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{
"abstract": "OBJECTIVE\nPericardial effusion with cardiac tamponade is an uncommon metastatic manifestation of ovarian tumors, with only one previously reported case involving a borderline ovarian tumor (BOT).\n\n\nMETHODS\nA 50-year-old woman was diagnosed and treated for a primary Stage IIc BOT. The disease recurred as an emergency pericardiocentesis eight years later, which was resected following pericardial effusion with a cardiac tamponade. This occurred two more times, and on the last occasion, drainage failed to relieve her symptoms. However, her symptoms resolved after the creation of a pericardium pleural window together with a pericardiectomy.\n\n\nCONCLUSIONS\nFor patients with a metastatic BOT, the creation of a pericardium pleural window and pericardiectomy is effective for recurrent pericardial tamponade, if the pericardial space is posteriorly located and/or segmented.",
"affiliations": null,
"authors": "Tanaka|Y|Y|;Amano|T|T|;Suzuki|T|T|;Kaku|S|S|;Tsuji|S|S|;Kimura|F|F|;Murakami|T|T|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-2936",
"issue": "38(3)",
"journal": "European journal of gynaecological oncology",
"keywords": null,
"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D002305:Cardiac Tamponade; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D010492:Pericardiectomy; D010496:Pericardium; D012008:Recurrence",
"nlm_unique_id": "8100357",
"other_id": null,
"pages": "473-475",
"pmc": null,
"pmid": "29693896",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pericardiectomy and pericardium window creation to treat recurrent pericardial tamponade involving a borderline ovarian tumor.",
"title_normalized": "pericardiectomy and pericardium window creation to treat recurrent pericardial tamponade involving a borderline ovarian tumor"
} | [
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"companynumb": "JP-CIPLA LTD.-2017JP31032",
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"abstract": "Cryptococcosis is a fungal disease which has been characterized by its identified risk groups. There are many risk factors identified. We present a surprising four cases of disseminated cryptococcosis in intravenous drug abuse (IVDA) patients in a short period of time and in one geographical area, this observation suggest that there may be a new association with IVDA and cryptococosis.",
"affiliations": "Department of Medicine/Division of Infectious Diseases, Marshall University, Huntington, WV, USA; Department of Medicine/Division of Infectious Diseases, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA.;Cabell Huntington Hospital, Huntington, WV, USA.;Department of Medicine/Division of Infectious Diseases, Marshall University, Huntington, WV, USA.;Department of Medicine/Division of Infectious Diseases, Duke University, Durham, NC, USA.",
"authors": "Shorman|Mahmoud|M|;Evans|Derek|D|;Gibson|Christy|C|;Perfect|John|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2016.12.003",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30058-610.1016/j.mmcr.2016.12.003Case ReportCases of disseminated cryptococcosis in intravenous drug abusers without HIV infection: A new risk factor? Shorman Mahmoud ab⁎Evans Derek cGibson Christy aPerfect John da Department of Medicine/Division of Infectious Diseases, Marshall University, Huntington, WV, USAb Department of Medicine/Division of Infectious Diseases, University of Tennessee Graduate School of Medicine, Knoxville, TN, USAc Cabell Huntington Hospital, Huntington, WV, USAd Department of Medicine/Division of Infectious Diseases, Duke University, Durham, NC, USA⁎ Corresponding author at: Department of Medicine/Division of Infectious Diseases,University of Tennessee Graduate School of Medicine, Knoxville, TN, USA.02 12 2016 12 2016 02 12 2016 14 17 19 11 11 2016 28 11 2016 1 12 2016 © 2016 International Society for Human and Animal Mycology2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cryptococcosis is a fungal disease which has been characterized by its identified risk groups. There are many risk factors identified. We present a surprising four cases of disseminated cryptococcosis in intravenous drug abuse (IVDA) patients in a short period of time and in one geographical area, this observation suggest that there may be a new association with IVDA and cryptococosis.\n\nKeywords\nDisseminated cryptococcosisIVDUMeningitis\n==== Body\n1 Introduction\nCryptococcosis is a fungal disease which has been characterized by its identified risk groups. The “awakening giant” of invasive mycoses has been ushered to a front-seat of attention in medical mycology by the appearance of the HIV pandemic, transplantation growth and the use of corticosteroids for specific underlying diseases. With these risk factors the incidence of Cryptococcosis has been estimated at over 500,000 cases per year. There are other niche risk factors such as hematological malignancies, sarcoidosis, liver disease, biological immune modulators such as anti-TNF therapies and other T-cell antibodies, and possibly even diabetes/COPD. However, Cryptococcus can even produce disease in apparently normal hosts although this group is shrinking with the risk identification of CD4 lymphocytopenia and anti- GM-CSF antibodies in these hosts without apparent underlying diseases. On the other hand, generally the normal host may be exposed to cryptococcus and develops infection but not disease. Thus, clinicians are always attempting to identify and/or understand the underlying host disease or condition when disseminated cryptococcosis is diagnosed.\n\nIn this report, we present a surprising four cases of disseminated cryptococcosis in intravenous drug abuse (IVDA) patients in a short period of time and in one geographical area. IVDA as a risk factor for cryptococcosis has been previously linked to infection with HIV but only rarely has a IVDA patient who is HIV- negative been reported to have disseminated cryptococcosis [1] but the following are cases of a small outbreak of cryptococcosis in patients linked by their IVDA and this observation suggest that there may be a new association with IVDA and cryptococosis not linked to HIV infection.\n\n2 Case reports (Synopsis in Table)\n2.1 Case #1\nA 45year old male with past medical history of HCV, nicotine abuse, alcohol abuse, and IV heroin abuse for 15 years presented to our hospital via Emergency Medical Services (EMS) in June 2016 (at day 0) with a suspected drug overdose. Patient was given naloxone in the ER. A CT of head without contrast showed no acute findings and his chest X-ray showed no acute findings. AN EEG was unrevealing for seizures. Initially, he had a temperature as high as 100.8, blood cultures x2 were negative. He continued with altered mental status and an MRI of the brain with contrast showed extensive flair and enhancement with patchy areas of diffuse and leptomeningeal enhancement of left parietal lobe. He next underwent lumbar puncture (LP). Fluid was clear non-xanthochronic. WBC 138 mm−3, neutrophils 3%, monocytes 13%, lymphocytes 84%, RBC 20 mm−3, glucose 30 mg/dl, protein 66 mg/dl. Gram stain showed no organisms all on day zero. A Meningitis PCR Panel was positive for Cryptococcus neoformans/gattii and the yeast also grew on the aerobic bacterial culture on day +2. A serum cryptococcal antigen was positive and he was started on ambisome 450 mg intravenous (IV) daily and flucytosine 1500 mg per mouth (PO) every 6 h, he improved and was transferred to another facility for the remainder of his care (Table 1).\n\n2.2 Case #2\nA 54 year old male with past medical history of chronic low back pain, osteoarthritis, nicotine dependence, polysubstance abuse and IVDA, osteoarthritis, diabetes with neuropathy, presented to our hospital in March 2015 (day 0) with a 6–8 week history of worsening ataxia, recent falls, confusion and lethargy at home. He was evaluated initially by neurosurgery who recommended anterior cervical decompression and fusion at a later date due to his sleep apnea. He was afebrile on day zero. CT of his head without contrast showed no acute findings. Two blood cultures obtained from his right hand and arm grew coagulase-negative staphylococcus and one grew Cryptococcus neoformans at +3 day. Initially, he was placed on intravenous fluconazole then changed to ambisome and flucytosine. LP tried but could not be performed due to body habitus initially. Blood cultures were consistently positive for Cryptococcus neoformans on +2, +3, +4 days. He then underwent CT-guided LP on +5 d. No opening pressure recorded, cell counts: WBC 33 mm−3, neutrophils 15%, monocytes 5%, lymphocytes 80%, RBC 18 mm−3, glucose 24 mg/dl, protein 45 mg/dl. CSF culture grew Cryptococcus neoformans. HIV and HCV antibody were negative. CD4 count was 1028 mm−3. ANA and ANCA panel were both negative. Serum cryptococcus antigen was positive on day +2. He had a prolonged hospital course that was complicated by septic shock and acute respiratory failure due to acute cholecystitis on day +14. He completed 6 weeks of ambisome 450 mg IV daily, as could not tolerate flucytosine due to side effects, followed by high dose consolidation with fluconazole 800 mg po orally for 8 weeks then lower dose fluconazole 200 mg daily as a maintenance dose. He was last seen at month + eight of his treatment doing well.\n\n2.3 Case #3\nA 29 year- old male with past medical history of HCV, IVDA presented with altered mental status in July 2015 (day 0). His day zero MRI of the brain showed an atypical PRES pattern of edema. CT findings showed worsening hydrocephalus, cerebellar- tonsillar protrusion through the foramen magnum and compression of the fourth ventricle. Day +1 CTA of head and neck showed vasculitis and findings in posterior temporal lobe suggestive of encephalitis. He did not have a LP due to concern for herniation. He was seen by neurosurgery team who performed a biopsy of the brain on day +5 which showed yeasts consistent with cryptococcus. His biopsy cultures were negative. However, the serum cryptococcal antigen was positive. He was started initially on ambisome 400 mg iv daily for 2 weeks then changed to fluconazole 1000 mg po daily for 2 months with improvement. He was HIV negative, and CD4 cell count was 486 mm−3. He was then lost to follow up.\n\n2.4 Case #4\nA 39 year old male with past medical history of IVDA, HCV, aseptic meningitis two years prior to presentation, and a cerebral aneurysm status/post clipping, presented to the ER in November 2015 (day 0) with complaints of a 3-week history of progressively worsening headaches, pain in his lower extremities and inability to move his lower extremities. Cervical spine MRI showed extensive vertebral lesions from C2-T3 that were intramedullary and did not enhance. Initial LP performed and showed: WBC 556 mm−3, neutrophils 3%, monocytes 64%, lymphocytes 21%, macrophages 12%, RBC 117 mm−3, glucose 12 mg/dl, protein 1582 mg/dl. CSF culture was negative; Meningitis PCR Panel was negative; AFB smear was negative. He was started empirically on tuberculosis treatment for history of untreated latent tuberculosis. He was given corticosteroids per neurology and was undergoing plasmapheresis for transverse myelitis. Persistent ongoing weakness required another LP obtained on +8 day and cell count was WBC 97 mm−3, neutrophils 14%, monocytes 4%, lymphocytes 82%, RBC 1 mm−3glucose 1 mg/dl protein 544 mg/dl. CSF culture grew Cryptococcus neoformans. HIV test was negative. He was started on ambisome 370 mg IV daily and flucytosine 1500 mg po every 6 h for 4 weeks with improvement. Patient was lost to follow up after that.\n\n3 Discussion\nInfections due to Cryptococcus species occur worldwide with Cryptococcus neoformans being associated with the majority of the cases. Cryptococcus enters the host primarily through the respiratory tract, where it is usually contained by the host immune responses [2], [3].\n\nHowever, Cryptococcus is an encapsulated yeast that can mitigate antibody responsiveness and cell-mediated immunity allowing it to accumulate in tissue, especially in those who are immunocompromised [3], [4]. This encapsulated yeast began to emerge as a significant opportunistic pathogen with the development of immunosuppressive agents used for organ transplantation and the treatment of malignancies [5]. The incidence of cryptococcal disease significantly rose with the HIV/AIDS pandemic and this viral infection has contributed to more than 80% of cryptococcosis cases globally [2].\n\nDisseminated disease in immunocompetent patients is uncommon. However, in this case series, we have identified four cases of disseminated cryptococcosis in IVDA patients without HIV infection in the same geographical area within a 7 month time period. These cases occurred within a 60 mile range of each other in West Virginia. None of the patients in these cases were found to have any apparent underlying immunodeficiency condition or were receiving immunosuppressive therapy at presentation. The cases that we describe in this report are potentially linked to IVDA as a risk factor for disseminated cryptococcosis and might be considered an outbreak but this fungal infection is not a reportable CDC event so general prevalence of cryptococcosis in this area is not known. Interestingly and of uncertain importance all patients were HCV positive. Unfortunately, the identification of this small outbreak occurred after the ability to do detailed epidemiological studies. Thus, no specific link to a common source injectable material or practices could be obtained.\n\nCases of cryptococcal meningitis have been reported in immunocompetent non-HIV infected IVDA patients; however, the number of published individual cases is very limited [6], [7]. It is uncertain how disseminated cryptococcal disease might develop in this patient population. However, methamphetamine has been shown to promote dissemination of cryptococcus from the respiratory tract into the brain parenchyma in animal models [3]. Methamphetamine facilitates this process by acting as an immunosuppressive agent through altering phagocytosis and antigen processing by inhibition of endosomal acidification [3], [4], [8]. Furthermore, methamphetamine accumulation in the lungs can results in defects in macrophages and neutrophils creating conditions more likely to result in disease [3], [8]. For instance, adhesion of cryptococcus to lung tissue in the presence of methamphetamines stimulates the excessive release of glucuronoxylomannan (GXM) and biofilm formation thereby predicting the facilitation of dissemination to the central nervous system (CNS) [3].\n\nOn the other hand, given the time range, location of these case reports, and the amount of heroin abuse in this region, one must consider the potential for drug-related contamination. Outbreaks of disseminated candidiasis have been reported in IVDA who were using brown heroin. These outbreaks were attributed to contamination of the lemon juice used to dissolve the heroin. [1].\n\nThere has also been reports of the immune stimulant, levamisole, being used in heroin and possibly, it could have immune dysregulation potential. In our cases associated with heroin abuse, it is unknown what was used to dissolve the heroin or what it was cut with, or how it had been stored. As a result, the potential for contaminated drugs could not be excluded as a source of these cases of cryptococcal meningitis in this retrospective review [9].\n\nIn summary, this apparent small outbreak of cryptococcosis in IVDA should be noted and clinicians may consider it a potential risk factor for cryptococcosis even if patient is HIV-negative and allow for earlier work-ups for CNS fungal disease. Unfortunately, the retrospective nature of these cases did not allow for detailed epidemiologic enquires of each case as the microbiology laboratory did not save the isolated cryptococcus, but should provide stimulus for future cases in IVDA to consider what may have been injected to allow this fungus to grow and disseminate in the host.\n\nConflict of interest\nAuthors declare no conflict of interest.\n\nTable 1 synopsis of the four cases of disseminated cryptococcal infection.\n\nTable 1Age\t45\t54\t29\t39\t\nDrug Use\tIV heroin, alcohol abuse\tpolysubstance abuse, IVDA\tIVDA with suboxone and opiates\tIVDA with heroin\t\nMRI/CT findings\tCT Head without contrast showed no acute. MRI with contrast showed extensive flair and enhancement with patchy areas of diffuse and leptomeningeal enhancement of left parietal lobe\tCT Head without showed no acute findings.\tMRI of brain showed atypical PRES pattern of edema. CT head showed worsening hydrocephalus, cerebellar tonsillar protrusion through foramen magnum and compression of 4th ventricle\tCervical spine MRI showed extensive lesion from C2-T3 that was intramedullary and did not enhance.\t\nCell Count on presentation\tWBC 6500 RBC 20 Neutrophils 3 Monocytes 13 Lymphocytes 84 Glucose 30 Protein 66\tWBC 33 RBC 18 Neutrophils 15 Monocytes 5 Lymphocytes 80 Glucose 24 Protein 45\tNo LP as concern for herniation\tWBC 556 RBC 117 Neutophils 14 Monocytes 64 Lymphocytes 82 Macrophages 12 Glucose 12 Protein 1582\t\nSerum Cryptocococcus Ag\tpositive\tpositive\tpositive\tn/a\t\nSerum Cryptococcus Ag Titer\t1:160\t1:20\t1:5\tn/a\t\nCryptococcus Ag CSF\tpositive\tpositive\tnegative\tpositive\t\nCrytpococcus Ag Titer CSF\t1:2560\t1:280\tn/a\t>1:5120\t\nHIV result\tnegative\tnegative\tnegative\tnegative\t\nHCV result\tpositive\tpositive\tpositive\tpositive\t\nTiming of onset of sx prior to hospital\tunknown, presented as overdose\tataxia 6–8 months\theadache over 1 week\theadache over 3 weeks\n==== Refs\nReferences\n1 Bisbe J. Miro J.M. Latorre X. Disseminated candidiasis in addicts who use brown heroin: report of 83 cases and review Clin. Infect. Dis. 15 6 1992 910 923 1457662 \n2 Maziarz E.K. Perfect J.R. Cryptococcosis Infect. Dis. Clin. N. Am. 30 1 2016 179 206 \n3 Patel D. Desai G.M. Frases S. Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain MBio 4 2013 4 \n4 O’Meara T.R. Alspaugh J.A. The Cryptococcus neoformans capsule: a sword and a shield Clin. Microbiol. Rev. 25 3 2012 387 408 22763631 \n5 Perfect J.R. Bicanic T. Cryptococcosis diagnosis and treatment: what do we know now Fungal Genet. Biol. 78 2015 49 54 25312862 \n6 Monno L. Angarano G. Montagna M.T. Coppola S. Carbonara S. Bellisario A. Chronic cryptococcal meningitis in an intravenous drug addict without evidence of infection by HIV-1,2 in southern Italy Eur. J. Epidemiol. 10 6 1994 773 774 7672062 \n7 Nerín Sánchez C. Hermida Lazcano I. Martínez Alvarez R. Arazo Garcés P. Figueras Villalba P. Aguirre Errasti J.M. Cryptococcal meningitis in an intravenous drug abuse HIV negative person An. Med. Interna 14 5 1997 264 265 9235107 \n8 Tallóczy Z. Martinez J. Joset D. Methamphetamine inhibits antigen processing, presentation, and phagocytosis PLoS Pathog. 4 2 2008 e28 18282092 \n9 Vagi S.J. Sheikh S. Brackney M. Smolinske S. Warrick B. Reuter N. Schier J.G. Passive multistate surveillance for neutropenia after use of cocaine or heroin possibly contaminated with levamisole Ann. Emerg. Med. 61 4 2013 468 474 23374417\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "14()",
"journal": "Medical mycology case reports",
"keywords": "Disseminated cryptococcosis; IVDU; Meningitis",
"medline_ta": "Med Mycol Case Rep",
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"nlm_unique_id": "101598259",
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"pages": "17-19",
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"pmid": "27995054",
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"publication_types": "D016428:Journal Article",
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"title": "Cases of disseminated cryptococcosis in intravenous drug abusers without HIV infection: A new risk factor?",
"title_normalized": "cases of disseminated cryptococcosis in intravenous drug abusers without hiv infection a new risk factor"
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"abstract": "Aneurysmal degeneration after peripheral angioplasty is a potentially serious complication. In this case, the patient underwent repeated angioplasty of a prior vein bypass graft utilizing a paclitaxel-coated balloon. He subsequently developed a progressive aneurysmal degeneration, threatening his bypass, which ultimately required an urgent exclusion with a covered stent. This case represents a rare complication of peripheral bypass graft related to percutaneous intervention as well as paclitaxel-coated devices and warns other practitioners of the increased scrutiny and caution one should exercise in the use of such interventions.",
"affiliations": "Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.;Division of Vascular and Endovascular Surgery, Department of Surgery, 22165University of Arizona, Tucson, AZ, USA.",
"authors": "Chen|Winsor|W|https://orcid.org/0000-0003-1007-1729;Dyniewski|Brad|B|;Bobka|Thomas|T|;Kraemer|Codyjo|C|;Tan|Tze-Woei|TW|;Zhou|Wei|W|",
"chemical_list": "D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1177/1538574420978104",
"fulltext": null,
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"issn_linking": "1538-5744",
"issue": "55(4)",
"journal": "Vascular and endovascular surgery",
"keywords": "aneurysm/aneurysmal; complication(s); drug-coated balloon (DCB); drug-eluting balloon (DEB); paclitaxel",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D000368:Aged; D000783:Aneurysm; D000800:Angioplasty, Balloon; D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; D006083:Graft Occlusion, Vascular; D006801:Humans; D008297:Male; D017239:Paclitaxel; D058729:Peripheral Arterial Disease; D016896:Treatment Outcome; D062666:Vascular Access Devices; D058017:Vascular Grafting",
"nlm_unique_id": "101136421",
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"pages": "410-414",
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"publication_types": "D002363:Case Reports",
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"title": "Aneurysmal Degeneration After Paclitaxel-Eluting Balloon Angioplasty.",
"title_normalized": "aneurysmal degeneration after paclitaxel eluting balloon angioplasty"
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"abstract": "Synthetic stimulants are the largest class of novel psychoactive substances identified each year by forensic laboratories internationally. While hundreds of these drugs appear in drug powders, only a few proliferate in use among forensically relevant populations and eventually emerge in postmortem and clinical investigations. Beta-keto-methylenedioxyamphetamines (i.e., novel psychoactive substances with names ending in \"ylone\") are currently the most popular subclass of synthetic stimulants. Leading up to its federal scheduling in 2018, N-ethyl pentylone was the most encountered synthetic stimulant. The popularity of N-ethyl pentylone declined once it was scheduled, but it was quickly replaced by eutylone (bk-EBDB), a structurally related analog from the same family. In cases encountered between January 2019 and April 2020, eutylone was quantitatively confirmed in 83 forensic investigations, including postmortem cases and driving under the influence of drugs cases. Matrix types included blood, urine and tissue. Eutylone was identified in cases submitted from 13 states, demonstrating proliferation around the United States; Florida accounted for 60% of the positive cases. The mean concentration of eutylone in postmortem blood was 1,020 ng/mL (standard deviation = ±2,242 ng/mL; median = 110 ng/mL, range = 1.2-11,000 ng/mL, n = 67). The mean concentration of eutylone in blood from driving under the influence of drugs cases was 942 ng/mL (standard deviation = ±1,407 ng/mL; median = 140 ng/mL, range = 17-3,600 ng/mL, n = 7). This report includes cause and manner of death data for 22 postmortem cases. Further analysis of authentic human specimens revealed the presence of three eutylone metabolites, including one unique biomarker and one metabolite in common with butylone. Laboratories should be aware that eutylone may be present in cases of suspected Ecstasy, \"Molly\" and/or methylenedioxymethamphetamine use, causing or contributing to impairment or death.",
"affiliations": "Center for Forensic Science Research and Education at the Fredric Rieders Family Foundation, Willow Grove, PA 19090, USA.;NMS Labs, Toxicology Department, Horsham, PA 19044, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.;NMS Labs, Toxicology Department, Horsham, PA 19044, USA.;Department of Chemistry, Biochemistry and Physics, University of Tampa, Tampa, FL 33606, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.;NMS Labs, Toxicology Department, Horsham, PA 19044, USA.",
"authors": "Krotulski|Alex J|AJ|;Papsun|Donna M|DM|;Chronister|Chris W|CW|;Homan|Joseph|J|;Crosby|Michele M|MM|;Hoyer|Jennifer|J|;Goldberger|Bruce A|BA|;Logan|Barry K|BK|",
"chemical_list": "D000697:Central Nervous System Stimulants; D013287:Illicit Drugs; D000076742:Synthetic Drugs; D018817:N-Methyl-3,4-methylenedioxyamphetamine",
"country": "England",
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"mesh_terms": "D001334:Automobile Driving; D001344:Autopsy; D000697:Central Nervous System Stimulants; D002853:Chromatography, Liquid; D005431:Florida; D053593:Forensic Toxicology; D006801:Humans; D013287:Illicit Drugs; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D015813:Substance Abuse Detection; D000076742:Synthetic Drugs; D053719:Tandem Mass Spectrometry",
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"pubdate": "2021-02-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Eutylone Intoxications-An Emerging Synthetic Stimulant in Forensic Investigations.",
"title_normalized": "eutylone intoxications an emerging synthetic stimulant in forensic investigations"
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{
"abstract": "Acute vanishing bile duct syndrome, a rare but rapidly progressive destruction of the intrahepatic bile ducts with unknown pathogenesis, is most often a drug- or toxin-related. Toxic epidermal necrolysis is a serious dermatologic condition and a potentially life threatening disease, which is drug or infection induced. Ibuprofen associated acute vanishing bile duct syndrome and toxic epidermal necrolysis have not been reported previously in infants. We report a 7-month-old infant with ibuprofen associated toxic epidermal necrolysis, followed by severe and rapidly progressive vanishing bile duct syndrome. She recovered totally with supportive care.",
"affiliations": "Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea. ; Medical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea.;Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea. ; Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea.;Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea. ; Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea.",
"authors": "Kim|Hye-young|HY|;Yang|Hea Kyoung|HK|;Kim|Seong Heon|SH|;Park|Jae Hong|JH|",
"chemical_list": "D007052:Ibuprofen",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2014.55.3.834",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2471915610.3349/ymj.2014.55.3.834Case ReportPediatricsIbuprofen Associated Acute Vanishing Bile Duct Syndrome and Toxic Epidermal Necrolysis in an Infant Kim Hye-young 12Yang Hea Kyoung 1Kim Seong Heon 13Park Jae Hong 131 Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea.2 Medical Research Institute, Pusan National University Hospital, Busan, Korea.3 Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea.\nCorresponding author: Dr. Jae Hong Park, Department of Pediatircs, Pusan National University College of Medicine, Pusan National University Children's Hospital, 20 Geumo-ro, Yangsan 626-770, Korea. Tel: 82-55-360-2180, Fax: 82-55-360-2181, jhongpark@pusan.ac.kr01 5 2014 01 4 2014 55 3 834 837 26 4 2013 17 6 2013 31 7 2013 © Copyright: Yonsei University College of Medicine 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute vanishing bile duct syndrome, a rare but rapidly progressive destruction of the intrahepatic bile ducts with unknown pathogenesis, is most often a drug- or toxin-related. Toxic epidermal necrolysis is a serious dermatologic condition and a potentially life threatening disease, which is drug or infection induced. Ibuprofen associated acute vanishing bile duct syndrome and toxic epidermal necrolysis have not been reported previously in infants. We report a 7-month-old infant with ibuprofen associated toxic epidermal necrolysis, followed by severe and rapidly progressive vanishing bile duct syndrome. She recovered totally with supportive care.\n\nAcute vanishing bile duct syndrometoxic epidermal necrolysisinfant\n==== Body\nINTRODUCTION\nVanishing bile duct syndrome (VBDS) is a rare cause of progressive destruction and disappearance of the intrahepatic bile ductsm ultimately resulting in cholestasis. The acute form is often drug-related.1,2 The commonly implicated drugs are anticonvulsant and antidepressants.1,2 The pathogenesis of VBDS is unknown, and both immune-mediated and idiosyncrastic metabolic mechanisms have been proposed1,3 Toxic epidermal necrolysis (TEN) is an uncommon but severe dermatologic condition that is characterized by erythema with bullous and eroded lesions of skin and mucous membranes, often drug- or infection-induced.4,5 TEN is well recognized immune complex-mediated hypersensitivity reactions,1,4,5 suggesting shared immune mechanisms in the pathogenesis of both TEN and VBDS.1,4,5,6,7 VBDS with TEN is extremely rare and the prognosis is unknown, especially in children. To our best knowledge, ibuprofen-associated VBDS and TEN in infant have never been reported previously. We report herein a 7-month-old infant with ibuprofen-associated TEN, followed by severe and rapidly progressive VBDS.\n\nCASE REPORT\nA 7-month-old girl was hospitalized with complaints of fever and erythematous rashes on body. Two days earlier, she had fever and received ibuprofen at conventional pediatric doses (maximum of 30 mg/kg/day). She had no history of allergic disease. Three months ago, she had been treated with one-dose of ibuprofen (10 mg/kg) for sporadic fever. There was no family history of atopic disease, immunodeficiency or hepatobiliary disease. On admission, physical examination revealed macular erythematous eruption on her face, trunk, and arms, which progressed within 8 hours into the bullae around the arms, and involved the face and trunk. Skin lesion covered more than 30 percent of her body surface area. There were no lesions in the lips or in the eyes. A diagnosis of toxic epidermal necrolysis was made.\n\nThe initial peripheral white cell count was 5910/mm3 with 69.7% neutrophils, 20.3% lymphocytes, and 3% eosinophils. Hemoglobin level was 12.2 g/dL, platelets count 250000/mm3, erythrocyte sedimentation rate of 120 mm/h, and C-reactive protein 9 mg/dL. Aspartate aminotransferase (AST) level was 716 IU/L, alanine aminotransferase (ALT) 523 IU/L, alkaline phosphatase (ALP) 500 IU/L, total bilirubin (TB) 0.52 mg/dL and direct bilirubin (DB) 0.15 mg/dL. Serological test for hepatitis A, B, and C, Epstein Barr virus, parvovirus B19, herpes virus, adenovirus, cytomegalovirus, human immunodeficiency virus, leptospira, and mycoplasma were negative.\n\nAt hospital day 6, fever and cutaneous lesion resolved after supportive care but cholestatic picture was presented. AST level was 879 IU/L, ALT 723 IU/L, ALP 890 IU/L, TB 8.5 mg/dL, DB 5.7 mg/dL, gamma-glutamyl transferase 270 IU/L, and total cholesterol 760 mg/dL. The following laboratory findings were normal: amylase, lipase, prothrombin and partial thromboplastin time, α1-antitrypsin, immunoglobulins, complement levels, antinuclear antibody, anti-DNA antibody, anti-smooth muscle antibody, antimitochondrial antibody, anti-liver/kidney microsomal, anti-cytosol antibody, and antineutrophil cytoplasmic antibody. Abdominal ultrasound showed that the liver had homogeneous texture with normal bile ducts and gallbladder. Ursodeoxycholic acid treatment (15 mg/kg per day) was administered.\n\nAt hospital day 20, skin lesion recovered, but the TB and DB levels were still high (TB 9.5 mg/dL, DB 7.7 mg/dL). Liver biopsy was performed 20 days after admission. It showed lymphocyte infiltrations, marked degeneration of the interlobular bile duct epithelium, and the destructive narrowing of the ductules in the portal tracts and no intralobar bile ducts in at least 10 portal areas on H&E stain, suggesting VBDS (Fig. 1). Neither an organism nor viral cytopathic effect was identified. There was no significant hepatocellular damage and no evidence of sclerosing cholangitis or autoimmune hepatitis.\n\nThe diagnosis of VBDS associated with TEN was made. During a follow-up period of 3 months, clinical symptoms and biochemical data had shown tendency for resolution. The ursodeoxycholic acid treatment was discontinued. During the next three years, she has a normal physical status with normal liver synthetic functions.\n\nDISCUSSION\nDrug associated VBDS with TEN is extremely rare in children. In the present case, there was a close temporal relationship between ibuprofen administration and the appearance of skin lesion and liver dysfunction. Moreover, other drugs were not taken, and other potential causes were excluded on the basis of appropriate serological and histological results. Therefore, it may reasonably be ascribed to ibuprofen associated VBDS with TEN. To our knowledge, this patient is the first infant reported to have ibuprofen-associated VBDS with TEN.\n\nIbuprofen is a member of propionic acid class of nonsteroidal anti-inflammatory drug (NSAID), and appears to have low incidence of liver damage.1,2 The pattern of liver injury is typically hepatocellular but can be mixed or cholestatic.8 Most cases are mild-to-moderate in severity and rapidly reversible on stopping ibuprofen. Several reports have been published on severe protracted cholestasis and acute liver failure.9,10 The mechanism of drug induced VBSD is not fully understood, however, may be multi-factorial, and toxic, idiosyncratic and immune causes have been suggested.1,2,9,10 In our present case, first exposure to ibuprofen might have sensitized her. Liver injury might be due to an immune-allergic mechanism because of the association with TEN, which is immune complex medicated with hypersensitivity reactions.4\n\nDrug-induced VBDS and skin injury are still unknown particularly in children. A literature search revealed six pediatric case reports with drug-associated VBDS with skin lesion [TEN, Steven-Johnson syndrome (SJS), erythema multiforme] (Table 1). Including our present case, five of the seven were female. Culprit drugs were ibuprofen (3 cases), acetaminophen (2 cases), antibiotics (trimethoprim-sulfamethazole 1 case, cefdinir 1 case), and carbamazepine (1 case). VBDS with SJS has been reported in 3 children, in 2 children with TEN, and in 2 children with erythema multiforme. The interval between drug intake and VBDS development was variable: one patient had a history of drug-associate erythema multiforme 12 months before the episode of VBDS.11 The prognosis among those cases was also variable. In five of the seven cases, immunosuppressive drug was administrated. Despite immunosuppressive therapy, two cases showed an irreversible change of the intrahepatic bile duct,1,4 three cases improved after immunosuppressive treatment,2,7,12 and two cases, including our case, showed a favorable clinical course without immunosuppressive therapy.11 Further studies are needed to determine the risk group, effective treatment and overall mortality in children with drug-induced VBDS with skin involvement.\n\nIn conclusion, a rare case of ibuprofen-associated VBDS with TEN in an infant is presented. Ibuprofen is considered to be among the safest NSAID and generally well tolerated. Nevertheless, clinicians need to be aware of serious acute liver and cutaneous injury as rare adverse effects of this drug.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Liver histology shows portal lymphocytic infiltration with destruction of interlobular bile ducts (H&E, ×200) (A), (H&E, ×400) (B), intralobular canalicular cholestasis (H&E, ×200) (C), and absence of bile ducts demonstrated by cytokeratin 7 immunohistochemical staining (IHC, ×200) (D).\n\nTable 1 Main Characteristics of Six Pediatric Case of Drug Associacted VBDS with Skin Lesion (TEN, SJS, Erythema Multiforme)\n\ny, year; mo, month; TEN, toxic epidermal necrolysis; SJS, Stevens-Johnson syndrome; EM, erythema multiforme; UDCA, ursodeoxycholic acid; VBDS, vanishing bile duct syndrome.\n\n*This patient had a history of drug-associate erythema multiforme 12 months before the episode of VBDS.\n==== Refs\n1 Srivastava M Perez-Atayde A Jonas MM Drug-associated acute onset vanishing bile duct and Stevens-Johnson syndromes in a child Gastroenterology 1998 115 743 746 9721172 \n2 Taghian M Tran TA Bresson-Hadni S Menget A Felix S Jacquemin E Acute vanishing bile duct syndrome after ibuprofen therapy in a child J Pediatr 2004 145 273 276 15289784 \n3 Degott C Feldmann G Larrey D Durand-Schneider AM Grange D Machayekhi JP Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia Hepatology 1992 15 244 251 1735527 \n4 Karnsakul W Arkachaisri T Atisook K Wisuthsarewong W Sattawatthamrong Y Aanpreung P Vanishing bile duct syndrome in a child with toxic epidermal necrolysis: an interplay of unbalanced immune regulatory mechanisms Ann Hepatol 2006 5 116 119 16807519 \n5 Okan G Yaylaci S Peker O Kaymakoglu S Saruc M Vanishing bile duct and Stevens-Johnson syndrome associated with ciprofloxacin treated with tacrolimus World J Gastroenterol 2008 14 4697 4700 18698687 \n6 Morelli MS O'Brien FX Stevens-Johnson Syndrome and cholestatic hepatitis Dig Dis Sci 2001 46 2385 2388 11713940 \n7 Garcia M Mhanna MJ Chung-Park MJ Davis PH Srivastava MD Efficacy of early immunosuppressive therapy in a child with carbamazepine-associated vanishing bile duct and Stevens-Johnson syndromes Dig Dis Sci 2002 47 177 182 11837721 \n8 Stine JG Lewis JH Drug-induced liver injury: a summary of recent advances Expert Opin Drug Metab Toxicol 2011 7 875 890 21510822 \n9 Sternlieb P Robinson RM Stevens-Johnson syndrome plus toxic hepatitis due to ibuprofen N Y State J Med 1978 78 1239 1243 276660 \n10 Alam I Ferrell LD Bass NM Vanishing bile duct syndrome temporally associated with ibuprofen use Am J Gastroenterol 1996 91 1626 1630 8759674 \n11 Takeyama J Saito T Itagaki T Abukawa D Vanishing bile duct syndrome with a history of erythema multiforme Pediatr Int 2006 48 651 653 17168994 \n12 Tajiri H Etani Y Mushiake S Ozono K Nakayama M A favorable response to steroid therapy in a child with drug-associated acute vanishing bile duct syndrome and skin disorder J Paediatr Child Health 2008 44 234 236 18377375\n\n",
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"abstract": "Acute graft-versus-host disease (GvHD) has been a clinical problem in solid organ transplant that includes intestine due to the donor lymphoid tissue mass which accompanies the intestinal component of the graft. We report a case that demonstrated the efficacy and feasibility of ruxolitinib a JAK 1/2 inhibitor in the treatment of chronic steroid-refractory GVHD (SR-GVHD). The child developed SR-GVHD following a composite intestine transplant (small bowel, colon, liver, and pancreas). And after receiving ruxolitinib 1.25 mg (0.15 mg/kg/dose) per gastric tube (G-tube) daily, the child appeared to have improved skin rash and sigmoidoscopy was negative. Nonetheless, we encourage close monitoring of hematologic and infectious adverse effect during dose escalation, and individualizing patient maximum effective dose with the least adverse effect possible. We stress the importance of early diagnosis and hyper-alertness of GVHD in intestinal transplant patients.",
"affiliations": "Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;National Institute of Health, Bethesda, Maryland, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.",
"authors": "Ghobrial|Shahira|S|https://orcid.org/0000-0003-2168-3878;Gonzalez|Corina|C|;Yazigi|Nada|N|;Kaufman|Stuart|S|https://orcid.org/0000-0002-5308-4565;Matsumoto|Cal|C|;Fishbein|Thomas|T|;Hawksworth|Jason|J|;Kroemer|Alexander|A|;Khan|Khalid|K|",
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"keywords": "children; graft versus host disease; intestine; multivisceral; pediatric; ruxolitinib",
"medline_ta": "Pediatr Transplant",
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"pages": "e13836",
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"pubdate": "2021-05",
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"title": "Efficacy and feasibility of ruxolitinib in chronic steroid-refractory GVHD in a pediatric intestine transplant.",
"title_normalized": "efficacy and feasibility of ruxolitinib in chronic steroid refractory gvhd in a pediatric intestine transplant"
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"abstract": "BACKGROUND\nBone marrow transplantation is now an established treatment for some hematopoietic disorders and hematopoietic malignancies, and secondary solid tumors that develop after bone marrow transplantation have begun to attract attention.\n\n\nMETHODS\nHerein, we report 3 cases of esophageal carcinoma that developed after bone marrow transplantation. Case 1: 40-year-old female received cyclophosphamide and total body irradiation at 12 Gy for acute myeloid leukemia, followed by related bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as pulmonary complications and was administered cyclosporine. Nine years after the transplantation, she was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. She died of the primary disease 17 months after the surgery. Case 2: A 45-year-old male patient received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy for acute lymphocytic leukemia, followed by related bone marrow transplantation. He developed chronic graft-versus-host disease manifesting as liver dysfunction. Fifteen years after the transplantation, he was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. Seven months after the surgery, he died of the primary disease. Case 3: A 30-year-old female patient received cyclophosphamide and total body irradiation at 3 Gy for Fanconi anemia, followed by unrelated bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as a rash and was administered tacrolimus and methotrexate. Fifteen years after the transplantation, she was diagnosed as having esophageal carcinoma Stage III and underwent radical surgery. She died of sepsis 7 months after the surgery.\n\n\nCONCLUSIONS\nThe esophageal carcinomas developing after bone marrow transplantation had the characteristics of secondary solid tumors in all 3 patients, such as early onset, after total body irradiation, association with chronic graft-versus-host disease, and history of use of immunosuppressive drugs. Patients undergoing bone marrow transplantation require long-term follow-up after the transplantation, considering the possible development of secondary solid tumors, and in regard to secondary solid tumors developing in the gastrointestinal tract, it must be borne in mind that the risk of esophageal carcinoma is particularly high.",
"affiliations": "Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. sozawa@tokai.ac.jp.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.;Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.",
"authors": "Ninomiya|Yamato|Y|;Ozawa|Soji|S|http://orcid.org/0000-0001-6130-1753;Koyanagi|Kazuo|K|;Yamamoto|Miho|M|;Higuchi|Tadashi|T|;Yatabe|Kentaro|K|;Tajima|Kohei|K|",
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"fulltext": "\n==== Front\nSurg Case Rep\nSurg Case Rep\nSurgical Case Reports\n2198-7793\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n1157\n10.1186/s40792-021-01157-z\nCase Report\nThree resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation\nNinomiya Yamato\nhttp://orcid.org/0000-0001-6130-1753\nOzawa Soji sozawa@tokai.ac.jp\n\nKoyanagi Kazuo\nYamamoto Miho\nHiguchi Tadashi\nYatabe Kentaro\nTajima Kohei\ngrid.265061.6 0000 0001 1516 6626 Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193 Japan\n20 3 2021\n20 3 2021\n12 2021\n7 7312 2 2021\n12 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nBone marrow transplantation is now an established treatment for some hematopoietic disorders and hematopoietic malignancies, and secondary solid tumors that develop after bone marrow transplantation have begun to attract attention.\n\nCase presentation\n\nHerein, we report 3 cases of esophageal carcinoma that developed after bone marrow transplantation. Case 1: 40-year-old female received cyclophosphamide and total body irradiation at 12 Gy for acute myeloid leukemia, followed by related bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as pulmonary complications and was administered cyclosporine. Nine years after the transplantation, she was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. She died of the primary disease 17 months after the surgery. Case 2: A 45-year-old male patient received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy for acute lymphocytic leukemia, followed by related bone marrow transplantation. He developed chronic graft-versus-host disease manifesting as liver dysfunction. Fifteen years after the transplantation, he was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. Seven months after the surgery, he died of the primary disease. Case 3: A 30-year-old female patient received cyclophosphamide and total body irradiation at 3 Gy for Fanconi anemia, followed by unrelated bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as a rash and was administered tacrolimus and methotrexate. Fifteen years after the transplantation, she was diagnosed as having esophageal carcinoma Stage III and underwent radical surgery. She died of sepsis 7 months after the surgery.\n\nConclusion\n\nThe esophageal carcinomas developing after bone marrow transplantation had the characteristics of secondary solid tumors in all 3 patients, such as early onset, after total body irradiation, association with chronic graft-versus-host disease, and history of use of immunosuppressive drugs. Patients undergoing bone marrow transplantation require long-term follow-up after the transplantation, considering the possible development of secondary solid tumors, and in regard to secondary solid tumors developing in the gastrointestinal tract, it must be borne in mind that the risk of esophageal carcinoma is particularly high.\n\nKeywords\n\nEsophageal cancer\nBone marrow transplantation\nSecondary solid tumors\nChronic graft-versus-host disease\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nBone marrow transplantation (BMT) is used to treat many hematopoietic disorders and hematopoietic malignancies, and with the increasing number of cases and improved treatment outcomes, late complications occurring in long-surviving patients have begun to attract attention. Secondary solid tumors (SSTs) that develop after BMT are among the reported late complications, and recently there have been both isolated case reports and reports of large-scale studies of SSTs; however, few cases of esophageal carcinoma as SSTs have been reported until now [1–4]. Herein, we report 3 resected cases of esophageal carcinoma, considered as SSTs, after BMT.\n\nCases presentation\n\nCase 1: a 40-year-old woman\n\nShe had undergone related BMT from her older human leukocyte antigen (HLA)-matched sister at the age of 31 years for acute myeloid leukemia (M2), which was diagnosed when she was 30 years old. She received cyclophosphamide and total body irradiation at 12 Gy as pretreatment. Approximately 5 months after the BMT, she developed post-transplant chronic graft-versus-host disease (GVHD) manifesting as pulmonary complications, and received treatment with cyclosporine. Subsequently, she had no recurrence and was followed up on an outpatient basis. Nine years after the BMT, she became aware of difficulty in swallowing after meals and presented to our department. She had never undergone upper gastrointestinal endoscopy and had a 20-year history of habitual drinking of 2000 ml of beer/day and smoking 20 cigarettes/day. Detailed examination led to the diagnosis of esophageal carcinoma (Lt, Type 2, T3N0M0 Stage II) (Fig. 1). We thought that she was a high-risk case for neoadjuvant chemotherapy (NAC) as she had undergone BMT, and instead performed thoracoscopic thoracic esophagectomy and retrosternal gastric conduit reconstruction. She was discharged on the 20th postoperative day without any postoperative complications. The histopathological diagnosis of the resected specimen was moderately differentiated squamous cell carcinoma, Type 2, pT3N3 (8/94 metastasis positive lymph nodes) M0, pStage III, INFb, ly1, v2 (Fig. 2). She developed multiple lymph node and pulmonary metastases 12 months after the surgery and underwent a total of 4 courses of chemotherapy (CF therapy: cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2). She died of progressive esophageal carcinoma 17 months after the surgery.Fig. 1 Endoscopic findings in Case 1. A type 2 lesion was found in the lower thoracic esophagus\n\nFig. 2 Findings of the resected specimen in Case 1\n\nCase 2: a 45-year-old man\n\nHe was diagnosed as having acute lymphocytic leukemia at the age of 29 years and had undergone related BMT from his younger HLA-matched sister at the age of age 30 years. He received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy as pretreatment. After transplantation, he developed chronic GVHD manifesting as liver dysfunction. Fifteen years after the BMT, he became aware of difficulty in swallowing and presented to our department. He had never undergone upper gastrointestinal endoscopy and was not a smoker, but had a 25-year history of habitual drinking of 350 ml of beer/day. Detailed examination led to the diagnosis of esophageal carcinoma (LtAe, Type 3, T2N0M0 Stage II) (Fig. 3). And as in Case 1, he did not receive NAC, but underwent thoracoscopic thoracic esophagectomy with retrosternal gastric conduit reconstruction. He was discharged on the 19th postoperative day without any postoperative complications. The histopathological diagnosis of the resected specimen was well differentiated squamous cell carcinoma, Type 3, pT3N2 (2/56 metastasis positive lymph nodes) M0, pStage III, Infb, ly2, v1 (Fig. 4). He developed multiple pulmonary metastases 6 months after surgery and died of progressive esophageal carcinoma 7 months after surgery.Fig. 3 Endoscopic findings in Case 2. A type 3 lesion was found in the lower thoracic esophagus\n\nFig. 4 Findings of the resected specimen in Case 2\n\nCase 3: a 30-year-old woman\n\nShe was diagnosed as having Fanconi anemia at the age of 7 years and had undergone unrelated BMT from an unrelated HLA-mismatched male donor at the age of 15 years. She received cyclophosphamide and total body irradiation at 3 Gy as pretreatment. After the transplantation, she developed chronic GVHD manifesting as a rash and was initiated on treatment with tacrolimus and methotrexate. Fifteen years after the BMT, she became aware of difficulty in swallowing and presented to our department. She had never had an upper gastrointestinal endoscopy and was neither a habitual smoker nor drinker. Detailed examination led to the diagnosis of esophageal carcinoma (MtUt, Type 2, T3N1M0, Stage III) (Fig. 5), and like in Cases 1 and 2, she did not receive NAC, but underwent thoracoscopic thoracic esophagectomy with retrosternal gastric conduit reconstruction. She developed aspiration pneumonia postoperatively, but improved after 2 weeks of antibiotics and was discharged on postoperative day 37. The histopathological diagnosis of the resected specimen was moderately differentiated squamous cell carcinoma, Type 2, pT3N2 (5/41 metastasis positive lymph nodes) M0, pStage III, INFb, ly1, v1 (Fig. 6). She developed multiple bone metastases 6 months after the surgery and died of sepsis 7 months after the surgery.Fig. 5 Endoscopic findings in Case 3. A type 2 lesion was found in the middle thoracic esophagus\n\nFig. 6 Findings of the resected specimen in Case 3\n\nDiscussion\n\nSSTs commonly occur at sites with squamous epithelium, such as the skin and oral cavity, and are characterized by early onset and increasing risk of development with time after BMT [5]. Reported risk factors for SSTs include the use of immunosuppressive drugs, total body irradiation, and association with chronic GVHD, and in particular, esophageal carcinoma has been reported to be correlated with the development of chronic GVHD and long-term use of immunosuppressive drugs [5–7]. The esophageal carcinoma in all the 3 patients reported herein had the characteristics of SSTs, including early onset, total body irradiation, association with chronic GVHD, and history of use of immunosuppressive drugs (Table 1).Table 1 Characteristics of the 3 cases\n\n\tSex\tAge when EC was diagnosed\tpStage of EC\tHematological disorders\tDonor\tImmunosuppressants\tRadiation\tChronic GVHD\tPeriod from BMT to EC diagnosed\t\nCase 1\tFemale\t40\tT3N3M0, Stage III\tAcute myeloid leukemia\tHLA-matched sister\tCyclophosphamide, cyclosporine\t12 Gy\tPulmonary complications\t9 years\t\nCase 2\tMale\t45\tT3N2M0, Stage III\tAcute lymphocytic leukemia\tHLA-matched sister\tCyclophosphamide, VP-16\t13.2 Gy\tLiver dysfunction\t15 years\t\nCase 3\tFemale\t30\tT3N2M0, Stage III\tFanconi anemia\tUnrelated HLA-mismatched male\tCyclophosphamide, tacrolimus, methotrexate\t3 Gy\tRash\t15 years\t\nEC, esophageal carcinoma; GVHD, graft-versus-host disease; BMT, bone marrow transplantation; HLA, human leukocyte antigen\n\nA study of the late complications after BMT in 17,545 subjects enrolled in the Nationwide Survey of the Japan Society for Hematopoietic Cell Transplantation between 1990 and 2007 reported the standard incidence ratio (SIR) of SSTs by site at various periods after transplantation [7]. They reported an increase in the risk of SSTs with time after BMT and a higher risk of development of SSTs at sites of squamous epithelium, such as the oral cavity, skin and esophagus. The SIR of SSTs in the esophagus was 6.5 between 1 and 4 years, 12.6 between 5 and 9 years, and 16.8 at ≥ 10 years after BMT, indicating an increase in the risk with time after BMT and a higher risk of development in the esophagus than in other organs. Three patients reported herein had advanced cancer at the time of diagnosis, and none of the 3 patients had undergone regular screening. Thus, it is considered necessary to regularly screen patients who have undergone BMT, bearing in mind the high risk of development of esophageal carcinoma [8, 9].\n\nAlthough there have been few reports until now on the treatment of SSTs, SSTs are often treated like general primary cancers [10]. No consensus has been reached on the specific aspects of treatment of esophageal carcinoma developing after BMT; however, in previously reported cases, local treatment such as endoscopic treatment, surgery or radiotherapy had been used according to the disease stage and site [3, 4, 10]. The three cases reported herein (they were 3 out of a total of 738 patients who underwent esophagectomy at our hospital between 2010 and 2020 [0.4%]) had cStage II or III advanced esophageal carcinoma, and would have been considered for NAC. Although there is no established evidence of chemotherapy for esophageal carcinoma after BMT, chemotherapy has been reported to cause serious myelosuppression; therefore, use of chemotherapy should be considered carefully [11]. We performed surgery without NAC, considering the potential adverse effects of chemotherapy on the hematopoietic function. On the other hand, all the 3 patients showed recurrence within 1 year after the surgery, and perhaps adjuvant therapy should be considered.\n\nIn regard to the postoperative management of SSTs after esophagectomy, there is a report that recommends prophylactic antimicrobial drug administration, because of the high incidence of pneumonia and the risk of severe disease [11]. All three patients herein were followed up carefully for complications of bacterial infections such as pneumonia, but only one patient developed aspiration pneumonia and improved with prompt initiation of antimicrobial therapy. In the postoperative management of SSTs patients undergoing esophagectomy, there is need to pay attention to the risk of development and severe disease of postoperative pneumonia.\n\nThe prognosis of esophageal carcinoma as an SST has been investigated using data from hematopoietic cell transplantation registries and population-based cancer registries in Japan, and there was no statistical difference in the 3-year overall survival between patients who developed esophageal carcinoma after BMT and those with primary esophageal carcinoma in the general population (after transplantation vs. primary: 34% vs. 42%, P = 0.40) [12]. On the other hand, three patients in our study with advanced cancer who developed recurrence early after the surgery died. As described above, we think that early detection by screening is important to improve the prognosis.\n\nIn regard to follow-up after surgery for SSTs, since there have been some reports of double cancers as SSTs, follow-up should be performed with attention paid not only to recurrence of esophageal carcinoma, but also to the occurrence of cancers of other organs, in particular, cancers arising from squamous epithelium, such as of the oral cavity, pharynx and skin [8, 9]. Endoscopists should be aware of the development of cancer of the tongue, pharynx and esophagus and should examine them carefully for early detection.\n\nConclusions\n\nLong-term follow-up is required in patients after BMT, considering the possible development of SSTs, and in regard to SSTs of the gastrointestinal tract, it should be borne in mind that the risk of esophageal carcinoma, in particular, is high.\n\nAbbreviations\n\nBMT Bone marrow transplantation\n\nSSTs Secondary solid tumors\n\nHLA Human leukocyte antigen\n\nGVHD Graft-versus-host disease\n\nNAC Neoadjuvant chemotherapy\n\nSIR Standard incidence ratio\n\nAcknowledgement\n\nNot applicable.\n\nAuthors' contributions\n\nYN and SO have made substantial contributions to the concept and design of the case report. KK, MY, TH, KY and KT conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved final manuscript.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent for participation\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors' information\n\nYN and MY are Senior lecturers of Department of Gastroenterological Surgery. SO is a Professor and Chairman of Department of Gastroenterological Surgery. KK is an Associate Professor of Department of Gastroenterological Surgery. TH, KY and KT are Assistant professors of Tokai University Graduate School of Medicine.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Yokota A Ozawa S Masanori T Secondary solid tumor after allogeneic hematopoietic SCT in Japan Bone Marrow Transplant 2012 47 95 100 10.1038/bmt.2011.23 21358690\n2. Tichelli A Beohou E Labopin M Evaluation of second solid cancers after hematopoietic stem cell transplantation in European patients JAMA Oncol 2019 2 229 235 10.1001/jamaoncol.2018.4934\n3. Nomura K Iizuka T Daisuke K Secondary esophageal squamous cell carcinoma after hematopoietic stem cell transplantation J Cancer Res Clin Oncol 2020 10.1007/s00432-020-03500-7 32088782\n4. Miyawaki Y Imoto I Tokairin Y Esophageal squamous cell carcinoma developed 11 years after allogeneic bone marrow transplantation for acute lymphatic leukemia Jpn J Clin Oncol 2013 43 69 73 10.1093/jjco/hys184 23225908\n5. Curtis RE Rowlings PA Deeg HJ Solid cancers after bone marrow transplantation N Engl J Med 1997 336 897 904 10.1056/NEJM199703273361301 9070469\n6. Shimada K Yokozawa T Atsuta Y Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis Bone Marrow Transplant 2005 36 115 121 10.1038/sj.bmt.1705020 15908969\n7. Atsuta Y Suzuki R Yamashita T Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease Ann Oncol 2014 25 435 441 10.1093/annonc/mdt558 24399081\n8. Majhail NS Rizzo JD Lee SJ Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation Biol Blood Marrow Transplant 2012 18 348 371 10.1016/j.bbmt.2011.12.519 22178693\n9. Inamoto Y Shah NN Savani BN Secondary solid cancer screening following hematopoietic cell transplantation Bone Marrow Transplant 2015 50 1013 1023 10.1038/bmt.2015.63 25822223\n10. Schmuziger GF Hofer S Passwg J Treatment of solid tumors following allogeneic bone marrow transplantation Bone Marrow Transplant 2000 25 895 898 10.1038/sj.bmt.1702339 10808212\n11. Kato F Daiko H Kanamori J Esophagectomy for the patients with squamous cell carcinoma of the esophagus after allogeneic hematopoietic stem cell transplantation Int J Clin Oncol 2020 25 82 88 10.1007/s10147-019-01549-0 31549271\n12. Inamoto Y Matsuda T Tabuchi K Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation Blood Adv 2018 2 1901 1913 10.1182/bloodadvances.2018020966 30087108\n\n",
"fulltext_license": "CC BY",
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"keywords": "Bone marrow transplantation; Chronic graft-versus-host disease; Esophageal cancer; Secondary solid tumors",
"medline_ta": "Surg Case Rep",
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"title": "Three resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation.",
"title_normalized": "three resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation"
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"abstract": "To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).\nRetrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.\nDII can trigger CMV retinitis in immunocompetent patients.",
"affiliations": "Westmead Hospital, Westmead, Sydney, New South Wales, Australia.;Westmead Hospital, Westmead, Sydney, New South Wales, Australia.",
"authors": "Chaudhry|Sarah G|SG|;Fung|Adrian T|AT|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00046-3\n10.1016/j.ajoc.2021.101055\n101055\nCase Report\nCytomegalovirus retinitis following dexamethasone intravitreal implant\nChaudhry Sarah G. a\nFung Adrian T. adrian.fung@sydney.edu.au\nabc∗\na Westmead Hospital, Westmead, Sydney, New South Wales, Australia\nb Westmead and Central Clinical Schools, Discipline of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2145, Australia\nc Department of Ophthalmology, Faculty of Medicine, Health and Human Sciences, Macquarie University, New South Wales, 2109, Australia\n∗ Corresponding author. Department of Ophthalmology, Westmead Hospital, Retina & Macula Specialists, 1A/12, Corner of Hawkesbury and Darcy Roads, NSW, 2145, Australia. adrian.fung@sydney.edu.au\n04 3 2021\n6 2021\n04 3 2021\n22 1010551 8 2020\n7 11 2020\n21 2 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTo describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).\n\nObservations\n\nRetrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.\n\nConclusion and Importance\n\nDII can trigger CMV retinitis in immunocompetent patients.\n\nKeywords\n\nCytomegalovirus (CMV)\nRetinitis\nDexamethasone intravitreal implant (DII)\nImmunocompetent\n==== Body\n1 Introduction\n\nWe present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.\n\n2 Case report\n\nAn 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.\n\nOn examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nA provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).\n\nFollowing a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.\n\n3 Discussion\n\nCMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.\n\nA thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.\n\nOne factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.\n\n4 Conclusion\n\nDII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.\n\nPatient consent\n\nThe patient has provided written consent for publication of their case in AJO.\n\nFunding\n\nNo funding or grant support.\n\nIntellectual property\n\nWe confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.\n\nResearch ethics\n\nWritten consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).\n\nAuthorship\n\nAll listed authors meet the ICMJE criteria. \nWe attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.\n\nDeclaration of competing interest\n\nNo conflict of interest exists.\n\nWe wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.\n\nAcknowledgements\n\nNil.\n==== Refs\nReferences\n\n1 Ganatra J.B. Chandler D. Santos C. Kuppermann B. Margolis T.P. Viral causes of the acute retinal necrosis syndrome Am J Ophthalmol 129 2 2000 166 172 10682968\n2 Takakura A. Tessler H.H. Goldstein D.A. Viral retinitis following intraocular or periocular corticosteroid administration: a case series and comprehensive review of the literature Ocul Immunol Inflamm 22 3 2014 175 182 24655372\n3 Shah A.M. Oster S.F. Freeman W.R. Viral retinitis after intravitreal triamcinolone injection in patients with predisposing medical comorbidities Am J Ophthalmol 149 3 2010 433 440 e1 20172069\n4 Voros G. Pandit R. Snow M. Griffiths P. Unilateral Recurrent Acute Retinal Necrosis Syndrome Caused by Cytomegalovirus in an Immune-Competent Adult 2006 SAGE Publications Sage UK London, England\n5 Thrane A.S. Hove M. Kjersem B. Krohn J. Acute retinal necrosis and ocular neovascularization caused by cytomegalovirus following intravitreal dexamethasone implant (Ozurdex®) in an immunocompetent patient Acta Ophthalmol 94 8 2016 e813 e814 27274005\n6 Radwan A. Metzinger J.L. Hinkle D.M. Foster C.S. Cytomegalovirus retinitis in immunocompetent patients: case reports and literature review Ocul Immunol Inflamm 21 4 2013 324 328 23662740\n7 Stewart M.W. Bolling J.P. Mendez J.C. Cytomegalovirus retinitis in an immunocompetent patient Arch Ophthalmol 123 4 2005 572 574 15824240\n8 Vertes D. Snyers B. De Potter P. Cytomegalovirus retinitis after low-dose intravitreous triamcinolone acetonide in an immunocompetent patient: a warning for the widespread use of intravitreous corticosteroids Int Ophthalmol 30 5 2010 595 597 20931263\n9 Haller J.A. Bandello F. Belfort R. Jr. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results Ophthalmology 118 12 2011 2453 2460 21764136\n10 Kapoor K. Wagner M. Wagner A. The Sustained-Release Dexamethasone Implant: Expanding Indications in Vitreoretinal Disease. Taylor & Francis 2015 475 481\n11 Barshes N.R. Goodpastor S.E. Goss J.A. Pharmacologic immunosuppression Frontiers in bioscience: J Vis Literacy 9 2004 411\n12 Witmer M.T. Connolly B.P. Cytomegalovirus retinitis after an intravitreal dexamethasone implant IN an immunocompetent patient Retin Cases Brief Rep 2019\n13 Vannozzi L. Bacherini D. Sodi A. Cytomegalovirus retinitis following intravitreal dexamethasone implant in a patient with central retinal vein occlusion Acta Ophthalmol 94 2 2016 e158 e160 26172582\n14 Dogra M. Rohilla V. Dogra M. Singh R. Macular cytomegalovirus retinitis following dexamethasone intravitreal implant combined with phacoemulsification Indian J Ophthalmol 66 9 2018 1361 30127173\n15 Pawelec G. Age and immunity: what is “immunosenescence”? Exp Gerontol 105 2018 4 9 29111233\n16 Pawelec G. Derhovanessian E. Larbi A. Strindhall J. Wikby A. Cytomegalovirus and human immunosenescence Rev Med Virol 19 1 2009 47 56 19035529\n17 Ginaldi L. Loreto M.F. Corsi M.P. Modesti M. De Martinis M. Immunosenescence and infectious diseases Microb Infect 3 10 2001 851 857\n18 Pawelec G. Akbar A. Beverley P. Immunosenescence and Cytomegalovirus: where do we stand after a decade? Immun Ageing 7 1 2010 13 20822513\n\n",
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"issue": "22()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cytomegalovirus (CMV); Dexamethasone intravitreal implant (DII); Immunocompetent; Retinitis",
"medline_ta": "Am J Ophthalmol Case Rep",
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"title": "Cytomegalovirus retinitis following dexamethasone intravitreal implant.",
"title_normalized": "cytomegalovirus retinitis following dexamethasone intravitreal implant"
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"abstract": "BACKGROUND\nDirect-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients.\n\n\nMETHODS\nAll patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification.\n\n\nRESULTS\nA total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively.\n\n\nCONCLUSIONS\nThe direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.",
"affiliations": "Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.;Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.;Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.;Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.;Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.;Universidade Federal de São Paulo (UNIFESP), Disciplina de Gastroenterologia, São Paulo, SP, Brasil.",
"authors": "Michels|Fernanda Bellini Lunardi|FBL|http://orcid.org/0000-0003-0581-4487;Amaral|Ana Cristina de Castro|ACC|http://orcid.org/0000-0002-8290-7073;Carvalho-Filho|Roberto José de|RJ|http://orcid.org/0000-0002-9795-5705;Vieira|Gustavo de Almeida|GA|http://orcid.org/0000-0003-0186-388X;Souza|Ana Lucia da Silva|ALDS|http://orcid.org/0000-0001-8639-6963;Ferraz|Maria Lucia Gomes|MLG|http://orcid.org/0000-0001-8992-8494",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D051436:Renal Insufficiency, Chronic; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014633:Valine; D019562:Viral Load",
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"title": "HEPATITIS C TREATMENT OF RENAL TRANSPLANT AND CHRONIC KIDNEY DISEASE PATIENTS: EFFICACY AND SAFETY OF DIRECT-ACTING ANTIVIRAL REGIMENS CONTAINING SOFOSBUVIR.",
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"abstract": "The Jarisch-Herxheimer reaction (JHR) is a well-described entity most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, in addition to worsening of cutaneous manifestations of syphilis. Severe reactions are uncommon but may include signs of exaggerated systemic inflammatory response. We report a case of a 33-year-old male with secondary syphilis who was treated with ceftriaxone and subsequently developed fluid-refractory hypotension requiring vasopressor administration and intensive care unit admission. To our knowledge, this is the first report of severe hypotension as a result of JHR in a patient with syphilis who was treated with cephalosporin antibiotics.",
"affiliations": "Internal Medicine-Pediatrics, University of Louisville, Louisville, USA.;Internal Medicine, University of Louisville, Louisville, USA.",
