIAL AND METHODS Newly diagnosed DLBCL patients <60 years old who were treated at the Second Hospital Affiliated with Xi'an Jiaotong University between January 2004 and December 2013 (n=198, 18-60 years) were included in the study. The high-intensity group included 107 patients (54.0%) who received >8 courses of chemotherapy (high-dose CHOP, CHOP-E, EPOCH, MAED, MMED, and HyperCVAD). The control group included 91 patients (46.0%) who received 6-8 courses of CHOP-based treatment. Response rate (RR), survival, relapse, and adverse effects were compared. RESULTS Baseline characteristics of the patients were similar between the 2 groups. Median follow-up was 64.5 months. RR in the high-intensity and control groups was 88.8% and 84.6% (P=0.387), respectively; 5-year overall survival was 66.4% and 36.3% (P<0.001), respectively; 5-year progression-free survival was 56.1% and 28.6% (P<0.001), respectively; 5-year disease-free survival was 54.2% and 24.2% (P<0.001), respectively; and relapse rate during follow-up was 29.5% and 67.5% (P<0.001), respectively. There were no significant differences in adverse effects between the 2 groups. CONCLUSIONS High-intensity chemotherapy is associated with better prognosis of patients <60 years old with newly diagnosed high-risk DLBCL.",
"affiliations": "Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).;Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China (mainland).",
"authors": "Ma|Xiaorong|X|;Xu|Yan|Y|;Zhang|Wanggang|W|;Wang|Jin|J|;Cao|Xingmei|X|;Chen|Yinxia|Y|;He|Aili|A|;Liu|Jie|J|;Wang|Jianli|J|;Zhao|Wanhong|W|;Yang|Yun|Y|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.12659/msm.895383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1234-1010",
"issue": "22()",
"journal": "Medical science monitor : international medical journal of experimental and clinical research",
"keywords": null,
"medline_ta": "Med Sci Monit",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016022:Case-Control Studies; D002681:China; D015331:Cohort Studies; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011241:Prednisone; D011379:Prognosis; D012189:Retrospective Studies; D014750:Vincristine",
"nlm_unique_id": "9609063",
"other_id": null,
"pages": "1792-800",
"pmc": null,
"pmid": "27232105",
"pubdate": "2016-05-27",
"publication_types": "D016428:Journal Article",
"references": "21460380;14504078;23168367;17299093;12402390;25445718;16877734;15322522;21912688;22997459;1831987;23375551;15057285;20202462;11935217;20587042;20093241;2300381;17329192;18954744;16092591;16720929;24048801;25090026;2291455;18226581;2056971;23901002",
"title": "High-Intensity Chemotherapy is Associated with Better Prognosis in Young Patients with High-Risk Diffuse Large B-Cell Lymphoma: A 10-Year Single-Center Retrospective Cohort Study.",
"title_normalized": "high intensity chemotherapy is associated with better prognosis in young patients with high risk diffuse large b cell lymphoma a 10 year single center retrospective cohort study"
} | [
{
"companynumb": "CN-ROCHE-1779602",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Background: Disseminated superficial actinic porokeratosis (DSAP) is a rare dermatologic disorder of the epidermis. Often misdiagnosed as chronic UV-damage or actinic keratoses, patients are treated for years with different therapeutic options with little success. Current treatment options include imiquimod, ingenol mebutate, cryosurgery, photodynamic therapy and topical or systemic therapy with retinoids. Since those approaches show only little success or come along with major side effects, therapeutic alternatives are strongly requested. Methods: We report a series of five female patients with history of DSAP that were successfully treated with chemical peels. Results: All patients suffered from the disease for 14.4 years on average and all were refractory to at least two therapeutic options, mostly imiquimod and topical tretinoin. Patients were treated with glycolic acid 50% and salicylic acid 25% in a two-layer-technique. After a mean of three cycles every 6 weeks a clear reduction in lesion was assessed by physicians. Patients were highly satisfied with outcome and rare occurrence of side effects as assessed by TSQM questionnaire. Conclusion: Chemical peels are safe and well tolerated treatment options for patients with refractory porokeratosis. As characteristic for chronic diseases, frequent repetition of treatment is needed in order to control disease activity.",
"affiliations": "Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.;Department of Dermatology, University Medicine Mainz, Mainz, Germany.",
"authors": "Lang|Berenice M|BM|http://orcid.org/0000-0002-4679-3777;Peveling-Oberhag|Adriane|A|;Zimmer|Sebastian|S|;Wegner|Joanna|J|;Sohn|Anna|A|;Grabbe|Stephan|S|;Staubach|Petra|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2019.1610551",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "31(7)",
"journal": "The Journal of dermatological treatment",
"keywords": "Porokeratosis; chemical peels; patient-reported outcome; rare disease",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D000368:Aged; D002615:Chemexfoliation; D005260:Female; D006801:Humans; D008875:Middle Aged; D017499:Porokeratosis; D035583:Rare Diseases; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "744-748",
"pmc": null,
"pmid": "31018713",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effective treatment of disseminated superficial actinic porokeratosis with chemical peels - customary treatment for a rare disease.",
"title_normalized": "effective treatment of disseminated superficial actinic porokeratosis with chemical peels customary treatment for a rare disease"
} | [
{
"companynumb": "DE-TOLMAR, INC.-20DE023920",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional": "3",
... |
{
"abstract": "Expressive aphasia (non-fluent aphasia) is characterized by the inability to produce words or sentences. The most common cause of expressive aphasia is stroke, usually due to thrombus or emboli in the middle cerebellar artery or internal carotid artery affecting Broca's area. We present an important, reversible, and previously undescribed cause of a purely expressive aphasia secondary to steroid use. A case of a steroid-induced expressive aphasia has not yet been described in the medical literature. Recognition of this presentation is critical to appropriate therapy and excess morbidity, particularly as steroid (dexamethasone) utilization has increased since the COVID-19 pandemic.",
"affiliations": "Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, USA.;Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, USA.;Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, USA.",
"authors": "Rizwan|Aliza|A|;Mor|Yechiel S|YS|;Frank|Allan P|AP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.18863",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18863\nInternal Medicine\nNeurology\nRheumatology\nA Case of Steroid-Associated Expressive Aphasia\nMuacevic Alexander\nAdler John R\nRizwan Aliza 1\nMor Yechiel S 1\nFrank Allan P 1\n1 Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, USA\nAliza Rizwan rishaikh42@gmail.com\n18 10 2021\n10 2021\n13 10 e1886318 10 2021\nCopyright © 2021, Rizwan et al.\n2021\nRizwan et al.\nhttps://creativecommons.org/licenses/by/3.0/ 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.\nThis article is available from https://www.cureus.com/articles/62859-a-case-of-steroid-associated-expressive-aphasia\nExpressive aphasia (non-fluent aphasia) is characterized by the inability to produce words or sentences. The most common cause of expressive aphasia is stroke, usually due to thrombus or emboli in the middle cerebellar artery or internal carotid artery affecting Broca’s area. We present an important, reversible, and previously undescribed cause of a purely expressive aphasia secondary to steroid use. A case of a steroid-induced expressive aphasia has not yet been described in the medical literature. Recognition of this presentation is critical to appropriate therapy and excess morbidity, particularly as steroid (dexamethasone) utilization has increased since the COVID-19 pandemic.\n\naphasia\nsteroid\nbroca’s\nreversible\nreversible adverse effect\nThe 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\npmcIntroduction\n\nExpressive aphasia, also known as Broca's aphasia, is characterized by partial loss of the language ability (spoken, manual, or written), while comprehension remains intact. Broca’s aphasia results from injury to the inferior frontal gyrus known as Broca's area. Aphasia affects about two million Americans and is more common than Parkinson’s Disease, cerebral palsy, or muscular dystrophy. Nearly 180,000 Americans acquire the disorder each year. The most common cause of expressive aphasia is stroke, usually due to thrombus or emboli in the middle cerebellar artery or internal carotid artery. Other causes include traumatic brain injury, tumors, brain infections, and degenerative illnesses. We present a previously undescribed, reversible cause of purely expressive aphasia without other focal findings caused by dexamethasone use, a corticosteroid. Corticosteroids are naturally produced by the adrenal gland but synthetic forms of corticosteroids have been used since the 1950s to treat several medical conditions due to their potent anti-inflammatory and immunosuppressive properties. Despite their numerous side effects and spontaneous adverse reactions including those affecting the central nervous system, the use of corticosteroids remains widespread for a large array of clinical conditions, most recently the marked inflammation accompanying COVID-19 infection.\n\nCase presentation\n\nA 35-year-old female with a history of sickle cell thalassemia and bronchial asthma presented to the emergency department due to new-onset confusion and weakness beginning that afternoon. She also reported uncontrolled generalized sickle-cell type pain for the prior two days. The initial differential for her encephalopathy included hypoxia, metabolic and infectious (meningitis/encephalitis).\n\nOn admission the patient was hypotensive with a blood pressure of 88/51 mmHg and hypoxic with oxygen saturation 68% at room air, increasing to 95% on 3L nasal cannula. Significant labs on admission are mentioned in Table 1.\n\nTable 1 Labs on admission and discharge.\n\nCRP: C-reactive protein; AST: Aspartate transaminase.\n\nVariable\tReference Range\tOn Admission\tOn Discharge\t\nWhite blood cell count\tK/CUMM\t21.7\t9.1\t\nAbsolute neutrophil count\tK/CUMM\t18.4\t5.0\t\nHemoglobin\tgm/dl\t5.5\t7.2\t\nRBC\tM/CUMM\t1.83\t2.45\t\nPlatelets\tK/CUMM\t223\t234\t\nSodium\tmMol/L\t135\t138\t\nPotassium\tmMol/L\t4.3\t4.2\t\nUrea nitrogen (BUN)\t7-25 mg/dL\t45\t13\t\nCreatinine\t0.6-1.2 mg/dL\t3.88\t0.95\t\nCreatine phosphokinase\t30-223 units/L\t57\t26.5\t\nLactate dehydrogenase\t100-240\t754\t-\t\nD-dimer\t<<0.5 mg/L\t2.81\t-\t\nFerritin\t11-306 ng/mL\t1805\t-\t\nCRP\tmg/L\t \t-\t\nAmmonia\t16-53 micromole/L\t81\t-\t\nAST\t13-39 units/L\t73\t-\t\nT. Bili\t<1.5 mg/dL\t4.43\t-\t\nPneumococcal antigen\tNegative\tPositive\t-\t\nCovid PCR\tNegative\tNegative\t-\t\n\nChest X-ray was negative for acute cardiopulmonary condition. CT brain showed no acute intracranial abnormality; CT venography showed no evidence of cerebral venous thrombosis. Her neuro exam revealed normal speech, showed no deficit other than confusion. She was empirically started on cefepime, vancomycin, and IV dexamethasone 10mg every 6 hours for a working diagnosis of meningitis. She received Lactulose for elevated ammonia. Lumbar puncture returned negative for infectious etiology. Aside from a leukocytosis, she was afebrile with no findings otherwise suggestive of infection or metabolic abnormalities. Empiric antibiotics were de-escalated to ceftriaxone.\n\nThe patient's mentation gradually improved: she became alert and oriented to person, place, and time, but was left with an acute expressive aphasia. She spoke incoherently but did demonstrate signs of comprehension. Dexamethasone, initially started due to suspicion of meningitis, was discontinued on day 4. Twenty-four hours post discontinuation her expressive aphasia improved and by 48 hours she had returned to her baseline with full comprehension and speaking abilities. She was discharged home after complete resolution of the expressive aphasia, attributed to dexamethasone use. The patient did not get MRI brain done on discharge, although MRI brain several months post discharge was unremarkable. Labs on discharge are mentioned in Table 1.\n\nA transient localized neurological deficit (expressive aphasia) could be associated with high-dose steroid use in our patient with sickle-cell thalassemia and bronchial asthma. Focal neurological symptoms began after dexamethasone use and resolved 48hr after its discontinuation, thus suggesting a possible causal relationship. Several case reports link steroid use to central nervous system (CNS) arterial occlusion (retinal artery, corpus callosum, basal arteries, etc.) and the association between thromboembolism and oral contraceptives is also well known in the medical literature. However, there is no previous literature describing a temporal lobe alteration associated with steroid use.\n\nDiscussion\n\nCorticosteroids with anti-inflammatory or anti-asthmatic actions are synthetic analogs of the natural adrenal cortical hormone hydrocortisone (cortisol). Various modifications in the molecular structure of hydrocortisone influence the intrinsic potency of the steroids and alter some of their pharmacokinetic properties [1].\n\nThe use of dexamethasone is widespread amongst a broad spectrum of clinical conditions which benefit from its immunosuppressive and anti-inflammatory effects, such as chronic inflammatory lung disease, various dermatomal disorders, allergic reactions, treating several retinal diseases, for the acute treatment of CNS trauma/adjunct treatment for disease, bowel disorders, arthritis, immune system disorders, blood/hormone disorders, and cancer. Dexamethasone has been a staple of neurology and neurosurgical treatment for over half a century. In the context of malignant brain tumors, it is used to control peri-tumoral edema and to alleviate symptoms of high intracranial pressure or focal neurologic symptoms.\n\nThere are various factors that influence both the therapeutic and adverse effects of glucocorticoids including: dosing, time of the doses, duration of treatment, biological potency, metabolism, and pharmacokinetic properties of the glucocorticoid. Corticosteroids act mainly via three principal mechanisms of action: 1) inducing the expression of anti-inflammatory proteins by IkB and MAPK phosphatase I, 2) inhibiting the synthesis of inflammatory proteins blocking NF-kB, and 3) inhibiting 5-lipoxygenease and cyclooxygenase-2 [2].\n\nAlthough dexamethasone has a wide range of uses it has been associated with a variety of adverse events including muscular weakness, hyperglycemia, cushingoid symptoms, mental disorders, and gastrointestinal ulceration [3]. Steroid use is also associated with blood viscosity, RBC column buildup, vasoconstriction, etc. As demonstrated in an in vivo study - The influence of corticosteroids on human erythropoiesis - findings complement the results of in vitro studies, indicating that erythropoiesis in normal human bone marrow is stimulated by corticosteroid therapy [4]. Marks et al. reported steroid-induced vasoconstriction: glucocorticoid antagonist studies demonstrated the vasoconstrictor effects of topical steroids are mediated by occupancy of classical glucocorticoid receptors, rather than by nonspecific pharmacological mechanisms [5].\n\nThe use of corticosteroids has previously been associated with the development of neurological/psychiatric side effects, due to the wide expression of glucocorticoid receptor (GR) in the brain leading to functional and anatomical alterations due to their long-term modulation [6]. Encephalopathy with neurotoxicity can have various manifestations with ranging severities. Mild encephalopathy is characterized by impaired attention, disorientation, short-term memory with preserved alertness. Whereas, severe neurotoxicity often began as mild somnolence, disorientation, impaired attention, and difficulty naming before progressing to global aphasia, myoclonus, depressed level of consciousness, encephalopathy, and seizures [7].\n\nLocalized CNS effects due to specific arterial occlusions are associated with steroid use, as demonstrated in the case of central retinal artery occlusion associated with steroid injection for a periocular juvenile hemangioma [8]. Another case reports of quadriparesis and brainstem herniation after selective cervical transforaminal block; a potential role for corticosteroid particulate embolus leading during unintended intra-arterial injection as a potential mechanism [9]. Deleterious effects of intra-arterial administration of particulate steroids on microvascular perfusion in a mouse model have also been reported. Several particulate steroids have an immediate and massive effect on microvascular perfusion because of the formation of RBC aggregates associated with the transformation of RBCs into spiculated RBCs [10]. This supports the idea of specific vascular occlusion rather than generalized brain alteration.\n\nWe reasoned corticosteroids induce RBC column buildup, milliary emboli, and vasoconstriction leading to localized obstructive encephalopathy that may have caused expressive aphasia (characterized by partial loss of the ability to produce spoken, manual, or written language with preserved comprehension) in our patient occurred as a rare adverse reaction to dexamethasone with complete resolution upon its discontinuation. The patient had several other risk factors for localized obstructive encephalopathy such as sickle cell anemia + thalassemia (chronic anemia + tissular hypoxia). Bronchial asthma (chronic hypoxemia, even though no acute lung alterations were discovered), leukocytosis (hypercoagulability/viscosity, elevated O2 consumption by WBC worsening hypoxia), hyperammonemia, and elevated BUN also increase osmolality/viscosity. While ammonia may cause encephalopathy by itself, it is usually in the higher range - the patient only had mild hyperammonemia (64 mmol/L) but elevated BUN (45mg/dl) on admission. Polycythemia and thrombocytosis, both increase the viscosity - the patient's RBC and platelets were within normal limits. Several articles associate local corticosteroid use (facial/cranial injections) to local arterial occlusion so it is definitely a possibility, considering risk factors for hyperviscosity. There are several case reports linking steroid use to retinal artery occlusion, cerebral infarction (corpus callosum), and other vascular complications [4,5]. Some patients in case reports are known for chronic conditions, often autoimmune or vascular (alopecia areata, vitiligo, sickle cell, asthma). Other reports are known for anabolic steroid abuse. This is a rare case, unreported in the literature to date, that we encountered. However, generalized encephalopathy would have also had generalized manifestations. Expressive aphasia was the only sign in this case. Risk factors seem to be related to altered blood viscosity or dosage abuse. Further investigational studies are warranted to determine the correlation of dosage and duration of steroid use on this observed side effect.\n\nConclusions\n\nWe described a rare case of reversible expressive aphasia associated with steroid use. As steroids continue to be incorporated in the medical management of a variety of pathological conditions, including COVID-19 infection, knowing hyperviscosity risk factors, steroid-associated thrombi formation, and dose-dependent vascular adverse effects to possible vascular complications, both central or peripheral is paramount to properly inform patient management. Further investigational studies are warranted to determine the correlation of dosage and duration of steroid use on this observed side effect. Also, whether the addition of high-dose anticoagulant agents such as rivaroxaban/clopidogrel upon admission in high-risk population (blood viscosity increased due to infection, hypoxia, leukocytosis/polycythemia/thrombocytosis, diabetes, hyperammonemia, etc.) who need steroids for optimum management would outweigh the risk of vascular complication.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Mechanisms of action of topical corticosteroids in psoriasis Int J Endocrinol Uva L Miguel D Pinheiro C Antunes J Cruz D Ferreira J Filipe P 561018 2012 2012 23213332\n2 Neurotoxicity by synthetic androgen steroids: oxidative stress, apoptosis, and neuropathology: a review Curr Neuropharmacol Pomara C Neri M Bello S Fiore C Riezzo I Turillazzi E 132 145 13 2015 26074748\n3 Corticosteroid-related central nervous system side effects J Pharmacol Pharmacother Ciriaco M Ventrice P Russo G Scicchitano M Mazzitello G Scicchitano F Russo E 94 98 4 2013\n4 The influence of corticosteroids on human erythropoiesis. An in vivo study Am J Pediatr Hematol Oncol King DJ Brunton J Barr RD 313 315 10 1988 3239707\n5 Steroid-induced vasoconstriction: glucocorticoid antagonist studies J Clin Endocrinol Metab Marks R Barlow JW Funder JW 1075 1077 54 1982 7061698\n6 Reversible global aphasia as a side effect of quetiapine: a case report and literature review Neuropsychiatr Dis Treat Chien CF Huang P Hsieh SW 2257 2260 13 2017 28894370\n7 Confusion vs Broca aphasia: a case report Perm J Wang R Wiley C 19 61 24 2020 https://pubmed.ncbi.nlm.nih.gov/31852049/\n8 Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma Ophthalmic Surg Shorr N Seiff SR 229 231 17 1986 https://pubmed.ncbi.nlm.nih.gov/3714192/ 3714192\n9 Adverse central nervous system sequelae after selective transforaminal block: the role of corticosteroids Spine J Tiso RL Cutler T Catania JA Whalen K 468 474 4 2004 https://www.sciencedirect.com/science/article/abs/pii/S1529943003005564#! 15246308\n10 Deleterious effects of intra-arterial administration of particulate steroids on microvascular perfusion in a mouse model Radiology Laemmel E Segal N Mirshahi M 731 740 279 2016 26761719\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "aphasia; broca’s; reversible; reversible adverse effect; steroid",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e18863",
"pmc": null,
"pmid": "34804716",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "3239707;15246308;24347992;3714192;26761719;28894370;23213332;26074748;7061698;31852049",
"title": "A Case of Steroid-Associated Expressive Aphasia.",
"title_normalized": "a case of steroid associated expressive aphasia"
} | [
{
"companynumb": "US-ALVOGEN-2021-ALVOGEN-117886",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "1",... |
{
"abstract": "A 37-year-old woman was examined for a large, dark brown plaque on her left hip that had been present for three years and a second, similar plaque that had subsequently appeared on her right knee. Every four to five months the areas became swollen, red, and painful. She had been taking metronidazole intermittently for twenty years for the treatment of trichomoniasis; this drug on challenge proved to be the cause of the eruptions.",
"affiliations": null,
"authors": "Shelley|W B|WB|;Shelley|E D|ED|",
"chemical_list": "D008795:Metronidazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "39(5)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000328:Adult; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008795:Metronidazole",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "393-4",
"pmc": null,
"pmid": "2953560",
"pubdate": "1987-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fixed drug eruption due to metronidazole.",
"title_normalized": "fixed drug eruption due to metronidazole"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP003624",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANHYDROUS CITRIC ACID\\ASPIRIN\\SODIUM BICARBONATE... |
{
"abstract": "We report on a 10-year-old female who rapidly developed a left atrial (LA) mass two months after orthotopic heart transplant. Nine days prior to detection of the mass, she received high-dose corticosteroids for acute cellular rejection (grade 2). Despite negative echocardiogram five days prior to detection, a large echogenic mass was noted in the LA (18 x 12 x 24 mm); it was surgically resected after unsuccessful anticoagulation treatment. Pathogenesis of this LA thrombus remains uncertain, but immunosuppression, acute rejection, and high-dose steroid therapy may have contributed. Surgical thrombectomy is a safe and effective treatment option for LA thrombus.",
"affiliations": "Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE; Department of Pediatrics, The Unterberg Children's Hospital at Monmouth Medical Center, Long Branch NJ.;Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.;Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.;Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE. Electronic address: ttsuda@nemours.org.",
"authors": "Alloah|Qais|Q|;Pelletier|Glenn|G|;Prada-Ruiz|Adriana C|AC|;Tsuda|Takeshi|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2021.04.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": null,
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": null,
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33894179",
"pubdate": "2021-04-21",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Rapid Growth of Left Atrial Thrombus in a Pediatric Heart Transplant Recipient.",
"title_normalized": "rapid growth of left atrial thrombus in a pediatric heart transplant recipient"
} | [
{
"companynumb": "US-TEVA-2022-US-2037137",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nAdjuvant chemotherapy can cause neutropenia by inhibition of hematopoiesis. However, little information is known about the effects of chemotherapy-induced neutropenia (CIN) on the outcomes of direct-to-implant (DTI) immediate breast reconstruction after skin-sparing mastectomy.\n\n\nMETHODS\nA retrospective review was performed for all patients with DTI immediate breast reconstruction after skin-sparing mastectomy (n=372) between January 2011 and December 2019. The demographic and complication of patients who experienced CIN during chemotherapy and those who did not were compared.\n\n\nRESULTS\nMajor infection requiring surgical management occurred in 4 patients (7.1%) in the CIN group (n=56) and 2 (3.6%) in the non-CIN group (n=55). Minor infection requiring antibiotics treatment occurred in 1 patient (1.8%) in the CIN group and 1 (1.8%) in the non-CIN group. Skin necrosis occurred in 7 patients (12.5%) in CIN group and 11 patients (19.6%) in non-CIN group. There were no significant difference in incidence of all complications between two groups.\n\n\nCONCLUSIONS\nCIN may not significantly increase the incidence of severe complications in the patients who received adjuvant chemotherapy after DTI immediate breast reconstruction. However, close observation is required for possible breast complication and adequate treatment is needed.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Yeungnam University College of Medicine, Daegu, Korea.;Department of Plastic and Reconstructive Surgery, Yeungnam University College of Medicine, Daegu, Korea.;Department of Plastic and Reconstructive Surgery, Yeungnam University College of Medicine, Daegu, Korea.",
"authors": "Sakong|Yong|Y|;Choi|Man Ki|MK|;Lee|Jun Ho|JH|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "China",
"delete": false,
"doi": "10.21037/apm-21-508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "10(5)",
"journal": "Annals of palliative medicine",
"keywords": "Breast implantation; chemotherapy; surgical wound infection",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D016462:Mammaplasty; D008408:Mastectomy; D009503:Neutropenia; D011183:Postoperative Complications; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "5181-5187",
"pmc": null,
"pmid": "33894733",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The impact of chemotherapy-induced neutropenia on the outcome of direct-to-implant immediate breast reconstruction.",
"title_normalized": "the impact of chemotherapy induced neutropenia on the outcome of direct to implant immediate breast reconstruction"
} | [
{
"companynumb": "KR-TEVA-2021-KR-1942094",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Cryptococcus neoformans is an opportunistic fungal infection affects predominately the central nervous system in HIV patients and patients with other immunocompromised states. It has rarely been described in immunocompetent patients. It is a serious infection with a high of mortality rate. We describe a case of a 48-year-old patient diagnosed with lupus nephritis treated with corticosteroids and mycophenolate mofetil who developed central nervous cryptococcosis complicated by septicemia. She died despite the use of antifungals. Cryptococcal infection is an uncommon, but often a fatal complication of systemic lupus erythematosus. Timely diagnosis and effective antifungal therapy could improve its prognosis.",
"affiliations": "Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.;Department of Nephrology, La Rabta Hospital, Tunis, Tunisia.",
"authors": "Beji|Soumaya|S|;Hajji|Meriam|M|;El Kateb|Hanene|H|;Kosai|Imen|I|;Jebali|Hela|H|;Kheder|Rania|R|;Fatma|Lilia Ben|LB|;Rais|Lamia|L|;Laameri|Lamia|L|;Krid|Madiha|M|;Zouaghi|Karim|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.220874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "28(6)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D003455:Cryptococcus neoformans; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D016919:Meningitis, Cryptococcal; D008875:Middle Aged; D009173:Mycophenolic Acid; D009894:Opportunistic Infections; D016896:Treatment Outcome",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "1435-1439",
"pmc": null,
"pmid": "29265061",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Disseminated cryptococcosis as a complication of lupus nephritis.",
"title_normalized": "disseminated cryptococcosis as a complication of lupus nephritis"
} | [
{
"companynumb": "TN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-215004",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "We report the case of a 64-year-old woman who was admitted for cardiogenic shock caused by a permanent junctional reciprocating tachycardia. If this incessant and drug-refractory form of tachycardia is a well-known cause of tachycardia-induced cardiomyopathies in infants, its occurrence during adulthood is extremely rare. Catheter ablation is the recommended treatment of this condition.",
"affiliations": "Cardiac Intensive Care Unit, Lille University Hospital, France.;Department of Electrophysiology, Lille University Hospital, France.;Cardiac Intensive Care Unit, Lille University Hospital, France.",
"authors": "Boulé|Stéphane|S|;Détis|Nicolas|N|;Lamblin|Nicolas|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2048872616676604",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-8726",
"issue": "9(6)",
"journal": "European heart journal. Acute cardiovascular care",
"keywords": "Cardiogenic shock; catheter ablation; heart failure; permanent junctional reciprocating tachycardia; tachycardia-induced cardiomyopathy",
"medline_ta": "Eur Heart J Acute Cardiovasc Care",
"mesh_terms": "D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D006801:Humans; D008875:Middle Aged; D035583:Rare Diseases; D012770:Shock, Cardiogenic; D054139:Tachycardia, Reciprocating",
"nlm_unique_id": "101591369",
"other_id": null,
"pages": "NP3-NP5",
"pmc": null,
"pmid": "27798173",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Permanent junctional reciprocating tachycardia: a rare, but not to be missed, cause of cardiogenic shock in adults.",
"title_normalized": "permanent junctional reciprocating tachycardia a rare but not to be missed cause of cardiogenic shock in adults"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1037047",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": "3",
... |
{
"abstract": "A 28-year-old primigravida was evaluated for complaints of difficulty urinating and pelvic pain of 6-weeks duration. She denied fever, night sweats, weight loss or fatigue. Pelvic ultrasonography revealed a single fetal pole with cardiac activity and a 7 cm mass in the anterior vagina which encased the urethra. The diagnosis of diffuse large B-cell lymphoma germinal centre type was made on analysis of biopsied pelvic mass. Whole body MRI revealed the disease was limited to the vagina. The patient received six cycles of Rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone with significant improvement in her symptoms. Serial ultrasounds over the subsequent months showed appropriate development of the fetus. Whole body MRI after treatment showed decreased size and decreased signal of the primary pelvic mass compatible with favourable treatment response. Challenges in the management of this rare presentation of lymphoma are discussed.",
"affiliations": "Department of Hematology and Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA nwabundo.anusim@beaumont.edu.;Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA.;Department of Anatomic and Clinical Pathology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA.;Department of Hematology and Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA.",
"authors": "Anusim|Nwabundo|N|;Ionescu|Filip|F|;Afolayan-Oloye|Olabisi|O|;Gaikazian|Susanna S|SS|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233145",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(1)",
"journal": "BMJ case reports",
"keywords": "malignant and benign haematology; obstetrics, gynaecology and fertility; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D053159:Dysuria; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D017699:Pelvic Pain; D011241:Prednisone; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D000069283:Rituximab; D014463:Ultrasonography; D014625:Vaginal Neoplasms; D014750:Vincristine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31900300",
"pubdate": "2020-01-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diffuse large B-cell lymphoma of the vagina in pregnancy.",
"title_normalized": "diffuse large b cell lymphoma of the vagina in pregnancy"
} | [
{
"companynumb": "US-CELLTRION INC.-2020US019326",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE\\DOXORUBICIN\\PREDNISONE\\VINCRISTINE"
... |
{
"abstract": "Obstructive bronchiolitis (OB) is an intractable disease causing stenosis in the surrounding bronchiolar region and bronchiolar lumen obstruction. Causes of OB are lung and hematopoietic stem-cell transplantation, collagen diseases, infections, and foods, but there are very few reports of drug-induced OB [1]. Imatinib is a drug used for the treatment of leukemia, gastrointestinal stromal tumors, etc. Although there are some reports of imatinib-induced lung injury as a complication (Ohnishi et al., 2006; Ma et al., 2003; Yamasawa et al., 2008; Koide et al., 2011) [[2], [3], [4], [5]], OB has not been reported. We have encountered a patient with OB related to imatinib administered for chronic myelogenous leukemia, who we have followed for 10 years. Drug-induced OB is very rare, but our case demonstrates the importance of considering the possibility of airway lesions by evaluating pulmonary function and expiratory computed tomography in patients with respiratory symptoms despite no shading on imaging.",
"affiliations": "Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Pathology, Tokyo Medical University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.;Tokyo Medical and Dental University, Tokyo, Japan.;Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan.",
"authors": "Yajima|Chika|C|;Kokuho|Nariaki|N|;Toriyama|Kazutoshi|K|;Kawagoe|Junichiro|J|;Togashi|Yuki|Y|;Matsubayashi|Jun|J|;Nakayama|Hideaki|H|;Setoguchi|Yasuhiro|Y|;Abe|Shinji|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101052",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(19)30282-5\n10.1016/j.rmcr.2020.101052\n101052\nCase Report\nA case of imatinib-related obstructive bronchiolitis followed long term\nYajima Chika a Kokuho Nariaki s7035@nms.ac.jpa∗ Toriyama Kazutoshi a Kawagoe Junichiro a Togashi Yuki a Matsubayashi Jun b Nakayama Hideaki a Setoguchi Yasuhiro c Abe Shinji a a Department of Respiratory Medicine, Tokyo Medical University, Tokyo, Japan\nb Department of Pathology, Tokyo Medical University, Tokyo, Japan\nc Tokyo Medical and Dental University, Tokyo, Japan\n∗ Corresponding author. s7035@nms.ac.jp\n04 4 2020 \n2020 \n04 4 2020 \n30 10105214 9 2019 26 3 2020 2 4 2020 © 2020 The Authors. Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Obstructive bronchiolitis (OB) is an intractable disease causing stenosis in the surrounding bronchiolar region and bronchiolar lumen obstruction. Causes of OB are lung and hematopoietic stem-cell transplantation, collagen diseases, infections, and foods, but there are very few reports of drug-induced OB [1]. Imatinib is a drug used for the treatment of leukemia, gastrointestinal stromal tumors, etc. Although there are some reports of imatinib-induced lung injury as a complication (Ohnishi et al., 2006; Ma et al., 2003; Yamasawa et al., 2008; Koide et al., 2011) [[2], [3], [4], [5]], OB has not been reported. We have encountered a patient with OB related to imatinib administered for chronic myelogenous leukemia, who we have followed for 10 years. Drug-induced OB is very rare, but our case demonstrates the importance of considering the possibility of airway lesions by evaluating pulmonary function and expiratory computed tomography in patients with respiratory symptoms despite no shading on imaging.\n\nKeywords\nObstructive bronchiolitis (OB)Drug-induced lung injuryImatinibNilotinibDrug-induced OB\n==== Body\nAbbreviations list\nAaDO2partial pressure difference of alveolar-arterial oxygen\n\nCMLchronic myelogenous leukemia\n\nCTcomputed tomography scan\n\nDLcodiffusing capacity for carbon monoxide\n\nDLSTdrug-induced lymphocyte stimulation test\n\nEVGelastica van Gieson\n\nFEV1.0forced expiratory volume in one\n\nFEV1.0%forced expiratory volume ％ in one second\n\nFVCforced vital capacity\n\nICSinhaled corticosteroids\n\nLAMAlong-acting muscarinic antagonist\n\nNSIPnonspecific interstitial pneumonia\n\nOBobstructive bronchiolitis\n\nOPorganizing pneumonia\n\nPaO2partial pressure of arterial oxygen\n\nPaCO2partial pressure of arterial carbon dioxide\n\nPDGFRplatelet-derived growth factor receptor\n\nRVresidual volume\n\nSpO2saturation of percutaneous oxygen\n\nTLCtotal lung capacity\n\n1 Introduction\nObstructive bronchiolitis (OB) is an intractable disease that causes surrounding stenosis in the bronchiolar region and obstruction of the bronchiolar lumen. With advances in transplantation medical care [6], reports of OB have been increasing in recent years as a major cause of death from complications of transplantations. On the other hand, non-transplantation-associated OB, caused by collagen diseases, infections, drugs, foods, etc., have been reported [1], there have been very few reports on drug-induced OB. We encountered a patient who was diagnosed as having imatinib-related OB by pathological analysis, and report this case as we have been able to follow the patient for a long term (10 years).\n\n1.1 Case report\nA 54-year-old woman was diagnosed as having chronic myelogenous leukemia (CML) and started imatinib as the first treatment in February X years. After 7 months, she developed a cough and dyspnea. She had no history of pulmonary diseases or dust inhalation, and her smoking history was 18 pack-years. Physical findings were a body temperature of 36.2 °C, an SpO2 of 98% (room air), and no abnormalities in her respiratory sounds. Blood gas analysis demonstrated a decrease in PaO2 (72.9 Torr) and AaDO2 expansion. (Table 1). No significant findings were displayed on chest x-ray or inspiration CT, whereas expiration CT displayed a mosaic pattern in the upper lobe and air trapping in the lower lobe (Fig. 1A and B). Respiratory function tests showed a pattern suggestive of peripheral obstructive ventilatory disorder (Table 1).Table 1 Laboratory and physiological findings.\n\nTable 1Hematology\t\tSerological study\t\t\nWBC\t3,800\t/μL\tCRP\t1.0\tmg/dL\t\n Neu\t75.6\t%\tKL-6\t261\tUmL\t\n Lym\t16.1\t%\tSP-D\t42.6\tng/dL\t\n Eos\t2.8\t%\tIgG\t1,420\tmg/dL\t\n Hb\t11.8\tg/dL\tIgE\t34\tmg/dL\t\n PLT\t2.27 × 104\t/μL\tANA\t< × 40\t\t\n\t\t\tdsDNA ab\t(−)\t\t\nBiochemistry\t\tanti-SM ad\t(−)\t\t\n TP\t6.8\tg/dL\tanti-SSA ad\t(−)\t\t\n Alb\t3.7\tg/dL\tanti-Jo1 ad\t(−)\t\t\n AST\t21\tU/L\tanti-CCP ad\t(−)\t\t\n ALT\t18\tU/L\tMPO-ANCA\t(−)\t\t\n LDH\t233\tU/L\tPR3-ANCA\t(−)\t\t\n T-Bil\t0.5\tmg/dL\t\t\t\t\n BUN\t13.3\tmg/dL\t\t\t\t\n Cr\t0.6\tmg/dL\t\t\t\t\n\n\n\t\nDrug lymphocyte stimulation test\tBlood gas analysis (room air)\t\t\nimatinib\t560\tcpm\tpH\t4.714\t\t\nimatinib(S·I)\t307\t%\tPaO2\t72.9\tTorr\t\ncontrol\t182\tcpm\tPaCO2\t35.2\tTorr\t\n\t\t\tHCO3-\t22.2\tmEg/L\t\n\t\t\tAaDo2\t33.1\t\t\n\n\n\t\nPulmonary function tests\t\nFVC\t2.41\tL\t\t\t\t\n%FVC\t94.0\t%\t\t\t\t\nFEV1.0\t1.2\tL\t\t\t\t\nFEV1.0%\t50.2\t%\t\t\t\t\nTLC\t3.97\tL\t\t\t\t\nRV\t1.57\tL\t\t\t\t\nRV/TLC\t39.5\t%\t\t\t\t\nV50/V25\t3.14\t\t\t\t\t\nDLco/VA\t90.1\t%\t\t\t\t\nFig. 1 Chest images of the patient at initial presentation.\n\nNo significant findings were seen on chest inspiration CT (A), whereas expiration CT displayed a mosaic pattern in the upper lobe and air trapping in the lower lobe (B).\n\nFig. 1\n\nHistopathological analysis of surgical lung biopsy tissue showed extensive stenosis of the bronchiolar lumen, and fibrous stenosis owing to bronchiolar elastic fiber and collagen fiber proliferation by EVG staining (Fig. 2), and the patient was diagnosed as having OB. The involvement of infection and collagen disease was ruled out by the patient's clinical course and laboratory findings, and there was no history of transplantation or obvious antigen exposure, so we suspected drug-induced lung injury. We predicted imatinib as the causative drug and performed the drug-induced lymphocyte stimulation test (DLST). The DLST was positive, leading to the diagnosis of drug-related OB by imatinib. The patient began treatment with β2 stimulants for her symptoms of dyspnea at the time of onset of symptoms, and imatinib was discontinued 12 days after we suspected OB on pulmonary function tests and expiratory computed tomography (CT). Three-months later, long-acting muscarinic antagonist (LAMA) and inhaled corticosteroids (ICS) were added as symptomatic treatments, because the patient demonstrated a marked decrease in FEV1.0 (−Δ380 mL) and further worsened dyspnea. Regarding the patient's leukemia, she began interferon-α treatment 4 months after discontinuing imatinib treatment, and she went into remission. Her leukemia subsequently recurred 2 years later, and her treatment was changed to nilotinib. However, even after changing to nilotinib, her FEV1.0 and dyspnea did not worsen (Fig. 3).Fig. 2 Histopathological analysis of lung biopsy specimens.\n\nHigh stenosis was observed in the bronchiolar lumen by Hematoxylin Eosin staining (A, B), and fibrous stenosis owing to bronchiolar elastic fiber and collagen fiber proliferation was observed by EVG staining (C). Magnification:×40, × 400.\n\nFig. 2Fig. 3 Treatment course of the patient.\n\nThe patient initially started β-stimulant treatment for her dyspnea. Three months after onset, she additionally started LAMA and ICS because her forced expiratory volume in 1 second (FEV1.0) decreased markedly and her dyspnea deteriorated. Imatinib was discontinued 12 days after the onset of OB and her treatment was changed to interferon-α, and subsequently to nilotinib at the time of recurrence; however, deterioration of FEV1.0 was not observed in the subsequent 10 years.\n\nFig. 3\n\n2 Discussion\nOB is an intractable disease causing stenosis in the surrounding bronchiolar region, as well as bronchiolar lumen obstruction. There have been few reports of drug-induced OB, and the causative agents include d-penicillamine, gold, cocaine, talc, tiopronin, busulfan, papaverine (sauropus androgynus juice or powder), psyllium, sulfasalazine, rituximab, and afatinib [6,7]. These drugs are broadly classified into 2 types, i.e., those that are inhaled and those that are orally administered. Inhaled drugs include cocaine, talc, and psyllium. Their effects are caused by physical airway obstruction, and pathological findings are characterized by airway obstruction owing to the filling of the peripheral airways by the drug, as well as associated inflammatory cell infiltration [8,9]. On the other hand, regarding the orally administered drugs, papaverine used as a health food is the most famous, and it is widely known to cause sauropus androgynus-associated OB, owing to the reports of many cases of OB [10]. Regarding the reports of d-penicillamine, gold, tiopronin, and sulfasalazine, as these drugs are regularly used for rheumatoid arthritis and ulcerative colitis, the possibility of OB associated with the underlying disease cannot be completely denied [11]. Furthermore, busulfan has only been reported to increase the risk of transplant-associated OB in hematopoietic stem cell transplantation [12], indicating the difficulty in diagnosing drug-induced OB.\n\nThe present patient was taking rebamipide and lansoprazole in addition to imatinib when she first presented to our department. To date, there have been 2 reports of drug-induced lung injury by rebamipide [13,14]. However, all of the patients histologically demonstrated organizing pneumonia (OP) patterns, and no patients with OB patterns have been reported. Lansoprazole-induced lung injury has been reported to show a nonspecific interstitial pneumonia (NSIP) pattern [15]. Although DLST was not performed for these drugs, the patient's symptoms did not worsen upon taking any of these drugs. Therefore, it is unlikely that any of these drugs are the causative drug of OB.\n\nThe patient had no indications of obstructive pulmonary disease, such as bronchial asthma or COPD, and CT images displayed no bullae or emphysema. She had no history of transplantation or clear inhalation exposure that could have caused the OB, and we considered no infectious or autoimmune cause, owing to the low levels of inflammatory markers and absence of autoantibodies in the blood tests. DLST is found to be negative in some patients diagnosed with imatinib-induced lung injury [[16], [17], [18]], and hence a definitive diagnosis cannot be made only by DLST. However, if other diseases have been ruled out, we believe that the results of DLST will aid in the diagnosis of drug-related OB with imatinib.\n\nIn this patient, shortness of breath appeared 7 months after the start of imatinib administration. Previous reports have demonstrated that the time to onset of imatinib-induced lung injury is between 2 weeks and 10 months [7], whereas the time to onset of drug-induced OB varies widely from 5 weeks to 36 months [7,11,[19], [20], [21], [22], [23], [24], [25], [26], [27], [28]]. Therefore, the onset of OB 7 months after administration of the drug, as observed in this patient, is possible. For the above reasons, we believe that the reliability of our diagnosis is high, because we made our diagnosis after excluding all other possible causes.\n\nImatinib is normally used for the treatment of leukemia, gastrointestinal stromal tumors, etc. It has been reported that imatinib frequently causes lung injury, resulting in lymphocytic cell inflammation and polypoid intraluminal fibrosis. On the other hand, our present study is the first report to our knowledge demonstrating that imatinib administration can result in OB.\n\nImatinib is expected to have therapeutic effects against OB after transplantation [29,30], because of its inhibitory actions on fibrocyte migration and differentiation [31,32]. However it is also necessary to pay attention to the paradoxical effect that imatinib per se causes OB. In our present case, the patient was administered nilotinib, a second-generation tyrosine kinase activity inhibitor, for CML recurrence. Nilotinib is also an inhibitor of Bcr-Abl tyrosine kinase activity similar to imatinib. We were concerned about the recurrence of deterioration of OB caused by the use of a drug of the same family, but a decrease in FEV1 was not observed even after administration of nilotinib. Imatinib inhibits the tyrosine kinase activities of Bcr-Abl, v-Abl, c-Abl, platelet-derived growth factor receptor (PDGFR), and KIT, but nilotinib inhibits Bcr-Abl, PDGFR, and KIT. Abl-family kinases are crucial for the proper formation and remodeling of tissues [33,34]. Therefore, we consider the possibility that the active inhibitor component of v-Abl or c-Abl are involved in the onset of OB.\n\nThere is presently no effective treatment for OB [20]. Thus, we consider that the absence of FEV1.0 deterioration for 10 years was not owing to the effects of LAMA and ICS, which were administered as symptomatic treatments, but rather that the early discontinuation of imatinib was associated with a better prognosis.\n\n3 Conclusion\nWe encountered a case of drug-related OB caused by imatinib administration for treatment of CML, in which we were able to follow the patient's course long-term. Drug-induced OB is difficult to detect because unlike normal drug-induced lung injury, it does not cause shadows in the lung field. Therefore, when shortness of breath and cough appear in a patient receiving imatinib, it is important to search for airway lesions, by lung function analysis and expiratory CT. In addition, it is important to suspect the possibility of drug-induced OB and make a definitive diagnosis early, as a more favorable long-term prognosis can be expected by stopping drug administration.\n\nDeclaration of competing interest\nAll authors report no conflicts of interest and have no disclosures or financial support to report.\n\nFVC: forced vital capacity, FEV1.0: forced expiratory volume in one, FEV1.0%: forced expiratory volume ％ in 1 s, TLC: total lung capacity, RV: residual volume, DLco: diffusing capacity for carbon monoxide, PaO2: partial pressure of arterial oxygen, PaCO2: partial pressure of arterial carbon dioxide, AaDO2: partial pressure difference of alveolar-arterial oxygen.\n==== Refs\nReferences\n1 Barker A.F. Bergeron A. Rom W.N. Hertz M.I. Obliterative bronchiolitis N. Engl. J. Med. 370 19 2014 1820 1828 24806161 \n2 Ohnishi K. Sakai F. Kudoh S. Ohno R. Twenty-seven Cases of Drug-Induced Interstitial Lung Disease Associated with Imatinib Mesylate 2006 Leukemia England 1162 1164 \n3 Ma C.X. Hobday T.J. Jett J.R. Imatinib Mesylate-Induced Interstitial Pneumonitis 2003 Mayo Clin Proc England 1578 1579 \n4 Yamasawa H. Sugiyama Y. Bando M. Ohno S. Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis Respiration 75 3 2008 350 354 16449804 \n5 Koide T. Saraya T. Nakamoto K. Nakajima A. Ishii H. Fujiwara M. Shibata H. Oka T. Goya T. Goto H. [A case of imatinib mesylate-induced pneumonitis based on the detection of epithelioid granulomas by video-assisted thoracoscopic surgery biopsy in a patient with chronic myeloid leukemia] Nihon Kokyuki Gakkai Zasshi 49 6 2011 465 471 21735750 \n6 Aguilar P.R. Michelson A.P. Isakow W. Obliterative Bronchiolitis, Transplantation 100 2 2016 272 283 26335918 \n7 Kanaji N. Chiba Y. Sato A. Ueno M. Tadokoro A. Kita N. Ishii T. Watanabe N. Kadowaki N. Bandoh S. An autopsy case of bronchiolitis obliterans as a previously unrecognized adverse event of afatinib treatment Respir Investig 55 1 2017 58 62 \n8 Mc L.A. Rogers E. Dunham K.C. Talc pneumoconiosis Br. J. Ind. Med. 6 3 1949 184 194 18132351 \n9 Motomatsu K. Adachi H. Uno T. Two infant deaths after inhaling baby powder Chest 75 4 1979 448 450 446132 \n10 Lai R.S. Chiang A.A. Wu M.T. Wang J.S. Lai N.S. Lu J.Y. Ger L.P. Roggli V. Outbreak of bronchiolitis obliterans associated with consumption of Sauropus androgynus in Taiwan Lancet 348 9020 1996 83 85 8676721 \n11 Boehler A. Vogt P. Speich R. Weder W. Russi E.W. Bronchiolitis obliterans in a patient with localized scleroderma treated with D-penicillamine Eur. Respir. J. 9 6 1996 1317 1319 8804954 \n12 Santo Tomas L.H. Loberiza F.R. Jr. Klein J.P. Layde P.M. Lipchik R.J. Rizzo J.D. Bredeson C.N. Horowitz M.M. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia Chest 128 1 2005 153 161 16002929 \n13 Kajihara H. Yoshinaga T. Usijima S. [Case of drug-induced lung injury due to Rebamipide] Nihon Kokyuki Gakkai Zasshi 44 10 2006 716 720 17087338 \n14 Mochizuki H. Fujimori K. Suzuki E. Arakawa M. Gejyo F. A case of rebamipide-induced pneumonitis Nihon Kokyuki Gakkai Zasshi 40 1 2002 40 44 11925917 \n15 Atkins C. Maheswaran T. Rushbrook S. Kamath A. Lansoprazole-induced acute lung and liver injury: a case report Int. J. Clin. Pharm. Ther. 52 12 2014 1102 1104 \n16 Iritani E. Kondo M. Kanemura T. Hara Y. Tagaya E. Tamaoki J. Nagai A. Drug-induced pneumonia that may have been caused by imatinib mesylate administered for gastrointestinal stromal tumor Nihon Kokyuki Gakkai Zasshi 45 7 2007 577 581 17682471 \n17 Uchida A. Yamamotoa M. Matsuyamaa M. Kubota S. Hatanaka K. Inouea H. Imatinib mesylate-induced organizing pneumonia with disease progression after discontinuation of treatment, diagnosed by surgical lung biopsy Nihon Kokyuki Gakkai Zasshi 5 4 2016 208 212 \n18 Yokoyama T. Miyazawa K. Kurakawa E. Nagate A. Shimamoto T. Iwaya K. Akata S. Aoshima M. Serizawa H. Ohyashiki K. Interstitial Pneumonia Induced by Imatinib Mesylate: Pathologic Study Demonstrates Alveolar Destruction and Fibrosis with Eosinophilic Infiltration 2004 Leukemia England 645 646 \n19 Murphy K.C. Atkins C.J. Offer R.C. Hogg J.C. Stein H.B. Obliterative bronchiolitis in two rheumatoid arthritis patients treated with penicillamine Arthritis Rheum. 24 3 1981 557 560 7213434 \n20 Williams T. Eidus L. Thomas P. Fibrosing alveolitis, bronchiolitis obliterans, and sulfasalazine therapy Chest 81 6 1982 766 768 6122540 \n21 Holness L. Tenenbaum J. Cooter N.B. Grossman R.F. Fatal bronchiolitis obliterans associated with chrysotherapy Ann. Rheum. Dis. 42 5 1983 593 596 6414389 \n22 van de Laar M.A. Westermann C.J. Wagenaar S.S. Dinant H.J. Beneficial effect of intravenous cyclophosphamide and oral prednisone on D-penicillamine-associated bronchiolitis obliterans Arthritis Rheum. 28 1 1985 93 97 3966941 \n23 Fort J.G. Scovern H. Abruzzo J.L. Intravenous cyclophosphamide and methylprednisolone for the treatment of bronchiolitis obliterans and interstitial fibrosis associated with crysotherapy J. Rheumatol. 15 5 1988 850 854 3172099 \n24 Demaziere A. Maugars Y. Chollet S. Prost A. Non-fatal bronchiolitis obliterans possibly associated with tiopronin. A case report with long-term follow-up Br. J. Rheumatol. 32 2 1993 172 174 8428237 \n25 Schwartzman K.J. Bowie D.M. Yeadon C. Fraser R. Sutton E.D. Levy R.D. Constrictive bronchiolitis obliterans following gold therapy for psoriatic arthritis Eur. Respir. J. 8 12 1995 2191 2193 8666118 \n26 Takayama S. Ogawa T. Tominaga S. Yasui M. Ohno S. Ohkochi M. Inase N. Miura H. [Penicillamine-induced bronchiolitis obliterans diagnosed by transbronchial lung biopsy] Nihon Kokyuki Gakkai Zasshi 44 2 2006 128 133 17228807 \n27 Shen T. Braude S. Obliterative bronchiolitis after rituximab administration: a new manifestation of rituximab-associated pulmonary toxicity Intern. Med. J. 42 5 2012 597 599 22616969 \n28 Katsenos S. Antonogiannaki E.M. Psathakis K. Sulfasalazine-induced hypereosinophilic obliterative bronchiolitis Arch. Bronconeumol. 52 2 2016 108 25912939 \n29 Watanabe S. Waseda Y. Kimura H. Takato H. Ohata K. Kondo Y. Kasahara K. Nakao S. Imatinib for Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation 2015 Bone Marrow Transplant England 1250 1252 \n30 Stadler M. Ahlborn R. Kamal H. Diedrich H. Buchholz S. Eder M. Ganser A. Limited Efficacy of Imatinib in Severe Pulmonary Chronic Graft-Versus-Host Disease 2009 Blood United States 3718 3719 reply 3719-20 \n31 Distler J.H. Jungel A. Huber L.C. Schulze-Horsel U. Zwerina J. Gay R.E. Michel B.A. Hauser T. Schett G. Gay S. Distler O. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis Arthritis Rheum. 56 1 2007 311 322 17195235 \n32 Watanabe S. Kasahara K. Waseda Y. Takato H. Nishikawa S. Yoneda T. Hara J. Sone T. Abo M. Kimura H. Nakao S. Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation J. Heart Lung Transplant. 36 2 2017 138 147 27388852 \n33 Bradley W.D. Koleske A.J. Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts J. Cell Sci. 122 Pt 19 2009 3441 3454 19759284 \n34 Woodring P.J. Hunter T. Wang J.Y. Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases J. Cell Sci. 116 Pt 13 2003 2613 2626 12775773\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": "Drug-induced OB; Drug-induced lung injury; Imatinib; Nilotinib; Obstructive bronchiolitis (OB)",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101052",
"pmc": null,
"pmid": "32300523",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "16598305;21735750;18132351;12775773;11925917;446132;8676721;16002929;17087338;6122540;28012496;26052911;3172099;25912939;19759284;8428237;8804954;6414389;19850751;14724651;26335918;7213434;17228807;3966941;14661689;24806161;27388852;22616969;17195235;17682471;16449804;8666118;25373140",
"title": "A case of imatinib-related obstructive bronchiolitis followed long term.",
"title_normalized": "a case of imatinib related obstructive bronchiolitis followed long term"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1231228",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "REBAMIPIDE"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report outer retinal disruption and uveal effusion after gemcitabine and docetaxel combination therapy.\n\n\nMETHODS\nA 78-year-old woman presented with blurry vision after two cycles of gemcitabine and docetaxel combination chemotherapy for stage IV sarcoma. At presentation, visual acuity was finger counting and 20/25 in the right and left eyes, respectively. Slit-lamp examination and B-scan ultrasonography revealed severe uveal effusion in the right eye and choroidal folds in the left eye. Spectral domain optical coherence tomography showed disruption of photoreceptor inner segment ellipsoid band in the right eye. The patient was monitored weekly with ophthalmic examination and B-scan ultrasonography, while continuing with gemcitabine monotherapy. At 8 weeks follow-up, uveal effusion improved considerably and visual acuity was 20/40 and 20/20 in the right and left eyes, respectively.\n\n\nCONCLUSIONS\nUveal effusion and outer retinal disruption were reported after gemcitabine and docetaxel chemotherapy. Early detection and close ophthalmic monitoring may allow concurrent cancer treatment and prevention of possible chemotherapy-induced ocular side effects.",
"affiliations": "*MD, MPH †MD ‡PhD Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois (all authors).",
"authors": "Kord Valeshabad|Ali|A|;Mieler|William F|WF|;Setlur|Vikram|V|;Thomas|Merina|M|;Shahidi|Mahnaz|M|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1097/OPX.0000000000000571",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "92(5)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D009382:Neoplasms, Unknown Primary; D020419:Photoreceptor Cells, Vertebrate; D012509:Sarcoma; D043823:Taxoids; D041623:Tomography, Optical Coherence; D014603:Uveal Diseases; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "e110-3",
"pmc": null,
"pmid": "25822016",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "10715290;5416827;6939330;3980172;1386726;16414359;10030580;9294478;22232485;24949716;10776972;10894879;12695719;12714417;12879466;264409",
"title": "Posterior segment toxicity after gemcitabine and docetaxel chemotherapy.",
"title_normalized": "posterior segment toxicity after gemcitabine and docetaxel chemotherapy"
} | [
{
"companynumb": "US-PFIZER INC-2015148952",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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"drugadditional": null,
... |
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"abstract": "We conducted a population-based analysis of patient outcomes following treatment with bevacizumab and platinum-based chemotherapy for metastatic, recurrent, or persistent cervical carcinoma.\n\n\n\nEligible cases were identified using the BC Cancer provincial pharmacy database. Cases with small cell component or inadequate clinical follow-up were excluded. Overall response to therapy, progression-free survival (PFS), overall survival (OS), and toxicities were documented.\n\n\n\nTwenty-seven eligible cases were included with a median follow-up of 12.1 months. The median age at recurrence/metastatic diagnosis was 49 years (range, 27-83 years). Twenty-three of 27 women received carboplatin, paclitaxel, and bevacizumab as first-line treatment, and 4 of 27 as second-line treatment. The median number of cycles of bevacizumab delivered was 5.5 (range, 1-21). The overall response rate was 44% (12/27), with 11% (3/27) complete response and 33% (9/27) partial response. Median PFS and OS for the entire cohort were 5.3 and 12.1 months, respectively. In first-line therapy, the median PFS and OS were 6.3 and 17.5 months, respectively. Common toxicities included anemia (grade 1/2) 73% (19/27), and the following grade 2 or greater: neutropenia 38% (n = 10) with 1 occurrence of febrile neutropenia, hypertension 30% (n = 8), and thrombosis 22% (n = 6). The fistula rate was 3.7% (n = 1).\n\n\n\nIn this population-based analysis, the combination of bevacizumab and platinum-based chemotherapy as first-line therapy for metastatic, recurrent, or persistent cervical carcinoma was safely delivered and had outcomes comparable to results from the GOG 240 phase III trial.",
"affiliations": "Medical Oncology, BC Cancer, Vancouver.;Medical Oncology, BC Cancer, Victoria.;Diagnostic Imaging, BC Cancer, Vancouver.;Medical Oncology, BC Cancer, Surrey, British Columbia, Canada.",
"authors": "Tinker|Anna V|AV|;Fiorino|Leathia|L|;O'Dwyer|Helena|H|;Kumar|Aalok|A|",
"chemical_list": "D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000001351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "28(8)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1592-1599",
"pmc": null,
"pmid": "30247250",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bevacizumab in Metastatic, Recurrent, or Persistent Cervical Cancer: The BC Cancer Experience.",
"title_normalized": "bevacizumab in metastatic recurrent or persistent cervical cancer the bc cancer experience"
} | [
{
"companynumb": "CA-TEVA-2019-CA-1084146",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Geller et al reported a rare mutation in the mineralocorticoid receptor (MR) resulting in constitutive MR activity. Progesterone, normally an MR antagonist, acts as a potent agonist with this mutation. Progesterone levels can increase 100-fold during pregnancy and thus lead to increased MR activity in this setting, resulting in hypertension (HTN) and hypokalemia during pregnancy and resolution of hypokalemia after delivery.\nOur patient was a 33-year-old African American female with a history of pregnancy-induced HTN associated with hypokalemia during her last pregnancy. She presented with muscle weakness from profound hypokalemia complicated by nephrogenic diabetes insipidus (DI) and rhabdomyolysis.\nHer admission potassium was 1.9 mmol/L (3.5-5.1 mmol/L) with a 24-hour urine potassium of 35 mmol per day and an unmeasurable serum aldosterone level. Her potassium normalized 1 day after delivery off potassium supplementation and amiloride, which were last given 1 day prior to her delivery. Recurrent hypokalemia from nonaldosterone-mediated renal potassium wasting during pregnancy (with normal potassium in a nongestational state) is consistent with the cases of gain-of-function mutation in MR that Geller et al report. A definite diagnosis requires genetic analysis.\nHer hypokalemia was refractory to potassium replacement but quickly responded to an inhibitor of the epithelial sodium channel (ENaC), amiloride.\nHer potassium normalized on amiloride 10 mg per day and KCL 40 mEq daily during the remainder of her pregnancy, and her nephrogenic DI resolved after this correction of hypokalemia. After her delivery, her potassium remained normal off the potassium supplements and amiloride.\nPregnancy-induced hypokalemia from an activating MR mutation has rarely been reported. Pregnancy-induced HTN is often the first differential diagnosis in a patient who develops worsening in her HTN during pregnancy. We should also consider the possibility of a gain-of-function mutation in MR in these patients who also have associated hypokalemia.",
"affiliations": "East Georgia Kidney and Hypertension, Augusta, GA, USA.;Medical University of South Carolina, College of Medicine, Charleston, SC, USA.",
"authors": "Pintavorn|Pairach|P|https://orcid.org/0000-0002-5709-2378;Munie|Stephanie|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/20543581211017424",