"authors": "McKenzie|Caitlin|C|;Olges|Jennifer|J|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12750\nInternal Medicine\nInfectious Disease\nJarisch-Herxheimer Reaction After Cephalosporin Administration in Syphilis\nMuacevic Alexander Adler John R McKenzie Caitlin 1 Olges Jennifer 2 \n1 \nInternal Medicine-Pediatrics, University of Louisville, Louisville, USA \n\n2 \nInternal Medicine, University of Louisville, Louisville, USA \n\nCaitlin McKenzie camcke03@louisville.edu\n17 1 2021 \n1 2021 \n13 1 e1275017 1 2021 Copyright © 2021, McKenzie et al.2021McKenzie 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/45488-jarisch-herxheimer-reaction-after-cephalosporin-administration-in-syphilisThe Jarisch-Herxheimer reaction (JHR) is a well-described entity most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, in addition to worsening of cutaneous manifestations of syphilis. Severe reactions are uncommon but may include signs of exaggerated systemic inflammatory response. We report a case of a 33-year-old male with secondary syphilis who was treated with ceftriaxone and subsequently developed fluid-refractory hypotension requiring vasopressor administration and intensive care unit admission. To our knowledge, this is the first report of severe hypotension as a result of JHR in a patient with syphilis who was treated with cephalosporin antibiotics.\n\njarisch-herxheimersyphiliscephalosporinhypotensionThe 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\nThe Jarisch-Herxheimer reaction (JHR) is a well-reported phenomenon most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, which include but are not limited to fevers, chills, and myalgias, in addition to worsening of skin rash and other cutaneous manifestations of the disease. The reaction typically occurs within the first four to 12 hours after antibiotic administration and self-resolves within 24 hours. The mechanism of the JHR remains unknown, but cytokine release in response to treponemal lipoproteins is thought to be implicated in its pathogenesis. Severe reactions are uncommon but may include signs of an exaggerated systemic inflammatory response, including hemodynamic instability and thermoregulatory dysfunction. Herein, we report a case of secondary syphilis treated with ceftriaxone who subsequently developed fluid-refractory hypotension requiring vasopressor administration. This article was previously presented as a poster at the 2018 Kentucky American College of Physicians meeting on October 3, 2018.\n\nCase presentation\nA 33-year-old male with human immunodeficiency virus (HIV), not on highly active antiretroviral therapy (HAART) for the last two years, presented to an outside emergency department with a three-week history of subjective fever, arthralgias, myalgias, and a diffuse painful papular upper body rash. The rash had progressed from his trunk to involve his face, arms, and upper legs. He reported painless genital lesions preceding the diffuse rash, as well as two unprotected sexual encounters approximately one month prior. The patient took no home medications and had no known medication allergies. In the emergency department, he was found to have a temperature of 100.9°F, a heart rate of 130 beats per minute, and a respiratory rate of 22 breaths per minute. Urinalysis was not suggestive of infection, and chest radiograph demonstrated no infiltrate. Blood and urine cultures were obtained. He was given 1 L bolus of intravenous fluids and 1 g of ceftriaxone intravenously for presumed sepsis. He was subsequently transferred to our institution for further workup and management.\n\nUpon arrival to our emergency department six hours later, the patient was febrile to 102.8°F with a heart rate of 161 beats per minute and systolic blood pressure initially 89 mmHg. Physical exam was remarkable for normal mentation, tachycardia but no murmurs, and clear lung fields bilaterally. There were erythematous scaly papular and plaque-like lesions over the face, back, chest, arms, abdomen, and upper legs (Figures 1, 2). The rash spared the palms and soles. He also had an erythematous papule on the mucosa of the lower lip. The patient remained hypotensive, with a blood pressure of 82/53 mmHg, despite 3 L of normal saline. A central venous catheter was placed, and a norepinephrine drip was started. The patient also received empiric antibiotic treatment with vancomycin and cefepime for presumed septic shock. The patient was admitted to the medical intensive care unit, where he required less than 24 hours of vasopressor administration with norepinephrine to maintain adequate blood pressure.\n\nFigure 1 Scaly, erythematous papular lesions located diffusely over the patient's back. \nFigure 2 A closer view of the papulosquamous lesions over the patient's posterolateral arm and upper back.\nBlood and urine cultures obtained at the outside hospital prior to the first antibiotic dose were negative for bacterial growth. Broad-spectrum antibiotics were discontinued once cultures showed no growth for over 48 hours and the patient remained clinically stable. Blood cultures, fungal cultures, acid-fast bacilli smear and cultures, cerebrospinal fluid (CSF) cultures, cryptococcal serum and CSF antigens, Histoplasma galactomannan urine antigen, Neisseria gonorrhea polymerase chain reaction (PCR), and Chlamydia trachomatis PCR obtained at our facility were all negative. CSF studies demonstrated no red blood cells, no white blood cells, glucose 53 mg/dL (reference range 40-70 mg/dL), and protein 49.5 mg/dL (reference range 10-45 mg/dL), which was not thought to be consistent with aseptic meningitis. Rapid plasma reagin (RPR) was positive, and syphilis serum titer was 1:256 dL. CSF RPR was negative, and CSF Treponema pallidum IgG by immunofluorescence assay was nonreactive. The patient was also noted to have a CD4 T-cell count of 162/mm3 (reference range 338 to 1448 per mm3) and HIV-1 ribonucleic acid (RNA) of 456,000 copies/mL. Dermatology was consulted and deferred skin biopsy as exam findings were clinically consistent with secondary syphilis. The patient was treated with 2.4 million units of intramuscular benzathine penicillin. The remainder of his hospital course was uncomplicated, and he was discharged home after three days with close follow-up with Infectious Diseases with plans to resume HAART as an outpatient.\n\nDiscussion\nSince 2001, the incidence of primary and secondary syphilis in the United States has increased dramatically. In 2018, the rate of primary and secondary syphilis was 10.8 cases per 100,000 population, which marked a 14.9% increase from 2017 and a 71.4% increase from 2014 [1]. Syphilis is caused by the spirochete Treponema pallidum, and the infection’s manifestations depend upon the stage of the disease. Primary syphilis classically presents as a non-tender genital chancre. The chancre may go unnoticed if not in a highly visible location, and thus treatment often is delayed until further progression of the disease. Secondary syphilis typically occurs two to eight weeks after the initial infection, with a characteristic rash, often involving the trunk, face, and extremities. Classically, the lesions may involve the palms and soles, although lack of involvement does exclude the diagnosis. Moist, heaped-up intertriginous lesions known as condyloma lata may be present. Skin lesions are highly infectious, and biopsy of these lesions examined under dark-field microscopy will reveal treponemes. In addition to classic dermatologic manifestations, secondary syphilis may also present with aseptic meningitis, patchy alopecia, and other mucocutaneous involvement. If untreated, the infection may enter a latent phase in which there are no signs or symptoms of the disease, but serological tests remain positive. Endarteritis is the characteristic presentation of tertiary syphilis and may manifest with neurologic involvement, cardiovascular involvement, or gummatous syphilis. Neurologic sequelae include focal ischemia due to meningovascular involvement and general paresis. Tabes dorsalis, for instance, is defined by syphilitic involvement of the posterior columns of the spinal cord, which leads to sensory ataxia of the lower extremities. Cardiovascular involvement may lead to aortitis and aortic aneurysm. Gummatous disease presents as destructive lesions of the skin, soft tissue, and bony structures. Syphilis may also be transmitted from mother to fetus, and congenital syphilis has varied manifestations but will not be discussed in detail in this report.\n\nThe diagnosis of syphilis often begins with nontreponemal screening tests, including RPR and venereal disease research laboratory (VDRL). Patients with positive screening tests should be tested for specific treponemal markers, such as fluorescent treponemal absorption assay, treponemal particle agglutination, enzyme immunoassays, and chemiluminescence immunoassays. CSF analysis should be performed if there are any neurologic or ophthalmic symptoms at any stage of the disease.\n\nThe treatment of choice for all stages of syphilis is penicillin G. Primary, secondary, and early latent disease may be treated with a single injection of 2.4 million units of penicillin G benzathine. Tertiary syphilis and late latent disease require treatment duration of three weeks with daily benzathine penicillin injections. Neurosyphilis should be treated with 3 to 4 million units of intravenous crystalline benzathine penicillin every four hours for three weeks [2].\n\nOne of the most common complications of treatment is the Jarisch-Herxheimer reaction (JHR). Classically described with penicillin administration in patients with syphilis, the JHR is also known to occur in other spirochetal diseases, including leptospirosis and Borrelia infection. One prospective observational study reported a higher incidence of JHR in patients with HIV who were treated for syphilis compared to non-HIV infected patients (34.6% vs. 25.2%, respectively), although this difference was not statistically significant [3]. Symptoms of JHR include fevers, chills, headache, myalgia, and worsening of skin manifestations. The reaction typically occurs within the first four to six hours after induction of therapy, with peak symptoms occurring around six to eight hours and resolution of symptoms by 16 to 24 hours [4].\n\nThe exact mechanism of JHR remains unclear. The most widely accepted theory is that lipopolysaccharides, a constituent of bacterial cell membranes, are released during exposure to certain antibiotics and may cause a systemic inflammatory response [4,5]. It is postulated that treponemal lipoproteins, once released, undergo phagocytosis by macrophages, which then secrete tumor necrosis factor alpha. Other cytokines, including interleukins IL-6 and IL-8, are also implicated in the inflammatory response to these lipoproteins. In the early phases of the reaction, patients may exhibit vasoconstriction and elevated blood pressure. Later, there is often vasodilation and decreased peripheral resistance, leading to hypotension. There have been few reports of severe reactions requiring vasopressors for hypotension in patients with JHR after treatment of leptospirosis [6,7]. However, most patients recover spontaneously and require minimal supportive care.\n\nThe patient described here had a profound reaction to cephalosporin administration with fluid-refractory hypotension but had subsequent clinical improvement and no further complications during the remainder of his hospital stay. A comprehensive evaluation for other infectious etiologies of his symptoms was unrevealing. He had no known allergies and tolerated further cephalosporin administration; thus, anaphylaxis was not likely implicated as the etiology of his symptoms. Given the timing of his symptoms in relation to antibiotic administration and diagnosis of secondary syphilis, his clinical presentation was thought to be most consistent with JHR.\n\nConclusions\nWe report a case of a patient who required admission to the intensive care unit and vasopressor support in the setting of presumed JHR. To our knowledge, this is the first report of a patient with syphilis who experienced severe hypotension from presumed JHR requiring vasopressor administration after administration of a cephalosporin antibiotic. Providers must be aware that JHR may occur in patients who are treated for syphilis, and, although rare, severe reactions may occur.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n1 Sexually Transmitted Disease Surveillance 2018 1 2021 2018 http://cdc.gov/std/stats18/Syphilis.htm \n2 Sexually transmitted diseases treatment guidelines, 2015 MMWR Recomm Rep 6 2018 Workowski KA Bolan GA; Centers for Disease Control and Prevention 1 137 64 2015 https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm \n3 Jarisch-Herxheimer reaction after penicillin therapy among patients with syphilis in the era of the hiv infection epidemic: incidence and risk factors Clin Infect Dis Yang CJ Lee NY Lin YH 967 979 51 2010 \n4 The Jarisch-Herxheimer reaction after antibiotic treatment of spirochetal infections: a review of recent cases and our understanding of pathogenesis Am J Trop Med Hyg Butler T 46 52 96 2017 28077740 \n5 The Jarisch-Herxheimer reaction: revisited Travel Med Infect Dis Belum GR Belum VR Arudra SK Reddy BS 231 237 11 2013 23632012 \n6 Pressor support during a Jarisch Herxheimer reaction after initiation of treatment for Weil's disease Am J Emerg Med Connor-Schuler R Khan A Goyal N Zimny E 1211 35 2017 \n7 Leptospirosis and Jarisch-Herxheimer reaction QJM Takamizawa S Gomi H Shimizu Y Isono H Shirokawa T Kato M 967 968 108 2015 25862773\n\n",
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"abstract": "A 9-month-old girl with biliary atresia underwent successful living donor liver transplantation from her 42-year-old ABO blood-type incompatible mother. The postoperative course was uneventful until postoperative day (POD) 13 when the recipient displayed an increased volume of drained ascites and decreased her platelet count showing low-velocity portal venous inflow without hepatic venous outflow obstruction. We suspected potential veno-occlusive disease/sinusoidal obstruction syndrome (vod/sos) due to an acute cellular rejection (ACR) episode and performed a liver biopsy (LB). We diagnosed severe episode (Rejection Activity Index Score; P3V3B1 = 7) and started steroid pulse therapy. We performed a second LB on POD 27 because the patient showed weight gain and tender hepatomegaly, diagnosing moderate ACR (P1V3B1 = 5). We started a second course of steroid pulse therapy, but the patient's clinical findings did not improve. On POD 43, her third LB finding showed P1V1B1 with improved processes from ACR, but still displaying severe congestion and fibrotic obliteration of small hepatic veins. We suspected that her immunologic responses were associated with antibody-mediated rejection (AMR) because her anti-HLA class I and class II antibodies were positive by flow panel-reactive antibody method and donor-specific antigen class II and C4d staining were also positive. We added mycophenolate mofetil and administered high-dose intravenous immunoglobulin to control the AMR, and anticoagulant therapy for the VOD/SOS. Her clinical findings and graft venous abnormalities finally improved; she was eventually discharged without sequelae on POD 72.",
"affiliations": "Department of Transplant Surgery, Jichi, Medical University, Szhimotsuke-shi, Tochigi, Japan. yn708@jichi.ac.jp",
"authors": "Yamada|N|N|;Urahashi|T|T|;Ihara|Y|Y|;Sanada|Y|Y|;Wakiya|T|T|;Okada|N|N|;Mizuta|K|K|",
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"title": "Veno-occlusive disease/sinusoidal obstruction syndrome associated with potential antibody-mediated rejection after pediatric living donor liver transplantation: a case report.",
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"abstract": "Other iatrogenic immunodeficiency-associated lymphoproliferative disorders induced by immunosuppressive drugs, such as methotrexate (MTX-LPD), exhibit numerous pathological findings. We report the case of an 81-year-old Japanese woman diagnosed with MTX-LPD exhibiting two distinct pathological features from two different sites. Excisional biopsy of the left cervical lymph node revealed EBV-negative diffuse large B-cell lymphoma and biopsy of a pharyngeal ulcer revealed EBV-positive mucocutaneous ulcer. She was treated using an R-CHOP regimen and maintained complete remission for years. This case demonstrates the heterogeneous pathology of MTX-LPD and suggests the necessity of multiple biopsy.",
"affiliations": "Department of Hematology, Shinmatsudo Central General Hospital, Matsudo, Japan.;Department of Pathology, Tokai University School of Medicine, Isehara, Japan.;Department of Pathology, Tokai University School of Medicine, Isehara, Japan.;Department of Pathology, Tokai University School of Medicine, Isehara, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.;Department of Pathology, Tokai University School of Medicine, Isehara, Japan.",
"authors": "Moriya|Keiichi|K|;Kikuti|Yara Yukie|YY|;Carreras|Joaquim|J|;Kondo|Yusuke|Y|;Shiraiwa|Sawako|S|;Nakamura|Naoya|N|",
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"fulltext": "\n==== Front\nJ Clin Exp Hematop\nJ Clin Exp Hematop\njslrt\nJournal of Clinical and Experimental Hematopathology : JCEH\n1346-4280 1880-9952 JSLRT \n\n32224560\n19038\n10.3960/jslrt.19038\nCase Report\nMethotrexate-associated lymphoproliferative disorder demonstrating composite lymphoma of EBV-negative diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer\nMoriya Keiichi 12 Kikuti Yara Yukie 2 Carreras Joaquim 2 Kondo Yusuke 2 Shiraiwa Sawako 3 Nakamura Naoya 2 1)Department of Hematology, Shinmatsudo Central General Hospital, Matsudo, Japan, 2)Department of Pathology, Tokai University School of Medicine, Isehara, Japan, 3)Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan\nAUTHOR CONTRIBUTIONS: K.M., collection and assembly of data, data analysis and interpretation, and manuscript writing; Y.Y.K., Y.K., and S.S., collection and assembly of data, data analysis and interpretation; N.N., conception and design, administrative support, data analysis and interpretation, manuscript writing, and final approval of the manuscript. All authors approved the manuscript and agreed to be accountable for all aspects of the work.\n\nCorresponding author: Naoya Nakamura, Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya Isehara-shi Kanagawa, 259-1193, Japan., E-mail: naoya@is.icc.u-tokai.ac.jp\n28 3 2020 \n3 2020 \n60 1 11 16\n13 10 2019 30 12 2019 15 1 2020 © 2020 by The Japanese Society for Lymphoreticular Tissue Research2020The Japanese Society for Lymphoreticular Tissue\nResearchThis is an open-access article distributed under the terms of the\nCreative Commons Attribution ShareAlike (CC BY-NC-SA) 4.0 License.Other iatrogenic immunodeficiency-associated lymphoproliferative disorders induced by immunosuppressive drugs, such as methotrexate (MTX-LPD), exhibit numerous pathological findings. We report the case of an 81-year-old Japanese woman diagnosed with MTX-LPD exhibiting two distinct pathological features from two different sites. Excisional biopsy of the left cervical lymph node revealed EBV-negative diffuse large B-cell lymphoma and biopsy of a pharyngeal ulcer revealed EBV-positive mucocutaneous ulcer. She was treated using an R-CHOP regimen and maintained complete remission for years. This case demonstrates the heterogeneous pathology of MTX-LPD and suggests the necessity of multiple biopsy.\n\nKeywords: \n\nOther iatrogenic immunodeficiency-associated lymphoproliferative disordersmethotrexatediffuse large B-cell lymphomaEBV-positive mucocutaneous ulcerEpstein-Barr virus\n==== Body\nINTRODUCTION\nOther iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oiia-LPD) has been defined as lymphoproliferative disorders or lymphomas developing in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting.1 In particular, many rheumatoid arthritis (RA) patients are treated using methotrexate (MTX). The pathological features of MTX-LPD vary. Histology of diffuse large B-cell lymphoma (DLBCL) is predominant, followed by that of classic Hodgkin lymphoma (CHL).1,2\n\nAmong the different types of MTX-LPD, composite lymphoma of MTX-LPD has rarely been reported.3-7 All cases except one were a composite of B-cell lymphoma and T-cell lymphoma.3-6 The other was a composite of DLBCL and follicular lymphoma (FL).7 There has been no report of a case with Epstein-Barr virus (EBV)-positive mucocutaneous ulcers (EBVMCU). EBVMCU were recently reported to develop as MTX-LPD. EBVMCU are characterized by the proliferation of EBV-positive B-cells that exhibit almost the same histology as lymphoma and spontaneously regress.8\n\nAlthough MTX withdrawal is the first choice for patients with MTX-LPD leading to tumor regression, the rate of complete remission (CR) is not high.1,9 Chemotherapy is required for these patients, but there is no standard regimen.10 The choice of regimen in each case is usually based on the pathological diagnosis such as DLBCL and CHL.9 Pathological diagnosis of MTX-LPD is important, but the relationship between pathological findings and clinical courses of MTX-LPD is unclear.\n\nWe report a case of composite lymphoma in a patient with MTX-LPD. Two biopsies from different sites demonstrated DLBCL with EBV-negative and EBV-positive MCU. Multiple biopsy may be important for MTX-LPD, and we discuss chemotherapy in regards to coincidental pathological features.\n\nCASE PRESENTATION\nAn 81-year-old Japanese woman had a medical history of RA, hypertension, and hyperlipidemia. She had not received therapy for rheumatoid arthritis for years, but felt joint pain and swelling from 6 years before the first visit to the hematologist. She was administered oral methotrexate at 4 mg per week and prednisolone at 5 mg per day. These drugs were adjusted for her symptoms, and the final doses were methotrexate at 8 mg per week and prednisolone at 2.5 mg per day.\n\nShe came to our hospital for swelling of the left axillary mass. Physical examination revealed painless bilateral axillary lymph node swelling, which her attending physician thought to be Oiia-LPD. MTX was withdrawn immediately, and prednisolone was increased to 5 mg per day. She was followed up after 2 weeks for judgment of MTX withdrawal. Progression of axillary lymph node swelling was noted and new cervical lymph node swelling was evident. She was referred to a hematologist immediately. Blood testing and computed tomography were performed to evaluate lymph node localization. Main laboratory findings at that time were as follows: hemoglobin 12.2 g/dL (normal range, 11.5-15.5), serum lactate dehydrogenase 405 U/L (110-219), C-reactive protein 1.52 mg/dL (< 0.30), rheumatoid factor 17 IU/ml (< 20), and soluble interleukin-2 receptor 1830 U/mL (145-519) (Table 1). Computed tomography revealed splenomegaly, and bilateral cervical, axillary, mediastinal, intrapelvic, and inguinal lymph node swelling (Figure 1a, b). She was referred to an otolaryngologist for cervical lymph node biopsy, and laryngoscopy as a routine test before biopsy was carried out. Cryptogenic bilateral pharyngeal ulcers were found, and a biopsy sample from the right ulcer was taken for diagnosis. Then, excisional biopsy of left cervical lymph node was performed 11 days after pharyngeal ulcer biopsy.\n\nTable 1 The laboratory data at observation for left cervical lymph node swelling\n\t\t\tnormal range\t\t\t\t\tnormal range\t\nWBC\t6700\t/µL\t4000-8000\t\tBUN\t18\tmg/dL\t8\t\nRBC\t363\tx104/µL\t380-480\t\tCre\t0.6\tmg/dL\t0.5-0.8\t\nHb\t12.2\tg/dL\t11.5-15.5\t\tAlb\t3.6\tg/dL\t3.9-4.8\t\nHt\t37.5\t%\t34.0-42.0\t\tCRP\t1.52\tmg/dL\t< 0.3\t\nplt\t23.4\tx104/µL\t14.0-40.0\t\tGlu\t95\tmg/dL\t70-110\t\nAST (GOT)\t49\tIU/L\t< 30\t\tIgG\t1069\tmg/dL\t870-1700\t\nALT (GPT)\t42\tIU/L\t< 35\t\tIgA\t176\tmg/dL\t110-350\t\nLDH\t405\tIU/L\t110-219\t\tIgM\t28\tmg/dL\t30-180\t\nALP\t205\tIU/L\t100-310\t\tRF\t17\tIU/mL\t< 20\t\nγGTP\t20\tIU/L\t< 35\t\tsIL-2R\t1830\tIU/mL\t145-519\t\nT-Bil\t0.60\tmg/dL\t0.2-1.1\t\tEBV EADR IgG\t< 10\t\t< 10\t\nCK\t108\tIU/L\t30-140\t\tEBV EADR IgM\t< 10\t\t< 10\t\nUA\t4.7\tmg/dL\t3.0-6.0\t\tEBNA\t20\t\t< 10\t\nWBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, plt: platelet, AST: aspartate transaminase, GOT: glutamic oxaloacetic transaminase, ALT: alanine transaminase, GPT: glutamic pyruvic transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γGTP: γ glutamyl transpeptidase, T-Bil: total bilirubin, CK: creatine kinase, UA: uric acid, BUN: blood urea nitrogen, Cre: creatinine, Alb: albumin, CRP: C-reactive protein, Glu: glucose, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, RF: rheumatoid factor, sIL-2R: soluble interleukin-2 receptor, EADR: early antigen diffuse and restricted, EBNA: EBV nuclear antigen\n\nFig. 1 Radiological images. Computed tomography image shows bilateral axillary lymph node swelling (a) and splenomegaly (b). PET-CT shows that FDG uptake in systemic lymph nodes, spleen, tonsils, and upper limbs.\n\nAfter the diagnosis of MTX-LPD, surface lymph nodes slightly decreased in size, but the soluble interleukin-2 receptor level markedly increased from 1,830 to 6,260 U/ml. Positron emission tomography – computed tomography (PET-CT) revealed FDG uptake in systemic lymph nodes, spleen, tonsils, and upper limbs (Figure 1c). The hematologist decided to administer chemotherapy and she received 6 courses of R-CHOP therapy. She did not wish to consult an otolaryngologist again, but all FDG uptake, including in the pharyngeal area, disappeared after R-CHOP therapy. She is currently in CR.\n\nPATHOLOGICAL FINDINGS\nRight pharyngeal biopsy demonstrated an ulcer with partially missing squamous epithelium. Diffuse infiltration of many small lymphocytes with intermingled large-sized lymphocytes was observed. On immunohistochemistry, there were many CD3(+) small-sized T-cells and scattered CD20(+) large-sized B-cells. The latter were CD3(-), CD5(-), CD10(-), CD20(+), BCL2(+), BCL6(+), and MUM1(+). MIB1 reacted with almost all large lymphocytes (>95%). EBER in situ hybridization (ISH) demonstrated positive signals in large-sized B-cells with expression of LMP1 and EBNA2, indicating Latency III. The diagnosis of EBVMCU was made (Figure 2).\n\nFig. 2 EBV-positive mucocutaneous ulcer of the pharynx.\n\nBiopsy shows diffuse infiltration under squamous epithelium (a, hematoxylin-eosin staining, original magnification x20) and large lymphocytes are interspersed in small lymphocytes (b, hematoxylin-eosin staining, original magnification x400). Large lymphocytes are CD3-negative (c), CD20-positve (d), and EBER-positive (e). MIB1 reacted with almost all large lymphocytes (f).\n\nThe cervical lymph node was replaced by diffuse infiltration of large-sized immunoblasts with a prominent nucleolus. On immunohistochemistry, they were CD3(-), CD5(-), CD10(+, weak), CD20(+), BCL2(+), BCL6(+), and MUM1(+). The MIB1 index was 90%. EBER ISH was negative. On flow cytometry, large cells were positive for CD10, CD19, CD20, and kappa. The diagnosis of DLBCL was made (Figure 3).\n\nFig. 3 Diffuse large B-cell lymphoma of the lymph node.\n\nExcisional biopsy of the lymph node shows diffuse infiltration. (a, low-power field, x2, hematoxylin-eosin staining) Diffuse proliferation of large lymphocytes is seen (b, high-power field, x20, hematoxylin-eosin staining). Large lymphocytes are CD3-negative (c), CD20-positive (d), and EBER-negative (e). The MIB1 index of large lymphocytes is 90% (f).\n\nWe next performed polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain (IGH) gene rearrangements using extracted DNA from formalin-fixed paraffin-embedded tissue. A genescan of PCR products revealed the same peak at 241 base pairs in both specimens (Figure 4).\n\nFig. 4 PCR analysis of immunoglobulin heavy chain (IGH) gene. The upper panel is gene scan of PCR product from EBVMCU and lower panel is that from DLBCL. Both PCR products have the same peak at 241 base pairs.\n\nDISCUSSION\nWe report a case of MTX-LPD exhibiting composite lymphoma that consisted of EBV-negative DLBCL in the lymph node and EBVMCU in the pharynx. Moreover, PCR of IGH demonstrated the same clonal origin of two different lymphomas. Our case confirmed that MTX-LPD can include multiple clonal expansion.\n\nThe first point is the importance of multiple biopsy for MTX-LPD. MTX-LPD are mainly DLBCL and CHL, but rarely FL,9 peripheral T-cell lymphoma,8 etc. The pathological features are different, but all cases have the potential for tumor regression by MTX withdrawal. When tumor regression is not observed or tumor regrowth is observed after regression, pathological feature-sensitive chemotherapy is selected. The probability of regression is different among the pathological features. EBVMCU is a new entity from the WHO classification Revised 4th Edition, and almost all cases disappeared after MTX withdrawal.8 On the other hand, clinical features of DLBCL vary, and EBV-negative cases more often require immunochemotherapy.9 There are many predictive factors for tumor regression other than pathological features and EBV positivity such as T cell subset in peripheral blood,11 absolute lymphocyte count after MTX withdrawal,12 and serum lactate dehydrogenase, C-reactive protein, and soluble interleukin-2 receptor levels.13 This case followed a different pattern of tumor regression. EBVMCU disappeared only after MTX withdrawal, whereas DLBCL exhibited negative factors of tumor regression. When an abnormal clinical course of MTX-LPD is noted, biopsy should be performed again, especially if the first pathological feature suggested a good prognosis. Moreover, the chemotherapy regimen is often decided based on pathological findings from one biopsy, but biopsy of a few sites should be considered.\n\nAlthough no report of composite lymphoma of DLBCL and EBVMCU has been reported because of its relative newness, Goyal et al. reported a case of composite lymphoma of DLBCL and CHL with a literature review, and found that in most cases, the two components were clonally related.14 This is the first case of composite lymphoma demonstrating a clonal relationship with MTX-LPD.\n\nThe second point is therapy options. Although chemotherapy is required when regression by MTX withdrawal is not achieved, there is no standard regimen for MTX-LPD.10 There is no method to develop a regimen, and lymphomagenesis is thought to be caused by the immunosuppressive state under MTX, autoimmune disease, inflammation due to autoimmune disease, and EBV infection. This case had two different pathological features and we thought it was discordant lymphoma at first. IgH-PCR revealed that they had the same clonal origin by different genetic modification. This is reasonable because MTX-LPD patients frequently develop lymphoma via many lymphomagenesis factors. The incidence of coincidental lymphoma is not known. When multiple pathological features are present, the best regimen may be (R-)CHOP. CHL-type MTX-LPD were reported to require chemotherapy more frequently than DLBCL-type MTX-LPD, and AVBD is an effective therapy.15 Most CHL-type cases were treated by ABVD, but a few were treated using CHOP-like regimens.16 There was a limited number of cases, but their treatment outcomes were good. ABVD is used for CHL in general, but (R-)CHOP may be an alternative regimen considering coincidental lymphoma. As MTX-LPD patients often develop infection and have autoimmune disease, chemotherapy may be not always be performed because of their frailty. If their general condition does not allow for standard chemotherapy and less-intensive therapy, such as rituximab monotherapy, is needed, low-dose oral etoposide and radiation therapy may be administered.\n\nIn summary, we report a rare case of MTX-LPD exhibiting composite lymphoma, suggesting that multiple or repeated biopsy may be useful for MTX-LPD.\n\nCONFLICT OF INTEREST: The authors declare that they have no conflicts of interest regarding the publication of this paper.\n==== Refs\nREFERENCES\n1 Gaulard P, Swerdlow SH, Harris NL, Sundström C, Jaffe ES. Other iatrogenic immunodeficiency-associated lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed, Lyon, World Health Organization. 2017; pp. 462-464.\n2 Sato Y \nHighlights: focus on immunodeficiency-associated lymphoproliferative disorders.\n\nJ Clin Exp Hematop . 2019 ; 59 : 46 -47\n. 10.3960/jslrt.19020 31257344 \n3 Huwait H Wang B Shustik C Michel RP \nComposite cutaneous lymphoma in a patient with rheumatoid arthritis treated with methotrexate.\n\nAm J Dermatopathol . 2010 ; 32 : 65 -70\n. 10.1097/DAD.0b013e3181af7dee 20098085 \n4 Ichikawa A Arakawa F Kiyasu J \nMethotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression.\n\nEur J Haematol . 2013 ; 91 : 20 -28\n. 10.1111/ejh.12116 23560463 \n5 Makis W Ciarallo A Wang B Gonzalez-Verdecia M Probst S \nComposite cutaneous lymphoma (iatrogenic immunodeficiency-associated lymphoproliferative disorder) in a patient with rheumatoid arthritis treated with methotrexate: staging and evaluation of response to therapy with 18F-FDG PET/CT.\n\nNucl Med Mol Imaging . 2017 ; 51 : 261 -265\n. 10.1007/s13139-016-0463-4 28878854 \n6 Bräuninger A Spieker T Willenbrock K \nSurvival and clonal expansion of mutating “forbidden” (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma.\n\nJ Exp Med . 2001 ; 194 : 927 -940\n. 10.1084/jem.194.7.927 11581315 \n7 Ikeda J Morii E Tomita Y \nMethotrexate-associated lymphoproliferative disorder mimicking composite lymphoma.\n\nInt J Hematol . 2006 ; 83 : 363 -365\n. 10.1532/IJH97.05181 16757440 \n8 Ikeda T Gion Y Yoshino T Sato Y \nA review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects.\n\nJ Clin Exp Hematop . 2019 ; 59 : 64 -71\n. 10.3960/jslrt.18039 31257347 \n9 Tokuhira M Tamaru J Kizaki M \nClinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders.\n\nJ Clin Exp Hematop . 2019 ; 59 : 72 -92\n. 10.3960/jslrt.19007 31257348 \n10 Gion Y Iwaki N Takata K \nClinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types.\n\nCancer Sci . 2017 ; 108 : 1271 -1280\n. 10.1111/cas.13249 28380678 \n11 Saito S Suzuki K Yoshimoto K \nRestoration of decreased T helper 1 and CD8+ T Cell subsets is associated with regression of lymphoproliferative disorders developed during methotrexate treatment.\n\nFront Immunol . 2018 ; 9 : 621 . 10.3389/fimmu.2018.00621 29670617 \n12 Inui Y Matsuoka H Yakushijin K \nMethotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal.\n\nLeuk Lymphoma . 2015 ; 56 : 3045 -3051\n. 10.3109/10428194.2015.1022769 25721751 \n13 Tokuhira M Saito S Okuyama A \nClinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression.\n\nLeuk Lymphoma . 2018 ; 59 : 1143 -1152\n. 10.1080/10428194.2017.1369073 28877615 \n14 Goyal G Nguyen AH Kendric K Caponetti GC \nComposite lymphoma with diffuse large B-cell lymphoma and classical Hodgkin lymphoma components: A case report and review of the literature.\n\nPathol Res Pract . 2016 ; 212 : 1179 -1190\n. 10.1016/j.prp.2016.11.002 27887763 \n15 Berti A Felicetti M Peccatori S \nEBV-induced lymphoproliferative disorders in rheumatic patients: A systematic review of the literature.\n\nJoint Bone Spine . 2018 ; 85 : 35 -40\n. 10.1016/j.jbspin.2017.01.006 28196776 \n16 Miranda RN Loo E Medeiros LJ \nIatrogenic immunodeficiency-associated classical hodgkin lymphoma: clinicopathologic features of 54 cases reported in the literature.\n\nAm J Surg Pathol . 2013 ; 37 : 1895 -1897\n. 10.1097/PAS.0000000000000095 24145656\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1346-4280",
"issue": "60(1)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "EBV-positive mucocutaneous ulcer; Epstein-Barr virus; Other iatrogenic immunodeficiency-associated lymphoproliferative disorders; diffuse large B-cell lymphoma; methotrexate",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D058617:Composite Lymphoma; D003520:Cyclophosphamide; D004317:Doxorubicin; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016403:Lymphoma, Large B-Cell, Diffuse; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D010614:Pharynx; D011241:Prednisone; D000069283:Rituximab; D014456:Ulcer; D014750:Vincristine",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "11-16",
"pmc": null,
"pmid": "32224560",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20098085;31257348;28196776;28878854;24145656;28380678;31257347;31257344;25721751;23560463;11581315;27887763;28877615;29670617;16757440",
"title": "Methotrexate-associated lymphoproliferative disorder demonstrating composite lymphoma of EBV-negative diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer.",
"title_normalized": "methotrexate associated lymphoproliferative disorder demonstrating composite lymphoma of ebv negative diffuse large b cell lymphoma and ebv positive mucocutaneous ulcer"
} | [
{
"companynumb": "JP-ACCORD-178614",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "To describe out-of-hospital ketamine use, patient outcomes, and the potential contribution of ketamine to patient death.\n\n\n\nWe retrospectively evaluated consecutive occurrences of out-of-hospital ketamine administration from January 1, 2019 to December 31, 2019 reported to the national ESO Data Collaborative (Austin, TX), a consortium of 1,322 emergency medical service agencies distributed throughout the United States. We descriptively assessed indications for ketamine administration, dosing, route, transport disposition, hypoxia, hypercapnia, and mortality. We reviewed cases involving patient death to determine whether ketamine could be excluded as a potential contributing factor.\n\n\n\nIndications for out-of-hospital ketamine administrations in our 11,291 patients were trauma/pain (49%; n=5,575), altered mental status/behavioral indications (34%; n=3,795), cardiovascular/pulmonary indications (13%; n=1,454), seizure (2%; n=248), and other (2%; n=219). The highest median dose was for altered mental status/behavioral indications at 3.7 mg/kg (interquartile range, 2.2 to 4.4 mg/kg). Over 99% of patients (n=11,274) were transported to a hospital. Following ketamine administration, hypoxia and hypercapnia were documented in 8.4% (n=897) and 17.2% (n=1,311) of patients, respectively. Eight on-scene and 120 in-hospital deaths were reviewed. Ketamine could not be excluded as a contributing factor in 2 on-scene deaths, representing 0.02% (95% confidence interval 0.00% to 0.07%) of those who received out-of-hospital ketamine. Among those with in-hospital data, ketamine could not be excluded as a contributing factor in 6 deaths (0.3%; 95% confidence interval 0.1% to 0.7%).\n\n\n\nIn this large sample, out-of-hospital ketamine was administered for a variety of indications. Patient mortality was rare. Ketamine could not be ruled out as a contributing factor in 8 deaths, representing 0.07% of those who received ketamine.",
"affiliations": "ESO, Inc, Austin, TX; Department of Emergency Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: antonio.fernandez@eso.com.;ESO, Inc, Austin, TX.;ESO, Inc, Austin, TX.;Colorado Springs Fire Department, Colorado Springs, CO; El Paso County American Medical Response, Colorado Springs, CO; Plains to Peaks Regional Emergency Trauma Advisory Council, Colorado Springs, CO; El Paso-Teller County 911 Authority, Colorado Springs, CO.;Florida Department of Health, Tallahassee, FL; Palm Beach County Fire Rescue, West Palm Beach, FL.;Davie Fire and Rescue, Davie, FL; Coral Springs Fire Department, Coral Springs, FL; Southwest Ranches Fire Rescue, Southwest Ranches, FL.;ESO, Inc, Austin, TX.",
"authors": "Fernandez|Antonio R|AR|;Bourn|Scott S|SS|;Crowe|Remle P|RP|;Bronsky|E Stein|ES|;Scheppke|Kenneth A|KA|;Antevy|Peter|P|;Myers|J Brent|JB|",
"chemical_list": "D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.annemergmed.2021.02.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "78(1)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000778:Anesthetics, Dissociative; D002648:Child; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "123-131",
"pmc": null,
"pmid": "34112540",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Out-of-Hospital Ketamine: Indications for Use, Patient Outcomes, and Associated Mortality.",
"title_normalized": "out of hospital ketamine indications for use patient outcomes and associated mortality"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-03181",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"dru... |
{
"abstract": "Adult T-cell leukemia/lymphoma (ATL) is known for its aggressive behavior, frequently presenting with hypercalcemia. ATL tumor cells uniquely secrete parathyroid hormone-related protein, viral peptides, and inflammatory cytokines, inducing a state of high bone turnover and activation of the receptor activator of nuclear factor kappa-B signaling pathway resulting in hypercalcemia.\nA 54-year-old woman diagnosed with ATL presented with severe hypercalcemia refractory to bisphosphonate therapy. Treatment with denosumab was followed by protracted hypocalcemia and hypophosphatemia lasting approximately 5 months.\nHypercalcemia due to acute ATL was responsive in this case to denosumab therapy.\nClinicians should be aware of the possibility of protracted hypocalcemia in patients with ATL exposed to denosumab therapy.",
"affiliations": null,
"authors": "Japp|Emily Anne|EA|;Meron|Michal Kasher|MK|;Zonszein|Joel|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2018-0479",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "5(3)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e210-e213",
"pmc": null,
"pmid": "31967036",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "1751370;23685544;24915117;26860123;26093811;1424188;3915405;1675362;24890549;23660959;17297657;23198151;3690980;2388034;19249350;28943574;25421444;15176993",
"title": "A DRAMATIC RESPONSE TO DENOSUMAB: PROTRACTED HYPOCALCEMIA RELATED TO HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE 1-ASSOCIATED ADULT T-CELL LEUKEMIA/LYMPHOMA.",
"title_normalized": "a dramatic response to denosumab protracted hypocalcemia related to human t cell lymphotropic virus type 1 associated adult t cell leukemia lymphoma"
} | [
{
"companynumb": "US-AMGEN-USASP2018102437",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 3-month-old boy with primary congenital glaucoma developed a transient corneal endothelial opacity after needle bleb revision with adjunctive 5-fluorouracil. This case presents a rare toxicity that, although transient, is concerning due to the potential of amblyopia. The authors review prior cases of corneal opacity associated with 5-fluorouracil. [J Pediatr Ophthalmol Strabismus. 2016;53:e54-e57.].",
"affiliations": null,
"authors": "Fu|Gregory L|GL|;Alexander|Janet L|JL|;Saeedi|Osamah J|OJ|",
"chemical_list": "D000963:Antimetabolites; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3928/01913913-20161003-01",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0191-3913",
"issue": "53()",
"journal": "Journal of pediatric ophthalmology and strabismus",
"keywords": null,
"medline_ta": "J Pediatr Ophthalmol Strabismus",
"mesh_terms": "D000963:Antimetabolites; D003228:Conjunctiva; D015715:Corneal Edema; D005472:Fluorouracil; D006801:Humans; D006871:Hydrophthalmos; D007223:Infant; D056965:Injections, Intraocular; D008297:Male; D009339:Needles",
"nlm_unique_id": "7901143",
"other_id": null,
"pages": "e54-e57",
"pmc": null,
"pmid": "27783089",
"pubdate": "2016-10-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7980129;22878445;15665346;24308066;8155053;26997807;19835330;22029538;20973895",
"title": "Persistent Corneal Edema Associated With Subconjunctival 5-fluorouracil in an Infant With Primary Congenital Glaucoma.",
"title_normalized": "persistent corneal edema associated with subconjunctival 5 fluorouracil in an infant with primary congenital glaucoma"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201702414",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nPrimary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AECTCL) is a rare and aggressive lymphoma characterised by ulcerated lesions and a poor prognosis.\n\n\nOBJECTIVE\nTo present a case series of four previously misdiagnosed AECTCL patients and discuss the importance of early diagnosis.\n\n\nMETHODS\nAll patients in this study were identified from the database of the Dermatology Department of the Medical School of Bezmialem Vakif University, based on clinical and histopathological diagnosis of AECTCL between 2010 and 2018.\n\n\nRESULTS\nAECTCL cases may mimic many benign dermatoses and accurate diagnosis may be delayed.\n\n\nCONCLUSIONS\nBecause of its poor prognosis, early diagnosis of AECTCL may be helpful in improving the likelihood of patient survival, but further study is needed to address the challenges in diagnosing this rare and aggressive lymphoma.",
"affiliations": "Department of Dermatology, Bezmialem Vakif University Faculty of Medicine.;Department of Dermatology, Bezmialem Vakif University Faculty of Medicine.;Department of Dermatology, Bezmialem Vakif University Faculty of Medicine.;Department of Pathology, Bezmialem Vakif University Faculty of Medicine.;Department of Dermatology, Bezmialem Vakif University Faculty of Medicine.;Acibadem University Faculty of Medicine, Department of Pathology.;Department of Haematology, Bezmialem Vakif University Faculty of Medicine, İstanbulTurkey.;Acibadem University Faculty of Medicine, Department of Pathology.",
"authors": "Onsun|Nahide|N|;Dizman|Didem|D|;Emiroğlu|Nazan|N|;Yildiz|Pelin|P|;Akaslan|Tahsin Çağdaş|TÇ|;Tosuner|Zeynep|Z|;Çetin|Güven|G|;Demirkesen|Cuyan|C|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/ejd.2020.3843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "30(4)",
"journal": "European journal of dermatology : EJD",
"keywords": "CD8<td:hsp sp=\"0.25\" xmlns:td=\"http://www.thomsondigital.com/xml/common/dtd\" />+<td:hsp sp=\"0.25\" xmlns:td=\"http://www.thomsondigital.com/xml/common/dtd\" />; aggressive; cutaneous T-cell lymphoma; epidermotropic",
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000368:Aged; D018414:CD8-Positive T-Lymphocytes; D003937:Diagnosis, Differential; D018450:Disease Progression; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D011379:Prognosis; D012878:Skin Neoplasms; D012883:Skin Ulcer; D055815:Young Adult",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "358-361",
"pmc": null,
"pmid": "32969796",
"pubdate": "2020-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Challenges in early diagnosis of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma: a case series of four patients.",
"title_normalized": "challenges in early diagnosis of primary cutaneous cd8 aggressive epidermotropic cytotoxic t cell lymphoma a case series of four patients"
} | [
{
"companynumb": "TR-STRIDES ARCOLAB LIMITED-2021SP000175",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
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"activesubstancename": "PREDNISOLONE"
},
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{
"abstract": "BACKGROUND\nHerein we report a case of cutaneous granular bacteriosis, with discussion of the nosological setting of this entity based upon the clinical and histological findings.\n\n\nMETHODS\nA 62-year-old woman receiving methotrexate for Sezary syndrome was admitted for fever of 38.5̊C and overall impairment of her health. She presented a fistulous nodule on her right knee, and skin biopsy revealed a focus of ulcerated suppuration with quantities of Gram+ and Grocott+ granules containing no filament, enclosed by eosinophilic matter (Splendore-Hoeppli phenomenon). A sample of effusion from the sole of her right foot revealed a methicillin-sensitive strain of Staphylococcus aureus, which was also found in several blood cultures. Two abscessed nodules on the middle right lobe were visible on a thoracic CT scan despite the initial absence of respiratory symptoms. In view of this bacteraemia of cutaneous origin with sepsis caused by methicillin-sensitive S. aureus complicated by pulmonary abscesses, dual antibiotic treatment against staphylococci (cloxacillin-gentamicin followed by rifampicin-ofloxacin) was given over a two-month period.\n\n\nCONCLUSIONS\nThe histological picture of granular bacteriosis suggested the possibility of botryomycosis or mycetoma. Botryomycosis involves chronic, relapsing, weeping and ulcero-vegetating abscesses. Mycetoma consists of fistulous swellings that secrete a discharge composed of blood and serum and containing grains made up of filaments. Although the staphylococcal organism identified was evocative of botryomycosis, the clinical findings were not consistent with either of these entities, since they revealed an acute bacterial abscess. The most adequate term is thus the more generic name of septic cutaneous granular abscess.",
"affiliations": "Service de dermatologie, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France.;Service de dermatologie, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France.;Service d'anatomopathologie, hôpital Haut-Lévêque, CHU de Bordeaux, avenue de Magellan, 33604 Pessac, France.;Service de dermatologie, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France.;Service de dermatologie, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France; Inserm U1053, équipe 3 oncogenèse des lymphomes cutanés, université de Bordeaux, France.;Service de dermatologie, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France; Inserm U1053, équipe 3 oncogenèse des lymphomes cutanés, université de Bordeaux, France. Electronic address: anne.pham-ledard@chu-bordeaux.fr.",
"authors": "Mermin|D|D|;Védie|A-L|AL|;Jullie|M-L|ML|;Fauconneau|A|A|;Beylot-Barry|M|M|;Pham-Ledard|A|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2016.09.679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "144(4)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "Botryomycose; Botryomycosis; Pustule; Pustulosis; Sepsis; Sezary syndrome; Syndrome de Sézary",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D017577:Cutaneous Fistula; D003881:Dermatomycoses; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008169:Lung Abscess; D008727:Methotrexate; D008875:Middle Aged; D008271:Mycetoma; D018805:Sepsis; D012751:Sezary Syndrome; D013194:Staining and Labeling; D013203:Staphylococcal Infections; D013207:Staphylococcal Skin Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "275-278",
"pmc": null,
"pmid": "28034470",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous granular bacteriosis occurring in Staphylococcus aureus septicaemia.",
"title_normalized": "cutaneous granular bacteriosis occurring in staphylococcus aureus septicaemia"
} | [
{
"companynumb": "FR-ACCORD-047454",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "BACKGROUND\nCoronary artery vasospasm after administration of fluorouracil (5-FU) is a rare complication. Commonly presenting as chest pain during or shortly after 5-FU infusions, vasospasm can place patients at risk for ventricular dysrhythmia, myocardial ischemia, and infarction. Although not fully understood, any 5-FU cardiotoxicity seems to be multifactorial, and patients with coronary artery disease and renal dysfunction may be at particular risk.\n\n\nMETHODS\nA 46-year-old woman with no prior cardiovascular disease history presented with sudden-onset chest pain after initial administration of 5-FU continuous infusion therapy. The patient subsequently developed ventricular fibrillation arrest and underwent successful electrocardioversion. Coronary angiography was unremarkable for coronary stenosis or vasospasm. The presumed etiology was secondary to 5-FU cardiac toxicity. The patient was re-challenged with 5-FU therapy and developed repeat chest pain. The 5-FU was completely stopped and the patient's symptoms resolved, with no further dysrhythmic events 9 months after initial presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients who develop chest pain during or after 5-FU infusion should warrant strong consideration for admission and continuous cardiac monitoring for potential ventricular dysrhythmias and cardiac ischemia.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Florida, Jacksonville, Florida.;Department of Internal Medicine, Mayo Clinic, Florida, Jacksonville, Florida.;Department of Emergency Medicine, Mayo Clinic, Florida, Jacksonville, Florida.;Department of Emergency Medicine, Mayo Clinic, Florida, Jacksonville, Florida.",
"authors": "Ray|Jordan C|JC|;Cho|Paul|P|;Dragon|Marc|M|;Graham|Charles G|CG|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "50(1)",
"journal": "The Journal of emergency medicine",
"keywords": "FOLFOX; cardiac arrest; cardiotoxicity; chemotherapy; fluorouracil; vasospasm; ventricular tachycardia",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002637:Chest Pain; D005260:Female; D005472:Fluorouracil; D006323:Heart Arrest; D006801:Humans; D008875:Middle Aged; D014693:Ventricular Fibrillation",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e1-6",
"pmc": null,
"pmid": "26482827",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of 5-Fluorouracil-Induced Cardiac Arrest.",
"title_normalized": "a case of 5 fluorouracil induced cardiac arrest"
} | [
{
"companynumb": "US-ACCORD-035138",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
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"drugadditional": null,
"dru... |
{
"abstract": "Tuberous sclerosis complex (TSC) is an autosomal-dominant multi system disorder. The genetic basis of the disorder is mutations in the TSC1 or TSC2 gene, which leads to over activation of the mammalian target of rapamycin (mTOR) protein complex and results in development of benign tumors in different body systems such as brain, skin, lungs and kidney. The mTOR inhibitors are presently the main treatment option for patients with TSC. We here report a 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of largest AML decreased by ~24.0% in the longest diameter. A reduction of the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episode associated with skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well.",
"affiliations": "University Clinic of Nephrology, Skopje, Republic of North Macedonia.;Institute of Radiology, Skopje, Republic of North Macedonia.;University Clinic of Neurology, Skopje, Republic of North Macedonia.;University Clinic of Urology, Skopje, Republic of North Macedonia.;University Clinic of Neurosurgery, Skopje, Republic of North Macedonia.;University Clinic of Nephrology, Skopje, Republic of North Macedonia.",
"authors": "Rambabova Bushljetik|I|I|;Lazareska|M|M|;Barbov|I|I|;Stankov|O|O|;Filipce|V|V|;Spasovski|G|G|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.2478/bjmg-2020-0017",
"fulltext": "\n==== Front\nBalkan J Med Genet\nbjmg\nbjmg\nBalkan Journal of Medical Genetics : BJMG\n1311-0160\n2199-5761\nSciendo\n\nbjmg-2020-0017\n10.2478/bjmg-2020-0017\nCase Report\nBilateral Renal Angiomyolipomas and Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex: a Case Report and Review of The Literature\nRambabova Bushljetik I M.D., Ph.D. *1\nLazareska M 2\nBarbov I 3\nStankov O 4\nFilipce V 5\nSpasovski G 1\n1 University Clinic of Nephrology, Skopje, Republic of North Macedonia\n2 Institute of Radiology, Skopje, Republic of North Macedonia\n3 University Clinic of Neurology, Skopje, Republic of North Macedonia\n4 University Clinic of Urology, Skopje, Republic of North Macedonia\n5 University Clinic of Neurosurgery, Skopje, Republic of North Macedonia\n* Rambabova Bushljetik I, M.D., Ph.D., University Clinic of Nephrology, Vodnjanska 17, 1000 Skopje, Republic of North Macedonia. Tel.: +389-214-7191. Mobile: +389-72-216-581. Fax: +389-231-1188. irambabova@yahoo.com\n11 2020\n23 3 2021\n23 2 9398\n© 2020 Rambabova Bushljetik I, Lazareska M, Barbov I, Stankov O, Filipce V, Spasovski G, published by Sciendo\n2020\nRambabova Bushljetik I, Lazareska M, Barbov I, Stankov O, Filipce V, Spasovski G, published by Sciendo\nThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.\nAbstract\n\nTuberous sclerosis complex (TSC) is an autosomal-dominant multi system disorder. The genetic basis of the disorder is mutations in the TSC1 or TSC2 gene, which leads to over activation of the mammalian target of rapamycin (mTOR) protein complex and results in development of benign tumors in different body systems such as brain, skin, lungs and kidney. The mTOR inhibitors are presently the main treatment option for patients with TSC. We here report a 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of largest AML decreased by ~24.0% in the longest diameter. A reduction of the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episode associated with skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well.\n\nKeywords\n\nTuberous sclerosis complex (TSC)\nAngiomyolipoma (AML)\nSubependymal giant cell astrocytoma (SEGA)\nEverolimus (EVE)\n==== Body\nIntroduction\n\nTuberous sclerosis complex (TSC) is a rare disease, with a birth rate of 1 in 6,000 to 1 in 10,000 newborns [1]. It is a multisystemic, autosomal dominant condition that can result in formation of hamartomas in multiple organs, mainly in brain, kidney, skin and lung. The two thirds of affected patients have sporadic mutations [2].\n\nThe British dermatologist John James Pringle first observed papular facial rash in a female patient with intellectual impairment, describing it as “adenoma sebaceum” [3]. The French neurologist Désiré-Magloire Bourneville described potato-like tumors in the brain and associated them with the cutaneous manifestations and other clinical symptoms [4]. Hence, a historical text appeared as the “Bourneville-Pringle disease” [5,6].\n\nAt a molecular basis, TSC results from a mutation in one of two TSC1 and TSC2 genes (located in chromosomes 9 and 16, respectively). These two genes encode two proteins (hamartin and tuberin), form intracellular complexes and physiologically inhibit a serine-threoninekinase, known as mTOR (mammalian target of rapamycin). Their complete loss allows unregulated stimulation of cell growth and proliferation [7].\n\nThe first TSC Consensus Conference was held in 1998 and the recommendations for diagnosis and clinical management of patients with TSC were developed [8]. At the second International TSC Consensus Conference (2012), these criteria were reviewed and updated and recommendations for diagnosis, surveillance and management of TSC patients were issued [9].\n\nThe mTOR inhibitor rapamycin, and later the rapamycin derivate, everolimus, played a significant role in solid organ transplant protocols to prevent rejection, in oncology as an anticancer target therapy and for elution of vascular stents in interventional cardiology [10]. In 2010, everolimus became the first approved therapy by the US Food and Drug Administration (FDA) for treatment of TSC-associated subependymal giant cell astrocytoma (SEGA). Later, in 2012, everolimus was also approved by the FDA to treat renal angiomyolipomas (AMLs), in TSC patients [11].\n\nDiagnosis of TSC can be confirmed with clinical diagnostic criteria and gene testing, but in 10.0-25.0% of patients there is no gene mutation confirmed. Clinical diagnostic criteria consist of 11 major and six minor features. Definitive diagnosis can be confirmed with presence of two major or one major and two minor futures [9].\n\nAbout 85.0% of patients with TSC during childhood and adolescence manifest seizures, cognitive and/or behavioral problems (autism and autism spectrum disease). A subset of adult patients have normal mental status. The main brain lesions include cortical tubers, subependymal nodules and SEGA present in only 5.0-15.0% of TSC patients. Subependymal giant cell astrocytoma can lead to ventricular enlargement and hydrocephalus increasing the rate of morbidity and mortality among this group of patients [12].\n\nAngiomyolipomas are the most common renal lesions (~80.0% of cases) in TSC patients. They are typically multiple and bilateral, composed of abnormal blood vessels, immature smooth muscle and fat cells, and progressively enlarge from the first years of life and adolescence. Spontaneous bleeding may occur due to abnormal vasculature and aneurysm development. The size of tumors (AMLs) >4 cm is risk factors for bleeding. Except AMLs, TSC patients have been diagnosed also with multiple renal cysts [13].\n\nLung involvement, called lymphangioleiomyomatosis (LAM), is characterized by replacement of alveolar tissue by cystic changes and proliferation of the smooth muscle cells in pulmonary parenchyma. This condition is the third most common cause of TSC morbidity, affecting almost exclusively reproductive age females with TSC [14].\n\nCutaneous manifestations are observed in 90.0% of patients and present the most visible features of TSC. The most common are hypopigmented macules as pathognomonic sign for early diagnosis. Facial angiofibromas are observed in 85.0-90.0% of cases [15].\n\nCase report\n\nA 21-year-old female patient was diagnosed with sporadic TSC at the age of 12. She was the first child in the family, born at term with placenta previa. Because of presence of multiple hypopigmented macules on the skin at the time of birth, she was transferred to the Neo-natology Department at the University Pediatric Clinic, Skopje, Republic of North Macedonia. However, the exact diagnosis was not established. At 1 year of age, the first convulsion was reported and treatment with phenobarbitol was initiated. At the age of 5, multiple facial angiofibromas were noted in the medical records. Furthermore, some cosmetic procedures were performed. In 2010, at the age of 12, a new episode of convulsions appeared, and she was hospitalized. A complete check-up was performed and genetic analysis confirmed a deletion of exon 1 of the TSC2 gene and the upstream region of the TSC2 gene by multiplex ligation probe amplification (MLPA) method (MRC-Holland, Amsterdam, The Netherlands). No presence of mutation in the genetic analysis of the parents was confirmed, and it was described as a de novo mutation. Multiple major and minor features were described in the medical reports (Table 1).\n\nTable 1 The proband’s clinical diagnostic criteria.\n\nMajor Features\tMinor Features\t\nAngiomyolipomas\tMultiple renal cysts\t\nCortical tubers\tGingival fibromas\t\nSEGA\t\t\nHypopigmented macules\t\t\nFagial angiofibromas\t\t\nCardiac rhabdomyoma\t\t\nSEGA: subependymal giant cell astrocytoma.\n\nTreatment with mTOR inhibitor was suggested, but not initiated. In 2014, she was regularly transferred to the University Clinic of Nephrology, Skopje, Republic of North Macedonia, as an adult patient. Another investigation and laboratory tests were performed there. The patient was asymptomatic, without the presence of new episodes of epilepsy, flank pain and abnormal urinary sediment.\n\nUltrasonography of the urinary tract revealed multiple heterogenous lipid-rich lesions present in both kidneys. The largest formation in the upper pole of the right kidney had the longest diameter of ~11 cm. She was referred to the urologist, but surgical treatment or an embolization procedure was not suggested. In 2015, according to the guidelines for treatment of TSC patients, systematic therapy with everolimus was initiated.\n\nMagnetic resonance imaging of the urinary tract and brain were performed before initiation of everolimus treatment (Figures 1 and 2). After 12 months of treatment, reduction of the renal tumors and SEGA were registered (Figures 3 and 4). At 36 months, ~24.0% reduction in the longest diameter of the largest AML in right kidney was achieved. Reduction of SEGA was also observed (Figures 5 and 6). All biochemical parameters remained stable during the follow-up period. Normal renal function without a new onset of proteinuria was observed (Table 2).\n\nFigure 1 At the upper pole of the right kidney a large AML, longest diameter of 12.3 × 7.1 cm (arrow left) with heterogenous density, presence of microaneurisms at the posterior and lateral segments, with a dominant lipid component revealed on the urinary tract MRI (red arrow). At the lower pole of the left kidney, an AML with the dimension of 5.3 × 3.7 cm (arrow right) and other multiple AMLs with dimensions of 5-10 mm were found, as well as multiple cysts.\n\nFigure 2 On the brain MRI, multiple lesions as subependimal nodules, subcortical tubers and largest tumor mass presented in foramen Monro as SEGA (diameter 3.0 × 1.5 cm) were described.\n\nFigure 3 Magnetic resonance imaging of the urinary tract at 12 months after everolimus initiation.\n\nFigure 4 Magnetic resonance imaging of the brain at 12 months after everolimus initiation.\n\nFigure 5 Magnetic resonance imaging of the urinary tract at 36 months after everolimus treatment initiation.\n\nFigure 6 Magnetic resonance imaging of the brain at 36 months after everolimus treatment initiation.\n\nTable 2 Biochemical laboratory findings in the follow-up period.\n\nParameters\tFirst Year\tSecond Year\tThird Year\t\nHb (g/dL)\t12.1\t12.4\t12.6\t\nRBC (1012/L)\t3.9\t4.1\t4.0\t\nPlatelets (109/L)\t245.0\t254.0\t256.0\t\nProtein/albumin (g/dL)\t79.0/41.0\t82.0/42.0\t81.0/42.0\t\nSCR (μmol/L)\t62.0\t61.0\t63.0\t\nBUN (mmol/L)\t3.8\t2.9\t3.5\t\nCholesterol (mmol/L)\t4.0\t4.1\t4.0\t\nHDL (mmol/L)\t1.2\t1.3\t1.2\t\nLDL (mmol/L)\t2.3\t2.2\t2.1\t\nTriglycerides (mmol/L)\t0.96\t1.10\t1.10\t\nCRP (mg/L)\t1.9\t1.2\t1.6\t\nProteinuria (g/24 hours)\t0.13\t0.11\t0.17\t\nHb: hemoglobin; RBC: red blood cell count; SCR: serum creatinine;\n\nBUN: blood urea nitrogen; HDL: high-density lipoproteins;\n\nLDL: low-density lipoproteins; CRP: c-reactive protein test.\n\nDiscussion\n\nAccording to the established diagnostic criteria, our case displayed many major and two minor features for “definitive diagnosis,” also confirmed by genetic testing. The different disease presentation required a multi disciplinary approach for the patient to manage the epilepsy and renal involvement.\n\nOur patient started with everolimus treatment in the late phase of the disease presentation, with large AMLs in both kidneys (>12 cm). Everolimus tablets, 10 mg/day. were administered, with blood trough levels in the range of 5.015.0 ng/mL in accordance with the guidelines. Renal AMLs are the most frequent features of TSC as benign tumors. In the general population the prevalence of AML is rare (0.020.29%) of both males and females. Treatment of renal AML depends on its presentation [16]. According the guidelines for asymptomatic AMLs of >3 cm, they should be treated with mTOR inhibitors. In our case, the reduction of AML in the follow-up period was lower than presented literature results, as well as the reduction of the SEGA volume was not similar to the published studies, but still acceptable.\n\nPhase III EXIST-1 study (NCT00789828) included 117 patients at the age of 0.8-26.6 years with TSC-associated growing SEGA. Patients were randomly included in a 2:1 ratio to receive everolimus (n = 78) and placebo (n = 39). The median follow-up period was 9.7 months when 35.0% of the patients in the everolimus treatment group achieved >50.0% reduction in size of SEGA vs. 0.0% of the patients in the placebo group. The exploratory end points, AML response rate (>1 AML >1 cm in the longest diameter) 53.0% achieved response rate vs. 0.0% in the placebo group [17].\n\nThe everolimus for AML associated with TSC or sporadic lymphangiomyomatosis (EXIST-2) trial has confirmed the previous reports. It was a multi center, randomized, double blind, placebo-controlled, phase III trial of 118 patients with a definite TSC diagnosis and at least one AML >3 cm that showed 42.0% reduction of AML volume in everolimus compared to 0.0% in the placebo group [18].\n\nAfter 3 years of treatment, our patient reached approximately 24.0% reduction in the longest diameter of AML. No evidence of new AMLs or episodes of bleeding were observed.\n\nAn extension phase of the EXIST study included 112 patients who received >1 dose of everolimus, and 58.0% achieved AML response rate. Almost all patients (97.0%) achieved reduction in renal lesion volumes during the study period. Median duration of everolimus exposure was 46.9 months. Approximately 14.3% of patients experienced progression in AML size [19]. While previous reports have largely assessed the effect of everolimus for AMLs with longest diameter <10 cm, another case report included three patients suggesting this drug might also be effective for huge lesions of >20 cm in diameter [20].\n\nOf note, in our case during the period of treatment, some adverse events were registered. A few episodes of aphthous stomatitis requiring reduction of the dose of everolimus were observed. One febrile episode with zosterlike cutaneous rash on the lower extremity was treated at University Clinic of Dermatovenerology, Skopje, Republic of North Macedonia, with temporary everolimus treatment interruption.\n\nFacial angiofibromas were features of the disease with the highest response rate to treatment with good psychological effect on the patient. In the reported studies, proteinuria was one of the adverse events, but in our case the patient did not experience proteinuria, and had normal renal function for the whole period of treatment [18,19].\n\nDue to the presence of a large brain structural manifestation, continuous follow-up by a neurologist and a neurosurgeon was performed. The majority of TSC patients have neurological symptoms, ~90.0% of affected individuals experience seizures and almost half also experience cognitive impairments, autism, or other behavioral disorders. Epilepsy is seen in 70.0-90.0% of patients, most commonly presenting in the first year of life [12]. Our patient had normal mental status without autism and/or behavioral difficulties. However, seizures were present from the first year of life, with prescribed therapy till 5 years. At the age of 12 years, when the new onset of seizures was registered, an anticonvulsive treatment was reinitiated. After many years free of seizures, the anticonvulsive therapy was again ceased. Thus, after 3 years undergoing everolimus therapy, a new episode of seizure was reported and anticonvulsive therapy was administered. The patient was placed on lamotrigin. The MRI findings excluded hydrocephalus without necessity of surgical treatment. Based on the literature, surgical intervention of SEGA >3 cm has 67.0% risk of surgery-related complications and surgery on tumors >4 cm was associated with 73.0% risk of complications [21,22].\n\nIt is recommended that SEGAs are MRI-monitored every 1-3 years in patients younger than 25, as these tumors usually grow in children and young adolescents, but do not have a tendency to grow in adulthood [21,22]. Similar case reports are found in the literature with similar disease presentation and medical treatment [23].\n\nConclusions\n\nTuberous sclerosis complex is a multi systemic disorder with different symptom presentations and the highest rate of morbidity and mortality associated with renal and brain manifestations. Treatment with everolimus is beneficial for even such large AMLs, and the positive impact persisted during a long-term administration with a low rate of adverse effects. A positive impact of everolimus treatment was also observed on the brain tumors, especially SEGA.\n\nDeclaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.\n==== Refs\nReferences\n\n1 O’Callaghan FJ Shiell AW Osborne JP Martyn CN Prevalence of tuberous sclerosis estimated by capture-recapture analysis Lancet 1998 351 9114 1490\n2 Crino PB Nathanson KL Henske EP The tuberous sclerosis complex N Engl J Med 2006 355 13 1345 1356 17005952\n3 Jansen FE van Nieuwenhuizen O van Huffelen AC Tuberous sclerosis complex and its founders J Neurol Neurosurg Psychiatry 2004 75 5 770 15090576\n4 Brigo F Lattanzi S Trinka E Nardone R Bragazzi NL Ruggieri M et al First descriptions of tuberous sclerosis by Désiré-Magloire Bourneville (18401909 Neuro-pathology 2018 38 6 577 582\n5 Rodrigues DA Gomes CM Costa IM Tuberous sclerosis complex Ann Bras Dermatol 2012 87 2 184 196\n6 Portocarrero LKL Quental KN Samorano LP de Oliveira ZNP Rivitti-Machado MCDM Tuberous sclerosis complex: review based on new diagnostic criteria Ann Bras Dermatol 2018 93 3 323 331\n7 Pirson Y Tuberous sclerosis complex-associated kidney angiomyolipoma: From contemplation to action Nephrol Dial Transplant 2013 28 7 1680 1685 23413089\n8 Roach ES Gomez MR Northrup H Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria J Child Neurol 1998 13 12 624 628 9881533\n9 Northrup H Krueger DA; International Tuberous Sclerosis Complex Consensus Group Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference Pediatr Neurol 2013 49 4 243 254 24053982\n10 Gabardi S Baroletti SA Everolimus: A proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology Pharma-cotherapy 2010 30 10 1044 1056\n11 Capal JK Franz DN Profile of everolimus in the treatment of tuberous sclerosis complex: An evidence-based review of its place in therapy Neuropsychiatr Dis Treat 2016 12 2165 2172 27601910\n12 Curatolo P Moavero R de Vries PJ Neurological and neuropsychiatric aspects of tuberous sclerosis complex Lancet Neurol 2015 14 7 733 745 26067126\n13 Budde K Gaedeke J Tuberous sclerosis complex-associated angiomyolipomas: Focus on mTOR inhibition Am J Kidney Dis 2012 59 2 276 283 22130643\n14 McCormack FX Inoue Y Moss J Singer LG Strange C Nakata K et al Efficacy and safety of sirolimus in lymphangioleiomyomatosis N Engl J Med 2011 364 17 1595 1606 21410393\n15 Jacks SK Witman PM Tuberous sclerosis complex: An update for dermatologists Pediatr Dermatol 2015 32 5 563 570 25776100\n16 Murray TE Doyle F Lee M Transarterial embolization of angiomyolipoma: A systematic review J Urol 2015 194 3 635 639 25916674\n17 Franz DN Belousova E Sparagana S Bebin EM Frost M Kuperman R et al Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial Lancet 2013 381 9861 125 132 23158522\n18 Bissler JJ Kingswood JC Radzikowska E Zonnenberg BA Frost M Belousova E et al Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebocontrolled trial Lancet 2013 381 9869 817 824 23312829\n19 Bissler JJ Kingswood JC Radzikowska E Zonnenberg BA Belousova E Frost MD et al Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study PLoS One 2017 12 8 e0180939 28792952\n20 Toriu N Mizuno H Sawa N Sumida K Suwabe T Hayami N et al Everolimus reduces the size of tuberous sclerosis complex-related huge renal angiomyolipomas exceeding 20 cm in the longest diameter Case Rep Oncol 2018 11 2 258 267 29867433\n21 Kotulska K Borkowska J Roszkowski M Mandera M Daszkiewicz P Drabik K et al Surgical treatment of subependymal giant cell astrocytoma in tuberous sclerosis complex patients Pediatr Neurol 2014 50 4 307 312 24507694\n22 Roth J Roach ES Bartels U Jóźwiak S Koenig MK Weiner HL et al Subependymal giant cell astrocytoma: Diagnosis, screening, and treatment Recommendations from the International Tuberous sclerosis Complex Consensus Conference 2012. Pediatr Neurol 2013 49 6 439 444 24138953\n23 Stein JR Reidman DA Imaging manifestations of a subependymal giant cell astrocytoma in tuberous sclerosis Case Rep Radiol 2016 2016 3750450 26942030\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1311-0160",