"fulltext": "\n==== Front\nCan J Kidney Health Dis\nCan J Kidney Health Dis\nCJK\nspcjk\nCanadian Journal of Kidney Health and Disease\n2054-3581\nSAGE Publications Sage CA: Los Angeles, CA\n\n10.1177/20543581211017424\n10.1177_20543581211017424\nResearch Case Report\nA Case Report of Recurrent Hypokalemia During Pregnancies Associated With Nonaldosterone-Mediated Renal Potassium Loss\nhttps://orcid.org/0000-0002-5709-2378\nPintavorn Pairach 1\nMunie Stephanie 2\n1 East Georgia Kidney and Hypertension, Augusta, GA, USA\n2 Medical University of South Carolina, College of Medicine, Charleston, SC, USA\nPairach Pintavorn, East Georgia Kidney and Hypertension, 818 Saint Sebastian Way, Suite 300, Augusta, GA 30901, USA. Email: pintavorn@jhu.edu\n28 5 2021\n2021\n8 205435812110174246 3 2021\n11 4 2021\n© The Author(s) 2021\n2021\nCanadian Society of Nephrology, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nRationale:\n\nGeller et al reported a rare mutation in the mineralocorticoid receptor (MR) resulting in constitutive MR activity. Progesterone, normally an MR antagonist, acts as a potent agonist with this mutation. Progesterone levels can increase 100-fold during pregnancy and thus lead to increased MR activity in this setting, resulting in hypertension (HTN) and hypokalemia during pregnancy and resolution of hypokalemia after delivery.\n\nPresenting concerns:\n\nOur patient was a 33-year-old African American female with a history of pregnancy-induced HTN associated with hypokalemia during her last pregnancy. She presented with muscle weakness from profound hypokalemia complicated by nephrogenic diabetes insipidus (DI) and rhabdomyolysis.\n\nDiagnosis:\n\nHer admission potassium was 1.9 mmol/L (3.5-5.1 mmol/L) with a 24-hour urine potassium of 35 mmol per day and an unmeasurable serum aldosterone level. Her potassium normalized 1 day after delivery off potassium supplementation and amiloride, which were last given 1 day prior to her delivery. Recurrent hypokalemia from nonaldosterone-mediated renal potassium wasting during pregnancy (with normal potassium in a nongestational state) is consistent with the cases of gain-of-function mutation in MR that Geller et al report. A definite diagnosis requires genetic analysis.\n\nInterventions:\n\nHer hypokalemia was refractory to potassium replacement but quickly responded to an inhibitor of the epithelial sodium channel (ENaC), amiloride.\n\nOutcomes:\n\nHer potassium normalized on amiloride 10 mg per day and KCL 40 mEq daily during the remainder of her pregnancy, and her nephrogenic DI resolved after this correction of hypokalemia. After her delivery, her potassium remained normal off the potassium supplements and amiloride.\n\nNovel findings:\n\nPregnancy-induced hypokalemia from an activating MR mutation has rarely been reported. Pregnancy-induced HTN is often the first differential diagnosis in a patient who develops worsening in her HTN during pregnancy. We should also consider the possibility of a gain-of-function mutation in MR in these patients who also have associated hypokalemia.\n\nAbrégé\n\nJustification:\n\nEn 2000, Geller et coll. ont rapporté l’existence d’une rare mutation du récepteur des minéralocorticoïdes (RM) entraînant une activité RM constitutive. La progestérone, un antagoniste des RM, agit comme un puissant agoniste sur cette mutation. Pendant la grossesse, les taux de progestérone peuvent être multipliés par 100 et cela entraîne une augmentation de l’activité des RM dans ce contexte, ce qui provoque de l’hypertension (HTN) et de l’hypokaliémie pendant la grossesse, et la résolution de l’hypokaliémie après l’accouchement.\n\nPrésentation du cas:\n\nNotre patiente était une Afro-Américaine de 33 ans avec des antécédents d’HTN induite par la grossesse et associée à une hypokaliémie au cours de sa précédente grossesse. La patiente présentait une faiblesse musculaire due à une grave hypokaliémie compliquée par un diabète insipide (DI) néphrogénique et une rhabdomyolyse.\n\nDiagnostic:\n\nSon taux de potassium à l’admission était de 1,9 mmol/L (3,5-5,1 mmol/L) avec un taux de potassium urinaire sur 24 heures à 35 mmol par jour et un taux d’aldostérone sérique non mesurable. Son taux de potassium s’est normalisé un jour après l’administration d’amiloride et d’un supplément de potassium, lesquels ont été administrés pour la dernière fois un jour avant l’accouchement. L’hypokaliémie récurrente découlant d’une perte rénale de potassium non médiée par l’aldostérone pendant la grossesse (avec taux de potassium normal dans un état non gestationnel) était conforme aux cas de mutation à gain de fonction des RM rapportés par Geller et coll. Un diagnostic précis nécessite une analyze génétique.\n\nInterventions:\n\nL’hypokaliémie était réfractaire au remplacement du potassium, mais a rapidement répondu à l’amiloride, un inhibiteur du canal sodique épithélial (ENaC).\n\nRésultats:\n\nLe taux de potassium a été normalisé par l’administration de 10 mg d’amiloride et de 40 mEq de KCL par jour pour le reste de la grossesse. Le DI néphrogénique s’est résolu à la suite de cette correction de l’hypokaliémie. Après l’accouchement, le taux de potassium de la patiente est demeuré normal sans les suppléments de potassium et d’amiloride.\n\nPrincipales observations:\n\nL’hypokaliémie induite par la grossesse et découlant d’une mutation des RM activatrice a rarement été rapportée. L’HTN induite par la grossesse est souvent le premier élément de diagnostic différentiel chez une patiente dont l’HTN s’aggrave pendant la grossesse. Il convient aussi d’envisager une possible mutation à gain de fonction des MR chez ces patientes qui présentent également une hypokaliémie associée.\n\nrecurrent hypokalemia in pregnancy\npseudo-hyperaldosteronism\ngain-of-function mineralocorticoid receptor mutation\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nWe report a patient with a history of pregnancy-induced hypertension (HTN) who experienced hypokalemia during her last pregnancy.\n\nPresenting Concerns\n\nThe patient was a 33-year-old African American female G6P5005 who had a history of pregnancy-induced HTN since her first pregnancy when she was 16 years old. She developed persistent HTN after her fourth pregnancy in 2013. She developed hypokalemia during her fifth pregnancy in 2018, with serum potassium ranging from 2.9 to 3.1 mmol/L (3.5-5.1 mmol/L). Her blood pressure before the Cesarean section in 2018 was 189/93 and went down to 137/84 after the surgery. She had not been following with her primary care physician, and her potassium as well as her blood pressure were not checked after that pregnancy. Furthermore, her potassium level was not checked during her fourth pregnancy in 2013 at our hospital, and there was no information on the potassium level during her first 3 pregnancies. She had been taking labetalol 400 mg twice daily for her HTN over the past several years, and nifedipine was added during this pregnancy. She presented to our institution at 35-weeks pregnant with a 1-week history of generalized weakness with difficulty ambulating. She had also developed polydipsia and polyuria several days prior to admission. The patient denied having any diarrhea, nausea, vomiting, palpitations, diaphoresis, or anorexia, or any history of pica, surreptitious diuretics, or laxative use. She had been taking an elderberry supplement (without Licorice) once a day for years. Her family history was significant for HTN in her mother, but the patient was not aware of any hypokalemia in her family. She experienced frequent headaches, which usually worsened during pregnancy, and had used 90 tablets of Butalbital-acetaminophen-caffeine within 2 to 3 weeks for her headaches prior to admission.\n\nClinical Findings\n\nHer physical exam revealed a respiratory rate of 20, uncontrolled blood pressure of 182/86 without peripheral edema, and no signs suggestive of Cushing’s syndrome or abnormal sexual development. Her initial potassium was 1.9 mmol/L, and the obstetrics service arranged for potassium replacement. Her serum bicarbonate was 22 mmol/L (21-30 mmol/L) and magnesium 2.2 mg/dL (1.6-2.6 mg/dL).\n\nTimeline\n\nDiagnosis Focus and Assessment\n\nThe initial impression from her obstetrician was Butalbital-acetaminophen-caffeine-induced hypokalemia. However, she did not exhibit typical clinical constellations of Butalbital-acetaminophen-caffeine toxicities such as hypotension, nausea, and vomiting. The Butalbital-acetaminophen-caffeine dosage that she used (on average every 4 hours) was at the upper limit of the recommended dose. Furthermore, her caffeine level was normal at 3 µg/mL (≤ 20 ug/mL). A reported case of Butalbital-acetaminophen-caffeine-induced hypokalemia occurred in a patient with suspected massive overdose and was thought to be related to caffeine-induced diuresis.1 A 24-hour urine potassium, serum renin, and aldosterone were sent by her obstetrician on the day of her admission. A total of 120 mEq of potassium chloride (KCL) (60 mEq intravenous and 60 mEq oral) were given by obstetrics service without any significant improvement in her potassium level (potassium of 1.8 mmol/L the following day), and a nephrology consultation was requested. Table I in the supplementary material highlights some of her lab findings; findings were significant for aldosterone < 3 ng/dL, renin 0.5 ng/mL/hour (supine 0.2-1.6 ng/mL/hour; upright 0.5-4 ng/mL/hour), and 24-hour urine potassium of 35 mmol/TV. The urine potassium of 35 mmol per day in the setting of hypokalemia is consistent with renal potassium wasting. The trans-tubular potassium gradient (TTKG) value of 5 in the setting of hypokalemia is also supportive of renal potassium loss (with the limitation in interpreting the value from low urine sodium and osmolality).\n\nTherapeutic Focus and Assessment\n\nHer potassium only slightly improved to 2.2 mmol/L 2 days into her admission despite ongoing KCL replacement. Given the possibility of a gain-of-function MR mutation, amiloride 10 mg per day, a pregnancy category B agent, was added that morning with improvement of potassium to 3 mmol/L in the evening and 3.6 mmol/L the following day. DDAVP 1 mcg IV was given for a few doses that day as well when she had 16 L of urine per day without significant changes in urine output. Her urine output was about 7200 mL/day on her second day of admission, 16 100 mL/day on the third day of admission, 9000 mL/day 3 days after that, and 3000 mL/day 2 days after that (4 days after correction of hypokalemia). Her potassium remained normal around 4.5 to 5 mmol/L on amiloride 10 mg daily and KCL 40 mEq daily after her discharge. Her follow-up outpatient’s lab 2 days postdischarge showed hyponatremia and nongap acidosis with a sodium of 133 mmol/L (136-145 mmol/L), anion gap of 14 mmol/L (5.0-14.0 mmol/L), and CO2 of 16 mmol/L (21-30 mmol/L). Her serum albumin level was 3.8 g/dL (3.97-4.97 g/dL). The development of hyponatremia could be related to a side effect of amiloride or an unmasking of her pregnancy-associated hyponatremia after improvement in nephrogenic DI. Low serum bicarbonate similarly could be secondary to amiloride or an unmasking of a metabolic compensation in pregnancy-induced respiratory alkalosis after correction of pseudo-hyperaldosteronism with an ENaC blocker.\n\nFollow-Up and Outcomes\n\nHer amiloride and KCL were not given when she was readmitted for her regularly scheduled Cesarean section almost a week later. She took her last dose of amiloride and KCL in the morning 1 day prior to her delivery. She was maintained on nifedipine 60 mg daily and labetalol 400 mg twice daily with an acceptable blood pressure after the delivery. Her potassium 1 day postdelivery was normal at 4 mmol/L. She did a telehealth follow-up a few days later and reported a blood pressure of 116/65 on a lower dose of nifedipine at 30 mg daily and the same dose of labetalol. A follow-up chemistry panel, urine electrolytes, renin, aldosterone, and 24-hour urine for free cortisol and cortisone were ordered but not completed despite our recommendation.\n\nDiscussion\n\nIn normal pregnancy, there are alterations in fluid, electrolytes, renin-angiotensin-aldosterone system (RAS), and various gestational hormones. Hyponatremia and respiratory alkalosis are commonly encountered during pregnancy.2 Aldosterone levels are elevated with concentration as high as 10-fold increase compared with nonpregnant states. In preeclampsia, aldosterone levels are significantly lower than normal pregnancy approaching pregestational level.3 In pregnancy, there are several physiologic changes that can lead to hypokalemia specific to pregnancy. For example, hyperemesis gravidarum can lead to hypokalemia from gastrointestinal loss. In 2 pregnant patients with aldosterone-producing adenomas with activating CTNNB1 mutation with increased luteinizing hormone-chorionic gonadotropin and gonadotropin-releasing hormone encoding gonadal receptors, these patients developed HTN and hypokalemia during their pregnancies.4\n\nPrimary hyperaldosteronism (PA), often an underrecognized cause of HTN in pregnancy, needs to be considered in pregnant patients with severe HTN with or without hypokalemia. Elevated progesterone level during pregnancy competitively inhibits the action of aldosterone at the MR receptors; therefore, hypokalemia might not be present until postpartum. Diagnosis of PA is typically made in patients who have an elevated aldosterone-renin-ratio (ARR). This ratio can be falsely negative during pregnancy since renin production in pregnancy is relatively higher than aldosterone production resulting in a lowered ARR.5 Confirmatory tests of PA such as the saline loading test and captopril challenge test are contraindicated during pregnancy.6 Therefore, diagnosis of PA during pregnancy can be challenging.\n\nPseudo-hyperaldosteronism mimics the clinical effects of elevated aldosterone such as HTN, hypokalemia, and metabolic alkalosis. The differential diagnoses in a patient with HTN and hypokalemia associated with urinary potassium wasting without elevated serum aldosterone include ectopic ACTH production, Cushing syndrome, Liddle syndrome, apparent mineralocorticoid excess (AME) syndrome (which might be hereditary or acquired from Licorice use or azole antifungals use, such as with itraconazole or posaconazole), 11-beta hydroxylase deficiency (usually associated with virilization), 17-alpha hydroxylase deficiency (typically associated with abnormal sexual development), and an activating MR mutation.7,8 In our case, her urinary potassium excretion of 35 mmol per day in the setting of profound hypokalemia is consistent with renal potassium loss as the cause of her hypokalemia. Her serum aldosterone was unmeasurable. She lacked clinical features of Cushing syndrome with a fasting glucose of 81 mg/dL (74-106 mg/dL) on admission, normal ACTH, and normal cortisol albeit slightly elevated 24-hour urine cortisol but below the 3-fold increase threshold for diagnosis of Cushing disease. These findings are not supportive of ectopic ACTH and Cushing disease. She did not take any Licorice supplement. The hereditary form of AME syndrome is usually a disease of childhood. She does not have any abnormal sexual development to suggest 11-beta hydroxylase or 17-alpha hydroxylase deficiency. Patients with Liddle syndrome should have hypokalemia in a nongestational state as well. The normalization of potassium after delivery without amiloride or potassium supplement leads us to hypothesize that her recurrent pregnancy-induced hypokalemia can be explained by an MR mutation, as Geller et al described. Other causes of pseudo-hyperaldosteronism cannot be completely excluded with the lack of complete information about her potassium outside her pregnancy and peri-partum period due to non-compliance issues in follow-up. A definite diagnosis requires a genetic study.\n\nHer hypokalemia was resistant to potassium supplement but was rapidly responsive to amiloride which inhibits ENaC and thus indirectly ROMK activity. The development of hypokalemia-induced nephrogenic DI with her urine output as high as 16 L per day can worsen the degree of hypokalemia. Increased luminal flow in cortical collecting tubules is known to cause increased intracellular calcium concentration which leads to activation of flow-dependent Maxi-K channels.9 A brain MRI showed mild flattening of the pituitary without expansion of the sella turcica and without pituitary enlargement or macroadenoma. This suggested a partially empty sella turica (PES) which might be responsible for her headaches. Although PES can cause abnormal anterior and more infrequently posterior pituitary hormone secretion,10 her polyuria did not respond to DDAVP and spontaneously resolved a few days after correction of hypokalemia. This is supportive of hypokalemia-mediated nephrogenic DI rather than central DI.\n\nShe had a history of pregnancy-induced HTN since her first pregnancy, albeit no information on her potassium concentrations was available before her fifth pregnancy. It is conceivable that her potassium concentration might not have been checked like it was not during her fourth pregnancy or her hypokalemia was simply treated without follow-up. Geller et al11 described a gain-of-function mutation in MR, specifically a missense mutation resulting in substitution of leucine for serine at codon 810. Carriers for this mutation showed marked increase in HTN as well as suppression of aldosterone secretion. There was no significant hypokalemia among the carriers in a normal physiologic state. Twenty-one-carbon steroids, such as progesterone which normally acts as an antagonist to wild-type MR, activate MR in patients with this mutation. Interestingly, spironolactone, which normally inhibits wild-type MR, activates the mutant MR. In the report by Geller et al, 2 carriers with MR mutations developed exacerbation of HTN and hypokalemia during all their pregnancies. One carrier required urgent Cesarean section at 34-weeks’ gestation due to worsening in blood pressure (210/120 mm Hg). The other carrier had exacerbation of HTN requiring early delivery in the sixth and seventh months of gestation. Neither carrier had proteinuria or edema. In another report by Garg et al,7 a 23-year-old G2P1A0 developed hypokalemia during her first and second pregnancies with normal potassium after delivery. In this report, the patient’s blood pressure was 138/81 mm Hg when she was at 32-weeks of gestation. She had induction of labor at 37-weeks of gestation because of uncontrolled HTN and hypokalemia, but the exact blood pressure level was not specified.\n\nIn our case, the initial metabolic panels did not show evidence of an acid-base disorder. Metabolic alkalosis, which is a feature of hyperaldosteronism, was not mentioned in the report by Geller et al and was not present in the report by Garg et al.7,11 Metabolic compensation for chronic respiratory alkalosis which is common in pregnancy might mask the usual clues for detecting metabolic alkalosis. Similarly, in our case, with her normal bicarbonate level, blood gas was not performed. In retrospect, her urine pH was at the upper limit of normal at 8 (5-8), which might indicate renal compensation for respiratory alkalosis. The development of low serum bicarbonate several days after amiloride treatment might reflect a metabolic compensation of respiratory alkalosis that was unmasked after resolution of her hypokalemic metabolic alkalosis. Aldosterone activates Na+/H+ exchange, and hyperaldosteronism causes urinary acidification resulting in metabolic alkalosis from excessive urinary chloride loss.12,13,14 In our case, urine chloride was low at <20 mmol/dL. In the setting of respiratory alkalosis, the renal net acid secretion decreases largely from bicarbonaturia and decreases in the excretion of titratable acid.15 Urine pH can be alkaline in the setting of hyperaldosteronism if distal urinary acidification is impaired.12 We postulate that the concomitant respiratory alkalosis with renal compensation might explain the apparently normal acid-base values from the chemistry panel, alkaline urine, and low urinary chloride in our patient.\n\nConclusion\n\nPregnancy-induced HTN is often the leading differential diagnosis of worsening in HTN during pregnancy. This case illustrates the need to consider an activating MR mutation as a cause of exacerbation of HTN during pregnancy in the setting of hypokalemia that is secondary to nonaldosterone-mediated renal potassium wasting. Amiloride, a pregnancy category B agent, proved effective in both potassium and blood pressure control in our case.\n\nSupplemental Material\n\nsj-pdf-1-cjk-10.1177_20543581211017424 – Supplemental material for A Case Report of Recurrent Hypokalemia During Pregnancies Associated With Nonaldosterone-Mediated Renal Potassium Loss\n\nClick here for additional data file.\n\nSupplemental material, sj-pdf-1-cjk-10.1177_20543581211017424 for A Case Report of Recurrent Hypokalemia During Pregnancies Associated With Nonaldosterone-Mediated Renal Potassium Loss by Pairach Pintavorn and Stephanie Munie in Canadian Journal of Kidney Health and Disease\n\nEthics Approval and Consent to Participate: The patient gave verbal consent to publish her information in de-identified form.\n\nConsent for Publication: All authors reviewed this manuscript and provided consent for publication.\n\nAvailability of Data and Materials: Data are available from the authors upon reasonable request, according to the terms of relevant privacy legislation and regulation.\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\nORCID iD: Pairach Pintavorn https://orcid.org/0000-0002-5709-2378\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n\n1 Bryczkowski C Geib AJ. Combined butalbital/acetaminophen/caffeine overdose: case files of the Robert Wood Johnson medical school toxicology service. J Med Toxicol. 2012;8 :424-431.23011802\n2 Barta V Koncicki H. Electrolyte disorders in pregnancy. In: Sachdeva M Miller I , eds. Obstetric and gynecologic nephrology. Springer, Cham; 2020. doi:10.1007/978-3-030-25324-0_9.\n3 Weir RJ Brown JJ Fraser R , et al . Plasma renin, renin substrate, angiotensin II, and aldosterone in hypertensive disease of pregnancy. Lancet. 1973;1 (7798 ):291-294.4119172\n4 Ada ED Teo BA Garg S , et al . Pregnancy, primary hyperaldosteronism, and adrenal CTNNB1 mutations. N Engl J Med. 2015;373 :1429-1436.26397949\n5 Kilmartin C Opu T Podymow T Dayan N. Primary hyperaldosteronism presenting as persistent postpartum hypertension: illustrative case and systematic review. Obstet Med. 2018;12 (4 ):190-195.31853260\n6 Zelinka T Petrak O Rosa J Holaj R Strauch B Widimsky J. Primary aldosteronism and pregnancy. Kidney Blood Press Res. 2020:45 :275-285.32114578\n7 Garg AK Parajuli P Mamillapalli CK. Pregnancy complicated by hypertension hypokalemia. Am J Kidney Disease. 2020;76 (4 ):PA21-A22.\n8 Inderbinen SG Zogg M Kley M Smiesko M Odermatt A. Species-specific difference in the inhibition of 11 beta-hydroxysteroid dehydrogenase 2 by itraconazole and Posaconazole. Toxicol Appl Pharmacol. 2021;412 :115387. doi:10:1016/j.taap2020.115387.\n9 Woda CB Bragin A Kleyman TR Satlin LM. Flow-dependent K+ secretion in the cortical collecting duct is mediated by a Maxi-K channel. Am J Physiol Renal Physiol. 2001;280 (5 ):F786-93.\n10 Lambert M Gaillard RC Vallotton MB Megret M Delavelle J , Empty sella syndrome associated with diabetes insipidus case report review of the literature:. J Endocrinol Invest. 1989;12 (6 ):433-437.\n11 Geller DS Farhi A Pinkerton N , et al . Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;289 (5476 ):119-123.10884226\n12 Wagner C. Effect of mineralocorticoids on acid-base balance. Nephron Physiol. 2014;128 :26-34.25377117\n13 Oberleithner Weigt M Westphale HJ Wang W. Aldosterone activates Na+/H+ exchange and raises cytoplasmic pH in target cells of the amphibian kidney. Proc Natl Acad Sci U S A. 1987;84 (5 ):1464-1468.3029782\n14 Luke RG Galla JH. It is Chloride depletion alkalosis not contraction alkalosis. J Am Soc Nephrol. 2012;23 (2 ):204-207.22223876\n15 Krapf R Hartner D Hulter HN. Chronic respiratory Alkalosis- The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med. 1991;324 :1394-1401.1902283\n\n",
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"journal": "Canadian journal of kidney health and disease",
"keywords": "gain-of-function mineralocorticoid receptor mutation; pseudo-hyperaldosteronism; recurrent hypokalemia in pregnancy",
"medline_ta": "Can J Kidney Health Dis",
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"title": "A Case Report of Recurrent Hypokalemia During Pregnancies Associated With Nonaldosterone-Mediated Renal Potassium Loss.",
"title_normalized": "a case report of recurrent hypokalemia during pregnancies associated with nonaldosterone mediated renal potassium loss"
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"abstract": "A patient with a therapy-related acute myeloid leukaemia (AML), NPM1mut, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.",
"affiliations": "Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy, sperrone@hotmail.it.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Department of Translational and Precision Medicine, University \"La Sapienza,\", Rome, Italy.;Department of Translational and Precision Medicine, University \"La Sapienza,\", Rome, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Department of Diagnostic and Interventional Radiology, S. M. Goretti Hospital, Latina, Italy.;Department of Biomedicine and Prevention, University of Rome \"Tor Vergata,\", Rome, Italy.;Department of Biomedicine and Prevention, University of Rome \"Tor Vergata,\", Rome, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.",
"authors": "Perrone|Salvatore|S|;Ortu La Barbera|Elettra|E|;Viola|Federica|F|;Cipollone|Elena|E|;Scerpa|Maria Cristina|MC|;Siniscalchi|Roberta|R|;Ottone|Tiziana|T|;Voso|Maria Teresa|MT|;Cimino|Giuseppe|G|",
"chemical_list": "D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C000609080:gilteritinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000518356",
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"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "66(4)",
"journal": "Chemotherapy",
"keywords": "Acute myeloid leukaemia; CPX-351; Central nervous system; Cerebrospinal fluid; Gilteritinib; Myeloid sarcoma",
"medline_ta": "Chemotherapy",
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"title": "A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib.",
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"abstract": "Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the KCNA1 gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in KCNA1, previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.",
"affiliations": "Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy.;Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy.;Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.;Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy.;Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy.",
"authors": "Bianchi|Francesca|F|;Simoncini|Costanza|C|;Brugnoni|Raffaella|R|;Ricci|Giulia|G|;Siciliano|Gabriele|G|",
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"fulltext": "\n==== Front\nActa Myol\nActa Myol\nAM\nActa Myologica\n1128-2460 2532-1900 Pacini Editore Srl \n\n10.36185/2532-1900-007\nCase Report\nNeuromuscular tetanic hyperexcitability syndrome associated to a heterozygous Kv1.1 N255D mutation with normal serum magnesium levels\nBianchi Francesca 1 Simoncini Costanza 1 Brugnoni Raffaella 2 Ricci Giulia 1 Siciliano Gabriele 1 1 Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy\n2 \nNeurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy\nCorrespondence Gabriele Siciliano Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, via Roma 67, 56126 Pisa, Italy. Tel.: +39 050 993046; Fax: +39 050 550563. E-mail: gabriele.siciliano@unipi.itConflict of interest\n\nThe Authors declare no conflict of interest\n\n\n01 3 2020 \n3 2020 \n39 1 36 39\n06 2 2020 09 3 2020 ©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy2020This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentioning the license, but only for non-commercial purposes and only in the original version. For further information: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.enMutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the KCNA1 gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in KCNA1, previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.\n\nKey words\nhypomagnesemiatetanyKCNA1\n==== Body\nIntroduction\nVoltage-gated K channels are a family of membrane proteins involved in determining the potential of the cellular membrane at rest, shaping action potentials and controlling neuronal excitability 1. In these proteins, a central ion conduction channel is encircled by four subunits, each consisting of six transmembrane-spanning-helices (S1-S6) where segments S1-S4 form the voltage-sensing domain and segments S5-S6 form the pore domain 2. Among voltage-gated K channels, the Shaker-related group Kv1.1 is encoded by the KCNA1 gene and is abundantly expressed in excitable and non-excitable cells. Its mutations may cause both a significant reduction in current amplitude and altered kinetic properties related to K+ balance 1. So far, mutations in Kv1.1 have been linked to several disorders such as periodic episodic ataxia type 1 (EA1), presumably caused by defective Kv1.1 in the cerebellum 3, myokymia, caused by the alteration of Ca2+ homeostasis due to the dysfunction of juxtaparanodal Kv1.1 channels 4, and isolated neuromyotonia 5. The wide expression of Kv1.1 in the nervous system explains the manifold clinical phenotypes of its mutations 6. The molecular genetic testing of KCNA1 has further broadened the clinical spectrum of the disorders associated to mutations in the gene, e.g. delay in motor development, choreoathetosis, cognitive dysfunction, transient postural abnormalities in infancy, shortening of the Achilles tendon in children 6, non-ataxic cataplexy 7 and atypical episodic ataxia with migraine and hyperthermia 8.\n\nFinally, and interestingly, due to the Kv1.1 localization in the renal distal convoluted tubule segments, mutations in KCNA1 have also been related to hypomagnesemia leading to tetany and myokymia, as shown in a single family3. In kidney, the K+ secretion via Kv1.1 provides an electrical gradient that drives Mg2+ reabsorption via the permeable transient receptor potential cation channel TRPM6. The amino acid substitution of a highly conserved asparagine for an aspartic acid in the third transmembrane segment of Kv1.1 (p.Asn255Asp) results in a non-functional channel causing an autosomal dominant hypomagnesemia associated to muscle cramps, tetanic episodes, tremor, and muscle weakness3. The substitution of the asparagine with other hydrophobic, polar, or charged amino acids cause a nonfunctional channel, confirming in vitro the central role of asparagine in the right functioning of the channel1. An additional KCNA1 mutation resulting in a nonfunctional channel (p.Leu328Val) with hypomagnesemia has been reported in a young female patient affected by tetany who had an abnormal urinary Mg2+ excretion2. This finding suggested a possible role of KCNA1 mutations besides p.Asn255Asp in hypomagnesemia.\n\nNotwithstanding the large variability of symptoms in EA1, the most common phenotype associated to KCNA1 mutations, the penetrance of the hypomagnesemia phenotype has yet not been assessed, as it has rarely been reported in EA1 5. Here we describe a case of muscular spasms and tetanic episodes in a female patient affected by Kv1.1 N255D mutation with normal serum magnesium levels.\n\nCase report\nA 31 years old female patient came to our attention in 2012 at the Neuromuscular Unit in Santa Chiara Hospital, Pisa- Italy, for a history of recurrent muscular spasms, tetanic episodes, diffuse and persistent muscle weakness and diarrhea. The muscular spasms were mainly localized at face and hands, lasted from several minutes to one hour, were often associated to tachycardia and worsened with carbohydrates ingestion and physical effort. These symptoms started in infancy with low frequency and low intensity but exacerbated after her first delivery and during breastfeeding, so that she required a medical consult.\n\nThe patient had no track record of neuromuscular diseases in her family, except for a history of occasional muscular spasms in her father and a juvenile cardiac disease with heart conductance alterations in her grandmother, not better investigated. After an initial misdiagnose of a rheumatological disorder (fibromyalgia), the patient was asked for a neurological evaluation and thus came to our attention. The neurological examination was normal, except for a mild and fluctuating weakness of iliopsoas muscles (MRC 4/5 bilaterally). She had no signs of myotonia or dyskinetic movement, neither she had ataxia. Objective clinical signs of cerebellar dysfunction, including nystagmus, multistep or overshoot saccades, dysmetria in the finger-nose test, and decomposition of movement of the legs on heel-to-shin test, were absent.\n\nThe patient underwent an electromyography (EMG) showing polyphasic motor unit potentials suggestive for myopathic changes; the EMG tetany test resulted positive in several occasions, as after 1’30” of physical effort, grouped motor unit discharges appeared and persisted for over 2 minutes. All biochemical values were normal, including blood count, renal function, hepatic function, thyroid function, estroprogestinic hormones, parathormone, glucose metabolism, autoimmune tests, GAD antibodies, and iron balance. The blood dosage of aldolases, creatine phosphokinase and the lactic dehydrogenase also resulted normal. Due to a reduced ammonium production in the ischaemic lactate-ammonia test, the patient underwent a DNA analysis for myoadenylate deaminase deficiency, resulting negative. Since the history of cardiac disease in her grandmother, DNA analyses for LMNA gene was also performed, resulting negative. Based on the muscular transient weakness, serum acetylcholine receptors antibodies (Ab) and muscle-specific tyrosine kinase Ab were tested, also resulting negative. Muscular spams coupled with tetanic episodes suggested to dose blood electrolytes, discovering a mild hypocalcemia (ionized calcium 3.3 mg/dl with normal values of 4.4-4.9 mg/dl), while the magnesium dosage in the serum always resulted normal, although at lower limits.\n\nThe clinical picture therefore prompt us to perform genetic analysis for channelopathies. The NGS analysis showed a heterozygous mutation c.736A > G (p.Asn255Asp) in KCNA1, further confirmed with Sanger method, previously reported in association with autosomal dominant hypomagnesemia with sudden episodes of facial myokymia, tremor, muscle spasms with painful cramps, muscular weakness, and tetanic contraction episodes. A genetic test for mutations in exon 1 of KCNA1 on both parents was conducted through PCR amplification and direct sequencing, but resulted negative. This at first instance suggests that the patient’s KCNA1 mutation appeared de novo\n2. The patient completed the analysis with urinary magnesium excretion that showed a normal magnesium excretion (81,5 mg/24h with normal values less than 120). Following literature reports, a magnesium integration was added to her treatment, but was later discontinued due to a subjective worsening of the muscular symptoms. The same adverse effects were reported for a potassium supplementation. Several myorelaxants (e.g. baclofen, benzodiazepines, cyclobenzaprine, and tizanidine) and neuromodulator drugs (e.g. trazodone, pregabalin, and amitriptyline) were tested, but only calcium integration had a slight clinical benefit on the tetanic episodes and on the muscular weakness, whilst muscular cramps and spasms persisted. Eventually, a cerebral MRI and a cardiological balance with electrocardiogram, echocardiogram and troponine dosage all resulted normal. The patient is currently monitored on a yearly basis and appears in a stable condition.\n\nDiscussion\nSeveral genes are known to be involved in hereditary hypomagnesemia, including tight junction proteins claudin 16 and 19, the thiazide-sensitive sodium chloride cotransporter (NCC), the γ-subunit of the Na+/K+ ATPase (FXYD2), TRPM6, and the magnesiotropic hormone EGF 10. The c.736A > G (p.Asn255Asp) mutation in KCNA1 has been reported to cause an autosomal dominant hypomagnesemia with sudden episodes of facial myokymia, tremor, muscle spasms with painful cramps, muscular weakness, and tetanic contraction episodes 3. This is to be put in relation with the localization of Kv1.1 in the apical membrane of distal convoluted tubule (DCT) cells, where TRPM6 controls Mg2+ entry driven by its electrochemical potential. Mutations in Kv1.1 protein, while having no direct effect on TRPM6, exhibit reduced K+ conductance, thus depolarizing the apical membrane of DCT cells reducing the electrical driving force, favoring Mg2+ entry and leading to renal Mg2+ loss 9.\n\nPuzzling, hypomagnesemia has rarely been reported in relation to KCNA1 mutations. In the family described by Glaudemans et al. 3, the severity of the phenotype varied among affected members, with some cases of severe tetanic crises (in one case leading to death in infancy) and other cases having a milder muscular involvement. Low serum Mg2+ levels were observed in variable amounts among family members, whereas urinary Mg2+ excretion levels were normal, suggesting an impaired tubular Mg2+ reabsorption. In the patients described, both serum K+ and Ca2+ levels and urinary Ca2+ excretion levels were normal, in contrast with other forms of inherited hypomagnesemia 10. In these patients, magnesium integration led to partial clinical benefit, yet without a complete control on the muscular symptoms.\n\nIn the case here reported, the clinical phenotype concerning the muscular involvement was similar to that reported in previous literature. However, the patients’ serum and urinary magnesium dosages resulted normal in repeated measures. Interestingly, low values of serum ionized calcium were consistently reported, and calcium supplementation was indeed the only treatment that resulted effective in treating the symptoms, while magnesium integration resulted ineffective and perhaps worsened the symptoms, in contrast to what described in Glaudemans et al. 3. These findings are in accordance with a key role in DCT cells in ionic balance not only for Mg2+, but also for Na+, K+, and Ca2+. The presence of other channels co-expressed throughout the distal tubule, e.g. ROMK for K+ and ENac for Na+, makes it so that Kv1.1 is not the only contributing to apical conductance, underlying the complexity of the ionic balance system in vivo\n9. Altogether, our findings suggest to further research efforts in the characterization of the role of KCNA1 mutations hypomagnesemia and the related clinical treatment.\n\nAcknowledgements\nThe Authors acknowledge the ERN Euro-NMD for support.\n==== Refs\nReferences\n1 van der Wijst J Glaudemans B Venselaar H \nFunctional analysis of the Kv1. 1 N255D mutation associated with autosomal dominant hypomagnesemia\n. J Biol Chemistry \n2010 ;285 :171 -8\n. https://doi.org/10.1074/jbc.M109.041517 \n10.1074/jbc.M109.041517 \n2 van der Wijst J Konrad M Verkaart SA \nA de novo KCNA1 mutation in a patient with tetany and hypomagnesemia\n. Nephron \n2018 ;139 :359 -66\n. https://doi.org/10.1159/000488954 \n10.1159/000488954 29791908 \n3 Glaudemans B van der Wijst J Scola RH \nA missense mutation in the Kv1. 1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia\n. J Clin Investig \n2009 ;119 :936 -42\n. https://doi.org/10.1172/JCI36948 \n10.1172/JCI36948 19307729 \n4 Brunetti O Imbrici P Botti FM \nKv1. 1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature\n. Neurobiol Dis \n2012 ;47 :310 -21\n. https://doi.org/10.1016/j.nbd.2012.05.002 \n10.1016/j.nbd.2012.05.002 22609489 \n5 Eunson LH Rea R Zuberi SM \nClinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability\n. Ann Neurol \n2000 ;48 :647 -56\n. https://doi.org/10.1002/1531-8249(200010) \n10.1002/1531-8249(200010) 11026449 \n6 D’Adamo MC Hanna MG Di Giovanni G \nEpisodic ataxia type 1. Gene Reviews™[Internet] Internet \nSecond Edition \nNCBI Bookshelf , 2012 .\n7 Brownstein CA Beggs AH Rodan L \nClinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations\n. Neurogenetics \n2016 ;17 :11 -6\n. https://doi.org/10.1007/s10048-015-0460-2 \n10.1007/s10048-015-0460-2 26395884 \n8 D’Adamo MC Gallenmüller C Servettini I \nNovel phenotype associated with a mutation in the KCNA1 (Kv1. 1) gene\n. Front Physiol \n2015 ;5 :525 \nhttps://doi.org/10.3389/fphys.2014.00525 \n10.3389/fphys.2014.00525 25642194 \n9 Ellison DH \nThe voltage-gated K+ channel subunit Kv1. 1 links kidney and brain\n. J Clin Investig \n2009 ;119 :763 -6\n. https://doi.org/10.1172/JCI38835 \n10.1172/JCI38835 19348045 \n10 Viering DH de Baaij JH Walsh SB \nGenetic causes of hypomagnesemia, a clinical overview\n. Pediatric Nephrol \n2017 ;32 :1123 -35\n. https://doi.org/10.1007/s00467-016-3416-3 \n10.1007/s00467-016-3416-3\n\n",
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"title": "Neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous Kv1.1 N255D mutation with normal serum magnesium levels.",
"title_normalized": "neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous kv1 1 n255d mutation with normal serum magnesium levels"
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"abstract": "Murine typhus is a flea-borne disease of worldwide distribution with a recent reemergence in the United States of America. There are limited data about the presentation, treatment, and outcomes in the pregnant population. We report on two cases of murine typhus during pregnancy and review the literature to compile previously reported cases. A comprehensive search was performed via the PubMed database for published articles between 1990 and 2020. Seven articles met the criteria of symptomatic pregnant murine typhus infection. A total of 37 patients were identified. Patients frequently presented with a prolonged duration of fevers prior to presentation, headache, and elevated hepatic transaminases. The diagnosis was predominantly based on serology. Treatment varied. Overall, the pregnancy outcome was favorable. Murine typhus can mimic other pregnancy-related pathologies. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.;Department of Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.;Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.;Department of Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.",
"authors": "Tanabe|Melinda B|MB|0000-0003-3287-3327;Blanton|Lucas S|LS|;La Rosa|Mauricio|M|;Webb|Camille M|CM|",
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"fulltext": "\n==== Front\nPathogens\nPathogens\npathogens\nPathogens\n2076-0817\nMDPI\n\n10.3390/pathogens10020219\npathogens-10-00219\nArticle\nMurine Typhus Infection in Pregnancy: Case Series and Literature Review\nhttps://orcid.org/0000-0003-3287-3327\nTanabe Melinda B. 1*\nBlanton Lucas S. 1\nLa Rosa Mauricio 2\nWebb Camille M. 1\nStenos John Academic Editor\n1 Department of Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; lsblanto@utmb.edu (L.S.B.); cmwebbca@utmb.edu (C.M.W.)\n2 Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA; malarosa@utmb.edu\n* Correspondence: mbtanabe@utmb.edu\n18 2 2021\n2 2021\n10 2 21930 12 2020\n10 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nMurine typhus is a flea-borne disease of worldwide distribution with a recent reemergence in the United States of America. There are limited data about the presentation, treatment, and outcomes in the pregnant population. We report on two cases of murine typhus during pregnancy and review the literature to compile previously reported cases. A comprehensive search was performed via the PubMed database for published articles between 1990 and 2020. Seven articles met the criteria of symptomatic pregnant murine typhus infection. A total of 37 patients were identified. Patients frequently presented with a prolonged duration of fevers prior to presentation, headache, and elevated hepatic transaminases. The diagnosis was predominantly based on serology. Treatment varied. Overall, the pregnancy outcome was favorable. Murine typhus can mimic other pregnancy-related pathologies. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.\n\nmurine typhus\nendemic typhus\nopossums\npregnancy\ndoxycycline\nazithromycin\nRickettsia typhi\nrickettsioses\nfever in pregnancy\nCtenocephalides felis\n==== Body\n1. Introduction\n\nMurine typhus (MT) is a flea-borne disease caused by Rickettsia typhi [1]. MT has a worldwide distribution, but most reported infections arise from Southeast Asia, Northern Africa, Australia, China, and North America [2]. It is known to be prevalent in cities and ports where rats (Rattus spp.) and their fleas (Xenopsylla cheopis) thrive [3]. In the United States, the disease is endemic in Texas, Southern California, and Hawaii. In the past few years, there has been a reemergence of R. typhi infections in the United States (USA), likely due to shifts in the reservoir and vector [4,5]. Whereas the rat flea is the primary vector throughout the world, the cat flea (Ctenocephalides felis) is the contemporary vector in the USA [4,6]. Prior studies on the prevalence of R. typhi-infected fleas in cats have been contradictory, but even the low infection rates cannot exclude the role of cats in the transmission of the disease [7]. In Texas, R. typhi-infected cat fleas are carried mainly by opossums [4,7] (Figure 1).\n\nInfection is thought to be acquired when flea feces contaminated with the bacteria are inoculated into a wound (such as the flea bite) or mucous membranes (Figure 1). Other potential mechanisms are inhalation of infected flea feces or direct inoculation via a flea bite. The incubation period of most rickettsial diseases varies between 5 and 14 days. Infection in the general population tends to be mild, with patients presenting with an undifferentiated febrile illness. Severe manifestations, such as acute kidney injury, respiratory insufficiency, delirium, coma, and death may occur. Diagnosis is empirical, and it is confirmed by serology (usually with the indirect immunofluorescence assay (IFA)) demonstrating a fourfold increase in IgG (Immunoglobulin G) titers between acute- and convalescent-phase specimens. Studies from spotted fever group rickettsioses have shown that IgM is not more sensitive than the IgG isoform. IgM (Immunoglobulin M) is also subjected to higher cross-reactivity, making IgG more attractive for the diagnosis [8]. One of the main challenges regarding laboratory diagnosis is that reactive antibodies are usually not present during early illness [4]. Therefore, prompt clinical diagnosis and empiric treatment are important, as early treatment has been associated with good outcomes [9]. Other less common forms of diagnosis are polymerase chain reaction (PCR) amplification of rickettsial DNA and immunohistochemical demonstration of R. typhi from tissues or cultivation of the organisms in cell culture. Their high costs and need for specialized equipment limit their widespread use [8].\n\nThere have been efforts to alert physicians to the disease in the general population, as diagnosis relies on clinical suspicion. However, little is known about the incidence, presentation, treatment, and overall outcomes of MT during pregnancy. We herein present two cases of murine typhus during pregnancy from Texas. Subsequently, we reviewed the literature on all reported cases of symptomatic murine typhus during pregnancy in the past 30 years and summarized the clinical findings.\n\n2. Case Series\n\n2.1. Case Reports\n\n2.1.1. Case 1\n\nA 36-year-old G7P4 30-weeks-pregnant patient, with a past medical history of prior pregnancies complicated by preeclampsia, and chronic headaches, presented with fevers and worsening headaches (HAs) of 1-day duration. The HAs were frontal, dull, without radiation, 8/10 in intensity, and partially improved with acetaminophen. She was from East Texas. The family history and medications were noncontributory. On admission, the temperature was 38.3 °C, blood pressure 104/76 mmHg, heart rate 116 beats per minute (bpm), respiratory rate 18 respirations per minute (rpm), and the oxygen saturation was 96% at room air. The physical exam was appropriate for gestational age. The laboratories were significant for leukocytosis (15,140 cells/mm3 with bands), relative thrombocytopenia (196,000 cells/mm3 from a baseline of 258,000 cell/mm3), and hyponatremia (serum Na 130 mml/L). Her blood cultures, influenza swab, and urine culture were negative. There were no abnormalities on the fetal parameters or fetal ultrasound. She was given supportive care. On hospital day (HD) 4, the patient developed worsening HA, fever (39.4 °C), and respiratory distress (saturation of 88–90% on 4 L of supplemental oxygen). Her blood work revealed worsening thrombocytopenia (138,000 cells/mm3) and an abnormal liver profile (alkaline phosphatase (ALK) 40 IU/L, alanine aminotransferase (ALT) 76 IU/L, and aspartate aminotransferase (AST) 100 IU/L). Computed tomography of the chest showed no pulmonary embolism but demonstrated diffuse septal thickening and patchy central ground-glass opacities with reactive lymphadenopathy. An echocardiogram was unremarkable. She was started empirically on furosemide for fluid overload and ceftriaxone plus azithromycin for community-acquired pneumonia on HD 6. A respiratory PCR panel was negative for common pathogens. On HD 9, the patient continued to be febrile. The Infectious Diseases Consultation Service recommended continuing with azithromycin and obtain serologies for murine typhus. Due to persistent headaches, a magnetic resonance imaging of the brain without contrast and a magnetic resonance venography were performed, showing no acute intracranial abnormality and no evidence of venous sinus thrombosis. A lumbar puncture was performed, and analysis of the cerebrospinal fluid (CSF) revealed pleocytosis (White Blood Cell count (WBC) 120 cells/μL, 44% neutrophils), hypoglycorrhachia (44 mg/dL), and an elevated protein level (81 mg/dL). The bacterial, fungal, and acid-fast bacilli cultures were negative. On HD 10, MT serology revealed an IgM titer of 1:1024 and an IgG titer of 1:512 (Rickettsia IFA IgM and IgG kit, Semi-Quantitative Indirect Fluorescent Antibody, Focus Diagnostics Inc., Cypress, CA, USA). The patient’s symptoms improved, and a course of azithromycin was completed. The subsequent serology, performed 27 days after the last serology, revealed an MT IgM titer of >1:1024 and an IgG titer of 1:256 compatible with probable but not definite, MT, as a fourfold change in titers could not be confirmed. She had no further complications during her pregnancy, delivering a healthy baby via cesarean section due to non-reassuring fetal heart tones at 39 weeks.\n\n2.1.2. Case 2\n\nA 20-year-old G1P0 patient at 12 weeks of gestation with poor prenatal care, presented with 7 days of fever, headaches, myalgias, and a maculopapular rash. She was from Southeast Texas, and she reported contact with a flea-infested stray kitten. She had no significant family or social history. She was not taking any medications. On admission, her temperature was 38.5 °C, heart rate 124 bpm, blood pressure 131/78 mmHg, respiratory rate 18 rpm, and the oxygen saturation was 97% at room air. The physical exam was relevant for mild bilateral cervical lymphadenopathy, right leg tenderness to palpation without edema, and a maculopapular rash on her upper extremities. The laboratories demonstrated hyponatremia (Na 128 mmol/L), hypokalemia (K 3.2 mmol/L), glucose 94 mg/dL, elevated transaminases (ALT 216, AST 152 IU/L), bandemia (WBC 7.86 cells/mm3 with bands), and thrombocytopenia (PLT 145,000 cells/mm3, baseline 216,000 cells/mm3). The serologies for parvovirus, toxoplasmosis, bartonellosis, CMV, HIV, syphilis, and viral hepatitis were non-reactive. The blood cultures were negative. The urinalysis revealed 17 WBC and mild proteinuria. An abdominal ultrasound showed a normal liver and gallbladder. A lower extremity ultrasound showed no deep venous thrombosis. The fetal ultrasound and hemodynamic parameters were within normal limits. A lumbar puncture was performed, and the laboratory studies of the CSF were unremarkable. On HD 4, the patient was empirically treated with doxycycline, and sera were tested for typhus group antibodies given high concerns for MT. Her fever, rash, and other symptoms resolved. The R. typhi IFA demonstrated an IgM titer of 1:512 and an IgG of 1:128 (Rickettsia IFA IgM and IgG kit, Semi-Quantitative Indirect Fluorescent Antibody, Focus Diagnostics Inc., Cypress, CA, USA). The convalescent serum obtained 15 days after, showed an IgM titer of 1:1024 and an IgG of 1:1024, confirming the diagnosis of murine typhus. She subsequently delivered a healthy baby at 39 weeks via cesarean section due to fetal intolerance to labor.\n\n3. Materials and Methods\n\nA PubMed search was performed using the terms “murine typhus” “pregnancy”, “endemic typhus”, “R. mooseri”, and “R. typhi”. The only articles considered were those based on human symptomatic infection during pregnancy, electronically available in English, and published between January 1990 and November 2020. Exclusion criteria were asymptomatic murine typhus in pregnancy (based only on seropositivity) and undiagnosed febrile illness in pregnancy. Data were extracted based on the number of patients, demographics, past medical history, presentation, diagnosis, treatment, and overall pregnancy outcome after infection. Poor outcome was defined as stillborn, prematurity (<35 weeks), and fetal growth restriction (birth weight < 10th percentile). Full term was defined as delivery between 37–42 gestational weeks. Maternal comorbidity was defined as the presence of diabetes, hypertension, asthma, thyroid disorder, obesity, mental health conditions, co-infection with another pathogen (e.g., malaria, dengue, and scrub typhus), and substance and/or tobacco abuse [10]. Fever was defined as T > 38 °C. Lastly, hyponatremia was defined as < 134 mEq/L, absolute thrombocytopenia as PLT < 150,000 cells/mm3, and transaminitis as ALT > 40 IU/L. Information from the aforementioned cases was included in the analysis. A literature review was later performed based on available published data.\n\n4. Results\n\nResult Data\n\nSeven articles were found describing MT during pregnancy. Of those, five were case reports [11,12,13,14,15,16,17], and two were based on observational population studies [15,16].\n\nData from the reported cases are presented in Table 1. A total of 37 pregnant patients with fever due to murine typhus were identified. Overall, there was heterogeneity in gestational age during infection, with 7/22 patients presenting during the first trimester. The origins of the populations of these reports were diverse: Southeast Asia (n: 29), USA (n: 6), Australia (n: 1), and the Middle East (n: 1). The age ranged from 17 to 36 years. Maternal comorbidities were present mainly in the Asian studies, corresponding to smoking and co-infections with malaria, dengue, pyelonephritis, and scrub typhus. Only a few studies reported risk factors for infection (3/7).\n\nAll patients presented with fever (>38.5 °C), and the median for the duration of fever prior to admission/diagnosis was 7 days. They frequently presented with headache (21/22, 95%) and elevated liver enzymes (8/8, 100%). Diagnosis of MT was mainly based on serology, although some were positive by PCR. PCR results were exclusively reported from Asia, while cell-free next-generation sequencing was used twice in the USA.\n\nTreatment for MT varied. The use of erythromycin or ampicillin was noticed in earlier reports, while azithromycin and doxycycline were seen in later reports. From the Asian reports, eight cases were not treated and had spontaneous resolution with good outcomes. With the exception of the studies originating from Southeast Asia, there were no poor pregnancy outcomes noted in the USA, Australia, or Cyprus [11,12,13,14]. In the study by McGready et al., three patients had a poor outcome: one stillborn, one born prematurely, and two with low birth weight. Five patients in this study had other comorbidities (e.g., malaria co-infection, and smoking history) [15]. In the study by Chansamouth et al., a total of 15 patients were found with MT by serology or PCR. Most of the patients had a relatively uncomplicated pregnancy, except for two cases that had preterm births and coincidentally did not receive any anti-rickettsial treatments [16].\n\n5. Discussion and Literature Review\n\nArthropod-related infections are on the rise globally. From 2004 until 2016, the overall reported cases in the USA have tripled, with a total of 642,602 cases [18]. The national prevalence of MT is not accurately known due to variable reporting and underdiagnosis. In Texas, there have been 3507 cases reported from 2008 to 2018, while in California, 1185 cases were diagnosed between 2001 and 2020 [5,19]. The numbers are expected to be even higher in Southeast Asia. Accurate epidemiological data are lacking, but prevalence studies in the area range from 0–21.5% [20]. Geographical, socio-economic, vector distribution, and increased interest in the field are some of the reasons for these findings [20]. However, due to a lack of accurate point-of-care diagnostic methods as well as clinical recognition, they were often underreported. Studies investigating febrile illness during pregnancy differ on the main causal agent. In the Thai–Burmese population, the most common agent was malaria, compared to Laos, where dengue was more frequent [16,21]. However, nearly 5–10% of the patients had a co-infection with a rickettsial/rickettsial-like organism and up to 12% of patients had a rickettsial/rickettsial-like monoinfection [16,21,22]. In the past several years, there has been an increase in reports describing scrub typhus (an arthropod-borne disease caused by Orientia tsutsugamushi) during pregnancy associated with poor fetal outcomes [16,21,23]. Aside from a few observational studies, there are limited data regarding murine typhus during pregnancy. Unlike other tropical infections, such as leptospirosis and malaria, there are no data suggesting an increased incidence of MT in pregnancy [15,16].\n\nIn pregnancy, MT can mimic serious conditions that could impair the pregnancy if not addressed early. The differential diagnosis includes typical or atypical preeclampsia, given the presence of headache, thrombocytopenia, and abnormal liver function tests [6,21]. In up to 15% of patients, hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP) can present without concomitant hypertension or proteinuria [14]. Chorioamnionitis and other infectious etiologies, such as those belonging to Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes viruses (TORCH) syndrome and arthropod-borne illnesses (e.g., scrub typhus, malaria, dengue, and Zika), could present similarly to MT. The disease should be high on the differential diagnosis when there is a history of exposure and knowledge of local epidemiology. Based on the data herein presented, MT does not seem to occur preferentially at any particular gestational age. Based on our findings, most patients present with a history of fever (>7 days) and remain hemodynamically stable. They present with headache, myalgias, arthralgia, which may be accompanied by a faint maculopapular rash. The most common abnormal labs are elevated liver enzymes and thrombocytopenia. The confirmatory diagnosis was mainly based on serology and PCR amplification of rickettsial DNA. Recently, the use of microbial cell-free DNA in human plasma has become an attractive option for the diagnosis of MT, given the potential of higher sensitivity than conventional molecular diagnostic tests such as PCR [17,24,25]. However, this novel modality is not widely available as a standard diagnostic test.\n\nIn regard to the pregnancy outcome after these infections, natural history appears to be benign. In one study on the Thai–Burmese border, 33% of patients (n: 4) had poor prenatal outcome [15]. It is known that in resource-limited tropical countries, arthropod-borne infections in pregnancy are associated with poor outcomes [15,22]. In regard to MT during pregnancy, the relationship is less clear. Some observational studies in Southeast Asia have associated MT with low birth weight and stillbirths; however, the small sample makes it difficult to prove an independent association [21]. The pathogenesis of possible worse outcomes in pregnancy during rickettsial infections, if any, is unknown. Studies have speculated that endothelial damage causes a circulatory impediment, likely due to thrombotic occlusion or coagulopathy [26]. On the other hand, animal studies have shown no passage of the bacteria via placenta or through breastfeeding even when high blood concentrations of bacteria were noticed [6,27]. Based on our analysis, poor outcomes with R. typhi infections were noted only in limited-resource countries, where other cofounders such as poor nutrition, lack of perinatal care, and co-infections are present. In our review, there did not appear to be any differences in pregnancy outcomes and stage of pregnancy when patients were infected.\n\nIn the general population, first-line therapy for all rickettsioses, including MT, is tetracyclines. The use of tetracyclines in pregnancy has been an area of debate. Prior studies associating discoloration of developing permanent teeth in children and hepatic failure in pregnant women were based on the use of older formulations (e.g., tetracycline hydrochloride, oxytetracycline) but not doxycycline. Older tetracyclines caused discoloration of the primary teeth when taken during the 4th–5th month of gestation [6]. Large-scale observational studies and systematic review of the literature shows no increase in the incidence of congenital malformations with doxycycline [28,29]. Furthermore, case-control studies have shown that there was no significant difference in congenital abnormalities between the 2nd and 3rd month of gestation (the organogenesis period) with the exception of two cases with neural tube defect [30]. Despite all these recent data, the federal drug administration considers doxycycline a category D drug. Based on a systematic review of published data, the authors concluded that therapeutic doses of doxycycline are unlikely to have teratogenic risk, but more data are needed to strengthen the evidence for firmer recommendations [31].\n\nAlthough previously reported success with macrolides has made them an attractive alternative during pregnancy [15], a recent prospective randomized trial based on 216 non-pregnant patients showed that doxycycline was superior to azithromycin for uncomplicated MT. Azithromycin was inferior based on fever clearance time, the time-temperature area under the curve, and frequency of treatment failure [32].\n\nReports documenting the treatment of MT during pregnancy overwhelmingly use agents other than doxycycline. One study, analyzing data of patients with MT and scrub typhus, showed that azithromycin was the most frequently administered therapy (66% of cases), while ciprofloxacin and others with no anti-rickettsial activity (i.e., ceftriaxone, ertapenem, and piperacillin–tazobactam) were used to treat the remaining cases. Although unable to adjust data based on the severity of the disease, treatment delay, pregnancy stage, or recurrent illness, patients with shorter fever clearance time were higher in the azithromycin group as compared to other non-tetracycline antibiotics [15]. There was a trend toward less poor neonatal outcomes in those treated with azithromycin as compared to those not treated at all, although the difference was not statistically significant. There was also a higher proportion of normal neonatal outcomes in those treated as compared to those who were not. Chloramphenicol has also been used in rickettsial diseases, but it should be noted that the drug crosses the placenta and is excreted in milk. Side effects that preclude its use are aplastic anemia and “gray baby syndrome” in neonates.\n\nBased on the data available, it is not possible to make a conclusion on the optimal treatment for MT in pregnancy. The data favor the safety of doxycycline during pregnancy, which is the first-line therapy for the disease in non-pregnant patients. There is no specific protocol for the prevention of murine typhus. Infection is thought to occur due to the inoculation of infected flea feces into wounds or mucous membranes. Therefore, avoidance of the vectors and their hosts is recommended [33]. Experts recommend controlling flea-infested pets and rat populations around residencies and businesses. There are numerous commercial products available for use on pets and around homes [34].\n\nPassive immunization has been observed in the offspring of rats via colostrum or milk, regardless of the maternal antibody titer. However, the titers were usually undetectable by week 4 after birth [27]. Neonatal studies assessing the duration and protection of MT by maternal antibodies are lacking. There are currently no vaccines available to prevent MT, and prior efforts attempting to target other rickettsioses (e.g., Rocky Mountain spotted fever and louse-borne epidemic typhus) have been partially successful in animal models but inadequate for human use [1]. Vaccine development is imperative, as rickettsioses as a group have biological weapon potential given the aerosolized particle stability, high virulence, non-specific clinical diagnosis, inefficient diagnostic techniques, and low-level immunity [1].\n\nThe main limitation of this review is that the analyzed manuscripts were case reports and small prospective cohort studies; therefore, they are subject to recall and sampling bias as well as multiple confounding factors. Regarding our case reports, case #1 was defined as probable MT, not definite MT, as a fourfold change could not be observed. We were unable to test the specimens for PCR, as samples were not banked for a repository. Lastly, R. felis and R. typhi are sympatric and the possibility of some cases caused by R. felis instead of R. typhi is reasonable. However, prior studies in the Galveston area have shown a relatively low prevalence of R. felis in surveillance studies [4,7]. Furthermore, data from at least one person from Galveston during the disease’s local reemergence confirm that R typhi is circulating in humans [35].\n\nLarge-scale cohort studies exclusively studying MT during pregnancy are needed to fill gaps in knowledge regarding presentation, overall pregnancy outcome, and effectiveness of treatment during a particularly vulnerable state. This article provides an overview of MT presentation, diagnosis, and treatment in the pregnant population for the general clinician to consider, as it can mimic other pregnancy-related diseases requiring vastly different treatments.\n\n6. Conclusions\n\nMurine typhus in pregnancy is underreported. It can mimic other pregnancy-related pathologies. As noted in this literature review, confirmatory diagnosis is most often based on serology. The treatment varied, although doxycycline and azithromycin were the most frequently used. Overall, the pregnancy outcome seems to be favorable. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.\n\nAuthor Contributions\n\nAll authors contributed to the manuscript; conceptualization—M.B.T. and L.S.B.; writing—M.B.T. and L.S.B.; review and editing—M.B.T., C.M.W., L.S.B., and M.L.R. 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\nOur institution does not require ethical approval for reporting individual or small case series.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nThe data presented in this study is contained within the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 “R. typhi transmission cycle.” R. typhi can be transmitted via different vectors depending on the geographic location. The R. typhi-infected rat fleas are involved in the transmission via rats. Infected cat fleas have been found in opossums and cats. Both of the vectors play a role in the transmission to humans. Infection reaches the human via infected flea feces inoculated in mucosa or wounds.\n\npathogens-10-00219-t001_Table 1 Table 1 Published case series about murine typhus in pregnancy (1992–2020).\n\nSTUDY INFORMATION\t\nAuthor-Year\tGraves-1992\tKoliou-2007\tGutierrez-2010\tJolley-2010\tMcGready-2010\tChansamouth-2016\tTanabe-2019\tStafford-2020\t\nLocation (Country)\tAustralia\tCyprus\tUSA\tUSA\tThai-Burmanese border\tLaos\tUSA\tUSA\t\nNumber of patients\t1\t1\t1\t1\t14\t15\t2\t2\t\nMATERNAL HEALTH\t\nAge (mean/range)\t17\t30\t26\t33\t27 (16–36)\t\t28 (20–36)\t29 (24–34)\t\nGestational Age (mean/range)\t23\t30\t26\t32\t21 (7–39)\t39 (35–40)\t21 (12–30)\t22 (13–31)\t\nMaternal comorbidities (n) **\t\t\t✕\t✕\t✓ (5)\t✓ (5)\t✓ (1)\t✕\t\nPrior pregnancies (n)\t✕\t\t✕\t✕\t✓ (11)\t\t✓ (1)\t✓ (1)\t\nRisk factor for MT\t\t\t\tcats, opposums\t\t\tcats\tpets and fleas\t\nCLINICAL COURSE\t\nHeadache (n)\t✓\t✓\t✓\t✓\t✓ (13)\t\t✓ (2)\t✓ (2)\t\nRash (n)\t✓\t✓\t✕\t✓\t✕\t\t✓ (1)\t✓ (1)\t\nFever (n)\t✓\t✓\t✓\t✓\t✓\t\t✓ (2)\t✓ (2)\t\nTransaminitis (n)\t✓\t✓\t✓\t✓\t\t\t✓ (2)\t✓ (2)\t\nHyponatremia (n) #\t✕\t✕\t✓\t\t\t\t✓ (2)\t✕\t\nThrombocytopenia (n)\t✓\t✕\t✕\t✓\t\t\t✓ (2)\t✓ (1)\t\nDiagnosis\tserology\tserology\tserology\tserology\tserology, PCR\tserology, PCR\tserology\tmicrobial cell-free DNA\t\nTreatment\terythromycin\terythromycin\tampicillin\tazithromycin\tazithromycin\tazithromycin\tazithromycin, doxycycline\tazithromycin, doxycycline\t\nFETUS HEALTH\t\nBorn at term (n) ***\t✓ (1)\t✓ (1)\t✓ (1)\t✓ (1)\t✓ (10)\t✓ (8)\t✓ (2)\t✓ (1)\t\nPoor outcome (n) *\t✕\t✕\t✕\t✕\t✓ (4)\t✓ (2)\t✕\t✕\t\nREFERENCE\t11\t12\t13\t14\t15\t16\tn/a\t17\t\nFootnote: ✓: present ✕: absent.* Poor outcome: stillborn, abortion, prematurity (<35 weeks), and fetal growth restriction (birth weight < 10th percentile). ** Comorbidities: diabetes mellitus, hypertension, substance abuse, tobacco use, co-infections, dyslipidemia, heart disease, eclampsia/preeclampsia. *** TERM: 37–42 weeks. # Hyponatremia < 134 meq/dL, Absolute thrombocytopenia PLT < 150,000 cells/cm3, Transaminitis ALT > ULN (40). (BLANK): Information not given. The table was filled based on the best information provided by the article. Totals do not equal 100% as some patients’ data were missing.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Walker D.H. The realities of biodefense vaccines against Rickettsia Vaccine 2009 27 Suppl. 4 D52 D55 10.1016/j.vaccine.2009.07.045 19837287\n2. Tsioutis C. Zafeiri M. Avramopoulos A. Prousali E. Miligkos M. Karageorgos S.A. Clinical and laboratory characteristics, epidemiology, and outcomes of murine typhus: A systematic review Acta Trop. 2017 166 16 24 10.1016/j.actatropica.2016.10.018 27983969\n3. Civen R. Ngo V. Murine Typhus: An Unrecognized Suburban Vectorborne Disease Clin. Infect. Dis. 2008 46 913 918 10.1086/527443 18260783\n4. Blanton L.S. Idowu B.M. Tatsch T.N. Henderson J.M. Bouyer D.H. Walker D.H. Opossums and Cat Fleas: New Insights in the Ecology of Murine Typhus in Galveston, Texas Am. J. Trop. Med. Hyg. 2016 95 457 461 10.4269/ajtmh.16-0197 27273642\n5. Texas Department of State Health Services, Infectious Disease Control Unit Flea-Borne Typhus Statistics. Statistics 2017 Available online: https://www.dshs.texas.gov/IDCU/disease/murine_typhus/Statistics.aspx (accessed on 8 December 2020)\n6. Dotters-Katz S.K. Kuller J. Heine R.P. Arthropod-Borne Bacterial Diseases in Pregnancy Obstet. Gynecol. Surv. 2013 68 635 649 10.1097/OGX.0b013e3182a5ed46 25102120\n7. Blanton L.S. Vohra R.F. Fistein L. Quade B. Walker D.H. Bouyer D.H. Rickettsiae Within the Fleas of Feral Cats in Galveston, Texas Vector-Borne Zoonotic Dis. 2019 19 647 651 10.1089/vbz.2018.2402 30835649\n8. Paris D.H. Dumler J.S. State of the art of diagnosis of rickettsial diseases: The use of blood specimens for diagnosis of scrub ty-phus, spotted fever group rickettsiosis, and murine typhus Curr. Opin. Infect. Dis. 2016 29 433 439 10.1097/QCO.0000000000000298 27429138\n9. Pieracci E.G. Evert N. Drexler N.A. Mayes B. Vilcins I. Huang P. Campbell J. Behravesh C.B. Paddock C.D. Fatal Flea-Borne Typhus in Texas: A Retrospective Case Series, 1985–2015 Am. J. Trop. Med. Hyg. 2017 96 1088 1093 10.4269/ajtmh.16-0465 28500797\n10. Fridman M. Korst L.M. Chow J. Lawton E. Mitchell C. Gregory K.D. Trends in Maternal Morbidity Before and During Pregnancy in California Am. J. Public Health 2014 104 S49 S57 10.2105/AJPH.2013.301583 24354836\n11. Graves S.R. Banks J. Dwyer B. King G.K. A case of murine typhus in Queensland Med. J. Aust. 1992 156 650 651 10.5694/j.1326-5377.1992.tb121464.x 1625620\n12. Koliou M. Christoforou C. Soteriades E.S. Murine typhus in pregnancy: A case report from Cyprus Scand. J. Infect. Dis. 2007 39 625 628 10.1080/00365540601124047 17577832\n13. Gutierrez L. Surani S. Nelson D. El-Milady N. Murine Typhus in Pregnancy Am. J. Med Sci. 2010 339 378 379 10.1097/MAJ.0b013e3181cc8e9b 20186042\n14. Jolley J.A. Pelayo R. Hatfield T.J. McNulty J. Murine Typhus in a Pregnant Woman Obstet. Gynecol. 2010 116 Suppl. 2 541 543 10.1097/AOG.0b013e3181e24bea 20664448\n15. Mcgready R. Prakash J.A.J. Benjamin S.J. Watthanaworawit W. Anantatat T. Tanganuchitcharnchai A. Ling C.L. Tan S.O. Ashley E.A. Pimanpanarak M. Pregnancy Outcome in Relation to Treatment of Murine Typhus and Scrub Typhus Infection: A Fever Cohort and a Case Series Analysis PLoS Negl. Trop. Dis. 2014 8 e3327 10.1371/journal.pntd.0003327 25412503\n16. Chansamouth V. Thammasack S. Phetsouvanh R. Keoluangkot V. Moore C.E. Blacksell S.D. Castonguay-Vanier J. Dubot-Pérès A. Tangkhabuanbutra J. Tongyoo N. The Aetiologies and Impact of Fever in Pregnant Inpatients in Vientiane, Laos PLoS Negl. Trop. Dis. 2016 10 e0004577 10.1371/journal.pntd.0004577 27050192\n17. Stafford I.A. Centeno F.H. Al Mohajer M. Parkerson G. Woc-Colburn L. Burgos-Lee A.J. Rac M. Dunn J. Muldrew K. Successful Detection of Unrecognized Rickettsia typhi in Pregnancy Using Cell-Free Next-Generation Sequencing Case Rep. Obstet. Gynecol. 2020 2020 1 7 10.1155/2020/6767351 32547799\n18. Rosenberg R. Lindsey N.P. Fischer M. Gregory C.J. Hinckley A.F. Mead P.S. Paz-Bailey G. Waterman S. Drexler N. Kersh G. Vital Signs: Trends in Reported Vectorborne Disease Cases—United States and Territories, 2004–2016 MMWR Morb. Mortal. Wkly. Rep. 2018 67 496 501 10.15585/mmwr.mm6717e1 29723166\n19. California Department of Public Health, Vector Borne Disease Section Typhus (Flea-Borne) 2020 Available online: https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/Typhus.aspx (accessed on 28 January 2021)\n20. Aung A.K. Spelman D.W. Murray R.J. Graves S. Paintain L.S. Willey B. Kedenge S. Sharkey A. Kim J. Buj V. Rickettsial Infections in Southeast Asia: Implications for Local Populace and Febrile Returned Travelers Am. J. Trop. Med. Hyg. 2014 91 451 460 10.4269/ajtmh.14-0191 24957537\n21. Mcgready R. Ashley E.A. Wuthiekanun V. Tan S.O. Pimanpanarak M. Viladpai-Nguen S.J. Jesadapanpong W. Blacksell S.D. Peacock S.J. Paris D.H. Arthropod Borne Disease: The Leading Cause of Fever in Pregnancy on the Thai-Burmese Border PLoS Negl. Trop. Dis. 2010 4 e888 10.1371/journal.pntd.0000888 21103369\n22. Bonell A. Lubell Y. Newton P.N. Crump J.A. Paris D.H. Estimating the burden of scrub typhus: A systematic review PLoS Negl. Trop. Dis. 2017 11 e0005838 10.1371/journal.pntd.0005838 28945755\n23. Rajan S.J. Sathyendra S. Mathuram A.J. Scrub typhus in pregnancy: Maternal and fetal outcomes Obstet. Med. 2016 9 164 166 10.1177/1753495X16638952 27829876\n24. Camargo J.F. Ahmed A.A. Lindner M.S. Morris M.I. Anjan S. Anderson A.D. Prado C.E. Dalai S.C. Martinez O.V. Komanduri K.V. Next-generation sequencing of microbial cell-free DNA for rapid noninvasive diagnosis of infectious diseases in immun-ocompromised hosts F1000Research 2019 8 1194 10.12688/f1000research.19766.3 31814964\n25. Han D. Li R. Shi J. Tan P. Zhang R. Li J. Liquid biopsy for infectious diseases: A focus on microbial cell-free DNA sequencing Theranostics 2020 10 5501 5513 10.7150/thno.45554 32373224\n26. Paris D. Chansamouth V. Nawtaisong P. Löwenberg E. Phetsouvanh R. Blacksell S. Lee S. Dondorp A. Newton P. Van Der Poll T. Coagulation and inflammation in scrub typhus and murine typhus—A prospective comparative study from Laos Clin. Microbiol. Infect. 2012 18 1221 1228 10.1111/j.1469-0691.2011.03717.x 22192733\n27. Arango-Jaramillo S. Wisseman C.L. Jr. Azad A.F. Newborn Rats in the Murine Typhus Enzootic Infection Cycle: Studies on Transplacental Infection and Passively Acquired Maternal Antirickettsial Antibodies Am. J. Trop. Med. Hyg. 1988 39 391 397 10.4269/ajtmh.1988.39.391 3142287\n28. Cooper W.O. Hernandez-Diaz S. Arbogast P.G. Dudley J.A. Dyer S.M. Gideon P.S. Hall K.S. Kaltenbach L.A. Ray W.A. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations Paediatr. Périnat. Epidemiol. 2008 23 18 28 10.1111/j.1365-3016.2008.00978.x\n29. Cross R. Ling C. Day N.P.J. Mcgready R. Paris D.H. Revisiting doxycycline in pregnancy and early childhood—Time to rebuild its reputation? Expert Opin. Drug Saf. 2016 15 367 382 10.1517/14740338.2016.1133584 26680308\n30. Czeizel A.E. Rockenbauer M. Teratogenic study of doxycycline Obstet. Gynecol. 1997 89 524 528 10.1016/S0029-7844(97)00005-7 9083306\n31. Research Center for Drug Evaluation and Research Bioterrorism and Drug Preparedness—Doxycycline Use by Pregnant and Lactating Women 2017 Available online: https://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm131011.htm (accessed on 8 December 2020)\n32. Newton P.N. Keolouangkhot V. Lee S.J. Choumlivong K. Sisouphone S. Choumlivong K. Vongsouvath M. Mayxay M. Chansamouth V. Davong V. A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus Clin. Infect. Dis. 2019 68 738 747 10.1093/cid/ciy563 30020447\n33. Blacksell S.D. Robinson M.T. Newton P.N. Day N.P.J. Laboratory-acquired Scrub Typhus and Murine Typhus Infections: The Argument for a Risk-based Approach to Biosafety Requirements for Orientia tsutsugamushi and Rickettsia typhi Laboratory Activities Clin. Infect. Dis. 2018 68 1413 1419 10.1093/cid/ciy675\n34. Rust M.K. Dryden M.W. The Biology, Ecology, and Management of the Cat Flea Annu. Rev. Èntomol. 1997 42 451 473 10.1146/annurev.ento.42.1.451 9017899\n35. Blanton L.S. Vohra R.F. Bouyer D.H. Walker D.H. Reemergence of Murine Typhus in Galveston, Texas, USA, 2013 Emerg. Infect. Dis. 2015 21 484 486 10.3201/eid2103.140716 25695758\n\n",
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"keywords": "Ctenocephalides felis; Rickettsia typhi; azithromycin; doxycycline; endemic typhus; fever in pregnancy; murine typhus; opossums; pregnancy; rickettsioses",
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"title": "Murine Typhus Infection in Pregnancy: Case Series and Literature Review.",
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"abstract": "BACKGROUND\nLoperamide is an opioid available over the counter and in prescription form. Loperamide functions as a μ-agonist within the enteric nervous system to slow intestinal motility. Its antidiarrheal properties and primarily peripheral activity make loperamide an important tool in the management of inflammatory bowel disease.\n\n\nMETHODS\nA 42-year-old man was found unconscious in cardiac arrest, and emergency medical personnel restored normal sinus rhythm. Family reported complaints of abdominal pain and that he \"went through a lot\" of loperamide. In the emergency department, the patient exhibited symptoms consistent with an opioid overdose. Mental status improved after administration of naloxone, an opioid antagonist. An electrocardiogram revealed a prolonged QTc interval, which progressed into Torsades de Pointes rhythm during admission. The patient succumbed from hypoxic brain injury, and there was evidence of acute pancreatitis at autopsy. Loperamide and desmethylloperamide (loperamide metabolite) were detected in blood samples. Cause of death was ruled loperamide toxicity.\n\n\nCONCLUSIONS\nBecause of reduced central nervous system activity and associated euphoria at therapeutic doses, loperamide abuse is rarely reported. This case demonstrates that an overdose on loperamide can occur in patients seeking symptom alleviation, and may mimic the presentation of opioid overdose.",
"affiliations": "From the Western Michigan University Homer Stryker M.D. School of Medicine, Department of Pathology, Kalamazoo, MI.",
"authors": "Strzyzewski|Lauren|L|;Key|Phillip|P|;Jones|Prentiss|P|;Prahlow|Joseph A|JA|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Loperamide Abuse and Its Sequelae.",
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"abstract": "Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1-12.8) and 18.7 months (95% CI: 14.6-22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified a pathological complete response (pCR) in four patients (7%) and Ki67 expression in post-chemotherapy tumor specimens, inferior to 15% (median value), was associated with better PFS and survival. In the present study, the EDP-M regimen is confirmed to have a limited efficacy. Early disease progression does not mean treatment inefficacy. Surgery of residual disease in partially responding patients allows for the detection of pCR in few of them and this condition is predictive of long-term survival. Ki67 expression of post-chemotherapy residual disease could be an additional prognostic factor that deserves to be studied further.",
"affiliations": "Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Radiology Unit, ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.;Urology Unit, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia at ASST Spedali Civili of Brescia, 25123 Brescia, Italy.;Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, 10043 Turin, Italy.;Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.;Surgical Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy.",
"authors": "Laganà|Marta|M|;Grisanti|Salvatore|S|;Cosentini|Deborah|D|;Ferrari|Vittorio Domenico|VD|;Lazzari|Barbara|B|;Ambrosini|Roberta|R|;Sardini|Chiara|C|;Volta|Alberto Dalla|AD|0000-0001-8009-7663;Palumbo|Carlotta|C|;Poliani|Pietro Luigi|PL|0000-0002-5662-8978;Terzolo|Massimo|M|0000-0002-4171-2851;Sigala|Sandra|S|0000-0003-3294-4121;Tiberio|Guido Alberto Massimo|GAM|0000-0002-7635-1179;Berruti|Alfredo|A|",