"issue": "23(2)",
"journal": "Balkan journal of medical genetics : BJMG",
"keywords": "Angiomyolipoma (AML); Everolimus (EVE); Subependymal giant cell astrocytoma (SEGA); Tuberous sclerosis complex (TSC)",
"medline_ta": "Balkan J Med Genet",
"mesh_terms": null,
"nlm_unique_id": "9806959",
"other_id": null,
"pages": "93-98",
"pmc": null,
"pmid": "33816078",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "22570021;29924239;29867433;21410393;27601910;9881533;26942030;25916674;22130643;9605811;17005952;15090576;24138953;24507694;25776100;23158522;23413089;24053982;26067126;20874042;28792952;23312829;30215888",
"title": "Bilateral Renal Angiomyolipomas and Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex: a Case Report and Review of The Literature.",
"title_normalized": "bilateral renal angiomyolipomas and subependymal giant cell astrocytoma associated with tuberous sclerosis complex a case report and review of the literature"
} | [
{
"companynumb": "NVSC2021MK077648",
"fulfillexpeditecriteria": "1",
"occurcountry": "MK",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a benign lymphoproliferative lesion related to iatrogenic or age-related immunosuppression in patients with prior Epstein-Barr virus (EBV) infection. Although the clinical presentation may resemble malignant disease, the course of EBVMCU is indolent, and regression is expected when immunosuppression is reduced. We present a case of EBVMCU in the gingiva of a 59-year-old male patient with long-standing pemphigus vulgaris. The initial presentation was suspicious for oral cavity cancer, which was ruled out by biopsy. After reduction of immunosuppression, the ulceration regressed and an area of exposed necrotic bone remained. Complete healing was achieved after sequestrectomy and primary closure with a local gingival flap.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region.;Pathology Division, Queen Mary Hospital, Hong Kong Special Administrative Region.;Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: richsu@hku.hk.",
"authors": "Li|D T S|DTS|;Lo|A W I|AWI|;Su|Y-X|YX|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2020.01.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "49(10)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "Epstein–Barr virus; lymphoproliferative disorder; mucocutaneous ulcer",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D020031:Epstein-Barr Virus Infections; D005881:Gingiva; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D014456:Ulcer",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "1351-1354",
"pmc": null,
"pmid": "31982237",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Oral Epstein-Barr virus-positive mucocutaneous ulcer: gingival presentation of a benign lymphoproliferative lesion.",
"title_normalized": "oral epstein barr virus positive mucocutaneous ulcer gingival presentation of a benign lymphoproliferative lesion"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
"drugadmi... |
{
"abstract": "OBJECTIVE\nTo report a series of four patients with uterine sarcoma, including one with müllerian adenosarcoma (MA) and three with low-grade endometrial stromal sarcoma (LGESS), who developed intracranial meningiomas while receiving the progesterone agonist megestrol acetate.\n\n\nMETHODS\nThe hospital records, imaging studies, and pathology slides of four patients who were treated for uterine sarcomas and subsequently developed intracranial meningiomas were reviewed.\n\n\nRESULTS\nAll patients underwent surgery for their gynecologic cancers and received maintenance therapy with long-term hormonal suppression with megestrol acetate. Each of the four patients later developed neurologic symptoms secondary to intracranial meningiomas. Three patients had more than one meningioma. Histopathologic examination of all excised tumors showed strong immunoreactivity for progesterone receptors (PRs).\n\n\nCONCLUSIONS\nPatients with uterine sarcoma subtypes LGESS and MA may be predisposed to develop meningiomas, particularly in the setting of long-term treatment with megestrol acetate. Alternatively, preexisting, clinically silent meningiomas in these patients may have progressed to the point of clinical symptoms in the presence of the progesterone agonist megestrol acetate. Without previous imaging studies showing the presence or absence of meningioma before initiation of megestrol acetate treatment, there is no way to draw definitive conclusions regarding this possibility. Clinical and neuroradiologic surveillance for meningiomas should be strongly considered in patients with these uterine sarcoma subtypes, particularly in patients undergoing long-term suppressive therapy with megestrol acetate.",
"affiliations": "Department of Neurosurgery, Roswell Park Cancer Institute and School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA. tjgruber@buffalo.edu",
"authors": "Gruber|Thomas J|TJ|;Fabiano|Andrew J|AJ|;Deeb|George|G|;Lele|Shashikant B|SB|;Fenstermaker|Robert A|RA|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D019290:Megestrol Acetate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2011.03.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "76(5)",
"journal": "World neurosurgery",
"keywords": null,
"medline_ta": "World Neurosurg",
"mesh_terms": "D018931:Antineoplastic Agents, Hormonal; D005260:Female; D006801:Humans; D019290:Megestrol Acetate; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D012509:Sarcoma; D014594:Uterine Neoplasms",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "477.e16-20",
"pmc": null,
"pmid": "22152580",
"pubdate": "2011-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intracranial meningiomas in patients with uterine sarcoma treated with long-term megestrol acetate therapy.",
"title_normalized": "intracranial meningiomas in patients with uterine sarcoma treated with long term megestrol acetate therapy"
} | [
{
"companynumb": "US-TEVA-783088USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEGESTROL"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Sheehan syndrome refers to a series of clinical symptoms resulting from avascular necrosis of anterior pituitary due to various reasons.\n\n\n\nWe report a case of multiple myeloma patient after one cycle of chemotherapy consisting of bortezomib and dexamethasone diagnosis of Sheehan syndrome with obstinate diarrhea, low blood glucose, and coma symptom, especially, the fluorodeoxyglucose positron emission tomography (FDG-PET) and brain magnetic resonance imaging (MRI) revealed that the manifestations in the saddle area were in accordance with empty sella syndrome. A single administration with lenalidomide was given for both consolidative and maintenance treatment, and satisfactory efficacy was achieved. With the patient now remaining in satisfactory medical condition, the success of this therapy has been shown.\n\n\n\nThis is the first report showing a patient with combined multiple myeloma and rarely seen Sheehan syndrome, in which lenalidomide was given for treatment, and satisfactory efficacy was achieved.",
"affiliations": "Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China.;Department of Radiation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China.",
"authors": "Bing|Xia|X|0000-0003-3297-5702;Peifang|Liu|L|",
"chemical_list": "D007155:Immunologic Factors; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1002/cnr2.1171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2573-8348",
"issue": "2(4)",
"journal": "Cancer reports (Hoboken, N.J.)",
"keywords": "Sheehan's syndrome; bortezomib; chemotherapy; lenalidomide; multiple myeloma",
"medline_ta": "Cancer Rep (Hoboken)",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007018:Hypopituitarism; D007155:Immunologic Factors; D000077269:Lenalidomide; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D010902:Pituitary Gland; D000072078:Positron Emission Tomography Computed Tomography; D016896:Treatment Outcome",
"nlm_unique_id": "101747728",
"other_id": null,
"pages": "e1171",
"pmc": null,
"pmid": "32721123",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25648343;11275951;15809451;14763913;20944496;32721123;2592838;21183555;24295815;23775712;23945005",
"title": "Treatment-triggered onset and diagnosis of Sheehan syndrome in a multiple myeloma patient.",
"title_normalized": "treatment triggered onset and diagnosis of sheehan syndrome in a multiple myeloma patient"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-221406",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "Due to the anatomical peculiarity of the appendix, diagnosis of tumors arising from this area can be challenging by clinicoradiologic means. We report a case of a rare primary appendiceal signet ring carcinoma with an uncommon presentation. An 86-year-old woman was admitted to our hospital with subacute epigastric pain. Computed tomography demonstrated bowel wall thickening with fat stranding in the ileocecal region. The leading diagnostic consideration was inflammatory bowel disease. Upon colonoscopy, a swollen, distorted ileocecal valve was identified. The remaining colon was otherwise unremarkable. Extensive biopsy sampling of the ileocecal region and colon was performed. A lymphangitic signet ring carcinoma within the ileocecal region was diagnosed on biopsy; there was no dysplasia or carcinoma of the remaining biopsies. By cytomorphology and immunoprofile, a lymphangitic signet ring carcinoma of appendiceal origin was the primary consideration, further confirmed upon subsequent laparotomy. This case represents an unusual pattern of appendiceal tumor spread with localized, lymphangitic involvement, creating a milieu which closely simulates Crohn's disease on imaging modalities.",
"affiliations": "Tricia Murdock, Maryam Zenali, Department of Pathology, University of Vermont-College of Medicine/Fletcher Allen Health Care, Burlington, VT 05401, United States.;Tricia Murdock, Maryam Zenali, Department of Pathology, University of Vermont-College of Medicine/Fletcher Allen Health Care, Burlington, VT 05401, United States.;Tricia Murdock, Maryam Zenali, Department of Pathology, University of Vermont-College of Medicine/Fletcher Allen Health Care, Burlington, VT 05401, United States.",
"authors": "Murdock|Tricia|T|;Lim|Nicholas|N|;Zenali|Maryam|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i7.2206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(7)",
"journal": "World journal of gastroenterology",
"keywords": "Appendiceal signet ring carcinoma; Computed tomography; Crohn’s disease; Inflammatory bowel disease; Signet ring carcinoma",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000369:Aged, 80 and over; D001063:Appendiceal Neoplasms; D001706:Biopsy; D018279:Carcinoma, Signet Ring Cell; D003113:Colonoscopy; D003424:Crohn Disease; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007078:Ileal Neoplasms; D007080:Ileocecal Valve; D008207:Lymphatic Metastasis; D011237:Predictive Value of Tests; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2206-9",
"pmc": null,
"pmid": "25717258",
"pubdate": "2015-02-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11312162;22878887;12115365;23986852;22302267;21160886;21653683;20058100;16258711;23692577;16973770",
"title": "Lymphangitic spread from the appendiceal adenocarcinoma to the ileocecal valve, mimicking Crohn's disease.",
"title_normalized": "lymphangitic spread from the appendiceal adenocarcinoma to the ileocecal valve mimicking crohn s disease"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2015-056690",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "We report a case of a 49-year-old female who presented to the emergency department with blurred vision and vomiting, hours after taking two tablets of 250 mg of acetazolamide. The anterior chamber was bilaterally flat, with normal intraocular pressure in both eyes. An ultrasound biomicroscopic (UBM) examination showed bilateral ciliary effusion and complete appositional angle closure in all quadrants. Acetazolamide-induced bilateral angle closure was diagnosed. Steroid and cycloplegic therapy were initiated, and acetazolamide was discontinued. The following day, the anterior chamber had regained its volume without substantial change in the effusion size. Three weeks later, complete resolution of the ciliary effusion was verified by means of a third UBM scan.",
"affiliations": "Fundación de Cirugía Ocular Jorge Zambrano, Buenos Aires, Argentina.;Glaucoma Service, Hospital Oftalmológico Santa Lucía, Buenos Aires, Argentina.",
"authors": "Grigera|Julio Daniel|JD|;Grigera|Emilio Daniel|ED|",
"chemical_list": "D002257:Carbonic Anhydrase Inhibitors; D009184:Mydriatics; D013256:Steroids; D000086:Acetazolamide",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0004-2749.20170080",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2749",
"issue": "80(5)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D000086:Acetazolamide; D000867:Anterior Chamber; D002257:Carbonic Anhydrase Inhibitors; D005260:Female; D006801:Humans; D007429:Intraocular Pressure; D033401:Microscopy, Acoustic; D008875:Middle Aged; D009184:Mydriatics; D009216:Myopia; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "327-329",
"pmc": null,
"pmid": "29160547",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ultrasound biomicroscopy in acetazolamide-induced myopic shift with appositional angle closure.",
"title_normalized": "ultrasound biomicroscopy in acetazolamide induced myopic shift with appositional angle closure"
} | [
{
"companynumb": "AR-HERITAGE PHARMACEUTICALS-2018HTG00020",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditio... |
{
"abstract": "This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65-83). Study patients received an induction with idarubicin (8 mg/m(2) iv days 1-3) plus cytarabine (100 mg/m(2) iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). Median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy. This trial is registered at clinicaltrials.gov identifier: 00840346.",
"affiliations": "Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca emocio@usal.es.;Hospital Ramón y Cajal, Madrid.;Hospital Lozano Blesa, Zaragoza.;Hospital Universitario 12 de Octubre, Madrid.;Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville.;Hospital de la Santa Creu y Sant Pau, Barcelona.;Hospital Germans Trias i Pujol, Badalona.;Hospital San Carlos, Madrid.;Hospital Universitario La Fe, Valencia.;Hospital Ramón y Cajal, Madrid.;Hospital Universitario La Fe, Valencia.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Complejo Asistencial Universitario de Salamanca (IBSAL), Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca.;Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA), IDISNA, Pamplona, Spain.",
"authors": "Ocio|Enrique M|EM|;Herrera|Pilar|P|;Olave|María-Teresa|MT|;Castro|Nerea|N|;Pérez-Simón|José A|JA|;Brunet|Salut|S|;Oriol|Albert|A|;Mateo|Marta|M|;Sanz|Miguel-Ángel|MÁ|;López|Javier|J|;Montesinos|Pau|P|;Chillón|María-Carmen|MC|;Prieto-Conde|María-Isabel|MI|;Díez-Campelo|María|M|;González|Marcos|M|;Vidriales|María-Belén|MB|;Mateos|María-Victoria|MV|;San Miguel|Jesús F|JF|;|||",
"chemical_list": "D006877:Hydroxamic Acids; D007211:Indoles; D003561:Cytarabine; D000077767:Panobinostat; D015255:Idarubicin",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2015.129577",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "100(10)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids; D015255:Idarubicin; D007211:Indoles; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D060046:Maintenance Chemotherapy; D008297:Male; D020714:Maximum Tolerated Dose; D018365:Neoplasm, Residual; D000077767:Panobinostat; D011379:Prognosis; D012008:Recurrence; D016896:Treatment Outcome",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1294-300",
"pmc": null,
"pmid": "26160880",
"pubdate": "2015-10",
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"title": "Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study.",
"title_normalized": "panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia phase ib ii panobidara study"
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"abstract": "A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.",
"affiliations": "Department of Cardiovascular Medicine, Kitasato University School of Medicine, Japan.;Department of Cardiovascular Medicine, Kitasato University School of Medicine, Japan.;Department of Cardiovascular Medicine, Kitasato University Kitasato Institute Hospital, Japan.;Department of Cardiovascular Medicine, Kitasato University School of Medicine, Japan.",
"authors": "Yazaki|Mayu|M|;Nabeta|Takeru|T|;Inomata|Takayuki|T|;Ako|Junya|J|",
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"doi": "10.2169/internalmedicine.5150-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n32999224\n10.2169/internalmedicine.5150-20\nCase Report\nAn Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis\nYazaki Mayu 1\nNabeta Takeru 1\nInomata Takayuki 2\nAko Junya 1\n1 Department of Cardiovascular Medicine, Kitasato University School of Medicine, Japan\n2 Department of Cardiovascular Medicine, Kitasato University Kitasato Institute Hospital, Japan\nCorrespondence to Dr. Takeru Nabeta, nabetake@med.kitasato-u.ac.jp\n\n30 9 2020\n15 2 2021\n60 4 553556\n22 4 2020\n7 8 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.\n\ncardiac fibrosis\nbeta-blocker\nrenin-angiotensin-aldosterone system inhibitors\nmagnetic resonance imaging\n==== Body\nIntroduction\n\nDilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).\n\nWe experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.\n\nCase Report\n\nA 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.\n\nAn echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.\n\nCoronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.\n\nTwo and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).\n\nThree years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).\n\nFigure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).\n\nFigure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.\n\nAlthough medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).\n\nThe patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.\n\nFigure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance\n\nDiscussion\n\nWe demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.\n\nThe administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.\n\nReplacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.\n\nConclusion\n\nWe herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Konstam MA . Reliability of ventricular remodeling as a surrogate for use in conjunction with clinical outcomes in heart failure. Am J Cardiol 96 : 867-871, 2005.16169379\n2. Fonarow GC , Abraham WT , Albert NM , et al . Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure: findings from the OPTIMIZE-HF program. J Am Coll Cardiol 52 : 190-199, 2008.18617067\n3. Moon J , Ko YG , Chung N , et al . Recovery and recurrence of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy. Can J Cardiol 25 : e147-e150, 2009.19417864\n4. Eichhorn EJ , Bedotto JB , Malloy CR , et al . Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation 82 : 473-483, 1990.1973638\n5. Ishida J , Konishi M , von Haehling S . The appropriate dose of angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers in patients with dilated cardiomyopathy. The higher, the better? ESC Heart Fail 2 : 103-105, 2015.\n6. Halliday BP , Wassall R , Lota AS , et al . Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 393 : 61-73, 2019.30429050\n7. Nattel S , Rangno RE , Van Loon G . Mechanism of propranolol withdrawal phenomena. Circulation 59 : 1158-1164, 1979.436208\n8. Waagstein F , Caidahl K , Wallentin I , Bergh CH , Hjalmarson A . Long-term beta-blockade in dilated cardiomyopathy. effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation 80 : 551-563, 1989.2548768\n9. Westendorp B , Schoemaker RG , Buikema H , Boomsma F , van Veldhuisen DJ , van Gilst WH . Progressive left ventricular hypertrophy after withdrawal of long-term ACE inhibition following experimental myocardial infarction. Eur J Heart Fail 8 : 122-130, 2006.16084760\n10. Hori M , Sasayama S , Kitabatake A , et al . Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the multicenter carvedilol heart failure dose assessment (MUCHA) trial. Am Heart J 147 : 324-330, 2004.14760332\n11. Gulati A , Jabbour A , Ismail TF , et al . Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 309 : 896-908, 2013.23462786\n12. Becker MAJ , Cornel JH , Ven PM , Rossum AC , Allaart CP , Germans T . The prognostic value of late gadolinium-enhanced cardiac magnetic resonance imaging in nonischemic dilated cardiomyopathy: a review and meta-analysis. JACC Cardiovasc Imaging 11 : 1274-1284, 2018.29680351\n\n",
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"issue": "60(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "beta-blocker; cardiac fibrosis; magnetic resonance imaging; renin-angiotensin-aldosterone system inhibitors",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D002311:Cardiomyopathy, Dilated; D006333:Heart Failure; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009206:Myocardium; D016277:Ventricular Function, Left",
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"title": "An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.",
"title_normalized": "an irreversible worsening cardiac function after withdrawing medical treatments in a patient with dilated cardiomyopathy a pathological analysis"
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"abstract": "In the United States, approximately 15% of adults suffer from major depressive disorder (MDD), which results in an annual cost of over $200 billion per year. In the perioperative setting, MDD is associated with increased morbidity and mortality. The exact causes of the increase in adverse outcomes are unknown. Major depression affects virtually all major systems in the human body, and most antidepressants affect dopamine, norepinephrine, and serotonin levels or alter their target receptors. Unfortunately, anesthesia and medications used in the perioperative period affect the same neurotransmitters. As a result, patients with MDD are at an increased risk for cardiovascular effects, altered thermoregulation, and postoperative cognitive dysfunction. To determine when to continue or hold antidepressants preoperatively and avoid potential drug interactions, perioperative providers must understand the pharmacological action of antidepressants. This article reviews the pathophysiology of MDD, mechanism of action of antidepressants, and perioperative considerations for patients on antidepressant medications.",
"affiliations": "Nurse Anesthesia Track, School of Nursing, The University of Alabama at Birmingham, Birmingham, AL. Electronic address: earoke@uab.edu.;Gwinnett Medical Center, Lawrenceville, GA.;Nurse Anesthesia Track, School of Nursing, The University of Alabama at Birmingham, Birmingham, AL.",
"authors": "Aroke|Edwin N|EN|;Robinson|Alexis N|AN|;Wilbanks|Bryan A|BA|",
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"keywords": "anesthesia; anesthesia complications; antidepressants; depression; perioperative",
"medline_ta": "J Perianesth Nurs",
"mesh_terms": "D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D006801:Humans; D019990:Perioperative Care; D011183:Postoperative Complications",
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"title": "Perioperative Considerations for Patients With Major Depressive Disorder Undergoing Surgery.",
"title_normalized": "perioperative considerations for patients with major depressive disorder undergoing surgery"
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"abstract": "Herein, we present an unusual case of secondary infertility after prolonged use of low-dose finasteride for androgenetic alopecia in a 40-year-old man. We detected sperm DNA damage in the patient. Despite such a long-term use, we observed that impairment in semen parameters and sperm DNA fragmentation index regressed after the drug was discontinued. Consequently, pregnancy occurred and resulted in live birth.",
"affiliations": "Department of Urology, Faculty of Medicine, Rumi University, Aksinne Mah, Esmetaş Sok, No: 16, 42040 Meram, Konya, Turkey. drsalvarci@hotmail.com",
"authors": "Şalvarci|Ahmet|A|;Istanbulluoğlu|Okan|O|",
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"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000328:Adult; D000505:Alopecia; D004249:DNA Damage; D018120:Finasteride; D006801:Humans; D007248:Infertility, Male; D008297:Male; D055101:Semen Analysis; D013094:Spermatozoa",
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"title": "Secondary infertility due to use of low-dose finasteride.",
"title_normalized": "secondary infertility due to use of low dose finasteride"
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"abstract": "Our purpose was to determine the incidence of surgical site infection (SSI) in cancer patients receiving an intrathecal drug delivery system (IDDS) and compare that rate with the incidence of SSI in the general population receiving an IDDS or spinal cord stimulator. We attempted to describe risk factors for SSIs in cancer patients treated with IDDS in terms of exposure to cancer treatments.\n\n\n\nRetrospective review.\n\n\n\nLarge tertiary care center.\n\n\n\nCancer patients receiving an IDDS in 2006-2013.\n\n\n\nThe incidence of SSI was determined according to the US Centers for Disease Control and Prevention definition. Medication regimens and current cancer treatment were investigated to identify immunocompromised patients during IDDS placement. Microbacteriology, treatment, and overall outcomes were investigated.\n\n\n\nSixty-four patients had an IDDS implanted in 2006-2013. SSI developed in four patients (6.2%). All four patients had received chemotherapy or radiotherapy within three months before implantation. Three of the three were receiving dexamethasone, and three of the four required explantation of the IDDS.\n\n\n\nThe incidence of SSI was at the upper end of the published infection rates for IDDS. The risk of SSI may be increased in this population because of factors that alter the patient's immune status, including concomitant corticosteroid use, radiotherapy near the SSI, and presence of immunomodulators. The identification and mitigation of certain risk factors for this population may prevent infection in future patients.",
"affiliations": "Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Scanlon|Maura M|MM|;Gazelka|Halena M|HM|;Moeschler|Susan M|SM|;Hoelzer|Bryan C|BC|;Hooten|W M|WM|;Bendel|Markus A|MA|;Lamer|Tim J|TJ|",
"chemical_list": "D000700:Analgesics",
"country": "England",
"delete": false,
"doi": "10.1093/pm/pnw203",
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"issue": "18(3)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Cancer; Implantation; Infections; Intrathecal",
"medline_ta": "Pain Med",
"mesh_terms": "D000700:Analgesics; D005260:Female; D006801:Humans; D015994:Incidence; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010146:Pain; D059408:Pain Management; D012189:Retrospective Studies; D013530:Surgical Wound Infection",
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"title": "Surgical Site Infections in Cancer Patients with Intrathecal Drug Delivery Devices.",
"title_normalized": "surgical site infections in cancer patients with intrathecal drug delivery devices"
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"activesubstancename": "IRINOTECAN"
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"abstract": "Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days.\n\n\n\nThis is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged ≥65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2).\n\n\n\nWith a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged ≥65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related.\n\n\n\nIn conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients.",
"affiliations": "Institut Catalx00E0; d'Oncologia, Hospital Duran i Reynals, IDIBELL, Barcelona, Spain.",
"authors": "González-Barca|Eva|E|;Canales|Miguel A|MA|;Salar|Antonio|A|;Ferrer|Secundino|S|;Domingo-Domenech|Eva|E|;Vidal|María-Jesús|MJ|;Grande|Carlos|C|;Bargay|Joan|J|;Gardella|Santiago|S|;Oriol|Albert|A|;Briones|Javier|J|;García-Frade|Javier|J|;Bello|Jose L|JL|;Sánchez-Blanco|Jose J|JJ|;Peñalver|Francisco Javier|FJ|;Tomás|Jose Francisco|JF|;Asensio|Antonio|A|;López|Andrés|A|;Caballero|Dolores|D|;|||",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069585:Filgrastim; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008137:Longitudinal Studies; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D011092:Polyethylene Glycols; D011241:Prednisone; D011994:Recombinant Proteins; D012074:Remission Induction; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
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"title": "Long-Term Follow-Up of a Phase II Trial of Six Cycles of Dose-Dense R-CHOP-14 for First-Line Treatment of Diffuse Large B-Cell Lymphoma in Young and Elderly Patients.",
"title_normalized": "long term follow up of a phase ii trial of six cycles of dose dense r chop 14 for first line treatment of diffuse large b cell lymphoma in young and elderly patients"
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"abstract": "Laryngeal tuberculosis (TB) is a rare condition, occurring in less than 1% of patients infected with pulmonary TB. We present a case of a 57-year-old male patient, who presented in extremis with audible stridor, increased work of breathing and cyanosis. In addition, the patient had a complex medical history, including a recent diagnosis of congenital malformation of the epiglottis. Emergency intervention was required to secure the airway, and after initial attempts at intubation were unsuccessful, an emergency tracheostomy was performed. Four days after initial presentation, his sputum tested positive for acid-fast bacilli, and a subsequent CT chest revealed pulmonary as well as laryngeal TB, which was confirmed on biopsy of the larynx. The patient was commenced on a 24-week course of anti-tuberculous treatment and was successfully decannulated 6 months after the emergency airway was established.",
"affiliations": "Department of Anaesthetics, Whittington Health NHS Trust, London, UK.;Department of Anaesthetics, University College London Hospitals NHS Foundation Trust, London, UK.;Department of Anaesthetics, Whittington Health NHS Trust, London, UK.",
"authors": "Cole|Abigail Elizabeth|AE|;Heaton|Daniel|D|;Chekairi|Ahmed|A|",
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"keywords": "anaesthesia; ear, nose and throat/otolaryngology; tb and other respiratory infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000402:Airway Obstruction; D003490:Cyanosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012135:Respiratory Sounds; D014387:Tuberculosis, Laryngeal",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27837744;26556848;28352769;28383648;4027773",
"title": "Laryngeal tuberculosis: a rare cause of critical airway obstruction.",
"title_normalized": "laryngeal tuberculosis a rare cause of critical airway obstruction"
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"abstract": "Aim: Coronavirus disease 2019 is a life-threatening disease and how to improve survival of the patients is of great importance. Objective: To determine whether tocilizumab (TCZ) shows favorable results in coronavirus disease 2019 patients. Materials & methods: A retrospective study of four patients who received TCZ was conducted from 19 February to 31 March 2020 at Leishenshan Hospital, Wuhan, China. Clinical data of patients were compared before and after the administration of the agent. Results: There was not much difference in the clinical feature improvements and computed tomography images after TCZ administration in two mild patients. The other two severe patients died of disseminated intravascular coagulation and acute respiratory distress syndrome, respectively. Conclusion: Administration of TCZ was not shown a favorable outcome in this preliminary uncontrolled case series.",
"affiliations": "Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.;Department of Respiratory & Critical Care Medicine, Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.;Molecular Diagnostic Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Infectious Diseases, Wuhan Leishenshan Hospital, Wuhan, Hubei, China.;Department of Respiratory & Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medical, Shanghai, China.;Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.;Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.",
"authors": "Cui|Ran|R|https://orcid.org/0000-0003-4923-5882;Zhu|Ying|Y|https://orcid.org/0000-0002-0256-3216;Wang|Yulan|Y|;Chen|Xiao-Hua|XH|;Li|Qiang|Q|;Dai|Sheng-Ming|SM|;Tong|Qiang|Q|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/fvl-2020-0410",
"fulltext": "\n==== Front\nFuture Virol\nFuture Virol\nFVL\nFuture Virology\n1746-0794\n1746-0808\nFuture Medicine Ltd London, UK\n\n10.2217/fvl-2020-0410\nCase Series\nTocilizumab in the treatment of coronavirus disease 2019 pneumonia: real-world data from a case series\nhttps://orcid.org/0000-0003-4923-5882\nCui Ran ‡12\nhttps://orcid.org/0000-0002-0256-3216\nZhu Ying ‡3\nWang Yulan ‡4\nChen Xiao-Hua 25\nLi Qiang *6\nDai Sheng-Ming **1\nTong Qiang ***1\n1 1Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China\n2 2Department of Infectious Diseases, Wuhan Leishenshan Hospital, Wuhan, Hubei, China\n3 3Department of Respiratory & Critical Care Medicine, Seventh Medical Center of Chinese PLA General Hospital, Beijing, China\n4 4Molecular Diagnostic Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China\n5 5Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China\n6 6Department of Respiratory & Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medical, Shanghai, China\n* Author for correspondence: Liqres@163.com\n** Author for correspondence: shengmingdai@163.com\n***Author for correspondence: jasontong1985@outlook.com\n‡ Authors contributed equally\n\n24 5 2021\n5 2021\n24 5 2021\n10.2217/fvl-2020-041013 12 2020\n06 5 2021\n24 5 2021\n© 2021 Future Medicine Ltd\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 License\n\nAim: Coronavirus disease 2019 is a life-threatening disease and how to improve survival of the patients is of great importance. Objective: To determine whether tocilizumab (TCZ) shows favorable results in coronavirus disease 2019 patients. Materials & methods: A retrospective study of four patients who received TCZ was conducted from 19 February to 31 March 2020 at Leishenshan Hospital, Wuhan, China. Clinical data of patients were compared before and after the administration of the agent. Results: There was not much difference in the clinical feature improvements and computed tomography images after TCZ administration in two mild patients. The other two severe patients died of disseminated intravascular coagulation and acute respiratory distress syndrome, respectively. Conclusion: Administration of TCZ was not shown a favorable outcome in this preliminary uncontrolled case series.\n\nLay abstract\n\nPatients treated with tocilizumab was not indicated a favoring outcome with not much improvement in two moderate patients and two severe patients died. Early identification of cytokine release syndrome in treating coronavirus disease 2019 patients with IL-6 antagonist is required.\n\nKeywords: \n\nadverse events\nCOVID-19\ncytokine release syndrome\nIL-6\nIL-6R antagonists\nIL-6 receptor\ninflammatory response\nmortality\nSARS-CoV-2\ntocilizumab\n==== Body\nA pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has swept over worldwide. It is reported that approximately 17–29% of infected people with chronic comorbidities may rapidly deteriorate into acute respiratory distress syndrome (ARDS) and septic shock, 11–15% of which die of multiple organ failure [1,2]. So far, no specific therapeutic agent has been reported to decrease mortality substantially. A clinical trial of lopinavir–ritonavir in adults with severe novel coronavirus pneumonia (NCP) was found to have no beneficial outcomes [3]. Other potential therapies, such as remdesivir, hydroxychloroquine, convalescent plasma, etc., are still under investigation [4–6]. Tocilizumab (TCZ), an inhibitor of IL-6 receptor, was approved for the treatment of cytokine-release syndrome (CRS) by the US FDA, and it has been recommended as an optional therapy in the treatment of severe patients with COVID-19 in the seventh version of the guidelines published by the National Health Commission of China [7]. A small study of 21 patients concluded that TCZ is effective in treating severe cases, although there is still a paucity of data assessing the efficacy and safety of TCZ [8]. Later on, more publications reported that patients can benefit partially or totally from TCZ treatment [9–11]. However, in the very beginning when we applied TCZ treatment to the COVID-19 patients, we found some opposite findings. We herein report the cases series of four patients with COVID-19 in the administration of TCZ in the real world.\n\nMaterials & methods\n\nThe study was conducted at the Infectious Disease Department, Leishenshan Hospital, Wuhan, China, from 19 February to 31 March 2020, and the final follow-up date was 31 March 2020. The study was approved by the ethics committees as required from the hospital. Written informed consent was obtained from each patient involved or their family member.\n\nPatients\n\nPatients confirmed to have COVID-19 by a positive PCR test when they were first diagnosed were eligible to receive TCZ if they fulfilled the following criteria: they were severe patients for whom computed tomography (CT) images showed bilateral diffuse lung disease, their serum level of IL-6 was detected as being elevated continuously high.\n\nDisease severity classification\n\nTwo patients were classified as the moderate type. This type experiences the following conditions: fever; respiratory symptoms; pneumonia performance on x-rays or CT scans.\n\nTwo patients were considered as the severe type in admission and rapidly progressed to the critical type. Patients are classified as the severe type if they meet any of the following criteria: respiratory distress (RR ≥30/min); oxygen saturation ≤93% when breathing ambient air; arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤300 mmHg.\n\nPatients are classified as the critical type if they satisfy any of the following conditions: respiratory failure requiring mechanical ventilation; shock; failure of other organs requiring intensive care unit monitoring and management.\n\nClinical information\n\nClinical features, radiological abnormalities, and laboratory results were collected before and after TCZ treatment. Clinical features included: demographic data, basic information, days of admission from symptom onset and presenting symptoms, data related to the therapy plan and changes in clinical manifestations. Radiological abnormalities were assessed by x-ray and chest CT image. Laboratory data included white blood cell count, lymphocyte count, chemistry panels with liver and kidney function, inflammatory factors C-reactive protein (CRP), erythrocyte sedimentation rate and cytokines IL-6, TNF-α and IL-10.\n\nResults\n\nIn accordance with the National Health Commission of China’s guidelines, patients were admitted from 19 February 2020 to 29 February 2020. Two moderate, one severe and one critical patient met the diagnosis and treatment protocol for NCP defined in the seventh edition of the guidelines (demographic characteristics shown in Table 1). The initial symptoms were fever (4/4 patients), cough (3/4), sputum production (1/4), chest tightness (1/4), tachypnea (1/4), shortness of breath (4/4), fatigue (3/4), myalgia (1/4) and poor appetite (1/4). Symptoms of Cases 1 and 2 were mostly resolved, except for cough and remittent fever after TCZ management. Not much amelioration of symptoms was seen in Cases 3 and 4. As for comorbidities, diabetes was shown in three patients and hypertension in one. Moderate patients (Case 1 and Case 2) had diabetes and emphysema, respectively. The severe patient (Case 3) had a history of chronic hepatitis and diffuse large B-cell lymphoma. He had a long-term medication of entecavir and had undergone chemotherapy in combination with rituximab. Case 4 was a critically ill patient who had a history of hypertension and diabetes with an unstable condition.\n\nTable 1. Demographic characteristics of patients with novel coronavirus pneumonia.\n\n \tModerate cases in non-ICU\tSevere and critically severe cases in ICU\t\n \tCase 1\tCase 2\tCase 3\tCase 4\t\nAge\t69\t64\t47\t73\t\nGender\tFemale\tMale\tMale\tMale\t\nDate of onset of symptoms\t6 January 2020\t18 January 2020\t12 February 2020\t4 February 2020\t\nDate of admission\t29 February 2020\t29 February 2020\t29 February 2020\t19 February 2020\t\nDuration time (day)\t55\t43\t18\t16\t\nInitial symptoms\t \t \t \t√\t\n Fever (°C)\t37.8\t40\t40\t39\t\n Cough\t√\t√\t√\t \t\n Sputum production\t \t \t \t \t\n Chest tightness\t \t \t√\t \t\n Tachypnea\t \t \t√\t \t\n Shortness of breath\t√\t√\t√\t√\t\n Fatigue\t \t√\t√\t√\t\n Myalgia\t \t \t \t√\t\n Poor appetite\t \t \t√\t \t\nComorbidities\t \t \t \t \t\n Hypertension\t \t \t \t√\t\n Diabetes\t√\t \t√\t√\t\n Emphysema\t \t√\t \t \t\n Hepatitis\t \t \t√\t \t\n DLBCL\t \t \t√\t \t\nDLBCL: Diffuse large B-cell lymphoma; ICU: Intensive care unit; NCP: Novel coronavirus pneumonia.\n\nNasopharyngeal or oropharyngeal swab specimens were collected in all four cases, and the results were negative on admission, while positive when they were first diagnosed.\n\nBecause of an inadequate response to standard treatments in two moderate patients (Cases 1 and 2), TCZ (Roche Pharma [Schweiz] Ltd, Basel, Switzerland) was administered in 400 mg doses intravenously once for each patient (illness day 59 or hospital day 5 of case 1 and illness day 47 or hospital day 5 of case 2). The severe and critically ill patients (Cases 3 and 4) with high levels of IL-6 were administered TCZ at a dose of 8 mg/kg (672 mg of Case 3 in day 33 of symptom onset or hospital day 8 and 600 mg once of Case 4 in day 23 of symptom onset or hospital day 18) after failing to respond to the treatments of antiviral, antibiotics, immunomodulator and corticosteroid (See details in Table 2.) All patients were given oxygen supported by nasal cannula or BiPAP mask. Mechanical ventilation was used in two severe patients, and ECMO was applied to the Case 3 patient, whose condition developed rapidly to critical during the course of the disease.\n\nTable 2. Treatment and outcome of patients with novel coronavirus pneumonia.\n\n \tModerate cases in non-ICU\tCritically severe cases in ICU\t\n \tCase 1\tCase 2\tCase 3\tCase 4\t\nTreatment\t \t \t \t \t\n Antiviral\tArbidol hydrochloride + Lianhua Qingwen Capsule\tArbidol hydrochloride + Lianhua Qingwen Capsule\tArbidol hydrochloride\tLianhua Qingwen Capsule + ribavirin (0.5 g qd)\t\n Antibiotics\t \tMoxifoxacin (0.4 qd)\tMeropenem (2 g q8h) + vancomycin (0.5 g q12h)\tImipenem (1 g q12h) + vancomycin (0.5 g q12h) + tigercyclin (vancomycin discontinued, 100 mg q12h) + caspofungin (50 mg, qd) + voriconazole (caspofungin discontinued, 0.2 g q12h)\t\n Immunomodulator\t \tThymalfasin (1.6 mg biw)\t \tThymalfasin (1.6 mg qw)\t\n Corticosteroid\t \tMethylprednisolone (40 mg qd)\tMethylprednisolone (40 mg qd)\tMethylprednisolone (40 mg bid)\t\n Nutrition support\tHuman albumin (10 g once)\tHuman albumin (10 g qd)\tHuman albumin (30 g qd) + human immunoglobulin (10 g once)\tHuman albumin (10 g qd) + human immunoglobulin (10 g once)\t\n Tocilizumab\tTocilizumab (400 mg once)\n(illness day 59 or hospital day 5)\tTocilizumab (400 mg once)\n(illness day 47 or hospital day 5)\tTocilizumab (400 + 272 mg)\n(illness day 33 or hospital day 8)\tTocilizumab (600 mg once)\n(illness day 23 or hospital day 18)\t\nOxygen support\tNasal cannula (2 l/min)\tNasal cannula (2 l/min)\tNasal cannula 2 l/min + BiPAP mask\t \t\nMechanical ventilation\t \t \t \tInvasive mechanical ventilation\t\nECMO\t \t \tECMO\t \t\nOther supportive treatment\t \t \tSuspended RBC (2 U)\tClosed thoracic drainage\t\nCT image\tProgressed\tProgressed\tProgressed\tProgressed\t\nOutcome\tStable\tStable\tDie of DIC\tDie of ARDS\t\nARDS: Acute respiratory distress syndrome; CT: Computed tomography; DIC: Disseminated intravascular coagulation; ECMO: Extracorporeal membrane oxygenation; ICU: Intensive care unit; NCP: Novel coronavirus pneumonia; qd: Once a day; qw: Once a week; RBC: Red blood cells.\n\nAll radiological images of the four patients were examined, and the serum specimen was obtained. A chest CT scan was taken for Case 1 after 8 days of treatment with TCZ, which indicated that the bilateral peripheral opacifications progressed to streaky consolidation with internal bronchovascular bundle thickening, while a small pleural effusion was absorbed in the right lower lung (Figure 1A–B). Case 2’s chest CT image showed bilateral subpleural reticular opacities and enlarged and denser subpleural crescent-shaped consolidations (Figure 1C & D). Six days after Case 3’s administration, pneumonia was found to have invaded the left upper lung, as shown in the x-ray image. Case 3 deteriorated rapidly with invasive mechanical ventilation on Day 8 of hospitalization and died with the development of ARDS and disseminated intravascular coagulation at the hospital on Day 20 (45 days after disease onset) (Figure 1E & F). Case 4 developed a pneumothorax under the support of mechanical ventilation and died of ARDS on Day 22 of hospitalization (Figure 1G & H).\n\nFigure 1. Radiological images of four patients before and after tocilizumab administration.\n\nCase 1, a 69-year-old woman with diabetes (A) 59 days after symptom onset: multiple peripheral patchy ground-glass opacity with a small pleural effusion in the right lung (B) after tocilizumab administration (illness day 67): bilateral peripheral streaky opacities with internal bronchovascular bundle thickening. Case 2, a 64-year-old male with pulmonary emphysema (C) 46 days after symptom onset: subpleural reticular opacities in both lung and crescent-shaped consolidations in the left lung (D) after tocilizumab administration (illness day 54): enlargement and denser of bilateral pulmonary lesions. Case 3, a 47-year-old male with diabetes, chronic hepatitis and diffuse large B-cell lymphoma (E) 32 days after symptom onset: bilateral multiple patchy high-density opacities with bronchovascular bundle thickening (F) after tocilizumab administration (illness day 41): pneumonia invaded all through the right lung and left lower lobe. Case 4, a 73-year-old male with hypertension and diabetes (G) 21 days after symptom onset: pneumonia infiltration occurred in multi-lobes of the double sides (H) after tocilizumab administration (illness day 24): increased in density in the left lung and pneumothorax in the left lung.\n\nThe two severe patients showed elevated levels of neutrophils and reduced amounts of lymphocytes (Figure 2). The baseline level of serum IL-6 in the two moderate patients was lower than in the other two patients. Serum IL-6 indicated a surge 1–3 days after administration, followed by a decrease, though it still maintained a high level. Cytokines of TNF-α and IL-10 were shown with the same trend at a low level. CRP illustrated a downward tendency.\n\nFigure 2. Changes of cytokines IL-6, TNF-α, IL-10 and inflammatory markers CRP and count of neutrophil and lymphocyte before and after the treatment of tocilizumab.\n\n(A–D) Changes of IL-6 TNF-α, IL-10 and CRP in day 0, day 1, day 3, day 5, day 7, day 12 following intravenously infusion of tocilizumab in four cases. The reference range was below the dashed line. (E–F) Changes of TNF-α in day 0, day 1, day 3, day 5, day 7, day 12 following intravenously infusion of tocilizumab in four cases. The reference range was between the dashed line.\n\nCRP: C-reactive protein.\n\nDiscussion\n\nThis report describes TCZ as salvage therapy that failed to respond to severe patients with COVID-19 infection, in the beginning when TCZ was first introduced in the guidelines. In our clinical findings, two severe patients died without clinical improvement. As for the other two with mild symptoms, one showed inconspicuous amelioration, and the other displayed progression of their radiological abnormalities. We observed that after exposure to TCZ, the tendency of IL-6 was rising up at the beginning and subsequently declined but maintained a relatively high level in the two severe cases. This phenomenon of temporary increase is in accordance with the ‘Bathtub theory’ mechanism that had been found previously [12]. A potential explanation is that unbound IL-6 could undergo transient accumulation at the start of the drug use due to its receptor occupation. IL-6R inhibition had no direct impact on the level of serum IL-6 in our two moderate patients. The tentative administration of TCZ in the two moderate patients was based on the long duration of their symptoms and their IL-6 levels being three-times higher, indicating that IL-6 might not be a key factor in conditions where clinical manifestations are stable in spite of slightly increased IL-6 and CT abnormalities.\n\nTNF-α and IL-10 exhibited a similar trend and a small scope of variation compared with the normal range. The two counterparts maintained a balance between each other. Meanwhile, the inflammatory biomarker CRP illustrated a downward tendency. The CRP may indicate a sufficient dose of TCZ rather than acting as a simple disease activity index [13].\n\nThe IL-6 antagonist is recommended to treat severe patients with COVID-19 who appear to have a feature of a cytokine storm syndrome. The two severe cases in our report died after the administration of TCZ. A beneficial outcome was not achieved by the anticytokine storm treatment. Mechanical ventilation was applied to the two severe patients, which can make patients more prone to developing bacterial infections. Case 4 suffered from a pneumothorax with invasive ventilation and may have died of a co-infection of bacteria and the virus. ECMO was implemented for Case 3, who died 2 days later. The patient died from disseminated intravascular coagulation as well, with coagulation parameters such as increased D-Dimer and a marked diminishment of FIB. This phenomenon may indicate that attention should be given early on to changes in coagulation biomarkers, which might result in the rapid progress of and death from COVID-19 due to an impaired vascular endothelial cell expressing ACE2 extensively [14].\n\nFurther, we found that these two severe patients experienced increased amounts of neutrophils and fewer lymphocytes compared with the reference range, which was in line with the findings in a previous study of 201 cases [15]. In the study by Wu et al., they indicated that patients with progressive neutrophils are more inclined to develop ARDS and die. Neutrophils are the primary source of chemokines and pro-informatory cytokines. The elevation of IL-6 was rising after the treatment of TCZ, which was in part due to the instant response of the agent, and was also in part due to the elevated neutrophils. Besides this, decreased counts of lymphocytes were also observed in both severe cases of our study, which could be another factor to upgrade their disease severity.\n\nIn the current study, SARS-CoV-2 was not detectable on admission although they were confirmed by PCR when they were first diagnosed, which infers that the secondary infection or inflammatory cascade outweighs the virus invasion itself. However, whether inhibition of immune response is a viable choice at this time is still debatable. IL-6 has been recognized as the stimulant of the inflammatory response in a variety of autoimmune diseases, exacerbating the condition by promoting downstream cytokines secretion. It is closely related to pulmonary inflammation and extensive lung damage and may contribute to the CRS, an assumed leading cause of death at the late stage of COVID-19 [16,17]. Wang et al. found that alveolar macrophages as the target cells were activated by the S protein of SARS-CoV-2, triggering the cytokine storm syndrome, which speaks in favor of the IL-6/IL-6R antagonist as a potential therapeutic approach [18]. Clinical trials have shown the efficacy of TCZ in severe COVID-19 [8–11].\n\nHowever, we did not observe the effect of the TCZ on these patients nor obvious adverse events. Further, there is evidence that IL-6 is crucial for improving the survival of lung epithelial cells in mice infected with influenza virus [19,20]. Though many studies have found that increased levels of IL-6 associated with cytokine storm cascade existed in severe patients with COVID-19, the relationship between the CRS and the occurrence of ARDS is still unclear. More clinical evidence has indicated that serious infections have been found with a combination of the virus and bacteria in COVID-19 patients with long disease durations, which also can trigger the CRS and result in the deterioration of lung functions and sudden death. TCZ, as an immunosuppressive agent, may weaken the immune response to the severe infection and increase the risk of death, especially when used in the late stage of COVID-19.\n\nThe failure outcome of the treatment might be due to the patients’ long disease durations and we assumed that TCZ was administered in the midst or late stage of the patients experiencing cytokine storms, rather than in the early stage. Thus, whether TCZ exerts a positive role of immunosuppression or accelerates the disease progression is unclear. Patients were given methylprednisolone before TCZ; whether TCZ augments the function of immunosuppression without hyperinflammation was suspicious. We speculate that the optimal timing of intravenous infusion of this drug might be missed, and applying the agent at an inappropriate stage might curb the host inflammatory immune response confronting a secondary bacterial infection. Early intervention with TCZ may be more effective than application amid a cytokine storm cascade.\n\nHyperglycemia was another risk factor which would impair the therapeutic effect of TCZ in severe COVID-19 patients. The condition of patient 1 with diabetes was stable, while the blood glucose of patient 4 was not well-controlled. Hyperglycemia itself not only triggers an inflammatory response resulting in deteriorated COVID-19 disease, but overactivates the CRS, a negative prognostic factor for survival in severe patients [21]. Optimal control of glycemia in this kind of case subset needed to be considered. In addition to diabetic history, patient 4 was also suffered from long-term hypertension. The use of ACE inhibitors or angiotensin receptor blockers may interfere with ACE2 expression and its activity, which is a high risk factor and may make patients prone to be infected by SARS-CoV-2. Disruption of ACE2 pathways leads to worse prognosis by endothelial dysfunction, prothrombotic status and disseminated coagulopathy which could confer a worse prognosis [22,23].\n\nSerious adverse events including osteonecrosis of the jaws, severe infections, gastrointestinal reactions, etc. may worsen the condition of the patients [24]. In our cases, no safety issues were identified. More large-scale randomized clinical trials are required to evaluate the efficacy and safety of IL-6 antagonist in treating patients with COVID-19.\n\nThe study has several limitations. First, this was a small case series with quite heterogeneous patients, and all patients were transferred to the designated hospital after a long period of symptom onset. Thus, first-hand information was not obtained. Second, the administration of TCZ in two moderate patients took place within a tentative treatment. It might not seem suitable for such cases to benefit. Third, all patients were treated with multiple other medications, and the role of the interactions of these agents was not elucidated. At last, the optimal timing within the whole course of the disease required to achieve clinical benefits from the TCZ still needs to be clearly understood.\n\nGiven the limited benefit our patients received, we suggest that patients’ clinical conditions, comorbidities and disease severity should be taken into consideration to improve clinical decision making. Early intervention with TCZ may be more effective than application amid a cytokine storm cascade. More large-scale randomized clinical trials are required to evaluate the efficacy and safety of IL-6 antagonist in treating patients with COVID-19.\n\nSummary points\n\nCoronavirus disease 2019 (COVID-19) is a life-threatening disease and how to decrease the high mortality is of great importance.\n\nFour patients were administrated with tocilizumab, an IL-6 receptor antagonist to determine whether it shows favorable results in two severe COVID-19 patients as well as in two moderate patients with high levels of serum IL-6 who attained no benefit from standard care.\n\nThere was no much difference in the clinical feature improvements and computed tomography images in two moderate patients after treatment of IL-6R antagonist. The other two severe patients presented with recurrent fever and needed ventilation in intensive care unit and died of disseminated intravascular coagulation and acute respiratory distress syndrome, respectively.\n\nAdministration of tocilizumab was not shown to have a favorable outcome in this preliminary uncontrolled case series. Early identification of cytokine release syndrome in the treatment of COVID-19 patients with IL-6 antagonist is required.\n\nAuthor contributions\n\nQ Li, S-M Dai and Q Tong designed the study; R Cui, Y Wang and X Chen contributed to data collection; Y Zhu analyzed the data, wrote the manuscript and created figure and table with the assistance and feedback of all the other co-authors. Q Tong revised the manuscript and format.\n\nAcknowledgments\n\nWe respectfully and sincerely thank all front-line medical staff for their hard work and sacrifice.\n\nFinancial & competing interests disclosure\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThe study was approved by the Ethics Committee of Shanghai Sixth People’s Hospital (No. 2020-KY-020[K]). In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.\n\nData sharing statement\n\nThe datasets used and/or analyzed during the current study was original and available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n1. Chen N, Zhou M, Dong X Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395 , 507–513 (2020).32007143\n2. Huang C, Wang Y, Li X Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 , 497–506 (2020).31986264\n3. Cao B, Wang Y, Wen D A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19. N. Engl. J. Med. 382 (19 ), 1787–1799 (2020).32187464\n4. Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci. Trends 14 , 69–71 (2020).31996494\n5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases From the Chinese Center for Disease Control and Prevention. JAMA 323 (13 ), 1239–1242 (2020).32091533\n6. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J. Antimicrob. Chemother. 75 (7 ), 1667–1670 (2020).32196083\n7. Diagnosis and Treatment Guideline for NCP. www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml\n8. Xu X, Han M, Li T Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl Acad. Sci. USA 117 (20 ), 10970–10975 (2020).32350134\n9. Salama C, Han J, Yau L Tocilizumab in patients hospitalized with covid-19 pneumonia. N. Engl. J. Med. 384 (1 ), 20–30 (2021).33332779\n10. Galván-Román JM, Rodríguez-García SC, Roy-Vallejo E IL-6 serum levels predict severity and response to tocilizumab in COVID-19: an observational study. J. Allergy Clin. Immunol. 147 (1 ), 72–80.e8 (2021).33010257\n11. Toniati P, Piva S, Cattalini M Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun. Rev. 19 (7 ), 102568 (2020).32376398\n12. Ogata A, Hirano T, Hishitani Y, Tanaka T. Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin. Med. Insights Arthritis Musculoskelet. Disord. 5 , 27–42 (2012).22438671\n13. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112 , 3959–3964 (2008).18784373\n14. Leng Z, Zhu R, Hou W Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 11 (2 ), 216–228 (2020).32257537\n15. Wu C, Chen X, Cai Y Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 180 (7 ), 934–943 (2020).32167524\n16. Mehta P, McAuley DF, Brown M COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395 (10229 ), 1033–1034 (2020).32192578\n17. Wong CK, Lam CW, Wu AK Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 136 , 95–103 (2004).15030519\n18. Wang Chaofu, Xie Jing, Zhao Lei Aveolar macrophage activation and cytokine storm in the pathogenesis of severe COVID-19. Res.Sq. (2020) (Epub ahead of print).\n19. Lauder SN, Jones E, Smart K Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur. J. Immunol. 43 , 2613–2625 (2013).23857287\n20. Yang ML, Wang CT, Yang SJ IL-6 ameliorates acute lung injury in influenza virus infection. Sci. Rep. 7 , 43829 (2017).28262742\n21. Marfella R, Paolisso P, Sardu C Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients. Diabetes Metab. 46 (5 ), 403–405 (2020).32447102\n22. Sardu C, Maggi P, Messina V Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with covid-19 infection? Data From Centers of Southern Italy. J. Am. Heart Assoc. 9 (17 ), e016948 (2020).32633594\n23. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Hypertension, thrombosis, kidney failure, and diabetes: is covid-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J. Clin. Med. 9 (5 ), 1417 (2020).\n24. Bennardo F, Buffone C, Giudice A. New therapeutic opportunities for COVID-19 patients with Tocilizumab: possible correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws. Oral Oncol. 106 , 104659 (2020).32209313\n\n",
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"title": "Tocilizumab in the treatment of coronavirus disease 2019 pneumonia: real-world data from a case series.",
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"abstract": "A 35-year-old woman with a history of infertility, was presented to our hospital because of impaired consciousness and cerebellar ataxia, 14 days after in vitro fertilization. She received an embryo transfer under controlled ovarian hyper-stimulation. Magnetic resonance images revealed acute infarction in the cerebellum and brainstem. Magnetic resonance angiography showed a basilar artery occlusion at the end point. Following immediate intravenous rt-PA treatment, the symptoms disappeared completely. A transesophageal echocardiography revealed an atrial septal defect with a continuous left to right shunt. In addition, a Valsalva maneuver trans-esophageal echocardiography with injected saline showed the presence of jet bubbles in the left atrium crossing via the atrial septal defect. She was diagnosed with paradoxical cerebral embolism. Anticoagulant therapy was continued and she gave birth to a healthy baby. Deep vein thrombosis was associated with the ovarian hyper-stimulation syndrome that occurred during infertility treatment. As anti-phospholipid antibodies were weakly positive, the possibility of anti-phospholipid antibody syndrome was suggested. If a woman of childbearing age is presented because of stroke, it is important to administer initial therapy by keeping fertility in mind. Thrombolytic therapy for pregnant women should be carefully considered, because of the associated hazards; however, it is a very important treatment for maternal function after birth.",
"affiliations": "Tokushima Red Cross Hospital Division of Neuro-endovascular Surgery.",
"authors": "Tomura|Miki|M|;Satoh|Koichi|K|;Hanaoka|Mami|M|;Tamura|Tetsuya|T|;Kinouchi|Tomoya|T|;Shinno|Kiyohito|K|;Miyake|Hajimu|H|;Niki|Hitoshi|H|;Shoji|Akihiro|A|",
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"mesh_terms": "D000328:Adult; D016736:Antiphospholipid Syndrome; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007247:Infertility, Female; D020766:Intracranial Embolism; D018810:Magnetic Resonance Angiography; D020521:Stroke",
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"title": "A Case of Paradoxical Cerebral Embolism Developed during in vitro Fertilization Treatment.",
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"abstract": "BACKGROUND\nAtypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib.\n\n\nMETHODS\nHere we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT).\n\n\nCONCLUSIONS\nThis case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.",
"affiliations": "Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. nuno.cerveira@ipoporto.min-saude.pt.;Department of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal.;Department of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal.;Department of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal.;Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.;Department of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal.",
"authors": "Cerveira|Nuno|N|http://orcid.org/0000-0001-5098-3840;Ferreira|Rosa Branca|RB|;Bizarro|Susana|S|;Correia|Cecília|C|;Torres|Lurdes|L|;Lisboa|Susana|S|;Vieira|Joana|J|;Santos|Rui|R|;Campilho|Fernando|F|;Pinho Vaz|Carlos|C|;Leite|Luís|L|;Teixeira|Manuel R|MR|;Campos|António|A|",
"chemical_list": "D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 510010.1186/s12885-018-5100-4Case ReportPonatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report http://orcid.org/0000-0001-5098-3840Cerveira Nuno nuno.cerveira@ipoporto.min-saude.pt 1Ferreira Rosa Branca r.branca.s.ferreira@gmail.com 2Bizarro Susana susana.bizarro@ipoporto.min-saude.pt 1Correia Cecília ceciliacorreia@ipoporto.min-saude.pt 1Torres Lurdes mlurdes.torres@ipoporto.min-saude.pt 1Lisboa Susana susanalisboa@ipoporto.min-saude.pt 1Vieira Joana joana.vieira@ipoporto.min-saude.pt 1Santos Rui ruimssantos89@gmail.com 1Campilho Fernando campilho@ipoporto.min-saude.pt 2Pinho Vaz Carlos cpvaz@ipoporto.min-saude.pt 2Leite Luís luisclaudioleite@gmail.com 2Teixeira Manuel R. manuel.teixeira@ipoporto.min-saude.pt 13Campos António acampos@ipoporto.min-saude.pt 21 0000 0004 0631 0608grid.418711.aDepartment of Genetics, Portuguese Oncology Institute, Porto, Portugal 2 0000 0004 0631 0608grid.418711.aDepartment of Bone Marrow Transplantation, Portuguese Oncology Institute, Porto, Portugal 3 0000 0001 1503 7226grid.5808.5Institute of Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal 7 12 2018 7 12 2018 2018 18 122915 6 2018 16 11 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAtypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib.\n\nCase presentation\nHere we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT).\n\nConclusion\nThis case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-018-5100-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nCMLT315IRelapseHSCTPonatinibIncyte CorpNot applicableissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nChronic myeloid leukaemia (CML) is a myeloproliferative neoplasia caused by the fusion of the BCR and ABL1 genes, usually as the result of the reciprocal translocation t(9;22)(q34;q11.2). The exact breakpoint of the translocation and the molecular weight of the resulting fusion gene protein are variable, with most of the breakpoints on chromosome 22 falling in the major breakpoint cluster region (M-BCR), between exons 13 and 14 of the BCR gene, leading to a BCR–ABL1 mRNA with e13a2 or e14a2 junctions encoding for a p210 fusion protein [1]. Less than 5% of patients express atypical transcript types, of which e19a2, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein, is the most frequently encountered with a frequency of 0.7–2.7% of the cases [2, 3]. p230 CML has been associated with various clinical presentations and courses with variable responses to first-line imatinib, possibly confounded due to reporting bias in favour of cases with atypical features and/or responses [4–7]. The present study reports the case of a patient with p230 CML that was successfully treated with the third-generation tyrosine kinase inhibitor (TKI) ponatinib, following an early relapse with a T315I mutation after allogeneic stem cell transplantation.\n\nCase presentation\nIn November 2007, a 51 year-old man was admitted to the Centre Hospitalier Universitaire Vaudois in Switzerland for observation due to leucocytosis. His white blood cell (WBC) count was 232,000/μL, with 130,000/μL neutrophils (69.8%), 2300/μL basophils (1%), 7000/μL eosinophils (3%), 140 × 109/L platelets, 9.5 g/dL hemoglobin, and 2% peripheral blood blasts. He had no liver or spleen enlargement. The calculated Sokal, EUTOS and ELTS scores were low (0.64), low (7), and intermediate (1.639), respectively. A bone marrow aspirate showed marked hypercellularity and myelogenous hyperplasia without an increase in the blast ratio. Cytogenetic analysis showed the presence of a 46,XY,t(9;22)(q34;q11.2),+der(22)t(9;22) karyotype in 25 metaphases, and the presence of a BCR-ABL1 gene fusion was confirmed by FISH analysis. Molecular analysis revealed the presence of an e19a2 BCR-ABL1 transcript and the patient was diagnosed with an e19a2-positive chronic phase CML. The detection of an additional Ph+, a major route abnormality that has been reported as an adverse prognostic factor, does not mandate in daily practice a different initial treatment approach [8], therefore imatinib 400 mg QD was started. The patient rapidly achieved an haematological response and, after 3 months of treatment, a partial cytogenetic response (PCyR) was observed (28% Ph + metaphases), corresponding to an optimal response according to the ELN guidelines [8]. After 6 months of imatinib therapy, he lost his cytogenetic response (CyR), with all the metaphases analysed showing the same karyotype detected at diagnosis, which suggested treatment failure [8]. At this point, the patient interrupted the treatment and was lost to follow-up. In May 2010, the patient presented with hyperleukocytosis (300,000/μL), left abdominal pain and malaise. A CT scan revealed a splenomegaly of 20 cm and karyotype analysis showed the presence in 25 metaphases of the same karyotype observed at diagnosis. In view of the patient’s previous history, it was decided to initiate treatment with imatinib 600 mg QD. After 4 months of therapy, he was in haematological remission, but karyotype analysis showed only a minimal cytogenetic response (75% Ph + metaphases). In December 2010, 6 months after starting therapy, his cytogenetic response improved to a minor response (45% Ph + metaphases), corresponding to a sub-optimal response [8]. In February 2011, by decision of the patient, he was transferred to our institute (Additional file 1: Table S1). At the time of admission, he was in complete haematological response. Molecular analysis showed the presence of an e19a2 BCR-ABL1 transcript, but no cytogenetic analysis was performed. In order to quantitate the e19a2 BCR-ABL1 transcript and monitor response to treatment, a BCR exon 19 forward primer was designed (ENF007; 5′- CACTGAAGGCAGCCTTCGA-3′) and used with reverse primer ENR561 and probe ENP541 (7). A standard curve was established by tenfold dilutions of patient cDNA. Control ABL1 transcripts were detected as previously described [9]. At this point, 9 months after restarting imatinib therapy, the BCR-ABL1/ABL1 ratio was 40.258% (Fig. 1). Three months later, at the 12-month evaluation, the patient finally achieved a complete cytogenetic response (CCyR), with a BCR-ABL1 level of 0.846% (Fig. 1). At this point, and taking into account the good response to treatment, the patient was switched to imatinib 400 QD. However, 6 months later, karyotype analysis showed loss of CCyR (40% Ph + metaphases; minor CyR), with a concomitant rise in BCR-ABL1 levels (6.070%). Two months later, an additional rise in BCR-ABL1 levels to 15.820%, confirmed loss of molecular response and prompted search for mutations in the ABL1 kinase domain as previously reported [10]. Sanger sequencing allowed identification of an E255V mutation (Fig. 1), leading to start of second line dasatinib therapy (140 mg QD), and prompting search for an unrelated stem cell donor. Three months after start of dasatinib therapy, the patient achieved a CCyR with a BCR-ABL1 level of 0.365% and 5 months later, the patient maintained a CCyR, with a BCR-ABL1 level of 0.671%. However, in the following months, the patient showed a progressive loss of cytogenetic response: PCyR (17% Ph + metaphases), minor CyR (38% Ph + metaphases), and minor CyR (63% Ph + metaphases), 14 months, 17 months and 21 months after starting second-line dasatinib therapy, respectively. At this time, dasatinib therapy was stopped and the patient underwent allogeneic haematopoietic stem cell transplant (HSCT) from a 9/10 matched HLA unrelated donor (one HLA-B mismatch), after a non-myeloablative reduced-intensity conditioning (RIC) regimen that included busulfan, fludarabine and antithymocyte globulin (ATG). The graft-versus host disease (GVHD) prophylaxis consisted of the association of tacrolimus with mycophenolate mofetil (MMF). Neither acute GVHD nor other significant clinical complications were observed. One month after transplant, cytogenetic analysis showed persistence of disease (10% Ph + metaphases; PCyR), with a BCR-ABL1 level of 1.229%, which prompted start of nilotinib therapy (400 mg BID). Two months later, his BCR-ABL1 level rose to 8.132% with 23% Ph + metaphases (PCyR), suggesting resistant disease. Mutational analysis by Sanger sequencing revealed the presence of a T315I mutation, which led to the interruption of both nilotinib therapy and immunosuppression. Four months after transplant the patient lost his PCyR (70% Ph + metaphases; minor CyR) and his BCR-ABL1 levels increased to 12.477%. The patient showed mixed chimerism predominantly donor-derived. Since ponatinib was not available at the time at our institution and approval was pending, nilotinib therapy (400 mg BID) was restarted. One month later, karyotype analysis showed a minimal CyR (97% Ph + metaphases) and the patient was submitted to donor lymphocyte infusion (DLI), which resulted only in a minor CyR (90% Ph + metaphases) that nevertheless was maintained in the following months. This was, however, accompanied by increasing BCR-ABL1 levels to a maximum of 32.879%, 10 months after HSCT. The patient also showed progressive loss of donor chimerism (mixed chimerism with < 5% donor cells). At this point ponatinib approval was granted, nilotinib therapy was interrupted and ponatinib was started at the standard dose of 45 mg QD. Before ponatinib initiation, and considering its well-known cardiovascular toxicity profile, a comprehensive cardiologic and metabolic evaluation was performed. The only cardiovascular risk-factors identified were dyslipidaemia and arterial hypertension (AHT), which were already present since the beginning of the disease and were easily manageable with lifestyle modifications and therapy (enalapril/hydrochlorothiazide 20/12.5 mg, ½ tablet QD), respectively. Two months later, karyotype analysis showed a PCyR (17% Ph + metaphases) and a reduction of BCR-ABL1 levels (10.940%) was observed. Subsequently, four months later, the patient achieved a CCyR associated with a BCR-ABL1 level of 0.213%. In the following months a progressive decline in BCR-ABL1 levels was documented: 0.029% at 6 months (equivalent to a Major Molecular Response; MMR), 0.005% at 9 months (equivalent to a MR4.0), 0.001% at 12 months (equivalent to a MR4.5), and 0.000% at 15 months (equivalent to a MR5.0). The patient maintained ponatinib 45 mg QD treatment during an additional 16 months and, since a persistent and sustained MR5.0 with no detectable disease was documented, dosage was reduced to 15 mg QD. Treatment with ponatinib was well tolerated since the beginning of therapy with no evidence of toxicity. At the time of the last evaluation, 15 months after ponatinib dose reduction, the patient maintained a sustained MR5.0 with no detectable disease. No evidence of cardiovascular toxicity was observed at the last observation. Under ponatinib treatment, the patient maintained a mixed chimerism with < 5% donor cells. To evaluate if the T315I clone was present at low-levels in the earlier phases of the disease, we used CastPCR (Competitive Allele-Specific TaqMan PCR™, Applied Biosystems) specific for the T315I mutation in all the available RNA patient samples collected since he was admitted to our institution. For the T315I mutation detection, each sample was run in real-time PCR with the assay targeting both the mutation and the corresponding reference gene, according to the manufacturer’s instructions. After amplification, data files containing the samples Ct values were imported into Life Technologies Mutation Detector™ Software for post-PCR data analysis. CastPCR is highly specific and sensitive and can detect and quantitate rare amounts of mutated DNA/cDNA in a sample that contains large amounts of normal, i.e., non-mutated, DNA/cDNA, with a sensibility up to 0.1%. Using this approach, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after HSCT.Fig. 1 Monitoring of BCR-ABL1 levels (red) and cytogenetic response (green) during the different treatments of the patient. HSCT, haematopoietic stem cell transplant; DLI, donor lymphocyte infusion\n\n\n\nDiscussion and conclusions\np230 CML has been associated with various clinical presentations and courses [4, 5] with recent data suggesting that these patients have a poor response to front-line imatinib therapy, but better responses to second-line nilotinib and dasatinib [6, 7]. Point mutations in the kinase domain (KD) of the ABL1 gene represent the most common resistance mechanism to TKI therapy in CML, occurring in 30–90% of patients who develop resistance to imatinib [11], with more than 100 different mutations reported, although many are only rarely detected clinically [11]. The relative in vitro sensitivity of different mutants to the various available TKI varies considerably and correlates well with the outcome after subsequent therapy with a different TKI [12]. Similarly, mutants that are less likely to be inhibited by a given TKI are more likely to emerge clinically during therapy with such inhibitors [13].\n\nHere we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Recently, patients with E255K/V mutations have been described as having a particularly poor prognosis, regardless of the stage of the disease at detection, with a higher risk of transformation to advanced/blast phase, and a short survival [14]. Indeed, this mutation shows a high IC50 to all available TKIs, including third-generation ponatinb [15]. In this case, dasatinib has been suggested as the most likely option in terms of probability of response among all available TKIs [14]. Therefore, dasatinib treatment was initiated as a bridge to HSCT, and a CCyR was quickly achieved. However, in the following months, the patient lost CCyR and at the time of HSCT showed only a minor CyR. The best response achieved after HSCT was a PCyR, that was nevertheless quickly lost with mutation analysis revealing the presence of a T315I. Since the T315 mutation was retrospectively detected even before the detection of the E255V mutation, this suggests that at least two distinct BCR-ABL1 sub-clones were present at the start of therapy. This observation can be explained by differences in competitive advantage between mutant clones. Indeed, in vitro cell assays showed that selected mutant clones (for example, P-loop mutations Y253F, E255K) have higher transformation potency and proliferation rate compared with T315I, even in the absence of BCR-ABL1 inhibitors [16]. Assuming that imatinib has lower activity against these mutant clones with P-loop mutations, they may expand more rapidly than clones with the T315I mutation when exposed to imatinib [13]. On the other hand, it has been shown that dasatinib suppresses P-loop mutations to a greater extent than T315I [17], therefore a T315I positive clone may be able to increase its size during dasatinib treatment with relatively little competition from rapidly proliferating clones [13]. This hypothesis is supported by the observation that dasatinib treated patients seem to more frequently show T315I mutations [13]. This is in agreement with the model in which evolution of BCR-ABL1–positive cells is mainly shaped by TKI-selective pressure and the fitness of each ABL1 KD mutated population is the net result of the ability to survive treatment depending on the intrinsic sensitivity to the specific TKI administered and of the ability to survive the competition with all other coexisting populations [18].\n\nAlthough our patient did not develop adverse events related to ponatinib therapy, its expected benefits must be balanced against the potential risks, including arterial hypertension, and serious arterial occlusive and venous thromboembolic events, reported in the PACE trial in 19 and 5% of patients, respectively. Published data support the observation that adverse events appear to be related to certain pre-existing cardiovascular risk factors, ponatinib dose, or both [19]. For this reason, and since our patient was in sustained MR5.0 with no detectable disease after 27 months of ponatinib therapy, the dose was reduced to 15 mg OD. Fifteen months later, the patient maintains a sustained MR5.0 with no detectable disease. Ponatinib efficacy was previously observed in a CML e19a2 patient refractory to both imatinib and dasatinib therapy due to the presence of a T315I mutation [20]. These results suggest that ponatinib could be an excellent therapeutic option in the treatment of e19a2 CML harbouring the T315I mutation refractory to previous therapies including HSCT, although more studies are necessary to draw a definitive conclusion.\n\nAdditional file\n\nAdditional file 1: Table S1. Clinical and laboratory data of the patient. (DOCX 17 kb)\n\n \n\n\nAbbreviations\nAHTArterial hypertension\n\nATGAntithymocyte globulin\n\nCastPCRCompetitive Allele-Specific TaqMan PCR\n\nCCyRComplete cytogenetic response\n\nCMLChronic myeloid leukaemia\n\nCyRCytogenetic response\n\nDLIDonor lymphocyte infusion\n\nGVHDGraft-versus host disease\n\nHSCTHaematopoietic stem cell transplant\n\nM-BCRMajor breakpoint cluster region\n\nMMFMycophenolate mofetil\n\nMMRMajor molecular response\n\nPCyRPartial cytogenetic response\n\nRICReduced-intensity conditioning\n\nTKITyrosine kinase inhibitor\n\nWBCWhite blood cell\n\nμ-BCRMicro breakpoint cluster region\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis work was supported in part by an unrestricted grant from Incyte Corp.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nNC, RBF, MRT, and AC designed the study. RS was responsible for sample processing. NC and SB performed the molecular studies. CC, LT, SL and JV performed the cytogenetic analysis. RBF, FC, CPV, LL, and AC provided patient samples and clinical data. NC and RBF were responsible for the collection, analysis and interpretation of data. NC, RBF, MRT, and AC were involved in drafting the manuscript. All authors contributed to revisions, read, and approved the final version of this manuscript.\n\nEthics approval and consent to participate\nThis study is in accordance with the ethical standards of the Ethics Committee of the Portuguese Oncology Institute of Porto (approval number 38.010) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nConsent for publication\nWritten informed consent was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Goldman JM Melo JV Chronic myeloid leukemia: advances in biology and new approaches to treatment N Engl J Med 2003 349 15 1451 1464 10.1056/NEJMra020777 14534339 \n2. Saglio G Guerrasio A Rosso C Zaccaria A Tassinari A Serra A New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia Blood 1990 76 9 1819 1824 2224129 \n3. Wilson GA Vandenberghe EA Pollitt RC Rees DC Goodeve AC Peake IR Are aberrant BCR-ABL transcripts more common than previously thought? Br J Haematol 2000 111 4 1109 1111 10.1046/j.1365-2141.2000.02471.x 11167748 \n4. Crampe M Garry J Langabeer SE Murphy PT Sustained molecular response with nilotinib in imatinib-intolerant chronic myeloid leukaemia with an e19a2 BCR-ABL1 fusion Hematol Oncol Stem Cell Ther 2016 9 4 168 169 10.1016/j.hemonc.2016.05.007 27352262 \n5. How GF Tan LT Lim LC Chronic myeloid leukemia with e19a2 (c3a2) BCR/ABL fusion junction: is it truly a benign disease? Leukemia 1998 12 7 1166 1167 10.1038/sj.leu.2401055 9665206 \n6. Andrikovics H Nahajevszky S Szilvási A Bors A Adám E Kozma A First and second line imatinib treatment in chronic myelogenous leukemia patients expressing rare e1a2 or e19a2 BCR-ABL transcripts Hematol Oncol 2007 25 3 143 147 10.1002/hon.822 17530620 \n7. Qin YZ Jiang Q Jiang H Lai YY Shi HX Chen WM Prevalence and outcomes of uncommon BCR-ABL1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single Centre Br J Haematol 2018 182 5 693 700 10.1111/bjh.15453 29974949 \n8. Baccarani M Deininger MW Rosti G Hochhaus A Soverini S Apperley JF European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013 Blood 2013 122 6 872 884 10.1182/blood-2013-05-501569 23803709 \n9. Gabert J Beillard E van der Velden VH Bi W Grimwade D Pallisgaard N Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe against Cancer program Leukemia 2003 17 12 2318 2357 10.1038/sj.leu.2403135 14562125 \n10. Branford S Rudzki Z Walsh S Parkinson I Grigg A Szer J Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis Blood 2003 102 1 276 283 10.1182/blood-2002-09-2896 12623848 \n11. Jabbour E Kantarjian H Jones D Talpaz M Bekele N O'Brien S Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate Leukemia 2006 20 10 1767 1773 10.1038/sj.leu.2404318 16855631 \n12. Jabbour E Jones D Kantarjian HM O'Brien S Tam C Koller C Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations Blood 2009 114 10 2037 2043 10.1182/blood-2009-01-197715 19567878 \n13. Hughes TP Saglio G Quintás-Cardama A Mauro MJ Kim DW Lipton JH BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase Leukemia 2015 29 9 1832 1838 10.1038/leu.2015.168 26118315 \n14. Naqvi K Cortes JE Luthra R O'Brien S Wierda W Borthakur G Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations Int J Hematol 2018 107 6 689 695 10.1007/s12185-018-2422-6 29464484 \n15. Redaelli S Mologni L Rostagno R Piazza R Magistroni V Ceccon M Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors Am J Hematol 2012 87 11 E125 E128 10.1002/ajh.23338 23044928 \n16. Griswold IJ MacPartlin M Bumm T Goss VL O'Hare T Lee KA Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib Mol Cell Biol 2006 26 16 6082 6093 10.1128/MCB.02202-05 16880519 \n17. Gruber FX Ernst T Porkka K Engh RA Mikkola I Maier J Dynamics of the emergence of dasatinib and nilotinib resistance in imatinib-resistant CML patients Leukemia 2012 26 1 172 177 10.1038/leu.2011.187 21818112 \n18. Soverini S De Benedittis C Machova Polakova K Brouckova A Horner D Iacono M Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain Blood 2013 122 9 1634 1648 10.1182/blood-2013-03-487728 23794064 \n19. Iclusig (summary of product characteristics) ARIAD Pharma Ltd 2017 UK Leatherhead \n20. Ferri CA Bianchini M Bengió RM Moiraghi EB Gonzalez MS Noriega MF Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation Eur J Haematol 2015 94 3 270 272 10.1111/ejh.12358 24766374\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "CML; HSCT; Ponatinib; Relapse; T315I",
"medline_ta": "BMC Cancer",
"mesh_terms": "D016044:Fusion Proteins, bcr-abl; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D011724:Pyridazines; D012008:Recurrence",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "1229",
"pmc": null,
"pmid": "30526517",
"pubdate": "2018-12-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23044928;24766374;2224129;26118315;21818112;27352262;11167748;14534339;19567878;29974949;23803709;9665206;12623848;14562125;23794064;17530620;29464484;16855631;16880519",
"title": "Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report.",
"title_normalized": "ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a t315i mutation following allogeneic hematopoietic stem cell transplantation a case report"
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"abstract": "To report a case of dupilumab-associated blepharoconjunctivitis.\nA 48 year-old Caucasian male presented with bilateral blepharitis, multiple chalazia, dry eye disease and significant papillary conjunctivitis. The past medical history included fourteen years of severe atopic dermatitis. After failed attempts to treat atopic dermatitis with topical corticosteroids, the patient enrolled into a four-year clinical trial of biweekly dupilumab injections. Four to six weeks after initiation of dupilumab, the patient reported blurred vision, ocular irritation and redness. Slit lamp examination demonstrated bilateral meibomian gland dysfunction, edematous eyelids with multiple chalazia and significant papillary conjunctivitis. Meibography by Lipiscan revealed significant truncation, atrophy and bifurcation of meibomian glands bilaterally. The patient's multiple chalazia were excised and eyelid hygiene was closely followed. Cliradex wipes and Avenova were added to the patient's regime and one session of Lipiflow treatment was administered. The patient continued this eyelid hygiene regimen along with neomycin/polymyxin B/dexamethasone ophthalmic ointment after each dupilumab infusion.\nFive weeks after Lipiflow treatment with concomitant use of Cliradex and Avenova, visual acuity and ocular discomfort improved. Current treatment includes Cliradex eyelid wipes along with neomycin/polymyxin B/dexamethasone ophthalmic ointment for a week after each dupilumab infusion. Topical steroids and antibiotics with eyelid hygiene are effective ways to treat atopic dermatitis patients exhibiting dupilumab's ocular side effects. Lipiflow therapy may also help in treatment.",
"affiliations": "Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA.;Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA.;Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA.;Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA.",
"authors": "Paulose|Sefy A|SA|;Sherman|Suzanne W|SW|;Dagi Glass|Lora R|LR|;Suh|Leejee H|LH|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ajoc.2019.100550",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30401-810.1016/j.ajoc.2019.100550100550Case ReportDupilumab-associated blepharoconjunctivitis Paulose Sefy A. Sherman Suzanne W. Dagi Glass Lora R. Suh Leejee H. lhs2118@cumc.columbia.edu∗Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA∗ Corresponding author. Edward S. Harkness Eye Institute, Columbia University Medical Center, 635 West 165th Street, New York, NY, 10032, USA. lhs2118@cumc.columbia.edu05 9 2019 12 2019 05 9 2019 16 1005508 10 2018 13 1 2019 27 8 2019 © 2019 Published by Elsevier Inc.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a case of dupilumab-associated blepharoconjunctivitis.\n\nObservations\nA 48 year-old Caucasian male presented with bilateral blepharitis, multiple chalazia, dry eye disease and significant papillary conjunctivitis. The past medical history included fourteen years of severe atopic dermatitis. After failed attempts to treat atopic dermatitis with topical corticosteroids, the patient enrolled into a four-year clinical trial of biweekly dupilumab injections. Four to six weeks after initiation of dupilumab, the patient reported blurred vision, ocular irritation and redness. Slit lamp examination demonstrated bilateral meibomian gland dysfunction, edematous eyelids with multiple chalazia and significant papillary conjunctivitis. Meibography by Lipiscan revealed significant truncation, atrophy and bifurcation of meibomian glands bilaterally. The patient's multiple chalazia were excised and eyelid hygiene was closely followed. Cliradex wipes and Avenova were added to the patient's regime and one session of Lipiflow treatment was administered. The patient continued this eyelid hygiene regimen along with neomycin/polymyxin B/dexamethasone ophthalmic ointment after each dupilumab infusion.\n\nConclusions and Importance\nFive weeks after Lipiflow treatment with concomitant use of Cliradex and Avenova, visual acuity and ocular discomfort improved. Current treatment includes Cliradex eyelid wipes along with neomycin/polymyxin B/dexamethasone ophthalmic ointment for a week after each dupilumab infusion. Topical steroids and antibiotics with eyelid hygiene are effective ways to treat atopic dermatitis patients exhibiting dupilumab's ocular side effects. Lipiflow therapy may also help in treatment.\n\nKeywords\nDupilumabBlepharoconjunctivitisLipiflowAtopic dermatitisOcular side effects\n==== Body\n1 Introduction\nDupilumab is a fully human monoclonal antibody specifically preventing the signaling of IL-4 and IL-13 by inhibiting the IL-4 receptor alpha subunit. This treatment has been evaluated for diseases that are implicated by Th2 pathways predominant with IL-4 and IL-13 such as moderate-to-severe atopic dermatitis, asthma and chronic sinusitis. Dupilumab's dual antagonism against these cytokines potently inhibits the Th2 effector responses resulting in significant clinical improvements. Studies evaluating the administration of dupilumab have shown to be effective in terms of clinical outcome and patient-reported symptoms of anxiety and health-related quality of life.\n\nDupilumab has reported possible ocular side effects such as conjunctivitis, blepharitis, keratitis, eye pruritus and dry eye. Specifically, in patients with atopic dermatitis, studies have reported an increased incidence of conjunctivitis with dupilumab use. To our knowledge, this is the first report of blepharoconjunctivitis associated with dupilumab use.\n\n2 Case report\nA 48-year-old Caucasian male presented with bilateral blepharitis, multiple bilateral chalazia and dry eye complaining of blurred vision, ocular irritation and redness starting four to six weeks after dupilumab use. Fourteen years ago, the patient was diagnosed with severe atopic dermatitis. After failed treatment with several topical corticosteroids, the patient enrolled in a clinical trial of biweekly dupilumab injections for the past four years.\n\nApproximately four to six weeks following the initiation of dupilumab, significant improvement in symptoms of atopic dermatitis was noted. Six months later, multiple chalazia developed which worsened with topical antibiotic drops prescribed by an outside ophthalmologist. Instead, the patient attempted conservative care with warm compresses. Despite these efforts, persistent chalazia resulted in induced astigmatism and reduced vision and patient presented to our clinic for excisions. On presentation, his best corrected visual acuity was 20/40 in right eye and 20/30 in the left eye. Slit lamp examination revealed bilateral meibomian gland dysfunction, edematous eyelids with multiple chalazia and significant papillary conjunctivitis with inferior bulbar injection. There was a bilateral superficial punctate keratitis and a decreased tear breakup time noted. The rest of the exam was within normal limits. He was started on neomycin/polymyxin B/dexamethasone ophthalmic ointment and tobramycin/dexamethasone eyedrops twice a day. He ultimately underwent excision of his multiple chalazia.\n\nExamination three weeks after initiation of therapy showed newly presenting early corneal scarring in left eye with no significant improvement in his symptoms. His treatment was subsequently changed to loteprednol eye drops and frequent preservative-free artificial tears. Despite being on one month of loteprednol eye drops, the patient presented with persistent blepharoconjunctivitis and significant Meibomian gland disease. Under slit lamp examination, superficial punctate keratitis with bilateral peripheral corneal neovascularization were noted (Fig. 1). The patient felt that his ocular symptoms improved on the loteprednol but opted to stop as he felt it was causing depression. As a result, the patient was placed back on neomycin/polymyxin B/dexamethasone ophthalmic ointment.Fig. 1 External photographs showing bilateral blepharoconjunctivitis and left lower eyelid chalazion.\n\nFig. 1\n\nMeibography by LipiScan revealed significant truncation, atrophy and bifurcation of the patient's meibomian glands bilaterally (Fig. 2). The patient underwent manual debridement of his eyelids margin. Avenova and cliradex wipes were added to his lid hygiene regime followed by Lipiflow treatment.Fig. 2 LipiScan meibography image of the right and left eye, respectively, of a blepharoconjunctivitis patient showing overall truncation and atrophy of meiboimian glands.\n\nFig. 2\n\nAt follow up five weeks after the Lipiflow treatment, the best corrected visual acuity was 20/40 in both eyes. Patient reported significant improvement in ocular discomfort since the last visit. A cotton applicator test showed significant improvement of meibomian gland expression and a stimulation of 0.3 PSI pressure on the patient's eye by the meibomian gland evaluator examined the oil quality, quantity and number of functional glands. Slit lamp examination identified mild improvement of palpebral conjunctiva with stable corneal presentation. Current treatment includes Cliradex eyelid wipes, Avenova along with neomycin/polymyxin B/dexamethasone ophthalmic ointment for a week after each dupilumab infusion.\n\n3 Discussion\nAs the most common inflammatory skin disorder, atopic dermatitis affects 10% of the population worldwide with approximately 20% of patients suffering from moderate-to severe disease.1 Despite this high incidence, current treatment options are limited and symptoms for moderate-to-severe atopic dermatitis are inadequately controlled by topical corticosteroids. However, dupilumab is the first FDA-approved biological systemic treatment for moderate-to-severe atopic dermatitis.2 In addition to improving symptoms of atopic dermatitis, clinical trials have also reported a reduction of patient-reported symptoms of anxiety, depression and improvement in overall quality of life.3\n\nSeveral trials have reported ocular complications with dupilumab use for atopic-dermatitis.1,3, 4, 5 In a randomized, double-blind, placebo-controlled clinical trial, conjunctivitis was also reported in 16% of dupilumab users as compared to 9% of the placebo group.2 In another randomized placebo-controlled phase IIb trial, 2–11% of atopic dermatitis patients using dupilumab reported conjunctival infections, irritations and inflammations as compared to the 3% in the placebo group.1 In this trial, as well as another randomized placebo-controlled phase III trial, the incidence of ocular side effects varied depending on the patient's dupilumab dosing regimen.1,3\n\nA few further classified ocular side effects as non-infectious allergic conjunctivitis and infectious conjunctivitis which includes conjunctivitis of unspecified cause.3,5 One of these trials, indicated an increased occurrence of non-infectious conjunctivitis in patients using dupilumab ranging from 14 to 19% in contrast to 8% in the placebo group in a phase IIb trial.5 Unlike our patient, most reports of conjunctivitis events were noted to be mild to moderate in severity.5,6 More than 75% of the reported conjunctivitis resolved during the trial treatment, however one of 920 patients and one of 740 patients withdrew from the trial treatment due to adverse effects.3 Additionally, Barnes et al.7 presented a patient with severe-atopic dermatitis who discontinued dupilumab treatment due to eyelid inflammation and cicatricial ectropion.\n\nAlthough the underlying mechanism and cause of conjunctivitis in these cases are still unclear, dupilumab use for asthma or nasal polyposis was not associated to have higher rates of conjunctivitis. This suggests a unique relationship between dupilumab use for atopic dermatitis and ocular complications rather than an inherent effect of dupilumab.3,6\n\nStudies have not revealed why the incidence of conjunctivitis and severity of its presentation varies with dupilumab use. One trial found conjunctivitis occurrence in 3% and 5% of users in weekly and biweekly dose groups, respectively thus postulating that there may be an inverse relationship between serum concentrations of dupilumab.3 Some hypothesize that this inverse relationship may be due to the pharmacokinetics of dupilumab such that there is a higher target burden or lower tissue distribution.6 The local area's low serum concentration may play a role in the inhibition of TH2 cells ultimately leading to conjunctivitis.6 However, this inverse relationship is not reported in other varied dupilumab dosing regimen studies.1,5\n\nOthers suggest dupilumab's blocked IL-4 and IL-13 response may result in an increased activity of ligands involved in atopic keratoconjunctivitis.6 However, in the phase III trial, atopic keratoconjunctivitis was reported in less than 0.5% users with no significant difference between the trial and placebo group.6 Of note, these cases were not examined by ophthalmologists which may not render the true incidence of conjunctivitis or a subtype of conjunctivitis with dupilumab use.6\n\nIn our patient, dupilumab was helpful in treating the symptoms of atopic dermatitis. However, the continuous use of dupilumab resulted in significant blepharoconjunctivitis. Treatment of blepharoconjunctivitis includes a variety of therapies. Topical and oral antibiotics and steroids have shown to resolve most refractory cases of blepharoconjunctivitis. Stimulation of meibomian glands with warm lid compressions and eyelid hygiene have also been reported to alleviate blepharoconjunctivitis.8\n\nEyelid hygiene with Lipiflow, a thermal pulsation system, was elected due to the severity and recurrence of blepharoconjunctivitis, multiple chalazia and dry eye syndrome seen in our patient. Lipiflow is therapeutically used to increase the quality of gland secretion, lipid layer thickness, long term ocular surface disease index and standard patient evaluation of eye dryness (SPEED) in dry eye patients.9 Lipiflow treatment consists of heating both the inner and outer eyelid surfaces, while unblocking glandular plugs while simultaneously mechanically massaging meibomian glands to relieve any obstruction.9 Several studies have reported significant improvement of tear film break up time and dry eye symptoms after one twelve-minute treatment session with Lipiflow.9,10 A single Lipiflow session has also shown to be as effective as three months of twice daily warm compresses.10 In our particular case of blepharoconjunctivitis that was unresponsive to medical treatment, improving meibomian gland dysfunction using eyelid hygiene with Lipiflow treatment may have helped improve the blepharoconjunctivitis.\n\nIn our patient, dupilumab significantly improved symptoms of severe atopic dermatitis while also improving patient-reported quality of life. However, with continued use of dupilumab, adverse events such as blepharoconjunctivitis and dry eye disease were noted. Rather than discontinuing dupilumab, supportive care with topical steroids, topical antibiotics, and lid hygiene were seen to be successful. Treatment with Lipiflow may also help with the patient's signs and symptoms.\n\nPatient consent\nThe patient consented to publication of the case orally. This report does not contain any personal information that could lead to the identification of the patient.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nThe following authors have no financial disclosures: SAP, SWS, LDG, LHS.\n\nAuthorship\nEach of the authors has contributed to, read and approved this manuscript. All authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Thaci D. Simpson E.L. Beck L.A. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial Lancet 387 2016 40 52 26454361 \n2 Dupixent (Dupilumab) [package Insert] 2017 Regeneron Pharmaceuticals Inc. Tarrytown, NY \n3 Simpson E.L. Bieber T. Guttman-Yassky E. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis N Engl J Med 375 2016 2335 2348 27690741 \n4 Ou Z. Chen C. Chen A. Adverse events of Dupilumab in adults with moderate-to-severe atopic dermatitis: a meta-analysis Int Immunopharmacol 54 2018 303 310 29182975 \n5 Blauvelt A. de Bruin-Weller M. Gooderham M. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids: a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial Lancet 389 2017 2287 2303 28478972 \n6 Mennini M. Simpson E.L. Akinlade B. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis N Engl J Med 376 2017 1090 1091 \n7 Barnes A.C. Blandford A.D. Perry J.D. Cicatricial ectropion in a patient treated with dupilumab Am J Ophthalmol Case Rep 7 2017 120 122 29260094 \n8 Ianchenko S.V. Sakhnov S.N. Malyshev A.V. [Treatment of chronic allergic blepharoconjunctivitis] Vestn Oftalmol 130 78 2014 80 84 25715557 \n9 Blackie C.A. Carlson A.N. Korb D.R. Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation: a review Curr Opin Ophthalmol 26 2015 306 313 26058030 \n10 Zhao Y. Veerappan A. Yeo S. Clinical trial of thermal pulsation (LipiFlow) in meibomian gland dysfunction with preteatment meibography Eye Contact Lens 42 2016 339 346 26825281\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "16()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Atopic dermatitis; Blepharoconjunctivitis; Dupilumab; Lipiflow; Ocular side effects",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
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"pages": "100550",
"pmc": null,
"pmid": "31535057",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "25711068;26058030;26454361;26825281;27690741;28301105;28478972;29182975;29260094",
"title": "Dupilumab-associated blepharoconjunctivitis.",
"title_normalized": "dupilumab associated blepharoconjunctivitis"
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{
"abstract": "A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (β-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells.",
"affiliations": "Sidney Kimmel College of Medicine Thomas Jefferson University, Philadelphia, PA.;Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA.;Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA.;Department of Pathology Thomas Jefferson University, Philadelphia, PA.;Department of Pathology Thomas Jefferson University, Philadelphia, PA.;Department of Pathology Thomas Jefferson University, Philadelphia, PA.;Department of Medicine Thomas Jefferson University, Philadelphia, PA.;Department of Pathology Thomas Jefferson University, Philadelphia, PA.;Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA. Electronic address: ubaldo.martinezoutschoorn@jefferson.edu.",
"authors": "Mills|Teresa Anne|TA|;Orloff|Marlana|M|;Domingo-Vidal|Marina|M|;Cotzia|Paolo|P|;Birbe|Ruth C|RC|;Draganova-Tacheva|Rossitza|R|;Martinez Cantarin|Maria P|MP|;Tuluc|Madalina|M|;Martinez-Outschoorn|Ubaldo|U|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D027501:Monocarboxylic Acid Transporters; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D027981:Symporters; C421223:monocarboxylate transport protein 1",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0093-7754",
"issue": "42(6)",
"journal": "Seminars in oncology",
"keywords": null,
"medline_ta": "Semin Oncol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D002100:Cachexia; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D000074324:Ipilimumab; D008545:Melanoma; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters; D010257:Paraneoplastic Syndromes; D044162:Parathyroid Hormone-Related Protein; D027981:Symporters",
"nlm_unique_id": "0420432",
"other_id": null,
"pages": "909-14",
"pmc": null,
"pmid": "26615135",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14503917;3616618;2138442;1700240;8077382;8592727;8662561;8833902;9623520;9693191;15517871;15613700;17200368;17122988;18256357;19033663;19091948;20004617;20145205;20525992;20810794;21897221;22745236;22879438;23972703;23999443;24610577;24486645;25030953;25043816;25043053;25071126;25801618;25774832;26037642;11003603;11595884;11668474;11684439;12653746",
"title": "Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates.",
"title_normalized": "parathyroid hormone related peptide linked hypercalcemia in a melanoma patient treated with ipilimumab hormone source and clinical and metabolic correlates"
} | [
{
"companynumb": "US-AMGEN-USASP2016052746",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "A young man underwent Tc-tetrofosmin cardiac SPECT/CT for the evaluation of the 8-month history of exertional dyspnea without chest pain. Tc-tetrofosmin SPECT demonstrated absence of perfusion defects and a mildly decreased uptake in post-stress images, consistent with artifact, in the inferior myocardium. Cardiac catheterization showed a large right and a small left coronary artery opacified retrogradely by right collateral vessels without connections between the left main and the left coronary artery. In patients with anomalous coronary arteries, Tc SPECT can shows absence of perfusion defects, in the presence of a collateral circulation.",
"affiliations": "From the Departments of *Nuclear Medicine, and †Cardiology, Santa Maria della Misericordia Hospital; ‡Section of Adult Congenital and Adult Heart Disease, Cardiovascular Diagnosis and Endoluminal Interventions, Rovigo General Hospital, Rovigo, Italy; and §Department of Radiology, University of Southern California, Los Angeles, CA.",
"authors": "Rampin|Lucia|L|;Rinuncini|Massimo|M|;Zuin|Marco|M|;Rigatelli|GianLuca|G|;Roncon|Loris|L|;Colletti|Patrick M|PM|;Rubello|Domenico|D|",
"chemical_list": "D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; C078700:technetium tc-99m tetrofosmin",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000001271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "41(10)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000328:Adult; D003324:Coronary Artery Disease; D006801:Humans; D008297:Male; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "e452-3",
"pmc": null,
"pmid": "27276205",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Left Main Coronary Artery Atresia in Young Man Examined With 99mTc-Tetrofosmin SPECT: A Rare and Challenging Anomaly.",
"title_normalized": "left main coronary artery atresia in young man examined with 99mtc tetrofosmin spect a rare and challenging anomaly"
} | [
{
"companynumb": "IT-GE HEALTHCARE MEDICAL DIAGNOSTICS-MYVW-PR-1610L-0066",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TECHNETIUM TC-99M TETROFOSMIN"
... |
{
"abstract": "Tedizolid is a new oxazolidinone antibiotic with little real-life data on use outside of skin and soft tissue infections. There is a paucity of safety evidence in courses greater than 6 days. Our centre uses tedizolid predominantly when linezolid-associated adverse events have occurred. This service evaluation describes our experience to date. We performed a retrospective service evaluation by reviewing case notes, prescription charts, and laboratory system results for each patient prescribed tedizolid at our hospital and recording patient demographics, clinical details, and outcomes. Sixty patients received tedizolid between May 2016 and November 2018. Most were treated for bone or joint infections and had stopped linezolid prior to tedizolid prescription. Mean length of tedizolid therapy was 27 days. Haematological adverse effects were infrequent. Most patients (72%) finished the course and their clinical condition improved during treatment (72%). Adverse events were common, but often not thought to be tedizolid related. Tedizolid appears to be safe in prolonged courses within this context. It may be suitable for longer-term antibiotic therapy within a complex oral and parenteral outpatient antibiotic therapy (COPAT) service. Patients who do not tolerate linezolid can be safely switched to tedizolid if appropriate.",
"affiliations": "Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK. JoshAYork@gmail.com.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.;Department of Infection, Hull University Teaching Hospitals NHS Trust; Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ, UK.",
"authors": "York|Joshua A|JA|https://orcid.org/0000-0003-0036-9767;Adams|Kate|K|;Cullen|Lorraine|L|;Delahay|Joanne|J|;Ivan|Monica|M|;Lillie|Patrick J|PJ|;MacLachlan|Laura|L|;Barlow|Gavin|G|",
"chemical_list": "D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D013777:Tetrazoles; C546016:tedizolid; D000069349:Linezolid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-020-04015-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "40(2)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Antibiotic; Linezolid; Oxazolidinone; Stewardship; Tedizolid",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001850:Bone Diseases, Infectious; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones; D012189:Retrospective Studies; D013777:Tetrazoles; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "397-405",
"pmc": null,
"pmid": "32851509",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "23403680;29346119;30003513;29528251;31079589;29109162;30517641;25421472;28369418",
"title": "Tedizolid: a service evaluation in a large UK teaching hospital.",
"title_normalized": "tedizolid a service evaluation in a large uk teaching hospital"
} | [
{
"companynumb": "NVSC2021GB056730",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
"druga... |
{
"abstract": "The anti-CD38 antibody daratumumab is approved for treatment of refractory multiple myeloma and acts by depletion of plasma cells and modification of various T-cell functions. Its safety, immunological effects and therapeutic potential was evaluated in a 60-year old patient with life-threatening and treatment-refractory anti-CASPR2 encephalitis requiring medical care and artificial ventilation in an intensive care unit. His autoimmune dysfunction was driven by exceptional high anti-CASPR2 autoantibody titers combined with an abnormally increased T-cell activation. As he remained unresponsive to standard and escalation immunotherapies (methylprednisolone, plasma exchange, immunoadsorption, immunoglobulins, rituximab and bortezomib), therapy was escalated to 13 cycles of 16 mg/kg daratumumab. During the treatment period, clinical, radiological, histological and laboratory findings, including quantification of autoreactive and protective antibody levels and FACS-based immune phenotyping, were analyzed. Daratumumab treatment was associated with significant clinical improvement, substantial reduction of anti-CASPR2 antibody titers, especially in CSF, decrease of immunoglobulin levels and protective vaccine titers, as well as normalization of initially increased T-cell activation markers. However, the patient died of Gram-negative septicemia in a neurorehabilitation center. In conclusion, our findings suggest that daratumumab induces not only depletion of autoreactive long-lived plasma cells associated with improvements of neurological sequelae, but also severe side effects requiring clinical studies investigating efficacy and safety of anti-CD38 therapy in antibody-driven autoimmune encephalitis.",
"affiliations": "Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. franziska.scheibe@charite.de.;Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.;Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.;Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.;Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.",
"authors": "Scheibe|Franziska|F|;Ostendorf|Lennard|L|;Reincke|S Momsen|SM|;Prüss|Harald|H|;von Brünneck|Ann-Christin|AC|;Köhnlein|Martin|M|;Alexander|Tobias|T|;Meisel|Christian|C|;Meisel|Andreas|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; C403049:CNTNAP2 protein, human; D007155:Immunologic Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C556306:daratumumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-019-09585-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "267(2)",
"journal": "Journal of neurology",
"keywords": "Anti-CASPR2 encephalitis; Autoimmune encephalitis; Critical care; Daratumumab",
"medline_ta": "J Neurol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D020274:Autoimmune Diseases of the Nervous System; D004660:Encephalitis; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "317-323",
"pmc": null,
"pmid": "31630242",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30218501;25710470;29636948;27557302;27371488;27531679;30187160;28003505;29761122;28692708;23264341;27222480",
"title": "Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis.",
"title_normalized": "daratumumab treatment for therapy refractory anti caspr2 encephalitis"
} | [
{
"companynumb": "DE-CELLTRION INC.-2019DE027035",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nErlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR-sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination.\n\n\nMETHODS\nThis phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m(2) BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles.\n\n\nRESULTS\nForty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m(2) with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m(2). First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4-3.5), and median overall survival was 6.1 months (95 % CI 5.1-10.1).\n\n\nCONCLUSIONS\nThe MTD for the combination of capecitabine and erlotinib is 750 mg/m(2) BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.",
"affiliations": "Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.;Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK. Mary.O'Brien@rmh.nhs.uk.",
"authors": "Kumar|Rajiv|R|;Lu|Shir Kiong|SK|;Minchom|Anna|A|;Sharp|Adam|A|;Davidson|Michael|M|;Gunapala|Ranga|R|;Yap|Timothy A|TA|;Bhosle|Jaishree|J|;Popat|Sanjay|S|;O'Brien|Mary E R|ME|",
"chemical_list": "D000970:Antineoplastic Agents; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2950-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "77(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Adenocarcinoma; Capecitabine; Erlotinib; Non-small cell lung cancer; Phase 1",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "375-83",
"pmc": null,
"pmid": "26706729",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients.",
"title_normalized": "a phase 1b trial of the combination of an all oral regimen of capecitabine and erlotinib in advanced non small cell lung cancer in caucasian patients"
} | [
{
"companynumb": "GB-ASTELLAS-2013US010308",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Interstitial lung disease, also known as diffuse parenchymal lung disease, is a group of diseases that affects the interstitium of the lungs and can lead to progressive fibrosis of the lungs. The potential causes of interstitial lung disease are broad and includes infection, malignancy, autoimmune/connective tissues diseases, inhaled substances, and certain medications. One of the medications that can cause interstitial lung disease is nitrofurantoin. CASE REPORT A 88-year-old man with recurrent urinary tract infections was treated with long-term nitrofurantoin prophylactic therapy. He took 100 mg of nitrofurantoin on a daily basis for over 10 years as prophylactic therapy for recurrent urinary tract infections, and subsequently developed chronic respiratory failure requiring supplemental oxygen. Chest radiography and high-resolution computed tomography imaging were performed and revealed pulmonary fibrosis consistent with interstitial lung disease. CONCLUSIONS Although nitrofurantoin is one of the most commonly used antibiotics in the treatment of urinary tract infections and is often considered a relatively safe medication, long-term use can lead to the development of interstitial lung disease.",
"affiliations": "Department of Internal Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Internal Medicine, University Hospitals of Cleveland, Richmond Heights, OH, USA.;Department of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, Richmond Heights, OH, USA.;Department of Internal Medicine, University Hospitals of Cleveland, Richmond Heights, OH, USA.;Department of Internal Medicine, University Hospitals of Cleveland, Richmond Heights, OH, USA.",
"authors": "Chin|Andrew J|AJ|;Rashid|Saadri|S|;Gharibeh|Tarek R|TR|;Kibbe|Peter S|PS|;Wynbrandt|Jonathan H|JH|",
"chemical_list": "D000892:Anti-Infective Agents, Urinary; D009582:Nitrofurantoin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.920386",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32238797\n10.12659/AJCR.920386\n920386\nArticles\nInterstitial Lung Disease Secondary to Long-Term Nitrofurantoin Use\nChin Andrew J. ABCDEFG1 Rashid Saadri ABCDEFG2 Gharibeh Tarek R. ABCDEFG3 Kibbe Peter S. ABCDEFG2 Wynbrandt Jonathan H. ABCDEFG2 \n1 Department of Internal Medicine, University of Arizona College of Medicine, Tucson, AZ, U.S.A.\n\n2 Department of Internal Medicine, University Hospitals of Cleveland, Richmond Heights, OH, U.S.A.\n\n3 Department of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, Richmond Heights, OH, U.S.A.\nCorresponding Author: Andrew J. Chin, e-mail: Andrew.Chin@BannerHealth.comAuthors’ Contribution:\n\nA 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\nConflict of interest: None declared\n\n\n2020 \n02 4 2020 \n21 e920386-1 e920386-3\n28 9 2019 03 2 2020 17 2 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 88-year-old\n\nFinal Diagnosis: Interstitial lung disease\n\nSymptoms: Chronic dyspnea\n\nMedication: Nitrofurantoin\n\nClinical Procedure: None\n\nSpecialty: Pulmonology\n\nObjective:\nAdverse events of drug therapy\n\nBackground:\nInterstitial lung disease, also known as diffuse parenchymal lung disease, is a group of diseases that affects the interstitium of the lungs and can lead to progressive fibrosis of the lungs. The potential causes of inter-stitial lung disease are broad and includes infection, malignancy, autoimmune/connective tissues diseases, inhaled substances, and certain medications. One of the medications that can cause interstitial lung disease is nitrofurantoin.\n\nCase Report:\nA 88-year-old man with recurrent urinary tract infections was treated with long-term nitrofurantoin prophylactic therapy. He took 100 mg of nitrofurantoin on a daily basis for over 10 years as prophylactic therapy for recurrent urinary tract infections, and subsequently developed chronic respiratory failure requiring supplemental oxygen. Chest radiography and high-resolution computed tomography imaging were performed and revealed pulmonary fibrosis consistent with interstitial lung disease.\n\nConclusions:\nAlthough nitrofurantoin is one of the most commonly used antibiotics in the treatment of urinary tract infections and is often considered a relatively safe medication, long-term use can lead to the development of inter-stitial lung disease.\n\nMeSH Keywords:\nLung Diseases, InterstitialNitrofurantoinPulmonary FibrosisUrinary Tract Infections\n==== Body\nBackground\nInterstitial lung disease (ILD), also known as diffuse parenchymal lung disease (DPLD), is a group of diseases that affects the interstitium of the lungs and can lead to progressive fibrosis of the lungs. The potential causes of ILD are broad and include infection, malignancy, autoimmune/connective tissues diseases, inhaled substances, and certain medications. One of the medications that can cause ILD is nitrofurantoin.\n\nCase Report\nA 88-year-old man was hospitalized following a fall at home. Radiography was positive for intertrochanteric fracture of the proximal left femur, which required surgical repair by orthopedic surgery. During pre-operative risk assessment, a chest radiograph (Figure 1) revealed diffuse reticular and interstitial opacities prominent in the lung bases, consistent with a diagnosis of ILD. A physical exam was unremarkable, except for coarse breath sounds bilaterally, along with decreased range of motion in the left hip. The patient’s medical history included hypertension, diabetes mellitus, benign prostatic hyperplasia, and recurrent urinary tract infections (UTIs) for which he had been on long-term nitrofurantoin prophylactic therapy. In addition, he was a former tobacco smoker with a 40-pack-year smoking history. He stated that he worked at an office job and denied any significant workplace exposures, including exposures potentially leading to asbestosis, silicosis, or berylliosis. He denied any prior radiation therapy and stated that he had never been exposed to amiodarone, methotrexate, or any chemotherapeutic agents.\n\nAfter further questioning, the patient stated that he had undergone an extensive urological evaluation for his recurrent UTIs and was prescribed long-term nitrofurantoin prophylactic therapy. He stated that he took 100 mg of nitrofurantoin on a daily basis as prophylactic therapy for recurrent UTIs for over 10 years. He stopped taking the nitrofurantoin in 2008 due to concern about development of pulmonary fibrosis and chronic respiratory failure requiring supplemental oxygen. Pulmonary function testing at that time did not reveal any obstructive or restrictive lung disease. He stated that he was on supplemental oxygen for several years but was eventually able to be weaned off of the supplemental oxygen. A laboratory work-up was negative for ANA, SSA/SSB antibody, Jo-1 antibody, Scl-70 antibody, c-ANCA, and p-ANCA. High-resolution computed tomography (HRCT) (Figure 2) was performed and revealed diffuse bilateral reticular septal thickening with honeycombing of subpleural and bilateral lower lobe predominance, consistent with a diagnosis of ILD. While a biopsy would have been helpful in confirming the diagnosis, it was not performed, because the benefits of the procedure did not exceed the risks. Thankfully, the patient remained stable throughout his hospitalization and successfully underwent surgical repair of the intertrochanteric facture of the proximal left femur without any complications.\n\nDiscussion\nNitrofurantoin is an antibiotic commonly used in the management of UTIs. It can be used for treatment of acute UTIs as well as for prophylaxis in patients with recurrent UTIs.\n\nIt is especially commonly used during pregnancy due to its low teratogenic risk for the developing fetus. While nitrofurantoin is a relatively safe antibiotic, it can result in pulmonary injury [1]. Although the incidence of pulmonary injury from nitrofurantoin is estimated to be anywhere between 1 in 550 to 1 in 5400, it is probably underdiagnosed and underre-ported [2]. Both acute and chronic pulmonary injury can occur from nitrofurantoin use, and these occur by different mechanisms of action. The acute form of pulmonary injury is thought to be mediated by a hypersensitivity reaction to nitrofurantoin, while the chronic form of pulmonary injury is thought to occur due to a cell-mediated or toxic response to nitrofurantoin and can result in ILD.\n\nAcute pulmonary injury has been to observed even at small doses and there does not appear to be a relationship between the dose and the development of acute pulmonary injury [3]. The chronic form of pulmonary injury is much less common than the acute form of pulmonary injury and is usually found in patients who had been taking nitrofurantoin on a long-term basis. The exact dose of nitrofurantoin required to result in chronic pulmonary injury is unclear, although the amount of injury is suspected to be dose-related [4]. HRCT, which is the criterion standard imaging test for the diagnosis of ILD, can demonstrate honeycombing, ground-glass attenuation, inter-and intra-lobular septal thickening, and traction bronchiectasis [5]. The treatment for both acute and chronic forms of pulmonary injury is the immediate discontinuation of nitrofurantoin therapy. Due to the possible irreversibility of pulmonary fibrosis, it is important for providers to be aware of the risk of developing of ILD from long-term nitrofurantoin use.\n\nConclusions\nAlthough nitrofurantoin is one of the most commonly used antibiotics in the treatment of UTIs and is often considered a relatively safe medication, its long-term use can lead to development of ILD.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Radiograph of chest showing diffuse reticular and interstitial opacities, most prominent in the lung bases.\n\nFigure 2. High-resolution computed tomography (HRCT) image of chest showing diffuse bilateral reticular septal thickening with honeycombing of sub-pleural and bilateral lower lobe predominance.\n==== Refs\nReferences:\n1. Sovijärvi AR Lemola M Stenius B Idänpään-Heikkilä J Nitrofurantoin-induced acute, subacute and chronic pulmonary reactions Scand J Respir Dis 1977 58 41 841294 \n2. Prakash UB Pulmonary reaction to nitrofurantoin Semin Respir Dis 1980 2 71 75 \n3. D’Arcy PF Nitrofurantoin Drug Intell Clin Pharm 1985 19 540 47 3896715 \n4. Mendez JL Nadrous HF Hartman TE Ryu JH Chronic nitrofurantoin-induced lung disease Mayo Clin Proc 2005 80 1298 302 16212142 \n5. Martins RR Marchiori E Viana SL Chronic eosinophilic pneumonia secondary to long-term use of nitrofurantoin: High-resolution computed tomography findings J Bras Pneumol 2008 34 181 84 18392467\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
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"mesh_terms": "D000369:Aged, 80 and over; D000892:Anti-Infective Agents, Urinary; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D009582:Nitrofurantoin; D011658:Pulmonary Fibrosis; D014552:Urinary Tract Infections",
"nlm_unique_id": "101489566",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16212142;18392467;3896715;841294",
"title": "Interstitial Lung Disease Secondary to Long-Term Nitrofurantoin Use.",
"title_normalized": "interstitial lung disease secondary to long term nitrofurantoin use"
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"abstract": "Here, we present a case of chronic myeloid leukemia for which imatinib therapy was initated. Triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone was normal, and thyroid microsomal autoantibodies (TMA) were positive and patient was diagnosed as thyroiditis treated with corticosteroids for 1½ months which lead to resolution.",
"affiliations": "Department of Pharmacology, AIIMS, Jodhpur, Rajasthan, India.;Department of Pharmacology, AIIMS, Jodhpur, Rajasthan, India.",
"authors": "Singh|Surjit|S|;Sharma|Pramod Kumar|PK|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "India",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-48-45810.4103/0253-7613.186214Drug WatchImatinib-induced thyroiditis in Philadelphia chromosome-positive chronic myeloid leukemia Singh Surjit Sharma Pramod Kumar Department of Pharmacology, AIIMS, Jodhpur, Rajasthan, IndiaAddress for correspondence: Dr. Surjit Singh, E-mail: sehmby_ss@yahoo.comJul-Aug 2016 48 4 458 459 22 1 2016 05 6 2016 Copyright: © Indian Journal of Pharmacology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Here, we present a case of chronic myeloid leukemia for which imatinib therapy was initated. Triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone was normal, and thyroid microsomal autoantibodies (TMA) were positive and patient was diagnosed as thyroiditis treated with corticosteroids for 1½ months which lead to resolution.\n\nChronic myeloid leukemiaimatinibthyroiditis\n==== Body\nPhiladelphia chromosome results from reciprocal translocation of key genes Abelson murine leukemia viral oncogene homolog (ABL1) and breakpoint cluster region (BCR) between chromosome 9 and 22, respectively.[1] The fused ribonucleic acid BCR-ABL transcript encodes a 210 kDa BCR-ABL protein that has constitutive protein tyrosine kinase (TK) activity unlike the normal c-ABL protein (145 kDa) which is usually inactive.[1] This constitutive activity results in uncontrolled growth of the myeloid cells resulting in chronic myeloid leukemia (CML). Imatinib inhibits TK enzyme by competitive inhibition of adenosine triphosphate binding to BCR-ABL, CD-117 (c-Kit), and platelet-derived growth factor receptor.[1] Imatinib is currently recommended as a monotherapy in CML and CD-117 (c-Kit) - positive unresectable or metastatic gastrointestinal stromal tumors.[2] As compared to interferon-α plus cytarabine combination, imatinib has been shown to have significantly higher complete hematological response, complete cytogenetic response, major cytogenetic response, and estimated freedom from progression of disease. Based on high response rates and good tolerability in clinical trials, imatinib has become the first line treatment and the gold standard for treatment for CML.[2] Imatinib is generally well-tolerated, however, is associated with cramps and facial/limb swelling in some instances. As with any other recently introduced drug, the toxicity profile of imatinib is evolving. We present a case of imatinib-induced autoimmune thyroiditis.\n\nCase Report\nIn June 2004, a 58-year-old Asian female presented with anxiety, palpitations and breathlessness. Her blood pressure was 175/110 mm Hg. Laboratory analysis revealed total leukocyte count (TLC) of 56,000. Differential leukocyte count revealed blasts, promyelocytes, myelocytes, and metamyelocytes with decreased leukocytes. Bone marrow revealed hypercellularity with myeloid to erythroid ratio of 9:1. Uric acid was 8.8 mg/dl. Liver function test (LFT) and kidney function test (KFT) were normal. Leukocyte alkaline phosphatase was normal. Rest of the biochemistry was within normal limits. Cytogenetic report confirmed the diagnosis of Philadelphia positive CML. 99Technetium scan revealed irregularly increased osteoblastic activity in bilateral shoulder and sacroiliac joints. Rest of the skeleton system showed physiologically normal radiotracer distribution. The patient was started on imatinib 400 mg and folic acid 5 mg once daily in August 2004. Peripheral smear remission was seen in 2 months, i.e., TLC returned to normal value and hemoglobin and platelet counts normalized. One year later, the patient presented with bilateral redness of eyes and facial swelling which was treated with antihistamines. Following this, 1 month later, the patient presented with bilateral parotid swelling which was not evaluated. Parotid swelling resolved of its own within a month without any treatment. In August 2005, bone marrow biopsy revealed normocellular marrow spaces with adequate representation of all three marrow elements, i.e., complete hematological remission. The cytogenetic report showed Philadelphia positivity in 5% of cells. In November 2005, the patient complained of nervousness and loose motions off and on. Urine and stool examinations were normal. LFT and KFT were also normal. One month later, the patient presented with pain and tenderness over thyroid. A provisional diagnosis of acute thyroiditis was made. Triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone were normal, but thyroid microsomal autoantibodies (TMA) antibody was positive. Fine needle aspiration cytology was planned, but the patient did not consent for the investigation. A diagnosis of autoimmune thyroiditis was made. She was treated with corticosteroids for 1½ months. As the complaints resolved, steroids were gradually tapered off. Bone marrow biopsy done in February 2006 showed complete hematological remission. The cytogenetic report showed 12% of Philadelphia positive metaphases.\n\nDiscussion\nMost common adverse events reported with imatinib are edema, nausea, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and headache.[2] Cardiotoxicity including congestive heart failure has been reported with imatinib.[2] Grade 3 and 4 anemia, thrombocytopenia, and neutropenia have also been reported.[2] This case illustrates a possible occurrence of imatinib-induced autoimmune thyroiditis. In a case of thyroiditis, history is one of the most vital parts of evaluation. The differential diagnosis of thyroid pain includes acute, subacute thyroiditis, chronic thyroiditis, hemorrhage into a cyst, malignancy including lymphoma, and rarely, amiodarone-induced thyroiditis or amyloidosis. The absence of small tender asymmetric goiter, fever, dysphagia, and erythema over thyroid rules out bacterial or fungal causes of thyroiditis. The patient had bilateral parotid swelling 6 months before the presentation which resolved of its own. The absence of fever and presence of TMA ruled out mumps as a cause of thyroiditis. The absence of weight loss and acute presentation ruled out malignancy. Finally, the positive response to treatment with corticosteroids also ruled out infection and malignancy as a cause of pain in thyroid. There was no history of exposure to radiation, I131 exposure, and trauma. Thus, only possible cause can be autoimmune thyroiditis which responded well to the treatment with corticosteroids.\n\nImatinib was started in August 2004, and the patient presented with the thyroiditis in November 2005 establishing the temporal association of thyroiditis with imatinib. Use of Naranjo's probability scale[3] and WHO causalty scale assessment indicated imatinib as a possible cause of thyroiditis because the idiopathic cause of autoimmune thyroiditis cannot be ruled out. Sunitinib, a TK inhibitor, a drug of same class has been implicated as a cause of lymphocytic and destructive thyroiditis.[4] A review the literature of studies of thyroid dysfunction induced by TK inhibitors showed that thyroid dysfunction is not a rare entity with the use of TK inhibitors although not so common with the use of imatinib.[5]\n\nAs there was possibility of progression of CML when drug is withheld, drug withdrawal was not done to check the possible causation of thyroiditis by imatinib. Second, there was no increase in the thyroid hormone levels and the severity of thyroiditis did not mandate drug withdrawal.\n\nIt is possible that the bilateral parotid swelling was also related to imatinib use. Bilateral parotid swelling can be of autoimmune origin like thyroiditis. Hence, a possibility of activation of autoimmune diseases with the use of imatinib cannot be ruled out.\n\nConclusion\nIt cannot be excluded that imatinib like sunitinib can cause thyroiditis. Hence, clinicians should be aware of the possibility of thyroiditis with imatinib and should have an eye not to miss the event.\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\n1 Heisterkamp N Stephenson JR Groffen J Hansen PF de Klein A Bartram CR Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia Nature 1983 306 239 42 6316147 \n2 Saglio G Kim DW Issaragrisil S le Coutre P Etienne G Lobo C Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia N Engl J Med 2010 362 2251 9 20525993 \n3 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Amethod for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n4 Grossmann M Premaratne E Desai J Davis ID Thyrotoxicosis during sunitinib treatment for renal cell carcinoma Clin Endocrinol (Oxf) 2008 69 669 72 18394019 \n5 Ahmadieh H Salti I Tyrosine kinase inhibitors induced thyroid dysfunction: A review of its incidence, pathophysiology, clinical relevance, and treatment Biomed Res Int 2013 2013 725410\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "48(4)",
"journal": "Indian journal of pharmacology",
"keywords": "Chronic myeloid leukemia; imatinib; thyroiditis",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D013967:Thyroiditis, Autoimmune; D016896:Treatment Outcome",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "458-459",
"pmc": null,
"pmid": "27756963",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20525993;24282820;18394019;7249508;6316147",
"title": "Imatinib-induced thyroiditis in Philadelphia chromosome-positive chronic myeloid leukemia.",
"title_normalized": "imatinib induced thyroiditis in philadelphia chromosome positive chronic myeloid leukemia"
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"abstract": "Osteolytic lesions of the mandible are common, and there are two important differential diagnoses that must be considered: medication-related osteonecrosis of the jaws (MRONJ) and squamous cell carcinoma (SCC). In patients with a history of taking antiresorptive medication as well as risk factors for neoplasia it can be difficult to differentiate between the two. We describe two cases in both of which a mandibular osteolytic lesion was inadequately identified as either MRONJ or SCC because of confusing clinical and histopathological features. We also reviewed relevant publications to identify similar cases. Here we discuss our clinical dilemma when faced with two different conditions that present with similar clinical and histopathological features.",
"affiliations": "Oral and Maxillofacial Surgery Unit, Austin Hospital, Heidelberg, Melbourne, Victoria. Electronic address: shreyatocaciu@gmail.com.;Oral and Maxillofacial Surgery Unit, Austin Hospital, Heidelberg, Melbourne, Victoria.;Oral and Maxillofacial Surgery Unit, Austin Hospital, Heidelberg, Melbourne, Victoria.;Department of Pathology, Peter McCallum Cancer Centre, Melbourne, Victoria.;Oral and Maxillofacial Surgery Unit, Austin Hospital, Heidelberg, Melbourne, Victoria.",
"authors": "Tocaciu|S|S|;Breik|O|O|;Lim|B|B|;Angel|C|C|;Rutherford|N|N|",
"chemical_list": "D003287:Contrast Media",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.bjoms.2017.08.005",
"fulltext": null,