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"doi": "10.3390/cancers12040941",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n10.3390/cancers12040941\ncancers-12-00941\nArticle\nEfficacy of the EDP-M Scheme Plus Adjunctive Surgery in the Management of Patients with Advanced Adrenocortical Carcinoma: The Brescia Experience\nLaganà Marta 1† https://orcid.org/0000-0001-6922-1934Grisanti Salvatore 1† Cosentini Deborah 1 Ferrari Vittorio Domenico 1 Lazzari Barbara 1 https://orcid.org/0000-0002-4082-2303Ambrosini Roberta 2 Sardini Chiara 1 https://orcid.org/0000-0001-8009-7663Dalla Volta Alberto 1 https://orcid.org/0000-0002-6165-5276Palumbo Carlotta 3 https://orcid.org/0000-0002-5662-8978Poliani Pietro Luigi 4 https://orcid.org/0000-0002-4171-2851Terzolo Massimo 5 https://orcid.org/0000-0003-3294-4121Sigala Sandra 6 https://orcid.org/0000-0002-7635-1179Tiberio Guido Alberto Massimo 7 https://orcid.org/0000-0002-2952-9560Berruti Alfredo 1* 1 Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, 25123 Brescia, Italy; m.lagana001@unibs.it (M.L.); salvatore.grisanti@unibs.it (S.G.); d.cosentini@unibs.it (D.C.); vittorio.ferrari@asst-spedalicivili.it (V.D.F.); milaro66@libero.it (B.L.); c.sardini@unibs.it (C.S.); alberto.dallavolta@gmail.com (A.D.V.)\n2 Radiology Unit, ASST Spedali Civili, 25123 Brescia, Italy; roberta.ambrosini@asst-spedalicivili.it\n3 Urology Unit, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia at ASST Spedali Civili of Brescia, 25123 Brescia, Italy; c.palumbo003@unibs.it\n4 Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy; luigi.poliani@unibs.it\n5 Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, 10043 Turin, Italy; massimo.terzolo@unito.it\n6 Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; sandra.sigala@unibs.it\n7 Surgical Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili di Brescia, 25123 Brescia, Italy; guido.tiberio@unibs.it\n* Correspondence: alfredo.berruti@unibs.it; Tel.: +030-399-5410† These authors contributed equally to this work and are co-primary authors.\n\n\n10 4 2020 \n4 2020 \n12 4 94105 3 2020 08 4 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1–12.8) and 18.7 months (95% CI: 14.6–22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified a pathological complete response (pCR) in four patients (7%) and Ki67 expression in post-chemotherapy tumor specimens, inferior to 15% (median value), was associated with better PFS and survival. In the present study, the EDP-M regimen is confirmed to have a limited efficacy. Early disease progression does not mean treatment inefficacy. Surgery of residual disease in partially responding patients allows for the detection of pCR in few of them and this condition is predictive of long-term survival. Ki67 expression of post-chemotherapy residual disease could be an additional prognostic factor that deserves to be studied further.\n\nadrenocortical tumortreatmentEDPmitotane\n==== Body\n1. Introduction\nAdrenocortical carcinoma (ACC) is a rare tumor with an estimated incidence in Western countries of 0.7–2 new cases per million population per year [1].\n\nSurgery is the mainstay of therapy and represents the only treatment modality able to offer a chance of a cure. Unfortunately, in half of patients the disease is diagnosed at an advanced stage and most patients radically resected are destined to relapse within the first 2 years [1,2]. Advanced ACC patients, not eligible for surgery, are referred to systemic antineoplastic therapies. For decades, mitotane has been the reference drug for ACC. This compound is efficacious when serum levels reach the so-called therapeutic range (14–20 mg/L) [3], which is not usually attained before 2–3 months of therapy. The delayed efficacy of mitotane provides the main rationale for its association with chemotherapy. Chemotherapy in fact exerts a cytotoxic effect in the first months of treatment when mitotane levels are not in the therapeutic range [1]. Mitotane was also found to potentiate the cytotoxicity of certain chemotherapeutic drugs by interfering with the multidrug resistant gene 1 product P glycoprotein (Pgp), which is also expressed by ACCs [4,5]. The combination of etoposide, doxorubicin and cisplatin (EDP) is the standard chemotherapy regimen to be associated with mitotane (EDP-M) [2]. An EDP-M scheme was first introduced in 1992, when it was found to be active in the management of two young ACC patients, both obtaining a partial response lasting 7 and 21 months, respectively [6]. The feasibility of this regimen was subsequently assessed on 7 consecutive patients [7], then a formal prospective phase II trial was designed and conducted in Italy. The preliminary data of this prospective trial were published in 1998 [8] and the final results were published in 2005 [9]. In the Italian trial, the EDP-M regimen led to an overall response rate of 48.6% (95% CI: 37.1–60.3), 6.9% of patients attained a clinical complete response. The median progression free survival (PFS) and overall survival (OS) of the entire cohort were 9.1 and 28.5 months, respectively [9].\n\nThese data prompted the design and the conduction of a multicenter, multinational prospective phase III trial (the FIRM-ACT trial), in which the efficacy of the EDP-M regimen was compared to that of streptozotocyn plus mitotane (SZ-M) [10]. In this trial, patients receiving EDP-M obtained a significantly better response rate and PFS than those submitted to SZ-M. The OS also favored EDP-M (just failing to attain statistical significance), despite the crossover design of the study. The median time to progression (TTP) and OS of EDP-M treated patients were 5 months and 14.8 months, respectively, and 21% of patients were alive and free from progression after 2 years. Although the results of this multicenter randomized clinical trial revealed that EDP-M regimen has a limited efficacy in the management of advanced ACC patients, it is the only recommend treatment by current guidelines [2]. Modern therapies, such as molecular target therapy [11] and immunotherapy [12,13], have failed to demonstrate a clear efficacy in the management of ACC up to now. While we are waiting for new treatment strategies, we have to use the EDP-M scheme at its highest potential. In this paper, we present the outcome of a consecutive series of patients with advanced/metastatic ACC treated with EDP-M at a tertiary referral oncology center in Italy. The primary aim was to evaluate outcome measures such as disease response, PFS and OS, secondary aims were to evaluate the prognostic role of cytoreductive surgery, performed in patients attaining disease response and stabilization, and the prognostic role of Ki67 expression in residual disease specimens after surgery. According to this experience, we also provided some recommendations on how to best use the EDP-M regimen.\n\n2. Results\n2.1. Patients Characteristics\nFrom January 2012 to January 2020, 58 consecutive patients with stage III or IV ACC underwent the EDP-M chemotherapy regimen at the Medical Oncology Unit at Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili in Brescia. Their characteristics are summarized in Table 1.\n\nThe median age at diagnosis of ACC was 47 years (range 19–72); the male/female ratio was 18/40. At baseline conditions, six patients (10%) had unresectable locally advanced disease (stage III), the remaining 52 patients (90%) had metastatic disease (stage IV). According to modified European Network for the Study of Adrenal Tumors (ENSAT) classification (mENSAT), 25 patients (43%) presented at least two organs involved (stage IVa), 15 (26%) had three of their organs involved in the disease (stage IVb), and the remaining 12 patients (21%) had more than three tumor-involved organs (stage IVc). We also defined the Grade, R status, Age and Symptoms (GRAS) score [14] in 40 evaluable patients. Four of them (7%) were scored as GRAS grade 1, 11 patients (19%) were classified as grade 2 and 25 (43%) as grade 3. Thirty-one out of the 58 evaluable patients (53%) had hormone hypersecretion, which consisted in cortisol alone in nine patients (16%), or cortisol plus other hormones (androgens, estrogens and aldosterone) in 18 patients (31%). Two patients (3.4%) presented androgen hypersecretion alone, one patient (1.7%) presented estrogen and one (1.7%) presented aldosterone hypersecretion.\n\nThe median follow-up period for patients was 34 months (range: 12–145). At the last follow-up examination, on February 15th 2020, 38 patients (66%) were dead.\n\n2.2. Treatment\nA total of 280 EDP cycles were administered (median 5.5, range 1–8). Twenty-nine patients (50%) completed the treatment plan (at least six cycles); among them, 22 (38%) received six cycles, three patients (5%) received seven cycles and four patients received (7%) eight cycles.\n\nEDP-M therapy was associated with drugs able to induce a fast decrease in serum cortisol levels in 11 patients with Cushing syndrome. In particular, five of them received metyrapone and six received abiraterone, the last ones within a prospective clinical trial (ABACUS trial NCT 03145285).\n\nEDP-treatment was interrupted before the sixth cycle in 29 patients (50%) for the following reasons: progressive disease in 14 patients (24%), eligibility for surgical resection of the residual disease in 10 patients (17%), toxic death due to hemorrhagic shock, as a consequence of massive gastric bleeding, in one patient (2%).\n\nMoreover, four patients discontinued the chemotherapy due to severe asthenia and performance status (PS) deterioration, despite disease stabilization, at the fifth, fifth, fourth and third cycles, respectively.\n\nThe most frequent toxicities were asthenia (grade 1 or 2) in 31 patients (53%), followed by gastrointestinal side effects, such as nausea and vomiting in 23 patients (40%), diarrhea in three patients (5.2%) and constipation in four (7%). G1/G2 hematological toxicity at treatment recycle was found in 18 patients (31%), including a reduction in the absolute number of white blood cells or platelets. Both grade 3 neutropenia and grade 4 thrombocytopenia at recycle were observed in two patients (3.4%). One death was potentially related to EDP-M scheme toxicity (hemorrhagic shock caused by massive gastric bleeding).\n\n2.3. Outcome Measures\nMedian PFS in this series was 10.1 months (CI 95%: 8.1–12.8), (Figure 1).\n\nThe median OS was 18.7 months (CI 95%: 14.6–22.8), (Figure 2).\n\nAccording to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [15], no clinical complete responses were recorded. Twenty-nine patients achieved a clinical partial response (50%), 15 (26%) a stable disease, while disease progression was observed in 14 patients (24%). Early disease progression (after one to two cycles) was observed in five patients. In particular, three of them had a deterioration of PS whereas the other two had an increase in the number of metastasis. In five additional patients, however, whose disease progression at the first radiological evaluation after two cycles was characterized by an increase in the size of metastatic lesions already present at baseline (without the appearance of new lesions), the treatment was not discontinued. Mitotane serum level was below the therapeutic range in all of them. After two additional cycles, the disease remained stable in two patients, while a partial response was observed in the remaining three. Mitotane attained the therapeutic range after three months from treatment start in two patients and after four months in the remaining three. Interestingly, one of these patients with mediastinal disease was addressed to surgery and a pathological complete response was observed at the histology of the residual disease (Figure 3).\n\nTwenty-six patients with disease response or stabilization underwent a surgical resection of the residual disease. Twenty-five were submitted to abdominal surgery: laparotomy was adopted in 24 of them and laparoscopy in the remaining one. One patient underwent complete resection of a mediastinal metastasis. Abdominal surgery was followed by hyperthermic intraperitoneal chemotherapy treatment (HIPEC) in 14 patients. A disease-free status was attained in 13 patients that were operated on (50%)—12 after just one surgery and one after abdominal surgery followed by surgical removal of a mediastinal lesion performed 3 months later. On the contrary, a residual disease ≤10% persisted in 13 patients (50%) due to incomplete resection (R1 disease) in five of them or to the concomitant presence of small lung metastases in the remaining eight.\n\nA post-surgery histological evaluation of the residual disease revealed a pathologically complete response (pCR) in four patients (7%). All these patients continued mitotane therapy after surgery and none of them had disease recurrence at the last follow-up examination after 30+, 27+, 10+, and 8+ months, respectively.\n\n2.4. Prognostic Role of Debulking Surgery after EDP-M and Ki67 Expression in the Residual Disease\nPatients who had surgery after a disease response to EDP-M obtained a better PFS than their counterparts: median 13.1 months (CI 95%: 10.3–15.9) versus 7.4 months (CI 95%: 5.5–9.3, p = 0.053), (Figure 4).\n\nSimilarly, the median OS was longer in surgically resected patients than those who were not: 29.8 months (95% CI:16.5–43.1) versus 10.8 months (95% CI: 7.9–13.7), respectively (p = 0.000), (Figure 5).\n\nThe median Ki67 expression in post-chemotherapy histology was 15 (range 1–70). Patients with Ki67 expression below the median obtained a longer PFS (15.3 months, CI 95%: 13.3–17.3) than those with residual Ki67 above or equal to the median value (11.3 months, CI 95%: 8.9–13.6; p = 0.025) (Figure 6). The corresponding OS medians were 21.4 months (CI 95%: 18.9–23.9) and not reached, respectively (p = 0.073) (Figure 7). In the same patient subset, we also evaluated the Ki67 expression at baseline. The median value was 20 (range 10–50). In 10 patients (58%), there was a reduction in Ki67 values after chemotherapy, in 17 (35%) an increase, while in one (6%), the marker expression was unchanged. In this responding patient subset, baseline Ki67 above the median was associated with a longer PFS than Ki67 expression below or equal the median value (15.1 months [95% CI: 14.5–15.7] versus 12.3 months [95% CI: 1.1–23.5], respectively, p = 0.034), while no difference in OS was observed (p = 0.788).\n\n3. Discussion\nIn this series of advanced/metastatic ACC patients, uniformly treated in a reference oncology center for this rare disease in Italy, the EDP-M regimen was confirmed to be active. Both the overall response rate (ORR) according to RECIST criteria (50%) and the PFS (median 10 months) observed in this study were higher than the ones reported with EDP-M in the FIRM-ACT trial and were similar to those observed in the Italian phase 2 trial [9,10]. Moreover, the OS of the present ACC series was slightly longer than that of the FIRM-ACT trial, but inferior to the one observed in the published phase II study. These differences are not surprising, the efficacy of systemic antineoplastic therapies in oncology literature is often heterogeneous depending on patient selection and it appears higher in monocentric series and in phase II trials than in large multicentric clinical trials. In addition, in this series, the EDP-M was associated with side effects that were manageable in the majority of cases, although four non-progressing patients interrupted the treatment before the planned six cycles due to intense asthenia and PS deterioration, and one toxic death was seen. The effect of EDP-M in controlling hypercortisolism was not reported, since drugs able to induce a rapid decrease in cortisol levels, such as metyrapone and abiraterone [16,17,18], were associated to the scheme in 11 patients with Cushing syndrome.\n\nThe present series confirms that the EDP-M scheme has a limited efficacy but still remains the most effective therapy we actually have in the management of advanced ACC. On the basis of this single center experience, we can provide some recommendations on how to best use the EDP-M regimen in routine clinical practice.\n\nIn our series, five patients, who experienced an increase in the size of metastatic lesions already present at baseline did not interrupt the treatment plan. None of them showed disease progression at a subsequent CT scan; on the contrary, three obtained a partial disease remission and a complete pathological response was observed in one of them at subsequent histological evaluation after surgery. It is possible that this favorable outcome would not have been achieved if patients had suspended the treatment plan and had received a second-line therapy. In the clinical routine practice, an antineoplastic therapy is usually interrupted in the case of tumor progression according to the RECIST criteria. Our data suggest that this could be not the case in ACC patients receiving EDP-M, because disease control is subordinate not only to the cytotoxic effect of chemotherapy, but also to the achievement of mitotane therapeutic range, which usually occurs after 2–3 months from the beginning of the therapy. Therefore, early progression of ACC to EDP-M does not always mean treatment inefficacy; as a matter of fact, three patients with early disease progression obtained a partial response subsequently, in conjunction with the achievement of mitotane concentrations within therapeutic levels. Our data are consistent with a recently published case report [19].\n\nThe present paper also underlines the importance of a multidisciplinary approach in the management of ACC. All patients in our series without disease progression after 4–6 months were discussed by our multidisciplinary team and were pinpointed for surgery if a complete surgical removal of the disease was deemed feasible or the residual disease was estimated to be ≤10%.\n\nAs expected, patients who underwent surgery had a better outcome in terms of PFS and OS than those who did not. Of course, this does not mean that surgery in this setting is per se efficacious, since patients earmarked for surgery were selected among those already destined to have a good prognosis. However, post-chemotherapy surgery provided the advantage of reassessing the tumor after therapy. In our study, four patients (7%) attained a pathological complete response and none of them had recurred at the last follow-up. A pCR after EDP-M has already been described by our group in a single patient [20], who obtained a long-term survival. The finding of a 7% pCR rate in this series suggests that EDP-M could be very efficacious in a minority of ACC patients. pCR after neoadjuvant chemotherapy in breast cancer patients is associated to a better outcome and may be a potential surrogate of treatment efficacy [21]. Along these lines, the detection of pCR could identify a small subgroup of ACC patients who are destined to obtain a long-term benefit from the therapy.\n\nAnother advantage of post-chemotherapy surgery is the reassessment of the proliferation activity.\n\nKi67 expression is a major prognostic parameter in ACC [22]. In this series, we evaluated, for the first time, its prognostic role in residual tumors after EDP-M and observed that this marker, categorized by the median value, identified two patient groups with divergent PFS and OS. In early breast cancer patients, Ki67 immunostaining after neoadjuvant chemotherapy was found to have a stronger prognostic significance than its expression at baseline conditions [23]. In addition, Ki67 is a good intermediate marker to predict the efficacy of neoadjuvant hormone therapy [24,25]. Therefore, Ki67 at residual histology after EDP in ACC patients could have the same significance as in breast cancer and this issue deserves to be further explored. Noteworthily, in the patient subset who had surgery after EDP-M, who were carefully selected, we also evaluated the prognostic role of Ki67 assessed at baseline and an opposite result was observed, i.e., patients with higher Ki67 had a better prognosis. It should be noted that these patients were selected among those attaining a disease response after EDP-M and it is well known that chemotherapy efficacy is directly correlated with tumor proliferative activity. This is a possible explanation for the discrepant prognostic role of Ki67 observed before and after EDP-M. It should be noted, in any case, that baseline Ki67 in the majority of these patients was assessed in specimens obtained by a Tru-Cut biopsy and this has limited the accuracy of the assessment.\n\n4. Patients and Methods\nThis is a monocentric, retrospective study. Consecutive ACC patients treated with the EDP-M scheme at ASST Spedali Civili of Brescia were included.\n\nAll patients met the conventional eligibility criteria adopted for chemotherapy in adult ACC patients: age >18 years; Eastern Cooperative Oncology Group (ECOG) PS0–2; pathological diagnosis of ACC; locally advanced or metastatic disease not suitable for surgery; at least one unidimensional (RECIST criteria) measurable lesion; adequate bone marrow reserve (neutrophils ≥1500/mm3 and platelets ≥100,000/mm3, hemoglobin ≥9.0 g/dl); total bilirubin ≤1.5 times the upper limit of normal; serum creatinine ≤1.5 the upper limit of normal; effective contraception in premenopausal female and male patients; written informed consent. The patient could have had a history of prior malignancy radically resected with no evidence of disease for at least 3 years.\n\nExclusion criteria were the contraindications to chemotherapy, such as active clinically serious infections (greater than grade 2 National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0); decompensated heart failure (ejection fraction ≥45%); myocardial infarction or revascularization procedure during the previous 6 months; unstable angina pectoris; uncontrolled cardiac arrhythmia; hypertension not controlled by medications; pregnancy or breast-feeding conditions.\n\nEDP-M was administered with the following scheme: etoposide 100 mg/m2 (day 2–3–4), doxorubicin 20 mg/m2 (day 1), cisplatin 40 mg/m2 (day 3–4) [9]. Intravenous chemotherapy administration was performed every 4 weeks, for a maximum of 6-8 cycles. Treatment was delayed in the case of a neutrophil count <1500/mm3, platelet count <100,000/mm3, or grade >2 extra- hematological toxicity on treatment recycle. Moreover, a dose reduction was planned in the case of a neutrophil count <500/mm3 and/or platelet count <30,000/mm3 experienced at recycle. All patients received a prophylactic treatment with long-acting granulocyte colony-stimulating factor (G-CSF) after every chemotherapy cycle (administered 48 h after the end of the cycle, by subcutaneous injection).\n\nFrom 2016 onwards, drugs able to induce a rapid reduction of serum cortisol levels such as metyrapone [16] or abiraterone [17,18] were associated to the EDP-M in the first month of therapy.\n\nOral mitotane was administered concomitantly with chemotherapy at a starting dose of 1500 mg daily, with further progressive dose increments up to the maximum tolerated dose. Serum mitotane was monitored every 4 weeks and when the patients attained the therapeutic range, the mitotane dose was tapered to maintain serum concentration within 14 and 20 mg/L.\n\nCT scan and/or MRI were performed at baseline and every two cycles. Radiological response was assessed according to RECIST criteria [26]. Early PD after the first two cycles was not considered a strict criteria of treatment interruption. At each imaging reassessment, the patient was evaluated by a multidisciplinary team composed of medical oncologists, internal medicine physicians, surgeons and radiologists to discuss the further steps. A surgical approach with radical intent was decided if the patients attained a partial response or a stable disease after EDP-M and their metastatic disease appeared suitable for surgery. Cytoreductive surgery was also considered in patients with residual disease estimated to be ≤10%. For patients who underwent surgery, the Ki67% value at residual disease was assessed.\n\nAll included patients had given their written informed consent to the diagnostic and treatment procedures.\n\nThe following demographic, clinical, pathological and treatment data were collected: sex, age, medical history, physical examination, performance status, routine laboratory tests, endocrine work-up, chest and abdominal CT scan.\n\nThe stage of disease was assessed using the modified ENSAT (mENSAT) classification: stage III (invasion of tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or>3 metastatic organs, including N, respectively) [14].\n\nWe categorized the patients according to the GRAS score, considering grading, R status, age and symptoms, defined as tumor- or hormone-related symptoms at diagnosis [14]. GRAS score was defined as GRAS 1 (favorable): ≤1 risk factor in GRAS parameters; GRAS 2 (unfavorable): 2 risk factors in GRAS parameters; GRAS 3 (pejorative): ≥3 risk factors in GRAS parameters.\n\nPFS was defined as the time elapsed from the beginning of the EDP-M treatment until disease progression or death. Non-progressing patients still alive were censored at the last follow-up examination.\n\nOS was defined as the time interval between the date of EDP-M treatment start and the date of death from any cause or the last known date when the patient was alive.\n\nThe retrospective study was approved by the Ethical Review Board of ASST-Spedali Civili in Brescia (protocol no 3229; version 1.1, 1st December 2019).\n\nDescriptive statistics were used to analyze the patients’ clinical characteristics. Survival curves were calculated by the Kaplan–Meier method and differences were compared by the log rank test.\n\nStatistical significance was set at p < 0.05. SPSS v23.0 software was used for the statistical analyses (SPSS Inc., Chicago, IL, USA).\n\n5. Conclusions\nEDP-M is confirmed as having a limited efficacy in the management of advanced/metastatic ACC patients, although a small proportion of patients can obtain a long-term clinical benefit. Early progression to EDP-M does not always mean treatment inefficacy and treatment discontinuation would not be advisable in progressing patients without the appearance of new lesions, in whom serum mitotane levels have not reached therapeutic concentrations. Surgery of residual disease in responding patients allows for the detection of pCR in few of them and this condition is predictive of long-term clinical outcomes. The reassessment of proliferation activity by Ki67 immunostaining in post-chemotherapy surgical specimens could be an additional prognostic parameter that deserves to be studied further.\n\nAcknowledgments\nWe are grateful to our patients and their families.\n\nAuthor Contributions\nConceptualization, A.B.; methodology, S.G.; software, D.C., M.L., C.S.; validation, A.B., V.D.F., B.L.; formal analysis, M.L., D.C.; investigation, M.L., S.G., D.C., V.D.F., B.L., R.A., C.S., A.D.V., C.P., P.L.P., S.S., G.A.M.T., and A.B.; data curation, V.D.F., B.L., S.G.; writing—original draft preparation, A.B., M.L.; writing—review and editing, A.B., M.L.; visualization, A.B., S.G., V.D.F.; supervision, M.T., S.S., G.A.M.T.; surgery intervention, G.A.M.T.; radiological assessment, R.A.; project administration, A.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis work was granted by: AIRC project IG14411 (PI: A.B.), Fondazione Camillo Golgi, Brescia and Fondazione Internazionale di Ricerca in Medicina (F.I.R.M.) ONLUS, Cremona (Italy).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Progression-free survival.\n\nFigure 2 Overall survival.\n\nFigure 3 Thorax CT scan series of a patient attaining a pathological complete response after six cycles of etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M).\n\nFigure 4 Progression-free survival according to post-EDP surgery.\n\nFigure 5 Overall survival according to post-EDP surgery.\n\nFigure 6 Progression-free survival according to Ki67 after post-EDP surgery.\n\nFigure 7 Overall survival according to Ki67 assessed after post-EDP surgery.\n\ncancers-12-00941-t001_Table 1Table 1 Patients’ characteristics.\n\nPatients’ Characteristics\tNumber\tPercentage\t\n\nNo of patients\n\t58\t(100%)\t\n\nMedian Age (range)\n\t47\t[range 19–72]\t\n\nMale/Female ratio\n\t18/40\t(69%)\t\n\nmENSAT stage at Diagnosis\n\t\n\t\n\t\nIII\t6\t(10%)\t\nIVa\t25\t(43%)\t\nIVb\t15\t(26%)\t\nIVc\t12\t(21%)\t\n\nHormone Hypersecretion at Diagnosis\n\t\n\t\n\t\nCortisol alone\t9\t(16%)\t\nCortisol plus other hormones\t18\t(31%)\t\nAndrogens alone\t2\t(3.4%)\t\nEstrogens alone\t1\t(1.7%)\t\nAldosterone alone\t1\t(1.7%)\t\n\nPrevious treatments: Surgery\n\t35\t(60.3%)\t\n\nAdjuvant Mitotane\n\t26\t(44.8%)\t\n\nMitotane for advanced disease\n\t13\t(22.4%)\t\n\nGRAS score* (40 available patients)\n\t\n\t\n\t\nFavorable\t4\t(7%)\t\nUnfavorable\t11\t(19%)\t\nPejorative\t25\t(43%)\t\n* Grade, R status, Age and Symptoms (GRAS).\n==== Refs\nReferences\n1. Terzolo M. Daffara F. Ardito A. Zaggia B. Basile V. Ferrari L. Berruti A. Management of adrenal cancer: A 2013 update J. Endocrinol. Investig. 2014 37 207 217 10.1007/s40618-013-0049-2 24458831 \n2. Fassnacht M. Dekkers O.M. Else T. Baudin E. Berruti A. de Krijger R. Haak H.R. Mihai R. Assie G. Terzolo M. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors Eur. J. Endocrinol. 2018 179 G1 G46 10.1530/EJE-18-0608 30299884 \n3. Hermsen I.G. Fassnacht M. Terzolo M. Houterman S. den Hartigh J. Leboulleux S. Daffara F. Berruti A. Chadarevian R. Schlumberger M. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study J. Clin. Endocrinol. Metab. 2011 96 1844 1851 10.1210/jc.2010-2676 21470991 \n4. Bates S.E. Shieh C.Y. Mickley L.A. Dichek H.L. Gazdar A. Loriaux D.L. Fojo A.T. Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas J. Clin. Endocrinol. Metab. 1991 73 18 29 10.1210/jcem-73-1-18 1675220 \n5. Villa R. Orlandi L. Berruti A. Dogliotti L. Zaffaroni N. Modulation of cytotoxic drug activity by mitotane and lonidamine in human adrenocortical carcinoma cells Int. J. Oncol. 1999 14 133 138 10.3892/ijo.14.1.133 9863019 \n6. Berruti A. Terzolo M. Paccotti P. Veglio F. Pia A. Dogliotti L. Angeli A. Favorable response of metastatic adrenocortical carcinoma to etoposide, adriamycin and cisplatin (EAP) chemotherapy. Report of two cases Tumori 1992 78 345 348 10.1177/030089169207800512 1494808 \n7. Pia A. Berruti A. Terzolo M. Paccotti P. Letizia C. Dogliotti L. Angeli A. Feasibility of the association of mitotane with etoposide, adriamycin and cisplatin combination chemotherapy in advanced adrenocortical cancer patients. Report on 7 cases Ann. Oncol. 1995 6 509 510 10.1093/oxfordjournals.annonc.a059224 \n8. Berruti A. Terzolo M. Pia A. Angeli A. Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer Cancer 1998 83 2194 2200 10.1002/(SICI)1097-0142(19981115)83:10<2194::AID-CNCR19>3.0.CO;2-3 9827725 \n9. Berruti A. Terzolo M. Sperone P. Pia A. Della Casa S. Gross D.J. Carnaghi C. Casali P. Porpiglia F. Mantero F. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial Endocr. Relat. Cancer 2005 12 657 666 10.1677/erc.1.01025 16172198 \n10. Fassnacht M. Terzolo M. Allolio B. Baudin E. Haak H. Berruti A. Welin S. Schade-Brittinger C. Lacroix A. Jarzab B. Combination chemotherapy in advanced adrenocortical carcinoma N. Engl. J. Med. 2012 366 2189 2197 10.1056/NEJMoa1200966 22551107 \n11. Grisanti S. Cosentini D. Laganà M. Abate A. Rossini E. Sigala S. Berruti A. Are we failing in treatment of adrenocortical carcinoma? Lights and shadows of molecular signatures Curr. Opin. Endoc. Metab. Res. 2019 8 80 87 10.1016/j.coemr.2019.07.007 \n12. Cosentini D. Grisanti S. Dalla Volta A. Laganà M. Fiorentini C. Perotti P. Sigala S. Berruti A. Immunotherapy failure in adrenocortical cancer: where next? Endocr. Connect. 2018 7 E5 E8 10.1530/EC-18-0398 30400026 \n13. Fiorentini C. Grisanti S. Cosentini D. Abate A. Rossini E. Berruti A. Sigala S. Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma J. Oncol. 2019 2019 6072863 10.1155/2019/6072863 31057613 \n14. Libé R. Borget I. Ronchi C.L. Zaggia B. Kroiss M. Kerkhofs T. Bertherat J. Volante M. Quinkler M. Chabre O. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): An European Network for the Study of Adrenal Tumor (ENSAT) study Ann. Oncol. 2015 26 2119 2125 10.1093/annonc/mdv329 26392430 \n15. Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L.H. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \n16. Claps M. Cerri S. Grisanti S. Lazzari B. Ferrari V. Roca E. Perotti P. Terzolo M. Sigala S. Berruti A. Adding metyrapone to chemotherapy plus mitotane for Cushing’s syndrome due to advanced adrenocortical carcinoma Endocrine 2018 61 169 172 10.1007/s12020-017-1428-9 29019062 \n17. Claps M. Lazzari B. Grisanti S. Ferrari V. Terzolo M. Sigala S. Vezzoli S. Memo M. Castellano M. Berruti A. Management of severe cushing’s syndrome induced by adrenocortical carcinoma with abiraterone acetate: A case report AACE Clin. Case Rep. 2016 2 e337 e341 10.4158/EP151104.CR \n18. Fiorentini C. Fragni M. Perego P. Vezzoli S. Bonini S.A. Tortoreto M. Galli D. Claps M. Tiberio G.A. Terzolo M. Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study J. Clin. Endocrinol. Metab. 2016 101 4594 4602 10.1210/jc.2016-2414 27626976 \n19. Hescot S. Leboulleux S. Caramella C. Paci A. Lombes M. Berdelou A. Baudin E. Early progression under mitotane and polychemotherapy does not mean failure in adrenocortical carcinoma patient Ann. Endocrinol. 2017 78 67 69 10.1016/j.ando.2016.10.001 \n20. Sperone P. Berruti A. Gorzegno G. Paccotti P. Terzolo M. Porpiglia F. Angeli A. Dogliotti L. Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane J. Endocrinol. Investig. 2006 29 560 562 10.1007/BF03344148 16840836 \n21. Berruti A. Amoroso V. Gallo F. Bertaglia V. Simoncini E. Pedersini R. Ferrari L. Bottini A. Bruzzi P. Sormani M.P. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: A meta-regression of 29 randomized prospective studies J. Clin. Oncol. 2014 32 3883 3891 10.1200/JCO.2014.55.2836 25349292 \n22. Beuschlein F. Weigel J. Saeger W. Kroiss M. Wild V. Daffara F. Libe R. Ardito A. Ghuzlan A. Quinkler M. Major Prognostic Role of Ki67 in Localized Adrenocortical Carcinoma After Complete Resection J. Clin. Endocr. Metab. 2015 100 jc20143182 10.1210/jc.2014-3182 25559399 \n23. Bottini A. Berruti A. Bersiga A. Brizzi M.P. Bruzzi P. Aguggini S. Brunelli A. Bolsi G. Allevi G. Generali D. Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer Br. J. Cancer 2001 85 1106 1112 10.1054/bjoc.2001.2048 11710821 \n24. Klintman M. Dowsett M. Early Surrogate Markers of Treatment Activity: Where Are We Now? J. Natl. Cancer Inst. Monogr. 2015 2015 24 28 10.1093/jncimonographs/lgv002 26063881 \n25. Jones R.L. Salter J. A’Hern R. Nerurkar A. Parton M. Reis-Filho J.S. Smith I.E. Dowsett M. The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer Breast Cancer Res. Treat 2009 116 53 68 10.1007/s10549-008-0081-7 18592370 \n26. Therasse P. Eisenhauer E.A. Verweij J. RECIST revisited: A review of validation studies on tumour assessment Eur. J. Cancer 2006 42 1031 1039 10.1016/j.ejca.2006.01.026 16616487\n\n",
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"journal": "Cancers",
"keywords": "EDP; adrenocortical tumor; mitotane; treatment",
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"title": "Efficacy of the EDP-M Scheme Plus Adjunctive Surgery in the Management of Patients with Advanced Adrenocortical Carcinoma: The Brescia Experience.",
"title_normalized": "efficacy of the edp m scheme plus adjunctive surgery in the management of patients with advanced adrenocortical carcinoma the brescia experience"
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"abstract": "Acute subdural hematoma (aSDH) is a common pathology encountered in neurosurgery. Although most cases are associated with trauma and injuries to draining veins, traumatic aSDH from injury to arteries or spontaneous aSDH because of a ruptured intracranial aneurysm can occur. For some patients without a clear clinical history, it can be difficult to distinguish between these etiologies purely based on radiography. The objective of this research was to describe a case series in which imaging was suggestive of the presence of distal cortical intracranial aneurysm associated with aSDH, but operative management demonstrated no evidence of aneurysm.\n\n\n\nWe retrospectively reviewed 2 patients known to have aSDH with suspicion for associated aneurysm between May 2019 and September 2019 at our institution. Data collected included demographic, clinical, and operative course, including age, gender, past medical history, presenting symptoms, and pre and postoperative imaging.\n\n\n\nIn 2 patients presenting with aSDH with preoperative radiographic imaging suggesting distal middle cerebral artery aneurysms, surgical exploration revealed no aneurysm. In both cases, noniatrogenic active arterial bleeding from an injured cortical middle cerebral artery branch was identified.\n\n\n\nAlthough there are prior reports of arterial aSDH, to our knowledge, this is the first to describe the radiographic \"ghost aneurysm\" sign. It is important for clinicians to be aware of this potential misleading radiographic sign, which indicates active extravasation into a spherical cast of clot.",
"affiliations": "Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.;Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.;Departments of Neurological Surgery, Radiology, Mechanical Engineering, and Stroke and Applied Neuroscience Center, University of Washington, Seattle, Washington, USA. Electronic address: respub@uw.edu.",
"authors": "Abecassis|Zachary A|ZA|;Nistal|Dominic A|DA|;Abecassis|Isaac Josh|IJ|;Sen|Rajeev D|RD|;Levitt|Michael R|MR|",
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"journal": "World neurosurgery",
"keywords": "Active extravasation; Intracranial aneurysm; Mycotic aneurysm; Subdural hematoma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002533:Cerebral Angiography; D000072226:Computed Tomography Angiography; D020199:Hematoma, Subdural, Acute; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D020768:Middle Cerebral Artery; D012189:Retrospective Studies",
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"title": "Ghost Aneurysms in Acute Subdural Hematomas: A Report of Two Cases.",
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"abstract": "Docetaxel and paclitaxel are widely used in the treatment of various malignant neoplasms. Taxane-induced sclerosis is dose-dependent and usually not generalized. Little information on the pathogenesis of scleroderma is currently available. Here, we report a case of generalized scleroderma and a case of early-stage oedematous sclerosis, both of which presented with intense versican deposits after administration of taxane for angiosarcoma.",
"affiliations": "Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.;Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.;Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.;Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.;Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.;Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.",
"authors": "Okada|K|K|http://orcid.org/0000-0001-9455-5960;Endo|Y|Y|;Miyachi|Y|Y|;Koike|Y|Y|;Kuwatsuka|Y|Y|;Utani|A|A|",
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"mesh_terms": "D000077143:Docetaxel; D006025:Glycosaminoglycans; D006258:Head and Neck Neoplasms; D006394:Hemangiosarcoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D012535:Scalp; D012594:Scleroderma, Localized; D012598:Sclerosis; D012878:Skin Neoplasms; D043823:Taxoids; D053675:Versicans",
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"title": "Glycosaminoglycan and versican deposits in taxane-induced sclerosis.",
"title_normalized": "glycosaminoglycan and versican deposits in taxane induced sclerosis"
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{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse cutaneous drug reaction with mortality up to 10%. It is a rare condition with risk varying between 1 in 1000 and 1 in 10 000 drug exposures. The aim of the study was to describe clinical features, management and drugs responsible for causing DRESS. The study was retrospective, observational study. The data of patients admitted to hospital with diagnosis of DRESS during study period (March 2018 to February 2020), were retrieved and analyzed. The descriptive data of patients were summarized. The continuous variables were summarized as mean ± SD and/or median, depending on the skewness of the data. The categorical variables were expressed as absolute numbers, frequency, and proportions (%). The data was tabulated and analyzed in Microsoft Excel 2019 version. A total of 20 patients who met inclusion criteria (probable or definite DRESS as per RegiSCAR criteria) were included in the study. The mean age of the patients was 41.2 ± 15.7 years. The average latency period was 26.45 ± 5.65 days (range: 7-60). The commonest culprit drugs were dapsone and phenytoin, each in five (25%) patients. Commonest morphology of rash was morbilliform in 13 (65%) patients. One patient with targetoid rash had multi-organ involvement. Facial edema, periorbital edema, and conjunctival injection were seen in 17 (85%), seven (35%), and six (30%) cases, respectively. Eosinophilia was present in 18 (90%) patients with mean (±SD) value of 1976 ± 840 cells/μl. Liver was the commonest internal organ involved in 14 (70%) patients and kidney in three (15%) patients. The initial dose of prednisolone for treatment varied from 0.75 to 2 mg/kg/day. The mean duration of steroid treatment was 64 ± 21 days. Two patients were treated with intravenous methylprednisolone and one with intravenous immunoglobulin. Two patients (10%) had recurrence of adverse drug reaction >6 months after completion of initial treatment and two (10%) developed autoimmune thyroiditis during follow-up. Small sample size and retrospective nature of the study were main limitations. Selection bias is a possibility as study was carried out in tertiary care center. Tests for incriminating culprit drugs such as patch test, intradermal test, and lymphocyte transformation test were not performed. DRESS is a rare disease that can be diagnosed early with high index of suspicion and treated successfully with steroids. The internal organ involvement is common in DRESS and requires a thorough evaluation.",
"affiliations": "Department of Dermatology, Command Hospital Airforce Bangalore, India.;Department of Dermatology, Armed Forces Medical College, Pune, India.;Department of Dermatology, Armed Forces Medical College, Pune, India.;Department of Dermatology, Armed Forces Medical College, Pune, India.;Department of Pathology, Armed Forces Medical College, Pune, India.;Department of Dermatology, Armed Forces Medical College, Pune, India.",
"authors": "Sandhu|Sunmeet|S|0000-0002-9222-4006;Neema|Shekhar|S|;Vashisht|Deepak|D|0000-0001-7593-8480;Venugopal|Ruby|R|;Sengupta|Prashant|P|;Radhakrishnan|Subramaniyan|S|",
"chemical_list": "D003622:Dapsone; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14670",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "34(1)",
"journal": "Dermatologic therapy",
"keywords": "DRESS, drug rash with eosinophilia and systemic symptoms; drug hypersensitivity syndrome; severe cutaneous adverse drug reaction",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000328:Adult; D003622:Dapsone; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D006801:Humans; D008775:Methylprednisolone; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14670",
"pmc": null,
"pmid": "33314590",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Drug reaction with eosinophilia and systemic symptoms: A single center descriptive observational study.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms a single center descriptive observational study"
} | [
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"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-290683",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PANTOPRAZOLE"
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"abstract": "The coronavirus disease 2019 (COVID-19) pandemic has significantly affected health care organizations globally. Many aspects of this disease, as well as the risks for patients treated with multiple drug regimens to control severe COVID-19, are unclear. During emergency surgery for SARS-CoV-2-positive patients, the risk of SARS-CoV-2 exposure and transmission to the surgical staff has yet to be determined.\n\n\n\nIn this report, we describe a SARS-CoV-2-positive patient with severe respiratory syndrome treated with multiple doses of IL-6 inhibitors who presented with a perforated duodenal ulcer and underwent emergency surgery. During and after surgery, we tested for SARS-CoV-2 at the ulcer site and in the peritoneal fluid.\n\n\n\nThe history of the patient allows for two possible interpretations of the pathogenesis of the duodenal ulcer, which could have been a stress ulcer, or a gastrointestinal ulcer associated to the use of IL-6 inhibitors. We also noticed that the ulcer site and peritoneal fluid repeatedly tested negative for SARS-CoV-2. Therefore, we reviewed the pertinent literature on gastrointestinal bleeding in patients with COVID-19 and on SARS-CoV-2 detection in the peritoneal fluid of surgical patients and discussed possible prevention strategies for bleeding and the actual risk of infection for the surgical staff.\n\n\n\nThe first implication of this case is that the relation between repeated administration of IL-6 inhibitors and upper gastrointestinal bleeding and perforation must be investigated, and that the threshold for administering prophylactic proton pump inhibitors therapy should be carefully considered for patients with severe COVID-19. The second implication is that further testing should be performed on the peritoneal fluid of COVID-19 patients undergoing emergency surgical procedures to clarify the discordant results for the presence of SARS-CoV-2 in the peritoneal cavity and the possible risk of transmission to the surgical staff.",
"affiliations": "Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. annamaria.agnes@gmail.com.",
"authors": "Agnes|A|A|;La Greca|A|A|;Tirelli|F|F|;Papa|V|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D012367:RNA, Viral; C502936:tocilizumab",
"country": "Italy",
"delete": false,
"doi": "10.26355/eurrev_202012_24048",
"fulltext": null,
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"issn_linking": "1128-3602",
"issue": "24(23)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001202:Ascitic Fluid; D000086382:COVID-19; D000087123:COVID-19 Nucleic Acid Testing; D004381:Duodenal Ulcer; D006801:Humans; D008297:Male; D010438:Peptic Ulcer Hemorrhage; D010439:Peptic Ulcer Perforation; D012367:RNA, Viral; D000086402:SARS-CoV-2; D013312:Stress, Physiological",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "12516-12521",
"pmc": null,
"pmid": "33336771",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Duodenal perforation in a SARS-CoV-2-positive patient with negative PCR results for SARS-CoV-2 in the peritoneal fluid.",
"title_normalized": "duodenal perforation in a sars cov 2 positive patient with negative pcr results for sars cov 2 in the peritoneal fluid"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1042545",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"abstract": "Molecular-targeted agents are acceptable standards to treat advanced-stage hepatocellular carcinoma (HCC), however, their therapeutic benefit, ie, sorafenib, was significantly offset in case of major vessel invasion. Liver-directed concurrent chemo-radiotherapy (LD-CCRT) provided favorable outcomes in terms of survivals and tumor shrinkage, so, we appraised its long-term therapeutic efficacy.\nAdvanced HCC patients with portal vein invasion (main trunk or the 1st order branch) were enrolled. During a 5-week radiotherapy course, concurrent hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and leucovorin was administered through an implanted port on the first and last 5 days. Four weeks after LD-CCRT, a maintenance HAIC using 5-fluorouracil and cisplatin was administered every 4 weeks.\nAmong 152 patients, the objective response rates as the best response by modified Response Evaluation Criteria In Solid Tumors were 48.0% after LD-CCRT and 55.3% during subsequent HAIC maintenance. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging. Median overall survival and progression-free survival were 13.5 and 6.9 months, respectively.\nLD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients, resulting in long-term survival. Further prospective trials are warranted to confirm these results.",
"affiliations": "Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea.;Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.",
"authors": "Han|Sojung|S|;Lee|Hye Won|HW|;Park|Jun Yong|JY|;Kim|Seung Up|SU|0000-0002-9658-8050;Kim|Do Young|DY|;Ahn|Sang Hoon|SH|;Han|Kwang-Hyub|KH|;Seong|Jinsil|J|0000-0003-1794-5951;Won|Jong Yun|JY|0000-0002-8237-5628;Han|Dai Hoon|DH|;Kim|Beom Kyung|BK|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/JHC.S276528",
"fulltext": "\n==== Front\nJ Hepatocell Carcinoma\nJ Hepatocell Carcinoma\njhc\njhepc\nJournal of Hepatocellular Carcinoma\n2253-5969 Dove \n\n276528\n10.2147/JHC.S276528\nOriginal Research\nAppraisal of Long-Term Outcomes of Liver-Directed Concurrent Chemoradiotherapy for Hepatocellular Carcinoma with Major Portal Vein Invasion\nHan et alHan et alHan Sojung 12 Lee Hye Won 123 Park Jun Yong 123 http://orcid.org/0000-0002-9658-8050Kim Seung Up 123 Kim Do Young 123 Ahn Sang Hoon 123 Han Kwang-Hyub 1 http://orcid.org/0000-0003-1794-5951Seong Jinsil 4 http://orcid.org/0000-0002-8237-5628Won Jong Yun 5 Han Dai Hoon 267* Kim Beom Kyung 123* 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea\n2 Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea\n3 Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea\n4 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea\n5 Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea\n6 Liver Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea\n7 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea\nCorrespondence: Dai Hoon Han Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun–Gu, Seoul03722, Republic of KoreaTel +82-2-2228-2139Fax +82-2-313-8289 Email dhhan@yuhs.acBeom Kyung Kim Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun–gu, Seoul03722, Republic of KoreaTel +82-2-2228-1930Fax +82-2-393-6884 Email beomkkim@yuhs.ac* These authors contributed equally to this work.\n\n\n17 12 2020 \n2020 \n7 403 412\n16 9 2020 03 12 2020 © 2020 Han et al.2020Han et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Backgrounds and Aims\nMolecular-targeted agents are acceptable standards to treat advanced-stage hepatocellular carcinoma (HCC), however, their therapeutic benefit, ie, sorafenib, was significantly offset in case of major vessel invasion. Liver-directed concurrent chemo-radiotherapy (LD-CCRT) provided favorable outcomes in terms of survivals and tumor shrinkage, so, we appraised its long-term therapeutic efficacy.\n\nPatients and Methods\nAdvanced HCC patients with portal vein invasion (main trunk or the 1st order branch) were enrolled. During a 5-week radiotherapy course, concurrent hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and leucovorin was administered through an implanted port on the first and last 5 days. Four weeks after LD-CCRT, a maintenance HAIC using 5-fluorouracil and cisplatin was administered every 4 weeks.\n\nResults\nAmong 152 patients, the objective response rates as the best response by modified Response Evaluation Criteria In Solid Tumors were 48.0% after LD-CCRT and 55.3% during subsequent HAIC maintenance. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging. Median overall survival and progression-free survival were 13.5 and 6.9 months, respectively.\n\nConclusion\nLD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients, resulting in long-term survival. Further prospective trials are warranted to confirm these results.\n\nKeywords\nhepatocellular carcinomaportal vein invasionconcurrent chemoradiotherapyprognosisresponse\n==== Body\nPlain Language Summary\n-Treatment options other than molecular-targeted agents are still limited for advanced stage-hepatocellular carcinoma (HCC) with major portal vein invasion.\n\n-We assessed their survival outcomes undergoing liver-directed concurrent chemoradiotherapy (LD-CCRT) followed by maintenance hepatic arterial infusion chemotherapy (HAIC).\n\n-Among 152 patients, median overall survival and progression-free survival were 13.5 and 6.9 months, respectively. The objective response rates as the best response by modified Response Evaluation Criteria in Solid Tumors were 48.0% after LD-CCRT and 55.3% during the planned treatment course. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging.\n\n- LD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced stage-HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients. Further prospective trials are warranted to confirm these results.\n\nIntroduction\nApproximately 10–40% of hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage with major portal vein (PV) tumor invasion. The expected prognosis in such cases is typically poor, despite the administration of optimal systemic therapy according to the best practice guidelines.1–3 Sorafenib is the first approved oral multi-kinase inhibitor for prolonging the overall survival (OS) of patients with advanced-stage HCC. Along with lenvatinib, it is currently regarded as the standard of care.1,3,4 However, data supporting the survival benefits from molecular-targeted agents among patients with advanced-stage HCC with major PV invasion are still limited. For example, among patients treated with sorafenib,5 the OS markedly decreased from 14.3 to 5.7 months in case of extrahepatic spread and/or macrovascular invasion.6–8 Furthermore, although the median OS reached approximately 13 months in the Phase III trial comparing lenvatinib and sorafenib as the first-line treatment for advanced-stage HCC, patients with major PV invasion at baseline were primarily excluded in that phase III trial. Thus, there is a pressing need for more effective treatment strategies in these patients. Recently, we could observe many literatures indicating that alternative strategies including loco-regional treatment (LRT) could improve survival outcomes compared to molecular-targeted agents alone.1,9,10\n\nAmong various LRTs, external beam radiation therapy (EBRT) has become widely popular primarily due to technological advances, including the introduction of 3-dimensional conformal radiation therapy (3D-CRT) and more recently, intensity-modulated radiotherapy (IMRT).11,12 These technologies allow the delivery of high tumoricidal radiation doses with minimal risk of damage to adjacent non-tumorous tissues. As a result, a high-dose EBRT for advanced HCC can lead to a long-lasting local tumor control as well as a higher probability of down-staging which allows curative resection or OLT with improved survival, in comparison with historical controls.12–14 According to several observational studies, liver-directed concurrent chemoradiotherapy (LD-CCRT) for advanced-stage HCC was associated with the favorable clinical outcomes.15–17 In particular, Kim et al16 reported that the objective response rates (ORR) during the LD-CCRT-based treatment course was up to 53.2% and that 19.1% underwent curative resection or transplantation after down-staging, in contrast to only a minimal tumor shrinkage effect by sorafenib, ie at least about 2 ~5%.18,19 Another studies also supported anti-tumor effect by an intra-arterial infusion of 5-fluorouracil with or without EBRT.20–25\n\nBased on the available evidence that effective initial tumor shrinkage by LD-CCRT may facilitate subsequent treatments with curative intent among advanced-stage HCC patients with major PV invasion, we aimed to assess clinical outcomes of LD-CCRT, in terms of not only survival outcomes but ORR and the proportion of conversion to curative treatment, of LD-CCRT.\n\nPatients and Methods\nParticipants and Treatments\nPatients who underwent LD-CCRT for advanced-stage HCC between 2011 and 2016 at Severance Hospital, Seoul, Republic of Korea, were retrospectively analyzed. HCC was diagnosed by histological or radiological evaluation with reference to the international guidelines.1,3,26,27 The eligibility criteria for LD-CCRT are described in Table 1. For example, LD-CCRT was not performed for patients with diffuse or multifocal bi-lobal tumors which cannot be included in a technically feasible RT field from the viewpoint of safety based upon liver function and radiation dosage to organs. In addition, the exclusion criteria were also described in Table 1.Table 1 Patients’ Enrollment\n\nEligibility Criteria for LD-CCRT\t\nAge 20–75 years\t\nAt least one unidimensional lesion measurable according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST)\t\nPreserved liver function with a Child-Pugh score ≤ 7\t\nEastern Cooperative Oncology Group (ECOG) performance status score: 0 or 1\t\nWhite blood cell count ≥ 3000/µL\t\nAbsolute neutrophil count ≥ 750/µL\t\nPlatelet count ≥ 60×103/µL\t\nSerum alanine aminotransferase level < 10 times the upper limit of the normal range\t\nSerum creatinine level ≤2.0 mg/dL\t\nPrimary tumor confined to a technically feasible RT field, without diffuse intra-hepatic spread\t\nExclusion criteria enrollment\t\nHistory of other anti-cancer treatment for HCC after the diagnosis of advanced-stage HCC\t\nPresence of extrahepatic metastasis\t\nOther uncontrolled comorbidities or malignant neoplasm\t\nPrior organ transplant\t\nActive peptic ulcer\t\n\n\n\nLD-CCRT and subsequent maintenance HAIC were performed according to the previous studies by Kim et al16 and Park et al28 respectively. Provided that patients have intrahepatic lesions eligible for transarterial chemo-embolization (TACE),29–31 they could be included in the study at physicians’ discretion. The overall process of the treatment delivery was described in the Supplementary Table 1.\n\nThis study protocol was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and approved by the institutional review board (IRB) of Severance Hospital. The informed consent was waived because of the retrospective nature of the study. All patient identifiers were removed once the data from the patient medical record is collected.\n\nFollow-Up\nTreatment responses were assessed approximately 1 month after the completion of LD-CCRT and then every 8 ~ 12 weeks, using modified Response Evaluation Criteria in Solid Tumors (mRECIST).32 During follow up, patients who successfully achieved down-staging underwent curative surgical resection or orthotropic liver transplantation (OLT) under a multi-disciplinary approach.33 Such approaches were considered, when complete response (CR) or partial response (PR) by mRECIST32 was achieved and serum alpha-fetoprotein (AFP) and protein induced by the absence of vitamin K or antagonist-II (PIVKA-II) decreased to <20 ng/mL and <40 mAU/mL, respectively, through the treatment.15,34 Tumor resectability was determined in a multi-disciplinary approach through reviewing CT scans before and during the treatment.35 All gross lesions should be resected with a clear margin based on radiological image. The resection type was determined based on functional reserve of the liver (FRL) and patient’s performance status. For major liver resection defined as the resection of ≥3 anatomical segments, at least 40% of the total liver volume should be required as a future FRL. OLT was considered for patient with deteriorating liver function; those with pre-operative total bilirubin ≥2mg/dL or platelet counts <100,000/μL, or with future remnant liver volume/total liver volume <30% were considered for OLT.\n\nThe primary endpoint was the OS, and the secondary endpoints were progression-free survival (PFS), ORR (defined as the rate of CR or PR), and the proportion of patients undergoing curative surgical resection or OLT after down-staging. Patients were evaluated for any treatment-related adverse event throughout the planned treatment period. Adverse events were noted as per the standards and terminology set by the Cancer Therapy Evaluation Program’s Common Terminology Criteria for Adverse Events version 4.03.\n\nStatistical Analysis\nData are expressed as mean ± standard deviation, median (interquartile range [IQR]) or number (%). Differences among categorical variables were analyzed for statistical significance with chi-square test (or Fisher’s exact test, if appropriate), respectively. Survival outcome was estimated using Kaplan–Meier analysis with a comparison by Log rank test. Hazard ratios (HR) were calculated using Cox regression analysis. OS was calculated as the time interval from the date of treatment initiation to the date of death, whereas PFS was calculated as the time interval from the date of treatment initiation to the date of progression, or any kind of death in the absence of confirmed progression. The Statistical analyses were performed using IBM® SPSS® Statistics Version 25.0 (IBM Corporation in Armonk, NY, US). All statistical tests with p-value of <0.05 were considered as significant.\n\nResults\nPatient Characteristics\nIn total, 152 patients with major PV invasion who underwent LD-CCRT were analyzed (Supplementary Figure 1). Baseline characteristics are summarized in Table 2. The median age was 56 years (IQR 50–63 years), and the patients were predominantly male (90.1%). Chronic hepatitis B virus (HBV) infection was the most common etiology (84.9%), and 127 (83.6%) patients had cirrhosis at enrollment. The majority of patients (128 [84.2%]) belonged to Child-Pugh A, but 15.8% had Child-Pugh B.Table 2 Characteristics of the Study Patients (n=152)\n\nVariables\t\t\nAge (years)\t56 (50–63)\t\nMale\t137 (90.1%)\t\nEtiology of HCC\t\n HBV/HCV/Alcoholic/Others\t129(84.9%)/4(2.6%)/3(2.0%)/16(10.5%)\t\nCirrhosis\t127 (83.6%)\t\nChild-Pugh class A/B\t128(84.2%)/24(15.8%)\t\nALBI grade 1/2/3\t34 (22.4%)/110 (72.3%)/8(5.3%)\t\nALBI score\t-2.21 (-2.54 ~ -1.89)\t\nPerformance status, ECOG 0/1\t82(53.9%)/70(46.1%)\t\nTumor size (cm)*\t8.8 (6–8.8)\t\nNumber of tumors\t\n 1/2/3/4/≥5\t66(43.4%)/29(19.1%)/9(5.9%)/2(1.3%)/46(30.3%)\t\nDepth of portal vein invasion\t\n Vp3/Vp4\t95(62.5%)/57(37.5%)\t\nInfiltrative tumor morphology\t82 (53.9%)\t\nTumor invasion to the right atrium or IVC\t7 (4.6%)\t\nLocation of tumor\t\n One lobe/Bi-lobes\t109(71.7%)/43(28.3%)\t\nAFP (ng/ml)\t1656 (38–21591)\t\nPIVKA-II (mAU/ml)\t2000 (266–2167)\t\nWhite blood cells (×103/µl)\t5.63 (4.53–7.16)\t\nHemoglobin (g/dL)\t12.9 (11.6–13.9)\t\nPlatelet count (×103/µl)\t153.5 (111–209)\t\nALT (IU/L)\t37 (23–56)\t\nAlbumin (g/dL)\t3.5(3.2–3.9)\t\nTotal bilirubin (mg/dL)\t0.8 (0.6–1.1)\t\nProthrombin time-INR\t1.07 (1.0–1.15)\t\nAbbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; IVC, inferior vena cava; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II; ALT, alanine aminotransferase; INR, international normalized ratio.\n\n\n\n\nThe median size of the largest HCC was 8.8 cm (IQR 6–8.8 cm), and 46 patients (30.3%) had ≥5 tumors. There were 57 (37.5%) patients with tumor invasion into Vp4 and 95 (62.5%) with tumor invasion into Vp3. Eighty-two (53.9%) patients had infiltrative tumor morphology.36–38 Only 7 (4.6%) patients had direct tumor invasion into the inferior vena cava (IVC) and/or right atrium. The median AFP and PIVKA-II levels were 1655.5 (IQR 38–21,591) ng/mL and 2000 (IQR 266–2167) mAU/mL, respectively.\n\nTreatment Delivery and Responses\nFour weeks after LD-CCRT, the ORR was 48.0%. Subsequently, patients underwent a median of 4 (IQR 2–6) cycles of HAIC. During the planned treatment courses, the ORR as their best responses increased to 55.3% (Table 3). Among a subgroup (n=56) undergoing TACE before the start of LD-CCRT, the ORRs 4 weeks after LD-CCRT and during the planned treatment courses were 55.4% and 62.5%, respectively. Radiological responses of malignant portal vein thrombosis as a non-measurable lesion by mRECIST32 4 weeks after LD-CCRT were as follows; CR (n=2, 1.3%), PR (n=52, 34.2%), stable disease (n=85, 55.9%), and progressive disease (n=13, 8.6%). During the planned treatment courses, they were 2.0% (n=3), 37.5% (n=57), 52.0% (n=79), and 8.6% (n=13), respectively.Table 3 Treatment Response\n\nRadiological Response 4 Weeks After LD-CCRT\t\n CR\t2 (1.3%)\t\n PR\t71 (46.7%)\t\n SD\t52 (34.2%)\t\n PD\t27 (17.8%)\t\nRadiological Response During the Planned Treatment Courses\t\n CR\t3 (2.0%)\t\n PR\t81 (53.3%)\t\n SD\t41 (27%)\t\n PD\t27 (17.8%)\t\nBiological Response 4 Weeks After LD-CCRT\t\n AFP response\t70 (46.1%)\t\n PIVKA-II response\t80 (52.6%)\t\nBiological Response During the Planned Treatment Courses\t\n AFP response\t99 (65.1%)\t\n PIVKA-II response\t100 (65.8%)\t\nChanges in AFP Level\t\n 4 weeks after LD-CCRT\t553 (22 ~ 5282)*\t\n During the planned treatment courses\t50 (8 ~ 1793)*\t\nChanges in PIVKA-II Level\t\n 4 weeks after LD-CCRT\t257 (41 ~ 2000)*\t\n During the planned treatment courses\t76 (29 ~ 1019)*\t\nNote: *All p<0.001 from each baseline level by Wilcoxon signed ranks test.\n\nAbbreviations: LD-CCRT, liver-directed concurrent chemoradiotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II.\n\n\n\n\nFour weeks after LD-CCRT, 46.1% and 52.6% had favorable biological response (defined as a ≥ 50% decrease in tumor marker from the baseline) by AFP and PIVKA-II, respectively. During the planned treatment courses, they were 65.1% and 65.8%, respectively. In detail, from the baseline (median 1656 ng/mL, IQR [38–21,591]). The AFP level significantly decreased to 553 ng/mL (IQR 22 ~ 5282) 4 weeks after LD-CCRT and 50 (8 ~ 1793) during the planned treatment courses (both p<0.001 by Wilcoxon signed ranks test). Likewise, from the baseline (median 2000 mAU/mL, [IQR 266–2167]), the PIVKA-II level significantly decreased to 257 mAU/mL (IQR 41 ~ 2000) 4 weeks after LD-CCRT and 76 mAU/mL (29 ~ 1019) during the planned treatment courses (both p<0.001 by Wilcoxon signed ranks test). Detailed changes in tumor size and their correlations with tumor markers were described in waterfall plots (Supplementary Figure 2A, 2B, and 2C) and the association between radiological and biological responses were summarized in Supplementary Table 2 and Supplementary Figure 3.).\n\nNotably, during the planned treatment courses, 16 patients (10.5%) underwent curative resection or OLT after successful down-staging. The median time from the initiation of LD-CCRT to the last follow-up among these 16 patients was 34.8 (IQR 21.1–60.9) months. Seven cases of death were observed between 7.2 and 61.6 months (median 22.0 months, IQR 15.0–59.0 months). Overall, there was no post-operative complication of > grade III by the Clavien-Dindo classification,39 except one post-OLT mortality. There was one intra-operative complication of weak pulsation after hepatic artery anastomosis during living donor OLT, for which the anastomosis of right hepatic artery of the graft to the common hepatic artery of the recipient was switched to transposition anastomosis with the left gastric artery of the recipient; this patient had no significant post-OLT complication. Two patients developed biliary strictures most likely 6 months after OLT, both of which were successfully treated with the endoscopic and/or percutaneous approaches. Among patients undergoing surgical resection, there was no significant post-operative complication; 5 patients developed the small amount of pleural effusion, all of which resolved spontaneously without any intervention.\n\nSurvival Outcomes and Prognosis Factors\nOverall, a total of 107 patients died and the median OS was 13.5 months (95% confidence interval [CI] 11.003–16.077) (Figure 1). The median PFS was 6.9 months (95% CI 6.326–7.474) (Figure 2). Treatment modalities after progression of disease included continuing intra-arterial chemotherapy (6.1%), LRTs such as TACE or Transarterial chemoinfusion (TACI) (16.0%), and systemic chemotherapy including systemic 5-fluorouracil plus cisplatin chemotherapy (9.9%) and sorafenib (23.7%). Palliative radiotherapy was delivered to patients with bone metastases (1.5%). The majority of patients with disease progression (32.2%) received supportive care.Figure 1 Kaplan–Meier analysis of OS.\n\nFigure 2 Kaplan–Meier analysis of PFS.\n\n\n\nTable 4 shows that only significant prognostic factor for OS was ALBI score (HR 1.523, 95% CI 1.032–2.246; p=0.034).Table 4 Prognostic Factors for Overall Survival\n\nVariables\tHR (95% CI)\tp-value\t\nAge\t0.999 (0.980 - 1.018)\t0.935\t\nMale\t1.073 (0.574 - 2.006)\t0.826\t\nCirrhosis\t1.461 (0.863 - 2.475)\t0.158\t\nChild-Pugh class B\t1.528 (0.947 - 2.466)\t0.082\t\nALBI score\t1.523 (1.032 - 2.246)\t0.034\t\nTumor size ≥ 10 cm\t1.272 (0.864 - 1.874)\t0.223\t\nNumber of tumors ≥4\t1.194 (0.799 - 1.784)\t0.386\t\nDepth of portal vein invasion(Vp4)\t1.242 (0.842 - 1.833)\t0.275\t\nInfiltrative tumor morphology\t1.161 (0.789 - 1.707)\t0.448\t\nAFP ≥ 400 ng/ml\t1.132 (0.770 - 1.666)\t0.528\t\nPIVKA-II ≥ 1000 mAU/ml\t1.058 (0.724 - 1.548)\t0.770\t\nPlatelet count, ×103/µl\t1.000 (0.998 - 1.002)\t0.938\t\nAbbreviations: HR, hazard ratio; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II; INR, international normalized ratio.\n\n\n\n\nSubgroup Analysis for Patients with Elevated AFP or PIVKA-II Levels at Baseline\nAmong 126 (82.9%) patients with baseline AFP > 20 ng/mL, 54.0% showed the favorable biological response 4 weeks after LD-CCRT. Such AFP responders were more likely to have the higher ORR 4 weeks after LD-CCRT (57.4% vs 34.5%, respectively; p=0.010 by chi-square test), and the longer OS (22.4 vs 10.8 months; p<0.001 by Log rank test) and PFS (9.0 vs 5.1 months; p=0.003 by Log rank test) than non-responders.\n\nLikewise, among 137 (90.1%) patients with baseline PIVKA-II >40 mAU/mL, 58.4% showed the favorable biological response 4 weeks after LD-CCRT. Such PIKVA-II responders were more likely to have the higher ORR 4 weeks after LD-CCRT (65.0 vs 21.1%, respectively; p<0.001 by chi-square test) and the longer OS (20.3 vs 11.5 months, respectively; p=0.001 by Log rank test) and PFS (7.7 vs 5.7 months, respectively; p=0.016 by Log rank test) than non-responders.\n\nSubgroup Analysis for Patients with HBV-Related HCC\nAmong 129 patients with HBV-related HCC, the ORRs 4 weeks after LD-CCRT and during the planned treatment courses were 49.6% and 55.8%, respectively. Likewise, 43.4% and 53.5% had favorable biological response by AFP and PIVKA-II, respectively, 4 weeks after LD-CCRT. They were 63.6% and 65.9%, respectively, during the planned treatment courses. The median OS and PFS were 14.1 (95% CI 11.358–16.902) and 7.2 (95% CI 6.553–7.847) months, respectively.\n\nTreatment-Related Adverse Events\nTreatment-related adverse events during the planned treatment schedules are summarized in Table 5. Three key events associated with RT for liver, ie ascites, hepatic encephalopathy, and melena were evaluated using the SOMA-LENT grading classification.40 Overall, deterioration in liver function (defined as a shift in Child-Pugh score by 2 or more points from the baseline) after LD-CCRT was observed in 46 patients (30.3%), while 38 patients (25.0%) demonstrated newly developed ascites. Among 129 patients with chronic HBV infection, three patients (2.3%) developed virologic breakthrough, all of whom were treated with appropriate antiviral therapy.41 After LD-CCRT, 32 patients (21.1%) developed radiation gastritis, while 16 patients (10.5%) experienced upper gastrointestinal bleeding, which was successfully managed with endoscopic hemostasis and medical management. Among patients receiving maintenance HAIC after LD-CCRT, HAIC was discontinued in one patient due to HCC rupture, in one patient due to hepatic encephalopathy, and in two patients due to sepsis.Table 5 Treatment-Related Adverse Events\n\n\tTotal\tEarly Period of < 6 Months\tLate Period of ≥ 6 Months\t\n\t\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tGrade 1\tGrade 2\tGrade 3\tGrade 4\t\nAlanine aminotransferase elevation\t77 (50.7%)\t33 (21.7%)\t11 (7.2%)\t4 (2.6%)\t-\t29 (19.1%)\t7 (4.6%)\t1 (0.7%)\t-\t\nHyperbilirubinemia\t57 (37.5%)\t25 (16.4%)\t8 (5.3%)\t2 (1.3%)\t-\t23 (15.1%)\t7 (4.6%)\t1 (0.7%)\t-\t\nHypoalbuminemia\t120 (78.9%)\t27 (17.8%)\t61 (40.1%)\t-\t-\t21 (13.8%)\t37 (24.3%)\t2 (1.3%)\t-\t\nAnemia\t125 (82.2%)\t28 (18.4%)\t43 (28.3%)\t11 (7.2%)\t-\t34 (22.4%)\t31 (20.4%)\t8 (5.3%)\t-\t\nNeutropenia\t119 (78.3%)\t28 (18.4%)\t43 (28.3%)\t34 (22.4%)\t-\t13 (8.6%)\t30 (19.7%)\t10 (6.6%)\t-\t\nThrombocytopenia\t141 (92.8%)\t34 (22.4%)\t61 (40.1%)\t28 (18.4%)\t-\t25 (16.4%)\t40 (26.3%)\t19 (12.5%)\t-\t\nAKI\t17 (11.2%)\t6 (3.9%)\t1 (0.7%)\t-\t-\t8 (5.3%)\t1 (0.7%)\t1 (0.7%)\t-\t\nGastritis\t31 (20.4%)\t11 (7.2%)\t8 (5.3%)\t11 (7.2%)\t-\t-\t5 (3.3%)\t1 (0.7%)\t-\t\nMelena*\t16 (10.5%)\t-\t2 (1.3%)\t6 (3.9%)\t5 (3.3%)\t1 (0.7%)\t1 (0.7%)\t4 (2.6%)\t1 (0.7%)\t\nHepatic encephalopathy*\t10 (6.6%)\t-\t-\t-\t1 (0.7%)\t-\t2 (1.3%)\t3 (2.0%)\t4 (2.6%)\t\nAscites*\t38 (25.0%)\t-\t21 (13.8%)\t11 (7.2%)\t-\t-\t11 (7.2%)\t12 (7.9%)\t1 (0.7%)\t\nNote: *By LENT-SOMA grading.