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"issn_linking": "0266-4356",
"issue": "55(9)",
"journal": "The British journal of oral & maxillofacial surgery",
"keywords": "Bisphosphonate related osteonecrosis of the jaws (BRONJ); Medication-related osteonecrosis of the jaws (MRONJ); Osteonecrosis; squamous cell carcinoma (SCC)",
"medline_ta": "Br J Oral Maxillofac Surg",
"mesh_terms": "D000369:Aged, 80 and over; D001706:Biopsy; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D002294:Carcinoma, Squamous Cell; D003287:Contrast Media; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008339:Mandibular Neoplasms; D011862:Radiography, Panoramic; D012307:Risk Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8405235",
"other_id": null,
"pages": "e53-e57",
"pmc": null,
"pmid": "28851496",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnostic dilemma between medication-related osteonecrosis and oral squamous cell carcinoma in a mandibular lytic lesion.",
"title_normalized": "diagnostic dilemma between medication related osteonecrosis and oral squamous cell carcinoma in a mandibular lytic lesion"
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"abstract": "Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 μg/mL and 3.31 ± 3.14 μg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis.",
"affiliations": "Division of Pharmacy, Chiba University Hospital, Chiba, Japan. Electronic address: z7p1008@chiba-u.jp.;Division of Pharmacy, Chiba University Hospital, Chiba, Japan.;Division of Pharmacy, Chiba University Hospital, Chiba, Japan.;Division of Pharmacy, Chiba University Hospital, Chiba, Japan.;Department of Neurosurgery, Chiba University Graduate School of Medicine, Chiba, Japan.;Division of Pharmacy, Chiba University Hospital, Chiba, Japan.",
"authors": "Ishikawa|Masayuki|M|;Yamazaki|Shingo|S|;Suzuki|Takaaki|T|;Uchida|Masashi|M|;Iwadate|Yasuo|Y|;Ishii|Itsuko|I|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002556:Cerebrospinal Fluid Proteins; D012709:Serum Albumin; D014640:Vancomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.10.013",
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"issn_linking": "1341-321X",
"issue": "25(2)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Bacterial meningitis; Cerebrospinal fluid; Therapeutic drug monitoring; Vancomycin",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D002556:Cerebrospinal Fluid Proteins; D005260:Female; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial; D008875:Middle Aged; D012189:Retrospective Studies; D012709:Serum Albumin; D014640:Vancomycin",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "124-128",
"pmc": null,
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"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio.",
"title_normalized": "correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid serum albumin ratio"
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"abstract": "BACKGROUND\nEpidural hematoma is a possible complication after neuraxial procedures. Recently, caudal epidural pulsed radiofrequency (PRF) stimulation was reported as an effective method for controlling several types of chronic pain. Herein, we report on a patient who developed a lumbar epidural hematoma after receiving caudal epidural PRF stimulation.\nA 75-year-old woman, who was taking oral warfarin (2 mg/d), received caudal epidural PRF stimulation for symmetrical neuropathic pain in both legs due to chronic idiopathic axonal polyneuropathy. She did not discontinue warfarin use before undergoing the procedure. Three days and 12 hours after the procedure, motor weakness suddenly manifested in the right leg (manual muscle testing [MMT] = 2-3).\nLumbar magnetic resonance imaging (MRI) performed 7 days after the PRF procedure showed a spinal epidural hematoma at the L1 to L5 levels, compressing the thecal sac. The international normalized ratio was 6.1 at the time of the MRI.\n\n\nMETHODS\nDecompressive laminectomy from L1 to L5 with evacuation of the hematoma was performed.\n\n\nRESULTS\nThree months postoperatively, the motor weakness in the patient's right leg improved to MMT = 4 to 5.\n\n\nCONCLUSIONS\nThis case suggests that clinicians should carefully check if patients are taking an anticoagulant medication and ensure that it is discontinued for an appropriate length of time before a caudal epidural PRF procedure is performed.",
"affiliations": "Department of Neurosurgery.;Department of Physical Medicine and Rehabilitation, Spine Center, College of Medicine, Yeungnam University, Namku, Daegu, Republic of Korea.",
"authors": "Kim|Sang Woo|SW|;Chang|Min Cheol|MC|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30407313MD-D-18-0496610.1097/MD.0000000000013090130903300Research ArticleClinical Case ReportEpidural hematoma after caudal epidural pulsed radiofrequency stimulation A case reportKim Sang Woo MDaChang Min Cheol MDb∗NA. a Department of Neurosurgeryb Department of Physical Medicine and Rehabilitation, Spine Center, College of Medicine, Yeungnam University, Namku, Daegu, Republic of Korea.∗ Correspondence: Min Cheol Chang, Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, 317-1 Daemyungdong, Namku, Daegu 705-717, Republic of Korea (e-mail: wheel633@gmail.com).11 2018 09 11 2018 97 45 e1309017 7 2018 11 10 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nEpidural hematoma is a possible complication after neuraxial procedures. Recently, caudal epidural pulsed radiofrequency (PRF) stimulation was reported as an effective method for controlling several types of chronic pain. Herein, we report on a patient who developed a lumbar epidural hematoma after receiving caudal epidural PRF stimulation.\n\nPatient concerns:\nA 75-year-old woman, who was taking oral warfarin (2 mg/d), received caudal epidural PRF stimulation for symmetrical neuropathic pain in both legs due to chronic idiopathic axonal polyneuropathy. She did not discontinue warfarin use before undergoing the procedure. Three days and 12 hours after the procedure, motor weakness suddenly manifested in the right leg (manual muscle testing [MMT] = 2–3).\n\nDiagnoses:\nLumbar magnetic resonance imaging (MRI) performed 7 days after the PRF procedure showed a spinal epidural hematoma at the L1 to L5 levels, compressing the thecal sac. The international normalized ratio was 6.1 at the time of the MRI.\n\nInterventions:\nDecompressive laminectomy from L1 to L5 with evacuation of the hematoma was performed.\n\nOutcomes:\nThree months postoperatively, the motor weakness in the patient's right leg improved to MMT = 4 to 5.\n\nLessons:\nThis case suggests that clinicians should carefully check if patients are taking an anticoagulant medication and ensure that it is discontinued for an appropriate length of time before a caudal epidural PRF procedure is performed.\n\nKeywords\ncaudal epidural stimulationchronic idiopathic axonal neuropathyepidural hematomapulsed radiofrequencyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRecently, pulsed radiofrequency (PRF) stimulation has been used for managing several types of chronic pain.[1–6] Although the mechanism of its pain-relieving effects has not been clearly elucidated, the electrical filed generated by PRF has been suggested to be responsible for its clinical effect.[7] Typically, PRF is applied to nerve tissues like the dorsal root ganglia and medial branch nerves of the spine[1,5]; however, depending on the origin of pain, various PRF stimulation methods, such as intraarticular, interfascial, and caudal epidural stimulations, are being applied.[3,4,6] Caudal epidural PRF stimulation is used for alleviating chronic idiopathic axonal polyneuropathy (CIAP), coccygodynia, and postherpetic neuralgia.[4,8,9] Previous studies reported the effectiveness of PRF for managing several kinds of chronic pain[4,8,9]; however, the complications have not been reported.\n\nEpidural hematoma is one complication that can occur after neuraxial procedures, such as interlaminar epidural and caudal steroid injections.[10–13] The damage of neural structures from an epidural hematoma results from the expansion of the hematoma within the enclosed space of the spinal canal and can be devastating if early decompression is not performed.[14] Anticoagulation with heparin and warfarin is known to be one of the most important risk factors for epidural hematoma after neuraxial procedures.[15]\n\nIn the present study, we report a case involving the development of an epidural hematoma after a caudal epidural PRF stimulation in a patient who was taking warfarin.\n\n2 Case report\nA 75-year-old woman underwent caudal epidural PRF stimulation at the rehabilitation department in our hospital to alleviate chronic neuropathic leg pain due to CIAP lasting for 9 years. She had symmetrical neuropathic pain rated as a 6 on a numeric rating scale localized to the bilateral legs below knees. The electrophysiologic findings were compatible with a diagnosis of axonal sensory polyneuropathy.\n\nThe caudal epidural PRF stimulation was performed under fluoroscopy guidance (Fig. 1). A 22-gauge cannula (SMK pole needle, 150 mm with a 20 mm active tip; Cotop International BV, Amsterdam, the Netherlands) was inserted to the epidural space through the sacral hiatus.[4] The needle tip was advanced to the S3 vertebral body level. After confirming correct needle placement with contrast dye, an electrode was connected to the cannula and stimulation was conducted (Cosman G4 radiofrequency generator, Cosman Medical, Burlington, MA). PRF was administered at 5 Hz using a 5-ms pulse width for 600 s at 55 V so as not to exceed an electrode tip temperature of 42°C. Three days and 12 hours after the PRF procedure, the patient developed motor weakness in the right leg. During the next 3.5 days, the patient observed her symptoms by herself without any treatment. One week after the PRF procedure, she visited our department due to the motor weakness. On the physical examination, her motor power was as follows (manual muscle testing [MMT]): hip flexor 2/5, knee extensor 2/5, ankle dorsiflexor 3/5, and extensor hallucis longus 3/5. In addition, decreased sensation with light touch and pinprick was noted in the right L2-4 dermatomes. Motor weakness and sensory deficits were not found on the left leg, and bladder and bowel symptoms were not present. Based on the medical history, she reported that she was taking oral warfarin (2 mg/d) for preventing recurrent pulmonary embolism, and the international normalized ratio (INR) was 6.1.\n\nFigure 1 Fluoroscopy-guided caudal epidural pulsed radiofrequency (PRF) stimulation procedure. (A) Lateral view. (B) Anteroposterior view. A 22-gauge curved-tip cannula was inserted into the epidural space (S3 vertebral level) through the sacral hiatus and the caudal epidural space was confirmed using contrast.\n\nA lumbar magnetic resonance image (MRI) was urgently obtained, which showed a spinal epidural hematoma from the L1 to L5 levels, which was large enough to cause thecal sac compression (Fig. 2). Posterior approach and decompressive subtotal laminectomy on L1 and total laminectomy on L2 to L5 with evacuation of the hematoma were performed. During the operation, neither a bleeding focus nor an abnormal vessel was not found. Three months after the operation, the patient's motor weakness in the right hip flexor and knee extensor had improved to MMT 4. Motor weakness in right ankle dorsiflexor and extensor hallucis longus and sensory deficits in right leg were not observed. Written informed consent was obtained from the patient for publication of this case report. The study was approved by the local Institutional Review Board of our hospital.\n\nFigure 2 Magnetic resonance image one week after the PRF procedure shows (A) spinal epidural hematoma at L1 to L5 in sagittal T2-weighted image and (B) thecal sac compression by hematoma at the L3 to L4 level in the axial T2-weighted image.\n\n3 Discussion\nWe report a patient who had an epidural hematoma after a caudal epidural PRF stimulation procedure. Kreppel et al performed the meta-analysis, and reported that idiopathic, anticoagulant therapy, vascular malformation, and spinal procedure are the most common causes of epidural hematoma.[16] Considering the fact that a bleeding focus or abnormal vessel was not observed in our patient during the operation, and the history of the PRF procedure 3 to 4 days before the diagnosis of epidural hematoma, there is a high possibility that epidural hematoma occurred due to the caudal epidural PRF stimulation procedure. We believe that the epidural hematoma resulted from the piercing or injury of the plexus of epidural veins or the epidural arteries which surround the epidural space. The blood from the injured vessels in the sacral epidural space seems to have risen to the L1 to L5 level on the spinal canal.\n\nIn our patient, before the procedure, the bleeding risk was not evaluated despite the fact that she was taking oral warfarin daily. Because patients taking anticoagulants are at risk for bleeding during spinal procedure, Spine Intervention Society stated that anticoagulants should be discontinued ≥4 days before spinal procedures with a normalized INR level.[17] Therefore, in our case, we should have instructed the patient to stop oral warfarin ≥4 days before the procedure and perform the PRF procedure after the INR level was normalized.\n\nIn addition, in our patient, although the outcome of neurological recovery was relatively complete, diagnosis and treatment were delayed by 3.5 days. Several studies reported that rapid diagnosis and emergency surgical treatment could minimize nerve injury and maximize neurological recovery.[14,18,19] Delayed diagnosis and delayed treatment of an epidural hematoma can lead to a poor outcome, thus it is necessary to inform patients who have risk factors for bleeding of the possibility of epidural hematoma after the procedure and to explain the need to visit the hospital emergently if neurological symptoms occur. Moreover, the epidural venous plexus is gathered in the anterior part of the sacral canal and usually ends at the S4 level or lower.[20] Therefore, a caudal epidural PRF stimulation procedure can injure the venous plexus and cause a spinal epidural hematoma. Use of small-gauge cannulas would help in decreasing the possibility of vessel trauma.\n\nSo far, several studies reported the occurrence of epidural hematoma after spinal procedures[10–13]; however, regarding the procedure performed through the sacral hiatus, only 1 study has reported an epidural hematoma. In 2017, Choi reported a lumbar epidural hematoma from the L2-S1 levels with concomitant central canal compromise at the L2/L3 and L3/L4 levels about 6 hours after caudal epidural steroid injection.[11] The patient's symptoms were completely resolved after an emergent operation.\n\nIn the present study, we reported a patient who had a lumbar epidural hematoma and presented with motor weakness and sensory deficits in right leg after caudal epidural PRF stimulation. This is the first study to report the occurrence of an epidural hematoma after a caudal epidural PRF stimulation. Clinicians should carefully check whether a patient is taking an anticoagulant medication and discontinue the medication ≥4 days before spinal procedure. Also, clinicians should be mindful of the possibility of this complication when performing neuraxial procedures, such as caudal epidural PRF stimulation.\n\nAuthor contributions\nConceptualization: Sang Woo Kim.\n\nData curation: Sang Woo Kim.\n\nMethodology: Min Cheol Chang.\n\nResources: Sang Woo Kim.\n\nWriting – original draft: Sang Woo Kim, Min Cheol Chang.\n\nWriting – review and editing: Min Cheol Chang.\n\nAbbreviations: CIAP = chronic idiopathic axonal polyneuropathy, INR = international normalized ratio, MMT = manual muscle testing, MRI = magnetic resonance image, PRF = pulsed radiofrequency.\n\nThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2017R1C1B5017714).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Arsanious D Gage E Koning J \nPulsed dose radiofrequency before ablation of medial branch of the lumbar dorsal ramus for zygapophyseal joint pain reduces post-procedural pain . Pain Physician \n2016 ;19 :477–84 .27676664 \n[2] Chang MC \nEfficacy of pulsed radiofrequency stimulation in patients with peripheral neuropathic pain: a narrative review . Pain Physician \n2018 ;21 :E225–34 .29871378 \n[3] Cho IT Cho YW Kwak SG \nComparison between ultrasound-guided interfascial pulsed radiofrequency and ultrasound-guided interfascial block with local anesthetic in myofascial pain syndrome of trapezius muscle . Medicine (Baltimore) \n2017 ;96 :e6019.28151904 \n[4] Lee DG Chang MC \nThe effect of caudal epidural pulsed radiofrequency stimulation in patients with refractory chronic idiopathic axonal polyneuropathy . Pain Physician \n2018 ;21 :E57–62 .29357341 \n[5] Lee DG Cho TW Ahn SH \nThe effect of bipolar radiofrequency treatment on chronic lumbosacral radicular pain refractory to monopolar pulsed radiofrequency treatment . Pain Physician \n2018 ;21 :E97–103 .29565952 \n[6] Sluijter ME Teixeira A Serra V \nIntra-articular application of pulsed radiofrequency for arthrogenic pain—report of six cases . Pain Pract \n2008 ;8 :57–61 .18211593 \n[7] Van Zundert J de Louw AJ Joosten EA \nPulsed and continuous radiofrequency current adjacent to the cervical dorsal root ganglion of the rat induces late cellular activity in the dorsal horn . Anesthesiology \n2005 ;102 :125–31 .15618796 \n[8] Atim A Ergin A Bilgiç S \nPulsed radiofrequency in the treatment of coccygodynia . Agri \n2011 ;23 :1–6 .21341145 \n[9] Rohof OJ \nCaudal epidural of pulsed radiofrequency in post herpetic neuralgia (PHN); report of three cases . Anesth Pain Med \n2014 ;4 :e16369.25237634 \n[10] Alkhudari AM Malk CS Rahman A \nEpidural hematoma after routine epidural steroid injection . Surg Neurol Int \n2016 ;7 :55.27213109 \n[11] Choi JJ Chang YJ Jung WS \nDiscordant lumbar epidural hematoma after caudal steroid injection: a case report (CARE-compliant) . Medicine (Baltimore) \n2017 ;96 :e7127.28614233 \n[12] Page J Moisi M Oskouian RJ \nLumbar epidural hematoma following interlaminar fluoroscopically guided epidural steroid injection . Reg Anesth Pain Med \n2016 ;41 :402–4 .26982079 \n[13] Sanders RA Bendel MA Moeschler SM \nEpidural hematoma following interlaminar epidural injection in patient taking aspirin . Reg Anesth Pain Med \n2018 ;43 :310–2 .29319605 \n[14] Goodman BS Posecion LW Mallempati S \nComplications and pitfalls of lumbar interlaminar and transforaminal epidural injections . Curr Rev Musculoskelet Med \n2008 ;1 :212–22 .19468908 \n[15] Morse K Weight M Molinari R \nExtensive postoperative epidural hematoma after full anticoagulation: case report and review of the literature . J Spinal Cord Med \n2007 ;30 :282–7 .17684896 \n[16] Kreppel D Antoniadis G Seeling W \nSpinal hematoma: a literature survey with meta-analysis of 613 patients . Neurosurg Rev \n2003 ;26 :1–49 .12520314 \n[17] Bogduk N \nPractice Guidelines for Spinal Diagnostic and Treatment Procedures . San Francisco \nInternational Spine Intervention Society , 2nd ed \n2013 :9–17 .\n[18] Baek BS Hur JW Kwon KY \nSpontaneous spinal epidural hematoma . J Korean Neurosurg Soc \n2008 ;44 :40–2 .19096655 \n[19] Yu HP Fan SW Yang HL \nEarly diagnosis and treatment of acute or subacute spinal epidural hematoma . Chin Med J (Engl) \n2007 ;120 :1303–8 .17711732 \n[20] Ogoke BA \nCaudal epidural steroid injections . Pain Physician \n2000 ;3 :305–12 .16906188\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(45)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000763:Anesthesia, Caudal; D000925:Anticoagulants; D005260:Female; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D011115:Polyneuropathies; D061208:Pulsed Radiofrequency Treatment; D014859:Warfarin",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e13090",
"pmc": null,
"pmid": "30407313",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21341145;27676664;29871378;19096655;28151904;19468908;29565952;28614233;16906188;29319605;29357341;18211593;12520314;25237634;27213109;17711732;17684896;26982079;15618796",
"title": "Epidural hematoma after caudal epidural pulsed radiofrequency stimulation: A case report.",
"title_normalized": "epidural hematoma after caudal epidural pulsed radiofrequency stimulation a case report"
} | [
{
"companynumb": "KR-MYLANLABS-2018M1091199",
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"activesubstancename": "WARFARIN"
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{
"abstract": "BACKGROUND\nThe introduction of oral antineoplastic agents in therapeutics has caused a change in the treatment strategy against cancer. The objective of this study was to analyze the adherence in patients to treatment with capecitabine, their adverse events, and the overall health status of patients, as well as the relationship of these factors with adherence.\n\n\nMETHODS\nAn observational, prospective study at 7 months, in a cohort of patients on capecitabine treatment, including treatment initiations and continuations, regardless of diagnosis or indication. The data collected were: demographic variables (age, gender), diagnostic (breast cancer, colorectal cancer, gastric cancer, off-label), adherence (tablet count, Morisky test,Sackett test), safety (assessment of adverse events, clinical evaluation by the oncologist) and quality of life (performance status, SF-12 test).\n\n\nMETHODS\nelectronic clinical records (IANUS®), dispensing program for outpatients (SILICON®) and interviews with patients.\n\n\nRESULTS\nThere were 111 evaluable patients, with a mean age of 66.7 years (range 32-86), ECOG PS 1 in 76.6%. Adherence level: 78.4% (81.7% in the initiation sub-group vs. 72.5% in the continuation sub-group). Adverse events: skin toxicity (33.33%), asthenia (25.22%), gastrointestinal toxicity (24.32%) and neurological toxicity (24.32%), mostly G1.Health status, SF-12 test: subjective evaluation as \"good\" in 33.30% of cases. Conclusions: The low level of adherence in the continuation sub-group can be associated with the duration of treatment, toxicities, clinical evolution, and perception of their health status. It is necessary to conduct individualized monitoring in this group of patients in order to obtain a favorable clinical response.",
"affiliations": "Pharmacy Unit.Complejo Hospitalario Universitario de Pontevedra.. francisca.fernandez.ribeiro@sergas.es.;Pharmacy Unit.Complejo Hospitalario Universitario de Pontevedra.. francisca.fernandez.ribeiro@sergas.es.;Pharmacy Unit.Complejo Hospitalario Universitario de Pontevedra.. francisca.fernandez.ribeiro@sergas.es.",
"authors": "Fernández-Ribeiro|Francisca|F|;Olivera-Fernández|Rosario|R|;Crespo-Diz|Carlos|C|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine",
"country": "Spain",
"delete": false,
"doi": "10.7399/fh.2017.41.2.10596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-6343",
"issue": "41(2)",
"journal": "Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria",
"keywords": null,
"medline_ta": "Farm Hosp",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010349:Patient Compliance; D011446:Prospective Studies",
"nlm_unique_id": "9440679",
"other_id": null,
"pages": "204-221",
"pmc": null,
"pmid": "28236798",
"pubdate": "2017-03-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Adherence and safety study in patients on treatment with capecitabine.",
"title_normalized": "adherence and safety study in patients on treatment with capecitabine"
} | [
{
"companynumb": "ES-ROCHE-1904350",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nCurrent chemotherapy protocols for gastric cancer present high toxicity. The FOLFIRI regimen has shown promising results with elderly colorectal cancer patients and for gastric cancer patients but this is the first report on elderly gastric cancer patients.\n\n\nMETHODS\nIn this multicenter non-randomized phase II trial, we administered the FOLFIRI chemotherapy protocol (irinotecan [180 mg/m(2)], fluorouracil [5-FU] [400 mg/m(2)] and folinic acid 400 mg/m(2) or 200mg/m(2) of l-folinic acid) to patients aged over 70 years with locally-advanced or metastatic gastric cancer combined with Comprehensive Geriatric Assessment (CGA). Responses were assessed at 2 months.\n\n\nRESULTS\nForty-two patients received eight cycles of the FOLFIRI regimen, with 82.5% of patients showing disease control: 10 patients (26%) showing objective (partial or complete) responses and 23 (57.5%) showing stable disease. One-year overall survival (OS) was 41.5% [95%CI 26.5-56.0] and one-year progression-free survival (PFS) was 31.8% [95%CI 18.4-46.1%]. We observed 10 Grade 3/4 hematologic toxicities with one febrile neutropenia. CGA data demonstrated that geriatric functions were not altered by treatment and that nutritional status improved over treatment.\n\n\nCONCLUSIONS\nResults show excellent disease control and relatively high survival rates with limited toxicity similar to younger patients indicating that this regimen should be considered as a possible treatment in advanced gastric cancer of the elderly.",
"affiliations": "Department of Medical Oncology, Institut Bergonié, 229, cours de l'Argonne, 33076 Bordeaux cedex, France. fonck@bergonie.org",
"authors": "Fonck|Marianne|M|;Brunet|Réné|R|;Becouarn|Yves|Y|;Legoux|Jean-Louis|JL|;Dauba|Jérôme|J|;Cany|Laurent|L|;Smith|Denis|D|;Auby|Dominique|D|;Terrebonne|Eric|E|;Traissac|Laurent|L|;Mertens|Cécile|C|;Soubeyran|Pierre|P|;Bellera|Carine|C|;Rainfray|Muriel|M|;Mathoulin-Pélissier|Simone|S|",
"chemical_list": "D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2011.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7401",
"issue": "35(12)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": null,
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D013274:Stomach Neoplasms",
"nlm_unique_id": "101553659",
"other_id": null,
"pages": "823-30",
"pmc": null,
"pmid": "21907007",
"pubdate": "2011-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Evaluation of efficacy and safety of FOLFIRI for elderly patients with gastric cancer: a first-line phase II study.",
"title_normalized": "evaluation of efficacy and safety of folfiri for elderly patients with gastric cancer a first line phase ii study"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1011484",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Salivary duct carcinoma (SDC) has a poor prognosis owing to the high incidence of distant metastasis. Approximately 40 % of SDCs are positive for human epidermal growth factor receptor 2 (HER2), suggesting that anti-HER2 therapy for cases with distant metastasis may be effective. However, the pathological response of SDC metastases to anti-HER2 therapy has not been reported. A 44-year-old man was diagnosed with HER2-positive SDC of the submandibular gland with multiple distant metastases. After six cycles of trastuzumab/docetaxel therapy, the patient achieved clinical partial response for the primary tumor and complete response for the neck and distant metastases. Subsequently, the patient underwent submandibular gland resection and neck dissection. On histopathological examination, very few viable cancer cells were identified in the resected primary tumor. Unfortunately, the patient died of multiple distant metastases 12 months after initial treatment. Trastuzumab/docetaxel therapy can elicit a clinical and pathological response in HER2-positive SDC.",
"affiliations": "1Division of Head and Neck surgery, Niigata Cancer Center Hospital, Kawagishi-cho 2-15-3, Chuo-Ku, Niigata, 951-8566 Japan.;2Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan.;1Division of Head and Neck surgery, Niigata Cancer Center Hospital, Kawagishi-cho 2-15-3, Chuo-Ku, Niigata, 951-8566 Japan.;3Department of Otolaryngology-Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;4Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan.;1Division of Head and Neck surgery, Niigata Cancer Center Hospital, Kawagishi-cho 2-15-3, Chuo-Ku, Niigata, 951-8566 Japan.",
"authors": "Ueki|Yushi|Y|;Tada|Yuichiro|Y|;Togashi|Takafumi|T|;Kawakita|Daisuke|D|;Nagao|Toshitaka|T|;Sato|Yuichiro|Y|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-016-0247-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "5(3)",
"journal": "International cancer conference journal",
"keywords": "Docetaxel; HER2; Metastases; Salivary duct carcinoma; Trastuzumab",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "150-153",
"pmc": null,
"pmid": "31149444",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": "12653946;12907212;14645349;15911866;16763282;17563907;17938328;18059220;23429737;24101045;24191589;24529560;24553861;3798106;8078666",
"title": "Pathological response of salivary duct carcinoma to trastuzumab and docetaxel therapy.",
"title_normalized": "pathological response of salivary duct carcinoma to trastuzumab and docetaxel therapy"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1038756",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Limbic encephalitis associated with anti-LGI1 antibody (LGI1 encephalitis) presents with a variety of features, the most prominent of which include seizures and progressive disturbance of memory and behaviour. Although varied in semiology, recognition of the pattern of seizures in LGI1 encephalitis is important, as early diagnosis and definitive treatment may prevent subsequent development of cognitive impairment. We present a patient with LGI1 encephalitis and \"faciobrachial dystonic seizures-plus\", which began as classic faciobrachial dystonic seizures and progressed to focal seizures with impaired awareness, dacrystic/gelastic-like outbursts, ictal speech, manual automatisms, and autonomic signs (tachycardia). Recognition of the broad range of seizure types associated with LGI1 encephalitis is crucial for early diagnosis and definitive treatment. [Published with video sequence on www.epilepticdisorders.com].",
"affiliations": "Department of Neurology, University of Michigan, Michigan, USA.;Department of Neurology, University of Michigan, Michigan, USA.",
"authors": "Beimer|Nicholas J|NJ|;Selwa|Linda M|LM|",
"chemical_list": "D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D011506:Proteins",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2017.0936",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "19(4)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "LGI1; dystonic; encephalitis; faciobrachial; ictal speech; temporal",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D001323:Autoantibodies; D004660:Encephalitis; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D011506:Proteins; D012640:Seizures",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "461-464",
"pmc": null,
"pmid": "29171405",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizure semiology of anti-LGI1 antibody encephalitis.",
"title_normalized": "seizure semiology of anti lgi1 antibody encephalitis"
} | [
{
"companynumb": "US-TEVA-2018-US-877714",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m(2) intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m(2) intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.",
"affiliations": "Department of Hematology F4-224, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.h.vanoers@amc.uva.nl",
"authors": "van Oers|Marinus H J|MH|;Klasa|Richard|R|;Marcus|Robert E|RE|;Wolf|Max|M|;Kimby|Eva|E|;Gascoyne|Randy D|RD|;Jack|Andrew|A|;Van't Veer|Mars|M|;Vranovsky|Andrej|A|;Holte|Harald|H|;van Glabbeke|Martine|M|;Teodorovic|Ivana|I|;Rozewicz|Cynthia|C|;Hagenbeek|Anton|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2006-05-021113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "108(10)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012074:Remission Induction; D000069283:Rituximab; D016879:Salvage Therapy; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3295-301",
"pmc": null,
"pmid": "16873669",
"pubdate": "2006-11-15",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial.",
"title_normalized": "rituximab maintenance improves clinical outcome of relapsed resistant follicular non hodgkin lymphoma in patients both with and without rituximab during induction results of a prospective randomized phase 3 intergroup trial"
} | [
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"abstract": "BACKGROUND\nWe aimed to evaluate the clinical characteristics and outcomes of mild-severe COVID-19 pneumonia cases in liver transplant (LT) recipients.\n\n\nMETHODS\nTen LT recipients diagnosed as having COVID-19 pneumonia in a 6-month period in our transplantation center were included. Demographic and medical data of the recipients were retrospectively collected; clinical courses, treatment responses, and outcomes were evaluated.\n\n\nRESULTS\nTen LT recipients were male, had a median age of 57 years (min-max, 36-69 years; interquartile range [IQR], 13 years), and had right lobe from living donor LT performed in a median of 11 months (min-max, 1-72 months; IQR, 12 months). Five patients had severe pneumonia, and the remaining patients had mild/moderate pneumonia. The most frequent symptoms were fever (90%) and cough (70%). Favipiravir, enoxaparin sodium, and corticosteroid were initiated at the time of the diagnosis; immunosuppressive drug doses were reduced or discontinued in 3 cases. Lymphopenia median: 510/mL (min-max, 90-1400 mL; IQR, 610 mL), increased levels of C-reactive protein median: 4.72 (min-max, 0.31-23.4; IQR, 8.5), and ferritin median: 641 (min-max, 40 to ≥ 1650; IQR, 1108) were frequent. Four patients required antibacterial treatments because of emerging bacterial pneumonia and/or sepsis. All patients were hospitalized for a median of 10 days. One patient with sepsis died on the 26th day after intensive care unit admission, and the remaining 9 survived. No further complication was recorded for 1-month follow-up.\n\n\nCONCLUSIONS\nCommencing favipiravir, enoxaparin sodium, and corticosteroid treatments; close follow-up of the developing complications; the temporary reduction or cessation of immunosuppression; a multidisciplinary approach; early awareness of the bacterial infections; and the initiation appropriate antibiotic treatments can contribute to success.",
"affiliations": "Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey. Electronic address: adem.kose@inonu.edu.tr.;Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of Chest Diseases, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of Medical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of Medical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey.;Liver Transplantation Institute, Faculty of Medicine, Inonu University, Malatya, Turkey.;Liver Transplantation Institute, Faculty of Medicine, Inonu University, Malatya, Turkey.;Liver Transplantation Institute, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey.",
"authors": "Kose|Adem|A|;Toplu|Sibel Altunisik|SA|;Yalcinsoy|Murat|M|;Yakupogullari|Yusuf|Y|;Otlu|Baris|B|;Otan|Emrah|E|;Aydin|Cemalettin|C|;Yilmaz|Sezai|S|;Bayindir|Yasar|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.06.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000086382:COVID-19; D000086742:COVID-19 Testing; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2481-2489",
"pmc": null,
"pmid": "34261580",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Characteristics and Outcomes of Liver Transplantation Recipients With COVID-19 Pneumonia.",
"title_normalized": "clinical characteristics and outcomes of liver transplantation recipients with covid 19 pneumonia"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2021-24988",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "A three-week-old girl presented for surgery for congenital pyloric stenosis. The anaesthetic technique included intravenous induction with thiopentone and neuromuscular blockade with atracurium. The administration of these drugs was followed within 2-3 minutes by oedema of the eyelids and epiglottis, reduced peripheral circulation and central cyanosis. There was no previous exposure to either drug and no definite family history of allergy. Analysis of subsequent sequential blood samples indicated that the reaction mechanism was non-immune and was presumed to be due to pharmacological release of histamine.",
"affiliations": null,
"authors": "Pollock|E M|EM|;MacLeod|A D|AD|;McNicol|L R|LR|",
"chemical_list": "D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D001279:Atracurium; D013874:Thiopental",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2044.1986.tb13176.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2409",
"issue": "41(2)",
"journal": "Anaesthesia",
"keywords": null,
"medline_ta": "Anaesthesia",
"mesh_terms": "D000707:Anaphylaxis; D000771:Anesthesia, Intravenous; D001279:Atracurium; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D013874:Thiopental",
"nlm_unique_id": "0370524",
"other_id": null,
"pages": "178-80",
"pmc": null,
"pmid": "3754095",
"pubdate": "1986-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylactoid reaction complicating neonatal anaesthesia.",
"title_normalized": "anaphylactoid reaction complicating neonatal anaesthesia"
} | [
{
"companynumb": "GB-PFIZER INC-2020170873",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATRACURIUM BESYLATE"
},
"drugadditional": "3",... |
{
"abstract": "Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated.",
"affiliations": "Cardiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.;Hematology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.;Hematology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.;Vascular Medicine and Hemostasis, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.;Pathology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.;Nephrology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.",
"authors": "Van Keer|Jan|J|;Delforge|Michel|M|;Dierickx|Daan|D|;Peerlinck|Kathelijne|K|;Lerut|Evelyne|E|;Sprangers|Ben|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/6020691",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2016/6020691Case ReportRenal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma Van Keer Jan \n1\nDelforge Michel \n2\nDierickx Daan \n2\nPeerlinck Kathelijne \n3\nLerut Evelyne \n4\nSprangers Ben \n5\n\n*\n1Cardiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium2Hematology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium3Vascular Medicine and Hemostasis, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium4Pathology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium5Nephrology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium*Ben Sprangers: ben.sprangers@uzleuven.beAcademic Editor: Marie-Christine Kyrtsonis\n\n2016 16 5 2016 2016 602069128 2 2016 28 4 2016 Copyright © 2016 Jan Van Keer et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated.\n==== Body\n1. Introduction\nThrombotic microangiopathy (TMA) is a rare cause of renal disease in multiple myeloma (MM) patients. It is defined by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. Pathological features are arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall [1]. TMA consists of a spectrum of multiple syndromes: thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), atypical HUS, and drug-induced TMA. TMA has been described in MM patients who received the proteasome inhibitor bortezomib [2–6]. In this report, we describe a case of renal TMA in a MM patient associated with exposure to bortezomib, with recurrence after reexposure.\n\n2. Case Presentation\nA 51 year-old Caucasian man was found to have acute kidney injury (AKI) three weeks after start of bortezomib- (1.3 g/m2) thalidomide- (100 mg) dexamethasone (40 mg) (VTD) therapy for newly diagnosed IgG kappa, Durie-Salmon stage IIIa, and ISS high risk multiple myeloma (MM). He had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS) during the investigation of ulcerating acral skin lesions 9 years previously. M-protein level at diagnosis of MGUS had been 4.36 g/L. Workup for autoimmunity and cryoglobulinemia had been negative and biopsy of the skin lesions had shown nonspecific findings. The extent of the skin lesions seemed to correlate with the M-protein level. For this reason the patient had been treated with rituximab (7 doses of 375 mg/m2) and therapeutic plasma exchange (TPE). Other medical history included hypertension and hypothyroidism. His medications were amlodipine 5 mg, aspirin 80 mg, levothyroxine 75 μg, and transdermal fentanyl 50 μg/h. The patient had been smoking cigarettes for 30 years. The patient had received no other nephrotoxic medication and was well hydrated. Blood pressure was 150/83 mmHg. The patient's acral ulcers, which had been relatively well controlled with biweekly TPE for the last 9 years, had worsened, with development of a livedoid rash and painful edema of hands and feet and multiple necrotising ulcers (see Figure 1).\n\nLaboratory investigation showed a creatinine elevation from 1.3 mg/dL prior to start of VTD therapy to 2.7 mg/dL (see Table 1). Figure 2 illustrates the relation between the onset of acute kidney injury and the administration of bortezomib. Proteinuria rose from 0.6 g/24 h before start of therapy to nephrotic range proteinuria, with a maximum of 3.2 g/24 h 3 months after start of VTD therapy (considerably later than the rise of creatinine had occurred; see Figure 3). There was dysmorphic hematuria (>2000 RBC/μL). Platelet count was 119,000/μL, Hb 7.5 g/dL with schistocyte excess on peripheral blood smear and haptoglobin < 0,1 g/L, indicative of microangiopathic hemolytic anemia. There was hypocomplementemia (C3 0.68 g/L, C3d 5.9%, and C4 0.14 g/L); cryoglobulins were absent; Coombs test, hepatitis B en C serology, ANF, and ANCA were negative. ADAMTS-13 activity was mildly reduced (34%). Genetic screening for complement mutations was negative. Renal sonogram revealed normal size kidneys with increased reflectivity of renal parenchyma. Punch biopsy of the livedoid skin rash showed nonspecific changes. Renal biopsy showed 7 out of 36 obsolete glomeruli and 15% chronic tubulointerstitial damage. One glomerulus had a capillary thrombus, with intimal edema of the afferent arteriole. These findings are indicative of a renal TMA lesion (see Figure 4). There were no arguments for paraprotein associated renal lesions, such as cast nephropathy, amyloidosis, light chain deposition disease, membranoproliferative glomerulonephritis, or cryoglobulinemia. Electron microscopy ruled out cryocrystalglobulinemia.\n\nBased on the renal biopsy findings of TMA and the concomitant worsening acral ulcerations, TPE was intensified from biweekly to once every two days. Bortezomib was stopped after a total of 3 cycles, mainly because of the necrotising skin ulcers. Kidney function partially recovered to a new baseline creatinine of 2.1 mg/dL. Proteinuria diminished from 3.2 to 0.8 g/24 h over the following months. The patient was then started on lenalidomide- (15 mg) dexamethasone (40 mg). This therapy had to be stopped after 7 months due to pancytopenia, despite dose reduction. After 8 months of watchful waiting there was disease progression with both increase in serum paraprotein level and bone lesions on MRI. Based on the good initial hematological response to VTD, the patient was restarted on VD (bortezomib and dexamethasone). Note that, at that time, the possible link between TMA and bortezomib was not clear. Baseline creatinine before reexposure to bortezomib was 2.9 mg/dL. Other medications at that time included (total daily doses) nifedipine 120 mg, levothyroxine 75 μg, omeprazole 40 mg, duloxetine 20 mg, amitriptyline 20 mg, calcium carbonate 1000 mg, cholecalciferol 880 E, and acetaminophen 4000 mg. Blood pressure was well controlled.\n\nFour weeks later, after 3 doses of bortezomib, the patient presented with a severe hypertension (188/102 mmHg), marked increase in serum creatinine (2.9 to 7.5 mg/dL; see Figure 5), macroscopic hematuria, proteinuria (1.2 to 2.7 g/24 h), microangiopathic hemolytic anemia (Hb of 7.9 g/dL), and severe thrombopenia (14,000/μL). The patient was oliguric. He had excruciating pain in his extremities due to a flare up of the chronic ulcers. Because of fluid overload, acidemia, and hyperkalaemia, hemodialysis had to be started. TPE was again intensified to once every two days. After withdrawal of bortezomib, there was a gradual recovery. Proteinuria dropped again to 0.6 g/24 h.\n\nHemodialysis could be stopped after 2 months, with a new baseline creatinine of 3.2 mg/dL. Kidney function remained stable during 3 months of follow-up.\n\n3. Discussion\nWe report a case of renal thrombotic microangiopathy (TMA) associated with the use of bortezomib in a multiple myeloma (MM) patient. Bortezomib is a first-generation proteasome inhibitor used in the treatment of MM. TMA has not been reported as a drug-related adverse event in CREST [7] and SUMMIT [8], the Phase 2 trials leading to bortezomib's approval. Ironically, bortezomib is even used successfully in the treatment of TTP (ADAMTS-13-deficiency-mediated TMA) [9], by depleting the causative antibodies. We identified five other cases of bortezomib-associated TMA in the literature, featuring various combinations microangiopathic hemolytic anemia and renal TMA. Morita et al. [2] and Moore and Romeril [3] described a picture of severe microangiopathic hemolytic anemia without significant renal insufficiency. Salmenniemi and Remes [4], Mehta et al. [5], and Chan et al. [6] described the same hematological picture, with renal insufficiency. In both cases a renal TMA lesion was suspected, but no kidney biopsy was performed. In Salmenniemi and Remes's case, a gingival biopsy was consistent with TMA. Ours is the first report of a documented renal TMA lesion after bortezomib exposure.\n\nCarfilzomib, a second-generation proteasome inhibitor, has been linked to TMA in MM patients as well. Sullivan et al. [10] presented a patient with severe renal insufficiency (without biopsy) and thrombocytopenia. Hobeika et al. [11] described a case without significant renal insufficiency or thrombocytopenia, but with prominent hypertension and proteinuria, in which renal biopsy showed renal TMA and podocytopathy. Finally, Lodhi et al. [12] reported a case of MAHA with severe renal insufficiency in which renal biopsy showed features of TMA.\n\nIn all these reports the temporal relationship between exposure to bortezomib or carfilzomib and occurrence of TMA, and the improvement after discontinuation point towards proteasome inhibition as a possible cause of TMA. Our case is unique in that we documented recurrence of renal TMA after reexposure to bortezomib 18 months after the initial episode. This further supports a causal role for proteasome inhibition in the pathogenesis of renal TMA in multiple myeloma patients.\n\nDrug-induced TMA can be caused by idiosyncratic (non-dose-related) immunologic reactions or by toxic (dose-related) effects [13]. The former type has been described after exposure to quinine [14], quetiapine [15], and gemcitabine [16] and might be attributed to endothelial damage by drug-dependent antibodies. The latter type has been described for many drugs, including antiplatelet, immunosuppressive, chemotherapeutic, and antiangiogenic agents [17]. Multiple reports of renal TMA have been described after exposure to bevacizumab. There is accumulating evidence that this could be a direct, on-target effect of the drug [18]. Eremina et al. [19] showed that survival of glomerular endothelial cells depends on VEGF from podocytes, by using conditional gene targeting: mice in which VEGF was selectively deleted from renal podocytes developed severe renal TMA. Although bortezomib has no direct effect on VEGF or its receptors, it has been shown that bortezomib triggers a dose-dependent inhibition of VEGF transcription via NF-κB pathways [20–22]. This downregulation of VEGF could lead to damage to the glomerular microvasculature.\n\nHowever, causality is difficult to establish. Hematopoietic stem cell transplantation, a known cause of TMA, could have played a role in 4 of the above-mentioned reports [2, 4, 11, 12]. Another possible culprit of TMA in MM patients is the paraprotein itself. TMA has been described in MM with an anti-ADAMTS-13 paraprotein [23]. In our case, each episode of AKI occurred after a rise in paraprotein levels: at diagnosis of MM and at disease progression. Moreover, renal function did not resolve completely after discontinuation of bortezomib, nor did the MAHA. Interestingly, the necrotising skin ulcers, which had started 9 years previously and were likely to be paraprotein-driven as they were rituximab and TPE responsive, flared up together with the two episodes of AKI. We therefore hypothesize that our patient had a latent vasculopathy, possibly paraprotein-induced, which predisposed him to development of TMA, possibly provoked by bortezomib-induced VEGF-deficiency.\n\nTreatment of drug-induced TMA is limited to drug avoidance and supportive care [17]. Some authors propose TPE [10]. TPE is an established therapy for TTP, restoring ADAMTS-13 activity by eliminating the causative antibodies. As the pathophysiology of drug-induced TMA is different from TTP, TPE is less likely to be beneficial. We intensified the on-going TPE therapy in our patient because of the favourable effect on his skin lesions. Whether this had a positive effect on the TMA is uncertain.\n\n4. Conclusion\nWe report a case of renal TMA in a MM patient who is treated with bortezomib. This is the sixth case of TMA associated with bortezomib exposure in the literature. To our knowledge, this is the first biopsy-proven case. In addition we show that reexposure to bortezomib caused recurrence of TMA 18 months later. The possible mechanisms remain to be elucidated.\n\nConsent\nThe patient gave written informed consent for the publication of this case report and the accompanying images.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Acral ulcers. Painful, necrotising ulcers on hands (a) and feet (b). Note the amputation of distal phalanxes 4 and 5 of the left hand.\n\nFigure 2 First episode of AKI. x-axis: time (weeks); 0 = start of first bortezomib administration; y-axis: plasma creatinine (mg/dL). VTD: bortezomib-thalidomide-dexamethasone; arrows: bortezomib administration; ∗: time of renal biopsy.\n\nFigure 3 Evolution of proteinuria. x-axis: time (months); 0 = start of first bortezomib administration; y-axis: 24 h proteinuria (g/24 h). VTD: bortezomib-thalidomide-dexamethasone; Rd: lenalidomide-dexamethasone; VD: bortezomib-dexamethasone.\n\nFigure 4 Renal biopsy. Renal biopsy showed 7 out of 36 obsolete glomeruli and 15% chronic tubulointerstitial damage. Note the capillary thrombus with intimal edema of the afferent arteriole (arrow).\n\nFigure 5 Second episode of AKI. x-axis: time (weeks); 0 = start of bortezomib rechallenge (18 months after first dose); y-axis: plasma creatinine (mg/dL). VD: bortezomib-dexamethasone; arrows: bortezomib administration.\n\nTable 1 Laboratory values.\n\n \t\nt = 0\n(Start BTZ)\t\nt = +3 w\n(Time of renal biopsy)\t\nt = +4 m\n(1 m after stop of BTZ) \t\nt = +18 m\n(Rechallenge BTZ)\t\nt = +19 m\n(Start dialysis)\t\nt = +22 m\n(After stop of dialysis)\t\nHb (g/dL)\t9.2\t7.5\t9.2\t9.8\t7.9\t8.7\t\nWBC (×109/L)\t2.43\t1.37\t2.19\t2.63\t3.07\t2.37\t\nPlatelets (×109/L)\t128\t119\t77\t34\t14\t42\t\nSchistocytes (/1000 RBC)\t<3\t4–7\t<3\t<5\t40–50\t<5\t\nHaptoglobin (g/L)\t—\t<0.1\t3.08\t1.33\t<0.1\t0.9\t\nLDH (U/L)\t156\t218\t102\t468\t419\t237\t\nCreatinine (mg/dL)\t1.35\t2.65\t2.04\t3.00\t7.49\t2.89\t\nUreum (mg/dL)\t39\t70\t33\t80\t147\t97\t\nProteinuria (g/24 h)\t1.2\t0.6\t1.52\t1.37\t2.69\t0.6\t\nHematuria (RBC/µL)\t258\t2079\t661\t—\tHematuria\tHematuria\t\nPyuria (WBC/µL)\t14\t24\t3\t—\t56\t4\t\nIgG (g/L)\t88.2\t—\t24.3\t16\t10.7\t—\t\n\nBTZ: bortezomib; w: weeks; m: months; —: not available.\n==== Refs\n1 Moake J. L. Thrombotic microangiopathies The New England Journal of Medicine 2002 347 8 589 600 10.1056/nejmra020528 2-s2.0-0037158606 12192020 \n2 Morita R. Hashino S. Shirai S. Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma International Journal of Hematology 2008 88 2 248 250 10.1007/s12185-008-0140-1 2-s2.0-56649121992 18636313 \n3 Moore H. Romeril K. Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post-bortezomib Internal Medicine Journal 2011 41 4 348 350 10.1111/j.1445-5994.2011.02458.x 2-s2.0-79955040869 21507163 \n4 Salmenniemi U. Remes K. Thrombotic microangiopathy associated with bortezomib treatment in a patient with relapsed multiple myeloma Hematology Reports 2012 4 2, article e13 \n5 Mehta N. Saxena A. Niesvizky R. Bortezomib-induced thrombotic thrombocytopaenic purpura BMJ Case Reports 2012 10.1136/bcr-2012-006461 \n6 Chan K.-L. Filshie R. Nandurkar H. Quach H. Thrombotic microangiopathy complicating bortezomib-based therapy for multiple myeloma Leukemia and Lymphoma 2015 56 7 2185 2186 10.3109/10428194.2014.977887 2-s2.0-84938124821 25547654 \n7 Jagannath S. Barlogie B. Berenson J. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma British Journal of Haematology 2004 127 2 165 172 10.1111/j.1365-2141.2004.05188.x 2-s2.0-5644250621 15461622 \n8 Richardson P. G. Barlogie B. Berenson J. A phase 2 study of bortezomib in relapsed, refractory myeloma The New England Journal of Medicine 2003 348 26 2609 2617 10.1056/nejmoa030288 2-s2.0-0037973279 12826635 \n9 Shortt J. Oh D. H. Opat S. S. ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura The New England Journal of Medicine 2013 368 1 90 92 10.1056/nejmc1213206 2-s2.0-84871810864 23281998 \n10 Sullivan M. R. Danilov A. V. Lansigan F. Dunbar N. M. Carfilzomib associated thrombotic microangiopathy initially treated with therapeutic plasma exchange Journal of Clinical Apheresis 2015 30 5 308 310 10.1002/jca.21371 2-s2.0-84944323229 25413611 \n11 Hobeika L. Self S. E. Velez J. C. Q. Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma BMC Nephrology 2014 15 1, article 156 10.1186/1471-2369-15-156 2-s2.0-84910648823 \n12 Lodhi A. Kumar A. Saqlain M. U. Suneja M. Thrombotic microangiopathy associated with proteasome inhibitors Clinical Kidney Journal 2015 8 5 632 636 10.1093/ckj/sfv059 26413293 \n13 Edwards I. R. Aronson J. K. Adverse drug reactions: definitions, diagnosis, and management The Lancet 2000 356 9237 1255 1259 10.1016/s0140-6736(00)02799-9 2-s2.0-0034619028 \n14 Kojouri K. Vesely S. K. George J. N. Quinine-associated thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes Annals of Internal Medicine 2001 135 12 1047 1051 10.7326/0003-4819-135-12-200112180-00008 2-s2.0-0035909844 11747383 \n15 Huynh M. Chee K. Lau D. H. M. Thrombotic thrombocytopenic purpura associated with quetiapine Annals of Pharmacotherapy 2005 39 7-8 1346 1348 10.1345/aph.1G067 2-s2.0-21744436488 15914516 \n16 Saif M. W. Xyla V. Makrilia N. Bliziotis I. Syrigos K. Thrombotic microangiopathy associated with gemcitabine: rare but real Expert Opinion on Drug Safety 2009 8 3 257 260 10.1517/14740330902942299 2-s2.0-67649364207 19505260 \n17 George J. N. Nester C. M. Syndromes of thrombotic microangiopathy The New England Journal of Medicine 2014 371 7 654 666 10.1056/nejmra1312353 2-s2.0-84906077328 25119611 \n18 Zhu X. Wu S. Dahut W. L. Parikh C. R. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis American Journal of Kidney Diseases 2007 49 2 186 193 10.1053/j.ajkd.2006.11.039 2-s2.0-33846638744 17261421 \n19 Eremina V. Jefferson J. A. Kowalewska J. VEGF inhibition and renal thrombotic microangiopathy The New England Journal of Medicine 2008 358 11 1129 1136 10.1056/nejmoa0707330 2-s2.0-40849130173 18337603 \n20 Roccaro A. M. Hideshima T. Raje N. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells Cancer Research 2006 66 1 184 191 10.1158/0008-5472.CAN-05-1195 2-s2.0-31544433927 16397231 \n21 Tamura D. Arao T. Tanaka K. Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2/M transition Cancer Science 2010 101 6 1403 1408 10.1111/j.1349-7006.2010.01544.x 2-s2.0-77954169427 20367638 \n22 Stangl K. Stangl V. The ubiquitin-proteasome pathway and endothelial (dys)function Cardiovascular Research 2010 85 2 281 290 10.1093/cvr/cvp315 2-s2.0-72949084163 19767293 \n23 Lechner K. Obermeier H. L. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases Medicine 2012 91 4 195 205 10.1097/md.0b013e3182603598 2-s2.0-84863719861 22732949\n\n",
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"issue": "2016()",
"journal": "Case reports in hematology",
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"medline_ta": "Case Rep Hematol",
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"pmid": "27293920",
"pubdate": "2016",
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"references": "17261421;26413293;25267524;20367638;22732949;22854237;11747383;12192020;16397231;19767293;22826795;25547654;19505260;15461622;12826635;15914516;25413611;18636313;25119611;18337603;23281998;11072960;21507163",
"title": "Renal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma.",
"title_normalized": "renal thrombotic microangiopathy associated with the use of bortezomib in a patient with multiple myeloma"
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"abstract": "There is no standard salvage chemotherapy for metastatic periampullary adenocarcinoma and duodenal adenocarcinoma and the prognosis of those who fail oxaliplatin, irinotecan, and 5FU is dismal. We examined nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for these two malignancies.\n\n\n\nPatients who failed oxaliplatin, irinotecan, and 5FU and whose archival tumors stained immunohistochemical (IHC) tumor positive for CK7 or MUC1 received nab-paclitaxel and gemcitabine therapy with or without cisplatin.\n\n\n\nThree patients, 2 with metastatic ampullary adenocarcinoma and 1 with duodenal adenocarcinoma with positive IHC staining for CK7 or MUC1 who failed 2 lines of chemotherapy with oxaliplatin, irinotecan, and 5FU received nab-paclitaxel and gemcitabine with or without cisplatin. All achieved excellent tumor response on CT scans with marked falls in tumor markers CA19-9 and CEA as well as ≥1 year of progression-free survival. All 3 have continued to survive 2-3 years since diagnosed with stage 4 metastatic adenocarcinoma.\n\n\n\nNab-paclitaxel plus gemcitabine with or without cisplatin should be investigated as a standard-of-care chemotherapy regimen for patients with ampullary adenocarcinoma and duodenal adenocarcinoma.",
"affiliations": "University of Texas McGovern Medical School at Houston, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.;Memorial Hermann-Texas Medical Center, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.;University of Texas McGovern Medical School at Houston, Houston, Texas.",
"authors": "Cen|Putao|P|0000-0001-5633-311X;Wray|Curtis J|CJ|;Zhang|Songlin|S|;Thosani|Nirav C|NC|;Dinh|Brian Cuong|BC|;Gonzalez|Anneliese|A|;Mohlere|Virginia|V|;Bynon|John Steven|JS|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D015415:Biomarkers; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
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"doi": "10.1002/cam4.2181",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 3110232310.1002/cam4.2181CAM42181Original ResearchClinical Cancer ResearchOriginal ResearchDurable response for ampullary and duodenal adenocarcinoma with a nab‐paclitaxel plus gemcitabine ± cisplatin combination CEN et al.Cen Putao https://orcid.org/0000-0001-5633-311XPutao.Cen@uth.tmc.edu \n1\nWray Curtis J. \n1\nZhang Songlin \n1\nThosani Nirav C. \n1\nDinh Brian Cuong \n2\nGonzalez Anneliese \n1\nMohlere Virginia \n1\nBynon John Steven \n1\n\n1 \nUniversity of Texas McGovern Medical School at Houston\nHouston\nTexas\n\n2 \nMemorial Hermann‐Texas Medical Center\nHouston\nTexas\n* Correspondence\n\nPutao Cen, University of Texas McGovern Medical School at Houston, Houston, TX.\n\nEmail: Putao.Cen@uth.tmc.edu\n17 5 2019 7 2019 8 7 10.1002/cam4.2019.8.issue-73464 3470 29 8 2018 13 2 2019 26 3 2019 © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground/Aim\nThere is no standard salvage chemotherapy for metastatic periampullary adenocarcinoma and duodenal adenocarcinoma and the prognosis of those who fail oxaliplatin, irinotecan, and 5FU is dismal. We examined nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) as salvage therapy for these two malignancies.\n\nMethods\nPatients who failed oxaliplatin, irinotecan, and 5FU and whose archival tumors stained immunohistochemical (IHC) tumor positive for CK7 or MUC1 received nab‐paclitaxel and gemcitabine therapy with or without cisplatin.\n\nResults\nThree patients, 2 with metastatic ampullary adenocarcinoma and 1 with duodenal adenocarcinoma with positive IHC staining for CK7 or MUC1 who failed 2 lines of chemotherapy with oxaliplatin, irinotecan, and 5FU received nab‐paclitaxel and gemcitabine with or without cisplatin. All achieved excellent tumor response on CT scans with marked falls in tumor markers CA19‐9 and CEA as well as ≥1 year of progression‐free survival. All 3 have continued to survive 2‐3 years since diagnosed with stage 4 metastatic adenocarcinoma.\n\nConclusions\nNab‐paclitaxel plus gemcitabine with or without cisplatin should be investigated as a standard‐of‐care chemotherapy regimen for patients with ampullary adenocarcinoma and duodenal adenocarcinoma.\n\nadenocarcinomaampullarycisplatinCK7duodenalgemcitabineMUC1nab‐paclitaxel source-schema-version-number2.0component-idcam42181cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:10.07.2019\n\n\nCen \nP \n, \nWray \nCJ \n, \nZhang \nS \n, \nThosani \nN \n, \nCuong Dinh \nB \n, \nSteven Bynon \nJ \n. Durable response for ampullary and duodenal adenocarcinoma with a nab‐paclitaxel plus gemcitabine ± cisplatin combination . Cancer Med . 2019 ;8 :3464 –3470 . 10.1002/cam4.2181 \n31102323\n==== Body\n1 INTRODUCTION\nPeriampullary carcinomas include ampullary carcinomas and carcinomas of the pancreas, distal bile duct, and periampullary duodenum. Ampullary carcinomas (adenocarcinomas of the ampulla of Vater) arise within the ampullary region distal to the bifurcation of the distal common bile duct and the pancreatic duct. The incidence of ampullary adenocarcinoma has increased over the past 30 years at an annual rate of 0.9%.1 Duodenum Adenocarcinoma are considered cancers of the small bowel. Approximately 10 470 new cases of small bowel adenocarcinoma are expected to be diagnosed in the United States in 2018.2 The prognosis of patients who relapse or who present with stage 4 metastatic ampullary or duodenal adenocarcinoma is poor.\n\nDue to the rarity of both ampullary and duodenal adenocarcinoma, no large randomized clinical trial has identified a standard chemotherapy regimen for these tumors. Historically, both ampullary and duodenal adenocarcinomas have been treated similarly to cholangiocarcinoma or colon cancer. Standard chemotherapy regimens include gemcitabine plus platinum compounds (cisplatin or oxalipatin), or fluoropyrimidine‐based chemotherapy (FOLFOX or FOLFIRI). These therapies generally achieve a median survival of ≤1 year.3, 4 In the absence of solid data, neither the National Comprehensive Cancer Network clinical practice guidelines nor the European Society for Medical Oncology provides treatment guidelines or recommendations for management of these malignancies. Thus, novels regimens and innovative approaches for these cancers with poor long‐term outcomes are desperately needed.\n\n2 METHODS\nWe performed immunohistochemical (IHC) tumor staining for CK7, CK20, CDX‐2, MUC1 (Mucin1), and MUC2 on patients' archival tumor specimen for patients with stage 4 ampullary adenocarcinoma and duodenal adenocarcinoma who had failed first‐ and second‐line chemotherapy with oxaliplatin, irinotecan, and 5FU. Diffuse positivity of CK7 or MUC1 was considered as positive. Those patients whose tumors were IHC positive for CK7 or MUC1 were selected to receive nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) 125 mg/m2 and gemcitabine 400‐500 mg/m2 with or without cisplatin 25 mg/m2, weekly. Tumor response on CT scans with tumor markers, patient progression‐free survival and overall survival were evaluated. A next generation sequencing (NGS) based assay (FoundationOne®) were performed on patients' tumors. (Appendix S1) All patients signed informed consent before the study.\n\n3 RESULT\nIn 2016‐2017, we performed IHC on tissues from 3 eligible patients; all 3 patients' tumors stained positive for CK7 or MUC1. Herein, we report 2 cases of ampullary adenocarcinoma and 1 case of duodenal adenocarcinoma with positive IHC tumor staining for CK7 or MUC1 that failed 2 lines of prior chemotherapy with oxaliplatin, irinotecan, and 5FU but successfully achieved durable and exceptional responses to nab‐paclitaxel and gemcitabine with or without cisplatin combinations. The Appendix (online only) provides genomic alterations in patients' tumors under a NGS based assay.\n\n3.1 Case 1: Ampullary adenocarcinoma, with peritoneal metastases, bone and soft tissue metastases\nA 57‐year‐old white woman presented in early 2016 with sepsis, jaundice, and left upper quadrant pain. An ampullary mass was found and biopsy revealed poorly differentiated adenocarcinoma. At exploratory laparotomy peritoneal metastases were found. Excisional biopsy of a 3‐cm omental mass confirmed poorly differentiated adenocarcinoma. Tumor cells were strongly and diffusely positive for CK7, CK19, MUC1 and negative for CK20, CDX‐2, MUC2 (Figures 1, 2, 3). The patient received FOLFOX for 10 months during which she developed worsening left shoulder and bilateral hips pain. A CT scan showed significant progression of disease in her left shoulder, bilateral hips, and peritoneal metastases, and her CEA level increased to 29 ng/mL. She received 1 dose of FOLFIRI but cancer pain worsened and while CEA levels increased to 37 ng/mL (Figure 4).\n\nFigure 1 H&E pathology slides showed poorly differentiated adenocarcinoma from excisional biopsy of omental implant\n\nFigure 2 Pathology slides showed metastatic cancer cells are strongly positive for CK7\n\nFigure 3 Pathology slides showed metastatic cancer cells are strongly positive for MUC1\n\nFigure 4 Tumor marker CEA increased during FOLFOX and FOLFIRI chemotherapy, but decreased during gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\nPositive IHC staining for CK7 and MUC1 was consistent with pancreatobiliary‐type ampullary adenocarcinoma. Chemotherapy was decided to switch to gemcitabine 400 mg/m2 and nab‐paclitaxel 125 mg/m2 weekly. The patient's cancer‐related bony pain rapidly reduced from 10/10 to 1/10 on a pain scale. Because the patient's CEA remained stable during gemcitabine nab‐paclitaxel treatment, cisplatin 25 mg/m2 was added to be given weekly, 3 weeks on and 1 week off, for 6 months (Figure 4). The patient reported that the new regimens gave her more energy over time and she gained appetite and weight. Restaging CT scans demonstrated significant tumor reduction compared to prior scans with a fall in tumor marker CEA (Figures 4, 5, 6, 7). The gemcitabine and nab‐paclitaxel regimen has been continued, with an ongoing tumor response for >1 year (3/2017‐5/2018). Cisplatin was placed on hold due to increased creatinine.\n\nFigure 5 Painful chest wall tumor mass had almost disappeared after new regimen gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\nFigure 6 Painful Hip soft tissue tumor mass had almost disappeared after given gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\nFigure 7 Painful shoulder bony metastasis has significant reduced after given gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\n3.2 Case 2: Stage IV ampullary adenocarcinoma with bulky mediastinal lymph node metastasis\nA 60‐year‐old white man presented with jaundice (total bilirubin of 12 mg/dL) in late 2015. A 2‐cm ampullary mass involved the distal common bile duct was found and biopsy showed a poorly differentiated adenocarcinoma involving the small‐intestine mucosa. Initial CT scans showed biliary duct dilatation, multiple 1 cm reginal lymph node enlargement and a large 4‐cm mediastinal lymph node. Biopsy of the large mediastinal showed poorly differentiated adenocarcinoma that stained positive for CK7 but negative for CDX2, TTF‐1, NapsinA, and CK 20, consistent with an ampullary origin. The patient received FOLFOX for 5 months at an outside institute during which the patient noticed progressive voice hoarseness and was discovered to have left vocal cord paralysis. In May 2016, restaging CT scans shows the mediastinal mass had increased to 5 cm (Figure 9). Due to disease progression, chemotherapy was switched to FOLFIRINOX for 2 months. Concurrent conventionally fractionated radiotherapy with 60 Gy in 30 fractions was also aimed to the patient's bulky mediastinal node. In September 2016, after concurrent chemoradiation, chest CT showed the mediastinal node had slightly decreased in size but several metastatic nodular pulmonary lesions had appeared with an increase in CEA tumor marker to 35 ng/dL, confirming continued tumor progression (Figure 8).\n\nFigure 8 Tumor marker CEA increased during FOLFIRINOX chemotherapy, but decreased during gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\nBecause the patient's tumor IHC profile (CK7 positivity) was consistent with pancreatobiliary‐type ampullary adenocarcinoma, therapy was switched to gemcitabine 400 mg/m2 and nab‐paclitaxel 125 mg/m2, given once every 10 days. On this regimen, the CEA levels rapidly decreased with disappearance of metastatic lung lesions and improvement in hoarseness. Because the patient's CEA decline reached a plateau after 10 months of gemcitabine and nab‐paclitaxel regimen, in July 2017, cisplatin 25 mg/m2 was added to the regimen, given 2 weeks on and 1 week off, for 3 months. Subsequent restaging with CT and EUS showed a marked decrease in mediastinal lymph node size to 1.4 cm and further CEA decrease to 4.8 ng/dL (Figures 8 and 9). EUS RFA in December 2017 was used to ablate the 1.4‐cm mediastinal node. As of this report, the patient is on maintenance chemotherapy with gemcitabine 300 mg/m2 and nab‐paclitaxel 125 mg/m2 weekly, 2 weeks on and 1 week off, and has maintained a stable, ongoing response for close to 3 years (9/2016‐present). Cisplatin is on hold due to increased creatinine and eGFR of 40 mL/min/1.73 m2.\n\nFigure 9 Large mediastinal nodal metastasis (causing have left vocal cord paralysis) had significant reduced after given gemcitabine nab‐paclitaxel ± cisplatin chemotherapy\n\n3.3 Case 3: Duodenal adenocarcinoma with peritoneal and liver metastases\nA 52‐year‐old woman presented in April 2014 with jaundice, pruritus, nausea, and vomiting. A duodenal mass was found obstructing her biliary tree. She received a Whipple procedure. Surgical pathology showed a 6.5‐cm adenocarcinoma, moderately differentiated with partial mucinous differentiation, arising in small intestinal tubulovillous adenoma with high‐grade dysplasia, invasive into peri‐intestinal soft tissue, with contiguous extension into pancreas, and 7 of 25 lymph nodes were involved with metastatic carcinoma. The patient's disease was pathological stage T4N2M0. IHC staining was positive for CK7, CK20, CDX‐2, and MUC‐1 (negative staining for MUC‐2), employing a cutoff threshold for positivity of 25%. Subsequently, the patient received 6 cycles of FOLFOX adjuvant chemotherapy.\n\nTwo years after her initial Whipple surgery, surveillance CT revealed development of extensive peritoneal metastatic disease in the abdomen and new hepatic hypo‐densities consistent with tumor recurrence. After 10 months of palliative FOLFIRI chemotherapy starting in June 2016, her cancer progressed on both CT scans and tumor marker CA19‐9. Because her tumor's immunophenotypic profile was positive not only for MUC1 and CK7 but also for CK20 and CDX‐2, her tumor was considered ambiguous with both pancreaticobiliary‐type and intestinal‐type features. Nab‐paclitaxel 125 mg/m2 plus gemcitabine 300‐400 mg/m2 was chosen as third‐line salvage chemotherapy with each given over 30 minutes weekly, 3 weeks on and 1 week off. Tumor response was demonstrated by CT scans and tumor marker CA19‐9 markedly declined from 452unit/ml to 42unit/ml and has remained stable for 1 year (5/2017‐3/2018) (Figure 10).\n\nFigure 10 Tumor marker CA19‐9 increased during FOLFIRI chemotherapy, but decreased during gemcitabine nab‐paclitaxel chemotherapy\n\n4 DISCUSSION\nThe current recommended chemotherapy regimens for ampullary and duodenal adenocarcinoma were extrapolated from limited small phase II trials, and the trials mostly for cholangiocarcinoma.3, 4, 5 The largest and most recent phase III randomized multicenter ABC‐02 trial included patients with both locally advanced (25%) and metastatic bile duct (n = 242), gallbladder (n = 148), or ampullary (n = 20) cancer. The median overall survival was 11.7 months with first line gemcitabine plus cisplatin combination treatment, compared with 8.1 months for gemcitabine alone.3 A recent small single‐center phase II studied 30 patients, including 23 (77%) with small bowel cancer (18 of duodenal origin and 5 of jejunal/ileal origin) and 7 patients (23%) with ampullary adenocarcinoma (5 of pancreaticobiliary subtype, 1 of mixed subtype, and 1 of intestinal subtype) who were given first line capecitabine and oxaliplatin plus bevacizumab and had median overall survival of 12.9 months.5\n\n\nAmpullary adenocarcinoma's histological subtypes and IHC staining patterns have been shown to have prognostic significance. However, conflicting data have been reported about the frequency of the two major subtypes of ampullary cancers (intestinal and pancreatobiliary type) due to the absence of reliable histomorphological standard or IHC markers for differential diagnosis. Survival in patient with tumors of pancreatobiliary type or CK7/MUC1‐positive or CDX2‐negative ampullary tumors seem to have a worse prognosis which is similar to that of patients with pancreatic cancer.6, 7, 8 In a Korean study of 37 patients with ampullary adenocarcinoma who underwent Whipple procedure, half of them (18/37) had CK7‐positive tumors. Multivariate analysis showed that CK7+/CK20− was a significant independent factor predicting poorer survival, whereas nodal positivity status was not predictive.7 In a retrospective cohort of 72 patients from Australia who underwent surgical resection for adenocarcinoma of the ampulla of Vater, 18 (25%) patients with a histo‐molecular pancreaticobiliary phenotype (MUC1‐positive, CDX‐negative) had significantly worse outcomes than those with an intestinal phenotype (CDX‐positive, MUC1‐negative), with a median survival of 16 versus 116 months.8 In an Italian study of 53 resected ampullary cancer cases, MUC1 expressed in 75% (40/53) of the total cases, with 97% (29/30) positive among pancreatobiliary type and 47% (11/23) positive among intestinal type cancers; CDX2 expressed in 60% (32/53) of the total cases, with 30% (9/30) positive among pancreatobiliary type and 100% (23/23) positive among intestinal type cancer. A longer survival was correlated with the expression of CDX2, when using a nuclear labeling cutoff of >10% cells (P = 0.14).9\n\n\nNab‐paclitaxel is nanoparticle albumin‐bound paclitaxel. In 2013, the FDA approved nab‐paclitaxel for the first‐line treatment of patients with metastatic adenocarcinoma of the pancreas. This indication was based on the multinational MPACT trial of 861 patients who were randomized to receive either the combination of nab‐paclitaxel (125 mg/m2) plus gemcitibine (1000 mg/m2, each given weekly, on days 1, 8, and 15 every 28 days) or gemcitabine alone (1000 mg/m2 weekly for 7 weeks, then on days 1, 8, and 15 every 4 weeks). Adding nab‐paclitaxel to gemcitabine was associated with a significantly higher objective response rate (23% vs 7%) and a significantly longer median overall survival (8.5 vs 6.7 months).10\n\n\nKapp et al11 from Germany retrospectively reported an exceptional response to nab‐paclitaxel and gemcitabine in 1 patient with refractory ampullary adenocarcinoma whose tumor IHC staining pattern was CK7‐positive and CK20‐ and CDX2‐negative.\n\nIn our study, we identified a distinct clinically relevant (pancreaticobiliary) phenotype by refining histologic classification with IHC staining (CK7 or MUC1 positivity) criteria and studied these patients for our novel chemotherapy regimen.\n\nAll 3 of our patients in the study had failed 2 lines of chemotherapy Oxaliplatin, Irinotecan, and 5FU with the diagnosis of stage 4 metastatic adenocarcinoma. By this criteria, their survival was expected to be dismal, with weeks or a few months of life expectancy, without any effective salvage chemotherapy. Both regimens—nab‐paclitaxel plus gemcitibine and nab‐paclitaxel plus gemcitibine with cisplatin—were very well‐tolerated for long‐term use in our patients, partially because gemcitabine was given at less than half (300‐500 mg/m2) of the standard dose (1000 mg/m2). Despite this, the efficacy of the regimens were not compromised and may actually have been improved. This was possibly due to the reduction in gemcitabine dosage–related grade 3‐4 cytopenic toxicity. Thus, our patients were better able to keep their weekly chemotherapy administration on schedule, and, in turn, achieved better tumor response and prolonged survival.\n\nCompared to other literatures, our study shows longer survival of 2‐3 years and marked tumor reduction that were successfully achieved in chemo‐resistant stage 4 metastatic ampullary and duodenal adenocarcinoma by using our novel approach in third line salvage chemotherapy with nab‐paclitaxel plus gemcitabine ± cisplatin.\n\nOne limitation of our study is that we have not administered nab‐paclitaxel to patients whose ampullary and duodenum adenocarcinomas are negative for both CK7 and MUC1. We plan to continue recruiting more patients and increase our sample size. If those with negative markers also achieve good response, it would suggest an even broader indication of nab‐paclitaxel for all ampullary and duodenum adenocarcinomas.\n\nNevertheless, nab‐paclitaxel plus gemcitibine with or without cisplatin should be considered as a standard‐of‐care chemotherapy regimen for patients with ampullary and duodenal adenocarcinoma. Further studies are urgently needed in these two rare cancers.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENT\nI thank Virginia Mohlere for editorial assistance.\n==== Refs\nREFERENCES\n1 \n\nAlbores‐Saavedra \nJ \n, \nSchwartz \nAM \n, \nBatich \nK \n, \nHenson \nDE \n. Cancers of the ampulla of vater: demographics, morphology, and survival based on 5,625 cases from the SEER program . J Surg Oncol . 2009 ;100 (7 ):598 ‐605 .19697352 \n2 \n\nSiegel \nRL \n, \nMiller \nKD \n, \nJemal \nA \n. Cancer statistics, 2018 . CA Cancer J Clin . 2018 ;68 (1 ):7 ‐30 .29313949 \n3 \n\nValle \nJ \n, \nWasan \nH \n, \nPalmer \nDH \n, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer . N Engl J Med . 2010 ;362 (14 ):1273 ‐1281 .20375404 \n4 \n\nOverman \nMJ \n, \nVaradhachary \nGR \n, \nKopetz \nS \n, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater . J Clin Oncol . 2009 ;27 (16 ):2598 ‐2603 .19164203 \n5 \n\nGulhati \nP \n, \nRaghav \nK \n, \nShroff \nRT \n, et al. Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater: A single‐center, open‐label, phase 2 study . Cancer . 2017 ;123 (6 ):1011 ‐1017 .27859010 \n6 \n\nWestgaard \nA \n, \nPomianowska \nE \n, \nClausen \nOP \n, \nGladhaug \nIP \n. Intestinal‐type and pancreatobiliary‐type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies? \nAnn Surg Oncol . 2013 ;20 (2 ):430 ‐439 .22956064 \n7 \n\nYun \nSP \n, \nSeo \nHI \n. Prognostic impact of immunohistochemical expression of CK7 and CK20 in curatively resected ampulla of Vater cancer . BMC Gastroenterol . 2015 ;15 :165 .26603157 \n8 \n\nChang \nDK \n, \nJamieson \nNB \n, \nJohns \nAL \n, et al. Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater . J Clin Oncol . 2013 ;31 (10 ):1348 ‐1356 .23439753 \n9 \n\nSessa \nF \n, \nFurlan \nD \n, \nZampatti \nC \n, \nCarnevali \nI \n, \nFranzi \nF \n, \nCapella \nC \n. Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability . Virchows Arch . 2007 ;451 (3 ):649 ‐657 .17653761 \n10 \n\nVon Hoff \nDD \n, \nErvin \nT \n, \nArena \nFP \n, et al. Increased survival in pancreatic cancer with nab‐paclitaxel plus gemcitabine . N Engl J Med . 2013 ;369 (18 ):1691 ‐1703 .24131140 \n11 \n\nKapp \nM \n, \nKosmala \nA \n, \nKircher \nS \n, \nLuber \nV \n, \nKunzmann \nV \n. Exceptional Response to Nanoparticle Albumin‐Bound Paclitaxel and Gemcitabine in a Patient with a Refractory Adenocarcinoma of the Ampulla of Vater . Case Rep Oncol . 2016 ;9 (1 ):15 ‐24 .26933414\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "8(7)",