\n\n\n\n\nDiscussion\nHCC with major portal vein invasion has poor prognosis and the median OS among such patients is expected to range from 7 to 8.5 months according to the real-life experience in the Republic of Korea.2,8 An effective systemic therapy is an important option for the treatment of HCC in the subset of patients with extrahepatic metastasis. However, considering that HCC is a rapidly growing locally aggressive disease frequently leading to the patients’ death before extrahepatic metastasis have developed, there has been various attempts to locally control the disease with LRTs, so far. For instance, the previous study showed that locally advanced HCC patients treated with LD-CCRT showed the higher ORRs at post-treatment 1 (46.8% VS 16.1%, respectively, P<0.001) and 3 (39.3% vs 21.4%, P=0.04) months than those treated with selective internal radiation therapy (SIRT), however, long-term response rates and survival rates were comparable.42 Two recent comparative trials comparing SIRT vs sorafenib in locally advanced HCC patients, ie SARAH and SIRveNIB, showed comparable median OS between the two treatment groups, but the response rate was higher in the SIRT as compared to sorafenib group, suggesting the potential of SIRT as more likelihood to control the tumor within the liver.18,43\n\nIn this study, we present locally advanced-stage HCC patients with major PV invasion receiving LD-CCRT with HAIC maintenance. Out of the total study population, 143 patients (94.0%) had poor oncological prognostic factors, including massive tumor (≥10 cm), infiltrative tumor morphology, tumor invasion into the main portal trunk (Vp4), tumor invasion into the IVC and/or right atrium, AFP level ≥400 ng/mL, or PIVKA-II level ≥1000 mAU/mL. In this population, LD-CCRT followed by maintenance HAIC demonstrated encouraging results, not only producing an objective response in 55.3% of subjects but also improving the median OS to 13.5 months. The median OS of 13.5 months in our study population with Vp3 or Vp4 invasion is notable given that patients with major PV invasion at baseline were excluded in that phase III trial. Even though our study is only a one-arm study with a retrospective design, our findings could at least reappraise the necessity of future prospective randomized clinical trials comparing the efficacy between active LRT and systemic chemotherapy in patients with advanced HCC with major PV invasion. Despite major portal vein invasion, LD-CCRT showed potential to convert unresectable HCC to resectable HCC. During the planned treatment courses, 10.5% of patients achieved successful down-staging from LD-CCRT and underwent curative resection or transplantation. The optimal treatment strategy for successful down-staging remains to be determined. Despite several positive results, repeated TACE alone is considered to be contraindicated in this population due to the potential of hepatic insufficiency resulting from ischemic insult.44–47 HAIC may be an eligible LRT option; however, the evidence for its efficacy remains weak.25 EBRT is also complicated by issues of systemic or local failure outside the RT field, notwithstanding the excellent intra-RT field disease control rate. Our findings indicate that EBRT-based LRT may be a useful strategy for down-staging of advanced-stage HCC.48\n\nOur treatment protocol for LD-CCRT has several advantages for the curative treatment for advanced-stage HCC. Most importantly, the FRL increased substantially after LD-CCRT,15 which is induced by a marked atrophy of the irradiated region and a compensatory enlargement of the non-irradiated region.49 Another advantage is that, optimal candidates for curative treatments could be selected through better assessment of the biological behaviors of advanced tumors during the period of so-called “neo-adjuvant” treatment. Finally, 5-fluorouracil could be useful as a radio-sensitizer for treating HCC as well as its anti-cancer effect;50–55 therefore, a synergistic effect against HCC might be expected. Although not all patients with advanced-stage HCC with major PV invasion would be eligible for EBRT-based active LRTs in real-world practice, the feasibility of EBRT-based active LRTs should be carefully assessed through a multi-disciplinary approach.\n\nThis study has several limitations. In the first place, it was a single-arm study with a retrospective design from the single institution and the higher proportion of male patients might be another problem, both of which can lead to selection bias. Therefore, additional multi-center, randomized controlled trials are required to prove the utility of LD-CCRT. However, our findings provided a rationale for further prospective clinical trials to assess the efficacy of alternative LRTs other than molecular-targeted agents alone as a recommended first-line modality in treating advanced-stage HCC with major PV invasion. Similarly, given that novel systemic agents such as atezolizumab plus bevacizumab will presently become available in the clinical setting,56 the potential benefits of induction LD-CCRT as a neo-adjuvant treatment should be studied further. Another limitation is that our results might not be generalizable to all HCC patients, since chronic HBV infection was the most predominant etiology among our study population.41,57,58 Furthermore, there was limited availability of second-line systemic agents in South Korea during the study period. Additional long-term follow-up to evaluate the entire clinical course of advanced-stage HCC is advisable.\n\nConclusion\nIn conclusion, LD-CCRT followed by maintenance HAIC demonstrated not only favorable outcomes through initial tumor size reduction but also acceptable tolerability in patients with advanced-stage HCC with major PV invasion. To confirm these results, further prospective clinical trials are required.\n\nDisclosure\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n1. Heimbach \nJK , Kulik \nLM , Finn \nRS , et al. AASLD guidelines for the treatment of hepatocellular carcinoma\n. Hepatology . 2018 ;67 (1 ):358 –380\n. doi:10.1002/hep.29086 28130846 \n2. Kim \nBK , Kim \nDY , Han \nKH , Seong \nJ . Changes in real-life practice for hepatocellular carcinoma patients in the Republic of Korea over a 12-year period: a nationwide random sample study\n. PLoS One . 2019 ;14 (10 ):e0223678 . doi:10.1371/journal.pone.0223678 31622424 \n3. Galle \nPR , Forner \nA , Llovet \nJM , EASL Clinical Practice . Guidelines: management of hepatocellular carcinoma\n. J Hepatol . 2018 ;69 (1 ):182 –236\n. doi:10.1016/j.jhep.2018.03.019 29628281 \n4. Kudo \nM , Finn \nRS , Qin \nS , et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised Phase 3 non-inferiority trial\n. Lancet . 2018 ;391 (10126 ):1163 –1173\n. doi:10.1016/S0140-6736(18)30207-1 29433850 \n5. Cheng \nAL , Kang \nYK , Chen \nZ , et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial\n. Lancet Oncol . 2009 ;10 (1 ):25 –34\n. doi:10.1016/S1470-2045(08)70285-7 19095497 \n6. Lee \nJM , Han \nKH . Positioning and indication of sorafenib in the treatment algorithm and real practice setting: western and eastern approach–Asian perspective\n. Oncology . 2010 ;78 (Suppl 1 ):167 –171\n. doi:10.1159/000315246 20616600 \n7. Bruix \nJ , Cheng \nAL , Meinhardt \nG , Nakajima \nK , De Sanctis \nY , Llovet \nJ . Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies\n. J Hepatol . 2017 ;67 (5 ):999 –1008\n. doi:10.1016/j.jhep.2017.06.026 28687477 \n8. Kim \nDY , Kim \nHJ , Han \nKH , et al. Real-life experience of sorafenib treatment for hepatocellular carcinoma in Korea: from gideon data\n. Cancer Res Treat . 2016 ;48 (4 ):1243 –1252\n.26910470 \n9. Liu \nPH , Huo \nTI , Miksad \nRA . Hepatocellular carcinoma with portal vein tumor involvement: best management strategies\n. Semin Liver Dis . 2018 ;38 (3 ):242 –251\n. doi:10.1055/s-0038-1666805 30041276 \n10. Lee \nD , Lee \nHC , An \nJ , et al. Comparison of surgical resection versus transarterial chemoembolization with additional radiation therapy in patients with hepatocellular carcinoma with portal vein invasion\n. Clin Mol Hepatol . 2018 ;24 (2 ):144 –150\n. doi:10.3350/cmh.2017.0041 29665630 \n11. Rim \nCH , Seong \nJ . Application of radiotherapy for hepatocellular carcinoma in current clinical practice guidelines\n. Radiat Oncol J . 2016 ;34 (3 ):160 –167\n. doi:10.3857/roj.2016.01970 27730805 \n12. Byun \nHK , Kim \nHJ , Im \nYR , Kim \nDY , Han \nKH , Seong \nJ . Dose escalation by intensity modulated radiotherapy in liver-directed concurrent chemoradiotherapy for locally advanced BCLC stage C hepatocellular carcinoma\n. Radiother Oncol . 2019 ;133 :1 –8\n. doi:10.1016/j.radonc.2018.12.025 30935563 \n13. Feng \nM , Suresh \nK , Schipper \nMJ , et al. Individualized adaptive stereotactic body radiotherapy for liver tumors in patients at high risk for liver damage: a phase 2 clinical trial\n. JAMA Oncol . 2018 ;4 (1 ):40 –47\n. doi:10.1001/jamaoncol.2017.2303 28796864 \n14. Sapisochin \nG , Barry \nA , Doherty \nM , et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis\n. J Hepatol . 2017 ;67 (1 ):92 –99\n. doi:10.1016/j.jhep.2017.02.022 28257902 \n15. Lee \nHS , Choi \nGH , Choi \nJS , et al. Surgical resection after down-staging of locally advanced hepatocellular carcinoma by localized concurrent chemoradiotherapy\n. Ann Surg Oncol . 2014 ;21 (11 ):3646 –3653\n. doi:10.1245/s10434-014-3652-3 24916746 \n16. Kim \nBK , Kim \nDY , Byun \nHK , et al. Efficacy and safety of liver-directed concurrent chemoradiotherapy and sequential sorafenib for advanced hepatocellular carcinoma; a prospective phase 2 trial\n. Int J Radiat Oncol Biol Phys . 2020 .\n17. Han \nKH , Seong \nJ , Kim \nJK , Ahn \nSH , Lee \nDY , Chon \nCY . Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis\n. Cancer . 2008 ;113 (5 ):995 –1003\n. doi:10.1002/cncr.23684 18615601 \n18. Shim \nJH , Park \nJW , Choi \nJI , Park \nBJ , Kim \nCM . Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a hepatitis B virus-endemic area\n. J Cancer Res Clin Oncol . 2009 ;135 (4 ):617 –625\n. doi:10.1007/s00432-008-0496-x 18846384 \n19. Llovet \nJM , Ricci \nS , Mazzaferro \nV , et al. Sorafenib in advanced hepatocellular carcinoma\n. N Engl J Med . 2008 ;359 (4 ):378 –390\n. doi:10.1056/NEJMoa0708857 18650514 \n20. Ishikawa \nT , Imai \nM , Kamimura \nH , et al. Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil: a pilot study\n. World J Gastroenterol . 2007 ;13 (41 ):5465 –5470\n.17907289 \n21. Choi \nJH , Chung \nWJ , Bae \nSH , et al. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis\n. Cancer Chemother Pharmacol . 2018 ;82 (3 ):469 –478\n. doi:10.1007/s00280-018-3638-0 29982870 \n22. Song \nMJ , Bae \nSH , Chun \nHJ , et al. A randomized study of cisplatin and 5-FU hepatic arterial infusion chemotherapy with or without adriamycin for advanced hepatocellular carcinoma\n. Cancer Chemother Pharmacol . 2015 ;75 (4 ):739 –746\n. doi:10.1007/s00280-015-2692-0 25663125 \n23. Lyu \nN , Kong \nY , Mu \nL , et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma\n. J Hepatol . 2018 ;69 (1 ):60 –69\n. doi:10.1016/j.jhep.2018.02.008 29471013 \n24. He \nM , Li \nQ , Zou \nR , et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial\n. JAMA Oncol . 2019 ;5 (7 ):953 –960\n. doi:10.1001/jamaoncol.2019.0250 31070690 \n25. Moriya \nK , Namisaki \nT , Sato \nS , et al. Bi-monthly hepatic arterial infusion chemotherapy as a novel strategy for advanced hepatocellular carcinoma in decompensated cirrhotic patients\n. Clin Mol Hepatol . 2019 ;25 (4 ):381 –389\n. doi:10.3350/cmh.2019.0037 31405269 \n26. Kim \nTH , Kim \nSY , Tang \nA , Lee \nJM . Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma: 2018 update\n. Clin Mol Hepatol . 2019 ;25 (3 ):245 –263\n. doi:10.3350/cmh.2018.0090 30759967 \n27. Kim \nYY , Park \nMS , Aljoqiman \nKS , Choi \nJY , Kim \nMJ . Gadoxetic acid-enhanced magnetic resonance imaging: hepatocellular carcinoma and mimickers\n. Clin Mol Hepatol . 2019 ;25 (3 ):223 –233\n. doi:10.3350/cmh.2018.0107 30661336 \n28. Park \nJY , Ahn \nSH , Yoon \nYJ , et al. Repetitive short-course hepatic arterial infusion chemotherapy with high-dose 5-fluorouracil and cisplatin in patients with advanced hepatocellular carcinoma\n. Cancer . 2007 ;110 (1 ):129 –137\n. doi:10.1002/cncr.22759 17508408 \n29. Bannangkoon \nK , Hongsakul \nK , Tubtawee \nT , Piratvisuth \nT . Safety margin of embolized area can reduce local recurrence of hepatocellular carcinoma after superselective transarterial chemoembolization\n. Clin Mol Hepatol . 2019 ;25 (1 ):74 –85\n. doi:10.3350/cmh.2018.0072 30813680 \n30. Miyayama \nS . Ultraselective conventional transarterial chemoembolization: when and how?\n\nClin Mol Hepatol . 2019 ;25 (4 ):344 –353\n. doi:10.3350/cmh.2019.0016 31022779 \n31. Park \nMS , Kim \nSU , Park \nJY , et al. Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis\n. Cancer Chemother Pharmacol . 2013 ;71 (1 ):165 –173\n. doi:10.1007/s00280-012-1993-9 23079897 \n32. Lencioni \nR , Llovet \nJM . Modified RECIST (mRECIST) assessment for hepatocellular carcinoma\n. Semin Liver Dis . 2010 ;30 (1 ):52 –60\n. doi:10.1055/s-0030-1247132 20175033 \n33. Ahn \nKS , Kang \nKJ . Appropriate treatment modality for solitary small hepatocellular carcinoma: radiofrequency ablation vs. resection vs. transplantation?\n\nClin Mol Hepatol . 2019 ;25 (4 ):354 –359\n. doi:10.3350/cmh.2018.0096 31006225 \n34. Chong \nJU , Choi \nGH , Han \nDH , et al. Downstaging with localized concurrent chemoradiotherapy can identify optimal surgical candidates in hepatocellular carcinoma with portal vein tumor thrombus\n. Ann Surg Oncol . 2018 ;25 (11 ):3308 –3315\n. doi:10.1245/s10434-018-6653-9 30083834 \n35. Han \nDH , Choi \nGH , Park \nJY , et al. Lesson from 610 liver resections of hepatocellular carcinoma in a single center over 10 years\n. World J Surg Oncol . 2014 ;12 .\n36. Burt \nAD , Alves \nV , Bedossa \nP , et al. Data set for the reporting of intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma: recommendations from the international collaboration on cancer reporting (ICCR)\n. Histopathology . 2018 ;73 (3 ):369 –385\n. doi:10.1111/his.13520 29573451 \n37. Reynolds \nAR , Furlan \nA , Fetzer \nDT , et al. Infiltrative hepatocellular carcinoma: what radiologists need to know\n. Radiographics . 2015 ;35 (2 ):371 –386\n. doi:10.1148/rg.352140114 25763723 \n38. Demirjian \nA , Peng \nP , Geschwind \nJF , et al. Infiltrating hepatocellular carcinoma: seeing the tree through the forest\n. J Gastrointest Surg . 2011 ;15 (11 ):2089 –2097\n. doi:10.1007/s11605-011-1614-7 21725699 \n39. Clavien \nPA , Barkun \nJ , de Oliveira \nML , et al. The Clavien-Dindo classification of surgical complications: five-year experience\n. Ann Surg . 2009 ;250 (2 ):187 –196\n. doi:10.1097/SLA.0b013e3181b13ca2 19638912 \n40. Routledge \nJA , Burns \nMP , Swindell \nR , Khoo \nVS , West \nCM , Davidson \nSE . Evaluation of the LENT-SOMA scales for the prospective assessment of treatment morbidity in cervical carcinoma\n. Int J Radiat Oncol Biol Phys . 2003 ;56 (2 ):502 –510\n. doi:10.1016/S0360-3016(02)04578-9 12738327 \n41. KASL . KASL clinical practice guidelines for management of chronic hepatitis B\n. Clin Mol Hepatol . 2019 ;25 (2 ):93 –159\n. doi:10.3350/cmh.2019.1002 31185710 \n42. Song \nJE , Jung \nKS , Kim \nDY , et al. Transarterial radioembolization versus concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma: a propensity score matching analysis\n. Int J Radiat Oncol Biol Phys . 2017 ;99 (2 ):396 –406\n.28871990 \n43. Gebski \nV , Gibbs \nE , Gandhi \nM , et al. VESPRO: an individual patient data prospective meta-analysis of selective internal radiation therapy versus sorafenib for advanced, locally advanced, or recurrent hepatocellular carcinoma of the SARAH and SIRveNIB trials\n. JMIR Res Protoc . 2017 ;6 (2 ):e17 . doi:10.2196/resprot.7016 28202430 \n44. Kim \nJH , Yoon \nHK , Kim \nSY , et al. Transcatheter arterial chemoembolization vs. chemoinfusion for unresectable hepatocellular carcinoma in patients with major portal vein thrombosis\n. Aliment Pharmacol Ther . 2009 ;29 (12 ):1291 –1298\n. doi:10.1111/j.1365-2036.2009.04016.x 19392861 \n45. Yamada \nR , Sato \nM , Kawabata \nM , Nakatsuka \nH , Nakamura \nK , Takashima \nS . Hepatic artery embolization in 120 patients with unresectable hepatoma\n. Radiology . 1983 ;148 (2 ):397 –401\n. doi:10.1148/radiology.148.2.6306721 6306721 \n46. Lee \nHS , Kim \nJS , Choi \nIJ , Chung \nJW , Park \nJH , Kim \nCY . The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study\n. Cancer . 1997 ;79 (11 ):2087 –2094\n. doi:10.1002/(SICI)1097-0142(19970601)79:11<2087::AID-CNCR5>3.0.CO;2-M 9179054 \n47. Costentin \nCE , Ferrone \nCR , Arellano \nRS , Ganguli \nS , Hong \nTS , Zhu \nAX . Hepatocellular carcinoma with macrovascular invasion: defining the optimal treatment strategy\n. Liver Cancer . 2017 ;6 (4 ):360 –374\n. doi:10.1159/000481315 29234639 \n48. Yoon \nSM , Ryoo \nBY , Lee \nSJ , et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial\n. JAMA Oncol . 2018 ;4 (5 ):661 –669\n. doi:10.1001/jamaoncol.2017.5847 29543938 \n49. Imada \nH , Kato \nH , Yasuda \nS , et al. Compensatory enlargement of the liver after treatment of hepatocellular carcinoma with carbon ion radiotherapy - relation to prognosis and liver function\n. Radiother Oncol . 2010 ;96 (2 ):236 –242\n. doi:10.1016/j.radonc.2010.03.025 20416964 \n50. Ben-Josef \nE , Normolle \nD , Ensminger \nWD , et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies\n. J Clin Oncol . 2005 ;23 (34 ):8739 –8747\n. doi:10.1200/JCO.2005.01.5354 16314634 \n51. Lee \nIJ , Seong \nJ . Radiosensitizers in hepatocellular carcinoma\n. Semin Radiat Oncol . 2011 ;21 (4 ):303 –311\n.21939860 \n52. McIntosh \nA , Hagspiel \nKD , Al-Osaimi \nAM , et al. Accelerated treatment using intensity-modulated radiation therapy plus concurrent capecitabine for unresectable hepatocellular carcinoma\n. Cancer . 2009 ;115 (21 ):5117 –5125\n. doi:10.1002/cncr.24552 19642177 \n53. Jang \nJW , Kay \nCS , You \nCR , et al. Simultaneous multitarget irradiation using helical tomotherapy for advanced hepatocellular carcinoma with multiple extrahepatic metastases\n. Int J Radiat Oncol Biol Phys . 2009 ;74 (2 ):412 –418\n. doi:10.1016/j.ijrobp.2008.08.034 18963538 \n54. Stillwagon \nGB , Order \nSE , Guse \nC , et al. 194 hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: a radiation therapy oncology group study\n. Int J Radiat Oncol Biol Phys . 1989 ;17 (6 ):1223 –1229\n. doi:10.1016/0360-3016(89)90530-0 2557307 \n55. Kim \nJS , Han \nKH , Lee \nDY , et al. Concurrent chemo-radiation therapy for advanced hepatocellular carcinoma with portal vein thrombosis\n. Taehan Kan Hakhoe Chi . 2002 ;8 (1 ):71 –79\n.12499819 \n56. Finn \nRS , Qin \nS , Ikeda \nM , et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma\n. N Engl J Med . 2020 ;382 (20 ):1894 –1905\n. doi:10.1056/NEJMoa1915745 32402160 \n57. Kim \nBH , Park \nJW . Epidemiology of liver cancer in South Korea\n. Clin Mol Hepatol . 2018 ;24 (1 ):1 –9\n. doi:10.3350/cmh.2017.0112 29249129 \n58. Liang \nLY , Wong \nGL . Unmet need in chronic hepatitis B management\n. Clin Mol Hepatol . 2019 ;25 (2 ):172 –180\n. doi:10.3350/cmh.2018.0106 30754963\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "7()",
"journal": "Journal of hepatocellular carcinoma",
"keywords": "concurrent chemoradiotherapy; hepatocellular carcinoma; portal vein invasion; prognosis; response",
"medline_ta": "J Hepatocell Carcinoma",
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"pages": "403-412",
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"pmid": "33365287",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
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"title": "Appraisal of Long-Term Outcomes of Liver-Directed Concurrent Chemoradiotherapy for Hepatocellular Carcinoma with Major Portal Vein Invasion.",
"title_normalized": "appraisal of long term outcomes of liver directed concurrent chemoradiotherapy for hepatocellular carcinoma with major portal vein invasion"
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"abstract": "Twenty-two asymptomatic women with rising CA 125 levels after chemotherapy for ovarian cancer were entered into a trial of isotretinoin combined with calcitriol. Tumours were evaluated according to precise criteria based on serial CA 125 levels and by comparing regression slopes of CA 125 before and during therapy. There was no evidence based on CA 125 of any responses or significant change in tumour growth rate.",
"affiliations": "Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK.",
"authors": "Rustin|G J|GJ|;Quinnell|T G|TG|;Johnson|J|J|;Clarke|H|H|;Nelstrop|A E|AE|;Bollag|W|W|",
"chemical_list": "D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D015474:Isotretinoin; D002117:Calcitriol",
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"doi": "10.1038/bjc.1996.568",
"fulltext": "\nBritsh Joumal of Cancer (1996) 74, 1479-1481\n\n? 1996 Stockton Press All rights reserved 0007-0920/96 $12.00\n\nTrial of isotretinoin and calcitriol monitored by CA 125 in patients with\novarian cancer\n\nGJS Rustin', TG Quinnell', J Johnson', H Clarke2, AE Nelstrop' and W Bollag3\n\n'Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex\nHA6 2RN, UK; 2Department of Medical Oncology, Charing Cross Hospital, London W6 8RF, UK; 3Pharmaceutical Research, F\nHoffmann-La Roche Ltd., CH-4002, Basle, Switzerland.\n\nSummary Twenty-two asymptomatic women with rising CA 125 levels after chemotherapy for ovarian cancer\nwere entered into a trial of isotretinoin combined with calcitriol. Tumours were evaluated according to precise\ncriteria based on serial CA 125 levels and by comparing regression slopes of CA 125 before and during\ntherapy. There was no evidence based on CA 125 of any responses or significant change in tumour growth rate.\n\nKeywords: calcitriol; isotretinoin; CA 125; ovarian cancer\n\nRetinoids have been shown in vitro and in animal\nexperiments to have inhibitory activity against a wide range\nof solid tumours. The single-agent activity in man has been\ndisappointing apart from in acute promyelocytic leukaemia\n(Smith et al., 1992). However, combination therapy with\ninterferon has shown considerable activity against cervical\ncarcinoma (Lippman et al., 1992). This has suggested that\nretinoids should be tested with a variety of other biologically\nactive agents. The vitamin D metabolite, 1,25 dihydroxy\nvitamin D3 (calcitriol), is one agent that has shown additive\nor synergistic activity on differentiation, angiogenesis and\nproliferation when combined with retinoids (Bollag et al.,\n1994). A trial of alphacalcidol in low-grade non-Hodgkin's\nlymphoma showed evidence of response in four of seven\npatients (Rains et al., 1991). Topical calcipotriol produced\npartial responses in three of 14 patients with drug-resistant\nbreast carcinoma (Bower et al., 1991). The combination of\nisotretinoin (13 cis-retinoic acid) and calcitriol has been\nshown to lead to remissions in some patients with cutaneous\nT-cell lymphoma, basal cell and squamous cell carcinomas\n(French et al., 1994; Majewski et al., 1994; Thomsen, 1995).\n\nOvarian cancer was chosen for the investigation of\nretinoids as all-trans retinoic acid causes growth inhibition\nin ovarian carcinoma cell lines (Caliaro et al., 1994).\nAdditional factors favouring ovarian carcinoma are that it\nis rarely associated with hypercalcaemia, and relapsing\ntumour detected by rising levels of serum CA 125 can be\nasymptomatic for several months (Van der Burg et al., 1990).\nThese patients can, therefore, receive the isotretinoin and\ncalcitriol combination for a sufficient period, so that\nstabilisation of disease owing to tumour differentiation can\nbe manifested. CA 125 is elevated in over 90% of patients\nwith advanced ovarian cancer and has been shown to predict\ntumour response and progression accurately (Rustin et al.,\n1993, 1996a, b), but this is, to our knowledge, the first trial in\nwhich it has been used as the main mediator of efficacy.\n\nPatients and methods\n\nAll eligible patients had histologically or cytologically proven\ndiagnosis of epithelial ovarian carcinoma. Essential criteria\nwere: prior treatment with at least one standard chemother-\napy regimen, a greater than 3 month interval since\ncompleting the last course of chemotherapy; progression of\n\nCorrespondence: GJS Rustin\n\nReceived 4 March 1996; revised 1 May 1996; accepted 21 May 1996\n\ndisease, defined as a CA 125 level that had risen to more than\n100 U ml-'; a Karnofsky performance status of at least 60;\nan ability to take oral medication; a serum creatinine less\nthan 1.5 x upper limit of normal; LFTs and bilirubin less\nthan 2 x upper limit of normal; serum calcium within normal\nrange; and no serious concomitant physical or psychiatric\ndisease.\n\nTreatment consisted of isotretinoin 1 mg kg-' per day\norally, which was continued throughout the study, unless\nthey experienced severe cheilitis or skin toxicity, when the\ndose was halved. Calcitriol was taken orally initially at a dose\nof 0.5 Mg per day. It was escalated every week by 0.5 ,g, to a\nmaximum of 4 ,g, provided the corrected serum calcium\nremained below 3 mmol-' 1. Calcitriol was taken at least 4 h\nafter the last meal to reduce absorption of calcium from the\ngut, and thus reduce the risk of hypercalcaemia. Calcitriol\nwas stopped for 1 week if the serum calcium rose above\n3 mmol '1, and then reintroduced at 1 Mg a day less than\npreviously. Other treatments were allowed to be administered\nas required, provided the treatment was not known to affect\nthe tumour type in question.\n\nToxicity was recorded daily by patients using a diary card.\nThis listed the expected toxicities and asked patients to assign\na number against each toxicity each day, recording 0 as no\ntoxicity, 1 as a little, 2 as moderate and 3 as severe. Patients\nwere considered evaluable for toxicity if they completed 1\nmonth of treatment. They continued treatment, toxicity\npermitting, until there was evidence of disease progression.\nThis progression could be clinical, radiological or defined\naccording to serum CA 125, if after two samples there was a\n25% rise confirmed by a fourth sample, or a serial rise of\n50% over three samples (Rustin et al., 1993).\n\nSerum calcium was measured weekly for the first 8 weeks\nand then monthly thereafter. Serum CA 125 was assessed\nwith similar frequency. Full blood count, renal and liver\nfunction were assessed monthly.\n\nStatistical analysis\n\nThe regression slope of serial CA 125 levels in log units was\ncalculated before and during therapy. For each patient, serial\nCA 125 levels during the trial period were compared with\nlevels over the equivalent time period immediately before the\ntreatment. If the patient had undergone other anti-cancer\ntherapy within that preceding period, then the pretrial\nCA 125 trend was taken from the end of that therapy.\nResponse according to CA 125 was also predicted to have\noccurred if, after two samples, there had been a 50% fall,\nconfirmed by a fourth sample, or there had been a serial fall\nof 75% over three samples. The final sample had to be at\nleast 28 days after the previous sample (Rustin et al., 1996a).\n\nAo.,& isotretinoin and caicitriol trial in ovarian cancer\nr_opql GJS Rustin et al\n1480\n\nIn order not to miss minor falls in CA 125 levels, the above\ndefinitions were also modified to examine 40% and 10% falls\nin CA 125 levels.\n\nResults\n\nA total of 22 patients were treated in this study, 14 at Mount\nVernon Hospital and eight at the Charing Cross Hospital.\nThe duration of therapy is shown in Table I. Breaks in\ntherapy occurred as a result of corrected serum calcium\n> 3.0 mmol ' 1 in 11 patients, holiday in one patient, surgery\nin another and both hypercalcaemia and unexplained hip\npains in another. The maximum achievable dose of calcitriol\nwas 4.0 ,ug in three patients, 3.5 ig in one, 3.0 ,ug in five,\n2.5 Mg in four, 2.0 Mg in six, 1.5 Mg in two and 1.0 Mg in one.\nThe corrected serum calcium was > 3 mmol-1 1 in 14\npatients, but this level was not reached in the three patients\nwho achieved 4.0 Mug calcitriol. The reasons for going off\nstudy were clinical tumour progression in 15 cases, patient\nrequest because of restriction on eating before taking\ncalcitriol in two cases (one after 44 weeks on study), and\ntoxicity plus knowledge of rising CA 125 in two more. Two\npatients came of study after 65 and 85 weeks before surgery.\n\nToxicity\n\nThe trial therapy was generally well tolerated, possibly\nbecause these patients had all received prior cisplatin or\ncarboplatin, which was far more toxic. Patients were all\nadvised on use of moisturising creams and lip balms to\nreduce the toxicity. Table II summarises the most severe side-\neffects experienced by 22 patients during the study. Toxicity\ndata were not recorded in the patient who came off study\nafter just 2 weeks. The highest grade of toxicity according to\nNCIC/CTC criteria wvas: haemoglobin grade 2, three patients;\ngrade 1, five patients; lymphocytes grade 2, one patient; grade\n1, six patients; no white blood cell or platelet toxicity;\ncreatinine grade 3, one patient; grade 2, one patient; grade 1,\nten patients; alkaline phosphatase grade 2, one patient; grade\n1, five patients.\n\nTable I Duration on time study\n\nWeeks on studya Number of patients Number with breaks\n\n<4 1 0\n4-8 5 1\n9-20 9 5\n21-74+ 7 7\n\n'Actual weeks receiving both isotretinoin and calcitriol, excluding\nbreaks owing to hypercalcaemia.\n\nTable II Toxicity\n\nToxicity Grade I Grade 2 Grade 3\nSore lips 7 11 4\nDry skin 7 10 2\nSore eyes 8 4 2\nNausea 3 4 7\nVomiting 5 4 1\nJoint aches 6 3 8\nSkin rash 6 2 3\nFatigue 5 5 3\nHeadaches 6 4 0\nAnorexia 4 6 1\nPain 5 6 3\nHair loss 4 2 0\nMouth ulcers 3 0 0\nConstipation 0 2 1\nDizziness 1 0 0\n\nMaximum toxicity based on diary cards completed by 22 patients.\nGrade l, a little; 2, moderate; 3, severe.\n\nTumour response\n\nSixteen patients received at least 9 weeks of isotretinoin and\ncalcitriol and were considered evaluable for response\naccording to CA 125 criteria. No patients had a 50% or\n75% response according to our CA 125 definitions (Rustin et\nal., 1996a). When the percentage fall of CA 125 levels was\nreduced to 40% to qualify for a response, one patient was\nclassified as 'improving', and when reduced to a 10% fall,\ntwo patients were classified as 'improving'. The regression\nslope of CA 125 in log units increased in six cases during\ntherapy, and in ten cases it decreased compared with the\npretreatment regression slope. This provides no evidence of a\ntreatment effect (P = 0.45) (binomial test). Clinical evidence of\ntumour progression while on therapy was seen in 11 of 17\nevaluable patients. A serial rise in CA 125 levels of >25%\nwas seen in 12 of 16 evaluable patients during the study.\n\nThree of the 16 evaluable patients have no evidence of\ntumour progression on study. One of these stopped after 44\nweeks at her request and had a treatment-free interval before\nentering the study of almost 4 years, suggesting a slowly\nprogressive tumour. Another with a treatment-free interval of\nalmost 2 years continues on therapy after 52 weeks, as her\nCA 125 level has plateaued. The only patient who may have\nbenefited from this trial had a stage 3 borderline serous\ncarcinoma diagnosed in 1984. Since 1990, she has received\nfive different chemotherapy regimens for symptomatic\nprogressive tumour before starting on the isotretinoin and\ncalcitriol trial. There has been a steady decline in CA 125\nlevels since then, and she has remained symptomatically\nbetter than at any period since 1990. Apart from a few delays\ncaused by hypercalcaemia and unexplained hip pain that\nresolved spontaneously, she continued on study in for 85\nweeks. Remaining tumour was then removed surgically.\n\nDisscussion\n\nThe absence of any responses among 16 evaluable patients\nsuggests that treatment of recurrent ovarian carcinoma with a\ncombination of isotretin and calcitriol is not effective. There\nwas probable benefit in one patient with borderline ovarian\nserous carcinoma, which was behaving in a malignant,\ninvasive manner. That this woman has had a longer period\nwithout progression since on this combination than after any\nof her previous five lines of chemotherapy is suggestive of\nsome effect on her tumour.\n\nThe previous reports of responses to isotretinoin and\ncalcitriol were all in tumour types that have been associated\nwith responses to retinoids alone. The lack of responses to\nthis combination in patients with ovarian carcinoma could\nbe a result of this tumour type lacking the appropriate\nreceptors. Animal studies have shown responses of breast\ncancer to combinations of retinoids and hormones or\ncytokines. It would be difficult to test this combination in\npatients with breast cancer owing to the associated high\nincidence of hypercalcaemia. New vitamin D analogues,\nwhich have a greater anti-proliferative than hypercalcaemic\neffect, will enable these studies to take place (Coombes,\n1993).\n\nThis study has demonstrated the merits of using serum\nCA 125 for new drug evaluation. Patients who have a\nconfirmed rise of CA 125 levels that have risen to twice the\nupper limit of normal after initial chemotherapy for ovarian\ncarcinoma were shown in a study of 130 evaluable women to\nhave a greater than 98% chance of developing clinical\nevidence of tumour progression (Rustin et al., 1996b).\nRequiring a rise of CA 125 to > 100 U ml-' is even stronger\n\nevidence of recurrent disease. It is currently unclear whether\nearly reintroduction of chemotherapy is of any value to these\nwomen, many of whom will remain free of symptoms for\nlong periods. Once these women are aware of a rising CA 125\nvalue, many desire some form of therapy. They are, therefore,\nideal candidates for assessment of drugs, such as differentiat-\n\nIsotretinoin and calcitriol trial in ovarian cancer\nGJS Rustin et a!\n\n1481\n\ning or anti-metastatic agents, that may only induce disease\nstabilisation and may require to be given for long periods to\nasymptomatic women.\n\nMany studies have included analysis of CA 125 trends\nduring therapy, but we believe that this is the first study in\nwhich CA 125 was the main method of tumour assessment.\nWe have previously shown that response to initial\nchemotherapy can be accurately measured by using precise\ndefinitions based on either a 50% or 75% fall in CA 125\nlevels (Rustin et al., 1996a). These response definitions based\non CA 125 have been studied in phase II trials of seven\ndifferent new drugs and in each case have clearly shown\nwhich drugs are active and which are inactive (Rustin et al.,\n1996c). The lack of responses according to CA 125 in the\npresent study can. therefore, be relied upon. Because we were\n\nalso looking for disease stabilisation, we examined the rate of\nrise of CA 125 during therapy and compared this slope with\na similar period before therapy. The lack of significant\ndifference between the regression slopes plus the observation\nof clinical progression in 11 of 16 evaluable patients is\nevidence that the vitamin combination did not induce\nstabilisation. The observation that a >25% rise in CA 125\nlevels was seen in 12 of 16 evaluable women during the\ntherapy is further evidence of tumour progression.\n\nAcknowledgements\n\nThis work was supported in part by a grant from Roche Products\nLtd. We thank C Froy for statistical help.\n\nReferences\n\nBOLLAG W, MAJEWSKI S AND JABLONSKA S. (1994). Biological\n\ninteractions with cytokines and vitamin D analogs as a basis for\ncancer combination chemotherapy. In Retinoids: from Basic\nScience to Clinical Applications. Livrea MA, Vidali G. (eds). pp.\n267-280. Birkhauser Verlag: Basle.\n\nBOWER M, COLSTON KW, STEIN RC, HEDLEY A, GAZET J-C, FORD\n\nHT AND COOMBES RC. (1991). Topical calcipotriol treatment in\nadvanced breast cancer. Lancet, 1, 701-702.\n\nCALIARO MJ, MARMOUGET C, GUICHARD S, MAZARS PH,\n\nVALETTE A, MOISAND A, BUGAT R AND JOZAN S. (1994).\nResponse of four human ovarian carcinoma cell lines to all-trans\nretinoic acid: relationship with induction of differentiation and\nretinoic acid receptor expression. Int. J. Cancer, 56, 743 -748.\n\nCOMMBES RC. (1993). Vitamin D and cell proliferation. Mol.\n\nAspects Med., 14, 407 -41 1.\n\nFRENCH LE, RAMELET AA AND SAURAT J-H. (1994). Remission of\n\ncutaneous T-cell lymphoma with combined calcitriol and\nacitretin. Lancet, 344, 686-687.\n\nLIPPMAN SM, KAVANAGH JJ, PAREDES-ESPINOZA M, DELGADIL-\n\nLO-MADRUENO F, PAREDES-CASILLAS P, HONG WK, HOLD-\nENER E AND KRAKOFF IH. (1992). 13-cis-Retinoic acid plus\ninterferon alpha-2a: highly active systemic therapy for squamous\ncell carcinoma of the cervix. J. Natl Cancer Inst., 84, 241.\n\nMAJEWSKI S, SKOPINSKA M, BOLLAG W AND JABLONSKA S.\n\n(1994). Combination of isotretinoin and calcitriol for precancer-\nous and cancerous skin lesions. Lancet, 344, 1510- 1511.\n\nRAINS V, CUNNINGHAM D AND SOUKOP M. (1991). Alfacalcidol is\n\na nontoxic, effective treatment of follicular small-cleaved cells\nlymphoma. Br. J. Cancer, 63, 463 -465.\n\nRUSTIN GJS, VAN DER BURG MEL AND BEREK JS. (1993). Tumour\n\nmarkers. Ann. Oncol., 4, S71 -S77.\n\nRUSTIN GJS, NELSTROP A, AND MCLEAN P. (1996a). Defining\n\nresponse of ovarian carcinoma to initial chemotherapy according\nto serum CA 125. J. Clin Oncol., 14, 1545- 1551.\n\nRUSTIN GJS, NELSTROP AE, TUXEN MK AND LAMBERT HE.\n\n(1996b). Defining progression of ovarian carcinoma during\nfollow-up according to CA 125: A North Thames Ovary Group\nStudy. Ann Oncol., 7, 361-364.\n\nRUSTIN GJS, NELSTROP A AND MCCLEAN P. (1996c) Use of serum\n\nCA 125 to define response. In Ovarian Cancer 4. Sharp F, Blackett\nT, Leake R, Berek J. (eds). pp. 129- 134. Chapman Hall: London.\nSMITH MA, PARKINSON DR, CHESON BD AND FRIEDMAN MA.\n\n(1992). Retinoids in Cancer Therapy. J. Clin. Oncol., 10, 839-\n864.\n\nTHOMSEN K. (1995). Cutaneous T-cell lymphoma and calcitriol and\n\nisotretinoin treatment. Lancet, 345, 1583.\n\nVAN DER BURG MEL, LAMMES FB AND VERWEIJ J. (1990). The role\n\nof CA 125 in the early diagnosis of progressive disease in ovarian\ncancer. Ann. Oncol., 1, 301-302.\n\n",
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"issue": "74(9)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D002117:Calcitriol; D005260:Female; D006801:Humans; D015474:Isotretinoin; D010051:Ovarian Neoplasms",
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"pages": "1479-81",
"pmc": null,
"pmid": "8912548",
"pubdate": "1996-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Trial of isotretinoin and calcitriol monitored by CA 125 in patients with ovarian cancer.",
"title_normalized": "trial of isotretinoin and calcitriol monitored by ca 125 in patients with ovarian cancer"
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"abstract": "Pertuzumab is a monoclonal antibody that targets and down regulates HER-2/neu expression in ductal breast tumors. Other HER-2/neu monoclonal antibodies, particularly trastuzumab, have been implicated to induce infusion related reactions such as cytokine release syndrome (CRS). Here, we report a case of pertuzumab associated CRS prior to infusion of trastuzumab which warranted hospitalization for symptom management.",
"affiliations": "College of Pharmacy, University of Florida, Gainesville, FL, USA.;Department of Anesthesia, Faculty of Health Sciences, McMaster University, Hamilton, ON, USA.;College of Medicine, University of Florida, Gainesville, FL, USA.;College of Medicine, University of Florida, Gainesville, FL, USA.",
"authors": "Khoury|Adonice|A|;Parihar|Vikas|V|;O'steen|Lillie|L|;Cherabuddi|Kartikeya|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C485206:pertuzumab; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.12943",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-122X",
"issue": "24(3)",
"journal": "The breast journal",
"keywords": "HER-2/neu monoclonal antibodies; cytokine release syndrome; infusion related reactions; pertuzumab",
"medline_ta": "Breast J",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D023341:Chills; D016207:Cytokines; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D013577:Syndrome; D013610:Tachycardia; D000068878:Trastuzumab; D014839:Vomiting",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "383-384",
"pmc": null,
"pmid": "29027290",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pertuzumab and trastuzumab infusion related cytokine release syndrome in a chemotherapy naive patient with metastatic breast cancer.",
"title_normalized": "pertuzumab and trastuzumab infusion related cytokine release syndrome in a chemotherapy naive patient with metastatic breast cancer"
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"abstract": "We studied occurrence, presentation, disease course, effect of adjunctive dexamethasone, and prognosis of bacterial meningitis in patients using immunosuppressive medication. Patients were selected from our nationwide, prospective cohort on community-acquired bacterial meningitis performed from March 1, 2006 through October 31, 2014. Eighty-seven of 1447 episodes (6 %) of bacterial meningitis occurred in patients using immunosuppressive medication, and consisted of corticosteroids in 82 %. Patients with bacterial meningitis using immunosuppressive medication were less likely to present with headache (P = 0.02) or neck stiffness (P = 0.005), as compared those not on immunosuppressive medication. In 46 % of episodes CSF leukocyte count was below 1000/mm3. CSF cultures revealed S. pneumoniae in 41 % and L. monocytogenes in 40 % of episodes. Outcome was unfavorable in 39 of 87 episodes (45 %) and death occurred in 22 of 87 episodes (25 %). Adjunctive dexamethasone was administered in 52 of 87 (60 %) episodes, and mortality tended to be lower in those on adjunctive dexamethasone therapy as compared to those without dexamethasone therapy (10 of 52 [19 %] vs 12 of 35 [34 %], P = 0.14). We conclude that bacterial meningitis in patients using immunosuppressive medication is likely to present with atypical clinical and laboratory features, and is often caused by atypical bacteria, mainly L. monocytogenes. Adjunctive dexamethasone is widely prescribed in these patients and was not associated with harm in this study.",
"affiliations": "Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD, Amsterdam, the Netherlands.;Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD, Amsterdam, the Netherlands.;Department of Medical Microbiology and The Netherlands Reference Laboratory for Bacterial Meningitis, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.;Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD, Amsterdam, the Netherlands. d.vandebeek@amc.uva.nl.",
"authors": "van Veen|Kiril E B|KEB|;Brouwer|Matthijs C|MC|;van der Ende|Arie|A|;van de Beek|Diederik|D|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1007/s11481-016-9705-6",
"fulltext": "\n==== Front\nJ Neuroimmune PharmacolJ Neuroimmune PharmacolJournal of Neuroimmune Pharmacology1557-18901557-1904Springer US New York 970510.1007/s11481-016-9705-6PerspectiveBacterial Meningitis in Patients using Immunosuppressive Medication: a Population-based Prospective Nationwide Study van Veen Kiril E. B. 12Brouwer Matthijs C. 1van der Ende Arie 3van de Beek Diederik d.vandebeek@amc.uva.nl 11 0000000084992262grid.7177.6Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD Amsterdam, the Netherlands 2 0000 0004 0395 6796grid.414842.fDepartment of Neurology, Medical Center Haaglanden, The Hague, the Netherlands 3 0000000084992262grid.7177.6Department of Medical Microbiology and The Netherlands Reference Laboratory for Bacterial Meningitis, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 9 9 2016 9 9 2016 2017 12 2 213 218 10 5 2016 29 8 2016 © The Author(s) 2016\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.We studied occurrence, presentation, disease course, effect of adjunctive dexamethasone, and prognosis of bacterial meningitis in patients using immunosuppressive medication. Patients were selected from our nationwide, prospective cohort on community-acquired bacterial meningitis performed from March 1, 2006 through October 31, 2014. Eighty-seven of 1447 episodes (6 %) of bacterial meningitis occurred in patients using immunosuppressive medication, and consisted of corticosteroids in 82 %. Patients with bacterial meningitis using immunosuppressive medication were less likely to present with headache (P = 0.02) or neck stiffness (P = 0.005), as compared those not on immunosuppressive medication. In 46 % of episodes CSF leukocyte count was below 1000/mm3. CSF cultures revealed S. pneumoniae in 41 % and L. monocytogenes in 40 % of episodes. Outcome was unfavorable in 39 of 87 episodes (45 %) and death occurred in 22 of 87 episodes (25 %). Adjunctive dexamethasone was administered in 52 of 87 (60 %) episodes, and mortality tended to be lower in those on adjunctive dexamethasone therapy as compared to those without dexamethasone therapy (10 of 52 [19 %] vs 12 of 35 [34 %], P = 0.14). We conclude that bacterial meningitis in patients using immunosuppressive medication is likely to present with atypical clinical and laboratory features, and is often caused by atypical bacteria, mainly L. monocytogenes. Adjunctive dexamethasone is widely prescribed in these patients and was not associated with harm in this study.\n\nKeywords\nCorticosteroidsBacterial meningitisListeria monocytogenesImmunosuppressive medicationStreptococcus pneumoniaehttp://dx.doi.org/10.13039/501100001826ZonMw916.13.078016.116.358European Research Council (BE)281156issue-copyright-statement© Springer Science+Business Media New York 2017\n==== Body\nIntroduction\nCommunity-acquired bacterial meningitis is a severe infectious disease with high morbidity and mortality rates (Brouwer et al. 2010), and is most commonly caused by Streptococcus pneumoniae (van de Beek et al. 2004b). Acquired immunodeficiency previously has been associated with an increased risk of bacterial meningitis (Adriani et al. 2013; van Veen et al. 2016; Weisfelt et al. 2010). One of the most common acquired conditions causing immunodeficiency is the use of immunosuppressive medication, including corticosteroids. The proposed mechanisms by which corticosteroids cause immunosuppression are decreased production, function and migration of inflammatory cells and decreased antibody production (Fardet et al. 2007). A meta-analysis showed an increased risk of systemic infections for patients using corticosteroids compared to patients not using corticosteroids, with a relative risk of 1.6 (95 % confidence interval [CI] 1.3–1.9), although it remains unclear whether corticosteroids or the underlying disease increased the risk of infection (Stuck et al. 1989). The use of immunosuppressive medication has been reported to be an important predisposing factor for infections with Listeria monocytogenes (Yildiz et al. 2007). Glucocorticoids can also mask the symptoms of infection and therefore delay treatment because patients present at an advanced stage of disease (Fardet et al. 2007).\n\nLittle is known about the clinical course of bacterial meningitis in patients using immunosuppressive medication.\n\nRandomized clinical trials have evaluated the efficacy of adjunctive corticosteroid therapy in community-acquired bacterial meningitis (Brouwer et al. 2015; de Gans and van de Beek 2002; van de Beek et al. 2004a; van de Beek et al. 2010). As a result, adjunctive dexamethasone has been incorporated in treatment guidelines for bacterial meningitis (Tunkel et al. 2004; van de Beek et al. 2012; van de Beek et al. 2006). However, patients on immunosuppressive medication were excluded from the clinical trial and guidelines generally discourage the use of adjunctive dexamethasone in patients using immunosuppressive medication (Tunkel et al. 2004; van de Beek et al. 2012; van de Beek et al. 2006).\n\nWe studied clinical features and outcome of community-acquired bacterial meningitis in adults using immunosuppressive medication identified in a nationwide prospective cohort study, and evaluated the effect of adjunctive dexamethasone in this particular subgroup of patients.\n\nMethods\nWe conducted a nationwide, prospective cohort study on community-acquired bacterial meningitis. Methods have been described in detail previously (Bijlsma et al. 2016). From this cohort we selected all patients who were reported to use immunosuppressive medication. Immunosuppressive medication were classified in four main groups: glucocorticoids, small molecule drugs (e.g. cyclosporine, tacrolimus, everolimus, mycophenolate mofetil, azathioprine), protein drugs (e.g. horse or rabbit antithymocyte globulin, rituximab) and cytostatic drugs (Halloran 2004). Between March 2006 and October 2014, patients with bacterial meningitis over 16 years old were included. Bacterial meningitis was defined as a positive cerebrospinal fluid (CSF) culture or as a positive blood culture with a relevant pathogen, positive PCR or antigen test in cerebrospinal fluid, in combination with at least one CSF finding predictive of bacterial meningitis consisting of a CSF leukocyte count >2000 cells/mm3, polymorphonuclear leukocyte count >1180 cells/mm3, glucose level < 1.9 mmol/L, protein level > 2gL, or CSF/blood glucose ratio < 0.23 (Spanos et al. 1989).\n\nPatients with a neurosurgical device, neurosurgical operation or procedure and patients with neurotrauma within one month of the onset of meningitis were excluded from the cohort. Data on patient history, symptoms and signs on admission, laboratory findings, radiologic examination, treatment, and outcome were prospectively collected by means of a case record form (CRF). Dosage of immunosuppressive medication was collected retrospectively from the discharge letters. For corticosteroids the dosage was calculated as the daily prednisolone equivalent dose. To this end dosage of hydrocortisone was divided by 4 and dosage of dexamethasone was multiplied by 6.7. All patients underwent neurologic examination at hospital discharge, and outcome was graded using the Glasgow Outcome Scale (GOS). A favorable outcome was defined as a score of 5, and an unfavorable outcome was defined as a score of 1 to 4.\n\nThe study was approved by the ethical committee of the Academic Medical Center.\n\nStatistical analyses were performed with the use of SPSS statistical software, version 22 (SPSS Inc.). For numerical and ordinal data the student t-test or Mann-Whitney U test were used. For categorical data the Fisher exact test was used. Logistic regression was used to examine the association between potential predictors and the likelihood of an unfavorable outcome and of death. Odds ratios (OR) and 95 % confidence intervals were used to quantify the strength of these associations. Possible predictors of an unfavorable outcome and death were chosen on the basis of previous research (Koopmans et al. 2013; van de Beek et al. 2004b). All tests were 2-tailed, and p < 0.05 was considered significant.\n\nResults\nPatients and Immunosuppressive Medication\nA total of 1447 episodes of bacterial meningitis were included in the cohort between March 2006 and October 2014. Medication on admission was known for 1435 patients (99 %). In 87 of these episodes (6 %) in 86 patients, patients were reported to use immunosuppressive medication.\n\nThe immunosuppressive treatment consisted of glucocorticoids in 71 episodes and was used as monotherapy in 45 episodes, and in combination with other immunosuppressive treatment in 26 episodes (Table 1). Auto-immune diseases (e.g. rheumatoid arthritis, ulcerative colitis) in 38 of 87 episodes (44 %) and cancer in 21 of 87 episodes (24 %) were the most frequent indications for immunosuppressive therapy. For corticosteroids, the median daily dosage was 20 mg prednisone (interquartile range [IQR] 7–30 mg). The median age of patients using immunosuppressive medication at the time of the episode of bacterial meningitis was 65 years (range 19–91 years; Table 2). Other co-existing conditions increasing the risk of meningitis were diabetes mellitus (in 16 episodes), alcoholism (in six episodes), and splenectomy (in four episodes). Distant foci of infection were identified in 25 of 82 episodes (31 %). One patient had a recurrence of bacterial meningitis during the study period and had a medical history of kidney transplantation.Table 1 Groups of immunosuppressive agents and categories of indication\n\nImmunosuppressive medication\tn/N (%)\tIndication\tn/N (%)\t\nGlucocorticoids\t45/87 (52)\tAuto-immune disease\t38/87 (44)\t\nGlucocorticoids + small molecule drugs\t13/87 (15)\t Rheumatoid arthritis\t12/38 (32)\t\nGlucocorticoids + cytostatic drugs\t9/87 (10)\t Ulcerative colitis\t7/38 (18)\t\nGlucocorticoids + protein drugs\t3/87 (3)\t Polymyalgia rheumatica\t5/38 (13)\t\nGlucocorticoids + SMD + PD\t1/87 (1)\t Auto-immune hepatitis\t3/38 (8)\t\nCytostatic drugs\t9/87 (10)\t Systemic lupus erythematosus\t3/38 (8)\t\nCytostatic drugs + protein drugs\t1/87 (1)\t Other auto-immune disease\t8/38 (21)\t\nSmall molecule drugs\t6/87 (7)\tCancer\t21/87 (24)\t\nMedian dosage prednisone in mga\n\t20 (7–30)b\n\tRenal transplantation\t6/87 (7)\t\n\t\tOther\t11/87 (13)\t\n\t\tUnknown\t4/87 (5)\t\n\nPD protein drugs, SMD small molecule drugs\n\n\naKnown in 46 of 71 patients\n\n\nbInterquartile range\n\n\nTable 2 Comparison between patients with and without immunosuppressive medicationa\n\n\nCharacteristic\timmunosuppressive medication +\timmunosuppressive medication –\tP-value\t\nAge (years)\t65 (19–91)\t61 (17–94)\t0.002\t\nFemale\t30/87 (34)\t674/1348 (50)\t0.006\t\nSymptoms and signs on admission\t\n Headache\t56/78 (72)\t962/1161 (83)\t0.02\t\n Neck stiffness\t51/85 (60)\t945/1261 (75)\t0.005\t\n Triad of fever, neck stiffness, and change in mental status\t31/86 (36)\t543/1283 (42)\t0.26\t\n Absence of fever, neck stiffness, and change in mental status\t7/87 (8)\t43/1334 (3)\t0.03\t\nPredisposing factorsb\n\t23/87 (26)\t266/1348 (20)\t0.13\t\nDistant focus of infection\t25/82 (30)\t581/1289 (45)\t0.01\t\nBlood chemistry testsc\n\t\n Leukocyte count (×109/L)\t13.9 (0.1–45.6)\t17.1 (0.1–99.8)\t0.0001\t\n C-reactive protein (mg/L)\t163 (3–500)\t192 (0–752)\t0.28\t\nIndexes of inflammation in CSFd\n\t\n Leukocyte count (cells/mm3)\t1368 (5–46,500)\t2560 (0–463,149)\t0.003\t\n Leukocyte count <1000 cells/mm3\n\t39/85 (46)\t401/1234 (32)\t0.02\t\n Protein (g/L)\t3.00 (0.45–11.0)\t4.00 (0.02–50.0)\tP < 0.0005\t\n CSF/blood glucose ratio\t0.17 (0.0–0.89)\t0.04 (0.0–1.67)\t0.003\t\nCausative organism\t\n \nStreptococcus pneumoniae\n\t37/87 (43)\t981/1348 (73)\tP < 0.0001\t\n \nListeria monocytogenes\n\t35/87 (40)\t43/1348 (3)\t\nP < 0.0001\t\n \nHaemophilus influenzae\n\t6/87 (7)\t44/1348 (3)\t0.12\t\n \nNeisseria meningitidis\n\t2/87 (2)\t147/1348 (11)\t0.006\t\n Othere\n\t7/87 (8)\t133/1348 (10)\t0.71\t\nOutcome\t\n Unfavorable outcome\t39/87 (45)\t495/1348 (37)\t0.14\t\n Mortality\t22/87 (25)\t219/1348 (16)\t0.04\t\n Neurological sequelae\t18/53 (34)\t360/997 (36)\t0.88\t\n\nCSF cerebrospinal fluid\n\n\naData are presented as n/N (%), or median (range)\n\n\nbOther than immunosuppressive medication\n\n\ncLeukocyte count was known in 86 and 1327 episodes and C-reactive protein in 85 and 1283\n\n\ndCSF leukocyte count was known in 85 and 1234 episodes, CSF protein levels in 85 and 1275 episodes, and CSF blood to glucose ratio in 77 and 1249 episodes\n\n\neSee Table 2 for details of causative organisms\n\n\n\n\nClinical Features\nHeadache occurred in 56 of 78 episodes (72 %), neck stiffness in 51 of 85 episodes (60 %), fever in 64 of 86 episodes (74 %), and a change in mental status (defined by a GOS score below 14) in 61 of 87 of episodes (70 %). The classic triad of fever, neck stiffness, and a change in mental status was present in 31 of 86 of episodes (36 %). In 7 of 87 of episodes (8 %), fever, neck stiffness, and a change in mental status were all absent. Headache and neck stiffness were less often present in patients using immunosuppressive medication compared to patients not using immunosuppressive medication (respectively 56 of 78 [72 %] vs 961 of 1161 [83 %], P = 0.02 and 51 of 85 [60 %] vs 945 of 1261 [75 %], P = 0.005; Table 2).\n\nA lumbar puncture was performed in all patients. Independent predictors of bacterial meningitis (Spanos et al. 1989) were present in 72 of 87 (83 %) patients. Median CSF leukocyte count was 1368 cells/mm3 (IQR 443–3166 cells/mm3). Patients using immunosuppressive medication had lower CSF leukocyte count as compared to bacterial meningitis patients not using immunosuppressive medication (1368 cells/mm3 vs 2560 cells/mm3, P = 0.003) and more often a leukocyte count <1000 cells/mm3 (39 of 85 [46 %] vs. 401 of 1234 [32 %], P = 0.02).\n\nBlood chemistry tests showed patients using immunosuppressive medication often had no or only mildly elevated whole blood leukocyte counts (median 13.9 × 109/L [IQR 9.1–20.0 × 109/L]). In 30 of 86 of episodes (35 %) patients had blood leukocyte counts of <11.0 × 109/L.\n\nNeuroimaging (computed tomography) was performed on admission in 75 of 87 episodes (86 %) concerning patients using immunosuppressive medication, and showed abnormalities in 26 patients: brain abscess in two, sinus or mastoid opacification in nine, generalized brain edema in eight, a hypodense lesion presumed to be infarction in three, subdural effusion in two, and hydrocephalus in one. Both patients with brain abscess had listerial meningitis. Of the patients with a brain abscess one presented with aphasia and confusion while the other had no focal neurologic deficits.\n\nCSF cultures revealed S. pneumoniae in 36 episodes (41 %), L. monocytogenes in 35 episodes (40 %), Haemophilus influenzae in six episodes (7 %), and Neisseria meningitidis in two episodes (2 %). One patient had a negative CSF culture, but had a positive antigen test for S. pneumoniae as causative organism. Other causative organisms were Escherichia coli in two episodes and Nocardia farcinica, Streptococcus anginosus, Streptococcus mitis, and Pseudomonas aeruginosa in one episode each. Pneumococcal and meningococcal meningitis occurred less often in patients using immunosuppressive medication compared to those who did not (37 of 87 [43 %] vs. 981 of 1348 [73 %], P = <0.0001 and 2 of 87 [2 %] vs. 147 of 1348 [11 %], P = 0.006), whilst listerial meningitis was encountered more frequently (35 of 87 [40 %] vs. 43 of 1348 [3 %], P < 0.0001). Inadequate initial antimicrobial therapy was started in seven of 86 patients (8 %) and consisted of failure to start amoxicillin in patients with L. monocytogenes meningitis in five patients.\n\nOutcome\nOutcome was unfavorable in 39 of 87 episodes (45 %) of bacterial meningitis in patients using immunosuppressive medication and in 22 of 87 episodes (25 %) the patient died. The rate of unfavorable outcome was similar between patients with and without immunosuppressive medication (39 of 87 [45 %] vs. 495 of 1348 [37 %], P = 0.14) but mortality was higher in those using immunosuppressive medication (22 of 87 [25 %] vs. 219 of 1348 [16 %], P = 0.04). In a univariable analysis, the use of immunosuppressive medication was associated with death (OR 1.75; 95 % CI 1.05–2.89, P = 0.03). In a multivariable analysis adjusting for age (categories: < 40, 40–70, > 70 years), otitis or sinusitis, diabetes mellitus, neck stiffness, score on GOS, CSF leukocyte (<1000 cells/mm3), CSF protein (g/l), thrombocyte count (< 150 × 1012/L), C-reactive protein (mg/l) and L. monocytogenes, the use of immunosuppressive medication was no longer associated with death (OR 0.94, 95 % CI 0.46–1.93, P = 0.86).\n\nNeurological sequelae occurred in 18 of 53 surviving patients (34 %) and consisted mostly of cognitive impairment in eight of 52 episodes (15 %) and cranial nerve palsies in eight of 53 episodes (15 %). The use of immunosuppressive medication did not influence the risk of sequelae (OR 1.09; 95 % CI 0.62–1.91; P = 0.76).\n\nAdjunctive Dexamethasone Therapy\nIn 52 of 87 episodes (60 %), patients were treated with adjunctive dexamethasone according to guideline recommendations (10 mg four times per day for 4 days, administered before or together with the antibiotics). In three episodes dexamethasone was started but discontinued because L. monocytogenes was identified as the pathogen. Baseline characteristics between those who did and did not receive dexamethasone were similar. Unfavorable outcome was observed in 21 of 52 episodes (40 %) of patients treated with adjunctive dexamethasone and in 18 of 35 episodes (51 %) not treated with adjunctive dexamethasone (P = 0.289). There was a trend towards protection against death for patients treated with dexamethasone (10 of 52 [19 %] vs 12 of 35 [34 %], P = 0.14). In an univariable analysis, for patients using immunosuppressive medication the OR of adjunctive dexamethasone treatment for death was 0.46 (95 % CI 0.17–1.22, P = 0.12). The effect size was not influenced by known predictors of death – age, score on GOS and L. monocytogenes as causative organism – in a multivariable analysis (OR 0.46; 95 % CI 0.16–1.31; P = 0.15). No adverse events related to the treatment with adjunctive dexamethasone were reported.\n\nDiscussion\nPatients with bacterial meningitis using immunosuppressive medication are less likely to present with typical clinical characteristics of meningitis, such as headache and neck stiffness, and have less marked CSF white cell counts. About half of patients had a CSF white cell count below 1000 per mm3; however, about 80 % had one of more independent CSF predictors of bacterial meningitis (Spanos et al. 1989). Cultures often reveal L. monocytogenes (40 %) or other atypical causative organisms, such as Nocardia or Pseudomonas. To prevent diagnostic and therapeutic delay, a low threshold should be kept for performing a lumbar puncture in patients using immunosuppressive medication, even those with a low clinical suspicion of bacterial meningitis. Adjunctive dexamethasone is widely prescribed for patients using immunosuppressive medication who are admitted with bacterial meningitis and is not associated with harm.\n\nThe association of Listeria infections with immunosuppressive medication, and glucocorticoids especially, has been well recognized by earlier studies (Hooper et al. 1982; Yildiz et al. 2007). The predilection for immunocompromised hosts may be explained by the intracellular life cycle of L. monocytogenes by which it avoids host bactericidal mechanisms. Resistance to infection is predominantly mediated by cellular immunity and their elimination requires T lymphocytes mediated cytotoxicity (Horta-Baas et al. 2013). Guidelines advise the use of a third generation cephalosporin combined with ampicillin or amoxicillin if L. monocytogenes is suspected (Chaudhuri et al. 2008; Tunkel et al. 2004). Based on the high frequency of L. monocytogenes as causative organism in patients using immunosuppressive medication identified in our cohort, empiric treatment for patients using immunosuppressive medication should be broad and include ampicillin or amoxicillin for listeria coverage in combination with an extended spectrum cephalosporin.\n\nAdjunctive dexamethasone did not influence rates of unfavorable outcome. However, there was trend towards protection against death for patients treated with dexamethasone. This observed effect size was similar to that of the total population of bacterial meningitis patients and was not influenced by known other risk factors of mortality (de Gans and van de Beek 2002). Patients treated with adjunctive dexamethasone did not experience a higher rate of dexamethasone-related complications such as hyperglycemia requiring insulin, gastric bleeding, and herpes simplex infection. Randomized controlled trials on the effect of adjunctive dexamethasone in bacterial meningitis either do not report on the use of corticosteroids or immunosuppressive medication (de Gans and van de Beek 2002; Molyneux et al. 2002; Nguyen et al. 2007), or have glucocorticoids or immunosuppressive medication as an exclusion criterion (Peltola et al. 2007; Scarborough et al. 2007). With the number of patients included in this analysis we lack power to identify a significant association of dexamethasone, but we found a similar effect as was identified in previous studies. Based on these findings the use of adjunctive dexamethasone should be considered in patients using immunosuppressive medication.\n\nOur study has limitations. The observational design of the study is sensitive to the introduction of confounding factors, which hinder the evaluation of dexamethasone effectiveness.\n\nOther limitations of this study were that only patients with culture-proven meningitis were included in our cohort study. Not all patients with suspected bacterial meningitis may undergo a lumbar puncture, e.g. patients with coagulopathy due to sepsis or those with space-occupying lesions on cranial imaging. These patients were not included in our cohort. As the use of immunosuppressive medication is a risk factor for brain abscess, we could have missed cases of bacterial meningitis in patients use of immunosuppressive medication (Selby et al. 1997).\n\nIn conclusion, patients with bacterial meningitis using immunosuppressive medication are less likely to present with typical clinical characteristics of meningitis and have less marked CSF abnormalities. Cultures often reveal L. monocytogenes (40 %) or other atypical causative organisms. Adjunctive dexamethasone is widely prescribed for patients using immunosuppressive medication who are admitted with bacterial meningitis and was not found to be associated with harm, although studies in larger sample size are needed to validate these findings.\n\nCompliance with Ethical Standards\nStudy Funding\nThis study has been funded by grants from the Netherlands Organization for Health Research and Development (ZonMw; NWO-Veni grant 2012 [916.13.078] to MB, NWO-Vidi grant 2010 [016.116.358] to DB), the Academic Medical Center (AMC Fellowship 2008 to DB), and the European Research Council (2011 ERC Starting Grant 281,156 to DB). The Netherlands Reference Laboratory for Bacterial Meningitis is supported by the National Institute of Public health and the Environmental Protection, Bilthoven.\n\nConflicts of Interest\nThe authors declare that they have no conflict of interest.\n\nInformed Consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\nAdriani KS, Brouwer MC, van der Ende A, van de Beek D (2013) Bacterial meningitis in adults after splenectomy and hyposplenic states vol 88. doi:10.1016/j.mayocp.2013.02.009\nBijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, van der Ende A, van de Beek D (2016) Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis 16(3):339--47. doi:10.1016/S1473-3099(15)00430-2\nBrouwer MC, Tunkel AR, van de Beek D (2010) Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis vol 23. doi:10.1128/CMR.00070-09\nBrouwer MC, McIntyre P, Prasad K, van de Beek D (2015) Corticosteroids for acute bacterial meningitis vol 9. doi:10.1002/14651858.CD004405.pub5\nChaudhuri A et al. (2008) EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults vol 15. doi:10.1111/j.1468-1331.2008.02193.x\nde Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study I (2002) Dexamethasone in adults with bacterial meningitis vol 347. doi:10.1056/NEJMoa021334\nFardet L, Kassar A, Cabane J, Flahault A (2007) Corticosteroid-induced adverse events in adults: frequency, screening and prevention vol 30.\nHalloran PF (2004) Immunosuppressive medication for kidney transplantation vol 351. doi:10.1056/NEJMra033540\nHooper DC, Pruitt AA, Rubin RH (1982) Central nervous system infection in the chronically immunosuppressed vol 61.\nHorta-Baas G, Guerrero-Soto O, Barile-Fabris L (2013) Central nervous system infection by Listeria monocytogenes in patients with systemic lupus erythematosus: analysis of 26 cases, including the report of a new case vol 9. doi:10.1016/j.reuma.2013.04.011\nKoopmans MM, Brouwer MC, Bijlsma MW, Bovenkerk S, Keijzers W, van der Ende A, van de Beek D (2013) Listeria monocytogenes sequence type 6 and increased rate of unfavorable outcome in meningitis: epidemiologic cohort study vol 57. doi:10.1093/cid/cit250\nMolyneux EM et al. (2002) Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial vol 360.\nNguyen TH et al. (2007) Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis vol 357. doi:10.1056/NEJMoa070852\nPeltola H et al. (2007) Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial vol 45. doi:10.1086/522534\nScarborough M et al. (2007) Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa vol 357. doi:10.1056/NEJMoa065711\nSelby R, Ramirez CB, Singh R, Kleopoulos I, Kusne S, Starzl TE, Fung J (1997) Brain abscess in solid organ transplant recipients receiving cyclosporine-based immunosuppression vol 132.\nSpanos A, Harrell FE, Jr., Durack DT (1989) Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations vol 262.\nStuck AE, Minder CE, Frey FJ (1989) Risk of infectious complications in patients taking glucocorticosteroids vol 11.\nTunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ (2004) Practice guidelines for the management of bacterial meningitis vol 39. doi:10.1086/425368\nvan de Beek D, de Gans J, McIntyre P, Prasad K (2004a) Steroids in adults with acute bacterial meningitis: a systematic review vol 4. doi:10.1016/S1473-3099(04)00937-5\nvan de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M (2004b) Clinical features and prognostic factors in adults with bacterial meningitis vol 351. doi:10.1056/NEJMoa040845\nvan de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community-acquired bacterial meningitis in adults vol 354. doi:10.1056/NEJMra052116\nvan de Beek D et al. (2010) Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data vol 9. doi:10.1016/S1474-4422(10)70023-5\nvan de Beek D, Brouwer MC, Thwaites GE, Tunkel AR (2012) Advances in treatment of bacterial meningitis vol 380. doi:10.1016/S0140-6736(12)61186-6\nvan Veen KE, Brouwer MC, van der Ende A, van de Beek D (2016) Bacterial meningitis in patients with HIV: A population-based prospective study. doi:10.1016/j.jinf.2016.01.001\nWeisfelt M, de Gans J, van der Ende A, van de Beek D (2010) Community-acquired bacterial meningitis in alcoholic patients vol 5. doi:10.1371/journal.pone.0009102\nYildiz O, Aygen B, Esel D, Kayabas U, Alp E, Sumerkan B, Doganay M (2007) Sepsis and meningitis due to Listeria monocytogenes vol 48.\n\n",
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"keywords": "Bacterial meningitis; Corticosteroids; Immunosuppressive medication; Listeria monocytogenes; Streptococcus pneumoniae",
"medline_ta": "J Neuroimmune Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008089:Listeria monocytogenes; D008297:Male; D016920:Meningitis, Bacterial; D008875:Middle Aged; D009426:Netherlands; D011159:Population Surveillance; D011446:Prospective Studies; D055815:Young Adult",
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"title": "Bacterial Meningitis in Patients using Immunosuppressive Medication: a Population-based Prospective Nationwide Study.",
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"abstract": "Cancer treatment-related toxicities often require dose reductions and delays. Herbal medicine use is prevalent among cancer patients. Though evidence is lacking regarding benefits in treatment outcomes and immunity, a large body of evidence supports the use of herbals for reducing treatment-induced toxicities. We present three cases where herbal medicine provided relief from side effects of anti-cancer treatment, enabling the completion of treatment protocols. In the first case, a 79 year-old female patient with metastatic breast cancer developed flushing and excessive sweating from Tamoxifen treatment. Herbal medicine reduced symptoms significantly, enabling the continuation of treatment with partial disease resolution. In the second case, a 69 year-old male with esophageal cancer terminated treatment on the adjuvant treatment protocol because of severe nausea and vomiting, diarrhea, peripheral neuropathy and fatigue. Herbal medicine reduced symptom severity and chemotherapy was reinstituted. In the third case, a 58 year-old female patient with advanced metastatic colon cancer was referred by her oncologist for treatment with herbal medicine for alleviation of fatigue and weakness, flushing and palpitations, mouth ulcers and dyspnea. Despite significant symptom reduction, with completion of treatment regimens, her disease progressed and she subsequently succumbed to the disease. In summary, the above cases illustrate potential benefits of herbal medicine in the reduction of cancer treatment-related symptoms, enabling patients to complete their anti-cancer treatment regimen. Further research examining the efficacy and safety of herbal compounds is needed, in light of potential toxicity and negative interactions with conventional treatment.",
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"title": "Use of herbal medicine for cancer treatment-related toxicities.",
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"abstract": "A 54-year-old female presented after taking an overdose of an unknown amount of hydrochlorothiazide, doxazocin, atenolol and amlodipine. She was initially refractory to treatment with conventional therapy (intravenous fluids, activated charcoal, glucagon 5 mg followed with glucagon drip, calcium gluconate 10%, and atropine). Furthermore, insulin at 4 U/kg was not effective in improving her hemodynamics. Shortly after high dose insulin was achieved with 10 U/kg, there was dramatic improvement in hemodynamics resulting in three of five vasopressors being weaned off in 8 h. She was subsequently off all vasopressors after six additional hours. The role of high dose insulin has been documented in prior cases, however it is generally recommended after other conventional therapies have failed. However, there are other reports that suggest it as initial therapy. Our patient failed conventional therapies and responded well only with maximum dose of insulin. Physicians should consider high dose insulin early in severe beta blocker or calcium channel blocker overdose for improvement in hemodynamics. This leads to early discontinuation of vasopressors. It is important that emergency physicians be aware of the beneficial effects of high dose insulin when initiated early as opposed to waiting for conventional therapy to fail; as these patients often present first to the emergency department. Early initiation in the emergency department can be beneficial in these patients.",
"affiliations": "Department of Internal Medicine, University of Florida, College of Medicine, Jacksonville, United States. Electronic address: karan.seegobin@jax.ufl.edu.;Department of Internal Medicine, University of Florida, College of Medicine, Jacksonville, United States.;Department of Internal Medicine, University of Florida, College of Medicine, Jacksonville, United States.;Department of Internal Medicine, University of Florida, College of Medicine, Jacksonville, United States.",
"authors": "Seegobin|Karan|K|;Maharaj|Satish|S|;Deosaran|Ansuya|A|;Reddy|Pramod|P|",
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"journal": "The American journal of emergency medicine",
"keywords": "Beta-blocker; Calcium channel blocker; High dose insulin; Medication overdose",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D003131:Combined Modality Therapy; D003956:Dialysis; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D005440:Fluid Therapy; D006439:Hemodynamics; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008875:Middle Aged; D011654:Pulmonary Edema; D013406:Suicide, Attempted; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents",
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"title": "Severe beta blocker and calcium channel blocker overdose: Role of high dose insulin.",
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"abstract": "Postoperative chemotherapy during pregnancy after first trimester is essential for patients with initial disease stage 1, grade 2 ovarian immature teratoma and it associates with lower disease progression and recurrence.",
"affiliations": "Cancer Research Center Mashhad University of Medical Sciences Mashhad Iran.;Cancer Research Center Mashhad University of Medical Sciences Mashhad Iran.",
"authors": "Homaei Shandiz|Fatemeh|F|;Emadi Torghabeh|Ali|A|https://orcid.org/0000-0003-2090-8182",
"chemical_list": null,
"country": "England",
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"doi": "10.1002/ccr3.4456",
"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/ccr3.4456\nCCR34456\nCase Report\nCase Reports\nManagement of ovarian immature teratoma grade‐II in pregnancy, two cases report and literature review\nHOMAEI SHANDIZ and EMADI TORGHABEH\nHomaei Shandiz Fatemeh 1 2\nEmadi Torghabeh Ali https://orcid.org/0000-0003-2090-8182\n1 2 EmadiTA@mums.ac.ir\n\n1 Cancer Research Center Mashhad University of Medical Sciences Mashhad Iran\n2 Faculty of Medicine Department of Radiotherapy and Oncology Mashhad University of Medical Sciences Mashhad Iran\n* Correspondence\nAli Emadi Torghabeh. Cancer Research Center, Mashhad University of Medical Sciences, Omid Hospital, Koohsangi Street, Mashhad 9176613775 Iran.\nEmail: EmadiTA@mums.ac.ir\n\n10 7 2021\n7 2021\n9 7 10.1002/ccr3.v9.7 e0445608 5 2021\n04 2 2021\n31 5 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\nPostoperative chemotherapy during pregnancy after first trimester is essential for patients with initial disease stage 1, grade 2 ovarian immature teratoma and it associates with lower disease progression and recurrence.\n\nPostoperative chemotherapy during pregnancy after first trimester is essential for patients with initial disease stage 1, grade 2 ovarian immature teratoma and it associates with lower disease progression and recurrence.\n\nchemotherapy\novarian immature teratoma grade 2\npregnancy\nsource-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:10.07.2021\nHomaei Shandiz F , Emadi Torghabeh A . Management of ovarian immature teratoma grade‐II in pregnancy, two cases report and literature review. Clin Case Rep. 2021;9 :e04456. 10.1002/ccr3.4456\n==== Body\n1 INTRODUCTION\n\nThe occurrence of immature ovarian teratoma is a rare condition during pregnancy. Considering the difficulties of surgery and adjuvant chemotherapy in high‐grade cases during the pregnancy, its management is controversial. Here, two cases of grade‐II ovarian immature teratomas in two pregnant women along with their management and outcomes were presented.\n\nOvarian germ cell tumors are considered as a rare female malignancy accounting for less than five percent of all ovarian tumors with an incidence rate of 0.34 per 100,000 women per years. 1 , 2 The occurrence of this ovarian tumor during the pregnancy is extremely scarce, and currently, there are not enough data on its clinical presentation, appropriate diagnostic work‐up, and management except some case reports.\n\nThe immature ovarian teratomas of ovaries are originated from the three germ layers (endo‐, meso‐ and ectoderm). Histological tumor grades, based on the amount of immature neuroepithelium within the tumoral tissue, determine the prognosis of patients directly. 3 , 4\n\nIn nonpregnant patients, treatments mainly depend on the surgical resection of the primary tumor with adjuvant chemotherapy in high‐grade tumors. However, during the pregnancy, the management of these tumors is controversial considering the difficulties of surgery and also adjuvant chemotherapy in this situation.\n\nHere, two cases of grade‐II ovarian immature teratoma in two pregnant women along with their management and outcomes were presented.\n\n2 CASE 1\n\nThe patient was a primigravid 21‐year‐old woman whose complaint was abdominal pain in the sixth week of pregnancy. She has no specific past medical history, and the familial history was negative. The patient underwent abdomen‐pelvic ultrasonography showing a live embryo at the age of 6–7 weeks along with a right ovarian cyst at the size of 140 × 150 mm consists of the solid component. Laboratory assessments were normal. The patient underwent laparotomy and right ovarian cystectomy. Pathological assessment of the ovarian tumor revealed a yellow 150 × 140 mm solid cystic lesion on the right ovary that microscopically there were embryonic tissues from all three cell lines including adipose, cartilage, and neurogenic connective tissues, confirming the diagnosis of grade‐II immature teratoma (Figure 1). Then, the patient referred and evaluated in a multidisciplinary team (MDT) recommended a metastasis wok‐up using a chest x‐ray (CXR) by shielding of abdomen and pelvis and initiation of adjuvant chemotherapy by BEP regimen (bleomycin 30 unit on days 1, 8, 15 plus etoposide 100 mg/m2 days 1–5 plus cisplatin 20 mg/m2 days 1–5) while the pregnancy continued. In addition, for comprehensive staging, the MDT recommended that complete surgical staging by a fertility‐preserving approach be considered after delivery.\n\nFIGURE 1 Immature component of teratoma including neuroepithelial elements with rosette formation\n\nResults of the prechemotherapy evaluation were normal. At the 15 weeks 6‐day gestational age, chemotherapy by BEP regimen every 3 weeks began. After the third cycle of chemotherapy, whereas the age of the fetus was 26 weeks, the patient underwent cesarean section (C/S) due to gestational hypertension followed by eclampsia. During C/S, a complete surgical staging by a fertility‐preserving approach using the complete right oophorectomy and peritoneal fluid sampling was performed. Pathologic assessment of right ovary and peritoneal fluid was negative for malignancy. The general condition of the patient was good, but unfortunately, a male newborn died due to immaturity. Thereafter, the patient followed in our clinic every 2–3 months. After 2 years of follow‐up, all clinic and paraclinical evaluations including tumor markers, imaging of chest, and abdomen‐pelvic are normal. Besides, she got pregnant 15 months after the completion of treatment and now she has a 1‐year‐old baby.\n\n3 CASE 2\n\nThe patient was a multigravid 2, live 1, 29‐year‐old woman complaining of abdominal pain in the second month of pregnancy. The abdomen‐pelvic ultrasonography reported an intrauterine 7‐week live embryo along with an 82 × 64 mm left adnexal cystic mass consisted of a 58* 41 mm solid component (Figure 2). After 1 month, she underwent laparoscopic resection of the left ovarian mass. Pathologic assessment of ovarian tumor revealed immature teratoma, grade 2 (Figure 3). The patient was evaluated in an MDT in our department, and metastasis work‐up by a fetus protected CXR, and initiation of adjuvant chemotherapy using BEP regimen and completion of pregnancy were recommended.\n\nFIGURE 2 Ovarian cystic mass with solid component\n\nFIGURE 3 Mature ectodermal component including squamous epithelium and hair follicles\n\nThe CXR was normal. However, the patient revoked her consents to perform adjuvant chemotherapy until the delivery. At the delivery, she underwent C/S, resection of the abdominal mass, and a male baby was born. The surgeon reported multiple tumoral implants in the bowel meso and omentum along with hemorrhagic ascites. Pathologic assessment of the resected mass revealed \"metastatic immature teratoma, grade 2 with positive ascites fluid for the presence of malignant cells.\" After the surgery, there were an increased level of alpha‐fetoprotein (AFP); 117 U/ml (0.2–8.5) and cancer antigen 125 (CA125); 146 U/ml (0–35) with a normal human chorionic gonadotropin (BHCG). Three cycles of chemotherapy based on BEP regimen were administered, and postchemotherapy evaluation showed a significant decrease in the level of AFP and CA125 (7.3 U/ml and 14 U/ml, respectively). A whole‐body CT scan showed evidence of peritoneal seeding and implants around the liver and in sub‐diaphragmatic, paracolic, and pelvic regions and also two bilateral supra‐diaphragmatic lymphadenopathies. The chemotherapy was continued for two more cycles, and the laboratory assessment showed a continuum reduction of AFP and CA125 (4.9 and CA125 = 19.9, respectively). Despite the reduction of tumor markers, the CT scan showed evidence of radiologic disease progression. Based on MDT recommendation, the patient underwent a needle biopsy from supra‐diaphragmatic lymphadenopathies showing mature teratoma on the pathological evaluation. Considering the low tumor marker salvage surgical resection of all tumoral masses was recommended by MDT; however, the surgeon reported diffuse tumoral seeding in the abdominal wall and considered the lesion inoperable. Subsequently, the patient received six cycles of paclitaxel (175 mg/m2) + carboplatin (AUC = 5) every 3 weeks. After 4 years of diagnosis, the patient was progression‐free.\n\n4 DISCUSSION\n\nPure immature teratomas, first characterized by Norris et al. in 1976, are rare germ cell tumors that involve three germ layers with at least one of the components having an immature appearance. 2 , 5 Survival is determined by the size and stage of teratomas, but the grade of the primary tumor is the most important determinant of the likelihood of extra ovarian spread and for the subsequent course. Grading is based on the amount of immature neural tissue. 2 Zhang R. et al reported a 5‐year survival rate as 92% for immature teratoma based on 63 (nonpregnant) cases with immature teratoma among 145 malignant ovarian germ cell tumor cases, and histology, surgical approach, chemotherapy, and regimens were not predictive of 5‐year survival rates. Moreover, they concluded that fertility‐sparing treatment should be considered for ovarian germ cell tumors regardless of the FIGO stage. 6\n\nYoung et al. showed that the prognosis for ovarian malignancies was not complicated by concurrent gestation if adequate treatment is administered timely. 7 Management of ovarian tumors in pregnancy requires a multidisciplinary approach, and therapeutic decision should take into account histology, grade and stage of the tumor, and the pregnancy age. 8 The prognosis for immature teratomas has improved due to the routine use of imaging during pregnancy and because of chemotherapy, and most ovarian cancers associated with pregnancy are detected by ultrasonography. 9 The main presenting symptom for ovarian immature teratomas during pregnancy is adnexal mass followed by abdominal or pelvic pain. Some patients present with combined abdominal pain and mass, and some patients are asymptomatic and detect by routine ultrasonography and by elevated serum AFP. 10 Both our patients also refer with the primary complaint of abdominal pain. Given malignant ovarian germ cell tumors are usually unilateral, except advanced stage cases with metastasis to the contralateral ovary, unilateral salpingo‐oophorectomy with preservation of the contralateral ovary and uterus is appropriate for treatment of most cases. If metastatic disease is detected during surgery, cytoreductive surgery is recommended. Second look laparotomy for germ cell tumors is controversial, and if inadequate staging was present at the first operation, second‐look surgery or CT should be considered. 11 The poor prognosis of malignant germ cell tumors treated by surgery alone indicates a need for adjuvant chemotherapy. 4 The risk of major malformation during the first trimester of pregnancy is 10% for single‐agent chemotherapy and 25% for combination chemotherapy. 5 , 6 , 8 Afterward, the second trimester seems safer for chemotherapy.\n\nBased on NCCN guideline, patients affected by stage 1, grade 1 ovarian immature teratoma, have an excellent prognosis without adjuvant chemotherapy; therefore, these patients only observe postoperatively. The patients with stage1 and grade 2 or 3 of immature teratoma and the patients with stages 2 or 3 at any grades need postoperative chemotherapy by BEP regimen for 3–4 cycles every 3 weeks. After completion of chemotherapy, if you have complete clinical responses in laboratory and imaging studies, observation is recommended. But if the imaging studies reveal residual disease with normal tumor marker level, both surgery and observation are advisable and ultimately, if the tumor marker level is high and the imaging studies reveal residual disease too, salvage or high‐dose chemotherapy is recommended.\n\nAlthough there is limited experience for using this regimen during pregnancy, 12 , 13 , 14 , 15 , 16 the BEP treatment has been associated with ventriculomegaly, transient neonatal neutropenia, and bilateral sensorineural hearing loss. Considering the co‐occurrence of blood hypertension and eclampsia during administration of BEP regimen, more data are mandatory for safety profile of this regimen.\n\n5 CONCLUSION\n\nBased on our two mentioned cases and the other data, it seems that postoperative chemotherapy during pregnancy after the first trimester is essential for patients with initial disease stage 1, grade 2 ovarian immature teratoma and it associates with lower disease progression and recurrence.\n\nCONSENT STATEMENT\n\nPublished with written consent of the patient.\n\nACKNOWLEDGEMENTS\n\nThanks to Drs. Jamshidi and Ziaolhagh for their assistance in preparing pathologic reports and figures. Thanks to Mahla Babaei for English editing.\n\nAUTHOR CONTRIBUTIONS\n\nAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.E.T.; Methodology, F.H.Sh.; Investigation, A.E.T., F.H.Sh; Writing—Original Draft, A.E.T., F.H.Sh; Writing—Review & Editing, A.E.T., F.H.Sh; Supervision, F.H.Sh; Project Administration, F.H.Sh.; Validation, A.E.T., F.H.Sh.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing was not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nREFERENCES\n\n1 Tewari K , Cappuccini F , Desai PJ , Berman ML , Manetta A , Kohler MF . Malignant germ cell tumours of the ovary. Obstet Gynecol. 2000;95 (1 ):128‐133.10636515\n2 Smith HO , Berwick M , Verschraegen CF , et al. Incidence and survival rates for female malignant germ cell tumours. Obstet Gynecol. 2006;107 (5 ):1075‐1085.16648414\n3 Norris HJ , Zirkin HJ , Benson WL . Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976;37 (5 ):2359‐2372.1260722\n4 Christman JE , Teng NN , Lebovic GS , Sikic BI . Delivery of a normal infant following cisplatin, vinblastine, and bleomycin (PVB) chemotherapy for malignant teratoma of the ovary during pregnancy. Gynecol Oncol. 1990;37 :292‐295.1693127\n5 Murali M , Ben Haj Hassine A , El Fekih C , et al. Immature teratoma of the ovary and pregnancy. (In French). Tunis Med. 2010;88 :507‐512.20582889\n6 Helge S , Borghese B , Delaney C , Alexandre J , Chopin N . Ovarian immature teratoma during pregnancy. (In French). Presse Medicale. 2011;40 :102‐105.\n7 Clinkard DJ , Khalifa M , Osborne RJ , Bouffet E . Successful management of medulloblastoma arising in an immature ovarian teratoma in pregnancy. Gynecol Oncol. 2011;120 :311‐312.21075436\n8 Mendivil AA , Brown JV III , Abaid LN , et al. Robotic‐assisted surgery for the treatment of pelvic masses in pregnant patients: a series of four cases and literature review. J Robot Surg. 2013;7 :333‐337.27001871\n9 Bakri YN , Ezzat A , Akhtar, Dohami, Zahrani. Malignant germ cell tumours of the ovary. Pregnancy considerations. Eur J Obstet Gynecol Reprod Biol. 2000;90 :87‐91.10767517\n10 Hasdemir PS , Juvenal T , Menekse S , et al. Ovarian immature teratoma detected during pregnancy. J Med Sci Discov. 2016;3 (1 ):1‐6.\n11 Gershenson DM , del Junco G , Silva EG , Copeland LJ , Wharton JT , Rutledge FN . Immature teratoma of the ovary. Obstet Gynecol. 1986;68 :624‐629.3763073\n12 Han JY , Nava‐Ocampo AA , Kim TJ , Shim JU , Park CT . Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumours: report of 2 cases. Reprod Toxicol. 2005;19 :557‐561.15749271\n13 Elit L , Bocking A , Kenyon C , Natale R . An endodermal sinus tumour diagnosed in pregnancy: case report and review of the literature. Gynecol Oncol. 1999;72 :123‐127.9889045\n14 Poremba C , Dockhorn‐Dworniczak B , Merritt V , et al. Immature teratomas of different origin carried by a pregnant mother and her fetus. Diagn Mol Pathol. 1993;2 :131‐136.8269278\n15 Shahidsales S , Farazestanian M , Sharifi‐Sistani N , Rasta S , Javadinia SA . The uterine adenosarcoma in a young woman treated by TAH/BOS and combined adjuvant therapy: a case report. Acta Med Iran. 2020;58 (3 ):138‐141.\n16 Javadinia SA , Shahidsales S , Fanipakdel A , et al. Therapeutic potential of targeting the Wnt/β‐catenin pathway in the treatment of pancreatic cancer. J Cell Biochem. 2019;120 (5 ):6833‐6840. 10.1002/jcb.27835\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(7)",
"journal": "Clinical case reports",
"keywords": "chemotherapy; ovarian immature teratoma grade 2; pregnancy",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"title": "Management of ovarian immature teratoma grade-II in pregnancy, two cases report and literature review.",
"title_normalized": "management of ovarian immature teratoma grade ii in pregnancy two cases report and literature review"
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"abstract": "In response to the report of Ong and colleagues of a series of patients with levodopa/dopa decarboxylase inhibitor associated microscopic colitis, we report a case of entacapone associated microscopic colitis. We agree that chronic diarrhoea in patients with Parkinson's disease should prompt consideration of drug-induced microscopic colitis as the cause.",
"affiliations": "Movement Disorder Unit, Westmead Hospital, Cnr Hawkesbury and Darcy Road, Westmead, NSW, 2145, Australia; Sydney Medical School, The University of Sydney, NSW, 2006, Australia; St Stephen's Hospital, Hervey Bay, Urraween, QLD, 4655, Australia. Electronic address: alessandro.fois@sydney.edu.au.;Sullivan Nicolaides Pathology, 24 Hurworth Street, Bowen Hills, QLD, 4006, Australia.;St Stephen's Hospital, Hervey Bay, Urraween, QLD, 4655, Australia.",
"authors": "Fois|Alessandro F|AF|;Conrad|Rod|R|;Hampe|Toni|T|",
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"doi": "10.1016/j.parkreldis.2021.09.010",
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"keywords": "COMT inhibitors; Entacapone; Lymphocytic colitis; Microscopic colitis; Parkinson's disease",
"medline_ta": "Parkinsonism Relat Disord",
"mesh_terms": null,
"nlm_unique_id": "9513583",
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"pages": "83-84",
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"pubdate": "2021-10",
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"title": "Entacapone - Another Parkinson's medication associated with lymphocytic colitis.",
"title_normalized": "entacapone another parkinson s medication associated with lymphocytic colitis"
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"abstract": "A 57-year-old man with a known anterior mediastinal mass presented with abdominal distension, jaundice, and signs of urinary and bowel obstruction. Labs revealed leukocytosis, transaminitis, direct hyperbilirubinaemia and elevated levels of alkaline phosphatase, lactate dehydrogenase and uric acid. Subsequent imaging revealed the anterior mediastinal mass and diffuse liver lesions consistent with metastatic disease. MRI of the spine and brain were negative for metastases. Liver biopsy and immunohistochemistry revealed basaloid squamous cell carcinoma of thymic origin. Treatment with capecitabine was initiated but was complicated by worsening liver and kidney failure. Eventually, due to continued worsening of the patient's condition and minimal treatment response, capecitabine was stopped during cycle 1 and the patient was discharged to inpatient hospice with comfort care. In this case report, we highlight the presenting features, imaging findings and management of a patient with metastatic thymic carcinoma.",
"affiliations": "Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.",
"authors": "Phen|Samuel|S|;Wang|Mindy X|MX|http://orcid.org/0000-0002-3457-9327;Kelling|Matthew|M|;Bhattal|Gurjaspreet K|GK|",
"chemical_list": null,
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"issue": "12(9)",
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"keywords": "cancer intervention; chemotherapy; drugs: gastrointestinal system; liver disease; oncology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001706:Biopsy; D002294:Carcinoma, Squamous Cell; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D000070659:Patient Comfort; D013953:Thymus Neoplasms",
"nlm_unique_id": "101526291",
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"pmid": "31570341",
"pubdate": "2019-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20722491;12173853;16378197;19461509;10840838;21046508;28795997;26607199;28654574",
"title": "Metastatic basaloid squamous cell carcinoma of thymic origin.",
"title_normalized": "metastatic basaloid squamous cell carcinoma of thymic origin"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-05662",
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{
"abstract": "Anti-angiogenics have become an important part of the treatment of several types of tumours such as ovarian, breast, lung and colorectal cancer. Necrotising fasciitis has been reported with bevacizumab but no cases have been reported with aflibercept, ramucirumab or regorafenib in patients with colorectal cancer. Necrotising fasciitis is a rare complication affecting one in 5000 bevacizumab users. We report the case of a 64-year-old man with stage IV rectosigmoid cancer under treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) and aflibercept, who developed a Fournier's gangrene.",
"affiliations": "Medical oncologist at Elda University Hospital.;General surgeon at Puerta de Hierro Majadahonda University Hospital.;Medical oncologist at Puerta de Hierro Majadahonda University Hospital.",
"authors": "Gonzaga-López|A|A|;Muñoz-Rodriguez|J|J|;Ruiz-Casado|A|A|",
"chemical_list": "D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
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"doi": "10.1308/rcsann.2017.0143",
"fulltext": "\n==== Front\nAnn R Coll Surg EnglAnn R Coll Surg EnglannAnnals of The Royal College of Surgeons of England0035-88431478-7083Royal College of Surgeons 2876842610.1308/rcsann.2017.01432017.0143Online Case ReportponOncological surgerycolColorectalgenGeneral surgeryftlSoft tissue face, trunk or limbs injuriesplaPlastic surgeryNecrotising fasciitis in a patient treated with FOLFIRI-aflibercept for colorectal cancer: a case report Necrotising fasciitis in a patient treated with FOLFIRI-aflibercept for colorectal cancer: a case reportGonzaga-López Muñoz-Rodriguez Ruiz-CasadoGonzaga-López A 1Muñoz-Rodriguez J 2Ruiz-Casado A 31Medical oncologist at Elda University Hospital2General surgeon at Puerta de Hierro Majadahonda University Hospital3Medical oncologist at Puerta de Hierro Majadahonda University HospitalCORRESPONDENCE TO Ana Gonzaga-López, E: ana.gonzaga.lopez@gmail.com11 2017 27 10 2017 99 8 e225 e226 18 7 2017 Copyright © 2017, All rights reserved by the Royal College of Surgeons of England2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Anti-angiogenics have become an important part of the treatment of several types of tumours such as ovarian, breast, lung and colorectal cancer. Necrotising fasciitis has been reported with bevacizumab but no cases have been reported with aflibercept, ramucirumab or regorafenib in patients with colorectal cancer. Necrotising fasciitis is a rare complication affecting one in 5000 bevacizumab users. We report the case of a 64-year-old man with stage IV rectosigmoid cancer under treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) and aflibercept, who developed a Fournier’s gangrene.\n\nNecrotising fasciitisColorectal neoplasmsAngiogenesis inhibitorBevacizumabAflibercept\n==== Body\nIntroduction\nColorectal cancer is one of the most frequent worldwide tumours. The treatment of advanced colorectal cancer has improved with the development of new drugs as vascular endothelial growth factor (VEGF) blockers and anti-epidermal growth factor receptor. The typical adverse effects of anti-angiogenics are hypertension, bleeding, gastrointestinal fistula and thromboembolic events. Anti-angiogenics have also been associated with an increased risk of infection but this toxicity is rarely fatal.1,2 We present the case of a 64-year-old man with stage IV rectosigmoid cancer diagnosed with Fournier’s gangrene, probably related to aflibercept.\n\nCase history\nA 64-year-old man presented to the emergency department because of fever and buttock pain. He had a history of hypertension and hiatal hernia, and he was an ex-smoker and a mild drinker. Two years earlier, he had been diagnosed with stage IV RAS wild-type rectosigmoid adenocarcinoma with liver metastasis.\n\nThe patient underwent an open sigmoidectomy followed by FOLFOX6m as conversion chemotherapy . After four cycles with no response, second-line treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI)-cetuximab was initiated. Despite achieving a tumoral response, the decision at the multidisciplinary team meeting was made for radiofrequency ablation because of macroscopic steatosis confirmed during the first surgical procedure. Further treatments included capecitabine and bevacizumab (AVEX) for seven cycles with stable disease and yttrium-90 radioembolisation of liver metastasis. Six months later, a colonoscopy revealed a local relapse at the rectal ampulla and liver progression. After 12 cycles, a new progression (rectal and liver) was confirmed. The patient had received one cycle of FOLFIRI-aflibercept 23 days before admission.\n\nThe patient presented to the emergency department with right buttock inflammation of 24 hours’ duration, fever up to 39 degrees celsius and chills. On examination, his vital signs revealed a blood pressure of 80/50 mmHg, tachycardia of 120 beats/minute and erythema, induration and a tender area in the right buttock. Analysis revealed leucocytosis 42.17 × 10E3/μl (reference range 4.0–11.5) with neutrophilia 83.7%, C reactive protein 211.70 mg/l (range 0.1–10), renal failure with creatinine 2.39 mg/dl (range 0.6–1.2) and lactate value 5.9 mmol/l. Creatinin kinase was 230 u/l (range 24–195). Coagulation disorder was also noted with prothrombin activity of 50%.\n\nAfter a clinical diagnosis of Fournier’s gangrene, the surgeon performed an anal examination under anaesthesia and confirmed the diagnosis of necrotising fasciitis with perianal and right buttock involvement. An excisional debridement was performed. Blood and tissue cultures were collected and broad-spectrum empirical antibiotic treatment was initiated with meropenem, linezolid, metronidazole and fluconazole. The patient was admitted to intensive care and he underwent a further debridement after 24 hours of admission. Tissue cultures revealed polymicrobial infection with Klebsiella pneumoniae, Proteus mirabilis, Clostridium beijerinckii and Candida albicans. The evolution was satisfactory and he was discharged after 21 days to a rehabilitation hospital, where he remained for 3 months. The patient died 11 months after the diagnosis of Fournier’s gangrene.\n\nDiscussion\nFournier’s gangrene is a type of necrotising fasciitis defined by deep-tissue destruction, including muscle fascia and subcutaneous fat localised at the perineum, gluteal muscles and, in advanced cases, affecting the abdominal wall. Traditional risk factors of necrotising fasciitis are diabetes, drug use, obesity, immunosuppression, recent surgery and traumatism. Clinical manifestations usually are acute and rapidly progressive oedema, erythema and tender area. Advanced cases are defined by toxic symptoms as fever, tachycardia and hypotension. Two types of necrotising fasciitis are described. Type I is a mixed infection caused by aerobic and anaerobic bacteria and type II is a monomicrobial infection caused typically by group A streptococcus or other beta-haemolytic streptococcus.\n\nThe mechanism of action of anti-VEGF drugs is inhibition of VEGF signalling by blocking VEGF ligand or VEGF receptor function and altering the tissue and tumor vascularization. Bevacizumab was the first anti-angiogenic drug approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of colorectal cancer, associated to fluroropyrimidine-based chemotherapy, demonstrating an improvement in overall survival when used as first-line treatment. Later, in a phase III trial, aflibercept demonstrated a significant survival benefit associated with FOLFIRI in patients with metastatic colorectal cancer after treatment with an oxaliplatin-based chemotherapy.\n\nIn 2010, Gamboa et al. published the first case report of Fournier’s gangrene as a possible adverse effect of bevacizumab.3 A 67-year-old male with metastatic colorectal cancer treated with FOLFOX6m and bevacizumab developed a Fournier's gangrene, with no other risk factors apart from dyslipidaemia. In 2012, a report describing novel bevacizumab-related adverse events during FDA post-marketing surveillance was published.4 Necrotizing fasciitis was the described as a possible novel adverse event attributed to bevacizumab in 22 cases with an outcome of death in 13.6% of cases. The suggested mechanisms included subcutaneous artery thrombosis and tissue ischaemia, to which bevacizumab could contribute.\n\nAn increased risk of infections had been reported in several papers related to bevacizumab. Zhang et al.1 described a higher incidence of severe infections associated with aflibercept (7.3%) with a mortality of 2.2%. The risk of all-grade infections was much higher with aflibercept compared with bevacizumab (relative risk 4.07, P < 0.001).1\n\nIn our case, a 64-year-old man had developed a Fournier’s gangrene with the only known risk factor being immunosuppression related to chemotherapy. In addition, the patient was receiving treatment with aflibercept. Rectal relapse could be considered as another risk factor. To the best of our knowledge, this is the first reported case of Fournier’s gangrene in relation to an anti-angiogenic other than bevacizumab in colorectal cancer. In our opinion, necrotising fasciitis is a class adverse event related to anti-angiogenics.\n\nToxicity of oncological treatments is an important cause of hospital admission, morbidity and mortality. The quick diagnosis and the correct management of these complications is associated with a better outcome. The suspicion of necrotising fasciitis in a patient under treatment with anti-angiogenics is essential for prompt surgical treatment.\n\nConclusion\nThis is the first case of necrotising fasciitis in a colorectal cancer patient possibly related to aflibercept treatment. It is important to suspect this entity in patients with recent treatment with anti-angiogenics because of the high mortality, morbidity and the need of prompt instigation of the proper treatment.\n==== Refs\nReferences\n1. Zhang X , Ran Y , Shao Y et al \nIncidence and risk of severe infections associated with aflibercept in cancer patients: a systematic review and meta-analysis . Br J Clin Pharmacol \n2016 ; (1 ): 33 –40 .\n2. Qi W , Tang L , Shen Z , Yao Y \nTreatment-related mortality with aflibercept in cancer patients: a meta-analysis . Eur J Pharmacol \n2014 ; : 461 –467 .\n3. Gamboa EO , Rehmus HE , Haller N \nFournier’s gangrene as a possible side effect of bevacizumab therapy resected colorectal cancer . Clin Colorectal Cancer \n2010 ; : 55 –58 .20100690 \n4. Shamloo Bk , Chhabra P , Freedman AN , et al \nNovel adverse events of Bevacizumab in the USA FDA adverse events reporting system database: a disproportionality analysis . Drug Saf \n2012 ; : 507 –518 .22612854 \n5. Ruff P , Ferry DR , Lakomý R , et al \nTime course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy . Eur J Cancer \n2015 ; : 18 –26 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0035-8843",
"issue": "99(8)",
"journal": "Annals of the Royal College of Surgeons of England",
"keywords": "Aflibercept; Angiogenesis inhibitor; Bevacizumab; Colorectal neoplasms; Necrotising fasciitis",
"medline_ta": "Ann R Coll Surg Engl",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D015179:Colorectal Neoplasms; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D005472:Fluorouracil; D018934:Fournier Gangrene; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "7506860",
"other_id": null,
"pages": "e225-e226",
"pmc": null,
"pmid": "28768426",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22612854;24390630;25466509;26331893;20100690",
"title": "Necrotising fasciitis in a patient treated with FOLFIRI-aflibercept for colorectal cancer: a case report.",
"title_normalized": "necrotising fasciitis in a patient treated with folfiri aflibercept for colorectal cancer a case report"
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"activesubstancename": "FLUOROURACIL"
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"abstract": "OBJECTIVE\nTo review the reports of fatal adverse drug reactions (ADRs) submitted to the Ontario Medical Association Adverse Drug Reactions Monitoring Program between 1990 and 1994; to identify drugs associated with fatal outcomes; and to assess the causative role of the drug in these events and the completeness of the data in these reports.\n\n\nMETHODS\nDrug(s) identified on each ADR report as being responsible for the reaction were considered. Agents were classified by the Anatomical Therapeutic and Chemical classification system. The causality of each ADR report was evaluated by using an algorithmic rating scale.\n\n\nRESULTS\nFrom the Ontario Medical Association database, 97 cases of ADRs that resulted in death were reviewed. One hundred fourteen medications were implicated as \"suspect\" drugs in the 97 deaths. The most commonly implicated drug classes were musculoskeletal agents, blood and blood-forming organ agents, and nervous system agents. Patients over 65 years of age comprised 60% of this series. After independent assessment as to causality, 13% of the cases were rated as probable, 86% were rated as possible and 1% were rated as doubtful. Seventy per cent of reports did not include information regarding medical history. Forty-two per cent of cases failed to provide adequate information to evaluate the feasibility of the time to onset of the ADR. The use of concomitant drugs was not reported in 12% of cases.\n\n\nCONCLUSIONS\nThe drugs most frequently implicated in fatal ADRs were consistent with those reported in other studies. Algorithmic causality assessments were of limited value in these reports. The completeness of the reports and adequacy of the information were poor. The type of reporting forms and information provided were not homogenous. There is a need to improve quality of reporting and harmonize reporting forms between monitoring bodies. The feasibility of unique data collection forms and obligatory reporting for fatal ADRs should be considered.",
"affiliations": "Division of Geriatric Medicine and Clinical Pharmacology, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada. b.liu@utoronto.ca",
"authors": "Liu|B A|BA|;Knowles|S R|SR|;Mittmann|N|N|;Einarson|T|T|;Shear|N H|NH|",
"chemical_list": null,
"country": "Canada",
"delete": false,
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"fulltext": null,
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"issue": "8(2)",
"journal": "The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique",
"keywords": null,
"medline_ta": "Can J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D002675:Child, Preschool; D016208:Databases, Factual; D006801:Humans; D008875:Middle Aged; D009026:Mortality; D009864:Ontario; D011358:Product Surveillance, Postmarketing",
"nlm_unique_id": "9804162",
"other_id": null,
"pages": "84-8",
"pmc": null,
"pmid": "11493936",
"pubdate": "2001",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reporting of fatal adverse drug reactions.",
"title_normalized": "reporting of fatal adverse drug reactions"
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"companynumb": "CA-PFIZER INC-2018064692",
"fulfillexpeditecriteria": "1",
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"abstract": "OBJECTIVE\nRadiation exposure (RE) is a matter of concern for patients with congenital heart disease (CHD) who not infrequently need multiple interventional procedures under fluoroscopy guidance. We sought to evaluate the safety and feasibility of a minimally fluoroscopic approach in patients with CHD undergoing catheter ablation using a new image integration module (IIM).\n\n\nMETHODS\nConsecutive patients with CHD undergoing catheter ablation using the Carto Univu™ IIM were included. A near-zero fluoroscopy procedure was defined by an effective dose (ED) ≤ 1 mSv. RE parameters (total fluoroscopy time [TFT], total dose area product [tDAP], and ED), ablation outcomes, and complications were evaluated.\n\n\nRESULTS\nFifty-five patients with CHD underwent 63 ablation procedures (supraventricular tachycardia, n = 53; ventricular tachycardia, n = 10). The CHD was simple in 25%, moderate in 42%, and complex in 33%. The use of the IIM resulted in very low levels of RE (median TFT 0.13 min [IQR 0-1.04], median tDAP 54.5 cGy cm2 [IQR 9.5-176.4], median ED 0.136 mSv [IQR 0.02-0.49]). Patients with complex CHD had significantly higher RE when compared with patients with simple and moderate defects. A total of 56/63 ablation procedures (89%) were performed with an ED ≤ 1 mSv. One patient developed sinus node dysfunction requiring pacemaker implantation.\n\n\nCONCLUSIONS\nThe use of a minimally fluoroscopic approach was safe and feasible resulting in very low RE during catheter ablation of patients with CHD. A near-zero fluoroscopy ablation was possible in up to 89% of the procedures.",
"affiliations": "Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain. cano_osc@gva.es.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.;Electrophysiology Section, Cardiology Department, Hospital Universitari i Politècnic La Fe, Área de Enfermedades Cardiovasculares, Planta 4-Torre F, Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain.",
"authors": "Cano|Óscar|Ó|http://orcid.org/0000-0001-6783-0138;Saurí|Assumpció|A|;Plaza|Diego|D|;Osca|Joaquín|J|;Sancho-Tello|María-José|MJ|;Rueda|Joaquín|J|;Osa|Ana|A|;Martínez-Dolz|Luis|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-018-0467-3",
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"issn_linking": "1383-875X",
"issue": "56(3)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": "Catheter ablation; Congenital heart disease; Radiation exposure",
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"mesh_terms": "D000328:Adult; D017115:Catheter Ablation; D056149:Epicardial Mapping; D005240:Feasibility Studies; D005260:Female; D005471:Fluoroscopy; D006330:Heart Defects, Congenital; D006801:Humans; D008297:Male",
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"pubdate": "2019-12",
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"title": "Evaluation of a near-zero fluoroscopic approach for catheter ablation in patients with congenital heart disease.",
"title_normalized": "evaluation of a near zero fluoroscopic approach for catheter ablation in patients with congenital heart disease"
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"abstract": "Cryptosporidium infection is known to cause hepato-biliary involvement, mainly in association with T-cell immune deficiency. Hepato-biliary involvement in association with milder immunosuppression is less well described. We describe the first case, to our knowledge, of Cryptosporidium hominis hepato-biliary infection associated with tacrolimus in a patient with nephrotic syndrome.\nA 14 year old girl who had been on tacrolimus for nephrotic syndrome presented with diarrhea due to C. hominis. Nineteen days after her initial presentation she attended hospital with abdominal pain and deranged liver function tests. An ultrasound scan showed a thickened gall bladder. Her symptoms settled and her liver function tests returned to normal after treatment with nitazoxanide.\nCryptosporidium should be considered in the differential diagnosis of both diarrhea and hepato-biliary symptoms and abnormal liver function tests, even in the presence of relatively mild immunosuppression. Nitazoxanide was an effective treatment in this case.",
"affiliations": "Wye Valley NHS Trust, The County Hospital, Union Walk, Hereford, Herefordshire, HR1 2ER, UK.;Wye Valley NHS Trust, The County Hospital, Union Walk, Hereford, Herefordshire, HR1 2ER, UK.;Wye Valley NHS Trust, The County Hospital, Union Walk, Hereford, Herefordshire, HR1 2ER, UK.;Cryptosporidium Reference Unit, Public Health Wales Microbiology ABM, Singleton Hospital, Sgeti, Swansea, SA2 8QA, UK.;Cryptosporidium Reference Unit, Public Health Wales Microbiology ABM, Singleton Hospital, Sgeti, Swansea, SA2 8QA, UK.",
"authors": "Gupta|Sajal|S|;Johnson|Alison|A|;Meyrick|Simon|S|;Davies|Angharad P|AP|;Chalmers|R|R|",
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"doi": "10.1099/jmmcr.0.005159",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepjmmcrjmmcrJMM Case Reports2053-3721Microbiology Society jmmcr00515910.1099/jmmcr.0.005159Case ReportHepaticA case of hepato-biliary infection secondary to cryptosporidium in a patient on tacrolimus http://jmmcr.microbiologyresearch.orgGupta Sajal 1Johnson Alison 1*Meyrick Simon 1Davies Angharad P. 2Chalmers R. 21 Wye Valley NHS Trust, The County Hospital, Union Walk, Hereford, Herefordshire, HR1 2ER, UK2 Cryptosporidium Reference Unit, Public Health Wales Microbiology ABM, Singleton Hospital, Sgeti, Swansea, SA2 8QA, UK*Correspondence: Alison Johnson, alison.johnson@wvt.nhs.uk8 2018 20 7 2018 20 7 2018 5 8 e00515901 3 2018 18 6 2018 © 2018 The Authors2018This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction.\n Cryptosporidium infection is known to cause hepato-biliary involvement, mainly in association with T-cell immune deficiency. Hepato-biliary involvement in association with milder immunosuppression is less well described. We describe the first case, to our knowledge, of Cryptosporidium hominis hepato-biliary infection associated with tacrolimus in a patient with nephrotic syndrome.\n\nCase presentation.\n A 14 year old girl who had been on tacrolimus for nephrotic syndrome presented with diarrhea due to C. hominis. Nineteen days after her initial presentation she attended hospital with abdominal pain and deranged liver function tests. An ultrasound scan showed a thickened gall bladder. Her symptoms settled and her liver function tests returned to normal after treatment with nitazoxanide.\n\nConclusion.\n Cryptosporidium should be considered in the differential diagnosis of both diarrhea and hepato-biliary symptoms and abnormal liver function tests, even in the presence of relatively mild immunosuppression. Nitazoxanide was an effective treatment in this case.\n\ncryptosporidiumtacrolimushepato-biliarynitazoxanideOpenAccessEmbargo0\n==== Body\nIntroduction\nCryptosporidium is a protozoan parasite and is a common cause of diarrhoea. It can cause chronic diarrhoea in immunocompromised patients and this can be associated with pancreato-biliary infection. This severe manifestation of the infection is most frequently associated with severe T cell deficiency, such as is seen in HIV infection, with CD4 counts lower than 200; in haematological malignancies and in patients with primary T cell deficiencies [1].\n\nWe present a case of biliary involvement secondary to cryptosporidium infection in a patient on relatively mild immunosuppressive treatment whose symptoms resolved following treatment with nitazoxanide.\n\nCase report\nA 14 year old girl developed diarrhoea and vomiting and presented to hospital four days after symptom onset following a fainting episode. She had also experienced sharp colicky pains in her abdomen. She had been on holiday in the United Kingdom prior to the episode.\n\nThe patient had developed nephrotic syndrome at age 13 with a renal biopsy showing focal segmental glomerulosclerosis. She also had mild asthma, menorrhagia and pulmonary stenosis (diagnosed on echocardiogram).\n\nHer medications included tacrolimus, enalapril, atrovastatin, omeprazole, penicillin-V, levothyroxine and ferrous fumarate. The tacrolimus had been stopped a day before the start of illness as it had not produced any improvement in renal function or reduction in proteinuria. The tacrolimus had been commenced 14 months earlier at a dose of 5 mg twice daily. A tacrolimus level had last been assayed 2 months before onset of her illness. This was 7.3 µg l−1 i.e. within the normal therapeutic range.\n\nOn admission, she was felt to be fluid-depleted with mild dehydration and after initial treatment with a bolus of 500 ml of normal saline in the emergency department, was commenced on intravenous fluids in view of abdominal pain and vomiting. Her renal function was deranged with an acute kidney injury score of 2. Urea was 22.8 mmol l−1, previously having being in the range of 6.5–11.8 mmol l−1 and creatinine was raised to 157 µmol l−1, previously having being in the range of 70–95 µmol l−1. Liver function tests were normal. White blood cell count was normal (6.1×109 l−1). Enalapril was stopped in view of these results. She improved after 24 h of maintenance IV fluid therapy with 0.9 % saline and 5 % dextrose, renal function returning to previous levels (urea 16.7 mmol l−1, Creatinine 94 µmol l−1) and she was discharged. Subsequently, Cryptosporidium was detected on stool microscopy. This was confirmed to be Cryptosporidium hominis by PCR at the national reference laboratory. The sample was negative for all other pathogens tested for, including Escherichia coli 0157, Campylobacter, Salmonella and Shigella. Following discharge she continued to have some episodes of diarrhoea but no vomiting. She re-presented 19 days later with significant abdominal pain and infrequent small vomits which were non bilious, her diarrhoea had resolved.\n\nOn examination she had epigastric tenderness but no hepatomegaly. Her perfusion was adequate with a capillary refill time <2 s, pulse rate of 89, blood pressure was 104/58, both within the normal range for her age. However, her peripheral pulses were poor. She was commenced on maintenance intravenous fluids with 0.9 % saline and 5 % dextrose. Liver function tests were noted to be deranged with raised aspartate transaminase (451 IU l−1), alanine transaminase (267 IU l−1), gamma-glutamyl transferase (115 IU l−1) and lactate dehydrogenase (853 IU l−1). Her renal function showed raised urea (10 mmol l−1) and creatinine (72 µmol l−1) which were above baseline but within her usual range. Her liver function continued to deteriorate over the next 24 h (peak aspartate transaminase 1062 IU l−1, alanine transaminase 1292 IU l−1, lactate dehydrogenase 882 IU l−1, gamma-glutamyl transferase 209 IU l−1). An ultrasound showed a thickened gall bladder but otherwise normal liver and bile duct.\n\nAfter discussing the history and results with specialist paediatric hepatologists who, in view of the facts, that her stool was positive for Cryptosporidium hominis, she had worsening liver function tests and ultrasound evidence of cholangitis, recommended a three day oral course of nitazoxanide 500 mg twice daily. Following this, her liver function tests rapidly improved, returning almost to baseline after 4 days. Her appetite returned to normal and her abdominal symptoms resolved.\n\nDiscussion\nCryptosporidium infection should be considered in the differential diagnosis of both diarrhoea and hepato-biliary symptoms and abnormal liver function tests even in the presence of relatively mild immunosuppression.\n\nThe biliary system provides a reservoir for the Cryptosporidium parasite and cryptosporidiosis of the pancreato-biliary system is well-recognised in patients who are immune-compromised, especially in those with T-cell immune deficiency [2]. Sclerosing cholangitis as a result is well-described [3–6]. Cryptosporidium enteritis in solid organ transplant recipients has previously been associated with elevated tacrolimus concentrations [7] and there also exists one report of C. parvum-induced sclerosing cholangitis in an adult renal transplant patient taking tacrolimus [8]. To the best of our knowledge, this is the first report of C. hominis associated with use of tacrolimus in a patient with nephrotic syndrome. Clinicians should bear in mind the risk of cryptosporidiosis, including of the biliary tract, in patients taking tacrolimus.\n\nNitazoxanide is not licensed for treatment of cryptosporidiosis in the UK but is available on a named patient basis. It produces an improvement in diarrhoea in immunocompetent children [9] and in HIV patients with CD4 counts over 50 [10]. It produced an excellent symptom response in our patient with presumed hepato-biliary cryptosporidiosis and relatively minor immunosuppression. The suspension of tacrolimus probably also contributed to the resolution of symptoms by allowing resumption of the normal immune response.\n\nAbbreviations: CD4, cluster of differentiation 4; h, hour; HIV, human immunodeficiency virus; IV, intravenous; l, liter; ml, milliliter; mg, milligram; mmol, millimole; µg, microgram; PCR, polymerase chain reactions.\n\nFunding information\nThe authors received no specific grant from any funding agency.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n==== Refs\nReferences\n1 Davies AP Chalmers RM Cryptosporidiosis BMJ 2009 339 b4168 10.1136/bmj.b4168 19841008 \n2 Chalmers RM Davies AP Minireview: clinical cryptosporidiosis Exp Parasitol 2010 124 138 146 10.1016/j.exppara.2009.02.003 19545516 \n3 Cello JP Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease Am J Med 1989 86 539 546 10.1016/0002-9343(89)90381-1 2712061 \n4 Davis JJ Heyman MB Ferrell L Kerner J Kerlan R Sclerosing cholangitis associated with chronic cryptosporidiosis in a child with a congenital immunodeficiency disorder Am J Gastroenterol 1987 82 1196 1202 3674002 \n5 Dowsett JF Miller R Davidson R Vaira D Polydorou A Sclerosing cholangitis in acquired immunodeficiency syndrome. Case reports and review of the literature Scand J Gastroenterol 1988 23 1267 1274 10.3109/00365528809090203 3074460 \n6 McLauchlin J Amar CF Pedraza-Díaz S Mieli-Vergani G Hadzic N Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies Pediatr Infect Dis J 2003 22 329 334 10.1097/01.inf.0000059402.81025.cd 12690272 \n7 Bonatti H Barroso II LF Sawyer RG Kotton CN Sifri CD Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations Transpl Infect Dis 2012 14 635 648 10.1111/j.1399-3062.2012.00719.x 22340660 \n8 Abdo A Klassen J Urbanski S Raber E Swain MG Reversible sclerosing cholangitis secondary to cryptosporidiosis in a renal transplant patient J Hepatol 2003 38 688 691 10.1016/S0168-8278(03)00055-2 12713884 \n9 Amadi B Mwiya M Musuku J Watuka A Sianongo S Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial Lancet 2002 360 1375 1380 10.1016/S0140-6736(02)11401-2 12423984 \n10 Rossignol JF Hidalgo H Feregrino M Higuera F Gomez WH A double-'blind' placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico Trans R Soc Trop Med Hyg 1998 92 663 666 10.1016/S0035-9203(98)90804-5 10326116\n\n",
"fulltext_license": "CC BY",
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"keywords": "cryptosporidium; hepato-biliary; nitazoxanide; tacrolimus",
"medline_ta": "JMM Case Rep",
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"title": "A case of hepato-biliary infection secondary to cryptosporidium in a patient on tacrolimus.",
"title_normalized": "a case of hepato biliary infection secondary to cryptosporidium in a patient on tacrolimus"
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"abstract": "BACKGROUND Moyamoya disease (MMD) is an idiopathic disease caused by progressive steno-occlusion of the distal internal carotid artery. Ideal surgical treatment for adult patients with ischemic-type MMD has not been achieved. The aim of this study was to evaluate the efficacy of single-barrel superficial temporal artery-middle cerebral artery (STA-MCA) bypass in treatment for adult patients with ischemic-type MMD by analyzing clinical and radiological data retrospectively. MATERIAL AND METHODS The present study included 37 patients with non-hemorrhagic MMD, including 21 women and 16 men (21~55 years old, mean age 38.1 years). The bypass surgery was performed on 56 sides in the 37 patients. The clinical charts, angiographic revascularization, and hemodynamic changes were reviewed at 6-60 months after surgery. RESULTS Among the 37 patients, the clinical symptoms and signs of 32 patients were improved or stabilized. Five patients had complications, including 2 cases of acute cerebral infarction, 1 case of epidural hematoma, and 1 case of transient speech disturbance, and 1 patient died. Follow-up computed tomography perfusion (CTP) revealed that cerebral blood flow (CBF) was markedly improved after surgery (P<0.05). Time to peek (TTP) and mean transit time (MTT) were significantly decreased after surgery (P<0.05). No significant change in cerebral blood volume (CBV) was found after surgery (P>0.05). Postoperative patency was clearly verified in 52 bypasses (92.8%) of 56 bypasses on follow-up DSA imaging. CONCLUSIONS Single-barrel STA-MCA bypass can be considered as an effective surgical treatment, which exhibits satisfactory clinical efficacy in ischemic-type MMD patients.",
"affiliations": "Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).;Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).;Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).;Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).;Department of Neurosurgery, Suzhou Wuzhong People's Hospital, Suzhou, Jiangsu, China (mainland).;Department of Medical Imaging, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).;Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China (mainland).",
"authors": "Tao|Xiaoyang|X|;Liu|Yin|Y|;Chen|Jun|J|;Xu|Li|L|;Zhou|Zhijie|Z|;Lei|Haiyan|H|;Yin|Yiming|Y|",
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"fulltext": "\n==== Front\nMed Sci MonitMed. Sci. MonitMedical Science MonitorMedical Science Monitor : International Medical Journal of Experimental and Clinical Research1234-10101643-3750International Scientific Literature, Inc. 3033966110.12659/MSM.910252910252Clinical ResearchAssessment of Single-Barrel Superficial Temporal Artery-Middle Cerebral Artery Bypass in Treatment for Adult Patients with Ischemic-Type Moyamoya Disease Tao Xiaoyang 1ACE*Liu Yin 1BCD*Chen Jun 1BDFXu Li 1BDFZhou Zhijie 2BCDLei Haiyan 3BCYin Yiming 1AEG\n1 Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China\n2 Department of Neurosurgery, Suzhou Wuzhong People’s Hospital, Suzhou, Jiangsu, P.R. China\n3 Department of Medical Imaging, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. ChinaCorresponding Author: Yiming Yin, e-mail: yinyiming770831@126.comA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Xiaoyang Tao and Yin Liu contributed equally to this work\n\n2018 19 10 2018 24 7469 7474 27 3 2018 21 5 2018 © Med Sci Monit, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nMoyamoya disease (MMD) is an idiopathic disease caused by progressive steno-occlusion of the distal internal carotid artery. Ideal surgical treatment for adult patients with ischemic-type MMD has not been achieved. The aim of this study was to evaluate the efficacy of single-barrel superficial temporal artery-middle cerebral artery (STA-MCA) bypass in treatment for adult patients with ischemic-type MMD by analyzing clinical and radiological data retrospectively.\n\nMaterial/Methods\nThe present study included 37 patients with non-hemorrhagic MMD, including 21 women and 16 men (21~55 years old, mean age 38.1 years). The bypass surgery was performed on 56 sides in the 37 patients. The clinical charts, angiographic revascularization, and hemodynamic changes were reviewed at 6–60 months after surgery.\n\nResults\nAmong the 37 patients, the clinical symptoms and signs of 32 patients were improved or stabilized. Five patients had complications, including 2 cases of acute cerebral infarction, 1 case of epidural hematoma, and 1 case of transient speech disturbance, and 1 patient died. Follow-up computed tomography perfusion (CTP) revealed that cerebral blood flow (CBF) was markedly improved after surgery (P<0.05). Time to peek (TTP) and mean transit time (MTT) were significantly decreased after surgery (P<0.05). No significant change in cerebral blood volume (CBV) was found after surgery (P>0.05). Postoperative patency was clearly verified in 52 bypasses (92.8%) of 56 bypasses on follow-up DSA imaging.\n\nConclusions\nSingle-barrel STA-MCA bypass can be considered as an effective surgical treatment, which exhibits satisfactory clinical efficacy in ischemic-type MMD patients.\n\nMeSH Keywords\nCerebral RevascularizationMoyamoya DiseaseNeurosurgeryPostoperative Complications\n==== Body\nBackground\nMoyamoya disease (MMD) is an idiopathic disease caused by progressive steno-occlusion of the distal internal carotid artery, resulting in compensatory development of collateral vessels [1]. Patients with symptomatic MMD have a chronic decrease in blood flow [2]. Generally, classification of MMD can be split into ischemic-type and hemorrhagic type based on etiology [1,3]. Clinical manifestations of brain ischemia are quite specific in children, while intracranial hemorrhage and permanent or transient rain infarction often occur in adults [4].\n\nSuperficial temporal artery (STA)-middle cerebral artery (MCA) bypass is a surgery that causes low blood flow supply from the extracranial carotid to the distal MCA. STA-MCA bypass has been used clinically for cerebrovascular occlusive disease and as an adjuvant therapy for complex intracranial aneurysms [5]. Characteristics of patients clearly show that STA-MCA bypass revascularization provides good clinical outcomes in ischemic-type patients [6], but few studies on surgical type of hemorrhagic MMD have been reported. Indirect revascularization surgeries, such as extracranial-intracranial arterial bypass (EIAB) and modified encephaloduroarteriosynangiosis (mEDAS), are generally accepted as the treatment of choice in pediatric patients [7]. However, it is unclear which type of surgical technique is most effective in treating adult patients with ischemic-type MMD, although some retrospective studies have been conducted with the limitations of age ranges, numbers of patients, and short-term follow-up [3,8].\n\nThe primary purpose of the present study was to investigate the efficacy of single-barrel STA-MCA bypass surgery in treatment for adult patients with ischemic-type MMD by retrospectively analyzing clinical and radiological data.\n\nMaterial and Methods\nPatient population and inclusion criteria\nBetween June 2013 and June 2017, a total of 37 single-barrel STA-MCA bypass procedures in 56 surgical sessions were performed in 37 adult patients for treatment of ischemic-type MMD. Medical data were collected with permission of the Ethics Committee of Suzhou Municipal Hospital affiliated to Nanjing Medical University. Written information consent to participate was obtained from all patients. The inclusion criteria were: 1) All patients presented with ischemic symptoms, including motor, sensory, cognition, and vision impairment, who were treated by single-barrel STA-MCA bypass, aged ≥20 years; 2) MMD was diagnosed via digital subtraction angiography (DSA); 3) Symptomatic hemispheres were considered for the procedure if they displayed decreased perfusion and/or a lack of vascularity when analyzed on 6-vessel DSA, magnetic resonance (MR), and/or Diamox single-photon emission computed tomography (SPECT) or computed tomography perfusion (CTP) preoperatively. Characteristics of patients are shown in Table 1.\n\nSurgical technique\nAll patients underwent direct bypass only on the affected side after confirmation of hemodynamic impairment by SPECT and CTP. All bypass surgeries were performed by the same neurosurgeon. Bypass surgery was performed in the 37 patients presenting with ischemic symptoms at between 3 weeks and 3 months after a TIA or stroke (mean, 8.4 weeks). All patients who required bypass surgery treatments to both hemispheres were managed with staged operations, with an interval of 10–12 weeks between the 2 surgeries. Bypass surgery was implemented on the more symptomatic hemisphere first in bilateral bypass procedures. Nineteen patients received bilateral bypass procedures with 1 surgical session per side. Specific surgical methods were the following. The parietal or frontal branch of the STA was carefully dissected for approximately 6 cm following a curvilinear or linear skin incision of the temporalis muscle. After suspensory dura, a large craniotomy was performed more than 6 cm in diameter for wide dural opening. The arachnoid membrane was minimally dissected to expose suitable-sized cortical branches of the MCA as the recipient artery. Then, the blood flow of STA and MCA were blocked by use of an artery clamp. End-to-side anastomosis of donor and recipient arteries used interrupted 10-0 sutures under an operating microscope. The artery clamp was then removed and we checked for anastomotic bleeding and patency. All patients received 350 mg of acetylsalicylic acid as anticoagulant once per day postoperatively. The schematic diagram of the operation is shown in Figure 1A and 1B.\n\nEvaluation of curative effect\nA previous study [9] divided the clinical efficacy into 4 grades: Excellent indicated that preoperative clinical symptoms disappeared and without neurological dysfunction, Good indicated that preoperative clinical symptoms disappeared but with some nerve dysfunction, Secondary indicated that preoperative clinical symptoms were slightly relieved, and Poor indicated that preoperative clinical symptoms were aggravated (including death).\n\nRevascularization treatment can be evaluated by reviewing CTP or DSA and the efficacy can be divided into 2 grades: Good: 1/3 of middle cerebral artery supplying area was supplied by STA; Poor: only a small numbers of blood supply or even no blood supply from STA.\n\nStatistical analysis\nWe used SPSS 20.0 software (IBM SPSS, Armonk, NY, USA) for statistical analyses. Measurement data are presented by mean ± standard deviation. The Wilcoxon signed-rank test was used to assess the difference between preoperative and follow-up results within groups. P-value <0.05 was considered statistically significant.\n\nResults\nClinical outcomes after STA-MCA bypass surgery\nA total of 37 single-barrel STA-MCA bypass procedures in 56 surgical sessions were performed in 37 adult patients for treatment of ischemic-type MMD. Single-barrel STA-MCA anastomosis was technically successful in all 56 hemispheres. Among the 37 patients, the symptoms and signs of 32 patients were improved or stabilized. Five patients had complications, including 2 cases of acute cerebral infarction. It was worth mentioning that a 38-year-old man had an infarct in the MCA area 12 days after bypass surgery, after which his neurological status worsened. No definite reason for acute infarction was found in subsequent next evaluations. The patient partially recovered language function in 2 months postoperatively, although he was left with dysarthria. Among the 37 patients, 1 suffered from epidural hematoma and 1 had a transient speech disturbance. Although these patients with complications were symptomatic initially, they recovered without neurologic symptoms over time. However, among these patients, 1 died due to severe sepsis and respiratory failure. Complications are summarized in Table 2. According to clinical criteria, prognosis was excellent in 27 cases, good in 5 cases, secondary in 4 cases, and poor in 1 case. Follow-up imaging was performed in all 56 revascularized hemispheres to assess patency of the bypass. These studies were performed at 6–60 months after surgery. Fifty-two bypasses (92.8%) of 56 bypasses revealed the patency of the craniofacial vessels and the anastomotic stoma was good. Four bypasses (7.2%) of 56 bypasses demonstrated vascular obstruction or decreased of blood flow, which were evaluated as poor via imaging evaluation following STA-MCA bypass.\n\nChanges of CTP parameters after STA-MCA bypass surgery\nThe overall clinical outcomes were followed up at 6–62 months (mean, 28.3 months) after surgery. Complete sets of CTP results were obtained for 37 patients with 56 revascularized hemispheres in order to assess changes in CBF, CBV, MTT, and TTP. Follow-up computed CTP revealed that the cerebral hemodynamics in the revascularized hemispheres was noticeably improved after STA-MCA bypass (Figure 2). Cerebral blood flow (CBF) was markedly improved after surgery (P<0.05). Time to peek (TTP) and mean transit time (MTT) were significantly decreased after surgery (P<0.05). No significant change of cerebral blood volume (CBV) was detected after the operation (P>0.05) (Table 3). Postoperative patency was clearly verified via follow-up DSA imaging or three-dimensional (3D) reconstruction (Figure 1C–1F).\n\nDiscussion\nMMD is a rare cerebrovascular disorder characterized by progressive stenosis and occlusion of the internal carotid (ICA) and the anterior (ACA) and middle cerebral arteries (MCA). It can be diagnosed by confirming the cerebrovascular occlusion of the distal internal ICA, ACA, and the MCA through DSA and CTP [10]. Nevertheless, brain perfusion SPECT or MRI perfusion with/without acetazolamide can be performed to assess the hemodynamic status of the brain due to chronic hypoperfusion from diminished vascularity [11]. Generally speaking, MMD is diagnosed after a transient ischemic attack (TIA) in children and after a cerebral stroke in adults. Hence, it is necessary to intensively study use of revascularization surgery for treatment of MMD.\n\nPrevious studies reported that the combination of direct and indirect bypass is the optimal treatment in adult MMD [7,12]. It was reported that the annual risks of symptomatic infarction and hemorrhage were 0.2% and 0.4%, respectively, after analyzing 77 combined revascularization surgeries of 60 adult MMD patients and reported that the combined revascularization surgery resulted in satisfactory long-term improvement in clinical application, hemodynamic states, angiography, and prevention of recurrent stroke or TIA [13,14]. A potential mechanism is that direct revascularization could be effective at the early stage after surgery, maintaining its dominant role in collateralization, and these distal cerebral vessels progressively become partly or entirely occluded [15]. Thereafter, the indirect revascularization might replace these areas where blood flow could not reach through direct revascularization. To a certain extent, combined surgery might be more effective. Although combined revascularization surgery can immediately increase CBF and decrease the risk of ischemic attack, and combined revascularization surgery requires more time and is more complex [16]. The combined surgical procedure can lead to high risk of postoperative neurological morbidity, with hemodynamic compromises and bleeding-prone vasculopathy [17]. Hyperperfusion can also occur after combined revascularization surgery [18,19].\n\nIn the present study, we performed single-barrel STA-MCA direct bypass only, without the addition of an indirect revascularization procedure. A total of 56 surgeries in 37 adult MMD patients with hemodynamic impairment were analyzed, demonstrating the effectiveness of surgical treatment in adult ischemic-type MMD patients. Results revealed that among the 37 patients, the symptoms and signs of 32 patients were improved or stabilized; 5 patients had complications, including 2 cases of acute cerebral infarction, 1 case of epidural hematoma, and 1 case of transient speech disturbance, and 1 patient died due to severe sepsis and respiratory failure. To determine optimal targets for STA-MCA revascularization surgery, cerebral perfusion imaging is used to provide information about the severity and extent of the ischemic area. MTT and TTP values were observed to be significantly reduced and CBF was found to be markedly improved after direct revascularization treatment, but CBV was not significantly changed in these operated hemispheres. The results indicated that the corresponding cerebral hemodynamics improved after STA-MCA bypass at the surgical site. TTP and MTT maps can be quite sensitive to the presence of altered brain perfusion. During this specific phase of hemodynamic improvement, increased cerebral perfusion pressure can result in reduced MTT and TTP with or without vasodilatation. Nevertheless, in the absence of cerebral autoregulation induced by chronic cerebral hypoperfusion, CBV may remain within the previous range [20]. We hypothesize that CBF, as a subordinate sensitive parameter to changed brain perfusion, might have a better correlation with patency of the bypass artery [21]. However, CBF increasing markedly after surgery can directly reflect the graft patency to some extent. We did not find a statistically significant change in CBV in all surgical sessions, perhaps because CBV is a complex physiological parameter [22] composed of arterial, capillary, and venous compartments, as well as parenchymal and pial components, and the reduced perfusion pressure is variable due to the vasodilatory response of these different compartments [23].\n\nConclusions\nThe results of our preliminary study suggest that the direct revascularization of single-barrel STA-MCA bypass is a safe and durable method of cerebral revascularization in adult patients with ischemic-type MMD and can be considered as a potential treatment option for adult patients with ischemic-type MMD. Our promising results warrant further larger-scale clinical studies to determine the effect of STA-MCA bypass on the long-term outcome of MMD patients.\n\nConflict of interest\n\nNone.\n\nSource of support: This work was supported by Suzhou Introduction Medical Team Plan (No. SZYJTD201710), and National Key R&D Plan (No. 2016YFC0105904)\n\nFigure 1 The operation schematic diagram of a 39-year-old male is shown in A and B. Intraoperative photograph showing the anastomosis between the STA (black arrow) and the cortical branch of the MCA (white arrow), and the anastomosis (yellow arrow) can be clearly observed. Frontal (C) and lateral (D) views of the left external carotid artery angiogram after surgery. (E, F) Three-dimensional (3D) reconstruction of the left hemisphere after surgery. STA – superficial temporal artery; MCA – middle cerebral artery.\n\nFigure 2 CTP scans with CBV, CBF, TTP, and MTT obtained before and after surgery. CTP – computed tomography perfusion; CBV – cerebral blood volume; CBF – cerebral blood flow; MTT – mean transit time; TTP – time to peek.\n\nTable 1 Characteristics of patients.\n\nCharacteristics\tN=37\t\nAge\t38.1±11.9\t\nGender\t\n Male\t16\t\n Female\t21\t\nBilateral moyamoya\t\n Yes\t23\t\n No\t14\t\nInitial presentations\t\n TIA\t7\t\n ACI\t30\t\nSuzuki angiographic stage\t\n 3\t9\t\n 4\t17\t\n 5\t7\t\n 6\t4\t\nBilateral bypass\t\n Yes\t19\t\n No\t18\t\nTIA – transient ischemic attack; ACI – acute cerebral infarction.\n\nTable 2 Surgical complications.\n\nNumber of patients\tAges/sex\tSymptom onset post-operative (days)\tSymptoms\tRadiologic findings\tResults\t\n1\t38/Male\t12\tDysarthria\tAcute cerebral infarction\tPartial recovered\t\n2\t57/Female\t7\tDysarthria\tAcute cerebral infarction\tFull recovered\t\n3\t29/Male\t4\tSeizure\tEpidural hematoma\tFull recovered\t\n4\t31/Female\t9\tMotor aphasia\tTransient speech disturbance\tFull recovered\t\n5\t49/Female\t5\tSevere sepsis and respiratory failure\tAcute cerebral infarction\tDead\t\nTable 3 Changes of CTP parameters after STA-MCA bypass in 52 revascularized hemispheres.\n\nCTP parameters\tPreoperation\tPostoperation\tP value\t\nCBV\t3.19±1.47\t3.22±1.56\t0.649\t\nCBF\t47.66±8.16\t54.12±9.91\t0.013\t\nMTT\t5.27±1.08\t4.36±0.97\t0.007\t\nTTP\t13.16±3.54\t11.08±2.88\t0.003\t\nValue was presented as mean ± standard deviation. CTP – computed tomography perfusion; CBV – cerebral blood volume; CBF – cerebral blood flow; MTT – mean transit time; TTP – time to peek. P-value <0.05 was showed in bold fonts.\n==== Refs\nReferences\n1 Murchison J Wilson JM Ray C Moyamoya disease in an 18-month-old female Caucasian complicated by cerebral hyperperfusion syndrome following indirect revascularization Am J Case Rep 2017 18 1077 80 28989169 \n2 Ye Z Ai X You C Efficacy of surgery in the treatment of moyamoya disease compared with medical treatment J Craniofac Surg 2017 28 e799 e800 28968317 \n3 Kuroda S Strategy and tactics of bypass surgery for moyamoya disease Acta Neurochir (Wien) 2017 159 1495 96 28551837 \n4 Duan L Wei L Tian Y Novel susceptibility loci for moyamoya disease revealed by a genome-wide association study Stroke 2018 49 11 18 29273593 \n5 Ha M Choi CH Lee JI The efficacy of single-barrel superficial temporal artery-middle cerebral artery bypass in treatment of adult patients with ischemic-type moyamoya disease J Cerebrovasc Endovasc Neurosurg 2016 18 239 46 27847768 \n6 Esposito G Kronenburg A Fierstra J “STA-MCA bypass with encephalo-duro-myo-synangiosis combined with bifrontal encephalo-duro-periosteal-synangiosis” as a one-staged revascularization strategy for pediatric moyamoya vasculopathy Childs Nerv Syst 2015 31 765 72 25722049 \n7 Park SE Kim JS Park EK Direct versus indirect revascularization in the treatment of moyamoya disease J Neurosurg 2017 1 10 \n8 Tanabe N Yamamoto S Kashiwazaki D Indocyanine green visualization of middle meningeal artery before craniotomy during surgical revascularization for moyamoya disease Acta Neurochir (Wien) 2017 159 567 75 28050720 \n9 Xu B Song DL Mao Y Superficial temporal artery-middle cerebral artery bypass combined with encephalo-duro-myo-synangiosis in treating moyamoya disease: Surgical techniques, indications and midterm follow-up results Chin Med J (Engl) 2012 125 4398 405 23253709 \n10 Dai DW Zhao WY Zhang YW Role of CT perfusion imaging in evaluating the effects of multiple burr hole surgery on adult ischemic Moyamoya disease Neuroradiology 2013 55 1431 38 24153446 \n11 Kim YG Kweon EJ Chang WS Magnetic resonance-guided high-intensity focused ultrasound for treating movement disorders Prog Neurol Surg 2018 33 120 34 29332078 \n12 Zhao J Liu H Zou Y Clinical and angiographic outcomes after combined direct and indirect bypass in adult patients with moyamoya disease: A retrospective study of 76 procedures Exp Ther Med 2018 15 4 3570 76 29545885 \n13 Uchino H Kazumata K Ito M Novel insights into symptomatology of moyamoya disease in pediatric patients: Survey of symptoms suggestive of orthostatic intolerance J Neurosurg Pediatr 2017 20 485 88 28862519 \n14 Zhao M Zhang D Wang S Transient ischemic attack in pediatric patients with moyamoya disease: Clinical features, natural history, and predictors of stroke Pediatr Neurol 2017 75 48 54 28778481 \n15 Kazumata K Kamiyama H Saito H Direct anastomosis using occipital artery for additional revascularization in moyamoya disease after combined superficial temporal Artery-Middle cerebral artery and indirect bypass Oper Neurosurg (Hagerstown) 2017 13 213 23 28927214 \n16 Teo M Johnson J Steinberg GK Strategies for and outcome of repeat revascularization surgery for moyamoya disease: An American institutional series Neurosurgery 2017 81 852 59 28605467 \n17 Jiang H Ni W Xu B Outcome in adult patients with hemorrhagic moyamoya disease after combined extracranial-intracranial bypass J Neurosurg 2014 121 1048 55 25127415 \n18 Kazumata K Ito M Tokairin K The frequency of postoperative stroke in moyamoya disease following combined revascularization: A single-university series and systematic review J Neurosurg 2014 121 432 40 24605834 \n19 Bohara M Sugata S Nishimuta Y Effect of revascularization on headache associated with moyamoya disease in pediatric patients Hiroshima J Med Sci 2015 64 39 44 26688995 \n20 Sasagawa A Mikami T Hirano T Akiyama Y Mikuni N Characteristics of cerebral hemodynamics assessed by CT perfusion in moyamoya disease J Clin Neurosci 2018 47 183 89 29056445 \n21 Ladner TR Donahue MJ Arteaga DF Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD): A scoring system for moyamoya severity based on multimodal hemodynamic imaging J Neurosurg 2017 126 495 503 26967789 \n22 Harreld JH Sabin ND Rossi MG Elevated cerebral blood volume contributes to increased FLAIR signal in the cerebral sulci of propofol-sedated children Am J Neuroradiol 2014 35 1574 79 24699094 \n23 Ha M Choi CH Lee JI The efficacy of single barrel superficial temporal artery-middle cerebral artery bypass in treatment of adult patients with ischemic-type moyamoya disease J Cerebrovasc Endovasc Neurosurg 2016 18 239 46 27847768\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1234-1010",