"journal": "Cancer medicine",
"keywords": "CK7; MUC1; adenocarcinoma; ampullary; cisplatin; duodenal; gemcitabine; nab-paclitaxel",
"medline_ta": "Cancer Med",
"mesh_terms": "D000230:Adenocarcinoma; D000418:Albumins; D014670:Ampulla of Vater; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003841:Deoxycytidine; D004379:Duodenal Neoplasms; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "3464-3470",
"pmc": null,
"pmid": "31102323",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "29313949;17653761;22956064;19697352;23439753;27859010;26933414;19164203;31102323;26603157;20375404;24131140",
"title": "Durable response for ampullary and duodenal adenocarcinoma with a nab-paclitaxel plus gemcitabine ± cisplatin combination.",
"title_normalized": "durable response for ampullary and duodenal adenocarcinoma with a nab paclitaxel plus gemcitabine cisplatin combination"
} | [
{
"companynumb": "US-TEVA-2019-US-1098647",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Lung cancer is one of the leading causes of cancer-related mortality and is categorized into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). We present a patient with epidermal growth factor receptor (EGFR)-mutant-NSCLC who developed metastatic SCLC after initial therapy with second-generation EGFR-tyrosine kinase inhibitor, afatinib. A 65-year-old male non-smoker was diagnosed with adenocarcinoma of the right lung, stage IVA (M1a). Due to tumor positivity for EGFR-Exon 19 deletion, the patient was started on oral afatinib, which resulted in a partial response. After ten months of treatment, he presented in the office with abdominal pain, distension, weight loss and jaundice. He had diffuse skeletal and hepatic metastases on PET/CT scan with interval progression of his cancer. Although the recurrence of lung adenocarcinoma was suspected, the patient was diagnosed with SCLC on liver biopsy. He received two cycles of chemotherapy and died due to pneumonia and sepsis.",
"affiliations": "a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;a Internal Medicine Department , McLaren - Flint/Michigan State University , Flint , MI , USA.;b Department of Hematology/Oncology , Fox Chase Cancer Center , Philadelphia , PA , USA.",
"authors": "Wahab|Ahsan|A|;Kesari|Kavitha|K|;Chaudhary|Siddique|S|;Khan|Mahin|M|;Khan|Hafiz|H|;Smith|Susan|S|;Boumber|Yanis|Y|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2017.1394546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "18(12)",
"journal": "Cancer biology & therapy",
"keywords": "Adenocarcinoma of Lung; Afatinib; Bronchoalveolar Lavage; EGFR Receptors; Poorly differentiated Adenocarcinoma; Resistance; Small Cell Lung Cancer; Transformation; Tyrosine Kinase Inhibitors",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "940-943",
"pmc": null,
"pmid": "29157085",
"pubdate": "2017-12-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26424310;28031840;27751847;25846096;27160687;24768581;26400668;11851626;25934077;21430269;25758528;27895763;25589191",
"title": "Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?",
"title_normalized": "sequential occurrence of small cell and non small lung cancer in a male patient is it a transformation"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-063902",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "BACKGROUND\nFor multiple myeloma patients who respond to primary therapy, autologous hematopoietic stem cell transplant (HSCT) is considered standard of care with high-dose melphalan for transplant candidates. There are now two different melphalan formulations available, including a propylene glycol containing (PG-MEL) product and a propylene glycol-free (PG-free MEL) product. Although considered bioequivalent, there remains limited literature directly evaluating the adverse events between the two agents. We seek to assess the tolerability and severity of side effects between the two formulations in a real-life practice setting.\n\n\nMETHODS\nA retrospective, descriptive analysis was conducted of multiple myeloma patients who received autologous stem cell conditioning with either melphalan formulation when dosed at 100 mg/m2/dose for two consecutive doses. The primary outcome was the assessment of tolerability and severity of side effects. Tolerability was split into four major categories including hematologic toxicity, gastrointestinal toxicity, renal toxicity, and highest recorded mucositis grade.\n\n\nRESULTS\nThere were a total of 78 patients who received a melphalan preparation during the study. The median time to myeloablation and neutrophil engraftment was five and seven days post-HSCT, respectively, for all patients. Patients who received PG-free MEL were less likely to develop mucositis, with 22 (56%) reported highest grade 0, defined by World Health Organization oral toxicity scale, compared to those who received PG-MEL (33%), p = 0.04.\n\n\nCONCLUSIONS\nThere were minimal differences in tolerability or side effects observed between PG-free MEL and PG-MEL. These data may assist in better understanding the anticipated adverse effects of a high-dose melphalan conditioning therapy.",
"affiliations": "1 Department of Pharmacy, Dana Farber Cancer Institute, Boston, MA, USA.;2 Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA.;3 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.;3 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.;3 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.;2 Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA.",
"authors": "Xiang|Elaine|E|https://orcid.org/0000-0001-8088-5010;Ni|Jian|J|;Glotzbecker|Brett|B|;Laubach|Jacob|J|;Soiffer|Robert|R|;McDonnell|Anne M|AM|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D019653:Myeloablative Agonists; D019946:Propylene Glycol; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218804042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Multiple myeloma; autologous stem cell transplant; hematopoietic stem cell transplant; melphalan; propylene glycol-free melphalan",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D015331:Cohort Studies; D004339:Drug Compounding; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D019653:Myeloablative Agonists; D019946:Propylene Glycol; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1631-1637",
"pmc": null,
"pmid": "30336728",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluating the adverse effects of melphalan formulations.",
"title_normalized": "evaluating the adverse effects of melphalan formulations"
} | [
{
"companynumb": "US-TEVA-2019-US-1128825",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) are widely used and may induce long-term survival in various types of cancer. Yet, there is scarce evidence on potential effects on patient fertility and the necessity of cryopreservation before treatment onset. The aim of our study was to assess the prevalence of male infertility after initiation of ICI treatment.\n\n\n\nThis is a monocenter, cross-sectional pilot study. Fertility was investigated by spermiogram, analysis of sexual hormones and questionnaires on sexual function and sexual activity. Male patients under the age of 60 years previously or currently treated with ICI for cutaneous malignancies or uveal melanoma were included.\n\n\n\nTwenty-five patients were included, with a median age of 49 years. Eighteen of 22 (82%) available spermiograms showed no pathologies, all patients reported a normal sexual function and sexual activity. Of four patients with pathological spermiogram, three patients were diagnosed with azoospermia and one with oligoasthenoteratozoospermia. Three patients had significant confounding factors (previous inguinal radiotherapy, chemotherapy and chronic alcohol abuse, and bacterial orchitis). One patient with normal spermiogram before ICI treatment presented 1 year after initiation with azoospermia, showing an asymptomatic, inflammatory infiltrate with predominantly neutrophil granulocytes, macrophages and T-lymphocytes in the ejaculate. Infectious causes were ruled out; andrological examination was unremarkable. A second case with reduced sperm counts during treatment may be ICI-induced also.\n\n\n\nMost patients had no restrictions in fertility, yet an inflammatory loss of spermatogenesis seems possible. Cryopreservation should be discussed with all patients with potential future desire for children before treatment.",
"affiliations": "Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: martin.salzmann@med.uni-heidelberg.de.;Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology, University Hospital Essen, Essen, Germany.;Department of General Internal Medicine and Psychosomatics, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.",
"authors": "Salzmann|Martin|M|;Tosev|Georgi|G|;Heck|Melanie|M|;Schadendorf|Dirk|D|;Maatouk|Imad|I|;Enk|Alexander H|AH|;Hartmann|Martin|M|;Hassel|Jessica C|JC|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2021.04.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "152()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Adverse drug events; Fertility; Immune checkpoint inhibitor; Spermatogenesis",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D053713:Azoospermia; D003430:Cross-Sectional Studies; D015925:Cryopreservation; D005298:Fertility; D059247:Fertility Preservation; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D010865:Pilot Projects; D012017:Referral and Consultation; D055101:Semen Analysis; D012878:Skin Neoplasms; D013091:Spermatogenesis; D014604:Uveal Neoplasms",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "41-48",
"pmc": null,
"pmid": "34062486",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Male fertility during and after immune checkpoint inhibitor therapy: A cross-sectional pilot study.",
"title_normalized": "male fertility during and after immune checkpoint inhibitor therapy a cross sectional pilot study"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-310237",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
... |
{
"abstract": "Survival rates for elderly Hodgkin Lymphoma (HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered 'non-frail' according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced-intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression-free survival (PFS). Seventeen patients were in early stage (I-IIA), while 37 were advanced stage. Median age was 72 years and median follow-up was 76 months. Five-year PFS rates were 48% vs. 70% [adjusted Hazard ratio (HR) = 2·19, 95% confidence interval (CI) = 0·94-5·10, P = 0·068] and 5-year overall survival (OS) rates were 63% vs. 77% (adjusted HR = 1·67, 95% CI = 0·69-4·03, P = 0·254) for VEPEMB compared to ABVD. Overall treatment-related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients.",
"affiliations": "Haematology Department, SS Antonio & Biagio and C. Arrigo Hospital, Alessandria, Italy.;Haematology Department, SS Antonio & Biagio and C. Arrigo Hospital, Alessandria, Italy.;Unity of Clinical Epidemiology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino and CPO Piemonte, Torino, Italy.;Haematology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.;Haematology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.;Haematology, Azienda Ospedaliera BMM, Reggio Calabria, Italy.;Department of Surgery and Biomedicine, Division of Onco-haematology with Autologous Transplant, University of Perugia, Perugia, Italy.;Division of Haematology, Papardo Hospital, Messina, Italy.;Haematology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Haematology Division, Businco Hospital, Cagliari, Italy.;Division of Candiolo Cancer Institute, IRCCS University of Torino Medical School, Candiolo, Italy.;Oncology and Haematology Department, Azienda Unità Sanitaria Locale, Piacenza, Italy.;Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy.;Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy.;Unity of Clinical Epidemiology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino and CPO Piemonte, Torino, Italy.;Haematology Department, SS Antonio & Biagio and C. Arrigo Hospital, Alessandria, Italy.;Haematology Department, SS Antonio & Biagio and C. Arrigo Hospital, Alessandria, Italy.",
"authors": "Zallio|Francesco|F|;Tamiazzo|Stefania|S|;Monagheddu|Chiara|C|;Merli|Francesco|F|;Ilariucci|Fiorella|F|;Stelitano|Caterina|C|;Liberati|Anna Marina|AM|;Mannina|Donato|D|;Vitolo|Umberto|U|;Angelucci|Emanuele|E|;Rota Scalabrini|Delia|D|;Vallisa|Daniele|D|;Bellei|Monica|M|;Bari|Alessia|A|;Ciccone|Giovannino|G|;Salvi|Flavia|F|;Levis|Alessandro|A|",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D008942:Mitoxantrone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13904",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "172(6)",
"journal": "British journal of haematology",
"keywords": "Hodgkin Lymphoma; elderly; randomized study",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D003606:Dacarbazine; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008942:Mitoxantrone; D009367:Neoplasm Staging; D011344:Procarbazine; D016896:Treatment Outcome; D014747:Vinblastine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "879-88",
"pmc": null,
"pmid": "26763986",
"pubdate": "2016-03",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL).",
"title_normalized": "reduced intensity vepemb regimen compared with standard abvd in elderly hodgkin lymphoma patients results from a randomized trial on behalf of the fondazione italiana linfomi fil"
} | [
{
"companynumb": "IT-BAYER-2016-016130",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Penicillin-resistant viridans group streptococci (VGS) infections are an emerging issue in infectious diseases. Here, we present a case of mitral valve infective endocarditis caused by highly penicillin-resistant VGS (minimum inhibitory concentration >4 μg/mL), which was successfully treated with daptomycin. Although the clinical efficacy of daptomycin has not been established, it can be an alternative for the treatment of highly resistant VGS endocarditis.",
"affiliations": "Department of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.;Department of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.;Department of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.;Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan.;Department of Clinical Laboratory, St. Luke's International Hospital, Tokyo, Japan.;Department of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.;Department of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.",
"authors": "Matsuo|Takahiro|T|;Mori|Nobuyoshi|N|;Sakurai|Aki|A|;Kanie|Takayoshi|T|;Mikami|Yumiko|Y|;Uehara|Yuki|Y|;Furukawa|Keiichi|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01113",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00069-X\n10.1016/j.idcr.2021.e01113\ne01113\nCase Report\nEffectiveness of daptomycin against infective endocarditis caused by highly penicillin-resistant viridans group streptococci\nMatsuo Takahiro tmatsuo@luke.ac.jp\na⁎\nMori Nobuyoshi a\nSakurai Aki a\nKanie Takayoshi b\nMikami Yumiko c\nUehara Yuki acde\nFurukawa Keiichi a\na Department of Infectious Diseases, St. Luke’s International Hospital, Tokyo, Japan\nb Department of Cardiology, St. Luke’s International Hospital, Tokyo, Japan\nc Department of Clinical Laboratory, St. Luke’s International Hospital, Tokyo, Japan\nd Department of Microbiology, Juntendo University Faculty of Medicine, Tokyo, Japan\ne Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan\n⁎ Corresponding author at: Department of Infectious Diseases, St. Luke’s International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, Japan. tmatsuo@luke.ac.jp\n05 4 2021\n2021\n05 4 2021\n24 e011135 1 2021\n2 4 2021\n2 4 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPenicillin-resistant viridans group streptococci (VGS) infections are an emerging issue in infectious diseases. Here, we present a case of mitral valve infective endocarditis caused by highly penicillin-resistant VGS (minimum inhibitory concentration >4 μg/mL), which was successfully treated with daptomycin. Although the clinical efficacy of daptomycin has not been established, it can be an alternative for the treatment of highly resistant VGS endocarditis.\n\nKeywords\n\nPenicillin-resistant viridans group streptococci\nDaptomycin\nInfective endocarditis\n==== Body\nIntroduction\n\nReported as a frequent pathogen, viridans group streptococci (VGS) are responsible for 40–60 % of community-acquired native-valve endocarditis cases [1]. The number of VGS cases that were relatively or fully resistant to penicillin has been increasing over the decades and is an emerging issue in the field of infectious diseases [2]. As previously reported [3], the frequent long-term use of amoxicillin may induce VGS resistance to penicillin. We present a case of mitral valve infective endocarditis caused by highly penicillin-resistant VGS (minimum inhibitory concentration [MIC] >4 μg/mL), which was successfully treated with daptomycin.\n\nCase report\n\nA 35-year-old healthy woman had a past medical history of recurrent chronic sinusitis over several years and had been previously treated with amoxicillin-clavulanate and levofloxacin. She presented to our outpatient clinic with a two-week history of fever with temperatures up to 38 °C. Nine days before her first clinic visit, she was prescribed amoxicillin-clavulanate. On admission, the patient’s state was stable with clear consciousness, a temperature 37.6 °C, blood pressure 120/50 mmHg, heart rate 90 beats/min, and respiratory rate 16 breaths/min, and her oxygen saturation, measured by pulse oximetry, was 98 % on room air. The patient was noted to have a pan systolic murmur on the right sternal border and apex (Levine 4/6). She also had tenderness on the left, upper quadrant and had conjunctival petechiae and Janeway lesions on her left thigh. Laboratory findings revealed elevated white blood cell count 10,800/μL, hemoglobin level 12.6 g/dL, platelet count 410,000/μL, creatinine level 0.59 mg/dL, and C-reactive protein level 10.2 mg/dL. Transthoracic and transesophageal echocardiography revealed a mobile vegetation measuring 17 mm × 5 mm on her mitral valve associated with moderate mitral regurgitation (Fig. 1). A contrast whole trunk computed tomography scan revealed low-density attenuation in the spleen (Fig. 2) and an aneurysm measuring 6 mm in diameter in the superior mesenteric artery (SMA). Brain MRI indicated a cerebral infarction measuring 1 cm in diameter on the right occipital lobe. The patient was diagnosed with infective endocarditis in the mitral valve associated with multiple septic emboli, including splenic emboli, in addition to an SMA and cerebral artery aneurysm. As the vegetation was large, she underwent urgent mitral valve replacement with a biological valve on the same day.Fig. 1 Transthoracic echocardiogram revealed a mobile vegetation measuring 17 mm × 5 mm on the mitral valve.\n\nFig. 1\n\nFig. 2 A contrast whole trunk computed tomography scan revealed low-density attenuation in the spleen.\n\nFig. 2\n\nAmpicillin/cloxacillin intravenously (IV) 4 g every 4 h, ceftriaxone IV 2 g every 12 h, and vancomycin IV 1 g every 12 h were begun. On day 2, three sets of blood cultures (aerobic and anaerobic bottles for each set), obtained during admission, grew gram-positive cocci in chains, which was finally identified as Streptococcus mitis/oralis by VITEC 2 GP ID card (bioMérieux) and matrix-assisted laser desorption/ionization–time of flight mass spectrometry equipment, MALDI Biotyper (Bruker). Antimicrobial susceptibility testing was performed using the Mueller Hinton broth with 3% lysed horse blood using an MF 7 J panel in MicroScan Walkaway 96 plus (Beckman Coulter). MICs were as follows: penicillin G 4 μg/mL, cefotaxime 4 μg/mL, and vancomycin 1 μg/mL. MICs measured using Etest (bioMérieux) are also shown in Table 1 (daptomycin 0.25 μg/mL and meropenem 1.0 μg/mL). More than likely, because of hypoperfusion during surgery and the effect of multiple antimicrobial agents, acute kidney injury (creatinine level increased to 4.2 mg/dL) occurred on hospital day 3.Table 1 Susceptibility testing of Streptococcus mitis/oralis.\n\nTable 1\tMicroScan WalkAway 96 plus, MIC (μg/mL)\tE test, MIC (μg/mL)\tSusceptibility according to CLSI M100-28 breakpoints\t\nPenicillin G\t4\t4\tResistant\t\nCefotaxime\t4\t6\tResistant\t\nMeropenem\t2\t1\tSusceptible\t\nVancomycin\t1\t\tSusceptible\t\nDaptomycin\tNA\t0.25\tSusceptible\t\nCefotiam\t>4\t\tNo data\t\nErythromycin\t1\t\tResistant\t\nLevofloxacin\t1\t\tSusceptible\t\nMIC: Minimal inhibitory concentrations, NA: not available.\n\nCLSI: Clinical Laboratory Standards Institute.\n\nBased on this susceptibility result and acute kidney injury, antimicrobial therapy was switched to daptomycin IV 10 mg/kg every 48 h plus levofloxacin IV 250 mg every 24 h. Follow-up blood cultures were negative. The patient continued these antimicrobial therapies for two weeks, followed by a daptomycin regimen for four more weeks without any adverse effects except for mild stomach discomfort due to gastroesophageal reflux disease. This was verified via upper endoscopy. The kidney function improved five weeks after discontinuing the antimicrobials. One year after discontinuing antimicrobial therapy, the patient’s follow-up visit indicated that her general status was healthy without any particular sequelae. Informed consent was provided by the patient for the publication of the Case Report.\n\nDiscussion\n\nThe 33-year-old woman was successfully treated with daptomycin and levofloxacin for a subacute mitral valve infective endocarditis resulting from the highly penicillin-resistant Streptococcus mitis/oralis. There is a paucity of data on the recommended regimen against highly penicillin-resistant VGS.\n\nIt is difficult to determine the optimal antimicrobials for infective endocarditis caused by highly resistant VGS, on account of a lack of reported cases; consequently, there are no strong recommendations for highly resistant VGS by either the American Heart Association (AHA)/Infectious Diseases Society of America (IDSA) 2015 or the European Society of Cardiology (ESC) 2015 guidelines.\n\nAccording to the AHA/IDSA guideline [4], it is recommended to treat patients with infective endocarditis caused by penicillin-resistant VGS (MIC > 0.5 μg/mL) with a combination of ampicillin or penicillin G plus gentamicin (class 2a: level of evidence C). The guideline suggests this recommendation for treating Enterococcus sp. as well [4,5]. According to this, alternative regimens for Enterococci sp. were linezolid 600 mg administered intravenously or orally every 12 h for more than six weeks (Class 2b; Level of evidence C) or daptomycin 10–12 mg/kg administered intravenously for more than six weeks (Class 2b; Level of evidence C) if the Enterococcus species were resistant or intolerant to penicillin, aminoglycoside, or vancomycin.\n\nThe ESC 2015 guideline [6], which relies on a retrospective case series, also recommends a treatment regimen for highly resistant VGS, namely penicillin G or ampicillin or ceftriaxone combined with gentamicin for four weeks for native valve endocarditis [6]. This guideline also mentions that vancomycin could be an option, but this is based upon limited evidence. However, in a clinical setting, once acute kidney injury has occurred, continuing aminoglycoside could be difficult, and vancomycin use could be challenging for the maintenance of the appropriate trough level. Both guidelines have limited suggestions on the use of daptomycin.\n\nDaptomycin is a lipopeptide that is bactericidal against a wide range of gram-positive bacterial pathogens, including the antimicrobial-resistant pneumococci, enterococci, and staphylococci. Historically, daptomycin (6 mg/kg daily) was reported not to be inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis [7]. Subsequently, it had been widely used not only for right-sided endocarditis but also for left-sided endocarditis based upon several clinical trials [8]. Although there were few clinical reports related to endocarditis due to highly resistant VGS, in vitro data suggest that outcomes could be improved with higher doses for gram-positive bloodstream infections [9]. Despite daptomycin being a relatively new antimicrobial agent with little data regarding infective endocarditis, it could be an excellent candidate for further clinical trials targeting infective endocarditis due to highly resistant VGS.\n\nThe optimal duration of antimicrobials also remains unclear for highly penicillin-resistant VGS. A previous study suggested four- to six-week-long regimens (penicillin plus gentamicin, ceftriaxone plus gentamicin or vancomycin) for infective endocarditis caused by highly resistant VGS [10]. Given that the AHA/IDSA and ESC guidelines recommend a six-week regimen of linezolid or daptomycin for infective endocarditis due to penicillin-resistant enterococci [4], we accordingly continued daptomycin for six weeks. Our patient had been tolerant to daptomycin without any adverse effects, including eosinophilic pneumonia or rhabdomyolysis.\n\nFinally, in the case we describe, we combined levofloxacin with daptomycin for the first two weeks. Although there have been little data concerning the effectiveness of levofloxacin in combination with daptomycin, some studies have reported the efficacy of levofloxacin for the treatment of endocarditis due to VGS [11].\n\nIn conclusion, daptomycin could be an alternative to antimicrobial therapy for endocarditis caused by highly penicillin-resistant VGS. Further clinical studies regarding its effectiveness and side effects are warranted.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\n\nNot applicable.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\n\nTM wrote the manuscript. NM, AS, TK, YM, YU, and KF assisted in the writing the manuscript. All authors read and approved the final manuscript.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n\nAcknowledgment\n\nEditing support was provided by Editage.\n==== Refs\nReferences\n\n1 Mylonakis E. Calderwood S.B. Infective endocarditis in adults N Engl J Med 345 2001 1318 1330 11794152\n2 Prabhu R.M. Piper K.E. Baddour L.M. Steckelberg J.M. Wilson W.R. Patel R. Antimicrobial susceptibility patterns among viridans group streptococcal isolates from infective endocarditis patients from 1971 to 1986 and 1994 to 2002 Antimicrob Agents Chemother 48 2004 4463 4465 15504884\n3 Bryskier A. Viridans group streptococci: a reservoir of resistant bacteria in oral cavities Clin Microbiol Infect 8 2002 65 69 11952717\n4 Baddour L.M. Wilson W.R. Bayer A.S. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association Circulation 132 2015 1435 1486 26373316\n5 Elliott T.S.J. Foweraker J. Gould F.K. Perry J.D. Sandoe J.A. Guidelines for the antibiotic treatment of endocarditis in adults: report of the working party of the British Society for Antimicrobial Chemotherapy J Antimicrob Chemother 54 2004 971 981 15546974\n6 Habib G. Lancellotti P. Antunes M.J. ESC Guidelines for the management of infective endocarditis Eur Heart J 2015 36 2015 3075 3128\n7 Fowler V.G. Boucher H.W. Corey G.R. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus N Engl J Med 355 2006 653 665 16914701\n8 Carugati M. Bayer A.S. Miró J.M. High-dose daptomycin therapy for left-sided infective endocarditis: a prospective study from the international collaboration on endocarditis Antimicrob Agents Chemother 57 2013 6213 6222 24080644\n9 Kullar R. Casapao A.M. Davis S.L. A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis J Antimicrob Chemother 68 2013 2921 2926 23928022\n10 Fujitani S. Rowlinson M.-C. George W.L. Penicillin G-resistant viridans group streptococcal endocarditis and interpretation of the American Heart Association’s Guidelines for the treatment of infective endocarditis Clin Infect Dis 46 2008 1064 1066 18444825\n11 Chambers H.F. Liu Q.X. Chow L.L. Hackbarth C. Efficacy of levofloxacin for experimental aortic-valve endocarditis in rabbits infected with viridans group Streptococcus or Staphylococcus aureus Antimicrob Agents Chemother 43 1999 2742 2746 10543757\n\n",
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"affiliations": "Klinik und Poliklinik für Dermatologie und Allergologie der LMU, Frauenlobstraße 9-11, 80337, München, Deutschland. sascha.staender@gmx.de.;Hautarztpraxis Dr. Michael Ständer, Leutkirch im Allgäu, Deutschland.;Klinik und Poliklinik für Dermatologie und Allergologie der LMU, Frauenlobstraße 9-11, 80337, München, Deutschland.;Klinik und Poliklinik für Dermatologie und Allergologie der LMU, Frauenlobstraße 9-11, 80337, München, Deutschland.;Klinik und Poliklinik für Dermatologie und Allergologie der LMU, Frauenlobstraße 9-11, 80337, München, Deutschland.",
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"abstract": "BACKGROUND\nThe incidence and risk factors of severe anaphylaxis by intravenous anti-cancer drugs are unclear, whereas those of milder reactions have been reported.\n\n\nMETHODS\nElectronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non-epithelial malignancies were also included in the analysis. \"Severe anaphylaxis\" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887).\n\n\nRESULTS\nAmong 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person-day anti-cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person-based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%-0.67%) and the administration-based incidence was 0.031% (27/88,200, 95% CI 0.019%-0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin-induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%-13.1%). Carboplatin caused severe anaphylaxis after at least 9-min interval since the drip started. Thirteen out of 14 patients experienced carboplatin-induced severe anaphylaxis within a 75-day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life-long incidence of 0.93% (9/968, 95% CI 0.27%-1.59%).\n\n\nCONCLUSIONS\nWe elucidated the high-risk settings of chemotherapy-induced severe anaphylaxis.",
"affiliations": "Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Department of Obstetrics and Gynecology, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Chemotherapy Committee, Yokohama City University Hospital, Yokohama, Japan.;Department of Surgery, Yokohama City University Hospital, Yokohama, Japan.;Department of Otorhinolaryngology Head and Neck Surgery, Yokohama City University Hospital, Yokohama, Japan.;Department of Oncology, Yokohama City University Hospital, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Hospital, Yokohama, Japan.",
"authors": "Horita|Nobuyuki|N|https://orcid.org/0000-0002-8200-0340;Miyagi|Etsuko|E|;Mizushima|Taichi|T|;Hagihara|Maki|M|;Hata|Chiaki|C|;Hattori|Yuki|Y|;Hayashi|Narihiko|N|;Irie|Kuniyasu|K|;Ishikawa|Hideyuki|H|;Kawabata|Yusuke|Y|;Kitani|Yosuke|Y|;Kobayashi|Noritoshi|N|;Kobayashi|Nobuaki|N|;Kurita|Yusuke|Y|;Miyake|Yohei|Y|;Miyake|Kentaro|K|;Oguri|Senri|S|;Ota|Ichiro|I|;Shimizu|Ayako|A|;Takeuchi|Masanobu|M|;Yamada|Akimitsu|A|;Yamamoto|Kojiro|K|;Yukawa|Norio|N|;Masuda|Munetaka|M|;Oridate|Nobuhiko|N|;Ichikawa|Yasushi|Y|;Kaneko|Takeshi|T|",
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"fulltext": "\n==== Front\nCancer Med\nCancer Med\n10.1002/(ISSN)2045-7634\nCAM4\nCancer Medicine\n2045-7634\nJohn Wiley and Sons Inc. Hoboken\n\n34505396\n10.1002/cam4.4252\nCAM44252\nResearch Article\nClinical Cancer Researcher\nResearch Articles\nSevere anaphylaxis caused by intravenous anti‐cancer drugs\nHORITA et al.\nHorita Nobuyuki https://orcid.org/0000-0002-8200-0340\n1 horitano@yokohama-cu.ac.jp\n\nMiyagi Etsuko 2\nMizushima Taichi 1\nHagihara Maki 1\nHata Chiaki 1\nHattori Yuki 1\nHayashi Narihiko 1\nIrie Kuniyasu 1\nIshikawa Hideyuki 1\nKawabata Yusuke 1\nKitani Yosuke 1\nKobayashi Noritoshi 1\nKobayashi Nobuaki 1\nKurita Yusuke 1\nMiyake Yohei 1\nMiyake Kentaro 1\nOguri Senri 1\nOta Ichiro 1\nShimizu Ayako 1\nTakeuchi Masanobu 1\nYamada Akimitsu 1\nYamamoto Kojiro 1\nYukawa Norio 1\nMasuda Munetaka 3\nOridate Nobuhiko 4\nIchikawa Yasushi 5\nKaneko Takeshi 6\n1 Chemotherapy Committee Yokohama City University Hospital Yokohama Japan\n2 Department of Obstetrics and Gynecology Yokohama City University Hospital Yokohama Japan\n3 Department of Surgery Yokohama City University Hospital Yokohama Japan\n4 Department of Otorhinolaryngology Head and Neck Surgery Yokohama City University Hospital Yokohama Japan\n5 Department of Oncology Yokohama City University Hospital Yokohama Japan\n6 Department of Pulmonology Yokohama City University Hospital Yokohama Japan\n* Correspondence\nNobuyuki Horita, Chemotherapy Committee, Yokohama City University Hospital, 3‐9 Fukuura, Kanazawa‐ku, Yokohama 236‐0004, Japan.\nEmail: horitano@yokohama-cu.ac.jp\n\n10 9 2021\n10 2021\n10 20 10.1002/cam4.v10.20 71747183\n14 8 2021\n26 4 2021\n20 8 2021\n© 2021 The Authors. Cancer Medicine 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\nBackground\n\nThe incidence and risk factors of severe anaphylaxis by intravenous anti‐cancer drugs are unclear, whereas those of milder reactions have been reported.\n\nStudy Design\n\nElectronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non‐epithelial malignancies were also included in the analysis. \"Severe anaphylaxis\" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887).\n\nResults\n\nAmong 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person‐day anti‐cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person‐based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%–0.67%) and the administration‐based incidence was 0.031% (27/88,200, 95% CI 0.019%–0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin‐induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%–13.1%). Carboplatin caused severe anaphylaxis after at least 9‐min interval since the drip started. Thirteen out of 14 patients experienced carboplatin‐induced severe anaphylaxis within a 75‐day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life‐long incidence of 0.93% (9/968, 95% CI 0.27%–1.59%).\n\nConclusion\n\nWe elucidated the high‐risk settings of chemotherapy‐induced severe anaphylaxis.\n\n88,200 person‐days of chemotherapy provided for 5584 patients were reviewed. They induced 27 severe anaphylaxes defined by Brown’s criteria. Most were caused by carboplatin (14 cases) or paclitaxel (9 cases).\n\nanaphylaxis\ndrug hypersensitivity\nmedical oncology\nretrospective studies\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:19.10.2021\nHorita N , Miyagi E , Mizushima T , et al. Severe anaphylaxis caused by intravenous anti‐cancer drugs. Cancer Med. 2021;10 :7174–7183. 10.1002/cam4.4252\n\nMunetaka Masuda, Nobuhiko Oridate, Yasushi Ichikawa and Takeshi Kaneko are equally contributed for the work.\n\nFunding information\n\nNone.\n==== Body\npmc1 BACKGROUND\n\nAnaphylaxis is an acute, severe, and potentially life‐threatening allergic reaction that is caused by a variety of foreign substances. Food, venom, and medications including beta‐lactam antibiotics and non‐steroidal anti‐inflammatory drugs are common triggers of anaphylaxis. 1 , 2 Intravenous anti‐cancer drugs such as platinum agents and taxanes also often induce hypersensitivity reactions. 3 , 4 , 5 A patient with mild allergic reaction may have localized rash, itchiness, or rhinitis. 1 , 2 However, severe forms of drug‐induced anaphylaxis are iatrogenic critical events that demand life‐supporting maneuvers. 6 Therefore, severe anaphylaxis should be paid careful attention. However, few studies have focused on chemotherapy‐induced severe anaphylaxis, except for case reports. 7 Despite the recommended use of dexamethasone and H1/H2 antihistamine prophylactic pretreatment prior to chemotherapies, 5 , 8 some patients still experience severe anaphylaxis. Therefore, we need to know the incidence and risk factors of severe anaphylaxis caused by intravenous anti‐cancer drugs to prepare for acute‐onset critical events and to design novel regimens.\n\nIn 1999, Markman et al. studied 205 patients who were treated with carboplatin, observing that 24 (12%) of them developed hypersensitivity reactions of various severities. 8 Their observation also demonstrated that allergic reactions mainly developed at the 8th or later carboplatin treatment. 8 Another well‐known risk factor is carboplatin infusion after a 1‐year or longer interval. 9 , 10 , 11 In contrast, based on a report by Weiss et al. in 1990, paclitaxel hypersensitivity reactions of any grade occurred in 27 of 301 patients (9%) and caused mainly by the first or second exposure to paclitaxel. 12 However, it is not clear whether these rules can be applied for severe anaphylaxis because limited numbers of severe cases were reported in these studies. Furthermore, recently recommended prophylactic premedication might modify the epidemiology. In addition, numerous new anti‐cancer agents, especially molecular‐targeted drugs, have become available in the last two decades. Therefore, a comprehensive updated risk assessment is necessary to elucidate the incidence and high‐risk situations of chemotherapy‐induced severe anaphylaxis. The aim of this study was to assess the incidence of severe anaphylaxis caused by anti‐cancer medications and to elucidate high‐risk situations.\n\n2 METHODS\n\n2.1 Overview\n\nThis was a single‐center retrospective chart review study registered with the identification number UMIN000042887 and was approved by the Yokohama City University Hospital Institutional Ethical Review Board (ID: B201200069). Instead of informed consent, chance of opt out was offered for patients; however, none of the patient claimed opt out for this retrospective study.\n\n2.2 Data collection\n\nThe electronic medical charts of the Yokohama City University Hospital were retrospectively reviewed. In this hospital, prophylactic medications were routinely provided prior to high‐risk agents, such as carboplatin and paclitaxel. All out‐patients and in‐patients who underwent intravenous chemotherapy for any malignancy between 1 January 2013 and 30 October 2020 were identified. Since our study focused on intravenous anti‐cancer medications, anti‐cancer drugs though other routes, such as oral, hypo‐cutaneous, or intra‐arterial administration were excluded from our analysis. Non‐epithelial malignancies such as sarcoma and leukemia were also included in our analysis.\n\nBackground data such as age, sex, type of malignancies, and chemotherapy regimens were systematically extracted. Charts of patients who were given the International Classification of Disease Code (9th or 10th edition) of anaphylaxis, anaphylactic shock, or shock on the day of the chemotherapy were scrutinized in detail.\n\n2.3 Diagnosis of severe anaphylaxis\n\n\"Severe anaphylaxis\" was judged using Brown's criteria, 6 typical presentation of anaphylaxis and one or more of hypoxia with saturation of oxygen by pulse oximetry (SpO2) of 92% or lower, hypotension with systolic blood pressure below 90 mmHg, and neurologic compromise such as confusion, collapse, loss of consciousness, and incontinence. This criterion annotated 139 severe anaphylaxis cases (12.2%) out of 1149 patients with systemic hypersensitivity reactions due to a variety of triggers who visited or were transported to an emergency department. 6 When an anti‐cancer drug was intravenously started and then led to an allergic reaction within 30 min, the drug was considered to be the causative agent for our analysis. 1 , 8 Allergic reactions to monoclonal antibodies are often termed infusion reactions as distinguished from anaphylaxis. However, as long as the clinical presentation satisfied Brown's criteria, we counted allergic reaction caused by the monoclonal antibody as severe anaphylaxis in our analysis, following recent guidelines. 13\n\n2.4 Statistics\n\nWe calculated two types of incidences in this study. For administration‐based incidence, one person‐day treatment was considered as one administration. For example, when two cycles of gemcitabine (days 1, 8, and 15) were provided to a patient, this patient is considered to have 6 day‐persons of gemcitabine treatment regardless of the cycle count. On the other hand, person‐based lifetime incidence was calculated regardless of the total number of administrations for each patient. The Agresti–Coull method was used to estimate the 95% confidence interval (CI) of incidence, and the Mann–Whitney test was used to compare nonparametric numbers in two groups.\n\n3 RESULTS\n\n3.1 Background data of patients and use of drugs\n\nBetween January 2013 and October 2020, 5584 patients including 2964 males (53.1%) and 2620 females (46.9%) underwent anti‐cancer chemotherapy (Table 1). The median age at the first treatment during the observation period was 66 years (range 0–93, interquartile range (IQR) 56–73, Table 1). Of the 5584 patients, the most prevalent targeted malignancy, allowing multiple‐counting for double‐ and triple‐cancer patients, was pancreatic cancer (705 patients, 11.6%, Table 1) followed by colon cancer (643, 10.6%), biliary cancer (445, 7.3%), and head and neck cancers (444, 7.3%). Patients received median of 10 anti‐cancer intravenous administrations (range 1–222, IQR 5–22).\n\nTABLE 1 Background characteristics of patients\n\nN\t5584\t\nMedian age (interquartile range)\t66 (56–73)\t\nMan\t2964 (53.1%)\t\nWoman\t2620 (46.9%)\t\nCancer type\t\nPancreatic cancer\t705 (11.6%)\t\nColon cancer\t643 (10.6%)\t\nBiliary cancer\t445 (7.3%)\t\nHead and neck cancer\t444 (7.3%)\t\nBreast cancer\t430 (7.1%)\t\nNon‐Hodgkin lymphoma\t383 (6.3%)\t\nCervical cancer\t333 (5.5%)\t\nGastric cancer\t328 (5.4%)\t\nEsophageal cancer\t312 (5.1%)\t\nOvarian cancer\t255 (4.2%)\t\nNon‐small cell lung cancer\t227 (3.7%)\t\nEndometrial cancer\t155 (2.5%)\t\nOral cancer\t135 (2.2%)\t\nUrothelial carcinoma\t125 (2.1%)\t\nAcute lymphatic leukemia\t118 (1.9%)\t\nAcute myelogenous leukemia\t97 (1.6%)\t\nBrain tumor\t92 (1.5%)\t\nRenal cell carcinoma\t79 (1.3%)\t\nMalignant soft tissue tumor\t79 (1.3%)\t\nMalignant melanoma\t79 (1.3%)\t\nNon‐small cell lung cancer\t63 (1.0%)\t\nProstate cancer\t58 (1.0%)\t\nNote\n\nAge was determined by the day of first anti‐cancer therapy during the observation period.\n\nA patient who had double or triple cancer may be double counted in this table only for cancer type.\n\nCancers with prevalence >1% are listed.\n\nJohn Wiley & Sons, Ltd\n\nA total of 88,200 person‐days of treatment were performed at our institution, of which 34,991 (39.7%) were provided in ward and 53,209 (60.3%) were provided in the Outpatient Chemotherapy Center.\n\nThe most frequently used drug, fluorouracil, was administered 14,893 times to 1066 individual patients. Drugs infused more than 2000 times such as gemcitabine, cisplatin, and solvent‐based paclitaxel are listed in Table 2.\n\nTABLE 2 Frequently used anti‐cancer drugs\n\nDrug\tAdministration (Person‐day)\tPatients\tSevere anaphylaxis\t\nFluorouracil\t14,893\t1066\t0\t\nGemcitabine\t14,575\t1242\t0\t\nCisplatin\t10,305\t1643\t1\t\nPaclitaxel, solvent‐based\t8894\t1034\t9\t\nBevacizumab\t6743\t563\t0\t\nIrinotecan\t6263\t608\t0\t\nLevofolinate\t6106\t494\t0\t\nCarboplatin\t5581\t1037\t14\t\nCetuximab\t5239\t326\t1\t\nEtoposide\t4449\t360\t0\t\nOxaliplatin\t4321\t694\t0\t\nPaclitaxel, nanoparticle‐albumin‐bound\t3692\t434\t0\t\nCyclophosphamide\t3312\t697\t0\t\nVincristine\t3143\t483\t0\t\nNivolumab\t2927\t243\t0\t\nDoxorubicin\t2908\t468\t0\t\nTrastuzumab, non‐conjugated\t2903\t166\t1\t\nCytarabine\t2676\t159\t0\t\nIfomide\t2454\t167\t0\t\nMesna\t2215\t163\t0\t\nRituximab\t2137\t319\t0\t\nDocetaxel\t2079\t520\t1\t\nNote\n\nDrugs that were administrated >2000 times are listed.\n\nnab‐Paclitaxel, nanoparticle‐albumin‐bound Paclitaxel.\n\nJohn Wiley & Sons, Ltd\n\n3.2 Overall incidence\n\nWe identified 27 cases of severe anaphylaxis from our database despite 25 of them having preventive premedication, including dexamethasone (Table 3). The person‐based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%–0.67%) and administration‐based incidence was 0.031% (27/88,200, 95% CI 0.019%–0.043%). The causative drugs were carboplatin in 14 cases (52%), paclitaxel in 9 cases (33%), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each, 4%) (Table 3). Notably, 19 out of 27 patients were gynecological cases (13 ovarian, 4 cervical, and 2 endometrial). Otherwise, no age‐, or sex‐related predominance observed (Tables 1, 3 and 1, 3).\n\nTABLE 3 Case presentation of patients with severe anaphylaxis\n\nCase\tPrevention\tCausative drug\tDrug repeat\tInterval\tOnset (min)\tSymptoms and signs\tTreatment\t\n1) 77F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t3rd\t43 d\t15\tNausea, itchiness, dyspnea, generalized flush, O2 desaturation (87%), (relative shock (148/77 mmHg >108/75 mmHg))\tO2, hydrocortisone\t\n2) 49F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t5th\t75 d\t14\tFacial flush, itchiness, nausea, shock (87/46 mmHg), agonized look, neck discomfort, SpO2 93 (2 L)\tO2, hydration, cortisone, Fmt, CPM\t\n3) 48F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t6th\t21 d\t26\tChest distress, dyspnea, facial flush, perspiration, O2 desaturation (91%)\tO2, Ad im, cortisone, Cp\t\n4) 61F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t8th\t21 d\t24\tHot flush, nausea, facial flush, perspiration, dizziness, shock (75/35 mmHg), O2 desaturation (89%)\thydration, Ad im, cortisone\t\n5) 73F, Ovarian\tDex\tCarboplatin\t10th\t24 d\t30\tCervical confinement sensation, O2 desaturation (89%), itchiness of ear and upper arms\tO2, hydration, Cp\t\n6) 54F, Cervical\tDex, Dph, Rnt\tCarboplatin\t10th\t28 d\t25\tGeneralized flush, dyspnea, O2 desaturation (91%)\tO2, hydration, cortisone,\t\n7) 48F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t11th\t32 d\t12\tDiscomfort, nausea, vomiting, perspiration, facial flush, dyspnea, shock (56/42 mmHg), tachycardia (135/min), O2 desaturation (75% on O2 5 L/min mask)\tO2, Ad im, cortisone, Cp, Fmt\t\n8) 62F, Ovarian\tDex\tCarboplatin\t12th\t34 d\t12\tPalm rash, palm itchiness, face flush, conjunctival hyperemia, faintness, shock (unmeasurable), nausea, vomiting, O2 desaturation (93%)\tO2, hydration, cortisone, Cp, Fmt,\t\n9) 70F, Ovarian\tDex\tCarboplatin\t13th\t295 d\t12\tDyspnea, O2 desaturation (<90%), tachypnea (23/min)\tO2, hydration\t\n10) 83F, Ovarian\tDex\tCarboplatin\t13th\t28 d\t9\tNumb mouth, nausea, dyspnea, shock (57/35 mmHg), O2 desaturation (87%)\tO2, hydration, Ad im, cortisone\t\n11) 66F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t15th\t24 d\t23\tNausea, vomiting, shock (85/64 mmHg), facial flush, arm flush, perspiration\thydration\t\n12) 69F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t15th\t21 d\t30\tPalm flush, nausea, shock (55/38 mmHg), O2 desaturation (SpO2 94), slurred speech\tO2, hydration, cortisone\t\n13) 54F, Cervical\tDex, Dph, Rnt\tCarboplatin\t16th\t54 d\t15\tNausea, shock (81/52 mmHg), chest compression\tO3, hydration, CPM\t\n14) 68F, Ovarian\tDex, Dph, Rnt\tCarboplatin\t16th\t28 d\t20\tNausea, facial flush, puffy lips, shock (71/50 mmHg)\tO2, hydration, cortisone, Cp\t\n15) 55F, Cervical\tNone\tCisplatin\t3rd\t7 d\t20\tNumbness, facial flush, nausea, vomiting, O2 desaturation (SpO2 < 90%), hypotension (93/51 mmHg)\tO2, hydration, cortisone, CFM\t\n16) 59M, Gastric\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t15\tDyspnea, facial flush, O2 desaturation (85%), low‐grade fever (37.2°C), hypertension (100/77 mmHg > 177/119 mmHg)\tO2, prednisolone, Cp\t\n17) 68M, Esophagus\tDex, Cp, Rnt\tPaclitaxel\t1st\tNA\t4\tTransient blindness, O2 desaturation (90% on O2 4 L/min mask), shock (58/32 mmHg), bradycardia (56/min)\tO2, hydration, Ad im, cortisone\t\n18) 60M, Thymic\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t3\tNausea, dyspnea, perspiration, pale face, shock (unmeasurable), unconsciousness\tO2, hydration, Ad im, cortisone, Fmt, Cp\t\n19) 51F, Cervical\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t8\tFainting, shock (44/27 mmHg), abdominal pain, O2 desaturation (94% on O2 5 L/min mask), tachycardia (128/min), hoarseness, dyspnea, rash, itchiness, incontinence\tO2, hydration, Ad im, cortisone,\t\n20) 46F, Uterus\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t5\tFacial flush, dyspnea, O2 desaturation (88%), shock (67/50 mmHg), restlessness\tO2, hydration, Ad im, cortisone,\t\n21) 50F, Cervical\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t7\tDyspnea, cough, O2 desaturation (SpO2 80%), wheeze\tAd im\t\n22) 51F, Uterus\tDex, Dph, Rnt\tPaclitaxel\t1st\tNA\t6\tFacial flush, cyanosis, O2 desaturation (SpO2 90%)\tO2, hydration, Fmt, CPM\t\n23) 73F, Ovarian\tDex, Dph, Fmt\tPaclitaxel\t2nd\t21 d\t5\tO2 desaturation (90% on O2 4 L/min mask), shock (50/30 mmHg), low‐grade fever (37.1°C), generalized flush, perspiration\tO2, Ad im x2, cortisone, saltanol inhaler, Cp, Fmt\t\n24) 74M, Lung\tDex, Dph, Rnt\tPaclitaxel\t3rd\t28 d\t1\tUnconsciousness, shock (52/40 mmHg), O2 desaturation (76%), perspiration\tO2, hydration, cortisone\t\n25) 60M, Gastric\tDex\tDocetaxel\t1st\tNA\t5\tDyspnea, O2 desaturation (90%), facial flush, chest discomfort\tO2, hydration, cortisone\t\n26) 55F, Breast\tNone\tTrastuzumab\t1st\tNA\t14\tHigh fever (38.5°C), shivering, shock (unmeasurable), O2 desaturation (93% on O2 10 L/min mask), vomiting, wheezing\tO2, Ad im x2, Cp, benetorine nebulizer, aminophylline, Fmt\t\n27) 71M, Head/Neck\tDex, Cp\tCetuximab\t1st\tNA\t8\tO2 desaturation (86%), facial flush, dyspnea\tO2, cortisone\t\nNote\n\nAd im, adrenaline intramuscular shot, cortisone: hydrocortisone. Onset, interval from the first drip of the day to the onset. Drug repeat, cumulative number of causative drug administration including the administration leading to the event. Interval, interval since the last administration of the causative drug (day).\n\nAbbreviations: Cp, chlorpheniramine; Dex, Dexamethasone; Dph, Diphenhydramine; F, Female; Fmt, Famotidine; In‐P, Inpatient; M, Male; O2, oxygen; Out‐P, Outpatient; Rnt, Ranitidine.\n\nJohn Wiley & Sons, Ltd\n\nThree severe anaphylaxes (11%) were caused by one each of brand‐name cetuximab (Erbitux), non‐conjugated trastuzumab (Herceptin), and docetaxel (Taxotere); the other 24 events (89%) were caused by generic or biosimilar medications. This only reflected the frequency of use in our hospital. Majorities of cetuximab (96.1%) and non‐conjugated trastuzumab (99.1%) and 23.7% of docetaxel were brand‐name medication, while only generic drugs were administrated for cisplatin, solvent‐based paclitaxel, and carboplatin during the study period.\n\n3.3 Carboplatin and platinum\n\nDuring the review period, 5581 carboplatin administrations for 1037 patients induced a total of 14 severe anaphylaxes (Table 2), which yielded an administration‐based incidence of 0.25% (95% CI 0.11%–0.39%) and person‐based lifetime incidence for patients who received at least one carboplatin administration of 1.35% (95% CI 0.60%–2.10%).\n\nAccording to the data of these 14 patients, the total number of carboplatin administrations including those that led to the severe anaphylaxis ranged from 3 to 16 (median 11.5) (Table 3). Compared to the 13 events caused by the other drugs, a larger number of the same drug was administered to each person until the severe anaphylaxis (p < 0.001, Figure 1A). Once stratified by every five cumulative carboplatin administrations, the incidence of severe anaphylaxis was highest for patients who received their 11th–15th carboplatin administration (6/369 = 1.63%, 95% CI 0.16%–3.09%) followed by the 16th–20th treatment (2/129, 1.55%, 95% CI 0%–4.43%), whereas that of the 1st–5th treatment was 0.054% (2/3740, 95% CI 0%–0.16%) (Figure 2A). Among 124 patients who received at least 10 carboplatin administrations, 10 experienced severe anaphylaxes in their life (10/124, 8.1%, 95% CI 3.0%–13.1%). Out of 369 administrations as the 11th–15th treatment of the patient, 283 (77%) were treated for ovarian, endometrial, or cervical cancers and we believe this explain why only gynecological patients experienced carboplatin‐induced events (Figure 1A).\n\nFIGURE 1 High‐risk situations of severe anaphylaxis caused by carboplatin and the other drugs. p value: Mann–Whitney test. Drug repeat: cumulative number of causative drug administration including the administration leading to the event. Error bar: Median and interquartile range are presented\n\nFIGURE 2 Incidence stratified by total number of causative drug administration. Error bar: Agresti–Coull method was used to estimate 95% confidence interval\n\nThe first sign or symptom of carboplatin‐induced anaphylaxis was observed at a median of 17.5 min (IQR 12.5–24.75) after the first carboplatin drip of the day (Table 3). Compared to the 13 events caused by the other drugs such as paclitaxel, it took longer interval from the first drip of the day to the reaction onset (p < 0.001, Figure 1B).\n\nThe interval from the previous carboplatin treatment was then analyzed. A median interval from the previous carboplatin administration to the administration leading to the event was 28 days. Thirteen out of 14 patients experienced carboplatin‐induced severe anaphylaxis within a 75‐day interval, whereas one patient experienced severe event at an interval of 295 days. There was no severe anaphylaxis observed after a 360‐day or longer interval (Table 3).\n\nCisplatin, which was administrated 10,305 times for 1643 patients (Table 2), caused one severe anaphylaxis (Table 3).\n\nNo case of severe anaphylaxes was induced by the other platinum treatments in this study, including oxaliplatin (4321 administrations, 694 patients, Table 2) and nedaplatin (505 administrations, 153 patients).\n\n3.4 Paclitaxel and taxanes\n\nIntravenous solvent‐based paclitaxel was infused 8894 times in 1034 patients (Table 2). Paclitaxel induced nine severe anaphylaxes including six cases of shock. Seven of the nine patients had severe anaphylaxis during the first administration of paclitaxel. The second and third administrations caused one severe event each (Table 3). Because 66 of the 1034 patients in our database received their first paclitaxel treatment before January 2013, the remaining 968 patients in this database received their first paclitaxel administration during our observation period. Among them, the incidence of paclitaxel‐induced severe anaphylaxis during the first administration was 0.72% (7/968, 95% CI 0.12%–1.32%) (Figure 2B). For this population, the incidence of lifelong paclitaxel anaphylaxis during the first up to the third treatment was 0.93% (9/968, 95% CI 0.27%–1.59%).\n\nThe median duration from the first paclitaxel drip of the day to the first sign or symptom of anaphylaxis was 5 min (range 1 to 15, Table 3).\n\nNanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) was notably being increasingly administered, with 87 instances in 2013 and 718 in 2019. This drug was administered 3693 times in 434 cases, none of whom had severe anaphylaxis (Table 2).\n\nA total of 520 patients received 2079 docetaxel infusions (Table 2). The first‐course docetaxel caused severe anaphylaxis in a 60‐year‐old gastric patient 5 min after the initiation of the infusion (Table 3).\n\nNo cases of severe anaphylaxis were caused by cabazitaxel, a recently developed taxane, which was used in 13 patients.\n\n3.5 HER2 monoclonal antibody\n\nHER2 monoclonal antibody, trastuzumab, was administrated 2903 times for 166 patients who had breast cancer, Paget's disease, or gastric cancer (Table 2). A 55‐year‐old woman with breast cancer who did not have any prophylactic premedication suffered from anaphylactic shock with desaturation 14 min after trastuzumab infusion (Table 3). Intra‐muscular adrenaline was shot within a minute since blood pressure dropped below 90 mmHg. She was recovered from shock in 2 min. She was safely retreated with trastuzumab with prophylactic dexamethasone, diphenhydramine, and ranitidine 10 days after this event and successfully underwent total 45 doses of trastuzumab. She was the only patients who received the same drug after the severe anaphylaxis in our institute.\n\n3.6 EGFR monoclonal antibody\n\nCetuximab, an EGFR monoclonal antibody, was infused 5240 times in 249 patients with colon, oral, or head and neck cancers (Table 2). A 71‐year‐old male with head and neck carcinoma experienced a severe anaphylactic event 8 min after intravenous treatment with cetuximab (Table 3).\n\n3.7 Clinical courses of severe anaphylaxis\n\nOf the 27 patients who underwent the severe anaphylaxis, 22 (81%) had hypoxia, 15 (56%) had shock, and 6 (22%) had neurologic compromise (Table 3). In addition, 12 (44%) complained of dyspnea, 7 (26%) had noticeable perspiration, and 16 (59%) had generalized or facial flushing.\n\nAll patients were successfully treated with combinations of oxygen, hydration, intramuscular adrenaline, hydrocortisone, chlorpheniramine, or famotidine, and no one died. Intravenous aminophylline, inhaled salbutamol, and nebulized salbutamol were also used in a few patients. Intra‐muscular adrenaline was provided in 11 patients, of whom eight had active shock. Four of the eight patients who received an adrenaline shot recovered from shock within 5 min whereas each of the other four cases took 8, 12, 19 for the shock recovery, and 56 min, respectively.\n\n4 DISCUSSION\n\nAlthough many studies have warned about anaphylaxis caused by anti‐cancer drugs, 7 , 8 , 14 the risk factors for chemotherapy‐induced severe anaphylaxis remained unclear. This is partly because most studies on this topic have been published as case repots, which are unsuitable for estimates of incidence and risk factors. By contrast, retrospective database analysis is a reasonable strategy for this clinical question given the low incidence of severe anaphylaxis. We analyzed 88,200 person‐day treatments for 5584 patients and clarified that the repeated carboplatin infusion and the first few administrations of solvent‐based paclitaxel are distinct high‐risk situations for severe anaphylaxis, despite the use of prophylactic medications. In addition to carboplatin and taxanes, numerous cytotoxic agents have been frequently used (Table 2); however, most of these agents did not cause severe events at our hospital. In a few cases, monoclonal antibodies were the causative agents.\n\nCarboplatin is believed to induce IgE‐mediated type I hypersensitivity. 15 , 16 It typically occurs more than 10 min after the first drip of the 11th to 20th course of the drug (Table 3, Figures 1 and 2). This finding was compatible with numerous previous reports about carboplatin hypersensitivity of any grade. 3 , 7 , 8 , 9 However, the interval between the previous carboplatin administration and severe anaphylaxis remains controversial. O'Cearbhaill et al. reported that the median interval between prior platinum regimen and hypersensitivity reaction was 20 months. 9 Gadducci et al. assessed 69 patients of whom nine experienced anaphylactic events and noted that carboplatin re‐treatment after an interval longer than 23.4 months was a strong risk for hypersensitivity of any severity (odds ratio 7.1, p = 0.013). 10 A database analysis by Schwartz et al. involving 126 patients suggested that a prolonged platinum‐free interval longer than 24 months substantially increases severe carboplatin hypersensitivity of any severity (p = 0.009). 11 Nonetheless, no patient in our hospital experienced severe anaphylaxis caused by carboplatin after a 1 year interval or longer (Table 3). By contrast, 13 out of 14 patients in our study had events within 75 days from the previous carboplatin treatment (Table 3). Although we could not detect a definite clue for this discrepancy, the high‐risk situations of severe anaphylaxis might be different from those of milder hypersensitivity. In any case, a patient with repeated carboplatin infusion should be closely monitored even after a short interval from the last treatment. Various protocols have been advocated for patients who experience carboplatin hypersensitivity. 17 , 18 However, re‐administration of the trigger medication that caused severe anaphylaxis cannot be justified. 4 , 7 , 19 Interestingly, only gynecological patients experienced carboplatin‐induced severe anaphylaxis in our study, despite carboplatin being commonly used for a variety of cancers. This could be because 6th‐ or latter‐carboplatin administration was the risk factor for severe anaphylaxis and 6th‐ or latter‐carboplatin was mainly provided for gynecological patients (Figure 2A).\n\nIn our study, the first to third administration of taxanes caused severe anaphylaxis whereas fourth‐ or latter‐infusion did not, and most of these taxanes‐induced severe anaphylaxes occurred within 5 min. These findings consistent with those of previous studies regarding hypersensitivity of any grade. 8 , 14 Although some researchers mentioned that paclitaxel hypersensitivity is milder than that caused by carboplatin, 5 we should do recognize that paclitaxel‐induced severe anaphylaxis is not rare (Table 3). Paclitaxel re‐administration may be considered once mild symptoms subside. 8 , 20 However, paclitaxel re‐administration after severe anaphylaxis seems too risky. 4 , 7 , 19 Polyethylated castor oil solvent of paclitaxel is known to directly cause hypersensitivity via the non‐IgE mechanism. 5 , 21 , 22 By contrast, nab‐paclitaxel is believed to rarely cause hypersensitivity. 5 , 21 , 22 There was no nab‐paclitaxel‐induced severe anaphylaxis in our hospital, although this should be confirmed through another larger database.\n\nMonoclonal antibodies can cause acute hypersensitivity, including anaphylaxis mediated by IgE, similar to anaphylactoid reactions, infusion reactions, and cytokine release syndrome. 23 Cetuximab, a chimeric mouse‐human monoclonal antibody against EGFR is known to induce anaphylaxis when IgE antibodies target galactose. 23 , 24 A post‐marketing survey of trastuzumab, a humanized anti‐HER2 monoclonal antibody, covered 25,000 cases identified 74 patients (0.3%) with severe infusion‐related events mostly occurring shortly after infusion. Nine events leading to death were induced by the first administration of trastuzumab. 25 Although some might consider that hypersensitivity reaction to monoclonal antibody is not anaphylaxis but an infusion reaction, two of our cases presented typical symptoms of severe anaphylaxis and had excellent reaction to adrenaline (Table 3, cases 19 and 20). 1 , 13\n\nAs long as medical staff are prepared for severe anaphylaxis, it is easy to diagnose because most patients present with sudden‐onset typical symptoms during intravenous treatment (Table 3). In addition, the first‐choice medical therapeutic option, intramuscular epinephrine (0.3 mg = 0.3 ml of 0.1%), is effective for most patients. 2 , 26 Nonetheless, experts strongly believe that epinephrine is underused despite the recommendations of guidelines. 2 , 26 Most clinicians are used to administering 1 mg intravenous epinephrine for cardio‐pulmonary arrested patients; 27 however, they usually do not have enough chance to be trained administering intramuscular epinephrine for anaphylactic patients. Doctors and nurses who provide intravenous anti‐cancer drugs should know the risk situation illustrated in our analysis and be familiar with intramuscular adrenaline shots to deal with iatrogenic critical events.\n\nThe limitations of our study include the low evidence level due to the retrospective design, inconsistent prophylaxis regimens, and possibly omitted events 30 min after the first drip.\n\nIn conclusion, we conducted a retrospective database analysis of 88,200 person‐days of treatment for 5584 patients. Repeated carboplatin and the first few administrations of paclitaxel and docetaxel are high‐risk situation. The lifelong incidence of severe anaphylaxis was as high as 8.1% among patients who received at least 10 carboplatin administrations. Carboplatin typically caused severe anaphylaxis after 10‐min or longer interval since the first drip. Long interval since the last carboplatin treatment was not a risk of severe anaphylaxis. Paclitaxel‐induced severe anaphylaxis was typically caused by the first administration within 5 min from the first drip and the lifelong incidence was 0.93%. Monoclonal antibodies also caused a few severe anaphylaxes.\n\nCONFLICT OF INTEREST\n\nNobuyuki Horita reports personal fee from Taiho Pharmaceutical and research grant from Taiho Pharmaceutical and Daiichi Sankyo outside of the work. Etsuko Miyagi reports personal fee from MSD, Chugai Pharmaceutical, Takeda Pharmaceutical, and AstraZeneca and research grant from MSD and Chugai Pharmaceutical outside of the work. Taichi Mizushima reports personal fee from AstraZeneca outside of the work. Hideyuki Ishikawa reports personal fee from Novartis and Ono Pharmaceutical outside of the work. Noritoshi Kobayashi reports personal fee from Yakult Honsha and Novartis outside of the work. Nobuaki Kobayashi reports personal fee from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Bristol Myers Squibb, Eli Lilly, Kyowa Kirin and research grant from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, Kyowa Kirin, Daiichi Sankyo, Pfizer outside of the work. Akimitsu Yamada reports personal fee from Chugai Pharmaceutical, Kyowa Kirin, Taiho Pharmaceutical, Daiichi Sankyo, Pfizer outside of the work. Munetaka Masuda reports research grant from Chugai Pharmaceutical, Kaken Pharmaceutical, Shionogi, Daiichi Sankyo, and Takeda Pharmaceutical outside of the work. Nobuhiko Oridate reports personal fee from Ono Pharmaceutical, Bristol Myers Squibb, Merck Biopharma, Taiho Pharmaceutical, MSD, and AstraZeneca and research grant from Ono Pharmaceutical, Merck Biopharma, and Taiho Pharmaceutical outside of the work. Yasushi Ichikawa reports personal fee from Chugai Pharmaceutical and Eli Lilly and research grant from Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, and Shionogi outside of the work. Takeshi Kaneko reports personal fee from Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Pfizer, Sanofi and research grant from MSD, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Pfizer, Shionogi, Sanofi outside of the work.\n==== Refs\nREFERENCES\n\n1 Brown AF , McKinnon D , Chu K . Emergency department anaphylaxis: a review of 142 patients in a single year. J Allergy Clin Immunol. 2001;108 (5 ):861‐866.11692116\n2 Kemp SF , Lockey RF , Simons FE . Epinephrine: the drug of choice for anaphylaxis‐a statement of the world allergy organization. World Allergy Organ J. 2008;1 (7 Suppl ):S18‐S26.23282530\n3 Lenz HJ . Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12 (5 ):601‐609.17522249\n4 Shepherd GM . Hypersensitivity reactions to chemotherapeutic drugs. Clin Rev Allergy Immunol. 2003;24 (3 ):253‐262.12721396\n5 Lee C , Gianos M , Klaustermeyer WB . Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol. 2009;102 (3 ):179‐187; quiz 87‐89, 222.19354063\n6 Brown SG . Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004;114 (2 ):371‐376.15316518\n7 De Zoysa MY , Nakamaru NA , Kaiser SB , Ciccone MA , Muderspach LI , Matsuo K . Successful resuscitation after cardiac arrest secondary to carboplatin infusion: a case report. Gynecol Oncol Rep. 2018;23 :7‐9.29892682\n8 Markman M , Kennedy A , Webster K , et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol. 1999;17 (4 ):1141.10561172\n9 O'Cearbhaill R , Zhou Q , Iasonos A , et al. The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment. Gynecol Oncol. 2010;116 (3 ):326‐331.19944454\n10 Gadducci A , Tana R , Teti G , Zanca G , Fanucchi A , Genazzani AR . Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. Int J Gynecol Cancer. 2008;18 (4 ):615‐620.18754135\n11 Schwartz J , Bandera C , Bradley A , et al. Does the platinum‐free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women and Infants' Hospital. Gynecol Oncol. 2007;105 (1 ):81‐83.17157366\n12 Weiss RB , Donehower RC , Wiernik PH , et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8 (7 ):1263‐1268.1972736\n13 Roselló S , Blasco I , García Fabregat L , Cervantes A , Jordan K . Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28 (suppl_4 ):iv100‐iv118.28881914\n14 Lee TS , Kang SB , Kim YT , et al. Chemoradiation with paclitaxel and carboplatin in high‐risk cervical cancer patients after radical hysterectomy: a Korean Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys. 2013;86 (2 ):304‐310.23642625\n15 Castells M . Drug hypersensitivity and anaphylaxis in cancer and chronic inflammatory diseases: the role of desensitizations. Front Immunol 2017;8 :1472.29163536\n16 Sliesoraitis S , Chikhale PJ . Carboplatin hypersensitivity. Int J Gynecol Cancer. 2005;15 (1 ):13‐18.15670291\n17 Goldberg A , Confinocohen R , Fishman A , Beyth Y , Altaras M . A modified, prolonged desensitization protocol in carboplatin allergy. J Allergy Clin Immunol. 1996;98 (4 ):841‐843.8876561\n18 Hesterberg PE , Banerji A , Oren E , et al. Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management. J Allergy Clin Immunol. 2009;123 (6 ):1262‐1267.19501233\n19 Maindrault‐Goebel F , André T , Tournigand C , et al. Allergic‐type reactions to oxaliplatin: retrospective analysis of 42 patients. Eur J Cancer. 2005;41 (15 ):2262‐2267.16154353\n20 Peereboom DM , Donehower RC , Eisenhauer EA , et al. Successful re‐treatment with taxol after major hypersensitivity reactions. J Clin Oncol. 1993;11 (5 ):885‐890.8098057\n21 Gradishar WJ , Tjulandin S , Davidson N , et al. Phase III trial of nanoparticle albumin‐bound paclitaxel compared with polyethylated castor oil‐based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23 (31 ):7794‐7803.16172456\n22 Shitara K , Takashima A , Fujitani K , et al. Nab‐paclitaxel versus solvent‐based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open‐label, randomised, non‐inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2 (4 ):277‐287.28404157\n23 Hansel TT , Kropshofer H , Singer T , Mitchell JA , George AJT . The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9 (4 ):325‐338.20305665\n24 Chung CH , Mirakhur B , Chan E , et al. Cetuximab‐induced anaphylaxis and IgE specific for galactose‐alpha‐1,3‐galactose. N Engl J Med. 2008;358 (11 ):1109‐1117.18337601\n25 Cook‐Bruns N . Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology. 2001;61 (Suppl 2 ):58‐66.11694789\n26 AAAI Board of Directors . The use of epinephrine in the treatment of anaphylaxis. J Allergy Clin Immunol. 1994;94 (4 ):666‐668.7930298\n27 Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: section 6: pharmacology II: agents to optimize cardiac output and blood pressure. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation. 2000;102 (8 Suppl ):I129‐I135.10966670\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "10(20)",