"issue": "24()",
"journal": "Medical science monitor : international medical journal of experimental and clinical research",
"keywords": null,
"medline_ta": "Med Sci Monit",
"mesh_terms": "D000328:Adult; D002339:Carotid Arteries; D002548:Cerebral Revascularization; D002560:Cerebrovascular Circulation; D002681:China; D005260:Female; D006439:Hemodynamics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020768:Middle Cerebral Artery; D009072:Moyamoya Disease; D011183:Postoperative Complications; D011184:Postoperative Period; D012189:Retrospective Studies; D013699:Temporal Arteries; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "9609063",
"other_id": null,
"pages": "7469-7474",
"pmc": null,
"pmid": "30339661",
"pubdate": "2018-10-19",
"publication_types": "D016428:Journal Article",
"references": "24153446;28778481;27847768;26688995;25127415;29056445;28862519;29332078;24699094;28989169;26967789;28927214;28551837;28605467;25722049;29273593;23253709;28050720;29545885;28968317;24605834",
"title": "Assessment of Single-Barrel Superficial Temporal Artery-Middle Cerebral Artery Bypass in Treatment for Adult Patients with Ischemic-Type Moyamoya Disease.",
"title_normalized": "assessment of single barrel superficial temporal artery middle cerebral artery bypass in treatment for adult patients with ischemic type moyamoya disease"
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"companynumb": "CN-BAYER-2019-015971",
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"abstract": "BACKGROUND\nCarcinoid tumors are derived from enterochromaffin cells and may release physiologically active compounds into the systemic circulation, leading to the development of carcinoid syndrome. Occasionally, these tumors metastasize to the brain, warranting biopsy or resection. In these surgical patients, the perioperative implications for anesthetic management are not heretofore defined in the indexed literature.\n\n\nMETHODS\nPatients who had craniotomy for biopsy or resection of intracranial carcinoid tumors were retrospectively identified at a single medical center. Patient demographics, perioperative anesthetic management, adverse events, and outcome were summarized in this case series.\n\n\nRESULTS\nEleven patients were identified; median age was 60 years (range = 42-78 years), and 45% were male. Immediately before surgery, 4 patients (36%) were receiving a somatostatin analog drug, and no patient had unchecked carcinoid syndrome. All patients received general anesthesia that included inhaled isoflurane and nitrous oxide, and all had invasive arterial blood pressure monitoring. One patient developed sustained hypotension after induction of anesthesia, likely related to hypovolemia and anesthetic drugs, but the possibility of carcinoid mediator release cannot be excluded. There were no other signs or symptoms of carcinoid syndrome in this or any other patient. Of all 11 patients, 10 (91%) experienced either significant disease progression (n = 2; 18%) or death (n = 8; 73%) from carcinoid disease, its sequelae, or an undetermined cause within 3 years after surgery. Of note, 3 of the deaths occurred shortly after surgery, on postoperative days 3, 7, and 8.\n\n\nCONCLUSIONS\nIn our experience, carcinoid tumor metastasis to the brain-whether because of tumor makeup or prior treatment-is unlikely to produce symptoms of new-onset carcinoid syndrome intraoperatively; however, the risk cannot be completely excluded. Postsurgical prognosis was poor, both within the hospital and after hospital discharge.",
"affiliations": "Mayo Clinic, Department of Anesthesiology, 200 First St SW, Rochester, MN 55901, USA.;Mayo Clinic, Department of Anesthesiology, 200 First St SW, Rochester, MN 55901, USA. Electronic address: Pasternak.jeffrey@mayo.edu.;Mayo Clinic, Department of Anesthesiology, 200 First St SW, Rochester, MN 55901, USA.",
"authors": "Welch|Tasha L|TL|;Pasternak|Jeffrey J|JJ|;Lanier|William L|WL|",
"chemical_list": "D018685:Anesthetics, Inhalation; D007530:Isoflurane; D009609:Nitrous Oxide",
"country": "United States",
"delete": false,
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"issn_linking": "0952-8180",
"issue": "32()",
"journal": "Journal of clinical anesthesia",
"keywords": "Anesthetic management; Brain metastasis; Carcinoid",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000328:Adult; D000368:Aged; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D001921:Brain; D001932:Brain Neoplasms; D002276:Carcinoid Tumor; D005260:Female; D006801:Humans; D007530:Isoflurane; D008297:Male; D008875:Middle Aged; D009609:Nitrous Oxide; D012189:Retrospective Studies",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "281-8",
"pmc": null,
"pmid": "26422777",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anesthetic management of patients undergoing resection of carcinoid metastasis to the brain.",
"title_normalized": "anesthetic management of patients undergoing resection of carcinoid metastasis to the brain"
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"activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE"
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"abstract": "We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease.",
"affiliations": "Mayo Medical School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Wanous|Amanda|A|;McPhail|Ian R|IR|;Quevedo|J Fernando|JF|;Sandhu|Nicole P|NP|",
"chemical_list": "D000925:Anticoagulants; D011847:Radioactive Fallout",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218282",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "cancer - see oncology; cancer intervention",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D000971:Antineoplastic Combined Chemotherapy Protocols; D003937:Diagnosis, Differential; D006801:Humans; D015994:Incidence; D008297:Male; D008479:Mediastinal Neoplasms; D009373:Neoplasms, Germ Cell and Embryonal; D011847:Radioactive Fallout; D018239:Seminoma; D013479:Superior Vena Cava Syndrome; D013923:Thromboembolism; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28596199",
"pubdate": "2017-06-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11487036;11919246;17471115;17476012;19447309;20530278;20858789;22320869;23008318;23150697;24064342;24135138;24162670;2437455;25315643;3020061;7910232",
"title": "Mediastinal seminoma presenting with superior vena cava syndrome.",
"title_normalized": "mediastinal seminoma presenting with superior vena cava syndrome"
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"companynumb": "US-FRESENIUS KABI-FK201706866",
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"activesubstancename": "BLEOMYCIN SULFATE"
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"abstract": "Most chronic spontaneous urticaria (CSU) patients are female, and pregnancy can aggravate the disease activity of patients, but little is known about the efficacy and safety of omalizumab in pregnant CSU patients. We report two pregnant CSU patients treated with omalizumab and review the published information on omalizumab treatment during 11 pregnancies. The outcomes reported on patients with known pregnancies showed they had normal pregnancies and healthy babies as well as complete control of their CSU. The two new cases we reported support the view that omalizumab could be an effective and safe treatment option for pregnant and breastfeeding CSU patients. Further high-quality studies need to be carried out in order to obtain more information on the long-term efficacy and safety of the use of omalizumab during pregnancy in patients with chronic urticaria, including CSU.",
"affiliations": "Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.;Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.;Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.;Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Liao|Shuang-Lu|SL|;Yu|Miao|M|;Zhao|Zuo-Tao|ZT|;Maurer|Marcus|M|",
"chemical_list": "D018926:Anti-Allergic Agents; D000069444:Omalizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.652973",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.652973\nImmunology\nCase Report\nCase Report: Omalizumab for Chronic Spontaneous Urticaria in Pregnancy\nLiao Shuang-Lu 1 2 3\n\nYu Miao 1 2 3 4\n\nZhao Zuo-Tao 1 2 3 * †\n\nMaurer Marcus 5 * †\n\n1 Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China\n2 Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China\n3 National Clinical Research Center for Skin and Immune Diseases, Beijing, China\n4 Peking University School of Nursing, Beijing, China\n5 Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany\nEdited by: Marcelo Vivolo Aun, Albert Einstein Israelite Hospital, Brazil\n\nReviewed by: Christian Drouet, INSERM U1016 Institut Cochin, France; Rosana Agondi, University of São Paulo, Brazil\n\n*Correspondence: Marcus Maurer, marcus.maurer@charite.de; Zuo-Tao Zhao, zhaozuotaotao@163.com\n†These authors have contributed equally to this work and share senior authorship\n\nThis article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology\n\n16 3 2021\n2021\n12 65297314 1 2021\n01 3 2021\nCopyright © 2021 Liao, Yu, Zhao and Maurer\n2021\nLiao, Yu, Zhao and Maurer\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nMost chronic spontaneous urticaria (CSU) patients are female, and pregnancy can aggravate the disease activity of patients, but little is known about the efficacy and safety of omalizumab in pregnant CSU patients. We report two pregnant CSU patients treated with omalizumab and review the published information on omalizumab treatment during 11 pregnancies. The outcomes reported on patients with known pregnancies showed they had normal pregnancies and healthy babies as well as complete control of their CSU. The two new cases we reported support the view that omalizumab could be an effective and safe treatment option for pregnant and breastfeeding CSU patients. Further high-quality studies need to be carried out in order to obtain more information on the long-term efficacy and safety of the use of omalizumab during pregnancy in patients with chronic urticaria, including CSU.\n\nomalizumab\npregnancy\nchronic spontaneous urticaria\nwheals\nangioedema\nCharité – Universitätsmedizin Berlin10.13039/501100002839D052\n==== Body\nIntroduction\n\nChronic spontaneous urticaria (CSU) is a heterogeneous disorder with recurrent pruritic wheals and angioedema or both that markedly affects patients’ quality of life (1, 2). The anti-IgE antibody omalizumab is used in CSU patients resistant to antihistamine treatment (3). Most CSU patients are female, and little is known about the efficacy and safety of omalizumab in pregnant CSU patients. We treated patient #1 and patient #2 at Peking University First Hospital with omalizumab and reviewed the published information on this treatment during pregnancy.\n\nCase Description\n\nThe first patient is a 33-year-old woman diagnosed with CSU and comorbid symptomatic dermographism 2 years ago. She had a history of spontaneously occurring recurrent pruritic wheals, most often on the extremities and trunk, that would last less than 24 h. As confirmed by provocation testing, patient #1 also developed wheals in response to rubbing of skin that happened in real life, and this was true even with minor triggers such as drying herself with a towel after showering. Patient #1 had not experienced angioedema. Treatment with first cetirizine 10mg/day and then, due to drowsiness, ebastine 10mg/day for several weeks did not reduce disease activity. As Patient #1 did not consent to the use of a higher than standard dosed antihistamine, we initiated treatment with omalizumab, in June 2020, at 300mg/month, which led to complete control as assessed by the use of the urticaria control test (UCT). The UCT assesses disease control in patients with CSU with four questions, each with five answer options (scored with 0–4 points), where a low total score indicates poor disease control and the maximum total score of 16 reflects complete control (4, 5). The UCT score of patient #1, 4 weeks after starting omalizumab, was 16. During the first 4 weeks, patient #1 also experienced a marked improvement of quality of life (QoL) impairment as assessed by the Dermatology Life Quality Index (DLQI) and the Chronic Urticaria QoL Questionnaire (CU-Q2oL). For the DLQI and CU-Q2oL, higher scores reflect higher QoL impairment, and a score of 0–1, for the DLQI, and of 23, for the CU-Q2ol, indicated that there was no QoL impairment. A total of 4 weeks after the start of omalizumab application, the DLQI and CU-Q2oL scores were 0 and 23, respectively. After 10 days of the third omalizumab application (August 2020), 10 weeks after the first application, patient #1 was found to be 10 weeks pregnant. She chose to stop omalizumab, continued with cetirizine treatment, 10 mg every 3 days, and has remained free of CU signs and symptoms since then.\n\nThe second patient is a 36-year-old woman with CSU. She had recurrent generalized wheals with pruritus (daily or almost daily for 5 years) that lasted for several hours each time and occurred without known triggers. Serum total IgE concentration was measured by a chemiluminescent immunoassay (ImmunoCAP; Thermo-Fisher Scientific, Sweden), and levels of 100 kU/L or greater were defined as increased. Thyroid autoantibodies, including serum anti-thyroid peroxidase antibody (anti-TPO IgG) and anti-thyroglobulin antibody (anti-TG IgG), were determined using an electrochemiluminescence immunoassay (Roche Elecsys-2010; Roche Diagnostics, U.S.) with normal reference ranges of 0–34 IU/ml and 0–115 IU/ml, respectively; the serum total IgE of Patient #2 was low at 19.3 kU/L, anti-TPO IgG was found to be elevated at 87 IU/ml, and anti-TG IgG was normal at 20 IU/ml). A biopsy taken from lesional skin of patient #2 showed a perivascular inflammatory infiltrate of lymphocytes and eosinophils, erythrocyte extravasation, and scant edema within the superficial and mid dermis, without fibrinoid deposits and leukocytoclasis, consistent with urticaria. Patient #2, after being diagnosed with CSU in June 2018, was treated with cyclosporine and was controlled well during the 10 months of treatment. In May 2019, CSU showed exacerbation, cyclosporine was stopped, and omalizumab treatment was started (UCT:1; DLQI:15; CU-Q2ol:80). Three days after the first application (300 mg), she was free of CSU signs and symptoms but only for 5 days. We increased the dose of a second application after 4 weeks to 450 mg, which led to complete recovery within 3 days for 3 months, at 450 mg/month (UCT:16; DLQI:0; CU-Q2ol:23). We then decreased the dose to 300 mg/month, and complete control was maintained by this treatment until January 2020, when patient #2 experienced severe exacerbation of CSU phenotype (UCT:1; DLQI:12; Cu-Q2ol:65) and was found to be 12 weeks pregnant. With the patient’s informed consent, we increased the dose of omalizumab to 450 mg, and she regained complete control within 3 days. Two attempts to reduce to 300 mg/month failed, and 450 mg/month omalizumab treatment was maintained until August 2020, when patient #2 gave birth to a full-term healthy male infant (weight 3350g, length 50cm). Patient #2 is breastfeeding her child and is symptom-free with 450 mg/month omalizumab.\n\nPatient #1 and Patient #2 have given written informed consent to the publication of their case details. The study was conducted according to the Declaration of Helsinki. It was approved by the Chinese Ethics Committee of Registering Clinical Trial (ChiECRCT20190131) and registered with the Chinese clinical trial registry (ChiCTR1900024869).\n\nDiscussion\n\nTaken together, both patients described herein became pregnant while on omalizumab treatment, both achieved complete response during pregnancy (albeit at higher than the standard dose in one patient), and both pregnancies were unproblematic.\n\nAt this time, only 11 pregnancies in CSU patients treated with omalizumab were reported in the literature ( Table 1 (6–11)). Similar to patients #1 and #2, almost all patients previously reported had normal pregnancies and healthy babies as well as complete control of their CSU. Of note, increasing the dose of omalizumab during pregnancy was only reported in one previous CSU patient. In this patient, the first CSU patient ever reported to receive omalizumab during pregnancy, disease activity while on omalizumab 150mg/month increased markedly, and intervals were shortened to every 15 days, which resulted in complete remission (11). Patient #2 was also given an increased dose during pregnancy, from 300mg to 450mg omalizumab per month, and is the first pregnant CSU patient reported to receive more than the licensed dosed omalizumab. Nonresponse to standard dosed omalizumab in CSU had not previously been linked to high body weight, and patient #2 was 70–80 kg (before, during, and after pregnancy) and 165 cm, i.e., not overweight. Omalizumab blood concentrations of patient #2 had not been assessed as no assay to do so was available to us and nonresponse to standard dosed omalizumab in CSU had not previously been linked to altered blood levels of omalizumab.\n\nTable 1 Characteristics of reported cases of pregnant CU patients with omalizumab treatment.\n\n\tTitle\tAuthor\tyear\tdisease\tnumber of patients\tAge range\tTiming of exposure\tOmalizumab dose/interval\tEvidence of efficacy\tEvidence for safety\t\n\t\t\t\t\t\t\t\t\tMaternal adverse events\tLive births\tSmall for Gestational Age\tLow birth weight\tPreterm birth(<37wk)\tStillbirth/fetal death(≥20wk)\tSpontaneous abortion(<20wk)\tcongenital malformations\tneonatal adverse outcomes\t\n1\tOur study\tOur group\t2020\tCU\t2\t33,37\tFirst Trimester\t1/2:150-300mg/4 wk,\n1/2:300-450mg/4 wk\tcomplete control\t0/2\t1/1†\t0/1\t0/1\t0/1\t0/1\t0/1\t0/1\t0/1\t\n2\tOmalizumab concentrations in pregnancy and lactation: A case study\tSaito, J. et al.\t2020\tCSU\t1\t38\tFirst Trimester\t150mg/4 wk\tcomplete control\t0/1\t1/1\t0/1\t0/1\t0/1\t0/1\t0/1\tskin defect, aortic aneurysm\t0/1\t\n3\tOmalizumab as Third-Line Therapy for Urticaria During Pregnancy\tEnsina, L. F. et al.\t2017\tCSU\t2\t29,32\tFirst Trimester\t1/2:150 mg/4 wk,\n1/2:300mg twice with an interval of 12 wk\tcomplete control\t0/2\t3/3\t0/3\t0/3\t0/3\t0/3\t0/3\t0/3\t0/3\t\n4\tOmalizumab use during pregnancy for chronic spontaneous urticaria (CSU): report of two cases\tGonzález-Medina, M. et al.\t2017\tCSU\t2\t37,37\tFirst Trimester\t300 mg/4 wk\tcomplete control\t0/2\t2/2\t0/2\t0/2\t0/2\t0/2\t0/2\t0/2\t0/2\t\n5\tOmalizumab use during pregnancy for CIU: a tertiary care experience\tCuervo-Pardo L. et al.\t2016\tCSU\t4\t25-28\tFirst Trimester\t300 mg/4 wk\tcomplete control\t0/4\t4/4\t0/4\t0/4\t0/4\t0/4\t0/4\t0/4\t0/4\t\n6\tSuccessful and Safe Treatment of Chronic Spontaneous Urticaria with Omalizumab in a Woman during Two Consecutive Pregnancies\tGhazanfar, M. N. et.al.\t2015\tCSU\t1\t32\tFirst Trimester\t150mg/2wk,\n300mg/4wk\tcomplete control\t0/1\t2/2\t0/2\t0/2\t0/2\t0/2\t0/2\t0/2\t0/2\t\n7\tEffects of omalizumab in a patient with three types of chronic urticaria\tVieira Dos Santos R. et al.\t2014\tCSU\nCIndU\t1\t37\tFirst Trimester\t150mg/4wk,\n150mg/2wk\tcomplete control\t0/1\t1/1†\t0/1\t0/1\t0/1\t0/1\t0/1\t0/1\t0/1\t\n†The other patient was still pregnant. CU, Chronic Urticaria; CSU, Chronic Spontaneous Urticaria; CIndU, inducible urticaria.\n\nNo evidence of a relationship between omalizumab exposure and increased risk of adverse events in pregnant patients and their infants was reported (12). Omalizumab can be an effective option for pregnant CSU patients and those who want to become pregnant.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nS-LL: performed data analysis and drafted the manuscript. MY: performed data analysis and prepared the manuscript. Z-TZ: designed the study and prepared the manuscript, reviewed the article critically for important intellectual content. MM: drafted the manuscript, reviewed the article critically for important intellectual content. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAbbreviations\n\nCSU, Chronic Spontaneous Urticaria; UCT, Urticaria Control Test; DLQI, Dermatology Life Quality Index; CU-Q2ol, Chronic Urticaria Quality of Life Questionnaire.\n==== Refs\nReferences\n\n1 Agache I Rocha C Pereira A Song Y Alonso-Coello P Solà I . Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: A systematic review for the EAACI Biologicals Guidelines. Allergy (2021) 76 (1 ):59–70. 10.1111/all.14547 32767573\n2 Zuberbier T Aberer W Asero R Abdul Latiff AH Baker D Ballmer-Weber B . The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy (2018) 73 (7 ):1393–414. 10.1111/all.13397\n3 Zhao ZT Ji CM Yu WJ Meng L Hawro T Wei JF . Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol (2016) 137 (6 ):1742–50.e4. 10.1016/j.jaci.2015.12.1342 27040372\n4 Yu M Chen Y Liu B Song XZZ . Validation of Chinese version of urticaria control test (UCT). Chin J Dermatol (2020) 53 (7 ):52–7. 10.35541/cjd.20191190\n5 Weller K Groffik A Church MK Hawro T Krause K Metz M . Development and validation of the urticaria control test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol (2014) 133 (5 ):1365–72. 10.1016/j.jaci.2013.12.1076\n6 Saito J Yakuwa N Sandaiji N Uno C Yagishita S Suzuki T . Omalizumab concentrations in pregnancy and lactation: A case study. J Allergy Clin Immunol Pract (2020) 8 (10 ):3603–4. 10.1016/j.jaip.2020.05.054\n7 Ensina LF Cusato-Ensina AP Camelo-Nunes IC Solé D . Omalizumab as third-line therapy for urticaria during pregnancy. J Investig Allergol Clin Immunol (2017) 27 (5 ):326–7. 10.18176/jiaci.0179\n8 González-Medina M Curto-Barredo L Labrador-Horrillo M Giménez-Arnau A . Omalizumab use during pregnancy for chronic spontaneous urticaria (CSU): report of two cases. J Eur Acad Dermatol Venereol (2017) 31 (5 ):e245–e6. 10.1111/jdv.14034\n9 Cuervo-Pardo L Barcena-Blanch M Radojicic C . Omalizumab use during pregnancy for CIU: a tertiary care experience. Eur Ann Allergy Clin Immunol (2016) 48 (4 ):145–6. 10.23822/EurAnnACI.1764-1489\n10 Ghazanfar MN Thomsen SF . Successful and safe treatment of chronic spontaneous urticaria with Omalizumab in a woman during two consecutive pregnancies. Case Rep Med (2015) 2015 (2015 ):368053. 10.1155/2015/368053 25705229\n11 Vieira Dos Santos R Locks Bidese B Rabello de Souza J Maurer M . Effects of omalizumab in a patient with three types of chronic urticaria. Br J Dermatol (2014) 170 (2 ):469–71. 10.1111/bjd.12628\n12 Türk M Carneiro-Leão L Kolkhir P Bonnekoh H Buttgereit T Maurer M . How to treat patients with chronic spontaneous urticaria with Omalizumab: questions and answers. J Allergy Clin Immunol Pract (2020) 8 (1 ):113–24. 10.1016/j.jaip.2019.07.021\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "angioedema; chronic spontaneous urticaria; omalizumab; pregnancy; wheals",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D018926:Anti-Allergic Agents; D000080223:Chronic Urticaria; D005260:Female; D006801:Humans; D000069444:Omalizumab; D011247:Pregnancy; D011248:Pregnancy Complications; D011537:Pruritus; D011788:Quality of Life; D016896:Treatment Outcome",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "652973",
"pmc": null,
"pmid": "33796115",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "27040372;32544544;32767573;29057743;27868240;24102388;25705229;31374358;24522090;27425170;29336054",
"title": "Case Report: Omalizumab for Chronic Spontaneous Urticaria in Pregnancy.",
"title_normalized": "case report omalizumab for chronic spontaneous urticaria in pregnancy"
} | [
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"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-21207",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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{
"abstract": "BACKGROUND\nNo previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly.\n\n\nOBJECTIVE\nEvaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly.\n\n\nMETHODS\nThis is a prospective randomized study. We enrolled AF patients (age ≥ 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding.\n\n\nRESULTS\nA total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B ( P = 0.10).\n\n\nCONCLUSIONS\nUninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly.",
"affiliations": "1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.;1 Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, P R China.",
"authors": "Xing|Yangbo|Y|;Xu|Buyun|B|;Xu|Chao|C|;Peng|Fang|F|;Yang|Biao|B|;Qiu|Yufang|Y|;Sun|Yong|Y|;Wang|Shengkai|S|;Guo|Hangyuan|H|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028017712532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "51(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": "atrial fibrillation; catheter ablation; clinical trials; the elderly; warfarin",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012449:Safety; D020521:Stroke; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "735-742",
"pmc": null,
"pmid": "28573932",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and Safety of Uninterrupted Low-Intensity Warfarin for Radiofrequency Catheter Ablation of Atrial Fibrillation in the Elderly.",
"title_normalized": "efficacy and safety of uninterrupted low intensity warfarin for radiofrequency catheter ablation of atrial fibrillation in the elderly"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1062592",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "WARFARIN"
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... |
{
"abstract": "OBJECTIVE\nTo measure the incidence of agitation after traumatic brain injury (TBI) in an inpatient population and to identify any features associated with an adverse outcome.\n\n\nMETHODS\nProspective study of TBI admissions over 30 months in consecutive admissions with TBI to a regional neurorehabilitation unit. Outcome of agitation was compared to patient, injury and treatment features and any associations were sought. The presence of agitation was measured by the Agitation Behaviour Score. A good outcome for agitation was defined as a return to independent living with minimal care requirement at 6 months using an Extended Glasgow Outcome Scale (GOSE) score >4.\n\n\nRESULTS\nOver 30 months, there were 146 TBI admissions, of whom 53 cases had agitation (36.3%). Achieving 100% follow-up, 27 (51%) had a good outcome. On a multivariable logistic regression analysis, a good outcome was associated with the type of lesions seen on CT scan, the severity of agitation and the duration of the behaviour. Alcohol excess and type of treatment used for the behaviour were initially significant on univariate testing but dropped out of the logistic regression model.\n\n\nCONCLUSIONS\nOver a third of TBI admissions, developed agitation and poor functional outcome was associated with CT scan findings, severity and duration of agitation.",
"affiliations": "Osborn Neurorehabilitation Unit, Northern General Hospital , Sheffield , UK.",
"authors": "Singh|Rajiv|R|;Venkateshwara|Guru|G|;Nair|Krishnan P S|KP|;Khan|Muhammed|M|;Saad|Rafat|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/02699052.2013.873142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9052",
"issue": "28(3)",
"journal": "Brain injury",
"keywords": null,
"medline_ta": "Brain Inj",
"mesh_terms": "D000203:Activities of Daily Living; D000328:Adult; D000374:Aggression; D000437:Alcoholism; D001930:Brain Injuries; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D015994:Incidence; D015601:Injury Severity Score; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D011595:Psychomotor Agitation; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8710358",
"other_id": null,
"pages": "336-40",
"pmc": null,
"pmid": "24377492",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Agitation after traumatic brain injury and predictors of outcome.",
"title_normalized": "agitation after traumatic brain injury and predictors of outcome"
} | [
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"companynumb": "US-LEADING PHARMA, LLC-2070731",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
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{
"abstract": "Acyclovir has been widely used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV). The common adverse effects of this drug include nausea, diarrhea, headache, dizziness and mental changes. The immune thrombocytopenia induced by acyclovir is rare.\n\n\n\nA 67-year-old Chinese male who was given acyclovir 5 mg kg-1 8 hourly intravenously for treatment of VZV infection developed severe thrombocytopenia with fist sign in oral cavity within 10 days of starting using acyclovir. The patient's condition was improved by stopping using acyclovir and further supportive treatment. The acyclovir-dependent platelet antibody test showed positive results, which implicated acyclovir as the causative agent. The final definitive diagnosis of acyclovir-induced immune thrombocytopenia was established basing on the time correlation between the start of using acyclovir and the onset of symptoms of thrombocytopenia, combining with excluding of other common causes of thrombocytopenia.\n\n\n\nThere have been few reports of acyclovir-induced immune thrombocytopenia. This is the first case report and literature review of acyclovir-induced immune thrombocytopenia, with tongue hematoma as the first sign. Dentists should never overlook this rare adverse effect of acyclovir, as a rapid and appropriate treatment may prevent further severe life-threatening complications.",
"affiliations": "Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China.;State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.;Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China. wangzhiyong67@163.com.",
"authors": "Hong|Xiaowei|X|;Wang|Xiaoqian|X|;Wang|Zhiyong|Z|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-017-0120-2",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 12010.1186/s40360-017-0120-2Case ReportA rare case report of acyclovir-induced immune thrombocytopenia with tongue hematomas as the first sign, and a literature review Hong Xiaowei mydontcry@126.com 1Wang Xiaoqian xiaoqian0103@hotmail.com 2Wang Zhiyong +86 02583620323wangzhiyong67@163.com 11 0000 0001 2314 964Xgrid.41156.37Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008 People’s Republic of China 2 0000 0001 0807 1581grid.13291.38State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China 7 3 2017 7 3 2017 2017 18 125 7 2016 31 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAcyclovir has been widely used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV). The common adverse effects of this drug include nausea, diarrhea, headache, dizziness and mental changes. The immune thrombocytopenia induced by acyclovir is rare.\n\nCase presentation\nA 67-year-old Chinese male who was given acyclovir 5 mg kg−1 8 hourly intravenously for treatment of VZV infection developed severe thrombocytopenia with fist sign in oral cavity within 10 days of starting using acyclovir. The patient’s condition was improved by stopping using acyclovir and further supportive treatment. The acyclovir-dependent platelet antibody test showed positive results, which implicated acyclovir as the causative agent. The final definitive diagnosis of acyclovir-induced immune thrombocytopenia was established basing on the time correlation between the start of using acyclovir and the onset of symptoms of thrombocytopenia, combining with excluding of other common causes of thrombocytopenia.\n\nConclusion\nThere have been few reports of acyclovir-induced immune thrombocytopenia. This is the first case report and literature review of acyclovir-induced immune thrombocytopenia, with tongue hematoma as the first sign. Dentists should never overlook this rare adverse effect of acyclovir, as a rapid and appropriate treatment may prevent further severe life-threatening complications.\n\nKeywords\nAcyclovirThrombocytopeniaVaricella-zoster virusTongue hematomaCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAcyclovir, an acyclic purine nucleoside analogue, has been widely used because of its highly potent prohibitive properties for infections caused by HSV and VZV [1, 2]. Acyclovir has minimal toxicity to normal host cells, because the drug is only adsorbed by the virus infected cells [3]. Severe adverse effect like neurotoxicity, kidney disorders and psychiatric was not common, mostly related to high dose intravenous administrations [4–6]. Only a few reports of acyclovir-induced myelosuppressive have been published [7–9], and so far only two case reports of acyclovir-induced thrombocytopenic purpura have been reported [3, 10]. Our patient, a 67-year-old Chinese man who received acyclovir for the VZV infection, presented with oral hematomas as the first sign. We believe this is the first well-documented case report of acyclovir-induced immune thrombocytopenia as the first sign in oral cavity.\n\nCase presentation\nA 67-year-old man who was retired presented to the Oral Maxillofacial Surgery Department of Nanjing Stomatology Hospital, Nanjing, Jiangsu, China, with a 10-day history of a “lump” on the left part of his tongue. The patient felt pain when eating, and the “lump” gradually grew in size. There was a similar “lump” on the right side of his tongue, which then regressed with no treatment. Before having the “lump” on his tongue, the patient had sought treatment at a general hospital, and was given intravenous acyclovir 5 mg kg−1 8 hourly for 7 days because of a VZV infection. The patient denied fever, hematochezia, melena, hemoptysis, hematuria, and neurologic symptoms. He had no history of bibulosity, smoking, systemic diseases, or drug allergy. His family history, social history, and oral treatment history were unremarkable. No other drugs were taken during the treatment of the varicella-zoster virus infection.\n\nClinical examination\nExtraoral examination: There was no enlargement or change in texture of the maxillofacial and neck lymph nodes, and no limitation of mouth opening (mouth opened to 40 mm). No swelling or deformity of the maxillofacial area and neck were noted. There were several ecchymoses on the patient’s legs and feet (Fig. 1).Fig. 1 Extra-oral examination of patient: purple spots on patient’s legs and feet\n\n\n\n\nIntraoral examination: There were three main lesions in the patient’s mouth. The first lesion appeared on the left margin of the tongue, a dark purple hematoma, 1.5 cm × 1 cm in size, with a medium texture and hard base. The lesion was painful on compression, but did not change color when pressed. Bleeding at the margin of the lesion was detected (Fig. 2a and b). The second lesion was on the left side of the tongue tip, showing a dark purple spot 0.3 cm in diameter (Fig. 2a). It was not painful on compression. The third lesion was a 0.5 cm × 0.5 cm white plaque with a bleeding spot at the center (Fig. 2c), located on the right margin of the tongue, and eliciting no pain on compression.Fig. 2 Intraoral examination of the first visit (a-c), the second visit (d-f), and the third visit (g-i)\n\n\n\n\nLaboratory test\nA complete blood count, performed on the day of presentation, showed a hemoglobin concentration of 120 g/L (120–160 g/L), a white blood cell count of 8.75 × 103/mm3 (4.6–10.2 × 103/mm3) with 58.1% neutrophils (50–70%), 25.8% lymphocytes (20–40%), and 9.6% monocytes (2–10%); the platelet count was 10 × 109/L (100–300 × 109/L) (Fig. 3). Other laboratory tests showed normal liver function, a normal electrolyte profile, and normal haptoglobin, bilirubin (total and direct), and lactate dehydrogenase (LDH) levels. Creatinine clearance was 59.2 mL/min. Coagulation studies were normal. Tests for cytomegalovirus, hepatitis A and B viruses, and Epstein–Barr virus yielded negative results. The result for platelet factor 4 (PF4)/heparin antibodies using enzyme-linked immunoassay (ELISA) was positive. The following serotonin-release assay (SRA) yielded a negative result. ELISA was also applied for detection of acyclovir-dependent platelet antibodies in vitro, which showed positive results.Fig. 3 Time course of the patient’s platelet count after starting the treatment\n\n\n\n\nThese findings, taken together with the temporal relationship between the putative drug (acyclovir) and the onset of thrombocytopenia, along with the exclusion of the other most common known causes of thrombocytopenia, established a definitive diagnosis of acyclovir-induced immune thrombocytopenia.\n\nInitial treatment included telling the patient to stop using acyclovir, and giving him 5 units of donor platelets to elevate his platelet count. The patient was also treated with oral prednisone 60 mg daily for possible immune thrombocytopenic purpura (ITP).\n\nThe subsequent visits\nOne week later, the patient came back for a follow-up visit. We saw that the lesion on the left margin of tongue had regressed obviously. The lesion was of medium texture, had a softer base than before, was not painful on compression, and still had some bleeding spots on the margin (Fig. 2e). The lesions located on the left side of the tongue tip and the right margin of tongue were smaller, and the color had changed from purple to almost white (Fig. 2d and f). His platelet count was elevated to 39 × 109/L (Fig. 3). The third visit: Another 1 week later, the patient came for a second follow-up visit. The lesions located on the left side of the tongue tip and the right margin of tongue had disappeared (Fig. 2g and i). The lesion on the left margin of tongue was smaller, and the color changed from purple to white, with a soft base and no pain on compression. The patient’s platelet count was elevated to 98 × 109/L.\n\nDiscussion\nDITP is a challenging clinical problem that is under-recognized, difficult to diagnose, and associated with severe bleeding complications [11]. The first report of DITP was published as early as 1865 [12]. DITP can be triggered by a wide range of medications. There are more than 200 drugs, including some herbal medicines, that have been reported to be causeative of DITP [13, 14]. The incidence of DITP is not well defined; epidemiologic studies performed in the US and Europe showed that approximately 10 persons per million are affected by DITP [15–18]. Despite the low frequency, DITP is important to recognize because of the large number of drugs can be involved and the large number of patients that can be affected [19].\n\nThe etiology of DITP is complex. According to the mechanism responsible for the thrombocytopenia, DITP can be divided into two main categories, which are suppression of platelet production and increasing in clearance of peripheral platelets. The former one is caused mostly by myelosuppressive drugs. The latter one can be further divided into three subtypes: nonimmune DITP, immune DITP, and autoimmune DITP [19]. Most DITPs are thought to be caused by the second mechanism, which is mediated by a drug-dependent antibody, and most drugs are thought to cause thrombocytopenia by a drug-dependent immune mechanism. How drugs induce platelet antibodies and how platelets are destroyed by these antibodies are still poorly understood [14].\n\nPatients who experience an unexpected severe thrombocytopenia and an acute drop in platelet levels should be suspected of having DITP. Clinical key features of DITP are: 1) extensive petechiae or ecchymosis, with markedly low blood platelet levels (frequently <10 × 109/L), approximately 3 to 10 days after starting a putative medication [13, 14, 20, 21], and 2) platelet counts return to normal at approximately 7 days after stopping the putative drug (usually in 1–10 days) [22]. Serious bleeding, including intracranial hemorrhage, can occur [23], presenting a challenging diagnostic and management problem.\n\nThe diagnosis of DITP is mainly established by the exclusion of all the recognized causes of thrombocytopenia and the temporal association between the administration of the putative drug and the development of thrombocytopenia [10]. A careful, detailed history is crucial to patient evaluation. The patient should be asked specifically about drug exposure that can cause thrombocytopenia, including herbal medicine, tonics, certain foods, drinks, and health supplements. Aster and George have developed the clinical criteria and levels of evidence for diagnosis of DITP [14, 24].\n\nIn our case, the patient was given acyclovir as anti-varicella-zoster virus infection treatment. We first considered a bone marrow suppression and immunologic thrombocytopenia, which was associated with viral infections, including human immunodeficiency virus (HIV), hepatitides virus (including hepatitis B and C viruses), Epstein-Barr virus, and cytomegalovirus [25]. The tests for the a forementioned viruses were negative, and varicella-zoster virus is rarely involved in bone marrow suppression. From the complete blood test results, only platelets decreased markedly, and the white cells and hemoglobin concentration remained normal. Consequently, it was unlikely to be viral-induced thrombocytopenia.\n\nAs heparin-induced thrombocytopenia (HIT) is the most common cause of a decrease in platelet count [13], we considered excluding it, although the patient did not provide a clear history of having taken heparin. The result of the PF4/heparin antibody test was positive. PF4/heparin antibodies are sensitive and can be seen in some acute diseases, not specifically in HIT. Thus, we performed the SRA assay, which is considered the gold standard of diagnosis of HIT. The result of the SRA array was negative. We decided that HIT was unlikely to be the cause.\n\nDetection of the drug-dependent antiplatelet antibodies in blood can be helpful in diagnosis [22, 26], although waiting for results of this assay is time consuming, and the test may provide false-negative results. We did the assay and got a positive result. There was no detectable immunoglobulin when the patient’s serum was incubated with normal platelets without identification, and there were detectable levels of immunoglobulin when the patient’s serum was incubated with normal platelets in the presence of acyclovir.\n\nBased on the exclusion of other etiologies of thrombocytopenia, platelet count, and the positive antiplatelet antibodies, and with the temporal relationship between the acyclovir and the onset of thrombocytopenia, we could make the diagnosis of acyclovir-induced immune thrombocytopenia.\n\nFor most patients, the appropriate treatment is to stop the putative drug, herbal medicine, or food, administering platelet transfusions or other therapies if bleeding is severe [13, 19, 24]. Based on these principles, initial treatment included stopping the use of acyclovir and giving 5 units of donor platelets to for supportive treatment in our case.\n\nConclusion\nA 67-year-old man developed acyclovir-induced thrombocytopenia after receiving the drug for 10 days VZV infection. Tongue hematoma was the first sign of DITP.\n\nThis case highlights that acyclovir could be a causative drug of DITP and that clinicians should be aware of this potential adverse reaction. A hematoma in the oral cavity can be the first complaint, and patients may present to a dentist first. Dentists should be alert to the possibility of this condition.\n\nAbbreviations\nDITPDrug-induced immune thrombocytopenia\n\nELISAEnzyme-linked immunoassay\n\nHITHeparin-induced thrombocytopenia\n\nHSVHerpes simplex virus\n\nITPImmune thrombocytopenic purpura\n\nLDHLactate dehydrogenase\n\nPF4Platelet factor 4\n\nSRASerotonin-release assay\n\nVZVVaricella zoster virus\n\nAcknowledgements\nWe thank Dr. Tingting Wang and Dr. Shuangshuang Ren for the clinical data collection.\n\nFunding\nThis case report does not have any funding to support.\n\nAvailability of data and materials\nThe datasets generated and/or analysed during the current study are not publicly available due to privacy of those clinical results and information, the patient does not consent to share this information publicly but are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nWZY is the corresponding author and he contributed to the he design of the study. HXW and WXQ is co-first author, carried out the diagnosis and treatment of this case and participated in drafting the manuscript. All authors read and approved the final version of the manuscript.\n\nAuthors’ information\nXiaowei Hong: Oral and maxillofacial surgeon of Nanjing Stomatological Hospital, Medical School of Nanjing University.\n\nXiaoqian Wang: Doctoral student of West China Hospital of Stomatology, Sichuan University.\n\nZhiyong Wang: Oral and maxillofacial surgeon of Nanjing Stomatological Hospital, Medical School of Nanjing University.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nEthics approval and consent to participate\nThis study was approved by the Ethical Institutional Review Board of Stomatological Hospital of Nanjing University School of Medicine (NO. LC 2015-12/11).\n==== Refs\nReferences\n1. Dworkin RH Johnson RW Breuer J Gnann JW Levin MJ Backonja M Recommendations for the management of herpes zoster Clin Infect Dis 2007 44 S1 S26 10.1086/510206 17143845 \n2. Whitley RJ Gnann JW Jr Acyclovir: a decade later N Engl J Med 1992 327 782 789 10.1056/NEJM199209103271108 1288525 \n3. Kamboj J Wu F Kamboj R Suzue K Khosla P A rare case of acyclovir-induced thrombocytopenia Am J Ther 2014 21 e159 e162 10.1097/MJT.0b013e31826fc4be 23344109 \n4. Busso M Berman B Antivirals in dermatology J Am Acad Dermatol 1995 32 1031 1040 10.1016/0190-9622(95)91344-0 7751448 \n5. Adair JC Gold M Bond RE Acyclovir neurotoxicity: clinical experience and review of the literature South Med J 1994 87 1227 1231 10.1097/00007611-199412000-00006 7973922 \n6. Haefeli WE Schoenenberger RA Weiss P Ritz RF Acyclovir-induced neurotoxicity: concentration-side effect relationship in acyclovir overdose Am J Med 1993 94 212 215 10.1016/0002-9343(93)90186-S 8430717 \n7. Feder HM Jr Goyal RK Krause PJ Acyclovir-induced neutropenia in an infant with herpes simplex encephalitis: case report Clin Infect Dis 1995 20 1557 1559 10.1093/clinids/20.6.1557 7548511 \n8. Tuncer AM Evis B Kunak B Akçayöz N Ertem U Erythroblastopenia and leukopenia in the patient with severe herpes zoster treated with intravenous acyclovir Turk J Pediatr 1989 31 317 321 2486432 \n9. Grella M Ofosu JR Klein BL Prolonged oral acyclovir administration associated with neutropenia and thrombocytopenia Am J Emerg Med 1998 16 396 398 10.1016/S0735-6757(98)90138-3 9672461 \n10. Katsenos S Gkolias D Nikolopoulou M Acyclovir-induced immune thrombocytopenia in a patient with herpes zoster of the trigeminal nerve Pharmacotherapy 2010 30 1085 10.1592/phco.30.10.1085 \n11. Arnold DM Nazi I Warkentin TE Smith JW Toltl LJ George JN Kelton JG Approach to the diagnosis and management of drug-induced immune thrombocytopenia Transfus Med Rev 2013 27 137 145 10.1016/j.tmrv.2013.05.005 23845922 \n12. Vipan W Quinine as a cause of purpura Lancet 1865 86 37 10.1016/S0140-6736(02)39906-9 \n13. Aster RH Bougie DW Drug-induced immune thrombocytopenia N Engl J Med 2007 357 580 587 10.1056/NEJMra066469 17687133 \n14. Aster RH Curtis BR McFarland JG Bougie DW Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management J Thromb Haemost 2009 7 911 918 10.1111/j.1538-7836.2009.03360.x 19344362 \n15. Böttiger LE Böttiger B Incidence and cause of aplastic anemia, hemolytic anemia, agranulocytosis and thrombocytopenia Acta Med Scand 1981 210 475 479 10.1111/j.0954-6820.1981.tb09853.x 7331894 \n16. Danielson DA Douglas SW 3rd Herzog P Jick H Porter JB Drug-induced blood disorders JAMA 1984 252 3257 3260 10.1001/jama.1984.03350230017024 6151006 \n17. Pedersen-Bjergaard U Andersen M Hansen PB Thrombocytopenia induced by noncytotoxic drugs in Denmark 1968–91 J Intern Med 1996 239 509 515 10.1046/j.1365-2796.1996.486822000.x 8656144 \n18. Pedersen-Bjergaard U Andersen M Hansen PB Drug-specific characteristics of thrombocytopenia caused by non-cytotoxic drugs Eur J Clin Pharmacol 1998 54 701 706 10.1007/s002280050538 9923571 \n19. Chong BH Choi PY Khachigian L Perdomo J Drug-induced immune thrombocytopenia Hematol Oncol Clin North Am 2013 27 521 540 10.1016/j.hoc.2013.02.003 23714310 \n20. Chong BH Drug-induced immune thrombocytopenia Platelets 1991 2 173 181 10.3109/09537109109005508 21043926 \n21. George JN Raskob GE Shah SR Rizvi MA Hamilton SA Osborne S Vondracek T Drug-induced thrombocytopenia: a systematic review of published case reports Ann Intern Med 1998 129 886 890 10.7326/0003-4819-129-11_Part_1-199812010-00009 9867731 \n22. Visentin GP Liu CY Drug-induced thrombocytopenia Hematol Oncol Clin North Am 2007 21 685 696 10.1016/j.hoc.2007.06.005 17666285 \n23. Freiman JP Fatal quinine-induced thrombocytopenia Ann Intern Med 1990 112 308 309 10.7326/0003-4819-112-4-308 2297210 \n24. George JN Aster RH Drug-induced thrombocytopenia: pathogenesis, evaluation, and management Hematology Am Soc Hematol Educ Program 2009 2009 153 158 \n25. Salloum R Liu CY Weise AM Possible case of levofloxacin-induced thrombocytopenia Am J Health Syst Pharm 2011 68 1 43 46 10.2146/ajhp090564 21164064 \n26. Bougie DW Wilker PR Aster RH Patients with quinine-induced immune thrombocytopenia have both “drug-dependent” and “drug-specific” antibodies Blood 2006 108 922 927 10.1182/blood-2006-01-009803 16861345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-6511",
"issue": "18(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Acyclovir; Case report; Thrombocytopenia; Tongue hematoma; Varicella-zoster virus",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D006406:Hematoma; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D014059:Tongue",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "12",
"pmc": null,
"pmid": "28264696",
"pubdate": "2017-03-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23714310;17687133;9923571;7751448;1288525;17666285;9867731;21043926;17143845;8656144;2297210;16861345;7973922;2486432;19344362;23344109;21164064;8430717;7331894;7548511;9672461;23845922;20008194;6151006",
"title": "A rare case report of acyclovir-induced immune thrombocytopenia with tongue hematomas as the first sign, and a literature review.",
"title_normalized": "a rare case report of acyclovir induced immune thrombocytopenia with tongue hematomas as the first sign and a literature review"
} | [
{
"companynumb": "CN-GLAXOSMITHKLINE-CN2017041374",
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
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... |
{
"abstract": "The treatment of multiple myeloma is considered a continuously evolving paradigm as a result of the growing availability of new and highly effective drugs, including first- and second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Clinical trials advocate long-term rather than short-term treatment schedules with combinations of these new anti-myeloma drug classes. Although the overall toxicity profile of the recommended regimens can be considered favorable, their increasing complexity and prolonged use warrant a heightened vigilance for early and late side effects, a priori because real-life patients can be more frail or present with 1 or more comorbidities. The treatment decision process, at diagnosis and at relapse, therefore requires myeloma physicians to carefully balance efficacy and toxicity profiles for each individual patient. Early and/or unnecessary tapering or treatment discontinuation for drug-related adverse events may not only reduce patients' quality of life, but also negatively impact their outcome. Accurate knowledge in recognizing and managing the potential side effects of present-day treatment regimens is therefore a cornerstone in myeloma care. Using 5 case vignettes, we discuss how to prevent and manage the most common nonhematological adverse events of anti-myeloma treatment regimens containing proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.",
"affiliations": "Department of Hematology, University Hospital Leuven, Leuven, Belgium; and.;Wilhelminen Cancer Research Institute, First Department of Medicine, Center for Oncology, Haematology and Palliative Care, Wilhelminenspital, Vienna, Austria.",
"authors": "Delforge|Michel|M|0000-0002-0147-2291;Ludwig|Heinz|H|0000-0002-3302-8726",
"chemical_list": "D000700:Analgesics; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D061988:Proteasome Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-01-725705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "129(17)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000368:Aged; D000700:Analgesics; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D019468:Disease Management; D057915:Drug Substitution; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D057285:Precision Medicine; D061988:Proteasome Inhibitors; D011788:Quality of Life; D012074:Remission Induction",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2359-2367",
"pmc": null,
"pmid": "28275090",
"pubdate": "2017-04-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "How I manage the toxicities of myeloma drugs.",
"title_normalized": "how i manage the toxicities of myeloma drugs"
} | [
{
"companynumb": "BE-009507513-1706BEL000683",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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... |
{
"abstract": "BACKGROUND\nDespite screening for latent tuberculosis (TB), new cases of TB infection are detected in patients treated with anti-TNF-α and negative initial screening, some of them after long treatment, which points more to a new infection.\n\n\nOBJECTIVE\nTo describe the cases that have presumably developed a primary tuberculous infection during treatment with anti-TNF-α drugs.\n\n\nMETHODS\nRetrospective audit (1999-2012). Inclusion criteria were: a) anti-TNF-α treatment; b) initial latent TB screening negative; c) TB diagnosed during anti-TNF-α treatment; d) suspected primary TB infection (diagnosis after at least 12 months on anti-TNF-α). Clinical, epidemiological, therapeutic and outcome variables were reviewed.\n\n\nRESULTS\nTwo cases of primary TB infection were found out of of 771 anti-TNF-α treated patients (0.2%). One woman aged 41 suffered TB pneumonia after 35 months of treatment with adalimumab, and a male aged 37 who developed disseminated TB after 107 months of treatment with infliximab.\n\n\nCONCLUSIONS\nAlthough uncommon, during TNF antagonist therapy, TB risk persists despite negative initial screening, so clinicians should be aware of TB during the entire treatment.",
"affiliations": "Sección de Reumatología, Hospital General Universitario de Alicante, Alicante, España. Electronic address: drjoseantoniobernal@gmail.com.;Sección de Reumatología, Hospital General Universitario de Alicante, Alicante, España.;Sección de Reumatología, Hospital General Universitario de Alicante, Alicante, España.;Servicio de Neumología, Hospital General Universitario de Alicante, Alicante, España.;Sección de Reumatología, Hospital General Universitario de Alicante, Alicante, España.;Sección de Reumatología, Hospital General Universitario de Alicante, Alicante, España.",
"authors": "Bernal|José Antonio|JA|;Andrés|Mariano|M|;Jovaní|Vega|V|;García Sevila|Raquel|R|;Begazo|Alejandra|A|;Vela|Paloma|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069285:Infliximab; D000068879:Adalimumab",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-258X",
"issue": "12(2)",
"journal": "Reumatologia clinica",
"keywords": "Anti-TNF-α; Immunosuppression; Inmunosupresión; Reactivación tuberculosis latente; Reactivating latent tuberculosis; Tuberculosis",
"medline_ta": "Reumatol Clin",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D000069285:Infliximab; D055985:Latent Tuberculosis; D008297:Male; D012042:Registries; D012189:Retrospective Studies; D014376:Tuberculosis",
"nlm_unique_id": "101293923",
"other_id": null,
"pages": "81-4",
"pmc": null,
"pmid": "26099453",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary tuberculosis infection in patients treated with tumor necrosis factor-alpha antagonists and a negative initial screening.",
"title_normalized": "primary tuberculosis infection in patients treated with tumor necrosis factor alpha antagonists and a negative initial screening"
} | [
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"companynumb": "ES-JNJFOC-20150623293",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Data concerning idiopathic recurrent pericarditis in pregnancy are scarce.\n\n\n\nTo evaluate the management and outcome of idiopathic recurrent pericarditis during pregnancy.\n\n\n\nTwenty-one pregnancies were evaluated in fourteen women with a history of recurrent idiopathic pericarditis (mean maternal age 31.5 years, mean gestational age 39.0 weeks), and subdivided in 2 cohorts: eight pregnancies were analyzed retrospectively (2002-2010), thirteen (2011-2017) prospectively and followed according a predefined management protocol. Ten pregnancies were uneventful, three ended in spontaneous early abortion, one fetal death occurred at 19 weeks. Recurrences of pericarditis occurred in eight and were treated by adding NSAIDs in two cases; in five cases the dose of corticosteroids was increased and in two cases aspirin was started/increased; paracetamol was always allowed. Colchicine was used in two cases in the prospective cohort. HELLP syndrome occurred in one patient, which resolved after delivery, and one patient experienced arterial hypertension and elevated transaminase. All infants had a good outcome (mean birth weight 3114 g, 10 males). Birth weight was significantly lower in the retrospective cohort (respectively 2806 g vs. 3320 g, p-value 0.017) in which higher doses of corticosteroids were used (median dose respectively 10.0 mg vs. 2.5 mg, p-value 0.048). Five recurrences of pericarditis occurred after delivery, easily treated with standard therapy.\n\n\n\nGeneral outcomes of pregnancy in patients with idiopathic recurrent pericarditis is good, especially when patients are carefully followed by multidisciplinary teams according to standardized protocols.",
"affiliations": "Department of Biomedical and Clinical Science \"L. Sacco\", University of Milano, Italy.;Department of Cardiology, Maastricht University Medical Center (MUMC+) and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands. Electronic address: nikki.pluymaekers@mumc.nl.;Department of Biomedical and Clinical Science \"L. Sacco\", University of Milano, Italy.;Department of Obstetrics and Gynaecology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.;Department of Internal Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy.;Department of Obstetrics and Gynaecology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.;Department of Internal Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy.;The Gertner Institute, Sheba Medical Center, affiliated to Sackler Medical school, Tel Aviv University and the College for Academic Studies, Israel.;University Cardiology AOU, Città della Salute e della Scienza di Torino, Torino, Italy.",
"authors": "Brucato|Antonio|A|;Pluymaekers|Nikki|N|;Tombetti|Enrico|E|;Rampello|Stefania|S|;Maestroni|Silvia|S|;Lucianetti|Marzia|M|;Valenti|Anna|A|;Adler|Yehuda|Y|;Imazio|Massimo|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2019.02.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "282()",
"journal": "International journal of cardiology",
"keywords": "Management; Outcome; Pericarditis; Pregnancy; Recurrent pericarditis; Therapy",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D015331:Cohort Studies; D019468:Disease Management; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D010493:Pericarditis; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "60-65",
"pmc": null,
"pmid": "30773267",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Management of idiopathic recurrent pericarditis during pregnancy.",
"title_normalized": "management of idiopathic recurrent pericarditis during pregnancy"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-206125",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Angioedema (AE) is a transient capillary leak syndrome, caused by either histamine or bradykinin, that presents as an acute nonpitting swelling of the skin, subcutaneous tissues, and mucous membranes of the face, lips, tongue, upper airways, and gastrointestinal tract, with or without a rash. A lack of response to antihistamines, steroids, and epinephrine suggests a bradykinin-mediated AE. Bradykinin-AE may be inherited, acquired, or drug related. Mechanism of increased bradykinin can include decreased C1-esterase inhibitor (C1-INH) levels or activity, increased bradykinin production, or decreased bradykinin breakdown, the latter occurring during angiotensin converting enzyme inhibitor (ACEi). A 65-year-old woman had coronary artery bypass grafting, which was complicated by prolonged bradykinin-AE owing to ACEi, requiring prolonged endotracheal tube intubation. Treatment with a C1-esterase inhibitor (Berinert) on postoperative day 7 resulted in a dramatic improvement in airway edema and tongue swelling within 7 hours, and the patient was subsequently extubated. The case is unusual because of the prolonged course of AE and the benefit of late administration of C1-INH concentrate.",
"affiliations": "Department of Anesthesiology, Rhode Island Hospital, Providence, RI.;Department of Anesthesiology, Rhode Island Hospital, Providence, RI. Electronic address: amaslow@rcn.org.;Department of Anesthesiology, Rhode Island Hospital, Providence, RI.",
"authors": "Mukhdomi|Taif|T|;Maslow|Andrew|A|;Joyce|Maurice F|MF|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D050718:Complement C1 Inhibitor Protein; D001920:Bradykinin",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jvca.2019.12.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "34(7)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "C1 esterase inhibitor; angioedema; angiotensin converting enzyme inhibitor; bradykinin",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D001920:Bradykinin; D006348:Cardiac Surgical Procedures; D050718:Complement C1 Inhibitor Protein; D005260:Female; D006801:Humans",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "1890-1896",
"pmc": null,
"pmid": "31948888",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Prolonged Angioedema After Cardiac Surgery.",
"title_normalized": "a case of prolonged angioedema after cardiac surgery"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-50547",
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"patient": {
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"abstract": "Orthostatic tremor (OT) is a hyperkinetic movement disorder characterized by rapid tremor in the lower extremities or trunk upon standing.\n\n\n\nWe report two patients presenting with OT, whose symptoms improved markedly following asleep bilateral thalamic deep brain stimulation (DBS) surgery.\n\n\n\nMedically refractory OT can respond favorably to asleep bilateral DBS surgery similar to awake surgery, and may have the advantages of less psychological trauma to the patient, shorter procedure times, and less exposure to anesthesia.",
"affiliations": "Movement Disorders Center of Arizona, Scottsdale, AZ, USA.;Movement Disorders Center of Arizona, Scottsdale, AZ, USA.;Movement Disorders Center of Arizona, Scottsdale, AZ, USA.;Movement Disorders Center of Arizona, Scottsdale, AZ, USA.;Barrow Neurological Institute, Phoenix, AZ, USA.;Barrow Neurological Institute, Phoenix, AZ, USA.",
"authors": "Evidente|Virgilio Gerald H|VGH|;Baker|Zachary J|ZJ|;Evidente|Maris H|MH|;Garrett|Robin|R|;Lambert|Margaret|M|;Ponce|Francisco A|FA|",
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"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D8KS882GCase ReportsOrthostatic Tremor is Responsive to Bilateral Thalamic Deep Brain Stimulation: Report of Two Cases Performed Asleep Asleep DBS in Orthostatic TremorEvidente Virgilio Gerald H. 1*Baker Zachary J. 1Evidente Maris H. 1Garrett Robin 1Lambert Margaret 2Ponce Francisco A. 21 Movement Disorders Center of Arizona, Scottsdale, AZ, USA2 Barrow Neurological Institute, Phoenix, AZ, USALouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: vevidente@movementdisorders.us2018 27 7 2018 8 56615 4 2018 9 7 2018 © 2018 Evidente et al.2018Evidente et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nOrthostatic tremor (OT) is a hyperkinetic movement disorder characterized by rapid tremor in the lower extremities or trunk upon standing.\n\nCase Report\nWe report two patients presenting with OT, whose symptoms improved markedly following asleep bilateral thalamic deep brain stimulation (DBS) surgery.\n\nDiscussion\nMedically refractory OT can respond favorably to asleep bilateral DBS surgery similar to awake surgery, and may have the advantages of less psychological trauma to the patient, shorter procedure times, and less exposure to anesthesia.\n\nOrthostatic tremordeep brain stimulationasleepshaky legs syndrome\n==== Body\nIntroduction\nFirst reported in 1984, orthostatic tremor (OT) is a rare progressive hyperkinetic movement disorder characterized by imbalance and unsteadiness due to high‐frequency leg and body tremors that occur only when standing.1 Although early neurophysiological studies described the tremor to be of 13–18 Hz frequency, subsequent studies showed tremor outside that range.2 Tremors attenuate when sitting, walking, or leaning on an object or person. Early or mild OT may respond to benzodiazepines (most commonly clonazepam), beta‐blockers (most commonly propranolol), and antiepileptic drugs (most commonly gabapentin).2,3 For patients with moderate to severe disease, oral medications have proved to be ineffective or are associated with intolerable side effects. We have previously reported a case of medically refractory OT that responded well to bilateral awake deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus.4 Additionally, there have been 17 other cases of OT reported in the literature that have undergone thalamic VIM awake DBS surgery.5–12 We report on two patients with OT who responded favorably to bilateral thalamic asleep DBS.\n\nCase reports\nThe two OT patients presented herein were implanted with bilateral Medtronic quadripolar 3387 DBS electrodes, and a Medtronic ActivaTM PC implantable pulse generator. Our intraoperative asleep procedures and targeting for VIM DBS have been summarized in an earlier publication.13 Briefly, the VIM was targeted indirectly relative to the midcommissural point using preoperative stereotactic imaging, and final electrode placement was determined via intraoperative computed tomography scans. The stereotactic coordinates of contact 1 were compared with target coordinates to verify that the vector error was less than 2 mm.\n\nCase 1\nR.B. is a 73‐year‐old male who first presented at age 60 with tremors of the legs when standing. With time, the tremors involved the trunk while standing, and the hands during action or posture holding. Because of the leg tremors, he felt unsteady. By age 73, he claimed he could only stand in place for 15 seconds at a time. The leg tremors made him anxious, and proved resistant to several medications at maximum tolerated doses, including gabapentin (1,200 mg per day), clonazepam (1 mg per day), primidone (75 mg per day), and carbidopa/levodopa (25/100 0.5 mg tablet three times a day). His initial neurological evaluation revealed intact strength in all four limbs, reduced vibration sense and temperature sense in the distal upper and lower limbs, symmetric breakdown of rapid alternating movements, wide base upon standing but normal base when walking, moderate cautious gait, mild resting tremor in both hands, moderate action/postural tremor in both hands, mild tremor in either leg upon raising the leg while seated, moderate to severe bilateral leg tremors that were evident immediately upon standing in place, and no rigidity. During his initial examination, he could only stand for 7 seconds at most with feet wide apart before needing to lean or sit (Video 1). His blood tests were normal, including thyroid stimulating harmone (TSH), T3, and T4 levels. A brain DaTscan using ioflupane I‐123 was unremarkable. Surface electromyography (EMG) recordings showed 10–14 Hz tremors of both lower limbs proximally and distally that were noted when standing but not when seated, as well as 6–7 Hz hand tremors on posture holding or action.\n\nVideo 1. Case 1. Pre-deep brain stimulation (DBS). The patient had almost immediate onset of orthostatic leg tremors on standing and had extreme difficulty standing without holding on to the table or walls. Post DBS (10 months). The patient demonstrates no visible tremor on standing, and has no difficulty at all standing in place without support.\nThe patient underwent bilateral thalamic VIM asleep DBS surgery. The Talairach coordinates were (±14.25, –6.35, 0). Per protocol, contact 1 was targeted (Figure 1A). For both sides, the routine impedance check was normal and macrostimulation was unremarkable up to 8 V. The vector errors were 1.1 mm for both sides (Euclidean errors were also 1.1 mm bilaterally). Five days after surgery, initial programming was performed. The left VIM electrode settings were case(+), 0 and 2(–); amplitude 0.5 volt; pulse width 60 µs; and frequency 185 Hz. The right VIM electrode settings were case(+); contacts 8 and 10(–); amplitude 0.5 volt; pulse width 60 µs; and frequency 185 Hz. The double monopolar settings were chosen to target both his hand and leg areas, with transient paresthesias noted in the upper and lower limbs during programming. At these settings, the patient exhibited no hand tremors on action or posture holding, nor leg tremors at rest or upon raising his legs. He also had reduced tremor of the legs when standing. The patient was able to stand in place for 4 minutes before needing to sit or lean. Except for brief tingling in the extremities, no persistent side effects were noted after programming. At 1 month post‐DBS surgery, the patient was able to move unassisted and stand indefinitely without any OT symptoms. At 10 months post‐DBS surgery, he presented with no hand tremors or symptoms of OT (Video 1). He was able to perform any activity requiring prolonged standing without difficulty, reporting one occasion of remaining standing for 6 hours with no support. The programming settings at 10 months post‐surgery were as follows: for the left VIM, settings were case(+), 1 and 3(–); amplitude 2.6 volts; pulse width 60 µs; and frequency 185 Hz; for the right VIM, the settings were 11(+), 9 and 10(–); amplitude 2.7 volts; pulse width 60 µs; and frequency 185 Hz. Surface EMG recordings were performed at 10 months post DBS, with marked improvement of his OT with the stimulator on compared with that when the stimulator was off (Figures 2A,B).\n\nFigure 1 Imaging of Lead Placement. (A) Case 1. Preoperative magnetic resonance imaging and post‐lead intraoperative computed tomography (CT) scan are co‐registered using Medtronic FrameLink software. Targeted contacts are contact 1 on the left (L1) and contact 9 on the right (R2). On the left, the stereotactic error of contact 1 is 1.1 mm from the intended target (–14.25, 6.35, 0). On the right, the stereotactic error of contact 9 is 1.1 mm from the intended target (–14.25, 6.35, 0) (active contacts: left, case(+), 1–, 3–; right, 11+, 9–, 10–). (B) Case 2. Intraoperative post‐lead placement CT shows the position of contact 2 on the left ventralis intermedius (VIM) lead (L2), and contact 9 on the right VIM lead (R2). Contact 2 has a radial error of 0.9 mm off of the stereotactic plan targeting (–13.5, –6.75, 0). Contact 9 has a radial error of 0.7 mm off of the stereotactic plan targeting (13.5, –6.75, 0) (active contact: left, case(+), 2–; right, 11+, 8–,10–; contact 9 is shown because it is between contacts 8 and 10.\nFigure 2 Surface Electromyography (EMG) Recordings. (A) Postoperative surface electromyography (EMG) recording of the right tibialis anterior of case 1 while standing with the deep brain stimulator off. Note the prominent high‐frequency tremor of 10–13 Hz. (B) Postoperative surface EMG of the right tibialis anterior of case 1 while standing with deep brain stimulator on. Note the significant attenuation of the tremor activity in terms of frequency, amplitude, and continuity, with prolonged periods of quiescence.\nCase 2\nR.S. is a 68‐year‐old male with a history of diabetic neuropathy and Meniere’s disease, who first noticed bilateral hand tremors and imbalance in his forties. His tremors and gait difficulty worsened with time. Although his imbalance and gait disturbance were attributed to chronic Meniere’s disease, his hand tremors were thought to result from essential tremor. The tremors were resistant to a number of medications, including topiramate (100 mg per day), zonisamide (450 mg per day), and propranolol (10 mg per day). He experienced mild relief with clonazepam (0.5 mg twice a day). Initial examination revealed intact strength in all four limbs, reduced light touch and cold perception in the distal upper and lower limbs, moderate resting tremor of the hands, severe action tremor of both hands, symmetric breakdown in rapid alternating movements in all four limbs, moderate shuffling, moderately increased base on standing and walking, positive Romberg’s, and no rigidity. He had buckling of the knees and a fast frequency tremor of both legs when standing, and he could only stand in place without assistance or holding on to an object for only 5 seconds or less. He also often needed assistance from another person to stand in place or to walk slowly (Video 2). Surface EMG recordings showed a 10–12 Hz tremor of the lower limbs on standing, with subharmonics of 5–6 Hz tremor noted frequently. Additionally, recordings revealed 6–8 Hz tremor of the hands on posture holding. His labs were normal, including TSH, T3, T4, B12, and folate. His DaTscan was unremarkable.\n\nVideo 2. Case 2. Pre‐deep brain stimulation (DBS). Note buckling of the knees and severe difficulty standing in place because of severe orthostatic leg tremors that were apparent immediately upon standing. The patient requires assistance from one person to remain standing in place and intermittently with slow ambulation. Post DBS (1 month). There is improvement of the buckling of the knees on standing with little orthostatic leg tremor noted. The patient can stand better on his own or with a cane.\nThe patient underwent bilateral thalamic VIM asleep DBS surgery. The Talairach coordinates were (±13.25, –6.75, 0) (Figure 1B). For both sides, the impedance check was normal and macrostimulation was unremarkable up to 8 V. The vector error was 1.0 mm off plan on the left and 0.7 mm off plan on the right (Euclidean errors were 1.0 mm and 0.8 mm, respectively). Three days following surgery, initial programming was performed. The left VIM electrode settings were case(+), 2(–); amplitude 0.5 volt; pulse width 60 µs; and frequency 185 Hz. The right VIM electrode settings were 11(+), 8, and 10(–); amplitude 0.5 volts; pulse width 60 µs; and frequency 185 Hz. Although the single monopolar settings in the left electrode were sufficient to control the tremor in the right arm and leg, the double bipolar settings for the right electrode were more effective than the single bipolar or monopolar settings for controlling the tremor in the left arm and leg, with transient paresthesias noted in the upper and lower limbs during programming. One week post‐DBS surgery, he had no hand tremors, though his orthostatic leg tremors were only mildly improved. Apart from temporary tingling in both the hands and legs during programming adjustments, no lingering side effects were noted. One month post‐DBS surgery, his OT had improved, with much less buckling of the knees while standing, and he needed less assistance from a person or cane while standing in place (Video 2). Six months following DBS, he had only mild orthostatic leg tremors. He was able to stand in place for at least 5 minutes at a time, which to him was clinically significant as it allowed him to be more independent and perform activities while standing. He continued to have a wide base on standing and walking, and exhibit gait difficulty, which were thought to be related to chronic Meniere’s disease. At this time, the programming settings were the following: for the left VIM, settings were case(+), 1 and 0(–); amplitude 2.0 volts; pulse width 60 µs; and frequency 185 Hz; for the right VIM, settings were 10(+), 9(–); amplitude 2.8 volts; pulse width 60 µs; and frequency 130 Hz. Post DBS surgery, he was gradually weaned off clonazepam, topiramate, and propranolol, with no notable change in his hand or orthostatic leg tremors.\n\nDiscussion\nPrevious publications have reported the favorable response of medically refractory OT to thalamic VIM DBS surgery carried out in an awake patient, with better sustained benefit with bilateral DBS than with unilateral stimulation.3–12 A summary of patient clinical and demographic data for 17 OT patients who underwent DBS was recently published by Merola et al.12 in a multicenter international registry, while a summary of the target coordinates and programming parameters in 12 OT patients was recently published by Lehn et al.11 The two cases presented herein are the first two OT cases reported to respond favorably to asleep VIM DBS. The targeting method was identical to that used when treating upper extremity tremor: 25% the distance from posterior commissure to anterior commissure, 10.5 mm lateral to the wall of the lateral ventricle at the midcommissural plane. Thus, taking microelectrode recordings (MERs) searching for the leg somatotopic location within the VIM in an awake patient may not be necessary to guarantee improvement of OT with stimulation. We have previously reported intraoperative surface EMG recordings from leg muscles with the table partly inclined and the patient stepping onto a foot board.4 This setup may not be available in most centers, and may add significantly to the operative time. Taking MERs or intraoperative surface EMG recordings increases the duration of surgery and results in the potential exposure to more anesthesia. Thus, for OT patients who cannot tolerate awake DBS surgery with MERs, carrying out the surgery when the patient is asleep is a viable alternative. Both our cases have experienced sustained benefit from DBS of their OT at 6 and 10 months post‐DBS, and their balance and ability to stand have improved, which has translated to improvement of their daily activities requiring standing.\n\nThere are certain limitations to our study. One is the small number of subjects; OT is understandably a rare disorder, and those making it to DBS are even rarer. Second is the short postoperative follow‐up, though neither of the two cases has reported tolerance or waning of effect as of their last follow‐up.\n\nAlthough there are no studies comparing outcomes of asleep versus awake DBS in OT, asleep DBS appears to be just as effective in providing clinical improvement in OT patients who do not respond sufficiently to oral medications. Asleep DBS, especially with bilateral lead implantation, has the advantages of lessening the psychological trauma to the patient, faster procedure time, and less exposure to anesthesia.\n\nFunding: None.\n\nFinancial Disclosures: Dr. Evidente has received speaking honoraria from Medtronic.\n\nConflict of Interests: The authors have no actual or potential conflicts of interest.\n\nEthics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.\n==== Refs\nReferences\n1 Heilman KM Orthostatic tremor Arch Neurol 1984 41 880 881 10.1001/archneur.1984.04050190086020 6466163 \n2 Hassan A Ahlskog EJ Matsumoto JY Milber JM Bower JH Wilkinson JR Orthostatic tremor: clinical, electrophysiologic, and treatment findings in 184 patients Neurology 2016 86 458 464 10.1212/WNL.0000000000002328 26747880 \n3 Evidente VG Adler CH Caviness JN Gwinn KA Effective treatment of orthostatic tremor with gabapentin Mov Disord 1998 13 829 831 10.1002/mds.870130513 9756154 \n4 Lyons MK Behbahani M Boucher OK Caviness JN Evidente VG Orthostatic tremor responds to bilateral thalamic deep brain stimulation Tremor Other Hyperkinet Mov 2012 2 10.7916/D8TQ608K \n5 Guridi J Rodriguez‐Oroz MC Arbizu J Alegre M Prieto E Landecho I et al Successful thalamic deep brain stimulation for orthostatic tremor Mov Disord 2008 23 1808 1811 10.1002/mds.22001 18671286 \n6 Espay AJ Duker AP Chen R Okun MS Barrett ET Devoto J et al Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations Mov Disord 2008 23 2357 2362 10.1002/mds.22271 18759339 \n7 Magariños‐Ascone C Martínez Ruiz F San Millán A Montes E Regidor I del Alamo de Pedro M et al Electrophysiological evaluation of thalamic DBS for orthostatic tremor Mov Disord 2010 25 2476 2477 10.1002/mds.23333 20818606 \n8 Yaltho TC Ondo WG Orthostatic tremor: a review of 45 cases Parkinsonism Relat Disord 2014 20 723 725 10.1016/j.parkreldis.2014.03.013 24736049 \n9 Contarino MF Bour LJ Schuurman PR Blok ER Odekerken VJJ van den Munckhof P et al Thalamic deep brain stimulation for orthostatic tremor: clinical and neurophysiological correlates Parkinsonism Relat Disord 2015 21 1005 1007 10.1016/j.parkreldis.2015.06.008 26096797 \n10 Coleman RR Starr PA Katz M Intermediate nucleus thalamic deep brain stimulation in orthostatic tremor Stereotact Funct Neurosurg 2016 94 69 74 10.1159/000444127 27002536 \n11 Lehn AC O’Gorman C Olson S Salari M Thalamic ventral intermediate nucleus deep brain stimulation for orthostatic tremor Tremor Other Hyperkinet Mov 2017 7 10.7916/D8280JHR \n12 Merola A Fasana A Hassan A Ostrem JL Contarino MF Lyons M et al Thalamic deep brain stimulation for orthostatic tremor: a multicenter international registry Mov Disord 2017 32 1240 1244 10.1002/mds.27082 28631862 \n13 Chen T Mirzadeh Z Chapple K Lambert M Dhall R Ponce FA “Asleep” deep brain stimulation for essential tremor J Neurosurg 2016 124 1842 1849 10.3171/2015.6.JNS15526 26613177\n\n",
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"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Orthostatic tremor; asleep; deep brain stimulation; shaky legs syndrome",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D000368:Aged; D046690:Deep Brain Stimulation; D004244:Dizziness; D004576:Electromyography; D006801:Humans; D008297:Male; D013788:Thalamus; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014202:Tremor; D014851:Wakefulness",
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"other_id": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Orthostatic Tremor is Responsive to Bilateral Thalamic Deep Brain Stimulation: Report of Two Cases Performed Asleep.",
"title_normalized": "orthostatic tremor is responsive to bilateral thalamic deep brain stimulation report of two cases performed asleep"
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"abstract": "OBJECTIVE\nTo report a case of ventricular fibrillation caused by severe hypokalemia probably associated with sertraline use.\n\n\nMETHODS\nA 48-year-old male patient experienced ventricular fibrillation and cardiac arrest 2 hours after an uneventful coronary angiography procedure, which revealed normal, unobstructed coronary arteries. Blood chemistry was immediately obtained, revealing a very low potassium (K+) level of 2.44 mEq/L. Other blood electrolytes, including magnesium, ECG, and corrected QT intervals, were all within normal limits. A thorough search for an etiology of hypokalemia, including adrenal gland causes, herbal product consumption, and toxic exposure, did not reveal any identifiable cause. This led us to consider the only drug he was on--sertraline 50 mg per day--as the possible culprit.\n\n\nCONCLUSIONS\nThere has been no clear identification of severe hypokalemia associated with sertraline use in the literature. However, there have been a considerable number of self-reported cases of hypokalemia in patients on sertraline therapy. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between severe hypokalemia and sertraline use in our patient. No clear pathogenic mechanism for the effect of sertraline on serum K equilibrium is known. However, considering the number of self-reported incidences and this case report, the effect of sertraline on serum K levels warrants consideration.\n\n\nCONCLUSIONS\nThis is the first documented case report of severe hypokalemia probably associated with sertraline use.",
"affiliations": "Gaziosmanpasa Hospital, Istanbul, Turkey.",
"authors": "Izgi|Cemil|C|;Erdem|Guliz|G|;Mansuroglu|Denyan|D|;Kurtoglu|Nuri|N|;Kara|Mujdat|M|;Gunesdogdu|Fusun|F|",
"chemical_list": "D000928:Antidepressive Agents; D020280:Sertraline; D011188:Potassium",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028013512789",
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"issue": "48(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": "adverse drug reaction; hypokalemia; prolonged QT; sertraline",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000928:Antidepressive Agents; D006323:Heart Arrest; D006801:Humans; D007008:Hypokalemia; D008297:Male; D008875:Middle Aged; D011188:Potassium; D020280:Sertraline; D014693:Ventricular Fibrillation",
"nlm_unique_id": "9203131",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Severe hypokalemia probably associated with sertraline use.",
"title_normalized": "severe hypokalemia probably associated with sertraline use"
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"abstract": "OBJECTIVE\nTo examine the efficacy and safety of multi-target therapy using tacrolimus (TAC), mycophenolate mofetil (MMF) and a steroid as initial treatment for active lupus nephritis (LN).\n\n\nMETHODS\nWe conducted a retrospective analysis of the data of 16 consecutive patients who received the multi-target therapy for active Classes III-V LN at our department. We also compared the outcomes of the multi-target therapy with those of TAC therapy (TAC + steroid), a study of which we had conducted previously in 13 patients with active LN (TAC group).\n\n\nRESULTS\nAll the patients treated with multi-target therapy achieved complete remission (CR) (mean, 4.6 ± 3.8 months; range, 1-15 months). The clinical profiles of the patients of the multi-target group were similar to those of the TAC group at baseline, except for a significantly higher level of proteinuria (4.6 ± 2.8 vs. 2.5 ± 2.1 g/gCr, p = 0.033) in the former. The CR rate at 6 months was significantly higher in the multi-target group as compared with that in the TAC group (81% vs. 38%, p = 0.018). Two cases of serious adverse events were associated with cytomegalovirus infection in the multi-target group, namely gastric ulcer and pancytopenia, both of which were successfully treated by antiviral therapy.\n\n\nCONCLUSIONS\nMulti-target therapy was effective as initial treatment for active LN, with CR achieved early and in a high percentage of patients. Although this therapy was generally well tolerated, it is important to bear in mind the associated risk of cytomegalovirus infection.",
"affiliations": "Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine , Maebashi , Japan.",
"authors": "Ikeuchi|Hidekazu|H|;Hiromura|Keiju|K|;Takahashi|Satoshi|S|;Mishima|Keiichiro|K|;Sakurai|Noriyuki|N|;Sakairi|Toru|T|;Kaneko|Yoriaki|Y|;Maeshima|Akito|A|;Kuroiwa|Takashi|T|;Nojima|Yoshihisa|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "England",
"delete": false,
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"issue": "24(4)",
"journal": "Modern rheumatology",
"keywords": "Immunosuppressive therapy; Lupus nephritis; Multi-target therapy; Mycophenolate mofetil; Systemic lupus erythematosus; Tacrolimus",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011239:Prednisolone; D012074:Remission Induction; D012189:Retrospective Studies; D016559:Tacrolimus; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis.",
"title_normalized": "efficacy and safety of multi target therapy using a combination of tacrolimus mycophenolate mofetil and a steroid in patients with active lupus nephritis"
} | [
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"abstract": "Optical coherence tomography based microangiography (OMAG) is a new, non-invasive imaging modality capable of providing three dimentional (3D) retinal and choroidal microvascular maps without a need for exogenous dye. In this study, we evaluated the retinal and choroidal microvascular architecture of the macula in a patient with hydroxychloroquine (HCQ) toxicity using OMAG. Detailed microvascular information of the retina and the underlying choroid showed loss of parafoveal outer retinal vasculature with sparing of the central fovea vasculature.",
"affiliations": "1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.;1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.;1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.;1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.;1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.;1 Department of Ophthalmology, 2 Department of Bioengineering, University of Washington, Seattle, WA, USA.",
"authors": "Kam|Jason|J|;Zhang|Qinqin|Q|;Lin|Jason|J|;Liu|Jin|J|;Wang|Ruikang K|RK|;Rezaei|Kasra|K|",
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"keywords": "Optical coherence tomography-based angiography (OCT-based angiography); hydroxychloroquine toxicity; retinal vasculature",
"medline_ta": "Quant Imaging Med Surg",
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"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": "20657761;25230403;102610;23256081;19532651;22029360;25147962;26473588;25182842;26024126;25275721;22159170;12867385",
"title": "Optical coherence tomography based microangiography findings in hydroxychloroquine toxicity.",
"title_normalized": "optical coherence tomography based microangiography findings in hydroxychloroquine toxicity"
} | [
{
"companynumb": "US-ZYDUS-013002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTo report the first described case of combined haemolytic and acute angle closure glaucoma secondary to spontaneous intraocular haemorrhages in a patient on excessive anticoagulation. To the best of our knowledge, this is the first case reported in the literature presenting with raised intraocular pressure due to both mechanisms.\n\n\nMETHODS\nA 90-year-old woman presented with acute pain and reduction in vision in the left eye. Her intraocular pressure (IOP) was 55 mm Hg. There were red tinted blood cells in the anterior chamber giving it a reddish hue. The patient was known to have advanced wet macular degeneration. She was taking oral warfarin for atrial fibrillation. Her international normalised ratio (INR) was 7.7. B-scan ultrasound of posterior segment showed vitreous and suprachoroidal haemorrhages. An ultrabiomicroscopic examination confirmed open angles. A diagnosis of haemolytic glaucoma secondary to intraocular haemorrhages was made. The IOP was controlled medically. Warfarin was withdrawn and oral vitamin K therapy was initiated leading to a rapid INR reduction. Three days later, her anterior chamber became progressively shallower causing a secondary acute angle closure which was managed medically. After 2 months, the left IOP was well-controlled without any medications and the eye was not inflamed. Her vision in that eye remained perception of light.\n\n\nCONCLUSIONS\nPatients with suprachoroidal haemorrhages should be closely monitored as they might subsequently develop acute angle closure despite an initially open angle and well-controlled INR and IOP. Excessive anticoagulation needs to be prevented to minimise the risk of sight-threatening complications.",
"affiliations": "University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.;University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.;University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.",
"authors": "Andreatta|Walter|W|;Boukouvala|Stavroula|S|;Bansal|Atul|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000452440",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000452440cop-0007-0233Case ReportCombined Acute Haemolytic and Secondary Angle Closure Glaucoma following Spontaneous Intraocular Haemorrhages in a Patient on Warfarin Andreatta Walter Boukouvala Stavroula Bansal Atul *aUniversity Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK*Atul Bansal, MBBS, MRCOphth, MD, FRCSEd, FRCOphth, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, West Midlands CV2 2DX (UK), E-Mail bansalatul@doctors.org.ukSep-Dec 2016 14 11 2016 14 11 2016 7 3 233 238 16 8 2016 10 10 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Background\nTo report the first described case of combined haemolytic and acute angle closure glaucoma secondary to spontaneous intraocular haemorrhages in a patient on excessive anticoagulation. To the best of our knowledge, this is the first case reported in the literature presenting with raised intraocular pressure due to both mechanisms.\n\nCase Description\nA 90-year-old woman presented with acute pain and reduction in vision in the left eye. Her intraocular pressure (IOP) was 55 mm Hg. There were red tinted blood cells in the anterior chamber giving it a reddish hue. The patient was known to have advanced wet macular degeneration. She was taking oral warfarin for atrial fibrillation. Her international normalised ratio (INR) was 7.7. B-scan ultrasound of posterior segment showed vitreous and suprachoroidal haemorrhages. An ultrabiomicroscopic examination confirmed open angles. A diagnosis of haemolytic glaucoma secondary to intraocular haemorrhages was made. The IOP was controlled medically. Warfarin was withdrawn and oral vitamin K therapy was initiated leading to a rapid INR reduction. Three days later, her anterior chamber became progressively shallower causing a secondary acute angle closure which was managed medically. After 2 months, the left IOP was well-controlled without any medications and the eye was not inflamed. Her vision in that eye remained perception of light.\n\nConclusion\nPatients with suprachoroidal haemorrhages should be closely monitored as they might subsequently develop acute angle closure despite an initially open angle and well-controlled INR and IOP. Excessive anticoagulation needs to be prevented to minimise the risk of sight-threatening complications.\n\nKeywords\nAngle closureAnticoagulantsHaemolytic glaucomaMacular degenerationSuprachoroidal haemorrhage\n==== Body\nBackground\nSpontaneous vitreous and suprachoroidal haemorrhage are very rare complications in patients affected by neovascular age-related macular degeneration (AMD) on excessive anticoagulation. Nevertheless, they are extremely serious. While red blood cells haemolysis can result in uncontrolled intraocular pressure (IOP), suprachoroidal haemorrhages often lead to blindness. To our knowledge, this is the first case where spontaneous vitreous and suprachoroidal haemorrhages led to haemolytic glaucoma first, followed by an acute secondary angle closure attack.\n\nCase Description\nA 90-year-old Caucasian female presented to the eye casualty with a 2-day history of headaches, nausea, and a painful, red left eye with reduced vision.\n\nPast ocular history included stable primary open angle glaucoma, right-eye cataract surgery and bilateral age-related macular degeneration (AMD). The left eye was known to have a disciform scar, amblyopia, and hand movements vision. Her medical history included atrial fibrillation, chronic congestive heart failure, hypertension, hypercholesterolaemia, chronic kidney disease stage 3, and a previous cerebral vascular accident. She was on oral warfarin, furosemide, ramipril, and simvastatin.\n\nAt presentation, the corrected Snellen visual acuity was 6/15 in the right and hand movements in the left eye. The right eye was pseudophakic and had moderate dry AMD. The IOP in the left eye was 55 mm Hg, the ocular surface was deeply inflamed, the cornea oedematous, and the pupil fixed and mid-dilated.\n\nNevertheless, the anterior chamber (AC) was moderately deep on van Herick's test (grade 3), showing a red hue secondary to haemolysed red blood cells (Fig 1). The angles and fundus could not be appropriately assessed due to the oedematous cornea and dense cataract.\n\nThe international normalised ratio (INR) was 7.7, while all other haematological and biochemical tests were within normal limits. Ultrasound biomicroscopy (UBM) of the left anterior segment showed normal AC depth and open angles but the ocular ultrasound of the posterior segment revealed a diffuse suprachoroidal and vitreous haemorrhage (Fig 2). The patient was admitted and required intravenous acetazolamide, topical ocular hypotensive medications, dexamethasone 0.1%, cyclopentolate 1%, and oral glycerol to achieve a IOP of less than 21 mm Hg. Warfarin was omitted and the patient was given 5 mg of oral vitamin K which reduced the INR to 1.9. Warfarin was then re-started and the INR kept within the low therapeutic range.\n\nDespite good IOP and INR control, van Herick's grade progressed from 3 to 0 between the third and the sixth day of her hospital stay. Angle closure was confirmed on repeated ocular UBM (Fig 3). Considering the pathophysiology of the angle closure and the visual prognosis, YAG laser peripheral iridotomy was not performed.\n\nA vitreo-retinal opinion was sought, but drainage of the haemorrhage was not considered appropriate due to the risk of recurrent haemorrhage and poor prognosis.\n\nTwo months following the acute event, the left eye was comfortable, the corneal oedema had largely resolved, the AC was quiet and returned to its normal depth. Gonioscopy showed open angles and a reddish-brown pigment on the trabecular meshwork. The IOP was well-controlled without any ocular hypotensive agents. Despite the poor visual outcome, the patient was pleased that the left eye returned to be comfortable.\n\nDiscussion\nWe postulate that neovascular AMD predisposed our patient to a macular haemorrhage which progressed to a large vitreous and suprachoroidal bleed because of the high clotting time induced by warfarin. The migration of haemolysed red blood cells into the AC led to a rise in IOP despite the presence of open angles. Subsequently, the mass effect of the suprachoroidal haemorrhage and increasing uveal congestion resulted in secondary angle closure. To our knowledge, the occurrence of both mechanisms in a single patient has never been reported before.\n\nWhile vitreous haemorrhage can occur in neovascular AMD, haemolytic glaucoma is a rare complication [1, 2]. The IOP is believed to increase because of the obstruction of the trabecular meshwork caused by haemolysed red blood cells [1]. Haemolytic glaucoma is usually managed conservatively but AC washout with or without trans pars plana vitrectomy was required in cases with refractory raised IOP [1, 2].\n\nIn our case, the red hue of the AC directed us towards the correct diagnosis and the IOP responded well to medical treatment. Once the acute episode resolved, gonioscopy excluded rubeosis and other pathologies which can cause raised IOP in the presence of open angles.\n\nAlthough suprachoroidal haemorrhages most commonly occur intraoperatively, they can rarely be spontaneous in patients treated with thrombolytic agents, low molecular weight heparin and warfarin [3]. Other identified risk factors include hypertension, atherosclerosis, and advanced age.\n\nOnly a few case reports described acute angle closure secondary to spontaneous suprachoroidal haemorrhages in AMD patients on warfarin [4, 5, 6, 7]. These are usually managed conservatively but YAG laser peripheral iridotomies have been performed. In cases without angle closure, surgical evacuation has also occasionally been attempted [3].\n\nThe visual prognosis of these patients is very poor independently from their treatment. This condition can have catastrophic consequences if the affected eye is the better seeing eye as it might be the case in AMD patients. Therefore, the presence of advanced atrophic and neovascular AMD should always be considered in the risk assessment of a patient requiring anticoagulation. Similarly, the need for anticoagulation should be reviewed if a patient develops neovascular AMD as previous cases report the occurrence of spontaneous suprachoroidal haemorrhages in patients with INRs within therapeutic range [5].\n\nConclusion\nTo the best of our knowledge, this is the first reported case where vitreous and suprachoroidal haemorrhages led to secondary open angle haemolytic glaucoma and the subsequent anterior movement of the lens-iris diaphragm resulted in secondary acute angle closure.\n\nWe propose that patients with acutely raised IOPs on anticoagulants and a poor view of the fundus, irrespectively of the AC depth, should have an urgent ocular ultrasound scan and blood clotting profile. Patients with suprachoroidal haemorrhages should be closely monitored as they might develop acute angle closure despite well-controlled IOP and INR.\n\nGood communication between healthcare practitioners, the patients and their families is essential to ensure the best possible INR monitoring and minimise the risk of these complications.\n\nStatement of Ethics\nInformed consent was obtained.\n\nDisclosure Statement\nNo conflicting relationship exists for any author.\n\nFig. 1 Red hue of the aqueous due to haemolysed blood cells migrating from the posterior segment.\n\nFig. 2 B-mode ocular ultrasound of the left posterior segment shows an intraocular hyperechoic signal and vitreous opacities.\n\nFig. 3 Left eye anterior segment UBM demonstrates a shallow AC with closed angles.\n==== Refs\nReferences\n1 Phelps CD Watzke RC Hemolytic glaucoma Am J Ophthalmol 1975 80 690 695 1180308 \n2 Singh H Grand MG Treatment of blood-induced glaucoma by trans pars plana vitrectomy Retina 1981 1 255 257 7348846 \n3 Chu TG Green RL Suprachoroidal hemorrhage Surv Ophthalmol 1999 43 471 486 10416790 \n4 Chandra A Barsam A Hugkulstone C A spontaneous suprachoroidal haemorrhage: a case report Cases J 2009 2 185 19946495 \n5 Knox FA Johnston PB Spontaneous suprachoroidal haemorrhage in a patient with age-related macular degeneration on excessive anticoagulation therapy Eye 2002 16 669 670 12194098 \n6 Alexandrakis G Chaudhry NA Liggett PE Weitzman M Spontaneous suprachoroidal hemorrhage in age-related macular degeneration presenting as angle-closure glaucoma Retina 1998 18 485 486 9801053 \n7 Lewis H Sloan SH Foos RY Massive intraocular hemorrhage associated with anticoagulation and age-related macular degeneration Graefes Arch Clin Exp Ophthalmol 1988 226 59 64 3342978\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(3)",
"journal": "Case reports in ophthalmology",
"keywords": "Angle closure; Anticoagulants; Haemolytic glaucoma; Macular degeneration; Suprachoroidal haemorrhage",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "233-238",
"pmc": null,
"pmid": "27990116",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "19946495;12194098;1180308;3342978;10416790;7348846;9801053",
"title": "Combined Acute Haemolytic and Secondary Angle Closure Glaucoma following Spontaneous Intraocular Haemorrhages in a Patient on Warfarin.",
"title_normalized": "combined acute haemolytic and secondary angle closure glaucoma following spontaneous intraocular haemorrhages in a patient on warfarin"
} | [
{
"companynumb": "GB-TEVA-741909ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Pirarubicin (THP) is a newer generation anthracycline anticancer drug with antineoplastic efficacy against numerous tumors. Few studies have reported its application and efficiency in anti-osteosarcoma chemotherapeutic strategies. Ninety-six non-metastatic extremity osteosarcoma patients treated with THP or doxorubicin (DOX) in combination with high-dose methotrexate (HDMTX), cisplatin (DDP) and ifosfamide (IFO) within the past 9 years at our hospital were evaluated retrospectively to compare efficacy and side effects. Among the patients, 55.2% were male, 36.5% were ≤14 years old and 59.4% presented with a large tumor (≥1/3 of bone) to our department. The 5-year disease-free survival (DFS) rate of the patients treated with the THP-based chemotherapeutic regimen was 70.2%, significantly higher than that of the DOX-based regimen-treated group (53.1%). The THP-based chemotherapeutic regimen decreased the lung metastatic rate significantly compared with the DOX-based regimen (19.1% vs. 36.7%, P=0.045), as well as the relapse rate (31.9% vs. 49.0%, P=0.067). Both regimens were generally well tolerated. However, while the THP-based chemotherapeutic regimen did not alter toxicity in the hematologic system, liver or kidneys compared with the DOX-based regimen, it showed lower rates of alopecia (63.8% vs. 85.7%, P=0.012), nausea and vomiting (51.1% vs. 79.6%, P=0.003), and mucositis (48.9% vs. 75.6%, P=0.003). THP also resulted in lower cardiac toxicity. Our data demonstrate that the THP-based regimen is better than the DOX-based regimen in terms of the 5-year DFS rate, pulmonary metastasis rate, relapse rate and side effects.",
"affiliations": "Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.;Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 200233 Shanghai, People's Republic of China.",
"authors": "Zheng|Shuier|S|;Zhou|Shuhui|S|;Qiao|Guanglei|G|;Yang|Qingcheng|Q|;Zhang|Zhichang|Z|;Lin|Feng|F|;Min|Daliu|D|;Tang|Lina|L|;Li|Hongtao|H|;Sun|Yuanjue|Y|;Zhao|Hui|H|;Shen|Zan|Z|;Yao|Yang|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2156-6976",
"issue": "5(1)",
"journal": "American journal of cancer research",
"keywords": "Osteosarcoma; chemotherapy; disease-free survival; doxorubicin; overall survival; pirarubicin; relapse; side effects",
"medline_ta": "Am J Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "101549944",
"other_id": null,
"pages": "411-22",
"pmc": null,
"pmid": "25628949",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "20033628;18235123;17457949;12017378;496103;1717666;2706737;10580566;11821461;1389483;21342041;20690888;16246977;9615748;18185020;9369412;22580740;1516010;21748427;2448428;18048827;20435572;16206218;16831079;7060020;20357441;12022899;1370176;16206297;11347833;6526737;24345772;19582559;14635080;3712761;15266096;21438831;21933300;22560526;19214708",
"title": "Pirarubicin-based chemotherapy displayed better clinical outcomes and lower toxicity than did doxorubicin-based chemotherapy in the treatment of non-metastatic extremity osteosarcoma.",
"title_normalized": "pirarubicin based chemotherapy displayed better clinical outcomes and lower toxicity than did doxorubicin based chemotherapy in the treatment of non metastatic extremity osteosarcoma"
} | [
{
"companynumb": "CN-JNJFOC-20150202220",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "This phase 2 study was conducted to prospectively evaluate how clinical and biological factors correlate with outcome in patients with treatment-naive (TN) and relapsed (R) chronic lymphocytic leukemia (CLL) treated with lenalidomide and rituximab. Oral lenalidomide 10 mg was administered daily starting on day 9 of cycle 1. IV rituximab 375 mg/m2 was administered weekly during cycle 1 and every 4 weeks for cycles 3 to 12. Sequencing of a custom panel of 295 genes was performed in pretreatment bone marrow samples. The study included 61 patients with TN CLL and 59 with R CLL; the overall response rate (ORR) was 73% and 64%, respectively. A baseline β2-microglobulin level <4 mg/L was associated with higher ORR in both groups (both, P = .03), and absence of mutations in the NOTCH signaling pathway showed a trend for association with higher ORR in R CLL (P = .10). Median PFS was 50 months in TN patients and 28 months in R patients. On multivariate analysis, age ≥65 years (P = .02) was associated with shorter PFS in TN patients, whereas according to univariate analysis, >2 previous therapies (P = .02) was the only factor associated with shorter PFS in R patients. A trend for association between mutations in the NOTCH pathway and shorter PFS was observed in TN CLL (P = .15). Further exploration of the NOTCH pathway may help optimize the efficacy of this combination in patients with CLL. This study protocol was approved by the University of Texas MD Anderson Cancer Center institutional review board and registered at clinicaltrials.gov (#NCT01446133).",
"affiliations": "Department of Leukemia.;Department of Leukemia.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Leukemia.;Department of Genomic Medicine, and.;Department of Leukemia.",
"authors": "Strati|Paolo|P|;Takahashi|Koichi|K|;Peterson|Christine B|CB|0000-0003-3316-0468;Keating|Michael J|MJ|;Thompson|Philip A|PA|;Daver|Naval G|NG|0000-0001-7103-373X;Jain|Nitin|N|;Burger|Jan A|JA|0000-0002-6177-7572;Estrov|Zeev|Z|0000-0002-1623-3613;O'Brien|Susan M|SM|;Kantarjian|Hagop M|HM|0000-0002-1908-3307;Wierda|William G|WG|;Futreal|P Andrew|PA|;Ferrajoli|Alessandra|A|",
"chemical_list": "D007155:Immunologic Factors; D051880:Receptors, Notch; D000069283:Rituximab; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2019031336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "3(9)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009503:Neutropenia; D000077982:Progression-Free Survival; D051880:Receptors, Notch; D012008:Recurrence; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "1533-1539",
"pmc": null,
"pmid": "31076409",
"pubdate": "2019-05-14",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "28958469;25824652;26195701;12594956;25313353;18628480;29479067;29358183;23801633;18551193;28798068;19965642;18334676;21189385;22383743;18216293;25398834;23270003;26466571;24868031;27285853;12374742;17088571;28388253;28916311;15777657;21725050",
"title": "Efficacy and predictors of response of lenalidomide and rituximab in patients with treatment-naive and relapsed CLL.",
"title_normalized": "efficacy and predictors of response of lenalidomide and rituximab in patients with treatment naive and relapsed cll"
} | [
{
"companynumb": "US-CELGENEUS-USA-20190507325",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "To cure acromegalic patients, transsphenoidal surgery is considered first, especially for microadenoma. However, less than 50% of patients with macroadenoma achieve satisfactory biochemical control. Moreover, surgery may cause hypopituitarism. Medical therapy may offer the prospect of near normalization of growth hormone (GH)/insulin-like growth factor-1 levels with substantial tumor shrinkage in a significant number of patients. Here, we report two cases of acromegaly under treatment with somatostatin analogs alone for more than 10 years. Case 1 was a 54-year-old man with a pituitary macroadenoma. He received 4 years of octreotide treatment followed by 6 years of prolonged-release (PR) lanreotide resulting in normal GH level. Case 2 was a 60-year-old woman with a 1.3 cm pituitary tumor. She received 8 years of octreotide treatment followed by 6 years of PR lanreotide resulting in subnormal GH level and gallbladder sludge. She had received bilateral total hip replacement for hip osteoarthritis at the age of 59 years. These cases illustrate that long-term treatment with somatostatin analogs offers an alternative choice in selected acromegalic patients, such as those with pituitary tumor who cannot be cured by surgery, those who have unacceptable anesthetic risk and those who refuse surgery.",
"affiliations": "Far Eastern Polyclinic, Taipei, Taiwan.",
"authors": "Su|Deng-Huang|DH|;Liao|Kuo-Meng|KM|;Chen|Huan-Wen|HW|;Chang|Tien-Chun|TC|",
"chemical_list": "D010456:Peptides, Cyclic; C060347:lanreotide; D019382:Human Growth Hormone; D013004:Somatostatin; D015282:Octreotide",
"country": "Singapore",
"delete": false,
"doi": "10.1016/S0929-6646(09)60166-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-6646",
"issue": "105(8)",
"journal": "Journal of the Formosan Medical Association = Taiwan yi zhi",
"keywords": null,
"medline_ta": "J Formos Med Assoc",
"mesh_terms": "D000172:Acromegaly; D000236:Adenoma; D005260:Female; D019382:Human Growth Hormone; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide; D010456:Peptides, Cyclic; D010911:Pituitary Neoplasms; D013004:Somatostatin",
"nlm_unique_id": "9214933",
"other_id": null,
"pages": "664-9",
"pmc": null,
"pmid": "16935768",
"pubdate": "2006-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term primary medical therapy with somatostatin analogs in acromegaly.",
"title_normalized": "long term primary medical therapy with somatostatin analogs in acromegaly"
} | [
{
"companynumb": "TW-IPSEN BIOPHARMACEUTICALS, INC.-2017-00926",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LANREOTIDE ACETATE"
},
"dr... |
{
"abstract": "Seventeen neonates received an intravenous infusion of prostaglandin E1 for an average of 39 days (range 8 to 104). Seven (group 1) had transposition of the great arteries with no ventricular septal defect or a small one; eight (group 2) had ductus-dependent pulmonary flow (pulmonary atresia or stenosis in six and tricuspid atresia in two); and two (group 3) had aortic coarctation, one with no ventricular septal defect, the other with ventricular septal defect, isthmus hypoplasia and descending aortic flow supplied mainly by the ductus. An increase in the arterial partial pressure of oxygen (PO2) was seen in groups 1 and 2. Six patients from group 1 and two from group 2 developed heart failure; cortical hyperostosis of long bones was seen in three patients from group 1 and three from group 2; one from group 1 had refractory diarrhea. Other side effects seen at the beginning improved as the rate of infusion diminished. In group 3, the patient with complex coarctation had a decrease in blood pressure in the arms, an increase in pressure in the legs and restoration of renal function; in the patient with no ventricular septal defect, heart failure worsened during therapy. Histologic changes seen in three ductus were attributed to the closing process. When delaying surgery in selected ill infants with heart defects is deemed advantageous, long-term infusions of prostaglandin E1 are feasible.",
"affiliations": null,
"authors": "Teixeira|O H|OH|;Carpenter|B|B|;MacMurray|S B|SB|;Vlad|P|P|",
"chemical_list": "D011458:Prostaglandins E; D000527:Alprostadil",
"country": "United States",
"delete": false,
"doi": "10.1016/s0735-1097(84)80262-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "3(3)",
"journal": "Journal of the American College of Cardiology",
"keywords": null,
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D000527:Alprostadil; D001017:Aortic Coarctation; D001794:Blood Pressure; D001848:Bone Diseases, Developmental; D004374:Ductus Arteriosus, Patent; D006330:Heart Defects, Congenital; D006801:Humans; D006984:Hypertrophy; D007231:Infant, Newborn; D011458:Prostaglandins E; D011652:Pulmonary Circulation; D014188:Transposition of Great Vessels",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "838-43",
"pmc": null,
"pmid": "6537955",
"pubdate": "1984-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term prostaglandin E1 therapy in congenital heart defects.",
"title_normalized": "long term prostaglandin e1 therapy in congenital heart defects"
} | [
{
"companynumb": "CA-PFIZER INC-2017172207",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "ALPROSTADIL"
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... |
{
"abstract": "Hyperthermic intrathoracic chemotherapy (HITHOC) has been used in addition to radical surgery for primary and secondary pleural malignancies to improve local control, prolong survival, and improve the quality of life. This study was performed to study the indications, methodology, perioperative outcomes, and survival in patients undergoing HITHOC at Indian centers. A retrospective analysis of prospectively collected demographic and clinical data, perioperative and survival data of patients undergoing surgery with or without HITHOC was performed. From January 2011 to May 2018, seven patients underwent pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) with HITHOC and four had P/D or EPP alone at three Indian centers. P/D was performed in two and EPP in nine patients. The primary tumor was pleural mesothelioma in eight, metastases from thymoma in one, germ cell tumor in one, and solitary fibrous tumor of the pleura in one. HITHOC was performed using cisplatin. Grade 3-4 complications were seen in one patient in the HITHOC group and none in the non-HITHOC group, and one patient in the non-HITHOC group died of complications. At a median follow-up of 9 months, five patients of the HITHOC group were alive, four without recurrence, and one with recurrence. One patient in the non-HITHOC group was alive and disease-free at 24 months, and two died of progression at 18 and 36 months. HITHOC can be performed without increasing the morbidity of P/D or EPP. Most of these patients require multimodality treatment and are best managed by multidisciplinary teams.",
"affiliations": "Department of Surgical Oncology, Zydus Hospital, Zydus hospital road, SG highway, Thaltej, Ahmedabad, 380054 India.;Department of Surgical Oncology, MVR Cancer Centre and Research Institute, Calicut, India.;Department of Surgical Oncology, CHL, CBCC Cancer Centre, Indore, India.;Department of Surgical Oncology, Zydus Hospital, Zydus hospital road, SG highway, Thaltej, Ahmedabad, 380054 India.;Department of Anaesthesiology, Zydus Hospital, Ahmedabad, India.;Department of Anaesthesiology, Zydus Hospital, Ahmedabad, India.;Department of Surgical Oncology, Zydus Hospital, Zydus hospital road, SG highway, Thaltej, Ahmedabad, 380054 India.",
"authors": "Patel|Mahesh D|MD|;Damodaran|Dileep|D|;Rangole|Ashvin|A|;Shaikh|Sakina|S|;Shah|Kairav|K|;Bagwade|Rajendra|R|;Bhatt|Aditi|A|0000-0002-9808-6898",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13193-018-0859-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0975-7651",
"issue": "10(Suppl 1)",
"journal": "Indian journal of surgical oncology",
"keywords": "HITHOC; Pleural mesothelioma; Pleural metastases",
"medline_ta": "Indian J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "101532448",
"other_id": null,
"pages": "91-98",
"pmc": null,
"pmid": "30886500",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "1588364;17429100;18398658;19364962;19619785;20138534;20440397;21172935;22548052;22885228;23111024;23434448;23462236;23775415;23977551;24360321;24459636;26919243;28072694;29246008;29353975;29529693;8275441",
"title": "Hyperthermic Intrathoracic Chemotherapy (HITHOC) for Pleural Malignancies-Experience from Indian Centers.",
"title_normalized": "hyperthermic intrathoracic chemotherapy hithoc for pleural malignancies experience from indian centers"
} | [
{
"companynumb": "IN-ACCORD-117903",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "As opioid use disorder (OUD) reaches epidemic levels in the United States, medication-assisted treatment (MAT) plays a central role in its treatment. Methadone, a long-acting mu-opioid receptor agonist has been shown to be effective in managing OUD. It is also known that chronic opioid therapy may have the paradoxical effect of increased sensitivity to pain, a phenomenon called opioid-induced hyperalgesia (OIH). This presents a conundrum when a patient such as ours, on MAT presents with acute pain and OIH. This case report illustrates the current challenges health care providers encounter when treating patients on chronic MAT for non-opioid-related conditions. As this patient population ages, these encounters will become more common. These patients will need appropriate health care screening and chronic care management. This case serves two purposes; to highlight the difficulty in treating acute pain in patients on long-term high-dose methadone coupled with the missed opportunity for primary care for OUD patient population, and proposes that education reforms in this area be implemented now.",
"affiliations": "Internal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA.;Internal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA.;Internal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA.;Internal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA.;Internal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA.",
"authors": "Ezeh|Ebubechukwu|E|;Singh|Davinder|D|;Dobariya|Varun|V|;Akhigbe|Esiemoghie J|EJ|;Gilkerson|Christine|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.12345",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12345\nInternal Medicine\nPain Management\nOpioid-Induced Hyperalgesia in a Cancer Patient on High-Dose Methadone Maintenance Therapy: A Case for Subspecialty Opioid Use Disorder Primary Care\nMuacevic Alexander Adler John R Ezeh Ebubechukwu 1 Singh Davinder 1 Dobariya Varun 1 Akhigbe Esiemoghie J 1 Gilkerson Christine 1 \n1 \nInternal Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, USA \n\nEbubechukwu Ezeh ezehe@marshall.edu\n28 12 2020 \n12 2020 \n12 12 e1234528 12 2020 Copyright © 2020, Ezeh et al.2020Ezeh 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/48228-opioid-induced-hyperalgesia-in-a-cancer-patient-on-high-dose-methadone-maintenance-therapy-a-case-for-subspecialty-opioid-use-disorder-primary-careAs opioid use disorder (OUD) reaches epidemic levels in the United States, medication-assisted treatment (MAT) plays a central role in its treatment. Methadone, a long-acting mu-opioid receptor agonist has been shown to be effective in managing OUD. It is also known that chronic opioid therapy may have the paradoxical effect of increased sensitivity to pain, a phenomenon called opioid-induced hyperalgesia (OIH). This presents a conundrum when a patient such as ours, on MAT presents with acute pain and OIH. This case report illustrates the current challenges health care providers encounter when treating patients on chronic MAT for non-opioid-related conditions. As this patient population ages, these encounters will become more common. These patients will need appropriate health care screening and chronic care management. This case serves two purposes; to highlight the difficulty in treating acute pain in patients on long-term high-dose methadone coupled with the missed opportunity for primary care for OUD patient population, and proposes that education reforms in this area be implemented now. \n\nopioid-induced hyperalgesiahigh-dose methadone maintenance therapyopioid use disorderThe 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\nOpioid use disorder (OUD) has become an epidemic in the United States, and as such, medication-assisted treatment (MAT) has become an integral part of health care delivery. MAT has been found to reduce morbidity and mortality, decrease overdose deaths, reduce transmission of infectious disease, increase treatment retention, improve social functioning, and reduce criminal activity [1]. Thus, the number of federally approved Opioid Treatment Programs (OTPs) offering MAT has increased accordingly. For instance, the number of OTPs increased from approximately 1,100 in 2003 to almost 1,500 by the end of 2016 [2]. Methadone, a long-acting mu-opioid receptor agonist in use since 1964 for the treatment of OUD, may be dispensed in these OTPs. According to the Substance Abuse and Mental Health Services Administration, the number of clients receiving methadone increased from about 227,000 in 2003 to over 350,000 in 2015 [2]. Clients receiving treatment with methadone accounted for approximately 21% to 25% of all substance abuse treatment clients each year. The increase in the number of clients receiving methadone treatment coupled with the stability of the proportion of clients receiving this treatment indicates that the overall availability of methadone treatment has increased over time [2]. The implication of this is that clinicians will continue to encounter more patients who are on MAT, who will also need primary care screening and chronic care management that is currently lacking.\n\nWhen used in OUD, methadone prevents withdrawal symptoms for 24 hours or longer, decreases cravings for opioids, and decreases the euphoria associated with illicit opioid use by maintaining high levels of opioid tolerance [3]. Many individuals receiving methadone maintenance treatment (MMT) for opioid addiction may also require treatment for acute or chronic pain. However, effective pain management in this patient population is complicated by many factors, including heightened pain sensitivity, high opioid tolerance, and variable cross-tolerance to opioid pain medications. The phenomenon of heightened pain sensitivity referred to as opioid-induced hyperalgesia (OIH) presents a conundrum between controlling the acute pain of a cancer patient on MMT and managing OIH [4,5]. As this patient population ages, unique challenges will accompany their health care needs for non-opioid use-related conditions as described in our case. Thus, clinicians will need to be educated on best practices when they do encounter this patient population.\n\nCase presentation\nA 50-year-old male with a past medical history significant for chronic hepatitis C and opioid use disorder on MMT for 12 years was presented with a six-week history of left hip pain, left shoulder pain, and unintentional weight loss of over 25 pounds in two months. He also reported a productive cough with whitish sputum, shortness of breath, chest pain, and fatigue. He was on a daily dose of methadone 120 mg for the past 12 years for OUD. Physical examination findings showed a cachectic man with temporal wasting, evidence of dehydration, and a palpable right-sided abdominal mass. Initial labs were remarkable for marked hypercalcemia and findings suggestive of prerenal acute kidney injury (AKI). Imaging studies were remarkable for metastatic lung lesions, and multiple osteolytic lesions in the left femur, ribs, left humerus, C6, and T6 vertebrae. Abdominal imaging showed a large renal mass with renal vein thrombosis. The diagnosis of renal cell carcinoma as the primary malignancy was suspected. The prognosis was discussed with the patient, and he expressed his desire to move forward with treatment. The patient’s AKI improved with intravenous fluids. Hypercalcemia also improved after zoledronic acid treatment. However, the patient's reported pain score was constantly 9 out of 10. Attempts to reduce the dose of his MMT lead to opioid withdrawal symptoms. The pain management team was consulted, and a decision was made to split the patient’s total home methadone dose into 40 mg three times a day. Other non-opioid pain medications such as high-dose Tylenol and Toradol were added to his regimen but the patient reported little to no pain relief. Then, a short-acting opioid in the form of oxycodone 10 mg every four hours was added to control his breakthrough pain. However, the patient continued to have residual generalized body pain which he consistently rated 7 out of 10. His oxycodone was further increased to 20 mg which provided temporary pain relief. After a few days, his pain was still persistent and the decision was made to continue the oxycodone at 10 mg every 12 hours and add an extended-release form of oxycodone 10 mg to his methadone, Tylenol, and Toradol regimen.\n\nIt was at this point that the patient's pain score reduced to less than 4 out of 10 and he was discharged home on the new pain regimen. With this extensive course of narcotics, laxatives were added to prevent constipation. However, two weeks later, the patient presented complaining of generalized body pain. This time, oxycodone was increased from 10 mg to 45 mg, and finally, a Fentanyl patch of 25 mg every 72 hours was added to his overall pain regimen. The new regimen was able to provide sufficient pain relief.\n\nDiscussion\nThis case illustrates the unique challenges of trying to achieve pain control in a cancer patient on long-term opioid replacement therapy for OUD. It is our position that clinicians will encounter these situations more and more as this patient population ages. Chronic high-dose methadone therapy as in this patient leads to the development of tolerance and consequently reduced responsiveness to the analgesic effects of opioids [5]. Also, pain studies have shown that MMT patients have hyperalgesia and that cross-tolerance to other opioids may be present, suggesting that they may need more analgesia than non-MMT patients [5]. OIH is another compounding factor that should be considered when increasing opioid doses fails to provide analgesic effects or when there is unexplainable pain exacerbation following opioid treatment [6].\n\nThe potential hyperalgesic state accompanying opioid dependence complicates pain management [7]. The major challenge is determining when and how to achieve incremental opioid dosing and determining when to stop, assuming there is an end date. The key to that decision is dependent on the goal of treatment. If the goal is pain relief, the general approach to acute pain management in patients who take methadone is similar to the approach used for patients who take stable doses of other opioids on a chronic basis: continuation of the baseline opioid, which we did in this patient, and use of nonopioid analgesic strategies supplemented with incremental opioid if necessary. Once the acute pain subsides, the additional opioid should then be tapered down [8]. If tapering is not feasible, additional opioids for acute pain in these patients should not be withheld for fear of worsening the OUD. As long as medications for acute pain are tapered promptly as the pain resolves, the patient's course of treatment for OUD can continue undisrupted [8].\n\nWeaning a patient off methadone should be accomplished over months to years. That was not an option for our patient who has a new diagnosis of metastatic cancer. Also, methadone withdrawal signs must be anticipated and treated accordingly with other opioids during the weaning period. While we were eventually able to achieve pain control, the time to this was more prolonged as compared to someone with a similar clinical scenario who is not on chronic MMT. Given the advanced stage of the malignancy at presentation, it is conceivable that the high doses of methadone may have contributed to the patient not presenting earlier. Another factor that we feel contributed to this patient's late presentation is the lack of primary care involvement. He experienced progressive symptoms of weight loss, cough, and fatigue months prior to presentation without seeking any primary care attention. We feel periodic primary care assessment that coincided with this patient’s OUD treatment may have caught the disease process at a much earlier stage. The lack of available clinicians with expertise in this area contributed to the delay. In this regard, we propose that Continuing Medical Education (CME) training in this area be required for current practicing physicians. An example of such a training module is Providers' Clinical Support Services (PCSS). PCSS is a program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA) and was created in response to the opioid overdose epidemic to train primary care providers in the evidence-based prevention and treatment of OUD and treatment of chronic pain. We further advocate for the incorporation of similar training modules into the Graduate Medical Education (GME) curriculum to better prepare future clinicians to care for the increasing number of patients needing care for non-OUD conditions who are on MAT.\n\nConclusions\nBecause opioid cross-tolerance may be present, patients on MMT typically require high doses of opioids than opioid naïve patients. Undertreatment of acute pain is regarded as suboptimal medical management, and this patient population is at particularly high risk. Thus, pain should always be treated in these patients, irrespective of their MMT status. We were eventually able to achieve pain control; however, lack of expertise (both consultation and primary team) contributed to the delay. Clinicians will continue to encounter patients who are on chronic MAT for non-opioid use-related conditions such as our patient. A possible strategy to avoid this in the future could be the development of an OUD primary care specialty. Also, health care providers will need adequate training to better care for these patients. Integration of such training into the CME requirements and the General Medical Education (GME) curriculum would improve clinicians' knowledge about this pathology.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Medication-assisted therapies - tackling the opioid-overdose epidemic N Engl J Med Volkow ND Frieden TR Hyde PS Cha SS 2063 2066 29 2014 \n2 Trends in the use of methadone, buprenorphine, and extended-release naltrexone at substance abuse treatment facilities: 2003-2015 (update) 2017 Aug 22 The CBHSQ Report Alderks CE Rockville Substance Abuse and Mental Health Services Administration 2017 \n3 Pharmacology for opioid use disorder 12 2020 Strain Strain E (2020). Pharmacology for Opioid use disorder. In: Saxton AJ and Friedman M (Ed 2020 https://www.uptodate.com/contents/pharmacotherapy-for-opioid-use-disorder \n4 Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy Pain Mao J 213 217 100 2002 12467992 \n5 Management of acute pain in methadone maintenance therapy in-patients Drug Alcohol Rev Hines S Theodorou S Williamson A Fong D Curry K 519 523 27 2008 18696299 \n6 Opioid-induced hyperalgesia and tolerance: understanding opioid side effects Expert Rev Clin Pharmacol Grider JS Ackerman WE 291 297 1 2008 24422653 \n7 Pain management in the opioid-dependent patient Current Psychiatry Rep Streltzer J 489 496 3 2001 \n8 Management of acute pain in adults with opioid use disorder 12 2020 Coffa Coffa D D and Carr D ( April 2020 2020 https://www.uptodate.com/contents/management-of-acute-pain-in-adults-with-opioid-use-disorder?search=managemnet%20of%20acute%20pain%20in%20adults%20with%20opioid%20use%20disorder&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(12)",
"journal": "Cureus",
"keywords": "high-dose methadone maintenance therapy; opioid use disorder; opioid-induced hyperalgesia",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12345",
"pmc": null,
"pmid": "33520540",
"pubdate": "2020-12-28",
"publication_types": "D002363:Case Reports",
"references": "11707163;24758595;18696299;24422653;12467992",
"title": "Opioid-Induced Hyperalgesia in a Cancer Patient on High-Dose Methadone Maintenance Therapy: A Case for Subspecialty Opioid Use Disorder Primary Care.",
"title_normalized": "opioid induced hyperalgesia in a cancer patient on high dose methadone maintenance therapy a case for subspecialty opioid use disorder primary care"
} | [
{
"companynumb": "US-SPECGX-T202101542",
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"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "This randomized phase 3 study evaluated the efficacy and safety of cinacalcet in children with secondary hyperparathyroidism (SHPT) receiving dialysis.\n\n\n\nThis study had double-blind and open-label phases. Eligible patients aged 6-< 18 years were randomized to cinacalcet (starting dose ≤ 0.20 mg/kg) or placebo. The primary endpoint was ≥ 30% reduction from baseline in mean intact parathyroid hormone (iPTH). Secondary endpoints included mean iPTH ≤ 300 pg/mL; percentage change from baseline in corrected total serum calcium, phosphorus, and calcium phosphorus product (Ca × P); and safety.\n\n\n\nThe double-blind phase comprised 43 patients (cinacalcet, n = 22; placebo, n = 21). Nineteen months into the study, regulatory authorities were notified of a fatality; the study was subsequently terminated after a 14-month clinical hold. Before the hold, 12 patients (55%) on cinacalcet and four (19%) on placebo achieved the primary endpoint (p = 0.017), and 27% and 24%, respectively, achieved iPTH ≤ 300 pg/mL. The between-group differences (95% CI) in percentage changes for total serum calcium, phosphorus, and Ca × P were - 4% (- 9 to 1%), - 6% (- 21 to 8%), and - 10% (- 23 to 3%). The mean maximum actual weight-adjusted daily cinacalcet dosage administered was 0.99 mg/kg/day. Overall, 82% of patients on cinacalcet and 86% on placebo had ≥ 1 treatment-emergent adverse event; the most common were vomiting (32%, 24%, respectively), hypocalcemia (23%, 19%), nausea (18%, 14%), and hypertension (14%, 24%).\n\n\n\nDespite early termination, efficacy and safety outcomes observed with cinacalcet in children with SHPT on dialysis were consistent with adult observations, suggesting cinacalcet may meet an unmet medical need for this population.",
"affiliations": "Division of Pediatric Nephrology, Children's Mercy Kansas City, 2401 Gillham Road, 2MOB.17, Kansas City, MO, 64108, USA. bwarady@cmh.edu.;Amgen Inc., Thousand Oaks, CA, USA.;University Hospital Vall d' Hebron, Barcelona, Spain.;Amgen Europe GmbH, Zug, Switzerland.;Brody School of Medicine, East Carolina University, Greenville, NC, USA.;Amgen Inc., Thousand Oaks, CA, USA.;Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Ghent University, Safedpedrug, Ghent, Belgium.;Heidelberg University Hospital, Heidelberg, Germany.",
"authors": "Warady|Bradley A|BA|;Iles|Janet N|JN|;Ariceta|Gema|G|;Dehmel|Bastian|B|;Hidalgo|Guillermo|G|;Jiang|Xun|X|;Laskin|Benjamin|B|;Shahinfar|Shahnaz|S|;Vande Walle|Johan|J|;Schaefer|Franz|F|",
"chemical_list": "D057966:Calcimimetic Agents; D010281:Parathyroid Hormone; D010919:Placebos; D014807:Vitamin D; D002118:Calcium; D000069449:Cinacalcet",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-018-4116-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "34(3)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Calcimimetics; Chronic kidney disease; Cinacalcet; Parathyroid hormone; Pediatric patients; Secondary hyperparathyroidism",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D057966:Calcimimetic Agents; D002118:Calcium; D002648:Child; D000069449:Cinacalcet; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D006973:Hypertension; D006996:Hypocalcemia; D008297:Male; D009325:Nausea; D010281:Parathyroid Hormone; D010919:Placebos; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D016896:Treatment Outcome; D014807:Vitamin D; D014839:Vomiting",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "475-486",
"pmc": null,
"pmid": "30506144",
"pubdate": "2019-03",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "21454719;10491215;12093777;25490118;14580225;23637579;18504621;28667458;12595492;12472790;25590845;23382299;19838738;3626302;21947120;30681074;18288502;15071126",
"title": "A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis.",
"title_normalized": "a randomized double blind placebo controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0108147",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditional": null,
... |
{
"abstract": "Nephrolithiasis is a well-known side effect of many HIV protease inhibitors. However, there have not been reports of stones associated with ritonavir use. Here, we report the case of a 33-year-old woman with HIV on antiretroviral therapy who presented with sharp left flank pain and passed a stone that was later found to contain only ritonavir. Of note, the patient's treatment regimen had not included ritonavir for 2 years prior to this incidence. This case is notable both for the novel finding of a renal calculus composed entirely of ritonavir and the development of nephrolithiasis years after cessation of the aggravating drug. This finding suggests that patients on ritonavir should be more closely monitored and for longer periods of time for potential lithiasis formation.",
"affiliations": "Yale School of Medicine, New Haven, Connecticut, USA.;Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.",
"authors": "Zhao|Anna M|AM|;Angoff|Nancy R|NR|",
"chemical_list": "D017320:HIV Protease Inhibitors; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230487",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "HIV/AIDS; renal system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D005260:Female; D017320:HIV Protease Inhibitors; D006801:Humans; D007669:Kidney Calculi; D019438:Ritonavir",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31266762",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17502736;17457108;17053366;8782789;19776778;29623097;9107549;9338724;25852859;18405026;9850700;18370537;9868678;12685114;20458537;17879904;26064679;8992345;15090783;22820542;9338723;18771058;21269596;9084959;9142068;8894513;21716074;20005491;22429050",
"title": "Renal stone composed of ritonavir.",
"title_normalized": "renal stone composed of ritonavir"
} | [
{
"companynumb": "US-HETERO-HET2019US00944",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ATAZANAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Studies have been coming out focusing on the biological markers of suicide. Here, we present two cases with raised C-reactive protein who were admitted after attempts of suicide by overdose. There is a need to study the neuro-immuno-endocrinal changes in suicide systematically that will give insight into the biological underpinning.",
"affiliations": "Department of Psychiatry, Enam Medical College & Hospital, Dhaka, Bangladesh.;Department of Psychiatry, King George's Medical University, Lucknow, India.",