"journal": "Cancer medicine",
"keywords": "anaphylaxis; drug hypersensitivity; medical oncology; retrospective studies",
"medline_ta": "Cancer Med",
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"nlm_unique_id": "101595310",
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"pages": "7174-7183",
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"pmid": "34505396",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
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"title": "Severe anaphylaxis caused by intravenous anti-cancer drugs.",
"title_normalized": "severe anaphylaxis caused by intravenous anti cancer drugs"
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"abstract": "Female breast cancer accounts for 14% of all new cancer cases in the United States. Metaplastic breast carcinomas (MpBC) are less than 1% of all mammary tumors. Limited clinical information exists on the prognosis and treatments for MpBC due to its rarity and the histological diversity of the tumor cells. We report a case of metastatic MpBC with osseous differentiation who had a marked response to liposomal doxorubicin. This 54-year-old female presented with a 2.5 x 2.6 cm oval-shaped irregularly marginated density in the outer lower quadrant of the left breast, cT2N0M0. Biopsy revealed an invasive metaplastic carcinoma, triple negative, with osseous and focal chondroid differentiation. Genetic testing showed a mutation in the BRCA1 gene. Approximately seven months after a left mastectomy, the patient presented with biopsy-proven metastatic disease and was initiated on therapy with a single agent, liposomal doxorubicin, 50 mg/m(2) every 28 days. The patient achieved maximum response after cycle three and continued to have stable disease for 18 months (20 cycles). Based on the pathologic phenotype, we would have predicted that she would have had a poor and short response to anthracycline. This case illustrates an increased sensitivity of BRCA1-mutated cancers to anthracycline therapies, irrespective of pathologic classification.",
"affiliations": "Pharmacy, Roswell Park Cancer Institute.;Pathology, Roswell Park Cancer Institute.;Soft Tissue Medicine, Roswell Park Cancer Institute.;Soft Tissue Medicine, Roswell Park Cancer Institute.;Medical Oncology, Roswell Park Cancer Institute.;Radiation Medicine, Roswell Park Cancer Institute.",
"authors": "Hamad|Lamya|L|;Khoury|Thaer|T|;Vona|Karen|K|;Nestico|Jill|J|;Opyrchal|Mateusz|M|;Salerno|Kilian E|KE|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.454OncologyA Case of Metaplastic Breast Cancer with Prolonged Response to Single Agent Liposomal Doxorubicin Muacevic Alexander Adler John R Hamad Lamya 1Khoury Thaer 2Vona Karen 3Nestico Jill 3Opyrchal Mateusz 4Salerno Kilian E 51 \nPharmacy, Roswell Park Cancer Institute 2 \nPathology, Roswell Park Cancer Institute 3 \nSoft Tissue Medicine, Roswell Park Cancer Institute 4 \nMedical Oncology, Roswell Park Cancer Institute 5 \nRadiation Medicine, Roswell Park Cancer Institute \nLamya Hamad lamya.hamad@roswellpark.org11 1 2016 1 2016 8 1 e45423 11 2015 11 1 2016 Copyright © 2016, Hamad et al.2016Hamad 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 http://cureus.com/articles/3919-a-case-of-metaplastic-breast-cancer-with-prolonged-response-to-single-agent-liposomal-doxorubicinFemale breast cancer accounts for 14% of all new cancer cases in the United States. Metaplastic breast carcinomas (MpBC) are less than 1% of all mammary tumors. Limited clinical information exists on the prognosis and treatments for MpBC due to its rarity and the histological diversity of the tumor cells.\n\nWe report a case of metastatic MpBC with osseous differentiation who had a marked response to liposomal doxorubicin. This 54-year-old female presented with a 2.5 x 2.6 cm oval-shaped irregularly marginated density in the outer lower quadrant of the left breast, cT2N0M0. Biopsy revealed an invasive metaplastic carcinoma, triple negative, with osseous and focal chondroid differentiation. Genetic testing showed a mutation in the BRCA1 gene. Approximately seven months after a left mastectomy, the patient presented with biopsy-proven metastatic disease and was initiated on therapy with a single agent, liposomal doxorubicin, 50 mg/m2 every 28 days. The patient achieved maximum response after cycle three and continued to have stable disease for 18 months (20 cycles). Based on the pathologic phenotype, we would have predicted that she would have had a poor and short response to anthracycline. This case illustrates an increased sensitivity of BRCA1-mutated cancers to anthracycline therapies, irrespective of pathologic classification.\n\nmetaplastic carcinomaoncologybrca1anthracyclinesbreast cancertriple negative breast cancerThe 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\nFemale breast cancer accounts for 14% of all new cancer cases in the United States [1]. Metaplastic breast carcinomas (MpBC) are seen in less than 1% of all mammary tumors [2-3]. Limited clinical information on the prognosis and treatments exists for MpBC due to its rarity and the histological diversity of the tumor cells [1-4]. Metaplastic carcinomas are characterized by a combination of various cell types, most commonly spindle cell, squamous, and/or mesenchymal [2, 5]. Some studies suggest that these cells may have developed from multipotential undifferentiated cells [2].\n\nTreating patients with MpBC presents unique challenges. Song, et al. found that patients with MpBC presented with a larger tumor size, fewer lymph node metastases, a higher percentage of triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor-2-negative) cases, higher proliferation rates, and high expression of Ki-67 compared to those with invasive ductal carcinomas (IDC) [6]. Patients with MpBC have a poorer prognosis and are more likely to have local recurrences than IDC patients, even when compared only to patients with triple-negative IDC [6].The study also found that patients with MpBC were likely to develop distant metastases, specifically to the lungs [6]. The five-year survival rate in the MpBC group versus IDC was found to be 54.5% and 85.1%, respectively, whereas the five-year disease-free survival rate was 45.5% in MpBC patients versus 71.2% in the IDC group with 60.3% in triple-negative invasive carcinomas [6].\n\nTypically, patients with MpBC are treated similarly to those with IDC; however, studies have shown reduced response rates to chemotherapy among MpBC patients compared to IDC patients [3, 7]. Rayson, et al. found that standard chemotherapy regimens in the adjuvant setting are not as effective with MpBC compared to other types of breast cancers [3]. Of seven patients treated using a total of 14 separate chemotherapy regimens, only one response was observed to doxorubicin, with this patient exhibiting stable disease for 12 months [3]. The patient population in the Rayson, et al. study was predominantly metaplastic breast carcinomas with pure spindle cell differentiation, which may limit the generalizability of the study to other subtypes of MpBC. \n\nCase presentation\nA 54-year-old female presented with a 2.5 x 2.6 cm oval-shaped irregularly marginated density in the outer lower quadrant of the left breast with an irregular calcification within the mass. Informed patient consent was obtained. A biopsy revealed an invasive metaplastic breast carcinoma, triple-negative, with osseous and focal chondroid differentiation. A left mastectomy with sentinel node biopsy was performed. Pathology revealed a tumor size of 5.8 x 5.6 x 4.7 cm, margins were free of malignancy, and two sentinel lymph nodes were negative for tumor, pT3N0(sn)M0. The patient declined adjuvant therapy and proceeded with surveillance. Approximately four months later, a CT scan of the chest, abdomen, and pelvis revealed multiple new parenchymal lung nodules. The patient opted for continuing surveillance, and follow-up imaging three months later revealed a progressive increase in the size of the pulmonary nodules, highly concerning for metastases. The patient then presented to our oncology clinic. Lung biopsy confirmed high-grade malignancy similar to her initial diagnosis consistent with metastatic MpBC (Figure 1). Estrogen receptor, progesterone receptor, and HER2 protein were once again not expressed.\n\n\nFigure 1 Metaplastic mammary carcinoma with osseous differentiation (Hematoxylin and Eosin 10x)\n\n\n\nTreatment decision making took into consideration the rarity of MpBC, the lack of well-defined standard therapy, and that systemic therapy usually mimics that of IDC [7]. Doxorubicin is a preferred treatment option for both triple-negative breast cancers as well as many soft tissue sarcomas. Thus, the patient was initiated on systemic therapy with a single agent, liposomal doxorubicin, 50 mg/m2 every 28 days. A restaging CT of the chest, abdomen, and pelvis with contrast was done approximately every three months. Partial response was achieved on the first re-staging scan (Figure 2). As she developed hand and foot syndrome, dosing was extended to every five weeks with better tolerance.\n\n\nFigure 2 Representative picture of lung lesion at first restaging scan\n\n\n\nThe patient achieved maximum response after cycle three and continued to have stable disease for 18 months (20 cycles) before observing a mild progression of multiple pulmonary nodules and pleural masses. The patient’s alkaline phosphatase levels corresponded to the disease response, leading us to believe it was most likely produced by the cancer cells, as there was no evidence of bone invasion (Figure 3). Given the progression, therapy was changed to capecitabine, due to patient preference for oral therapy, without response. She is currently being evaluated for treatment on a clinical trial including PARP inhibitors or therapy with a platin-containing regimen. Five months after initiating therapy with liposomal doxorubicin, genetic testing by FoundationOne was performed to provide additional information for determination of options for future therapies. The FoundationOne report listed a genomic alteration in the BRCA1 gene, G511fs*21 mutation, which is expected to result in the truncation of the protein resulting in the loss of two BRCT (BRCA1 C-terminus) domains and, therefore, it was predicted to result in abrogation of function. The patient preferred to not have germline BRCA1 testing done; therefore, it is unknown if it is a germline mutation, although she does not have any family history of malignancies.\n\n\nFigure 3 Levels of alkaline phosphatase (IU/L) at baseline and during the course of therapy. Levels corresponded to her radiological response, with initial partial response followed by stable disease\n\n\n\nDiscussion\nThis case study presents a patient with triple-negative metastatic MpBC who had a prolonged response to liposomal doxorubicin. The initial treatment decision was based on the efficacy of anthracycline-based regimens in sarcomas and metastatic breast cancer. Some studies have explored the association between BRCA1 and BRCA2 mutations in tumors and sensitivity to anthracycline-based regimens [8-9]. The BRCA1 protein helps repair strand breaks in the DNA [10]. There are more than 1,800 mutations in the BRCA1 gene, many of which have been associated with an increased risk of breast cancer [10]. Doxorubicin interferes with DNA and RNA synthesis and inhibits topoisomerase-II at the point of DNA cleavage, resulting in DNA strand breaks. BRCA-deficient cancer cells are less able to repair damage caused by DNA-damaging cytotoxic chemotherapy agents; therefore, they are more sensitive to these agents [8]. A retrospective multicenter study involving 155 patients treated with second or third-line liposomal doxorubicin monotherapy or combined with platinum found that BRCA1 mutation carriers had longer median time to treatment failure, longer overall survival, and a better response rate [8]. The study concluded that among epithelial ovarian cancers, patients with defective BRCA1 genes are more sensitive to DNA-damaging agents as compared to other epithelial ovarian cancers [8]. In another study, Graeser, et al. found a correlation between functional homologous recombination deficiency and chemosensitivity to anthracycline-based regimens in sporadic breast cancer [9]. \n\nThis patient was found to have a G511fs*21 mutation of the BRCA1 gene, a missense mutation which most likely resulted in a decrease of functional protein. The G511fs*21 mutation has not been previously described, and since the patient did not have germline testing, it is unknown if it is germline or cancer-specific mutation. Germline BRCA1 mutations impair the DNA repair pathway, resulting in the accumulation of genetic defects that ultimately lead to the development of tumor cells [10]. \n\nIn general, MpBC has been associated with poor outcomes and chemoresistance. This case is unusual in its durable response to treatment with a single agent, liposomal doxorubicin. The BRCA1 mutation may have resulted in heightened chemosensitivity to anthracycline therapy. Based on the pathologic phenotype of this patient’s MpBC, we would have predicted a poor and short response to anthracycline. Therefore, genetic testing may be useful in choosing best treatment options for rare tumors without established standard therapies.\n\nConclusions\nThis case illustrates increased sensitivity of BRCA1 mutated cancers to anthracycline therapies, irrespective of pathologic classification. Therefore, a mutational analysis might help to predict responses and choice of treatment in select patients. For this patient, other therapies based on BRCA1 deficiency could be chosen. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy should be strongly considered. She is currently being evaluated for treatment on a clinical trial including PARP inhibitors or therapy with a platin-containing regimen. More comprehensive studies exploring mutations in this rare tumor type might reveal novel treatment options for selected patients. This case highlights that genetic variations might be more predictive of response to therapy than histologic classification alone.\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 SEER Stat Fact Sheets: Female Breast Cancer National 11 2015 SEER SEER 2015 http://seer.cancer.gov/statfacts/html/breast.html \n2 Metaplastic carcinoma of the breast clinical presentation, treatment results and prognostic factors Acta Oncol Al Sayed AD El Weshi AN Tulbah AM Rahal MM Ezzat AA 188 195 45 2006 16546865 \n3 Metaplastic breast cancer: prognosis and response to systemic therapy Ann Oncol Rayson D Adjei AA Suman VJ Wold LE Ingle JN 413 419 10 1999 10370783 \n4 Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies Exp Hematol Oncol Schwartz TL Mogal H Papageorgiou C Veerapong J Hsueh EC 31 2 2013 24499560 \n5 Metaplastic carcinoma with extensive chondroid differentiation in the breast (chondroid carcinoma) Yonsei Med J Kim YJ Shim HS Lee H Jung WH 259 263 47 2006 16642558 \n6 Unique clinicopathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators World J Surg Oncol Song Y Liu X Zhang G Song H Ren Y He X Wang Y Zhang J Zhang Y Sun S Liang X Sun Q Pang D 129 11 2013 23738706 \n7 Treatment options for metaplastic breast cancer ISRN Oncol Shah DR Tseng WH Martinez SR 706162 2012 2012 22778998 \n8 BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin Mol Cancer Ther Safra T Borgato L Nicoletto MO Rolnitzky L Pelles-Avraham S Geva R Donach ME Curtin J Novetsky A Grenader T Lai WC Gabizon A Boyd L Muggia F 2000 2007 10 2011 21835933 \n9 A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer Clin Cancer Res Graeser M McCarthy A Lord CJ Savage K Hills M Salter J Orr N Parton M Smith IE Reis-Filho JS Dowsett M Ashworth A Turner NC 6159 6168 16 2010 20802015 \n10 BRCA1 National 11 2015 2015 2015 http://ghr.nlm.nih.gov/gene/BRCA1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "8(1)",
"journal": "Cureus",
"keywords": "anthracyclines; brca1; breast cancer; metaplastic carcinoma; oncology; triple negative breast cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e454",
"pmc": null,
"pmid": "26918222",
"pubdate": "2016-01-11",
"publication_types": "D002363:Case Reports",
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"title": "A Case of Metaplastic Breast Cancer with Prolonged Response to Single Agent Liposomal Doxorubicin.",
"title_normalized": "a case of metaplastic breast cancer with prolonged response to single agent liposomal doxorubicin"
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"abstract": "BACKGROUND\nAllergic drug reactions are adverse drug reactions that result from a specific immunologic response to a medication. Considering the epidemiological and clinical importance of drug allergy, this retrospective analysis focused on drug hypersensitivity in a tertiary care university hospital emergency department (ED).\n\n\nMETHODS\nIn this study 74,929 ED records obtained from March 2012 to March 2015 were reviewed to determine the incidence, etiology, predictors and clinical features of drug hypersensitivity.\n\n\nRESULTS\nThe observed incidence of drug hypersensitivity was 0.87% of all ED admissions. It was significantly higher in female patients aged 18-29 years (2.26%; P < 0.0001) and during winter months (1.09%; P = 0.0058). Most patients had mild to moderate symptoms which regressed following ED treatment. Only five patients (7 per 100,000 ED visits) were diagnosed with drug-induced anaphylaxis, and only five patients were provisionally diagnosed with severe non-immediate reactions with systemic involvement. No patient died of drug hypersensitivity in the ED, and only a small proportion required subsequent hospitalization. The most common causes of drug hypersensitivity reactions were amoxicillin and paracetamol.\n\n\nCONCLUSIONS\nDrug hypersensitivity is a common reason for tertiary centre emergency admissions. This is the largest analysis of ED drug hypersensitivity admissions so far. Beta-lactams were identified as the leading cause of drug hypersensitivity requiring ED evaluation, which also explains the peak of drug hypersensitivity cases during winter months when the use of these medications is highest.",
"affiliations": "IQVIA Zagreb d.o.o., Radnicka cesta 80/17, 10000, Zagreb, Croatia.;Department of Internal Medicine, Intensive Care Unit, University Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia.;Department of Internal Medicine, Unit of Clinical Pharmacology, University Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia. RobertLikic@inet.hr.",
"authors": "Bielen|Cvijeta|C|;Bielen|Luka|L|;Likić|Robert|R|",
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"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-019-1499-0",
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"issn_linking": "0043-5325",
"issue": "131(13-14)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Adverse drug reaction; Anaphylaxis; Beta-lactam antibiotics; Drug hypersensitivity; Emergency department; Paracetamol; Serious non-immediate reactions with systemic involvement",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004342:Drug Hypersensitivity; D004636:Emergency Service, Hospital; D005260:Female; D006785:Hospitals, University; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012621:Seasons; D063128:Tertiary Healthcare",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "329-336",
"pmc": null,
"pmid": "31037361",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "15131563;15479276;15985812;19054930;19128352;21354651;21462805;22111719;24286446;24730413;24754355;24834769;24841773;24909803;25186447;25468198;25584917;25623506;27864093;28483312;28486935;28566489;29969686;29974031;29974032;7776802;9555760",
"title": "Incidence, etiology, predictors and outcomes of suspected drug hypersensitivity reactions in a tertiary care university hospital's emergency department : A retrospective study.",
"title_normalized": "incidence etiology predictors and outcomes of suspected drug hypersensitivity reactions in a tertiary care university hospital s emergency department a retrospective study"
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"companynumb": "HR-NOVPHSZ-PHHY2019HR183141",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
"drugadditional": "3"... |
{
"abstract": "Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma with unfavourable prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We report on a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization-European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Interestingly, readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a durable complete remission during the follow-up period of currently 17 months after autologous SCT. What's already known about this topic? Mycosis fungoides is a primary cutaneous T-cell lymphoma with unfavourable prognosis for the advanced stages of the disease. A refractory course of disease requires systemic therapy. What does this study add? We report on an unusual case of a patient with mycosis fungoides with cerebral involvement, in which a durable complete remission was achieved upon autologous stem cell therapy and interferon alfa-2a maintenance therapy.",
"affiliations": "Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Oncology and Pathology, Lund University, Lund, Sweden.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Institute of Pathology, Canton Hospital Winterthur, Winterthur, Switzerland.;Division of Hematology, University Hospital Zurich, Zurich, Switzerland.;Division of Hematology, University Hospital Zurich, Zurich, Switzerland.;Division of Hematology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.;Institute of Neuropathology, University of Zurich, University Hospital Zurich, Zurich, Switzerland.;Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Linz, Linz, Austria.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Doerschner|M|M|0000-0003-4956-4539;Pekar-Lukacs|A|A|;Messerli-Odermatt|O|O|;Dommann-Scherrer|C|C|;Rütti|M|M|;Müller|A M|AM|;Nair|G|G|;Kamarachev|J|J|;Kerl|K|K|;Beer|M|M|;Messerli|M|M|;Frauenknecht|K|K|;Haralambieva|E|E|;Hoetzenecker|W|W|;French|L E|LE|;Guenova|E|E|",
"chemical_list": "D000077190:Interferon alpha-2",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.17535",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "181(6)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077190:Interferon alpha-2; D008279:Magnetic Resonance Imaging; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D009182:Mycosis Fungoides; D009367:Neoplasm Staging; D016879:Salvage Therapy; D012867:Skin; D012878:Skin Neoplasms; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "1296-1302",
"pmc": null,
"pmid": "30565216",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interferon alfa-2a maintenance after salvage autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement.",
"title_normalized": "interferon alfa 2a maintenance after salvage autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-195418",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARMUSTINE"
},
"drug... |
{
"abstract": "The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin. Oxaliplatin improves the efficacy of this combination in patients with stage III colon cancer and moreover its toxicity is well tolerable. We describe a rare clinical case of acute dyspnoea probably related to oxaliplatin at one month from the end of the adjuvant treatment. A 74-year-old man developed a locally advanced sigmoid carcinoma (pT3N1M0). A port a cath attached to an open-ended catheter was implanted in order to administer primary chemotherapy safely according to the FOLFOX4 schedule. One month following the end of the 6th cycle, the patient referred a persistent cough and moderate dyspnoea. Chest radiography displayed a change in the lung interstitium, chest CT scan confirmed this aspect of adult respiratory distress syndrome, spirometry reported a decreased carbon monoxide diffusion capacity. Antibiotic and corticosteroids were administered for 10 d, then a repeated chest X ray evidenced a progressive pulmonary infiltration. A transbronchial biopsy and cytology did not show an infective process, a CT scan reported radiological abnormalities including linear and nodular densities which were becoming confluents. Antimicotic and antiviral drugs did not evidence any benefit. The antiviral therapy was stopped and high dose metilprednisolone was started. The patient died of pulmonary distress after 10 d.",
"affiliations": "Istituto Oncologico Veneto, Medical Oncology, Via Gattamelata 64, Padova 35128, Italy. laramary@libero.it",
"authors": "Pasetto|L M|LM|;Monfardini|S|S|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v12.i36.5907",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "12(36)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D004417:Dyspnea; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5907-8",
"pmc": null,
"pmid": "17007064",
"pubdate": "2006-09-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14755010;15175436;16483940;2202842;2300087",
"title": "Is acute dyspnea related to oxaliplatin administration?",
"title_normalized": "is acute dyspnea related to oxaliplatin administration"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1056974",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nThis article provides rationale for recommendations on how to initiate aripiprazole once-monthly 400 mg (AOM 400), an injectable suspension, in patients with schizophrenia, supported by pharmacokinetic (PK) data and based on clinical studies.\n\n\nMETHODS\nAn overview of data from a PK study, PK simulations, controlled clinical trials, and a naturalistic study is presented.\n\n\nRESULTS\nPharmacokinetic data support 400 mg as the starting and maintenance dose of AOM; the plasma concentration profile of aripiprazole after initiating AOM 400 was consistent with therapeutic concentrations observed with oral aripiprazole 10 to 30 mg/d. PK simulations and observed data from a single-dose clinical trial indicate that median aripiprazole plasma concentrations reach therapeutic levels within 7 days of initiating AOM 400. Because of interpatient variability, a 14-day overlap with oral aripiprazole or another antipsychotic medication is considered sufficient to ensure therapeutic concentrations. In clinical studies, when patients initiated AOM 400 with concomitant oral aripiprazole (10-15 mg/d based on stabilized dose) or continued their previous antipsychotic for ≤14 days, mean aripiprazole plasma concentration after 4 weeks (93 to 112 ng/mL) was in range of the therapeutic window established for aripiprazole (94.0-534.0 ng/mL). In clinical studies, the 400-mg starting dose of AOM was efficacious and well tolerated. Across studies of variable duration and design, 1296/1439 (90.1%) patients initiated AOM 400 and required no dose change. Overall rates of discontinuation due to lack of efficacy across clinical studies were low in patients treated with AOM 400 (range, 2.3%-10.0%). In a post hoc analysis from a naturalistic study, cross-titration from other oral antipsychotic therapies to oral aripiprazole before initiating AOM 400 was better tolerated with a >1- to 4-week cross-titration period versus a ≤1-week period, as evidenced by lower rates of discontinuation due to adverse events during cross-titration (2.7% [7/239] vs 10.4% [5/48]). The efficacy and safety of AOM 400 in the month after initiation in the pivotal maintenance studies were comparable between subpopulations of patients previously stabilized on 10- or 30-mg doses of oral aripiprazole.\n\n\nCONCLUSIONS\nFindings from PK data, PK simulations, and clinical studies all support that 400 mg is the appropriate initiation dose of AOM for patients with schizophrenia. When switching to oral aripiprazole before initiating AOM 400, tapering the prior oral antipsychotic while titrating up the oral aripiprazole dose (target dose 10-30 mg/d) over >1 to 4 weeks may be an effective strategy. The efficacy, safety, and tolerability of AOM 400 were comparable regardless of whether patients were previously stabilized on oral aripiprazole 10 or 30 mg/d or other antipsychotic therapy and continued to receive the same oral antipsychotic for the first 14 days after initiating AOM 400.",
"affiliations": "Otsuka Pharmaceutical Development & Commercialization, Inc. , Rockville, MD , USA.",
"authors": "Raoufinia|Arash|A|;Baker|Ross A|RA|;Eramo|Anna|A|;Nylander|Anna-Greta|AG|;Landsberg|Wally|W|;Kostic|Dusan|D|;Larsen|Frank|F|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1185/03007995.2015.1006356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-7995",
"issue": "31(3)",
"journal": "Current medical research and opinion",
"keywords": "Antipsychotic; Aripiprazole once-monthly; Dosing information; Long-acting injectable; Schizophrenia; Switching; Treatment initiation",
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D035843:Biomedical Research; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D015363:Quinolones; D012559:Schizophrenia; D016896:Treatment Outcome",
"nlm_unique_id": "0351014",
"other_id": null,
"pages": "583-92",
"pmc": null,
"pmid": "25586294",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Initiation of aripiprazole once-monthly in patients with schizophrenia.",
"title_normalized": "initiation of aripiprazole once monthly in patients with schizophrenia"
} | [
{
"companynumb": "US-OTSUKA-2015_001236",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMorphea is a rare chronic inflammatory disease that involves skin and subcutaneous tissues, causing skin sclerosis. Generalized morphea is characterized by extensive cutaneous involvement and poor response to therapy. Although the pathophysiology for morphea is not completely understood, abnormal signaling through the platelet-derived growth factor and transforming growth factor beta axes seems to play a major role in the inflammatory response and sclerotic process. Imatinib, a tyrosine kinase inhibitor, interferes with both transforming growth factor beta and platelet-derived growth factor signaling pathways. Recent studies proved imatinib's efficacy in the prevention and regression of fibrosis associated with systemic sclerosis, nephrogenic sclerosis, and bleomycin-related fibrosis.\n\n\nMETHODS\nWe present the case of a 50-year-old Caucasian man with a generalized morphea diagnosed 10 years ago, with multiple ulcers, who was treated with imatinib over the course of 12 months. At the end of the treatment, most of the skin ulcerations had healed, and cutaneous thickness was reduced as demonstrated by skin biopsy and ultrasound evaluation. The patient also experienced an improvement in articular mobility, sustained by a 20° increase in left knee extension.\n\n\nCONCLUSIONS\nAlthough controlled studies are necessary to access the antifibrotic effect of imatinib in morphea, the present report shows its potential role in the treatment of this condition.",
"affiliations": "Department of Dermatology and Venereology, Hospital de Curry Cabral, Lisbon, Portugal.",
"authors": "Coelho-Macias|Vasco|V|;Mendes-Bastos|Pedro|P|;Assis-Pacheco|Fernando|F|;Cardoso|Jorge|J|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.12387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "53(10)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012594:Scleroderma, Localized",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "1299-302",
"pmc": null,
"pmid": "24697802",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imatinib: a novel treatment approach for generalized morphea.",
"title_normalized": "imatinib a novel treatment approach for generalized morphea"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-294183",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
... |
{
"abstract": "The authors report a case of a 67-year-old woman with giant cell arteritis with acute Achilles tendon rupture, which occurred after 3 days of levofloxacin therapy introduced because of newly diagnosed erosive gastritis associated with Helicobacter pylori infection. The Achilles tendon rupture was surgically treated and the patient made a complete recovery. In view of the widespread use of levofloxacin in practice, this case report raises important clinical implications. Tendinopathies are a known complication, quite rare in the healthy population, but the risk of rupture significantly increases in the population of patients over 60 years of age, with chronic usage of glucocorticosteroids, impaired renal function and recipients of organ transplants. What needs underlining, there are also described differences between individual fluoroquinolones as a cause of tendon damage in this group. Considering the widespread use of this group of drugs in patients, knowledge about the risk of adverse events including tendinopathy promotes safe use of fluoroquinolones.",
"affiliations": "Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.;Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.",
"authors": "Stasiek|Małgorzata|M|;Głuszko|Piotr|P|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/reum.2019.91277",
"fulltext": "\n==== Front\nReumatologia\nReumatologia\nRU\nReumatologia\n0034-6233 2084-9834 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie \n\n91277\n10.5114/reum.2019.91277\nCase Report\nAcute Achilles tendon rupture after treatment with levofloxacin in a patient with giant cell arteritis\nStasiek Małgorzata Głuszko Piotr Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland\nAddress for correspondence: Małgorzata Stasiek, Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 1 Spartańska St., 02-637 Warsaw, Poland. e-mail: margo1801@o2.pl\n31 12 2019 \n2019 \n57 6 343 346\n21 10 2019 09 11 2019 Copyright: © 2019 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.The authors report a case of a 67-year-old woman with giant cell arteritis with acute Achilles tendon rupture, which occurred after 3 days of levofloxacin therapy introduced because of newly diagnosed erosive gastritis associated with Helicobacter pylori infection. The Achilles tendon rupture was surgically treated and the patient made a complete recovery. In view of the widespread use of levofloxacin in practice, this case report raises important clinical implications. Tendinopathies are a known complication, quite rare in the healthy population, but the risk of rupture significantly increases in the population of patients over 60 years of age, with chronic usage of glucocorticosteroids, impaired renal function and recipients of organ transplants. What needs underlining, there are also described differences between individual fluoroquinolones as a cause of tendon damage in this group.\n\nConsidering the widespread use of this group of drugs in patients, knowledge about the risk of adverse events including tendinopathy promotes safe use of fluoroquinolones.\n\nfluoroquinolonesAchilles tendontendinopathyrupture\n==== Body\nIntroduction\nFluoroquinolones (FQ) are currently used as common antibacterial drugs administered because of broad antibacterial spectrum and good bioavailability when used orally. FQ are considered as safe and well tolerated, which is why they have been extensively distributed in outpatient care over the past 30 years. Despite their usefulness, FQ treatment may cause adverse events. There are many reports indicating that FQ can cause pathologic lesions in the tendon tissue from tendinopathy to rupture [1].\n\nSome time ago the American Food and Drug Administration (FDA) as well as the European Medical Agency (EMA) decided to issue alerts regarding adverse events caused by this group of drugs. Despite the published alerts, the use of fluoroquinolones is abused in daily practice. Therefore we wish to recall adverse events in the musculoskeletal system and to indicate patients at higher risk. Most of the cases of rupture are associated with other risk factors such as older age, glucocorticoid use and rheumatic, vascular or renal diseases [2–4].\n\nDiagnosis of autoinflammatory disease such as giant cell arteritis and chronic therapy with glucocorticosteroids are significant predisposing factors for Achilles tendinopathy including tendon rupture. It is necessary for physicians, especially rheumatologists and orthopedists, to know about this possible complication of FQ treatment as well as factors favoring it, so that the choice of antibiotic therapy is considered in the context of risk factors for acute and chronic tendon damage. And for prophylaxis one should consider the choice of an antibiotic from another group in patients with existing risk factors for this complication.\n\nA case report\nA 67-year-old woman diagnosed with giant cell arteritis in 2014, chronically treated with methylprednisolone 4 mg daily in combination with methotrexate 20 mg once a week, was referred for gastroscopy due to epigastric pain despite the use of a proton pump inhibitor. Gastroscopic examination revealed erosive gastritis with the presence of Helicobacter pylori infection. The patient was consulted by a general practitioner (GP) and ordered H. pylori eradication therapy with the following scheme: levofloxacin 2 × 500 mg per day for 7 consecutive days in combination with amoxicillin and a proton pump inhibitor. The third day following the initiation of therapy, suddenly, the patient presented instability and impairment in walking. A sharp pain appeared in the Achilles tendon area of the left foot with swelling of the distal limb.\n\nThe patient visited the GP once again and received advice to complete eradication therapy according to the previously recommended schedule. The symptoms presented, according to the GP’s opinion, were considered as associated with rheumatic disease and the patient was instructed to report them to a rheumatologist, which was scheduled in three weeks. Therefore she continued FQ treatment for the next 3 weeks.\n\nThe consulting rheumatologist revealed a clear defect in the Achilles tendon on the left foot with a bulging muscle belly in the proximal calf consistent with a tendon rupture. A calf squeeze test revealed plantar flexion on the right but there was none on the left.\n\nBased on the clinical picture and physical examination, the possibility of Achilles tendon rupture was suspected. However, due to great difficulty in walking, persistent pain and swelling of the limb, deep vein thrombosis in the lower extremity could not be ruled out. The patient was referred urgently to the hospital for further instructions. The ultrasound scan confirmed a total rupture of the Achilles tendon and deep vein thrombosis was excluded. X-ray of the left foot and ankle revealed only soft tissue swelling. The patient underwent orthopedic surgery and was discharged to start a rehabilitation program. After about 6 weeks the patient was able to walk without any assistance.\n\nDiscussion\nAmong all possible events associated with FQ treatment, those from the musculoskeletal system are the most commonly discussed in the literature [5].\n\nThe first case of fluoroquinolone-related tendinopathy was described as early as in 1983. Since then, a number of reports indicated adverse events localized in the musculoskeletal system, from trivial ones such as arthralgia or myalgia to tendon ruptures or rhabdomyolysis. Most cases reported in the literature relate to tendon damage – inflammation, degeneration or rupture of the tendons. Several risk factors for tendinopathy have been identified, and the most important include: age over 60 years, long-term glucocorticoid therapy, sport activities, history of rheumatic diseases, diabetes, renal impairment and hemodialysis and organ transplants [5–8] (Table I).\n\nTable I Risk factors for tendinopathy during fluoroquinolone treatment [1, 8]\n\nRisk factors\t\nOlder age (> 60)\t\nMen > women (2 : 1) [8]\t\nGlucocorticosteroid treatment\t\nFluoroquinolone treatment duration\t\nRenal impairment\t\nChronic lung disease\t\nDiabetes\t\nHemodialysis\t\nUse of newer FQ\t\nConsidering age and history of chronic rheumatic diseases treated with glucocorticoid therapy, which certainly affects processes of tendon repair, our patient was undoubtedly at risk of tendinopathy.\n\nThe most common symptom of FQ-associated tendinopathy is pain, which in our patient appeared on the third day of FQ treatment. This pain is usually of a sudden onset, and may be accompanied by acute signs of inflammation and swelling, which was presented as well. The diagnosis is made by acute/sub-acute onset of pain and swelling over the tendon, together with a history of recent use of FQ and the absence of other obvious causes of tendinopathy [3].\n\nClinical examination can reveal a “gap sign” but after a time edema can obliterate this area and palpation becomes unreliable. Thompson’s test reveals failure of plantar flexion after compression of the gastrocnemius muscle in the patient lying in a prone position, which confirms tendon rupture. It is the best known and the easiest test, which was performed in our patient and was positive in the affected area. As many as 50% of reported cases manifested bilateral symptoms, but at the same time up to 50% of tendon rupture cases may not be preceded by any heraldic symptom [5, 7].\n\nThe Achilles tendon is most often affected (89.8% of all cases), although other tendons may also be involved [9]. The weight-bearing role of the Achilles tendon is thought to be the reason for the high preponderance of injury in this structure [10, 11]. Of all tendinopathies, up to 50% of patients may experience tendon rupture, of which almost 1/3 of ruptures occur in patients receiving long-term treatment with glucocorticosteroids [7]. The time of onset of tendinopathy after FQ treatment can be very different, from the appearance of symptoms up to 2 hours after the first dose of the drug, with the highest frequency during the first month, to manifestations up to 6 months after stopping the drug [12].\n\nIn our patient tendon rupture occurred on the third day of treatment. According to other reports the average time of rupture onset after use of FQ is 8 to 14 days [13]. The incidence rate for tendinopathy is 0.1% to 0.01%, and the incidence rate for tendon rupture is less than 0.01% [14]. Van der Linden et al. [15] estimate that between 2 and 6% of all Achilles tendon ruptures in patients over 60 years of age can be attributed to the use of FQ. According to Corrao et al. [16], patients over 60 years of age treated with FQ from 1 to 30 days have a 1.5–2.7 times higher risk of tendon injury including rupture compared to younger patients (under 60 years of age). Some reviews indicate that men are more likely to develop rupture [3, 12].\n\nSome authors believe that the different chemical structure of newer FQ (levofloxacin, ofloxacin and pefloxacin) makes them more toxic for cartilages and tendons than the older group of FQ (norfloxacin, ciprofloxacin and enoxacin) [17, 18]. The underlying pathophysiology of FQ-induced tendinopathy is not entirely known, although several concepts are suggested. Changes in tendons and their damage are associated with, among other things, chemical properties such as chelating abilities of fluoroquinolones. There was also proposed the hypothesis about molecular mechanisms such as inhibition of cellular proliferation in tendons, inhibition of tenocyte migration and increased expression of matrix metalloproteinase that induces collagen degradation and some others [19].\n\nFluoroquinolone-induced tendinopathies occur at recommended doses and treatment duration [10]. However, the severity of tendinopathy appears to be proportional to the treatment duration [10]. The diagnosis is usually clinical, although the use of imaging methods such as ultrasound or magnetic resonance imaging can be helpful. Typical US findings of tendinopathy are thickened tendon with increased blood flow seen in color Doppler examination [3]. Magnetic resonance imaging can be clinically helpful especially in the presence of questionable diagnosis or for tear localization during presurgical planning [20].\n\nManagement of FQ-induced tendinopathy is largely symptomatic – withdrawal of harmful, suspected drug, relief, ice packs, use of painkillers and physiotherapy. In the case of almost complete or complete rupture surgery is necessary to restore tendon continuity. Even with early diagnosis and appropriate management, tendinopathy heals slowly. The mean recovery time ranges from 3 weeks to 3 months [10]. Early and prolonged physical therapy is frequently required, particularly for elderly patients [10]. However, the most important is prevention of rupture, as most patients recover within 2 months of stopping therapy, but more than a quarter of them may suffer from persistent pain and disability [5].\n\nIn the present case report, the recommendation was to use levofloxacin as the first line therapy for eradication of H. pylori infection, but it is not the best first line treatment option for the described patient. Fluoroquinolones are a very effective group of antibiotics but current recommendations regarding the use of this group of antibiotics, after alerts of the FDA and EMA, should be narrowed to the justified medical situations listed in Table II. It is important because FQ can cause not only tendinopathy but also a prolonged (up to months or years), serious, disabling and potentially irreversible syndrome of symptoms from multiple systems of organs and senses (FQAD – long-term fluoroquinolone-associated disability) whose prevalence is probably underestimated because it mimics other diseases.\n\nTable II Disabling and potentially permanent adverse events lead to suspension or restrictions of quinolone and fluoroquinolone administration [www.ema.europa.eu]\n\nRestrictions on the use of fluoroquinolone antibiotics mean that they should NOT be used\t\nTo treat infections that might get better without treatment or are not severe (such as throat infections)\t\nTo treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis\t\nFor preventing traveler’s diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder)\t\nTo treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used\t\nThe clinical picture of FQAD includes tendinopathy, muscle weakness, peripheral polyneuropathy, autonomic nervous system dysfunction, sleep disorders, psychological symptoms, and even complete impairment of function and consciousness [21]. Especially, this group of drugs should not be used in a case of previous history of FQ-related tendinopathy, and should be avoided in elderly patients with chronic glucocorticoid use. According to the most recent meta-analysis, increase in risk sizes is between 4.68-fold of Achilles tendon rupture and 14.72-fold of Achilles tendinitis for patients simultaneously using FQ and glucocorticosteroids, compared with the initial estimates [22].\n\nConsidering the frequent, chronic use of glucocorticosteroids and the inflammatory and destructive involvement of tendons in rheumatic diseases, and the growing proportion of the elderly in the general population in Poland and other European countries, FQ should not be considered as first choice drugs in antimicrobial therapies.\n\nCurrently there are many other better and potentially safer therapeutic alternatives. However, if there is no better option, patients should be informed about possible side effects of the drug and they should refer all those suspected of tendinitis symptoms to the doctor. The severity of tendinopathy appears to be proportional to duration of the treatment [10] so early intervention as discontinuing the drug immediately gives the patient the chance to minimize side effects. A clear temporal relationship can be observed between the implementation of FQ and the onset of symptoms, which considerably increases the suspicion of drug-induced damage in differential diagnosis in our patient. Currently, due to the lack of effective conservative treatment, the surgical procedures and subsequent rehabilitation have remained the basic way of management in tendon damage after FQ treatment. Hence we remain prudent in using these drugs, with particular emphasis on the treatment in the patients in the risk groups for these complications, and conduct strict monitoring of patients during FQ use.\n\nConclusions\nLevofloxacin-induced tendinopathy and/or tendon rupture are uncommon but well-known complications. However, sometimes symptoms in association with risk factors such as older age and usage of glucocorticoids and damage such as a rupture may require surgery, may also cause irreversible disability. Therefore prevention which consists in avoiding the use of drugs in risk groups and obeying the rules according to the recommendations for subsequent lines of antibacterial therapy are vitally important.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Lewis T Cook J Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature J Athlet Train 2014 49 422 427 \n2 Morandé SC de Rada Lorente PD Clemente JD Bilateral Achilles tendon rupture secondary to levofloxacin Rev Esp Cir Ortop Traumatol (English Edition) 2010 54 238 240 \n3 Tam PK Ho CT Fluoroquinolone-induced Achilles tendinitis Hong Kong Med J 2014 20 545 547 25488035 \n4 Garg S Thilagarajah M Bilateral rupture of Achilles tendon (bilrat) without predisposing systemic disease or steroid use: a case report and review of the literature Int J Orthop Surg 2008 13 1 3 \n5 Hal MM Finnoff JT Smith J Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population PM R 2011 3 132 142 21333952 \n6 Emmerson AM Jones AM The quinolones: Decades of development and use J Antimicrob Chemother 2003 51 Suppl. 1 13 20 \n7 US Food and Drug Administration Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126085.htm \n8 Kim GK The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know? J Clin Aesthet Dermatol 2010 3 49 54 \n9 Yu C Guiffre BM Achilles tendinopathy after treatment with fluoroquinolone Australas Radiol 2005 49 407 410 16174181 \n10 Connelly S Bayliff C Mehta S Levofloxacin-induced bilateral Achilles tendinopathy Canad J Hosp Pharm 2002 55 212 214 \n11 Greene BL Physical therapist management of fluoroquinolone-induced Achilles tendinopathy Phys Ther 2002 82 1224 1231 12444881 \n12 Khaliq Y Zhanel GG Fluoroquinolone-associated tendinopathy: a critical review of the literature Clin Infect Dis 2003 36 1404 1410 12766835 \n13 Fernández-Cuadros ME Casique-Bocanegra LO Albaladejo Florín MJ Bilateral Levofloxacin-Induced Achilles Tendon Rupture: An Uncommon Case Report and Review of the Literature Clin Med Insights Arthritis Musculoskelet Disord 2019 12 1179544119835222 30858744 \n14 Haddow LJ Chandra Sekhar M Hajela V Gopal Rao G Spontaneous Achilles tendon rupture in patients treated with levofloxacin J Antimicrob Chemother 2003 51 747 748 12615887 \n15 van der Linden PD Sturkenboom MC Herings RM Increased risk of Achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids Arch Intern Med 2003 163 1801 1807 12912715 \n16 Corrao G Zambon A Bertù L Evidence of tendinitis provoked by fluoroquinolone treatment: a case control study Drug Saf 2006 29 889 896 16970512 \n17 Lado Lado FL Rodríguez Moreno C Velasco González M Rotura parcial bilateral aquílea asociada a levofloxacino An Med Interna (Madrid) 2005 22 28 30 \n18 Jeffrey K Aronson JK Meyler’s side effects of drugs 2016 16th ed Amsterdam Elsevier Science \n19 Tsai WC Yang YM Fluoroquinolone-associated tendinopathy Chang Gung Med J 2011 34 461 467 22035890 \n20 Ramirez MA Richardson LC Pulmonary embolism associated with spontaneous bilateral Achilles tendon rupture J Foot Ankle Surg 2007 46 283 287 17586442 \n21 Golomb BA Koslik HJ Redd AJ Fluoroquinolone-induced serious, persistent, multisymptom adverse effects BMJ Case Rep 2015 2015: \n22 Alves C Mendes D Marques FB Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis Eur J Clin Pharmacol 2019 75 1431 1443 31270563\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0034-6233",
"issue": "57(6)",
"journal": "Reumatologia",
"keywords": "Achilles tendon; fluoroquinolones; rupture; tendinopathy",
"medline_ta": "Reumatologia",
"mesh_terms": null,
"nlm_unique_id": "20130190R",
"other_id": null,
"pages": "343-346",
"pmc": null,
"pmid": "32226168",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12615887;21333952;26438672;15777120;31270563;24762232;30858744;17586442;12912715;12444881;25488035;20725547;22035890;12766835;12702699;16970512;16174181",
"title": "Acute Achilles tendon rupture after treatment with levofloxacin in a patient with giant cell arteritis.",
"title_normalized": "acute achilles tendon rupture after treatment with levofloxacin in a patient with giant cell arteritis"
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"abstract": "HIV infection can result in vision loss from different causes, including HIV retinopathy and uveitis secondary to other infections, such as toxoplasmosis and viral retinitis. It is imperative to identify any infectious causes of uveitis to successfully treat the condition and prevent further vision loss. Metagenomic deep sequencing (MDS) is an emerging technology that presents an unbiased approach to the evaluation of clinical syndromes, including uveitis, that have not been diagnosed by pathogen-specific testing. Herein we present a case of a woman living with HIV with 11 years of relapsing bilateral uveitis refractory to systemic corticosteroid therapy who was diagnosed with human T-lymphotropic virus type 1 (HTLV-1)-associated uveitis by this technology. We also briefly review the literature of MDS as a diagnostic tool and the epidemiology, pathogenesis, and diagnosis of HTLV-1-associated uveitis.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.;Emory Eye Center, Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA.;Emory Eye Center, Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Phadke|Varun K|VK|0000-0002-0318-4939;Shantha|Jessica G|JG|;O'Keefe|Ghazala|G|",
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"doi": "10.1093/ofid/ofaa078",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa078\nofaa078\nID Cases\nAcademicSubjects/MED00290\nRelapsing Uveitis due to Human T-lymphotropic Virus Type 1 in a Patient Living With HIV Diagnosed by Metagenomic Deep Sequencing\nhttp://orcid.org/0000-0002-0318-4939Phadke Varun K 1 Shantha Jessica G 2 O’Keefe Ghazala 2 1 \nDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA\n2 \nEmory Eye Center, Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA\nCorrespondence: Varun K. Phadke, MD, Division of Infectious Diseases, Health Sciences Research Building, Room W-328, 1760 Haygood Drive NE, Atlanta, GA 30322 (vphadke@emory.edu).\n3 2020 \n07 3 2020 \n07 3 2020 \n7 3 ofaa07828 11 2019 24 2 2020 06 3 2020 19 3 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nHIV infection can result in vision loss from different causes, including HIV retinopathy and uveitis secondary to other infections, such as toxoplasmosis and viral retinitis. It is imperative to identify any infectious causes of uveitis to successfully treat the condition and prevent further vision loss. Metagenomic deep sequencing (MDS) is an emerging technology that presents an unbiased approach to the evaluation of clinical syndromes, including uveitis, that have not been diagnosed by pathogen-specific testing. Herein we present a case of a woman living with HIV with 11 years of relapsing bilateral uveitis refractory to systemic corticosteroid therapy who was diagnosed with human T-lymphotropic virus type 1 (HTLV-1)–associated uveitis by this technology. We also briefly review the literature of MDS as a diagnostic tool and the epidemiology, pathogenesis, and diagnosis of HTLV-1-associated uveitis.\n\nHIVHTLV-1uveitismetagenomic deep sequencingNational Eye Institute of the National Institutes of HealthK23EY030159\n==== Body\nCASE REPORT\nA 54-year-old woman living with HIV presented to our clinic with recurrent uveitis. Fifteen years earlier, she was diagnosed with HIV infection and started on antiretroviral therapy. At the time of presentation, her CD4+ T-cell count was 300 cells/mm3 (18.4% CD4+ T cells) and the HIV viral load was undetectable (<20 copies/mL).\n\nEleven years before, she began experiencing episodic painless red eyes, initially in the left, then in both eyes, with associated floaters. These episodes initially occurred every 2–3 years and then increased in frequency. Her symptoms responded to topical corticosteroids, but 3 years before presentation to our institution, her symptoms became refractory to those agents. She had no history of ocular or sexually transmitted infections. She had no cat exposures. She had never received a blood transfusion or used injection drugs. She was born in the United States and had traveled briefly to Guyana and Costa Rica more than 10 years before the onset of her symptoms. She had no family history of eye or autoimmune disease or chronic infections.\n\nDuring our initial evaluation, her best corrected visual acuity was 20/40 in the right eye and 20/250 in the left eye, with intraocular pressures of 21 mmHg and 31 mmHg, respectively. Anterior segment exam of the right eye was normal but revealed keratic precipitates and 4+ cells with flare in the left eye. Vitritis was present in the left eye, as were areas of vascular sheathing. Fluorescein angiography demonstrated peripheral capillary dropout (Figure 1). A workup for infectious and noninfectious causes of uveitis was unrevealing (Table 1). She was started on oral prednisone and improved. Unfortunately, she could not be weaned off systemic corticosteroids without a flare of her uveitis, and after 2 years she developed worsening vitritis in the left eye.\n\nFigure 1. A, Fundus photo of the right eye with a clear view and area of retinal vasculitis (arrow). B, Fundus photo of the left eye with vitritis (as evidenced by the hazy view of the optic nerve, macula, and vessels) with retinal vasculitis (bracket). C, Normal fluorescein angiography image of the right eye. D, Fluorescein angiography of the left eye with delayed perfusion of the temporal retina and leakage of retinal vessels.\n\nTable 1. Diagnostic Evaluation of Bilateral Uveitis in Case Patient\n\nDiagnostic Test\tResult\tReference Range\t\nInfectious disease testing\t\t\t\nCytomegalovirus PCR of vitreous fluid\tNegative\tNegative\t\nHerpes simplex virus PCR of vitreous fluid\tNegative\tNegative\t\nVaricella-zoster virus PCR of vitreous fluid\tNegative\tNegative\t\n\nToxoplasma gondii serology\tNegative\tNegative\t\n\nToxoplasma gondii PCR of vitreous fluid\tNegative\tNegative\t\nRapid plasma reagin\tNonreactive\tNonreactive\t\nTreponemal antibody (IgG)\tNegative\tNegative\t\n\nBartonella henselae IgM/IgG\tNegative\t<1:16 for IgM, <1:64 for IgG\t\n\nBorrelia burgdorferi EIA\t0.13 LIV\t≤0.99 LIV\t\nInterferon-gamma release assay for Mycobacterium tuberculosisa\tNegative\tNegative\t\nNoninfectious disease testing\t\t\t\nErythrocyte sedimentation rate\t34 mm/h\t0–30 mm/h\t\nC-reactive protein\t0.87 mg/L\t0.30–8.00 mg/L\t\nAnti-double-stranded DNA (dsDNA)\tNegative\tNegative\t\nExtractable nuclear antibody (ENA) screen\tNegative\tNegative\t\nAntineutrophil cytoplasmic antibodies (ANCA)\tNegative\tNegative\t\nRheumatoid factor\t<20 IU/mL\t0–20 IU/mL\t\nAnticyclic citrullinated peptide antibody\t1.1 units/mL\t≤7 units/mL\t\nAngiotensin-converting enzyme\t28 U/L\t9–67 U/L\t\nHuman leukocyte antigen (HLA)–B27 typing\tNegative\tN/A\t\nAbbreviations: EIA, enzyme immunoassay; PCR, polymerase chain reaction.\n\n\naQuantiferon TB GOLD Plus.\n\nGiven the absence of obvious risk factors for any specific infectious etiology of her uveitis, we sent ocular fluid for unbiased metagenomic deep sequencing (MDS) to the Proctor Foundation’s Ralph & Sophie Heintz Laboratory (University of California San Francisco [UCSF], San Francisco, CA, USA). The sample was sequenced under a research protocol that adhered to the tenets of the Declaration of Helsinki. The UCSF Institutional Review Board approved the study, and informed consent forms were obtained from the patient. MDS was performed as previously described [1–5]. Ocular fluid was strongly positive for human T-lymphotropic virus type 1 (HTLV-1). On subsequent questioning, the patient reported no obvious risk factors for HTLV-1 infection, including birth or residence in an endemic region, family history of HTLV-1 infection, or a history of blood transfusions, injection drug use, or sexual partners with known HTLV-1 infection; however, she did note that the partner from whom she contracted HIV was originally from Guyana, where HTLV-1 is endemic. The diagnosis of HTLV-1 infection was confirmed serologically by enzyme-linked immunosorbent assay and Western blot (positive bands for GD21, p19, p24, p26, p28, p32, p36, p53, gp46, and rgp46-I with a negative band for rgp46-II) and qualitative testing for HTLV-1 proviral DNA in plasma.\n\nHer ocular disease is characterized by alternating episodes of vitritis requiring high-dose systemic corticosteroids to control, and she has since initiated azathioprine as a steroid-sparing immunosuppressant. Most recently, a dexamethasone intravitreal implant was used successfully to treat recurrent inflammation in her right eye, allowing her to be successfully weaned off systemic corticosteroids.\n\nDISCUSSION\nMetagenomic deep sequencing is an emerging technology that can assist in the diagnosis of clinical syndromes for which routine pathogen-directed workup is unrevealing [6]. In the workup of ocular inflammation, routine pathogen-specific diagnostics are often limited by the amount of fluid that can be sampled, low organism burden in the intraocular compartment, and limited availability of validated tests (specifically for HTLV-1) [7]. MDS overcomes these challenges by evaluating for viable and nonviable microorganisms in minute specimen volumes in an unbiased fashion. The potential application of MDS in diagnosing infectious uveitis has been previously described [1, 5]. MDS may be especially valuable in the evaluation of immunocompromised patients [8–12].\n\nUveitis in persons living with HIV may be due to a variety of infectious or noninfectious etiologies. Among individuals who achieve virologic suppression and immune reconstitution, the causes of uveitis parallel those seen in HIV-uninfected patients, and approximately one-third of cases remain idiopathic [13]. Here we described the use of MDS to establish HTLV-1 as the cause of uveitis, which was confirmed by serologic and virologic testing. HTLV-1-associated uveitis (HAU) is a distinct clinical manifestation of chronic HTLV-1 infection [14, 15]. It is a well-established cause of uveitis in parts of Japan where it is endemic [16], but in settings where seroprevalence is low, the burden of HTLV-1-related diseases is likely underappreciated.\n\nThe pathogenesis of HAU is thought to be immune-mediated, triggered by intraocular infiltration of HTLV-1-infected T cells, resulting in a local release of inflammatory cytokines [17]. Patients with HAU typically present with painless floaters and/or blurry vision, similar to the case patient. As observed in our patient, vitreous opacities are common fundoscopic findings, along with a mild retinal vasculitis, whereas chorioretinal lesions are usually absent [14]. Detection of proviral DNA in ocular fluid has been noted, but the diagnosis is usually made based on seropositivity for HTLV-1 and exclusion of other etiologies. Treatment options are limited and include either topical or systemic corticosteroids, but HAU has a propensity to relapse. Although some antiretrovirals have activity against HTLV-1, they have no proven role in the management of HAU. We were able to use intravitreal corticosteroids to successfully wean our patient off systemic corticosteroids.\n\nAcknowledgments\nThe authors would like to thank The Francis I. Proctor Foundation, the UCSF Department of Ophthalmology at the University of California, San Francisco, in San Francisco, California, and Dr. Thuy Doan (UCSF Department of Ophthalmology).\n\n\n\nPotential conflicts of interest. Dr. Shantha’s work is supported by the National Eye Institute of the National Institutes of Health (K23EY030159). Dr. O’Keefe has served on the advisory board of Eyepoint Pharmaceuticals. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nDoan T , Wilson MR , Crawford ED , et al. \nIlluminating uveitis: metagenomic deep sequencing identifies common and rare pathogens\n. Genome Med 2016 ; 8 :90 .27562436 \n2. \nSeitzman GD , Hinterwirth A , Zhong L , et al. \nMetagenomic deep sequencing for the diagnosis of corneal and external disease infections\n. Ophthalmology 2019 ; 126 :1724 –6\n.31421897 \n3. \nGonzales JA , Hinterwirth A , Shantha J , et al. \nAssociation of ocular inflammation and rubella virus persistence\n. JAMA Ophthalmol 2019 ; 137 :435 –8\n.30589932 \n4. \nGonzales J , Doan T , Shantha JG , et al. \nMetagenomic deep sequencing of aqueous fluid detects intraocular lymphomas\n. Br J Ophthalmol 2018 ; 102 :6 –8\n.29122821 \n5. \nDoan T , Acharya NR , Pinsky BA , et al. \nMetagenomic DNA sequencing for the diagnosis of intraocular infections\n. Ophthalmology 2017 ; 124 :1247 –8\n.28526549 \n6. \nSimner PJ , Miller S , Carroll KC . \nUnderstanding the promises and hurdles of metagenomic next-generation sequencing as a diagnostic tool for infectious diseases\n. Clin Infect Dis 2018 ; 66 :778 –88\n.29040428 \n7. \nDoan T , Pinsky BA \nCurrent and future molecular diagnostics for ocular infectious diseases\n. Curr Opin Ophthalmol 2016 ; 27 :561 –7\n.27585214 \n8. \nWilson MR , Zimmermann LL , Crawford ED , et al. \nAcute West Nile virus meningoencephalitis diagnosed via metagenomic deep sequencing of cerebrospinal fluid in a renal transplant patient\n. Am J Transplant 2017 ; 17 :803 –8\n.27647685 \n9. \nNaccache SN , Peggs KS , Mattes FM , et al. \nDiagnosis of neuroinvasive astrovirus infection in an immunocompromised adult with encephalitis by unbiased next-generation sequencing\n. Clin Infect Dis 2015 ; 60 :919 –23\n.25572898 \n10. \nChiu CY , Coffey LL , Murkey J , et al \nDiagnosis of fatal human case of St. Louis encephalitis virus infection by metagenomic sequencing, California, 2016\n. Emerg Infect Dis 2017 ; 23 :1964 –8\n.28930022 \n11. \nWilson MR , Suan D , Duggins A , et al. \nA novel cause of chronic viral meningoencephalitis: Cache Valley virus\n. Ann Neurol 2017 ; 82 :105 –14\n.28628941 \n12. \nWilson MR , O’Donovan BD , Gelfand JM , et al. \nChronic meningitis investigated via metagenomic next-generation sequencing\n. JAMA Neurol 2018 ; 75 :947 –55\n.29710329 \n13. \nRose-Nussbaumer J , Goldstein DA , Thorne JE , et al. \nUveitis in human immunodeficiency virus-infected persons with CD4+ T-lymphocyte count over 200 cells/mL\n. Clin Exp Ophthalmol 2014 ; 42 :118 –25\n.23777456 \n14. \nMochizuki M , Watanabe T , Yamaguchi K , et al. \nUveitis associated with human T-cell lymphotropic virus type I\n. Am J Ophthalmol 1992 ; 114 :123 –9\n.1642286 \n15. \nYoshimura K , Mochizuki M , Araki S , et al. \nClinical and immunologic features of human T-cell lymphotropic virus type I uveitis\n. Am J Ophthalmol 1993 ; 116 :156 –63\n.8352299 \n16. \nMiyanaga M , Shimizu K , Kawaguchi T , et al. \nA clinical survey of uveitis in HTLV-1 endemic region\n. Ocul Immunol Inflamm 2009 ; 17 :335 –41\n.19831567 \n17. \nOno A , Mochizuki M , Yamaguchi K , et al. \nImmunologic and virologic characterization of the primary infiltrating cells in the aqueous humor of human T-cell leukemia virus type-1 uveitis. Accumulation of the human T-cell leukemia virus type-1-infected cells and constitutive expression of viral and interleukin-6 messenger ribonucleic acids\n. Invest Ophthalmol Vis Sci 1997 ; 38 :676 –89\n.9071222\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(3)",