"authors": "Arafat|Sm Yasir|SY|https://orcid.org/0000-0003-0521-5708;Kar|Sujita Kumar|SK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X211042225",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211042225\n10.1177_2050313X211042225\nCase Report\nRaised C-reactive protein in medication overdose: A report of two cases\nhttps://orcid.org/0000-0003-0521-5708\nArafat SM Yasir 1\nKar Sujita Kumar 2\n1 Department of Psychiatry, Enam Medical College & Hospital, Dhaka, Bangladesh\n2 Department of Psychiatry, King George’s Medical University, Lucknow, India\nSM Yasir Arafat, Department of Psychiatry, Enam Medical College & Hospital, Dhaka 1340, Bangladesh. Email: arafatdmc62@gmail.com\n25 8 2021\n2021\n9 2050313X21104222512 6 2021\n9 8 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nStudies have been coming out focusing on the biological markers of suicide. Here, we present two cases with raised C-reactive protein who were admitted after attempts of suicide by overdose. There is a need to study the neuro-immuno-endocrinal changes in suicide systematically that will give insight into the biological underpinning.\n\nPoisoning\noverdose\nraised C-reactive protein\nsuicide in Bangladesh\nbiomarkers\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nSuicidal behavior is a leading cause of death across the globe as someone dies every 40 s and suicidal attempts are reportedly 20 times higher than suicides.1 However, researchers and academicians are still struggling to identify any precise risk factor and to notice correctly an individual who is suicidal as it is the end result of the complex interaction of diverse factors.2 A previous suicidal attempt has been considered the best predictor of further attempts as well as death by suicide in the future.2 Recent studies have been coming out focusing on the neurobiological aspects, immunological changes, and biological markers of suicide.3,4 Therefore, finding out a biomarker that can estimate the risk precisely could be an important target to prevent suicides.5\n\nAmong the few inflammatory markers like tumor necrosis factor-alpha, raised interleukin (IL)-6, and reduced IL-2, C-reactive protein (CRP) has shown a promising role even though, further robust studies are warranted.3,4 We present here reports of two cases with raised CRP who were admitted after non-fatal attempts by overdose.\n\nCases\n\nCase 1\n\nMrs. T, a 20-year-old woman was transferred from the emergency department after the initial assessment to the department of psychiatry for subsequent management in February 2020. She took 19 tablets of olanzapine 5 mg 3 h back after a quarrel with her husband. She studied up to grade 8 and married for 3 years. Currently, she is a housewife having one daughter and lives in a joint family with her husband and in-laws. Her husband is a chronic user of multiple addictive substances that heralded them to a bad conjugal relationship. During this suicide attempt, her intent was to die due to intolerable pain in daily life. However, no psychiatric diagnosis was established from her current mental status examination (MSE). Physical examination and electrocardiogram (ECG) revealed sinus tachycardia (130 beats/min) in a regular rhythm. All other investigations, that is, complete blood count, liver function test, renal function test, and routine urine analysis were found within normal range except raised CRP (15.7 mg/L (reference range = <6 mg/L)). She was managed conservatively and was discharged on request after 2 days.\n\nCase 2\n\nMrs. S, a 24-year-old married housewife was referred to psychiatry from the emergency department for inpatient admission and further management in March 2020. She took five tablets of amitriptyline (25 mg) 2 h ago with the intent to die after a quarrel with her husband while she was threatened to divorce. During admission, her vitals were normal. Her psychiatric evaluation revealed no psychiatric diagnosis. She thought that life will have no meaning if she would be forced to take a divorce. She studied up to grade 12, married for the last 8 years, and had one son and one daughter. All investigations, that is, complete blood count, liver function test, renal function test, routine urine analysis, and ECG were found within normal range except raised CRP (22.6 mg/L (reference range = <6 mg/L)). She was managed conservatively discharged on request on the following day (Table 1).\n\nTable 1. Profile of the cases.\n\nVariable\tCase 1\tCase 2\t\nAge in year\t20\t24\t\nSex\tFemale\tFemale\t\nEducation\tGrade 8\tGrade 12\t\nOccupation\tHousewife\tHousewife\t\nMarital status\tMarried\tMarried\t\nOverdose drug\tOlanzapine (5 mg × 19)\tAmitriptyline (25 mg × 5)\t\nRisk factor\tMarital discord\tMarital discord\t\nCRP (mg/L)\t15.7\t22.6\t\nCRP: C-reactive protein.\n\nThe cases are being reported by complying with the Declaration of Helsinki 1964. They are being reported anonymously and informed consent was taken to publish their anonymous information. No formal institutional review board permission was taken for this report. CRP was measured by an automated biochemistry analyzer, cobas c 311 (Roche-Hitachi, Japan).\n\nDiscussion\n\nIdentification of potentially useful biomarkers of suicide is one of the current focuses of suicide research. Here, we report two females with raised CRP after having an overdose of medications. The age of the suicide attempters was 20 and 24 years. In both of the cases, the CRP was raised, that is, 15.7 and 22.6 mg/L respective without any other sign of infection/and inflammation. Both cases have a history of early marriage, early age of having a first child, and they have to do activities outside the home. One case (Case 1) has enduring stressful life as her husband is a chronic poly-substance abuser. However, none of the cases had a history of physical and/or psychiatric co-morbidity or any medical cause that could explain the raised CRP.\n\nInflammation has been identified as a potential trigger for several psychiatric conditions specially depression and suicidal behavior.6 Studies have been reported that persons with suicidal behavior have evidence of having inflammation.7 Some studies3–7 have identified the potential inflammatory markers and revealed an association with the levels of the markers while some other studies8,9 revealed findings refuting such a relationship. Therefore, replicative studies across time and culture are warranted. Another study assessed the role of common infections on suicidality and revealed that common infections have no influential role on suicide and suicidal behavior.10 However, the role of inflammation and increased level of CRP has been noted in an other study.11 It has been postulated that chronic inflammatory response could have roles in influencing the suicidal behavior.11 Other studies3,4 reported an increased level of CRP in non-fatal suicidal attempts and CRP has been recommended as a potential trait marker of suicidal attempt.\n\nIn both cases, there was no information regarding the level of inflammatory marker CRP, before the suicidal attempt. The CRP levels were estimated after the hospitalization following suicidal attempts. Here, we speculate few possibilities such as elevated level of CRP prior to the suicidal attempt, which continued to persist, elevation of CRP following ingestion medications in overdose, the possibility of any inflammatory process in the hospital setting, the result of psychological disorder, and results of ongoing stress leading to activation of the hypothalamo-pituitary-adrenal axis. However, raised CRP due to the inflammatory process in the hospital was not justifiable as there was no clinical evidence of systemic inflammation and the hospital stay was short (2–3 days). In addition, raised CRP due to psychiatric disorders was also not explainable as the patients did not qualify for any psychiatric disorder on serial MSEs.\n\nWe hypothesize that individuals, who attempt or die by suicide, go through enormous psychological distress, which might be responsible for activation of the hypothalamo-pituitary-adrenal axis and alteration in the level of inflammatory parameters.3,4 However, several aspects should be considered as the measurement was done for a single time, follow-up investigations could reveal different scenarios and any change over time could not be assessed, and only two cases were assessed. We did not assess the body mass index of the patients. In addition, we did not assess the suicidal intent with any objective instrument due to the unavailability of culturally validated instruments. We acknowledge that it is difficult to identify any specific cause and effect relationship from this report as suicide itself is a complex phenomenon. However, this is the first report from Bangladesh which could raise the issue and it is expected that further well-designed studies will be initiated to investigate the immunological changes in persons with suicidal behavior. Furthermore, clinicians treating patients with suicidal behavior would consider the complex phenomenon of immunological changes without any explicit signs of inflammation in Bangladesh.\n\nConclusion\n\nThere is a need to study the neuro-immuno-endocrinal changes in the suicide attempters systematically that could give insight into the biological underpinning of suicidal behavior. Pieces of evidence have been coming out day by day assessing the predictive role of CRP in suicidal behavior. This report could help to support the increased CRP that may be associated with suicidal behavior. However, the relationship is yet to be established by further well-designed robust studies.\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\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: SM Yasir Arafat https://orcid.org/0000-0003-0521-5708\n==== Refs\nReferences\n\n1 World Health Organization (WHO). Preventing suicide: a global imperative. WHO, 2014, https://apps.who.int/iris/handle/10665/131056\n2 Zalsman G Hawton K Wasserman D , et al . Suicide prevention strategies revisited: 10-year systematic review. Lancet Psychiatry 2016; 3 (7 ): 646–659.27289303\n3 Gibbs HM Davis L Han X , et al . Association between C-reactive protein and suicidal behavior in an adult inpatient population. J Psychiatr Res 2016; 79 : 28–33.27135541\n4 Courtet P Jaussent I Genty C , et al . Increased CRP levels may be a trait marker of suicidal attempt. Eur Neuropsychopharmacol 2015; 25 (10 ): 1824–1831.26032768\n5 Ganança L Oquendo MA Tyrka AR , et al . The role of cytokines in the pathophysiology of suicidal behavior. Psychoneuroendocrinology 2016; 63 : 296–310.26546783\n6 Keaton SA Madaj ZB Heilman P , et al . An inflammatory profile linked to increased suicide risk. J Affect Disord 2019; 247 : 57–65.30654266\n7 Brundin L Bryleva EY Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacology 2017; 42 (1 ): 271–283.27377015\n8 Russell AE Mars B Wen CP , et al . Evidence for an association between inflammatory markers and suicide: a cohort study based on 359,849 to 462,747 Taiwanese adults. J Affect Disord 2021; 281 : 967–971.33250203\n9 Russell AE Ford T Gunnell D , et al . Investigating evidence for a causal association between inflammation and self-harm: a multivariable Mendelian Randomisation study. Brain Behav Immun 2020; 89 : 43–50.32473944\n10 Lindgren M Holm M Markkula N , et al . Exposure to common infections and risk of suicide and self-harm: a longitudinal general population study. Eur Arch Psychiatry Clin Neurosci 2020; 270 (7 ): 829–839.32219505\n11 Batty GD Bell S Stamatakis E , et al . Association of systemic inflammation with risk of completed suicide in the general population. JAMA Psychiatry 2016; 73 (9 ): 993–995.27532220\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "9()",
"journal": "SAGE open medical case reports",
"keywords": "Poisoning; biomarkers; overdose; raised C-reactive protein; suicide in Bangladesh",
"medline_ta": "SAGE Open Med Case Rep",
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"nlm_unique_id": "101638686",
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"pages": "2050313X211042225",
"pmc": null,
"pmid": "34457307",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32473944;26032768;26546783;27289303;27135541;27532220;27377015;30654266;33250203;32219505",
"title": "Raised C-reactive protein in medication overdose: A report of two cases.",
"title_normalized": "raised c reactive protein in medication overdose a report of two cases"
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"abstract": "A 37-year-old man with a history of renal transplantation in 2013 due to focal segmental glomerulosclerosis presented to the emergency room with a 2-week history of fever, chills, anorexia, weight loss, abdominal pain, diarrhea, and a new asymptomatic lesion on the right side of the neck. The patient worked as a truck driver and frequently traveled to Wisconsin; he had not traveled internationally in the past year. He lived with his brother who had a pet cat. He was compliant with his anti-rejection medication regimen, which included mycophenolate mofetil, tacrolimus, and prednisone. Physical examination of the neck revealed an 8-mm exophytic, friable, red papule with overlying blood crusts (Figure 1). The remainder of the mucocutaneous examination was unremarkable, and there was no palpable lymphadenopathy. The patient was started on empiric intravenous cefepime and metronidazole and admitted to the hospital for further management. A punch biopsy of the lesion was performed.",
"affiliations": "Department of Internal Medicine, Alameda Health System - Highland Hospital, Oakland, CA.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL; alan.zhou@northwestern.edu.",
"authors": "Mehrmal|Sino|S|;Mhlaba|Julia M|JM|;Zhou|Xiaolong A|XA|",
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"journal": "Skinmed",
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"medline_ta": "Skinmed",
"mesh_terms": "D000328:Adult; D016917:Angiomatosis, Bacillary; D000900:Anti-Bacterial Agents; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D009333:Neck; D011241:Prednisone",
"nlm_unique_id": "101168327",
"other_id": null,
"pages": "150-154",
"pmc": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19052161;16827686;22316326;24933445;32334794;21285862;8727133;17275532;10075597;2382668;9248882;17478135;31192986;19659429;31828013;14692837;25032975;1546924;6637883;22862881;25652715;23062935",
"title": "Cutaneous Bacillary Angiomatosis in a Renal Transplant Patient.",
"title_normalized": "cutaneous bacillary angiomatosis in a renal transplant patient"
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"abstract": "To assess the likelihood of detecting latent tuberculosis infection [LTBI] by the positive conversion of a serial tuberculin skin test [TST] at 1 year in inflammatory bowel disease [IBD] patients with negative baseline two-step TST.\nIn this multicentre prospective cohort study, we evaluated rate and predictors of conversion of TST at 1 year in patients with negative baseline TST. We also evaluated management of patients who had a positive TST at baseline or a conversion at 1 year. In all patients we assessed TB cases occurring during follow-up.\nOf the 192 IBD patients receiving anti-tumour necrosis factor [TNF] and 220 IBD controls not receiving anti-TNF, 35 [8.5%, 95% CI 5.7-11.3] had positive conversion (median TST induration 13 mm, interquartile range [IQR] 9-16). Ten anti-TNF cohort patients [5.2%, 95% CI 2.5-9.5] versus 25 controls [11.4%, 95% CI 7.5-16.3] had TST conversion [p = 0.029]. In multivariate analysis, conversion was associated with smoking habit (odds ratio [OR] 2.19, 95% CI 1.08-3.97; p = 0.028). Anti-TNF-treated patients had a lower conversion rate [OR 0.41, 95% CI 0.20-0.83; p = 0.013]. The likelihood of conversion correlates with fewer immunosuppressive therapies between baseline TST and TST at 1 year [p = 0.042]. One case of active TB [isoniazid-resistant strain] occurred in a patient with positive baseline TST receiving anti-TNF [0.05 events/100 patient-years].\nSerial TST at 1 year can detect LTBI in IBD patients receiving anti-TNF therapy with negative baseline TST. Serial TST seems to be advisable to reduce the risk of TB cases associated with inability to detect LTBI in pre-treatment screening.",
"affiliations": "Department of Gastroenterology, Hospital Clínico San Carlos and Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], Madrid, Spain.;Department of Gastroenterology, Hospital Infanta Leonor, Madrid, Spain.;Department of Gastroenterology, Hospital Universitario Central de Asturias and Instituto de Investigación Biosanitaria del Principado de Asturias [ISPA], Oviedo, Spain.;Department of Gastroenterology, Hospital Universitario de Fuenlabrada, Madrid, Spain.;Department of Gastroenterology, Hospital de Cabueñes, Gijón, Spain.;Department of Gastroenterology, Hospital La Paz, Madrid, Spain.;Department of Gastroenterology, Hospital de Galdakao, Galdakao, Spain.;Department of Gastroenterology, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.;Department of Gastroenterology, Complejo Hospitalario Universitario de Vigo, Vigo, Spain.;Department of Gastroenterology, Hospital Universitario Fundación Alcorcón, Madrid, Spain.;Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain.;Department of Gastroenterology, Hospital Puerta de Hierro, Madrid, Spain.;Department of Gastroenterology, Hospital Reina Sofía, Córdoba, Spain.;Department of Gastroenterology, Hospitales Virgen Macarena-Rocío, Sevilla, Spain.;Department of Gastroenterology, Hospital de Manises, Manises, Spain.;Department of Gastroenterology, Hospital Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón [IiSGM], Madrid, Spain.;Department of Gastroenterology, Hospital Universitario de Canarias, La Laguna, Spain.;Department of Gastroenterology, Hospital La Fe, Valencia, Spain.;Department of Gastroenterology, Hospital Universitario de Torrejón, Madrid, Spain.;Department of Gastroenterology, Hospital Universitario 12 de Octubre, Madrid, Spain.;Department of Gastroenterology, Hospital Clínico San Carlos and Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], Madrid, Spain.;Department of Gastroenterology, Hospital Universitario Marqués de Valdecilla, Santander, Spain.;Department of Gastroenterology, Hospital Clínico de Valladolid, Valladolid, Spain.;Department of Gastroenterology, Complejo Hospitalario de Navarra and Instituto de Investigación Sanitaria de Navarra [IdiSNA], Pamplona, Spain.;Department of Gastroenterology, Hospital Universitario Cruces, Bilbao, Spain.;Department of Gastroenterology, Hospital Clínico San Carlos and Instituto de Investigación del Hospital Clínico San Carlos [IdISSC], Madrid, Spain.;Department of Gastroenterology, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP] and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain.",
"authors": "Taxonera|Carlos|C|;Ponferrada|Ángel|Á|;Riestra|Sabino|S|;Bermejo|Fernando|F|;Saro|Cristina|C|;Martín-Arranz|María Dolores|MD|;Cabriada|José Luis|JL|;Barreiro-de Acosta|Manuel|M|;de Castro|María Luisa|ML|;López-Serrano|Pilar|P|;Barrio|Jesús|J|;Suarez|Cristina|C|;Iglesias|Eva|E|;Argüelles-Arias|Federico|F|;Ferrer|Isabel|I|;Marín-Jiménez|Ignacio|I|;Hernández-Camba|Alejandro|A|;Bastida|Guillermo|G|;Van Domselaar|Manuel|M|;Martínez-Montiel|Pilar|P|;Olivares|David|D|;Rivero|Montserrat|M|;Fernandez-Salazar|Luis|L|;Nantes|Óscar|Ó|;Merino|Olga|O|;Alba|Cristina|C|;Gisbert|Javier P|JP|;|||",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjy104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "12(11)",
"journal": "Journal of Crohn's & colitis",
"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000068879:Adalimumab; D000305:Adrenal Cortex Hormones; D000328:Adult; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069078:Seroconversion; D012882:Skin Tests; D012907:Smoking; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "1270-1279",
"pmc": null,
"pmid": "30052856",
"pubdate": "2018-11-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Serial Tuberculin Skin Tests Improve the Detection of Latent Tuberculosis Infection in Patients With Inflammatory Bowel Disease.",
"title_normalized": "serial tuberculin skin tests improve the detection of latent tuberculosis infection in patients with inflammatory bowel disease"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1037650",
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"abstract": "The association between treatment-related lymphopenia in multiple sclerosis, drug efficacy and the risk of infections is not yet fully understood.\n\n\n\nThe objective of this study was to assess whether lymphopenia is associated with short-term treatment response and infection rate in a real-life multiple sclerosis population treated with fingolimod and dimethyl-fumarate. We assessed the associations between baseline absolute lymphocyte count and the lymphocyte mean percentage decrease at 6 and 12 months with treatment response and the occurrence of adverse events over 12 months in the entire cohort of patients and in the two treatment groups separately.\n\n\n\nThis is a retrospective observational real-world study of patients with multiple sclerosis treated with fingolimod and dimethyl-fumarate at the MS Center of the University of Genoa between 2011 and 2018. Patients with at least 12 months of follow-up were eligible if [1] they had an Expanded Disability Status Scale assessment at baseline and 12 months after treatment onset, [2] they had undergone brain magnetic resonance imaging at baseline and after 12 months, and [3] absolute lymphocyte counts were available at baseline, 6 and 12 months. Patients shifting from dimethyl-fumarate to fingolimod or vice versa were excluded from the analysis.\n\n\n\nIn total, 137 and 75 patients treated with fingolimod and dimethyl-fumarate, respectively, were included in the analysis. At 12 months, fingolimod-treated patients were more likely to experience grade II and grade III lymphopenia compared with dimethyl-fumarate patients (p < 0.001, χ2 = 94) and had a higher lymphocyte mean percentage decrease (p < 0.001, U = 540). A higher number of previous therapies and a lower baseline absolute lymphocyte count were predictors of lymphopenia at 6 months (p = 0.047, odds ratio = 1.60 and p = 0.014, odds ratio = 1.1) and 12 months (p = 0.003, odds ratio = 1.97 and p = 0.023, odds ratio = 1.1). In fingolimod-treated patients only, female sex and a higher Expanded Disability Status Scale score were predictors of lymphopenia at 12 months (p = 0.006, odds ratio = 7.58 and p = 0.03, odds ratio = 1.56). Neither absolute lymphocyte count at 6 and 12 months nor the mean percentage decrease at 6 and 12 months predicted No Evidence of Disease Activity (NEDA-3) status at 1 year, the occurrence of relapses, disease activity on MRI or disability progression.\n\n\n\nOur findings suggest that peripheral blood lymphocyte changes are not associated with short-term treatment response and with the rate of infections during fingolimod and dimethyl-fumarate treatment in real-world patients. Higher treatment exposure and a lower baseline absolute lymphocyte count are risk factors for lymphopenia development during fingolimod and dimethyl-fumarate therapy.",
"affiliations": "Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Ospedale Policlinico San Martino IRCCS, Largo Daneo 3, 16100, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy. m.inglese@unige.it.",
"authors": "Boffa|Giacomo|G|;Bruschi|Nicolò|N|;Cellerino|Maria|M|;Lapucci|Caterina|C|;Novi|Giovanni|G|;Sbragia|Elvira|E|;Capello|Elisabetta|E|;Uccelli|Antonio|A|;Inglese|Matilde|M|",
"chemical_list": "D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40263-020-00714-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1172-7047",
"issue": "34(4)",
"journal": "CNS drugs",
"keywords": null,
"medline_ta": "CNS Drugs",
"mesh_terms": "D000328:Adult; D000069462:Dimethyl Fumarate; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007239:Infections; D018655:Lymphocyte Count; D008214:Lymphocytes; D008231:Lymphopenia; D008297:Male; D009103:Multiple Sclerosis; D012008:Recurrence; D012189:Retrospective Studies; D012306:Risk",
"nlm_unique_id": "9431220",
"other_id": null,
"pages": "425-432",
"pmc": null,
"pmid": "32193826",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "27347439;21729281;31066225;29182993;30658226;31511330;31738884;25361781;30859008;29296636;22992072;29656444;22992073;30316988;30524432;28043652;30918100;31258529;30706542;20089954;28959705;30227312;24685276;29304497;29497558;29193293;30851128;26550483;29075564;29649923;26943779;31583427",
"title": "Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population.",
"title_normalized": "fingolimod and dimethyl fumarate derived lymphopenia is not associated with short term treatment response and risk of infections in a real life ms population"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-07286",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
},
... |
{
"abstract": "Supraventricular tachycardia (SVT) is a common infant arrhythmia, for which beta-blockers are frequently chosen as therapy. Propranolol is a common choice though it is dosed every 6-8 h. We reviewed the clinical results of treating infant SVT with an extemporaneous preparation of nadolol. Retrospective cohort study of patients under 2 years old receiving nadolol for SVT at a single center. Patients were ascertained by patient and pharmacy databases. Twenty-eight infants received nadolol, of whom 25 had regular narrow complex tachycardia, 2 atrial flutter, and 1 focal atrial tachycardia. Patient age at initiation was a median 54 days (range 10-720). The final dose was 1 mg/kg/day in 22/28 patients (range 0.5-2). Once-daily dosing was used in 20 patients (71.4%); dosing was BID in 7, TID in 1. Among regular narrow complex tachycardia patients, 18/25 received nadolol monotherapy and 7 required additional agents; flecainide in 6, digoxin in 1. The median age of tachyarrhythmia onset was 18 days (range 1-180) with a median age of nadolol initiation of 30 days (range 11-390). Of the 20 regular narrow complex tachycardia patients initiated on nadolol monotherapy, 85% had no recurrences as of 1-year follow-up. Side effects were suspected in 3 of 28 (10.7%), including wheezing (n = 1, 3.5%), irritability and diarrhea (n = 1, 3.5%), and bradycardia (n = 1, 3.5%). Oral nadolol suspension was a successful treatment for SVT in 85% of patients with minimal adverse effects. Single daily dosing was used in the majority of patients.",
"affiliations": "Children's Hospital Colorado, 13123 East 16th Avenue, B100, Aurora, CO, 80045, USA. johannes.vonalvensleben@childrenscolorado.org.;University of Michigan, Ann Arbor, MI, USA.;University of Michigan, Ann Arbor, MI, USA.;University of Michigan, Ann Arbor, MI, USA.",
"authors": "von Alvensleben|Johannes C|JC|;LaPage|Martin J|MJ|;Caruthers|Regine|R|;Bradley|David J|DJ|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D009248:Nadolol; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-016-1544-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "38(3)",
"journal": "Pediatric cardiology",
"keywords": "Beta-blockers; Pediatrics; Supraventricular tachycardia",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D017668:Age of Onset; D000889:Anti-Arrhythmia Agents; D016208:Databases, Factual; D005260:Female; D005424:Flecainide; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008824:Michigan; D009248:Nadolol; D010372:Pediatrics; D012189:Retrospective Studies; D013617:Tachycardia, Supraventricular; D016896:Treatment Outcome",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "525-530",
"pmc": null,
"pmid": "27995288",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "14911279;21571035;1474163;2235896;11558866;21418251;12189406;7646286;1982759;2229769;8554021;22429067;16040;7229788;1538020;20644039;23827401;4721965;25929701;16391988;22762503;16265094;22962431;10673253;17645757;19514806;8842054;787953;619057",
"title": "Nadolol for Treatment of Supraventricular Tachycardia in Infants and Young Children.",
"title_normalized": "nadolol for treatment of supraventricular tachycardia in infants and young children"
} | [
{
"companynumb": "US-US WORLDMEDS, LLC-USW201701-000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NADOLOL"
},
"drugadditional": "1"... |
{
"abstract": "Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome. Clinical presentation ranges from chest pain alone to ST-segment-elevation myocardial infarction, ventricular fibrillation, and sudden death. The treatment of patients with spontaneous coronary artery dissection is challenging because the disease pathophysiology is unclear, optimal treatment is unknown, and short- and long-term prognostic data are minimal. We report the case of a 70-year-old woman who presented with an acute ST-segment-elevation myocardial infarction secondary to a spontaneous dissection of the left anterior descending coronary artery. She was treated conservatively. Cardiac tamponade developed 16 hours after presentation. Repeat coronary angiography revealed extension of the dissection. Medical therapy was continued after the hemopericardium was aspirated. The patient remained asymptomatic 3 years after hospital discharge. To our knowledge, this is the first reported case of spontaneous coronary artery dissection in association with cardiac tamponade that was treated conservatively and had a successful outcome.",
"affiliations": null,
"authors": "Goh|Anne C H|AC|;Lundstrom|Robert J|RJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14503/THIJ-14-4260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-2347",
"issue": "42(5)",
"journal": "Texas Heart Institute journal",
"keywords": "Acute coronary syndrome/therapy; aneurysm, dissecting/therapy; cardiac tamponade/etiology/therapy; disease management; elderly; female; myocardial infarction/etiology; rupture, spontaneous; thrombolytic therapy/contraindications; treatment outcome",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000784:Aneurysm, Dissecting; D002305:Cardiac Tamponade; D003323:Coronary Aneurysm; D017023:Coronary Angiography; D005260:Female; D006801:Humans; D009203:Myocardial Infarction; D016896:Treatment Outcome",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "479-82",
"pmc": null,
"pmid": "26504447",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "20448134;21041853;21489673;22800851;1747972;2320340;23078737;1570431;7834730;11996290;15156006;8732390;17901453;19046896;19496145;20440039",
"title": "Spontaneous Coronary Artery Dissection with Cardiac Tamponade.",
"title_normalized": "spontaneous coronary artery dissection with cardiac tamponade"
} | [
{
"companynumb": "US-ACTAVIS-2015-26723",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "Although the rifampin-cyclosporine interaction is well described, information on the extent, duration, and potency of the rifampin-tacrolimus interaction is limited. We describe a renal transplant recipient who demonstrated an increase in tacrolimus metabolism as a result of rifampin administration. A 40-year-old Asian woman received a cadaveric renal transplant for end-stage renal disease due to IgA nephropathy and was administered tacrolimus, thymoglobulin, mycophenolate mofetil, and prednisone, along with diltiazem for hypertension. On postoperative day (POD) 5, donor bronchioalveolar lavage revealed active tuberculosis. The recipient received rifampin 600 mg/d, and the diltiazem dose was increased. Over the next 12 days, the tacrolimus dose was increased to 32 mg/d to achieve a target trough level of 10 to 15 ng/mL, finally reached on POD34, when the serum creatinine was 145 micromol/L. The patient also received a course of fluconazole 100 mg/d and clarithromycin 1000 mg/d starting on POD38 and POD41, respectively. Despite this, there was no increase in tacrolimus levels. Rifampin was discontinued on POD76, after which therapeutic tacrolimus levels were finally attained with usual doses by POD132. Rifampin had potent and prolonged effects on tacrolimus metabolism. Induction of the hepatic cytochrome P4503A4 system by rifampin was sufficient to overcome the inhibitory effects of diltiazem; fluconazole, and clarithromycin, necessitating the use of large doses of tacrolimus. Close monitoring of tacrolimus levels and frequent dose adjustments are required whenever rifampin is administered posttransplant, regardless of P450 inhibitors used, to optimize allograft function.",
"affiliations": "Pharmacy, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Bhaloo|S|S|;Prasad|G V R|GV|",
"chemical_list": "D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D015725:Fluconazole; D003404:Creatinine; D004110:Diltiazem; D017291:Clarithromycin; D012293:Rifampin; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2003.08.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "35(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D017291:Clarithromycin; D003404:Creatinine; D065607:Cytochrome P-450 Enzyme Inhibitors; D004110:Diltiazem; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole; D006801:Humans; D007166:Immunosuppressive Agents; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D012293:Rifampin; D016559:Tacrolimus",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2449-51",
"pmc": null,
"pmid": "14611983",
"pubdate": "2003-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe reduction in tacrolimus levels with rifampin despite multiple cytochrome P450 inhibitors: a case report.",
"title_normalized": "severe reduction in tacrolimus levels with rifampin despite multiple cytochrome p450 inhibitors a case report"
} | [
{
"companynumb": "CA-SA-2021SA199563",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nHistoid leprosy (HL) is a rare form of lepromatous leprosy, characterized by hyperchromic indurated nodules above normal skin. Its main histopathological aspect is spindle cells. Because it may simulate other aspects, such as dermatofibroma and neurofibroma, histoid leprosy poses itself as a diagnostic challenge.\n\n\nMETHODS\nThis is a retrospective study with all patients having been selected from the leprosy clinic of the Hospital das Clínicas da Universidade de São Paulo from 2006 to 2016.\n\n\nRESULTS\nThere were 12 patients in this study, eight in the histoid group and four in the lepromatous leprosy group. The prevalence of HL was 1.12% in all leprosy subjects. All individuals from HL group were \"de novo\" cases, and the histopathological analysis of skin lesions presented spindle cells generating a storiform pattern. Immunohistochemistry for CD68, vimentin, and anti-BCG were positive in all 12 cases. Factor XIIIa was visualized only in the papillary dermis, and S100 protein was negative in all biopsies. Smooth-muscle actin was present in 62.5% of the HL samples.\n\n\nCONCLUSIONS\nThe prevalence of HL was similar to previous reports. However, all histoid patients were \"de novo\" cases, differing from published studies. Fusocellular macrophage transformation could be explained by the differences in cytoskeleton proteins expressed in histoid lesions in comparison to other leprosy variants, with emphasis on vimentin and smooth muscle actin.",
"affiliations": "Divisão de Clínica Dermatológica, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.;Divisão de Clínica Dermatológica, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.;Scientific researcher VI of Laboratório de Investigação Médica, Imunodermatologia, Instituto de Saúde da Secretaria de Estado da Saúde do Estado de São Paulo, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.;Divisão de Clínica Dermatológica, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.;Departamento de Patologia da Faculdade de Medicina da, Universidade de São Paulo, Sao Paulo, Brazil.;Departamento de Patologia da Faculdade de Medicina da, Universidade de São Paulo, Sao Paulo, Brazil.",
"authors": "Canuto|Maria J M|MJM|;Yacoub|Carolina R D|CRD|;Trindade|Maria A B|MAB|;Avancini|Joao|J|http://orcid.org/0000-0003-3038-6373;Pagliari|Carla|C|;Sotto|Mirian N|MN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ijd.13926",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "57(6)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000328:Adult; D017677:Age Distribution; D000554:Ambulatory Care Facilities; D001707:Biopsy, Needle; D001938:Brazil; D015331:Cohort Studies; D019353:Endemic Diseases; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007150:Immunohistochemistry; D015440:Leprosy, Lepromatous; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010808:Physical Examination; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "707-712",
"pmc": null,
"pmid": "29384191",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Histoid leprosy: clinical and histopathological analysis of patients in follow-up in University Clinical Hospital of endemic country.",
"title_normalized": "histoid leprosy clinical and histopathological analysis of patients in follow up in university clinical hospital of endemic country"
} | [
{
"companynumb": "PHHY2018BR007709",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOFAZIMINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "A 1-month-old boy was evaluated after a fall from a height of 3 feet and found to have right parietal skull fracture as well as right and left frontal traumatic hemorrhage. Ten days after the injury, he represented with a persistent left gaze preference. Further workup including MRI and EEG determined that this finding was most likely due to a small, focal, left-frontal eye field lesion. We review the horizontal gaze pathway and demonstrate that this is present at this very young age, and that a very focal and relatively minor injury can cause gaze disturbance.",
"affiliations": "Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass., USA.",
"authors": "Bourne|Sarah K|SK|;Duhaime|Ann-Christine|AC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000441680",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-2291",
"issue": "51(1)",
"journal": "Pediatric neurosurgery",
"keywords": null,
"medline_ta": "Pediatr Neurosurg",
"mesh_terms": "D000058:Accidental Falls; D001930:Brain Injuries; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D015835:Ocular Motility Disorders; D010294:Parietal Bone; D012887:Skull Fractures; D013345:Subarachnoid Hemorrhage; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9114967",
"other_id": null,
"pages": "42-7",
"pmc": null,
"pmid": "26636750",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transient Horizontal Gaze Palsy in a One-Month-Old Boy after a Fall.",
"title_normalized": "transient horizontal gaze palsy in a one month old boy after a fall"
} | [
{
"companynumb": "US-APOTEX-2018AP010194",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Dalbavancin is a lipoglycopeptide antibiotic with unique weekly dosing active against Gram-positive organisms. This retrospective study included 37 patients receiving a mean of 2.7 weeks of dalbavancin. Nine patients (24%) were re-admitted to the hospital within 30 days. A total of 617 hospital days were saved, estimated to result in US$1 495 336 in savings and a mean cost avoidance of US$40 414 per patient. Dalbavancin provides a valuable antibiotic option that may minimise healthcare expenditure.",
"affiliations": "Department of Pharmacy Services, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: streifel@ohsu.edu.;Department of Medicine, Division of Infectious Diseases, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.;Department of Pharmacy Services, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.;Department of Pharmacy Services, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Medicine, Division of Infectious Diseases, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.",
"authors": "Streifel|Amber C|AC|;Sikka|Monica K|MK|;Bowen|Christina D|CD|;Lewis|James S|JS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017334:Teicoplanin; C469289:dalbavancin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijantimicag.2019.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "54(5)",
"journal": "International journal of antimicrobial agents",
"keywords": "Dalbavancin; Gram-positive infection; OPAT; Outpatient parenteral antimicrobial therapy",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D017046:Cost Savings; D005260:Female; D006094:Gram-Positive Bacteria; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017192:Skin Diseases, Bacterial; D018461:Soft Tissue Infections; D017334:Teicoplanin; D055815:Young Adult",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "652-654",
"pmc": null,
"pmid": "31398481",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dalbavancin use in an academic medical centre and associated cost savings.",
"title_normalized": "dalbavancin use in an academic medical centre and associated cost savings"
} | [
{
"companynumb": "US-ALLERGAN-1947485US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DALBAVANCIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nRecently, elbasvir/grazoprevir combination therapy (EBR/GZR) was reported to have excellent antiviral effects for chronic genotype 1 hepatitis C virus (HCV) infection. However, it has not been recommended for patients with post-liver transplant (LT) HCV re-infections because of a lack of evidence for effectiveness and drug-drug interactions.\n\n\nMETHODS\nWe report the usage of EBR/GZR in five post-LT HCV re-infected patients with the kinetics of renal function and tacrolimus trough levels during and after therapy. Furthermore, to evaluate the antiviral effects, we examined the HCV kinetics during and after therapy and compared this with other interferon-free therapy in post-LT patients (n = 19).\n\n\nRESULTS\nAll patients treated with EBR/GZR therapy obtained rapid virologic response and sustained at 12 weeks post-treatment. There was no evidence of worsening estimated glomerular filtration rates. Three patients were given tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n = 8) and sofosbuvir/ledipasvir combination therapy (n = 11). The EBR/GZR combination was not inferior to other therapies in its early phase and late-phase antiviral effects.\n\n\nCONCLUSIONS\nAlthough further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post-LT genotype 1 HCV re-infection.",
"affiliations": "Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.",
"authors": "Miuma|Satoshi|S|;Miyaaki|Hisamitsu|H|;Soyama|Akihiko|A|;Hidaka|Masaaki|M|;Takatsuki|Mitsuhisa|M|;Shibata|Hidetaka|H|;Taura|Naota|N|;Eguchi|Susumu|S|;Nakao|Kazuhiko|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.13204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "48(12)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "elbasvir; grazoprevir; hepatitis C virus; liver transplantation",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1045-1054",
"pmc": null,
"pmid": "29908044",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Utilization and efficacy of elbasvir/grazoprevir for treating hepatitis C virus infection after liver transplantation.",
"title_normalized": "utilization and efficacy of elbasvir grazoprevir for treating hepatitis c virus infection after liver transplantation"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-04993",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Transplant renal artery stenosis (TRAS) is a common vascular complication after kidney transplantation, leading to worsening or refractory hypertension, deterioration in renal function, and possible cause of graft loss. Early diagnosis and an appropriate treatment are crucial for organ preservation. Endovascular treatment, including percutaneous transluminal angioplasty and stent implantation, is considered the first-line therapy for TRAS. Here we report the case of a 69-year-old woman with end-stage renal disease for chronic kidney disease not biopsy proven, who underwent a kidney transplant from expanded criteria donors on December 2018. Postoperative course was characterized by delayed graft function. Doppler ultrasonography (US) showed an increase of peak systolic velocity at the origin of the renal artery, and parvus-tardus waveform in periferic graft arteries and an abdominal computed tomography scan confirmed a stenosis at the origin of the main renal artery (TRAS). The patient underwent a percutaneous transluminal angioplasty. It was not possible to place a stent at the particular location of the stenosis at the anastomosis. Despite the improvement of the graft's perfusion, monitored with Doppler US, the patient showed a very poor improvement in renal function and remained on hemodialysis for months. A percutaneous needle biopsy reported a normal renal parenchyma and excluded acute rejection. During this period, the patient received immunosuppressive therapy. About 6 months after the transplant, the patient had an unexpected and slow renal function recovery until she was weaned completely from hemodialysis.",
"affiliations": "General and Transplant Surgery Department, University of L'Aquila, L'Aquila, Italy.;General and Transplant Surgery Department, University of L'Aquila, L'Aquila, Italy. Electronic address: alessandra.panarese@univaq.it.;General and Transplant Surgery Department, San Salvatore Hospital, L'Aquila, Italy.;General and Transplant Surgery Department, San Salvatore Hospital, L'Aquila, Italy.;General and Transplant Surgery Department, University of L'Aquila, L'Aquila, Italy; General and Transplant Surgery Department, San Salvatore Hospital, L'Aquila, Italy.",
"authors": "Montali|Filippo|F|;Panarese|Alessandra|A|;Binda|Barbara|B|;Lancione|Laura|L|;Pisani|Francesco|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.03.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D017130:Angioplasty; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D011183:Postoperative Complications; D020127:Recovery of Function; D012077:Renal Artery; D012078:Renal Artery Obstruction",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1272-1274",
"pmc": null,
"pmid": "33894988",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transplant Renal Artery Stenosis: A Case Report of Functional Recovery Six Months After Angioplasty.",
"title_normalized": "transplant renal artery stenosis a case report of functional recovery six months after angioplasty"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-320867",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
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"abstract": "Neurological complications are not uncommon in patients with renal transplantation, mostly affecting the central nervous system, and less frequently the peripheral nerves. BK virus infection is relatively common in transplant recipients and in some cases may lead to neurological complications. In this report, we present an interesting case of a patient who developed acute axonal motor polyneuropathy in the course of BK virus infection 3 months after kidney transplantation. After BK virus clearence in blood, a significant improvement was noted in her polyneuropathy. In patients with acute axonal motor polyneuropathy after transplantation BK virus-induced polyneuropathy should be excluded.",
"affiliations": "Department of Nephrology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey. hulyataskapan@yahoo.com.;Department of Infectious Diseases and Clinical Microbiology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey.;Department of Clinical Microbiology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey.;Department of Neurology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey.;Department of Nephrology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey.;Department of Nephrology, Turgut Ozal Medical Center, Medical Faculty, Inonu University, Malatya, Turkey.",
"authors": "Taskapan|Hulya|H|;Kayabas|Uner|U|;Otlu|Baris|B|;Kamisli|Ozden|O|;Yaprak|Cisel Yilmaz|CY|;Sahin|Fatma Terzioglu|FT|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-015-0179-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "5(1)",
"journal": "CEN case reports",
"keywords": "BK virus; Neuropathy; Renal transplantation",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "28509156",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "16573841;16421486;16299677;1857469;11709797;12138148;10397537;15712075;8599551;17234523;16206122;8391217;20060360",
"title": "BK virus-induced acute motor-axonal polyneuropathy in a renal transplant patient.",
"title_normalized": "bk virus induced acute motor axonal polyneuropathy in a renal transplant patient"
} | [
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"companynumb": "TR-MYLANLABS-2016M1029692",
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{
"abstract": "Relapsing Evans syndrome (ES) and systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome (APS) is very rare association. Coexistence of these syndromes is potentially fatal and require high-dose combined immunosuppressive therapy. We describe a case of successful use of Bortezomib and plasma exchange in a patient with ES and APS refractory to standard therapy. Thirty-two-year-old male who presented episodes of relapsing hemolytic anemia, pancytopenia and multiple thrombosis with positive direct and indirect antiglobulin test result, lupus anticoagulant and medium titer of anti-beta-2-glycoprotein 1 and anti-cardiolipin antibodies was diagnosed with ES and SLE with secondary APS. High-dose therapy by steroids and Cyclosporin A were started with temporary improvement. There was also no stable improvement with Rituximab and Cyclophosphamide. Bortezomib in combination with cyclosporine A and plasma exchange was introduced. He had stable improvement in hematological parameters with no evidence of relapse of hemolytic crisis or thrombosis during a follow-up for 1 year.",
"affiliations": "Center for Molecular Medicine, First Pavlov State Medical University of St. Peterburg, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia. Electronic address: tkachenie@mail.ru.;Center for Molecular Medicine, First Pavlov State Medical University of St. Peterburg, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia.;Rheumatology Department, V.A. Almazov North-West Federal Medical Research Center, 2 Akkuratova str., Saint Petersburg 19734, Russia.;Rheumatology Department, V.A. Almazov North-West Federal Medical Research Center, 2 Akkuratova str., Saint Petersburg 19734, Russia.;Center for Molecular Medicine, First Pavlov State Medical University of St. Peterburg, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia; Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, 7/9 Universitetskaya Emb., Saint- Petersburg 199034, Russia.;Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, 7/9 Universitetskaya Emb., Saint- Petersburg 199034, Russia.",
"authors": "Tkachenko|Olga|O|;Lapin|Sergey|S|;Maslyansky|Alexey|A|;Myachikova|Valentina|V|;Mikhailova|Liya|L|;Gilburd|Boris|B|",
"chemical_list": "D053482:beta 2-Glycoprotein I; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2018.12.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "199()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "Antiphospholipid syndrome; Bortezomib; Evans syndrome; Hemolysis; Thrombosis",
"medline_ta": "Clin Immunol",
"mesh_terms": "D000328:Adult; D000744:Anemia, Hemolytic, Autoimmune; D016736:Antiphospholipid Syndrome; D000069286:Bortezomib; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D010951:Plasma Exchange; D012008:Recurrence; D013921:Thrombocytopenia; D053482:beta 2-Glycoprotein I",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "44-46",
"pmc": null,
"pmid": "30543928",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Relapsing Evans syndrome and systemic lupus erythematosus with antiphospholipid syndrome treated with Bortezomib in combination with plasma exchange.",
"title_normalized": "relapsing evans syndrome and systemic lupus erythematosus with antiphospholipid syndrome treated with bortezomib in combination with plasma exchange"
} | [
{
"companynumb": "PHHY2019RU102448",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "RITUXIMAB"
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"abstract": "Various multimodal analgesic approaches have been proposed for spine surgery. The authors evaluated the effect of using a combination of four nonopioid analgesics versus placebo on Quality of Recovery, postoperative opioid consumption, and pain scores.\n\n\n\nAdults having multilevel spine surgery who were at high risk for postoperative pain were double-blind randomized to placebos or the combination of single preoperative oral doses of acetaminophen 1,000 mg and gabapentin 600 mg, an infusion of ketamine 5 µg/kg/min throughout surgery, and an infusion of lidocaine 1.5 mg/kg/h intraoperatively and during the initial hour of recovery. Postoperative analgesia included acetaminophen, gabapentin, and opioids. The primary outcome was the Quality of Recovery 15-questionnaire (0 to 150 points, with 15% considered to be a clinically important difference) assessed on the third postoperative day. Secondary outcomes were opioid use in morphine equivalents (with 20% considered to be a clinically important change) and verbal-response pain scores (0 to 10, with a 1-point change considered important) over the initial postoperative 48 h.\n\n\n\nThe trial was stopped early for futility per a priori guidelines. The average duration ± SD of surgery was 5.4 ± 2.1 h. The mean ± SD Quality of Recovery score was 109 ± 25 in the pathway patients (n = 150) versus 109 ± 23 in the placebo group (n = 149); estimated difference in means was 0 (95% CI, -6 to 6, P = 0.920). Pain management within the initial 48 postoperative hours was not superior in analgesic pathway group: 48-h opioid consumption median (Q1, Q3) was 72 (48, 113) mg in the analgesic pathway group and 75 (50, 152) mg in the placebo group, with the difference in medians being -9 (97.5% CI, -23 to 5, P = 0.175) mg. Mean 48-h pain scores were 4.8 ± 1.8 in the analgesic pathway group versus 5.2 ± 1.9 in the placebo group, with the difference in means being -0.4 (97.5% CI; -0.8, 0.1, P = 0.094).\n\n\n\nAn analgesic pathway based on preoperative acetaminophen and gabapentin, combined with intraoperative infusions of lidocaine and ketamine, did not improve recovery in patients who had multilevel spine surgery.",
"affiliations": "From the Department of General Anesthesiology (K.M., R.A., D.T., S.R., M.M., S.M., A. Kurz) Department of Quantitative Health Sciences (N.M.) Department of Neurosurgery (A. Krishnaney, A.M.) Department of Pain Management (R.R.) Department of Outcomes Research (K.M., D.I.S., N.M., M.T., S.R., A. Kurz), Cleveland Clinic, Cleveland, Ohio.",
"authors": "Maheshwari|Kamal|K|;Avitsian|Rafi|R|;Sessler|Daniel I|DI|;Makarova|Natalya|N|;Tanios|Marianne|M|;Raza|Syed|S|;Traul|David|D|;Rajan|Shobana|S|;Manlapaz|Mariel|M|;Machado|Sandra|S|;Krishnaney|Ajit|A|;Machado|Andre|A|;Rosenquist|Richard|R|;Kurz|Andrea|A|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000082:Acetaminophen; D007649:Ketamine; D000077206:Gabapentin; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/ALN.0000000000003143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3022",
"issue": "132(5)",
"journal": "Anesthesiology",
"keywords": null,
"medline_ta": "Anesthesiology",
"mesh_terms": "D000082:Acetaminophen; D000368:Aged; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007649:Ketamine; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010149:Pain, Postoperative; D013122:Spinal Diseases",
"nlm_unique_id": "1300217",
"other_id": null,
"pages": "992-1002",
"pmc": null,
"pmid": "32235144",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multimodal Analgesic Regimen for Spine Surgery: A Randomized Placebo-controlled Trial.",
"title_normalized": "multimodal analgesic regimen for spine surgery a randomized placebo controlled trial"
} | [
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"companynumb": "US-DENTSPLY PHARMACEUTICAL-2020SCDP000180",
"fulfillexpeditecriteria": "2",
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia characterized by a subacute course and favorable prognosis with corticosteroids. However, some patients show resistance to steroids. Macrolides have been used with success in those patients showing resistance to steroids. A few reports showed treatment failure with macrolides in patients with COP who were resistant to steroids. In this report, we described two cases of COP who showed different responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin.",
"affiliations": "Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.;Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.;Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.;Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.;Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.;Department of Thoracic Surgery, Soonchunhyang University Hospital, Seoul, Korea.;Department of Pathology, Soonchunhyang University Hospital, Seoul, Korea.;Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.",
"authors": "Oh|Ji Hyun|JH|;Oh|Dong Jun|DJ|;Koo|So-My|SM|;Kim|Yang Ki|YK|;Kim|Ki Up|KU|;Kim|Hyun Jo|HJ|;Kim|Dong Won|DW|;Uh|Soo-Taek|ST|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4046/trd.2015.78.4.401",
"fulltext": "\n==== Front\nTuberc Respir Dis (Seoul)Tuberc Respir Dis (Seoul)TRDTuberculosis and Respiratory Diseases1738-35362005-6184The Korean Academy of Tuberculosis and Respiratory Diseases 10.4046/trd.2015.78.4.401Case ReportDifferent Responses to Clarithromycin in Patients with Cryptogenic Organizing Pneumonia Oh Ji Hyun M.D.1Oh Dong Jun M.D.1Koo So-My M.D.1Kim Yang Ki M.D.Ph.D.1Kim Ki Up M.D.Ph.D.1Kim Hyun Jo M.D.Ph.D.2Kim Dong Won M.D.Ph.D.3Uh Soo-Taek M.D.Ph.D.11 Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Seoul, Korea.2 Department of Thoracic Surgery, Soonchunhyang University Hospital, Seoul, Korea.3 Department of Pathology, Soonchunhyang University Hospital, Seoul, Korea.Address for correspondence: Soo-Taek Uh, M.D., Ph.D. Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea. Phone: 82-2-709-9482, Fax: 82-2-793-9965, uhs@schmc.ac.kr10 2015 01 10 2015 78 4 401 407 22 4 2015 10 6 2015 30 6 2015 Copyright©2015. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved.2015It is identical to the Creative Commons Attribution Non-Commercial\nLicense (http://creativecommons.org/licenses/by-nc/4.0/)Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia characterized by a subacute course and favorable prognosis with corticosteroids. However, some patients show resistance to steroids. Macrolides have been used with success in those patients showing resistance to steroids. A few reports showed treatment failure with macrolides in patients with COP who were resistant to steroids. In this report, we described two cases of COP who showed different responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin.\n\nCryptogenic Organizing PneumoniaClarithromycinMacrolidesAdrenal Cortex HormonesSoonchunhyang University\n==== Body\nIntroduction\nCryptogenic organizing pneumonia (COP) is characterized by subacute illness of cough, flulike illness, and dyspnea and classified as one of acute or subacute idiopathic interstitial pneumonias (IIP). COP is discriminated with secondary organizing pneumonia which appears with collagen vascular disease, infection, and drug reaction. Diagnosis of COP can be made in the absence of associated such diseases. The histopathologic pattern is characterized primarily by organizing pneumonia involving alveolar ducts and alveoli with or without bronchial intraluminal polyps. High resolution computerized tomogram (HRCT) findings are nonspecific and usually includes patchy and often migratory consolidation in a subpleural, peribronchial, or band-like pattern1.\n\nMajority of patients recover completely with oral steroids, but some patient dose not respond to long-term use of steroid. Furthermore, relapses after discontinuing of steroid, residual and progressive interstitial fibrosis were observed in small number of patients2. For patients who do not respond to steroid, macrolides (clarithromycin or erythromycin) and cyclosporine A has been used for alternate treatment345. Few reports described treatment failure with clarithromycin in patients with COP who did not respond to steroid.\n\nHerein, we report two cases of COP who showed difference responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin.\n\nCase Report\n1. Case 1\nA 63-year old woman appeared with a 2-month history of aggravating dyspnea on exertion (modified British Medical Research Council, mMRC II). She denied any exposure to chemical agents, know toxin, and dusts. She had no symptoms related with rheumatic and collagen vascular diseases like arthralgia, skin rash, dry mouth, and Raynaud's phenomenon. She was never-smoker and a teacher of kindergarten. Physical examination showed no cyanosis and no fever, tachypnea (24/min), and bilateral inspiratory crackles on both lung fields.\n\nChest radiography showed irregular and patchy air-space consolidations in both lungs, more predominantly seen in basal and peripheral lungs (Figure 1) and HRCT showed peribronchial and subpleural patchy air space consolidation with ground glass attenuation (GGA), mostly located peripheral and lower lung areas (Figure 2). The hemoglobin was 13.1 g/dL, white blood cell count was 8,400/µL (neutrophil, 59.4%; lymphocyte, 27.3%; monocyte, 10.1%; eosinophil, 2.4%; basophil, 0.8%), platelet 264,000/µL, erythrocyte sedimentation rate (ESR) 35 mm/hr, and C-reactive protein 0.40 mg/dL. Arterial blood gas analysis showed pH 7.432, PaCO2 29.9 mm Hg, PaO2 75.7 mm Hg, SaO2 95.7%, and HCO3- 19.5 mmol/L. Pulmonary function test showed a forced vital capacity (FVC) of 1.86L/62% of the predicted value, forced expiratory volume in 1 second (FEV1) 1.44L/66% of the predicted value, FEV1/FVC ratio of 77%, diffusing lung capacity of carbon monoxide (DLCO) of 53% of predicted value, and DLCO/volume of alveolar 80% of predicted value. Cellular analysis of bronchoalveolar lavage (BAL) fluid revealed 55% of macrophages, 15% of neutrophils, and 25% of lymphocytes. No microbiological agents or malignancy were found. Antinuclear antibodies (ANA), anti-double stranded DNA, complement C3, C4, and angiotensin converting enzyme (ACE) were negative or within normal limits. And IgG, IgM, and IgA were all negative. Serology blood tests and other autoimmunity studies did not point any collagen vascular and autoimmune diseases. Echocardiogram showed no abnormal findings with ejection fraction (EF) of 76%.\n\nLung biopsy through video-assisted thoracoscopic surgery (VATS) was performed to differentiate COP, nonspecific interstitial pneumonia (NSIP), and resolving bacterial pneumonia on the third hospital day. Histology of lung biopsy showed anastomosing polypoid plugs of loose connective tissue protruding into the alveolar ducts and spaces. The alveolar walls are mildly thickened and interstitial inflammation is moderate (Figure 3). In addition, the lung tissue obtained by lung biopsy was submitted for cultures and specialized stain to detect organism, but none of tissue cultures and stains were positive.\n\nTherapy was started with prednisolone (PDL, total 50 mg, 1 mg/kg/day) on 13th hospital day. Her symptoms, FVC, and HRCT were worsened after 1-month treatment of PDL. We added cyclophosphamide (total 100 mg, 2 mg/kg/day) for next 1 month together with PDL, but HRCT (Figure 4A), her symptoms, FVC worsened. Clarithromycin 500 mg was added with reduced dose of PDL. Cyclophosphamide was stopped with start with clarithromycin. At three months after treatment with clarithromycin, HRCT (Figure 4B), her symptoms (mMRC I), and FVC (63% of predicted value) much improved. After 6 months of stopping PDL and clarithromycin, she complained no respiratory symptoms, HRCT and FVC (81% of predicted value) became to really normal (Figure 4C).\n\n2. Case 2\nAn 81-year-old woman complained of exertional dyspnea (mMRC II) and general weakness for 2 weeks. She denied any exposure to chemical agents, known toxin, and dusts. She had no symptoms related with rheumatic and collagen vascular diseases like arthralgia, skin rash, dry mouth, and Raynaud's phenomenon. She was never-smoker and a house-wife. Physical examination showed no cyanosis, afebrile, tachypnea (26/min), and bilateral inspiratory crackles on both lung fields.\n\nChest radiography showed peribronchiolar consolidation in bilateral lower lobes and lingular division. Air-bronchogram was observed in lingular division (Figure 5). HRCT showed multifocal areas of subpleural or peribronchial consolidations in both lungs with combined small amount of pleural effusion (Figure 6). The hemoglobin was 13.1 g/dL, white blood cell count 10,800/µL (neutrophil, 73.5%; lymphocyte, 17.3%; monocyte, 6.0%; eosinophil, 2.4%; basophil, 0.8%), platelet 181,000/µL, ESR 45 mm/hr, and C-reactive protein 0.67 mg/dL. Arterial blood gas analysis showed pH 7.454, PaCO2 28.7 mm Hg, PaO2 48.6 mm Hg, SaO2 86.9%, and HCO3- 19.7 mmol/L. Pulmonary function test showed a FVC of 1.19 L/63% of the predicted value, FEV1 1.03 L/85% of the predicted value, and FEV1/FVC ratio of 87%. Cellular analysis of BAL fluid revealed 50% of macrophages, 17% of neutrophils, and 26% of lymphocytes. No microbiological agents or malignancy were found. ANA, anti-double stranded DNA, complement C3, C4, and ACE were negative or within normal limits. And IgG, IgM, and IgA were all negative. Serology blood tests and other autoimmunity studies did not point any collagen vascular and autoimmune diseases.\n\nThe differential diagnosis included IIP such as NSIP and COP, bacterial pneumonia, and heart failure. Echocardiogram showed no abnormal findings with EF of 79%. We decided to perform surgical lung biopsy to know exact diagnosis in spite of relatively old age. VATS was performed on the seventh hospital day. Histology of lung biopsy showed polypoid plugs of loose organizing connective tissue within respiratory bronchioles, alveolar ducts and spaces. The alveolar walls are mildly thickened and interstitial inflammation is relatively mild. These findings suggested COP (Figure 7). In addition, the lung tissue obtained by lung biopsy was submitted for cultures and specialized stain to detect organism, but none of tissue cultures and stains were positive.\n\nTherapy was started with PDL (total 50 mg, 1 mg/kg/day) on 14th hospital day. Her exertional dyspnea was not changed, but FVC was decreased to 60% after 2 months treatment of PDL. We added cyclophosphamide (total 100 mg, 2 mg/kg/day) for next 1 month together with PDL, but her symptoms (mMRC II), FVC (58% of predicted value) were not improved. HRCT showed still consolidation and GGA (Figure 8A). Clarithromycin 500 mg was added with reduced dose of PDL and cyclophosphamide was stopped. At 3 months after treatment with clarithromycin, her symptoms (mMRC II) and FVC (57% of predicted value) still were not improved and HRCT showed no change of consolidation and GGA (Figure 8B). At 6 months after discontinuing of medication, her symptoms (mMRC II) and FVC (55% of predicted value) were not improved. Her HRCT showed still GGA and fibrotic changes (Figure 8C).\n\nDiscussion\nIn the present study, we showed clarithromycin-responsive and -resistant patients with COP who refractory to steroid. Generally, steroid in COP showed rapid resolution within several days or a few weeks and dramatic effect of majority patients. But, both of patients were not response to steroid 2 or 3 months, thus we used alternative therapy, macrolides.\n\nThe failure of treatment with clarithromycin was rarely reported. Almost all reports described good response to clarithromycin in patients with COP4567. Therefore we believe clarithromycin is good alternative drugs without failure in treatment of COP. Radzikowska et al.8 reported that the response rate of clarithromycin was 75% in 12 patients with organizing pneumonia; however, the population of patients in this study was mixed with COP and secondary organizing pneumonia (OP). One patient failed to respond to intravenous erythromycin, but the duration of treatment was only 3 days9. Therefore, we don't know yet the failure rate of macrolides in the treatment of COP.\n\nThe mechanism of macrolides in the treatment of COP is anti-inflammatory effects rather than antibiotic effects. Although the underlying mechanisms of anti-inflammatory effects are unknown, in vitro and in vivo studies suggest anti-inflammatory effects of macrolides may be related with the effect on polymorphonuclear cells and their products but also effect on T cells. Erythromycin decrease the number of neutrophils and the neutrophil-derived elastolytic-like activity in BAL fluid decreased significantly after treatment with erythromycin in patients with bronchiolitis10. Macrolides treatment for 1-24 months significantly reduced BAL fluid levels of interleukin (IL) 1β and IL-8 in parallel with BAL fluid neutrophils in patients with diffuse panbronchiolitis11. Furthermore, erythromycin decreased significantly the number of neutrophils recovered from lungs of mice responding to bacterial challenge12. Erythromycin was capable of inhibiting expression of the IL-8 genes in T cells through transcriptional inhibition13. In the presents cases, the level of neutrophils and lymphocyte in BAL fluid were not different between clarithromycin- responsive (case 1) and -nonresponsive (case 2) cases. These findings suggested the level of neutrophils and lymphocytes do not affect the response to clarithromycin, although only two cases were analyzed.\n\nThe discrepancy between cellular profiles in BAL fluid and histologic finding of lung biopsy was found in present cases. The level of neutrophils in BAL fluid was 13% and 15% in case 1 and 2, respectively, but, neutrophils in histology of lung biopsy were not observed as the level of BAL finding. This discrepancy may be explained by proximal bronchial airway obstruction preventing normal saline reaching diseased lung during BAL procedure.\n\nCohen et al.14 reported OP with rapidly progressive clinical course and poor outcome. The majority of these patients had secondary OP associated with autoimmune disorders. This finding suggested the presence of autoimmune and connective tissue disorders were important predictor of rapidly progressive OP. However, also, in case of COP, rapidly progressive and fatal patients were reported9. In our cases, both patients did not show any evidences of associated diseases.\n\nThe duration of macrolides in patients with COP was unknown yet. However, the majority of cases were successfully treated more than 3 months of macrolides without relapse347. One case of patient showed relapse of COP after a 3-week course was discontinued7, and the other case showed no improvement of clinical condition9. These finding suggested long-term use more than three months of macrolides are needed for treatment and prevention of relapse. In our cases, case 1 showed significant clinical improvement after 3-month course of medication and no relapse after discontinuation, but case 2 showed no clinical responses in spite of 3 months of clarithromycin. Further studies are needed to decide when we should stop macrolides in case of no-responsive to these drugs.\n\nLaboratory abnormalities, such as severe anemia (Hb less than 11 g/dL), high ESR (more than 60 mm/hr), and low serum albumin (less than 3.5 g/dL) could be associated with worse prognosis in 61 patients with COP and secondary OP1. And paucity of lymphocytes in BAL fluid was suggested as a risk factor for relapse. In present case, case 2 showed no abnormalities in anemia, ESR, and albumin level, and also lymphocytes in BAL fluid were similar level as case 1. Therefore, case 2 showed no risk factor for worsening of COP.\n\nGenerally, the disease severity of idiopathic pulmonary fibrosis is assessed on the basis of symptoms, pulmonary function test, and radiologic findings15. We applied these parameters to response to treatment in both two cases. We regarded improvement of disease in case of at least two of the above three parameters improved. In case 1, after use of clarithromycin showed improvement of every parameter, FVC, mMRC, and HRCT (Figure 4). But, in case 2, any drugs could not improve these parameters (Figure 8).\n\nThere is remarkable point that the age of the two patients was quite different. So, we suggest that age of patient may affect the results because of both patient's underlying immunological condition, lung biopsy setting, HRCT, initial FVC, and mMRC were similar.\n\nIn conclusion, we herein report clarithromycin-responsive and -resistant patients with COP who refractory to steroid. This clarithromycin-resistant case indicates that there is a need to evaluate the failure rate of macrolides including clarithromycin in treatment of COP.\n\nAcknowledgements\nThis study was supported by the Soonchunhyang University Research Fund.\n\nConflicts of Interest: No potential conflict of interest relevant to this article was reported.\n\nFigure 1 Chest posterior-anterior (A) and left lateral (B) X-ray showed irregular and patchy air-space consolidations in both lungs, more predominantly seen in the basal and peripheral lungs.\nFigure 2 (A-D) High resolution computerized chest tomogram showed peri bronchial and subpleural patchy air space consolidation with ground-glass att enuation, mostly located at the peripheral and lower lung areas.\nFigure 3 Microscopic examination shows anastomosing polypoid plugs of loose connective tissue protruding into the alveolar ducts and spaces. The alveolar walls are mildly thickened and interstitial inflammation is moderate (H&E stain, ×100).\nFigure 4 Summary of treatment agents, clinical course, and radiologic findings. High resolution chest computerized tomogram of a case that worsened after 2 months treatment of prednisolone and 1-month treatment of cyclophosphamide (A), and improved with 3 months treatment with clarithromycin (B). High resolution computerized tomogram, lung function tests, and dyspnea improved 6 months after ceasing administration of clarithromycin (C). PDL: prednisolone; Cyclo: cyclophosphamide; Clarith: clarithromycin; FVC: forced vital capacity; DLco: diffusion capacity of lung; mMRC: modified British Medical Research Council.\nFigure 5 Chest posterior-anterior showed peribronchiolar consolidation in the bilateral lower lobes and lingular division. Airbronchogram was observed in the lingular division.\nFigure 6 (A-D) High resolution computerized chest tomogram showed multifocal areas of subpleural or peribronchial consolidations in both lungs with a combined small amount of pleural effusion.\nFigure 7 Microscopic examination shows polypoid plugs of loose organizing connective tissue within respiratory bronchioles, alveolar ducts and spaces. The alveolar walls are mildly thickened and the interstitial inflammation is relatively mild.\nFigure 8 Summary of treatment agents, clinical course, and radiologic findings. High resolution chest computerized tomogram (HRCT) of a case that was improved in consolidations, but still with consolidation and ground glass attenuation (GGA) were observed after 3 months treatment of predniolone and 1-month treatment of clarithromycin (A). After three months treatment with clarithromycin, HRCT showed no change in consolidation and GGA (B). Six months after ceasing administration of clarithromycin, HRCT showed fibrotic change in both lung fields (C). PDL: prednisolone; Cyclo: cyclophosphamide; Clarith: clarithromycin; FVC: forced vital capacity; mMRC: modified British Medical Research Council.\n==== Refs\n1 Drakopanagiotakis F Paschalaki K Abu-Hijleh M Aswad B Karagianidis N Kastanakis E Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis Chest 2011 139 893 900 20724743 \n2 Yousem SA Lohr RH Colby TV Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors Mod Pathol 1997 10 864 871 9310948 \n3 Chang WJ Lee EJ Lee SY In KH Kim CH Kim HK Successful salvage treatment of steroid-refractory bronchiolar COP with low-dose macrolides Pathol Int 2012 62 144 148 22243785 \n4 Ichikawa Y Ninomiya H Katsuki M Hotta M Tanaka M Oizumi K Low-dose/long-term erythromycin for treatment of bronchiolitis obliterans organizing pneumonia (BOOP) Kurume Med J 1993 40 65 67 8231065 \n5 Lee J Cha SI Park TI Park JY Jung TH Kim CH Adjunctive effects of cyclosporine and macrolide in rapidly progressive cryptogenic organizing pneumonia with no prompt response to steroid Intern Med 2011 50 475 479 21372463 \n6 Adibelli Z Dilek M Kocak B Tulek N Uzun O Akpolat T An unusual presentation of sirolimus associated cough in a renal transplant recipient Transplant Proc 2007 39 3463 3464 18089408 \n7 Stover DE Mangino D Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia? Chest 2005 128 3611 3617 16304320 \n8 Radzikowska E Wiatr E Gawryluk D Langfort R Bestry I Chabowski M Organizing pneumonia: clarithromycin treatment Pneumonol Alergol Pol 2008 76 334 339 19003763 \n9 Nizami IY Kissner DG Visscher DW Dubaybo BA Idiopathic bronchiolitis obliterans with organizing pneumonia: an acute and life-threatening syndrome Chest 1995 108 271 277 7606970 \n10 Ichikawa Y Ninomiya H Koga H Tanaka M Kinoshita M Tokunaga N Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients Am Rev Respir Dis 1992 146 196 203 1626803 \n11 Sakito O Kadota J Kohno S Abe K Shirai R Hara K Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy Respiration 1996 63 42 48 8833992 \n12 Nelson S Summer WR Terry PB Warr GA Jakab GJ Erythromycin-induced suppression of pulmonary antibacterial defenses: a potential mechanism of superinfection in the lung Am Rev Respir Dis 1987 136 1207 1212 3314615 \n13 Aoki Y Kao PN Erythromycin inhibits transcriptional activation of NF-kappaB, but not NFAT, through calcineurin-independent signaling in T cells Antimicrob Agents Chemother 1999 43 2678 2684 10543746 \n14 Cohen AJ King TE Jr Downey GP Rapidly progressive bronchiolitis obliterans with organizing pneumonia Am J Respir Crit Care Med 1994 149 1670 1675 8004328 \n15 Raghu G Collard HR Egan JJ Martinez FJ Behr J Brown KK An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management Am J Respir Crit Care Med 2011 183 788 824 21471066\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-3536",
"issue": "78(4)",
"journal": "Tuberculosis and respiratory diseases",
"keywords": "Adrenal Cortex Hormones; Clarithromycin; Cryptogenic Organizing Pneumonia; Macrolides",
"medline_ta": "Tuberc Respir Dis (Seoul)",
"mesh_terms": null,
"nlm_unique_id": "101479418",
"other_id": null,
"pages": "401-7",
"pmc": null,
"pmid": "26508933",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "8833992;19003763;10543746;22243785;8004328;21372463;8231065;16304320;21471066;20724743;7606970;1626803;9310948;3314615;18089408",
"title": "Different Responses to Clarithromycin in Patients with Cryptogenic Organizing Pneumonia.",
"title_normalized": "different responses to clarithromycin in patients with cryptogenic organizing pneumonia"
} | [
{
"companynumb": "KR-BAUSCH-BL-2016-018409",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
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