"journal": "Open forum infectious diseases",
"keywords": "HIV; HTLV-1; metagenomic deep sequencing; uveitis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa078",
"pmc": null,
"pmid": "32206676",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "27647685;29122821;28930022;1642286;31421897;25572898;23777456;27562436;29040428;28628941;19831567;30589932;8352299;9071222;29710329;27585214;28526549",
"title": "Relapsing Uveitis due to Human T-lymphotropic Virus Type 1 in a Patient Living With HIV Diagnosed by Metagenomic Deep Sequencing.",
"title_normalized": "relapsing uveitis due to human t lymphotropic virus type 1 in a patient living with hiv diagnosed by metagenomic deep sequencing"
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"abstract": "Background: Nosocomial meningitis with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Acinetobacter baumannii is a life-threatening complication in neurosurgery. Treatment of these infections is challenging because of poor penetration of the available antibiotics into the cerebrospinal fluid (CSF). Intrathecal (ITH) or intraventricular (IVT) administration of antibiotics is increasingly used as the last treatment option against MDR/XDR Gram-negative bacteria meningitis not responding to intravenous (IV) regimens. However, pertinent data in pediatric patients is scarce. Case Presentation: A 14-year-old male patient developed meningitis from an MDR strain of A. baumannii following endoscopic endonasal resection of craniopharyngioma. Despite a combination therapy involving IV tigecycline, we observed clinical and bacteriologic failure. The patient was then successfully treated with an ITH and IV polymyxin B-based combination. Quantification of tigecycline and polymyxin B in CSF was performed with two-dimensional high-performance liquid chromatography (2D-HPLC) and HDLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively. Adverse drug reactions (neurotoxicity and skin hyperpigmentation), probably induced by polymyxin B, were acceptable and reversible. Conclusions: The case illustrates ITH and IV Polymyxin B-based combination is an optimal therapeutic option against MDR A. baumannii meningitis in this pediatric patient. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects.",
"affiliations": "Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.;Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.;Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China.;Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.;Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.;Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.;Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China.;Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China.;Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.",
"authors": "Xing|Haiyan|H|;Cheng|Caiyi|C|;Zhang|Yihua|Y|;Cai|Yongqing|Y|;Wang|Xianfeng|X|;Deng|Dongmei|D|;Xu|Lunshan|L|;Xu|Minhui|M|;Chen|Jianhong|J|",
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"doi": "10.3389/fped.2021.564991",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.564991\nPediatrics\nCase Report\nSuccessful Treatment With Intrathecal and Intravenous Polymyxin B-Based Combination Against MDR Acinetobacter baumannii Meningitis in Pediatric Patient: A Case Report\nXing Haiyan 1\n\nCheng Caiyi 1\nZhang Yihua 2\nCai Yongqing 1\n\nWang Xianfeng 1\nDeng Dongmei 1\nXu Lunshan 2\nXu Minhui 2\nChen Jianhong 1 *\n1Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China\n2Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China\nEdited by: Philippe Ovetchkine, University of Montreal, Canada\n\nReviewed by: Ilias Karaiskos, Hygeia Hospital, Greece; Rinawati Rohsiswatmo, RSUPN Dr. Cipto Mangunkusumo, Indonesia\n\n*Correspondence: Jianhong Chen chenjh-110@263.net\nThis article was submitted to Pediatric Infectious Diseases, a section of the journal Frontiers in Pediatrics\n\n27 7 2021\n2021\n9 56499125 7 2020\n29 6 2021\nCopyright © 2021 Xing, Cheng, Zhang, Cai, Wang, Deng, Xu, Xu and Chen.\n2021\nXing, Cheng, Zhang, Cai, Wang, Deng, Xu, Xu and Chen\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Nosocomial meningitis with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Acinetobacter baumannii is a life-threatening complication in neurosurgery. Treatment of these infections is challenging because of poor penetration of the available antibiotics into the cerebrospinal fluid (CSF). Intrathecal (ITH) or intraventricular (IVT) administration of antibiotics is increasingly used as the last treatment option against MDR/XDR Gram-negative bacteria meningitis not responding to intravenous (IV) regimens. However, pertinent data in pediatric patients is scarce.\n\nCase Presentation: A 14-year-old male patient developed meningitis from an MDR strain of A. baumannii following endoscopic endonasal resection of craniopharyngioma. Despite a combination therapy involving IV tigecycline, we observed clinical and bacteriologic failure. The patient was then successfully treated with an ITH and IV polymyxin B-based combination. Quantification of tigecycline and polymyxin B in CSF was performed with two-dimensional high-performance liquid chromatography (2D-HPLC) and HDLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively. Adverse drug reactions (neurotoxicity and skin hyperpigmentation), probably induced by polymyxin B, were acceptable and reversible.\n\nConclusions: The case illustrates ITH and IV Polymyxin B-based combination is an optimal therapeutic option against MDR A. baumannii meningitis in this pediatric patient. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects.\n\nmeningitis\nmultidrug resistance\nAcinetobacter baumannii\nPolymyxin B\ntigecycline\nintrathecal administration\n==== Body\nIntroduction\n\nPostoperative meningitis due to multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria is a life-threatening complication in neurosurgery. Acinetobacter baumannii has emerged as one of the major organisms isolated from the cerebrospinal fluid (CSF) cultures (1). Mortality of nosocomial meningitis caused by A. baumannii was reported as high as 72.7% (2). MDR/XDR A. baumannii strains possess an impressive armamentarium of resistance mechanisms, resulting in resistance to all, or almost all, commercially available antibiotics (3). This fact has led to the resurrection of polymyxins (polymyxin B and colistin) as salvage therapy (4). Considering the potentially suboptimal pharmacokinetic (PK)/pharmacodynamic (PD) and the increasing prevalence of multidrug resistance, combination therapy is recommended for polymyxins even though there is a lack of solid clinical evidence (5–7). Furthermore, due to the poor central nervous system (CNS) penetration of antibiotics (8), intrathecal (ITH) or intraventricular (IVT) routes have been considered as the last resort for the treatment of ventriculitis/meningitis caused by MDR/XDR Gram-negative bacteria not responding to intravenous (IV) regimens (9). However, the clinical efficacy and tolerability profile of ITH/IVT polymyxins therapy, especially in pediatric patients, remains obscure.\n\nThis report presents a case of a 14-year-old male patient who developed meningitis from an MDR strain of A. baumannii following endoscopic endonasal resection of craniopharyngioma. The patient has been successfully treated with ITH and IV Polymyxin B-based combination after a failed combined therapy involving IV tigecycline. In addition, concentrations of tigecycline and polymyxin B in CSF were retrospectively determined by two-dimensional high-performance liquid chromatography (2D-HPLC) and HPLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively (Supplementary Material).\n\nCase Presentation\n\nThe patient was admitted to our hospital on January 24, 2019, with blurred vision in both eyes for 1 week. Neurological examinations and laboratory evaluations revealed no abnormality. The patient was diagnosed with craniopharyngioma by neuroradiologic examinations (Figure 1A). Complete tumor removal was achieved via the endoscopic endonasal transsphenoidal approach on day 4. Perioperative IV antibiotic prophylaxis with ceftriaxone (2 g) was administered. The intraoperative course of the patient was uneventful. However, the postoperative MRI examination showed an incomplete skull base reconstruction on the following day (Figure 1B).\n\nFigure 1 Brain magnetic resonance imaging (MRI) and computed tomography (CT) image after patient admission. (A) Sagittal enhanced MRI of pituitary showed enlarged sella turcica with a mass of about 1.2 cm × 1.6 cm × 1.4 cm in it, pituitary stalk extension to the right side and optic chiasm compression pituitary (January 25, 2019). (B) Sagittal enhanced MRI of pituitary showed that the craniopharyngioma was completely removed, and the skull base was incompletely covered by mucosal flap (January 29, 2019). (C) On day 47 of admission (March 12, 2019), nonenhanced skull CT scan revealed that the cerebrospinal fluid leakage was successfully repaired owing to the skull base reconstruction with mucosal flap. (D) Whole-spine MRI revealed no obvious adhesion in the spinal canal after 4 days of polymyxin B treatment (March 19, 2019). Follow-up pituitary MRI revealed (E) no recurrence of tumor, well healed mucosal flap in skull base, and (F) no obvious hydrocephalus (January 16, 2020).\n\nThe immediate postoperative recovery of the patient was complicated by an episode of CSF rhinorrhoea. Ten days after surgery (day 14), the patient presented with remittent fever (peak at 39.6°C, Figure 2A) and irritative cough. CSF rhinorrhoea was highly suspected. The patient thus underwent two transnasal endoscopic repairs (on day 14 and 31), in which fibrin glue, dural substitutes, autologous fat tissue graft, and temporary lumbar drainage were used. The laboratory tests for CSF showed a slightly high level of white blood cell (WBC) and total cell counts (Table 1). In contrast, WBC count and neutrophilic granulocyte percentage (NEUT%) in his peripheral blood were significantly higher (Figures 2B,C). Consequently, regardless of negative CSF culture, nosocomial meningitis was considered. IV linezolid (600 mg twice daily) and IV ceftriaxone (2 g twice daily) were initiated empirically (day 15). During follow-up, the patient's fever gradually subsided. However, a sudden onset of fever (38.9°C) occurred on February 20th (day 27), with vomiting and neck rigidity. CSF analysis revealed a WBC count of 0.098 × 109/L, a total protein of 2.41 g/L, and glucose of 2.32 mmol/L (Table 1). The simultaneous blood glucose level was 6.34 mmol/L. CSF culture was positive for MDR A. baumannii (Table 2), which was sensitive to tigecycline, amikacin, and minocycline, and intermediate to cefoperazone/sulbactam based on the breakpoints from the Clinical and Laboratory Standards Institute (CLSI) (10). For tigecycline, the U.S. Food Drug Administration (FDA)-approved breakpoints were applied (11). Empiric treatment was quickly replaced by the therapeutic regimen of IV tigecycline (100 mg/day in two doses after a loading dose of 100 mg) combined with meropenem (2 g as a 3-h prolonged infusion every 8 h) and amikacin (7.5 mg/kg twice daily). CSF samples were collected from lumbar drainage before the initiation of the next dose of tigecycline and stored at −80°C for uniform testing. Concentrations of tigecycline were determined by 2D-HPLC with ultraviolet detection, and the signal was recorded at 340 nm (Figure 3A). Though the CSF cultures remained positive for A. baumannii, this therapy led to subsequent clinical and laboratory improvement. However, on day 46 after admission, the patient suffered from intolerable diarrhea without noticeable relief after symptomatic treatment. Considering the commonly reported side effects (12, 13), IV therapy with both tigecycline and amikacin was stopped (19 days from the start of IV tigecycline), while the IV meropenem was continued. Meanwhile, IV cefoperazone/sulbactam (3 g every 6 h) and minocycline (orally 200 mg/day in two doses after a loading dose of 200 mg) were added. However, during treatment, gradually decreased CSF drainage was observed. Therefore, the lumbar drainage was removed, while a new sterile lumbar catheter was positioned on day 4 of this therapy. Simultaneously, CSF obtained from the new lumbar drainage was cloudy with a marked increase in protein (3.65 g/L) and WBC count (4.054 × 109/L; Table 1), and the microbiological testing was consistently positive. Fortunately, a nonenhanced skull CT scan revealed successful repair of CSF leak (Figure 1C).\n\nFigure 2 Clinical course and skin hyperpigmentation of the patient. (A) Body temperature over the course of treatment. (B) White blood cell (WBC) count in the peripheral blood. (C) Neutrophil percentage (NEUT%) in the peripheral blood. (D) Serum creatinine (SCr) levels. (E) Skin hyperpigmentation and dark red papule appeared in the upper part of trunk of patient on the fourth day of polymyxin B treatment (March 18, 2019). (F) Skin hyperpigmentation gradually disappeared (January 16, 2020).\n\nTable 1 Laboratory tests for cerebrospinal fuid over the course of treatment.\n\nDate\tCell count (×109/L)\tWBC (×109/L)\tGlucose (mmoL/L)\tTotal protein (g/L)\tChlorine (mmoL/L)\t\n2019.02.07 (D14)\t0.040\t0.019\t3.30\t0.27\t119.0\t\n2019.02.20 (D27)\t2.075\t0.098\t2.32\t2.41\t112.4\t\n2019.02.23 (D30)\t0.405\t0.242\t2.86\t0.72\t122.9\t\n2019.02.26 (D33)\t0.643\t0.187\t1.95\t0.79\t120.7\t\n2019.03.01 (D36)\t0.018\t0.015\t1.88\t0.65\t122.0\t\n2019.03.03 (D38)\t0.045\t0.040\t2.95\t0.28\t125.0\t\n2019.03.06 (D41)\t0.020\t0.017\t3.13\t018\t122.3\t\n2019.03.09 (D44)\t0.009\t0.004\t2.90\t0.16\t121.9\t\n2019.03.11 (D46)\t0.008\t0.002\t4.40\t0.14\t120.9\t\n2019.03.14 (D49)\t4.142\t4.054\t0.33\t3.65\t118.5\t\n2019.03.15 (D50)\t3.649\t3.045\t0.36\t2.23\t114.6\t\n2019.03.16 (D51)\t0.382\t0.371\t2.46\t1.22\t115.7\t\n2019.03.17 (D52)\t0.567\t0.541\t1.38\t0.89\t112.9\t\n2019.03.18 (D53)\t0.150\t0.126\t2.32\t0.94\t110.6\t\n2019.03.19 (D54)\t1.305\t1.255\t1.10\t1.08\t119.2\t\n2019.03.20 (D55)\t0.008\t0.003\t3.26\t0.76\t97.1\t\n2019.03.22 (D57)\t0.412\t0.398\t2.20\t0.56\t115.1\t\n2019.03.26 (D61)\t0.010\t0.007\t2.68\t0.61\t121.1\t\n2019.04.03 (D69)\t0.070\t0.054\t2.90\t0.85\t123.2\t\n2019.04.11 (D77)\t0.050\t0.045\t3.02\t0.74\t121.8\t\nNormal reference ranges\t0-0.008\t0-0.008\t2.5-4.5\t0.15-0.45\t120-132\t\n\nTable 2 Antibiotics susceptibility tests for Acinetobacter baumannii in CSF.\n\nAntibiotics\tSusceptibility\tK-B (mm)\tMIC (μg/mL)\t\nMeropenem\tResistant\t8\tN/A\t\nMinocycline\tSusceptible\t16\tN/A\t\nCefoperazone/sulbactam\tIntermediate\t18\tN/A\t\nPiperacillin\tResistant\t6\tN/A\t\nAmikacin\tSusceptible\t22\tN/A\t\nTigecycline\tSusceptible\tN/A\t0.5\t\nAmpicillin\tResistant\tN/A\t≥32\t\nCefazolin\tResistant\tN/A\t≥64\t\nCeftriaxone\tResistant\tN/A\t≥64\t\nCefepime\tResistant\tN/A\t≥64\t\nCeftazidime\tResistant\tN/A\t≥64\t\nImipenem\tResistant\tN/A\t≥16\t\nPiperacillin/tazobactam\tResistant\tN/A\t≥128\t\nGentamicin\tIntermediate\tN/A\t8\t\nTobramycin\tSusceptible\tN/A\t≤ 1\t\nCiprofloxacin\tResistant\tN/A\t≥4\t\nLevofloxacin\tResistant\tN/A\t≥8\t\nTrimethoprim-sulfamethoxazole\tResistant\tN/A\t8\t\n\nFigure 3 Levels of tigecycline and polymyxin B in cerebrospinal fuid (CSF) of the patient. (A) CSF tigecycline concentrations were measured with Two-Dimensional High-Performance Liquid Chromatography (2D-HPLC) method. (B) CSF polymyxin B levels were determined using high performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Red circle represents the day of ITH polymyxin B treatment.\n\nThe antimicrobial therapy was changed to ITH polymyxin B (50,000 U once daily for 4 days, then 50,000 U once every other day), IV polymyxin B (450,000 U twice daily), and cefoperazone/sulbactam (3 g every 6 h) on March 15, 2019. Polymyxin B was dissolved in saline up to a total volume of 1 mL and slowly injected into the CSF (14). After each injection, the lumbar drainage was temporarily closed for 60 min to prevent untimely washout of the drug (1). CSF samples for laboratory examinations and concentration determinations were collected from the lumbar catheter before the next dose of polymyxin B. Direct quantification of polymyxin B in CSF was performed with HPLC-MS/MS equipped with electrospray (ESI) ionization interface (Figure 3B). CSF sterilization (a negative CSF culture) was achieved the next day, following remarkable improvement in CSF findings. Unfortunately, hyperpigmentation and dark red papule appeared in the upper part of the patient's trunk, especially on the face and neck on the fourth day of polymyxin B treatment, and gradually aggravated (Figure 2E). Over the next few days, the patient experienced mild memory loss, hypotonia, lumbosacral pain, and sore legs. However, whole-spine MRI revealed no apparent abnormality (Figure 1D), and renal function tests showed normal serum creatinine levels (Figure 2D). Because of the known neurotoxicity and skin hyperpigmentation induced by polymyxin B (15, 16), ITH polymyxin B was replaced with minocycline oral administration on March 24, 2019 (9 days from the onset of ITH polymyxin B), while IV polymyxin B and cefoperazone/sulbactam were continued. Ten days later, IV polymyxin B was discontinued. The signs of meningitis disappeared in a few days. Meanwhile, laboratory tests of CSF and radiological examination returned to normal. Thus, the patient was discharged on April 12, 2019.\n\nAt the 12-months follow-up, the patient was in good clinical condition without signs of intracranial infection. Neurologically, vision in both his eyes was normal. Skin hyperpigmentation (Figure 2F) and strength in his limbs were gradually recovered, and the patient could walk normally. Radiological signs were also normal (Figures 1E,F).\n\nDiscussion\n\nThis paper reports on a 14-year-old male patient who developed MDR A. baumannii meningitis following neurosurgical surgery and subsequent CSF rhinorrhoea. The risk factors such as CSF leakage, lumbar drainage placement, and repeated transnasal endoscopic repair may be significantly associated with subsequent A. baumannii meningitis of this patient (17). Nosocomial meningitis due to MDR A. baumannii seriously threatens patient survival. However, its treatment is challenging because of limited available therapeutic options, especially in pediatric patients (3).\n\nThe frequent emergence of carbapenem resistance of A. baumannii has led to the revival in polymyxins and tigecycline as the last resort antimicrobials (18). Since polymyxins were not always available and the susceptibility test for polymyxin B and colistin were not routinely performed in our hospital, tigecycline was initially administered intravenously with meropenem and amikacin according to the in vitro susceptibility testing. Although tigecycline is not approved for use in children by FDA, the results of a few available data suggest that it may be a valauble consideration for life-threatening infections in pediatric patients, alone or in combination with other antibiotics, when other therapies are not suitable (19, 20). Moreover, there are some reported cases of postoperative meningitis that were successfully treated with tigecycline (the same dosage regimen as in the present case) as a last line therapy (21, 22). Hence, the combination of IV tigecycline with amikacin and prolonged infusion of meropenem may be a potential alternative for salvage treatment in this case.\n\nUnfortunately, the tigecycline-based combination therapy failed to achieve microbiological eradication despite promising clinical and laboratory improvement. A previous study of tigecycline concluded that the administration of a dose of 1–2 mg/kg q12h in children aged 12 years or older, to a maximum dose of 50 mg, provided PK values similar to those reported to be effective in adults (23). However, our retrospective CSF determination showed that the steady-state concentration of tigecycline was 108.08–149.54 ng/mL, a value far below the FDA breakpoint (24). It suggests that personalized dosing of IV administration of tigecycline is necessary for a patient with MDR A. baumannii meningitis to avoid suboptimal drug exposure in the CSF. Thus, further pharmacological studies are required to describe the PK/PD profile of tigecycline in children of different ages and infection types to optimize the dosage regimen. Additionally, as described in recent studies, ITH/IVT administration of tigecycline may be another option for treating bacterial meningitis caused by MDR A. baumannii (14, 25). Regarding the safety profile, previous studies showed that the adverse events associated with tigecycline in children include nausea, vomiting, diarrhea, neutrophil engraftment delay, and acute pancreatitis (23). The patient in this case suffered from intolerable diarrhea leading to the discontinuation of tigecycline combination therapy. The result might also be attributed to other factors, such as a worse clinical condition and concomitant drugs (26). Therefore, additional data from controlled clinical studies are required to assess the safety of tigecycline, and particular caution should be given to off-label use of tigecycline, especially in pediatric patients.\n\nPolymyxins have been revived as a last-line defense against difficult-to-treat MDR A. baumannii in this pediatric patient following the failure of IV tigecycline. Although limited polymyxin B information is available, especially in pediatric patients, recently available data indicates that polymyxin B has significant PK/PD advantages in contrast to colistin, and its dosage regimens should not be adjusted according to the patient's renal function (27). As IV polymyxins demonstrate poor CNS penetration, ITH and IV routes have been employed to achieve high polymyxin concentrations in the CNS (28, 29). It is reported that the combination of IV and ITH/IVT polymyxins treatment has been used as an effective and safe therapeutic option against CNS infections caused by MDR Gram-negative bacteria, including in critically ill patients and children (30). Furthermore, polymyxin B monotherapy is not an ideal clinical option since dose escalation to achieve sufficiently high concentrations carries risks of rapid-onset nephrotoxicity (31). Thus ITH and IV polymyxin B-based combination was considered salvage therapy for this pediatric patient with lumbar drainage.\n\nTo the best of our knowledge the daily dose of polymyxins ranges between 5,000 IU (in infants) and 120,000 IU (divided into two doses) in children (32). The duration of therapy is quite variable (2–4 weeks), and shorter treatments (<1 week) may correlate with higher mortality (28). In this pediatric patient, the combination including a low dosage of ITH polymyxin B was administered. CSF sterilization was rapidly achieved without significant nephrotoxicity. However, the mild neurotoxicity and skin hyperpigmentation caused by polymyxin B was highly suspected, although it was difficult to isolate adverse reactions and clinical outcomes solely from this drug. As reported previously, the onset of polymyxin B-induced neurotoxicity and hyperpigmentation usually occurs shortly after IV infusion or within the first few days of polymyxin therapy and is generally reversible with drug discontinuation (33, 34). The major risk factors associated with neurotoxicity are the extended exposure (duration and concentration) to polymyxins; the presence of medical conditions such as myasthenia gravis, renal impairment, and hypoxia; concomitant use of other medications (e.g., sedatives, anesthetics, narcotics, and muscle relaxants); and gender (33). These findings are in accordance with the suspected adverse reactions observed in the present case. Moreover, recent case reports of polymyxin B-induced skin hyperpigmentation is associated with its position 6 D-Phe, because no such reports have been published on colistin to date (35). It has been reported that penetration of polymyxins into CSF is a crucial indicator for optimizing in vivo efficacy and minimizing toxicity (28). However, the PK information of polymyxins in CSF after ITH/IVT delivery remains largely unknown. Our retrospective CSF determination showed a wide range of steady-state concentrations of polymyxin B (1.33–29.41 mg/L), which may be closely associated with rapid bacterial eradication and highly suspected adverse reactions.\n\nThe present case enriched the PK information of polymyxin B in CSF, which may improve the clinical practice of polymyxins, especially in pediatric patients. However, it has limitations; for example, only one case has been reported. Additionally, the therapeutic drug monitoring (TDM) of tigecycline and polymyxin B in CSF were retrospectively performed after the end of treatment without TDM-based dosing optimization. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects.\n\nConclusions\n\nThis case highlights the issues involved in treating life-threatening A. baumannii meningitis of pediatric patients. IV tigecycline should not be recommended for CNS infections of MDR Gram-negative pathogens because of the poor penetration into CSF. ITH administration of polymyxin B is a convenient route, especially in pediatric patients with lumbar drainage. Additionally, combined treatment with IV and ITH polymyxin B is vital for CSF sterilization. However, the efficacy and safety of tigecycline and polymyxins for pediatric CNS infections need to be clarified. Given the narrow therapeutic windows of polymyxin B, it is necessary to identify a practical PK/PD profile for optimizing dosage regimens of ITH/IVT polymyxin therapy.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the ethics committee of Daping Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nHX: conceptualization. CC: methodology. YZ: case presentation. YC: writing-original draft. XW: data analysis. DD: data collection. LX and MX: validation, writing-review, and editing. JC: supervision and project administration. All authors have read the last version of this manuscript and agree this submission.\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors would like to thank Dr. Ji Ming Wang of the Laboratory of Molecular Immunoregulation in the Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick (Frederick, MD, USA) for reviewing and discussing of this manuscript. The authors would also like to thank all the members of the laboratory for the discussion and preparation of this manuscript.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2021.564991/full#supplementary-material\n\nClick here for additional data file.\n\nFunding. This work was supported in part by grants from the Chongqing Federation of Social Sciences Circles (grant number 2018PY79) and the Training Program of Clinical Medical Researcher of Army Medical University (grant number 2018XLC3072). This project was also supported by the grants from the Innovation Ability Training Program of Army Specialized Medical Center (Grant No. 2019CXLCC013). The funders had no role in the design and conduct of this case, as well as no role in the preparation and approval of the manuscript.\n==== Refs\nReferences\n\n1. Tsuji BT Pogue JM Zavascki AP Paul M Daikos GL Forrest A . International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. (2019) 39 :10–39. 10.1002/phar.2209 30710469\n2. Tuon FF Penteado-Filho SR Amarante D Andrade MA Borba LA . Mortality rate in patients with nosocomial Acinetobacter meningitis from a Brazilian hospital. Braz J Infect Dis. (2010) 14 :437–40. 10.1016/S1413-8670(10)70090-8 21221470\n3. Xiao JY Zhang CM Ye S . Acinetobacter baumannii meningitis in children: a case series and literature review. Infection. (2019) 47 :643–49. 10.1007/s15010-018-1234-1 30328074\n4. Tsolaki V Karvouniaris M Manoulakas E Kotlia P Karadontas V Fotakopoulos G . Intraventricular CNS treatment with Colistin-Tigecycline combination: a case series. J Crit Care. (2018) 47 :338–41. 10.1016/j.jcrc.2018.07.025 30097260\n5. Sharma R Patel S Abboud C Diep J Ly NS Pogue JM . Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes. Int J Antimicrob Agents. (2017) 49 :224–32. 10.1016/j.ijantimicag.2016.10.025 28040408\n6. Guo W Guo SC Li M Li LH Qu Y . Successful treatment of extensively drug-resistant Acinetobacter baumannii ventriculitis with polymyxin B and tigecycline - a case report. Antimicrob Resist Infect Control. (2018) 7 :22. 10.1186/s13756-018-0313-5 29456841\n7. Mizrahi CJ Benenson S Moscovici S Candanedo C Benifla M Spektor S . Combination treatment with intravenous tigecycline and intraventricular and intravenous colistin in postoperative ventriculitis caused by multidrug-resistant Acinetobacter baumannii. Cureus. (2019) 11 :e3888. 10.7759/cureus.3888 30911445\n8. Antachopoulos C Karvanen M Iosifidis E Jansson B Plachouras D Cars O . Serum and cerebrospinal fluid levels of colistin in pediatric patients. Antimicrob Agents Chemother. (2010) 54 :3985–87. 10.1128/AAC.01799-09 20585114\n9. Karaiskos I Galani L Baziaka F Giamarellou H . Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: a literature review. Int J Antimicrob Agents. (2018) 41 :499–508. 10.1016/j.ijantimicag.2013.02.006 23507414\n10. Clinical and Laboratory Standards Institute. CLSI. 2019. Performance Standards for Antimicrobial Susceptibility Testing, 29th Edn. CLSI Supplement M100. Clinical and Laboratory Standards Institute (CLSI) (2019).\n11. US Food and Drug Administration. Antibacterial Susceptibility Test Interpretive Criteria. Available online at: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm575163.htm (accessed April 6, 2019).\n12. Jenkins A Thomson AH Brown NM Semple Y Sluman C Macgowan A . Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review. J Antimicrob Chemother. (2016) 71 :2754–9. 10.1093/jac/dkw250 27494904\n13. Kwon YS Levin A Kasperbauer SH Huitt GA Daley CL . Efficacy and safety of tigecycline for Mycobacterium abscessus disease. Respir Med. (2019) 158 :89–91. 10.1016/j.rmed.2019.10.006 31622813\n14. Lauretti L D'alessandris QG Fantoni M D'inzeo T Fernandez E Pallini R . First reported case of intraventricular tigecycline for meningitis from extremely drug-resistant Acinetobacter baumannii. J Neurosurg. (2017) 127 :370–3. 10.3171/2016.6.JNS16352 27540902\n15. Zheng G Cao L Che Z Mao E Chen E He J . Polymyxin B-induced skin hyperpigmentation: a rare case report and literature review. BMC Pharmacol Toxicol. (2018) 19 :41. 10.1186/s40360-018-0226-1 29973293\n16. Mattos KPH Gouvea IR Quintanilha JCF Cursino MA Vasconcelos P Moriel P . Polymyxin B clinical outcomes: a prospective study of patients undergoing intravenous treatment. J Clin Pharm Ther. (2019) 44 :415–9. 10.1111/jcpt.12801 30666679\n17. Tunkel AR Hasbun R Bhimraj A Byers K Kaplan SL Scheld WM . 2017 infectious diseases society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis. (2017) 64 :e34–e65. 10.1093/cid/cix152 28203777\n18. Chiotos K Ross RK Han JH Miller M Gerber JS . Use of carbapenems, polymyxins, and tigecycline in united states children's hospitals, 2010–2014. Open Forum Infect Dis. (2017) 4 :ofx039. 10.1093/ofid/ofx039 28470018\n19. Kanik-Yuksek S Tezer H Ozkaya-Parlakay A Gulhan B Sayed-Oskovi H Kara A . Multidrug-resistant Acinetobacter baumannii bacteremia treated with tigecycline in two pediatric burn patients. Pediatr Infect Dis J. (2015) 34 :677. 10.1097/INF.0000000000000699 25970113\n20. Emiroglu M Alkan G Turk Dagi H . Tigecycline therapy in an infant for ventriculoperitoneal shunt meningitis. Pediatrics. (2017) 139 :e20160963. 10.1542/peds.2016-0963 27974589\n21. Tutuncu EE Kuscu F Gurbuz Y Ozturk B Haykir A Sencan I . Tigecycline use in two cases with multidrug-resistant Acinetobacter baumannii meningitis. Int J Infect Dis. (2010) 14 (Suppl 3 ):e224–6. 10.1016/j.ijid.2009.07.022 19962335\n22. Kooli I Brahim HB Kilani M Gannouni C Aouam A Toumi A . Successful treatment of postoperative multidrug-resistant Acinetobacter baumannii meningitis by tigecycline. J Glob Antimicrob Resist. (2016) 5 :62–3. 10.1016/j.jgar.2015.12.003 27436468\n23. Purdy J Jouve S Yan JL Balter I Dartois N Cooper CA . Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study. Clin Ther. (2012) 34 :496–507.e491. 10.1016/j.clinthera.2011.12.010 22249106\n24. Karageorgopoulos DE Kelesidis T Kelesidis I Falagas ME . Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. J Antimicrob Chemother. (2008) 62 :45–55. 10.1093/jac/dkn165 18436554\n25. Wu Y Chen K Zhao J Wang Q Zhou J . Intraventricular administration of tigecycline for the treatment of multidrug-resistant bacterial meningitis after craniotomy: a case report. J Chemother. (2018) 30 :49–52. 10.1080/1120009X.2017.1338846 28614982\n26. Ye S Zhang C Lin S . Preliminary experience with tigecycline treatment for severe infection in children. Eur J Pediatr. (2018) 177 :1489–96. 10.1007/s00431-018-3208-9 30008076\n27. Nation RL Forrest A . Clinical pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins: implications for therapeutic use. Adv Exp Med Biol. (2019) 1145 :219–49. 10.1007/978-3-030-16373-0_15 31364081\n28. Velkov T Dai C Ciccotosto GD Cappai R Hoyer D Li J . Polymyxins for CNS infections: pharmacology and neurotoxicity. Pharmacol Ther. (2018) 181 :85–90. 10.1016/j.pharmthera.2017.07.012 28750947\n29. Khan SA Waqas M Siddiqui UT Shamim MS Nathani KR Jooma R . Intrathecal and intraventricular antibiotics for postoperative Gram-negative meningitis and ventriculitis. Surg Neurol Int. (2017) 8 :226. 10.4103/sni.sni_81_17 29026662\n30. Ozdemir H Tapisiz A Ciftci E Ince E Mokhtari H Guriz H . Successful treatment of three children with post-neurosurgical multidrug-resistant Acinetobacter baumannii meningitis. Infection. (2010) 38 :241–4. 10.1007/s15010-010-0018-z 20358244\n31. Pogue JM Lee J Marchaim D Yee V Zhao JJ Chopra T . Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. (2011) 53 :879–84. 10.1093/cid/cir611 21900484\n32. Falagas ME Bliziotis IA Tam VH . Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: a systematic review of the available evidence. Int J Antimicrob Agents. (2007) 29 :9–25. 10.1016/j.ijantimicag.2006.08.024 17126534\n33. Falagas ME Kasiakou SK . Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. (2006) 10 :R27. 10.1186/cc3995 16507149\n34. Lahiry S Choudhury S Mukherjee A Bhunya PK Bala M . Polymyxin B-induced diffuse cutaneous hyperpigmentation. J Clin Diagn Res. (2017) 11 :FD01–F2. 10.7860/JCDR/2017/24278.9213 28384882\n35. Nang SC Azad MAK Velkov T Zhou QT Li J . Rescuing the last-line polymyxins: achievements and challenges. Pharmacol Rev. (2021) 73 :679–728. 10.1124/pharmrev.120.000020 33627412\n\n",
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"journal": "Frontiers in pediatrics",
"keywords": "Acinetobacter baumannii; Polymyxin B; intrathecal administration; meningitis; multidrug resistance; tigecycline",
"medline_ta": "Front Pediatr",
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"references": "28040408;20358244;22249106;21900484;16507149;17126534;28470018;27436468;28750947;27540902;31622813;21221470;33627412;25970113;18436554;19962335;27494904;27974589;30097260;30710469;30328074;28203777;30008076;28614982;30911445;31364081;29456841;28384882;30666679;23507414;29973293;29026662;20585114",
"title": "Successful Treatment With Intrathecal and Intravenous Polymyxin B-Based Combination Against MDR Acinetobacter baumannii Meningitis in Pediatric Patient: A Case Report.",
"title_normalized": "successful treatment with intrathecal and intravenous polymyxin b based combination against mdr acinetobacter baumannii meningitis in pediatric patient a case report"
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"abstract": "BACKGROUND\nFluoroquinolones are known to cause acute renal failure due to interstitial nephritis.\n\n\nMETHODS\nHere we present an elderly woman who developed oliguric acute kidney injury (AKI) after receiving oral and intravenous ciprofloxacin in a 48-hour period. Recently, several case reports have been published in the literature regarding the presence of crystals in the urine sediment of patients treated with ciprofloxacin for different types of systemic infections. Ciprofloxacin crystals precipitate in alkaline urine and provoke renal failure through intra-tubular precipitation.\n\n\nCONCLUSIONS\nConservative measures including intravenous hydration and avoidance of alkalinization of the urine can reverse this condition if applied in time.",
"affiliations": "Division of nephrology and Hypertension, Allegheny General Hospital, Temple University School of Medicine, Pittsburgh, PA, USA.;Division of nephrology and Hypertension, Allegheny General Hospital, Temple University School of Medicine, Pittsburgh, PA, USA.;Department of Medicine, Allegheny General Hospital, Pittsburgh, PA, USA.;Division of Nephrology and Hypertension, University of Miami, Miami, FL, USA.",
"authors": "Khan|Mahboob|M|;Ortega|Luis M|LM|;Bagwan|Nasreen|N|;Nayer|Ali|A|",
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"fulltext": "\n==== Front\nJ NephropatholJ NephropatholJ NephropatholJ NephropatholJNPJournal of Nephropathology2251-83632251-8819Society of Diabetic Nephropathy Prevention 10.12860/jnp.2015.06Case ReportCrystal-induced acute kidney injury due to ciprofloxacin Khan Mahboob \n1\nOrtega Luis M \n1\n*Bagwan Nasreen \n2\nNayer Ali \n3\n1Division of nephrology and Hypertension, Allegheny General Hospital, Temple University School of Medicine, Pittsburgh, PA, USA\n2Department of Medicine, Allegheny General Hospital, Pittsburgh, PA, USA\n3Division of Nephrology and Hypertension, University of Miami, Miami, FL, USA\n* Corresponding author: Luis M Ortega; Division of Nephrology and Hypertension, Allegheny General Hospital, Temple University School of Medicine, Pittsburgh, PA, USA. lortega@wpahs.org1 2015 01 1 2015 4 1 29 31 07 9 2014 18 12 2014 © 2015 The Author(s)2015\nPublished by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nhttp://nephropathol.com\nBackground: Fluoroquinolones are known to cause acute renal failure due to interstitial nephritis.\n\n\n\nCase Presentation: Here we present an elderly woman who developed oliguric acute kidney injury (AKI) after receiving oral and intravenous ciprofloxacin in a 48-hour period. Recently, several case reports have been published in the literature regarding the presence of crystals in the urine sediment of patients treated with ciprofloxacin for different types of systemic infections. Ciprofloxacin crystals precipitate in alkaline urine and provoke renal failure through intra-tubular precipitation.\n\n\n\nConclusions: Conservative measures including intravenous hydration and avoidance of alkalinization of the urine can reverse this condition if applied in time.\n\n\nAcute kidney injuryInterstitial nephritisFluoroquinolonesCrystalluria \nPlease cite this paper as: Khan M, Ortega LM, Bagwan N, Nayer A. Crystal-induced acute kidney injury due to ciprofloxacin. J Nephropathol. 2015; 4(1):29-31. DOI: 10.12860/jnp.2015.06\n==== Body\nImplication for health policy/practice/research/medical education:\nFluoroquinolones are known to cause acute renal failure due to interstitial nephritis. The crystals of this agent, precipitate under alkaline urine and provoke renal failure through intra-tubular precipitation. Conservative measures, that include hydration with standard intravenous fluid formulations and avoidance of alkalinization of the urine, can reverse this condition if applied on time.\n\n1. Introduction\n\nCiprofloxacin is an antimicrobial fluoroquinolone. Acute kidney injury (AKI) as a result of tubulointerstitial nephritis due to this drug has been described (1) Ciprofloxacin causes crystal nephropathy in experimental animals (2). Crystalluria due to ciprofloxacin has been recorded in two out of 63,000 patients (3). Unfortunately very few images of ciprofloxacin crystals are available in the literature (4). The crystals show a wide array of morphological appearances and precipitates in a urine pH> 6.8. The likelihood of occurring in humans with intact tubular function is low (4). Here we present a case of an elderly patient that developed oliguric AKI after receiving oral and intravenous ciprofloxacin in a 48-hour period. Previous cases have been described after receiving oral ciprofloxacin in a 24-hour period or after 8 days of therapy (5,6). To prevent crystalluria, patients should be well hydrated,and urine alkalization should be avoided (7).\n\n\n2. Case Presentation\n\nThe patient is a 72-year-old Caucasian woman with a past medical history significant for metastatic adenocarcinoma of the colon status post chemotherapy with FOLFIRI that was completed three months prior to admission. Previously she had an episode of bacteremia due to colitis and transient acute renal failure (ARF) requiring temporary renal replacement therapy. She presented with nausea, vomiting and abdominal pain. A non-contrast enhanced CT showed thickening of the rectosigmoid colon and possible proctocolitis. Serum creatinine (SCr) on admission was 0.91 mg/dl on day 1, increasing in the next 24-48 hours to 1.2 and 2.4 mg/dl, respectively. Patient received oral (500 mg BID) and later intravenous (400 mg BID) ciprofloxacin on days 1 and 2, stopped on day 3. The antibiotic regimen was changed to metronidazole after documented Clostridium Difficile infection in the stool culture. Serum creatinine continued to rise progressively up to a value of 3.54 mg/dl on day 7 (Figure 1). These increases coincided with a constant decrease in urine output below 500 cc for 6-8 days (Figure 2). We were consulted on day 6. Urine sediment showed stellate shaped crystals (Figure 3 and 4) that were birefringent to polarized light (Figure 5) and highly suspicious for ciprofloxacin crystals. Aggressive hydration with 0.9% NaCl was initiated avoiding alkalinization of the urine at all times (average urine pH=5, pH=7 on presentation) despite using sporadic infusions of sodium bicarbonate to treat worsening academia due to renal failure. Creatinine values improved in the following days down to 1.81 mg/dl. Repeat urine sediment examination showed complete resolution of crystals with sporadic granular casts (Figure 6) that probably contributed to the slow recovery in renal function. Patient fared well and was discharge uneventfully to her nursing home.\n\n\n\nFigure 1\n Serum creatinine trend \n\n\nFigure 2\n Urine output \n\n\nFigure 3\n Stellate-shaped ciprofloxacin crystals at low power \n\n\nFigure 4\n Stellate-shaped ciprofloxacin crystals at high power \n\n\nFigure 5\n Ciprofloxacin crystals under polarized light \n\n\nFigure 6\n Urine sediment post hydration showing abscence of crystals \n\n3. Discussion\n\nWe report an elderly woman with documented ciprofloxacin crystal-induced renal failure. This represents and addition to the few cases published in the literature in recent years. Ciprofloxacin can cause crystalluria in alkaline urine especially at pH>7.3 both in experimental animals and human subjects (8). Reports have shown crystal deposition in the renal tubular lumen even with a pH < 6.8 (9). Some case reports have also documented crystal-induced AKI with standard doses of ciprofloxacin during one to 8 days of therapy (6-9). Crystals present in different shapes and forms: needle shaped stellate, “sheaves”, “stars”, “fans” and “butterflies” as well as other unusual shapes all with a lamellar structure whose sizes ranged from 30×5 µm to 360×237 µm. Some crystals are colorless while others have a brownish hue. Under polarized light , ciprofloxacin crystals are birefringent (6). Our patient’s urine sediment demonstrated similar type of crystals as described above. Serum creatinine improved considerably with aggressive hydration, after ciprofloxacin was discontinued. Changes in urine output correlated, to certain extent, with renal function parameters (SCr) and estimated glomerular filtration rates. The fact that the final SCr did not return to baseline probably had to do with the presence of residual ATN. The teaching point is the awareness of crystal induced reversible AKI due to exposure to short courses of ciprofloxacin given orally or intravenously.\n\n\n4. Conclusions\n\nThe case also stresses the importance of microscopic examination of a urine sediment (using a polarizer), for the early diagnoses of quinolone induced reversible acute kidney injury, avoiding the need of a kidney biopsy. Treatment is conservative and includes hydration with isotonic or hypotonic solutions and prevention of alkalinization of the urine (7).\n\n\nAuthors’ contributions\n\nAll authors contributed to the manuscript equally.\n\n\nConflict of interests\n\nThe authors declared no competing interests.\n\n\nFunding/Support\n\nNone.\n==== Refs\nReferences\n1 Hottkins R Fenves AZ Stephens MK Acute renal failure secondary to oral ciprofloxacin: A presentation on three cases and a review of the literature Clin Nephrol 1989 32 75 8 2670382 \n2 Ball P Ciprofloxacin:an overview of adverse experiences J Antimicrob Chemother 1986 18 Suppl D 187 93 3542945 \n3 Boll P Tillotson G Tolerability of fluoroquinolone antibiotics Drug Safety 1995 13 344 58 \n4 Thorsteinsson SB Bergan T Oddsdottir S Rohwedder R Holm R Crystalluria and ciprofloxacin,influence of urinary pH and hydration Chemotherapy 1986 32 408 17 3019613 \n5 Sedlacek M Suriawinata AA Schoolwerth A Remillard BD Ciprofloxacin crystal nephropathy-A “new” case of acute renal failure Nephrol Dial Transplant 2006 21 8 2339 40 16611679 \n6 Fogazzi GB Garigali G Brambilla C Daudon M Ciprofloxacin crystalluria Nephrol Dial Transplant 2006 21 2982 3 16837513 \n7 Christ W Lehnert T Ulbrich B Specific toxicologic aspects of the quinolones Rev Infect Dis 1988 10 S141 6 3279489 \n8 Nix DE Spivey JM Norma A Schentag JJ Dose-ranging pharmacokinectic study of ciprofloxacin after 200, 300, and 400 mg intravenous doses Ann Pharmacother 1992 26 8 10 1606348 \n9 Stratta P Laczzarich E Canavese C Bozzola C Monga G Ciprofloxacin crystal nephropathy Am J Kidney Dis 2007 50 330 5 17660035\n\n",
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"keywords": "Acute kidney injury; Crystalluria; Fluoroquinolones; Interstitial nephritis",
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"title": "Crystal-induced acute kidney injury due to ciprofloxacin.",
"title_normalized": "crystal induced acute kidney injury due to ciprofloxacin"
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"abstract": "Opioid medications are commonly used to treat moderate-to-severe pain. While these medications are generally an effective means of pain control, they can, in rare cases, actually exacerbate the pain. This paradoxical reaction is called opioid-induced hyperalgesia (OIH). Patients experiencing OIH may benefit from decreasing or discontinuing the opioid, switching to an alternative opioid, and/or using a nonopioid medication for pain.",
"affiliations": "consultant pharmacist, Greensboro, North Carolina.",
"authors": "Martin|Caren McHenry|CM|",
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"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D006930:Hyperalgesia; D010146:Pain",
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"title": "When medications make pain worse: opioid-induced hyperalgesia.",
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"abstract": "BACKGROUND\nLactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. It is recognized as a potential complication of metformin use, particularly in patients with risk factors such as renal dysfunction, liver disease, and heavy alcohol ingestion. These conditions are associated with systemic hypoxemia, which may be caused by cardiorespiratory disease, major surgery, sepsis, dehydration, old age, and overdose. The reported frequency of lactic acidosis is 0.06 per 1000 patient-years, mostly in patients with predisposing factors. This case is important because it details the seriousness of metformin-associated lactic acidosis in a critically ill patient and because, to the best of our knowledge, our patient survived with minimal residual defect despite experiencing a cardiac arrest.\n\n\nMETHODS\nA 66-year-old Caucasian woman presented to our hospital with profound lactic acidosis, which was initially thought to be ischemic gut. She then survived an in-hospital pulseless electrical activity arrest.\n\n\nCONCLUSIONS\nMetformin-associated lactic acidosis is a diagnosis by exclusion; however, a high degree of clinical suspicion supplemented by prompt multisystem organ support can significantly influence the outcome in critically ill patients.",
"affiliations": "Intensive care unit, Critical care services, Level 4, Robert Gerard Wing, Royal Adelaide Hospital, North terrace, Adelaide, SA 5000, Australia. krishnaswamy.sundararajan@health.sa.gov.au.",
"authors": "Ncomanzi|Dumisani|D|;Sicat|Rhea Mae R|RM|;Sundararajan|Krishnaswamy|K|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-1592488465810.1186/1752-1947-8-159Case ReportMetformin-associated lactic acidosis presenting as an ischemic gut in a patient who then survived a cardiac arrest: a case report Ncomanzi Dumisani 1Ncomanzi6@yahoo.co.ukSicat Rhea Mae R 1rheamaesicatmd@yahoo.comSundararajan Krishnaswamy 12krishnaswamy.sundararajan@health.sa.gov.au1 Intensive care unit, Critical care services, Level 4, Robert Gerard Wing, Royal Adelaide Hospital, North terrace, Adelaide, SA 5000, Australia2 Senior Clinical Lecturer, Discipline of Acute care Medicine, University of Adelaide, Adelaide, SA 5000, Australia2014 21 5 2014 8 159 159 6 1 2014 28 4 2014 Copyright © 2014 Ncomanzi et al.; licensee BioMed Central Ltd.2014Ncomanzi et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nLactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. It is recognized as a potential complication of metformin use, particularly in patients with risk factors such as renal dysfunction, liver disease, and heavy alcohol ingestion. These conditions are associated with systemic hypoxemia, which may be caused by cardiorespiratory disease, major surgery, sepsis, dehydration, old age, and overdose. The reported frequency of lactic acidosis is 0.06 per 1000 patient-years, mostly in patients with predisposing factors. This case is important because it details the seriousness of metformin-associated lactic acidosis in a critically ill patient and because, to the best of our knowledge, our patient survived with minimal residual defect despite experiencing a cardiac arrest.\n\nCase presentation\nA 66-year-old Caucasian woman presented to our hospital with profound lactic acidosis, which was initially thought to be ischemic gut. She then survived an in-hospital pulseless electrical activity arrest.\n\nConclusion\nMetformin-associated lactic acidosis is a diagnosis by exclusion; however, a high degree of clinical suspicion supplemented by prompt multisystem organ support can significantly influence the outcome in critically ill patients.\n\nCardiac arrestGutIschemiaLactic acidosisMetformin\n==== Body\nIntroduction\nMetformin is an oral biguanide anti-diabetic agent. It is a small, non-plasma-protein-bound molecule, and 90% of metformin is excreted unchanged by the kidneys through glomerular filtration and possibly through tubular secretion. In addition to being relatively safe, its use has been advocated in the treatment of type 2 diabetes in patients who are obese and has been shown to slow cardiovascular complications associated with diabetes. By decreasing excess hepatic gluconeogenesis without raising insulin levels, it rarely leads to significant hypoglycemia when used as monotherapy [1-3]. Therapy with metformin has been associated with type B lactic acidosis.\n\nMetformin-associated lactic acidosis (MALA) is a grave but infrequent complication of metformin use and reportedly has a mortality rate up to 50%. There has been a serious debate about the exact role of metformin in the development of lactic acidosis. The Cochrane group [4], Comparative Outcomes Study of Metformin Intervention versus Conventional Approach (COSMIC) [5] study, and the United Kingdom Prospective Diabetes study [6] have disputed the existence of lactic acidosis in the presence of metformin and hence the term metformin-induced lactic acidosis has subsequently been changed to MALA. The independent effect of metformin on the development of lactic acidosis remains unclear. Metformin reduces pyruvate dehydrogenase activity and mitochondrial transport of reducing agents, and thus enhances anaerobic metabolism. This shift to anaerobic metabolism, in the presence of reduced insulin, increases production of precursors for the Krebs cycle. Consequently, there is a decreased ability to channel those precursors into aerobic metabolism, which, in turn, results in increased metabolism of pyruvate to lactate and increases net lactic acid production. MALA has non-specific presenting features; typically, patients have severe hypotension with low systemic vascular resistance and respiratory failure.\n\nA systematic review and meta-analysis showed no evidence that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other anti-hyperglycemic treatments if the drug is prescribed under study conditions, taking into account contraindications [7]. Of 194 studies considered, there were no cases of fatal or nonfatal lactic acidosis in 36,893 patient-years in the metformin group or in 30,109 patient-years in the non-metformin group [7]. In another review of 11,800 patients treated with metformin for a mean of about two years in Saskatchewan, Canada, only two patients developed lactic acidosis (incidence: nine cases per 100,000 years of exposure) [8].\n\nCase presentation\nA 66-year-old Caucasian woman with type 2 diabetes presented to our emergency department with a three-week history of generalized malaise, associated poor oral intake, and some diarrhea. Her enteric symptoms were vague and unquantifiable. She was obese and had a past medical history of poorly controlled type 2 diabetes for 15 years, hypertension, asthma, and depression. Her regular medication comprised metformin 3g daily, modified-release gliclazide 60mg daily, aspirin 100mg daily, atorvastatin 40mg daily, ramipril 10mg daily, and hydrochlorothiazide 25mg daily. Our patient was brought into hospital by ambulance; her pre-hospital observations were as follows: Glasgow Coma Scale score, 15; blood sugar level, 2.8mmol/L; blood pressure, 90/40mmHg; pulse, 54 beats per minute; respiratory rate, 32 breaths per minute; and peripheral oxygen saturation, 98% on 8L oxygen via a variable oxygen delivery mask. On arrival to our emergency department, she was confused with a Glasgow Coma Scale score of 14 out of 15 (E4V4M6), with the rest of her physiological parameters similar to her pre-hospital observations.\n\nHer initial investigations were as follows: serum sodium, 140mmol/L (normal range: 137 to 145mmol/L); serum potassium, 7.3mmol/L (normal range: 3.5 to 4.9mmol/L); serum chloride, 91mmol/L (normal range: 100 to 109mmol/L); serum bicarbonate, 1mmol/L (normal range: 22 to 32mmol/L); anion gap, 55mmol/L (normal range: 7 to 17mmol/L); serum glucose, 2.3mmol/L; urea, 30.8mmol/L (normal range: 2.7 to 8.0mmol/L); and serum creatinine, 768umol/L (normal range: 50 to 100umol/L). Results from liver function tests were normal. Her troponin level was 50ng/L (normal range: <30ng/L). Venous blood gas measurements revealed a profound metabolic acidemia: pH, 6.58; partial pressure of CO2, 38.6mmHg; HCO3, 3.6mmol/L; glucose, 2.0mmol/L; and lactate, 16.7mmol/L. Her initial resuscitation strategy included 2000mL of 0.9% sodium chloride solution, 10mL of 10% calcium gluconate, 15 units insulin (Actrapid) in 50mL 50% dextrose, and 1mL/kg of 8.4% sodium bicarbonate solution.\n\nMinutes after these initial investigations, our patient experienced a pulseless electrical activity cardiac arrest and was managed as per advanced life support protocol. She had a total downtime of 25 minutes. During cardiopulmonary resuscitation she was intubated and ventilated. Following return of spontaneous circulation, she required an infusion of adrenaline for blood pressure support. She had an unremarkable chest radiograph, electrocardiogram, and toxicology screen.\n\nWith a presumed diagnosis of ischemic bowel based on vague abdominal features and profound lactatemia, our patient was admitted to our intensive care unit (ICU) for preoperative optimization. In our ICU, she was sedated and ventilated on an inspired oxygen concentration of 40% and on modest ventilator paramters (peak inspiratory pressure <25cmH2O). To treat her severe circulatory shock, she was fluid-resuscitated with a total of 10,000mL crystalloid from a central venous pressure of 8cmH2O to 16cmH2O. In addition, she required very high doses of noradrenaline and adrenaline. Continuous veno-venous hemodiafiltration was commenced at exchange rates of 50mL/kg/h using Hemosol B0 solution. She was empirically started on vancomycin and piperacillin and tazobactam (Tazocin) as broad-spectrum antimicrobial cover.\n\nOur patient went to theater 26 hours post admission for an exploratory laparotomy, which revealed no significant findings. We continued her broad-spectrum antimicrobial cover despite negative microbiological cultures. Renal replacement therapy continued and our patient’s acid-base balance slowly normalized over three days. Having excluded all causes of a high anion gap lactic acidosis, including negative red blood cell transketolase activity for thiamine deficiency, we presumed our patient to have had a severe MALA ‘triggered’ by an acute kidney injury from dehydration. This was supported by a serum metformin level of 4mg/L. Her renal function slowly improved with continuous veno-venous hemodiafiltration and she slowly recovered with a total of 35 days stay in ICU.\n\nDiscussion\nA high anion gap metabolic acidosis commonly occurs secondary to ketoacidosis (in diabetes, alcoholism, starvation), toxins (alcohol, ethylene, glycol, methanol, and paraldehyde), kidney injury, and lactic acidosis (shock, hypoxia, carbon monoxide, cyanide, and metformin). A diagnosis of MALA should always form part of the differential in a patient with high anion gap metabolic acidosis. Even though MALA masquerading as an ischemic gut has previously been reported, our case is different because our patient survived, as compared to the previous report in which the diagnosis was made posthumously [9].\n\nTreatment of MALA is largely supportive, comprising adequate resuscitation, treating any underlying confounding disease process, and renal replacement therapy for acidosis and drug elimination. Lactic acidosis, though extremely rare, is associated with 50% mortality. An analysis of 49 cases of lactic acidosis associated with metformin use found the overall mortality was not correlated with plasma lactate concentrations. Paradoxically, plasma metformin concentrations were about three times higher in patients who survived. All cases of lactic acidosis had, in addition to metformin use, acute or chronic comorbidities predisposing to lactic acidosis, suggesting that lactic acidosis may be coincidental rather than causally associated with metformin use [10]. Another case series concluded that the extent of acidosis and accumulation of metformin was less important than other coexisting factors [11]. A good predictive factor of death is an acute liver dysfunction as assessed by prothrombin time.\n\nOur patient had multiple risk factors, including renovascular disease, an acute kidney injury from dehydration, and continued intake of nephrotoxic angiotensin-converting enzyme inhibitor and thiazide diuretic. In addition, she had continued taking her usual metformin dose. We believe that there was an accumulation of metformin due to reduced renal clearance. Her severe lactic acidosis with increasing inotrope requirement while in our ICU led to an emergency laparotomy, which did not show any intra-abdominal pathology. Her plasma metformin level subsequently came back as 4mg/L, which is suggestive of our diagnosis in the absence of any other cause in a patient presenting with a raised anion gap (44.6mmol/L) metabolic acidosis. It is worth noting that the incidence of MALA estimated from metformin serum concentration measurements in patients with type 2 diabetes mellitus is 5 to 16 times higher than reported in the literature [11].\n\nOur case typifies MALA in that there were high serum metformin levels, profound lactatemia in the presence of an Acute kidney injury, and concurrent illness. In this regard, is metformin causal, co-responsible, or coincidental? The debate rages on.\n\nConclusion\nMALA is rare but life threatening. Although controversy surrounding causality exists, current guidelines advocate metformin review and/or withdrawal for patients with renal impairment, during periods of tissue hypoxia, two days before general anesthesia, and for three days following use of contrast-medium-containing iodine. Early renal replacement therapy forms the mainstay of treatment in critical illness because it provides both symptomatic and etiological treatment by eliminating lactate and metformin, in addition to cardiorespiratory organ support. Goals of supportive treatment are to maintain adequate tissue perfusion, correct electrolyte imbalance and hypoglycemia, and perform mechanical ventilation in patients with respiratory distress and hemodynamic instability.\n\nConsent\nWritten informed consent was initially obtained from the patient’s next of kin as the patient was too unwell to sign a valid consent form at the time of obtaining the consent. Subsequently, written informed consent was also obtained from the patient as she had recovered completely and was deemed to be mentally competent to give her consent for her case to be published. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nICU: intensive care unit; MALA: metformin-associated lactic acidosis.\n\nCompeting interests\nThe authors declare that they have no competing interests\n\nAuthors’ contributions\nDN obtained background information about the patient, performed the literature search and prepared the manuscript. RS assisted with literature search, writing the manuscript and providing information about the patient. KS obtained consent from the patient and family and supervised the work along with editing the manuscript and offering intellectual input and technical expertise in finalizing the manuscript. All authors have read and approved the final manuscript.\n\nAcknowledgements\nDr David Evans (Staff Specialist, Intensive care unit, Royal Adelaide Hospital).\n==== Refs\nWiholm BE Myrhed M Metformin-associated lactic acidosis in Sweden 1977–1991 Eur J Clin Pharmacol 1993 44 589 591 10.1007/BF02440866 8405019 \nNathan DM Buse JB Davidson MB Ferrannini E Holman RR Sherwin R Zinman B American Diabetes Association Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care 2009 32 1 193 203 10.2337/dc08-9025 18945920 \nRodbard HW Jellinger PS Davidson JA Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control Endocr Pract 2009 15 6 540 559 10.4158/EP.15.6.540 19858063 \nSalpeter S Greyber E Pasternak G Risk of fatal and non fatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst Rev 2010 4 CD0002967 \nCryer DR Nicholas SP Henry DH Mills DJ Stadel BV Comparative outcomes study of metformin intervention versus conventional approach: the COSMIC Approach study Diabetes Care 2005 28 539 543 10.2337/diacare.28.3.539 15735184 \nEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group Lancet 1998 352 854 865 9742977 \nSalpeter SR Greyber E Pasternak GA Salpeter EE Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis Arch Intern Med 2003 163 21 2594 2602 10.1001/archinte.163.21.2594 14638559 \nStang M Wysowski DK Butler Jones D Incidence of lactic acidosis in metformin users Diabetes Care 1999 22 925 10.2337/diacare.22.6.925 10372243 \nCorreia CS Bronander KA Metformin-associated lactic acidosis masquerading as ischemic bowel Am J Med 2012 125 5 e9 10.1016/j.amjmed.2011.11.012 22365024 \nLalau JD Race JM Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug Saf 1999 20 377 384 10.2165/00002018-199920040-00006 10230584 \nde Laar IR VB-v Vermeij CG Doorenbos CJ Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements J Clin Pharm Ther 2011 36 3 376 382 10.1111/j.1365-2710.2010.01192.x 21545617\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007004:Hypoglycemic Agents; D007422:Intestines; D007511:Ischemia; D008687:Metformin; D012307:Risk Factors",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "159",
"pmc": null,
"pmid": "24884658",
"pubdate": "2014-05-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18945920;10372243;8405019;15735184;21545617;9742977;20393934;14638559;10230584;22365024;19858063",
"title": "Metformin-associated lactic acidosis presenting as an ischemic gut in a patient who then survived a cardiac arrest: a case report.",
"title_normalized": "metformin associated lactic acidosis presenting as an ischemic gut in a patient who then survived a cardiac arrest a case report"
} | [
{
"companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2014-01134",
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"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
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{
"abstract": "Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%; Plog rank = .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%, PGray = .02; 5-year EFS, 73% ± 8% vs 91% ± 4%, Plog rank = .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.",
"affiliations": "Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Department of Pediatrics, St. Anna Children's Hospital/Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria.;Dutch Childhood Oncology Group, The Hague, The Netherlands.;Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; and.;Dutch Childhood Oncology Group, The Hague, The Netherlands.;Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.",
"authors": "Uffmann|Madita|M|;Rasche|Mareike|M|;Zimmermann|Martin|M|;von Neuhoff|Christine|C|;Creutzig|Ursula|U|;Dworzak|Michael|M|;Scheffers|Lenie|L|;Hasle|Henrik|H|;Zwaan|C Michel|CM|;Reinhardt|Dirk|D|;Klusmann|Jan-Henning|JH|0000-0002-1070-0727",
"chemical_list": "D000970:Antineoplastic Agents; D003561:Cytarabine; D005047:Etoposide; D015255:Idarubicin",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-01-765057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "129(25)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8; D003561:Cytarabine; D020732:Cytogenetic Analysis; D018572:Disease-Free Survival; D004314:Down Syndrome; D005047:Etoposide; D005260:Female; D006801:Humans; D015255:Idarubicin; D007223:Infant; D007951:Leukemia, Myeloid; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D014314:Trisomy",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3314-3321",
"pmc": null,
"pmid": "28400376",
"pubdate": "2017-06-22",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial.",
"title_normalized": "therapy reduction in patients with down syndrome and myeloid leukemia the international ml ds 2006 trial"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1054245",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IDARUBICIN"
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... |
{
"abstract": "Infants and young children who undergo allogeneic cord blood transplantation (CBT) are at increased risk for late effects because of exposure of developing organs to chemotherapy and radiation therapy typically used in transplant conditioning regimens. Busulfan (Bu)-based myeloablative regimens were developed to eliminate radiation exposure in these young children with the hope that late effects would be minimized. We now describe the late effects in 102 consecutive patients surviving a minimum of 5 years (median follow-up, 12.9 years) post-CBT. Patients were conditioned with high-dose chemotherapy using Bu-containing regimens. No patient received total body irradiation. The median age at transplant was 1 year (range, .1 to 2). Diagnoses included inherited metabolic diseases (59.8%), leukemia (17.6%), congenital immune deficiency (20.2%), bone marrow failure/myelodysplastic syndrome (3.9%), and hemoglobinopathy (2%). Among patients surviving 5 years, the overall survival rate at 10 years post-CBT was 93% (95% CI, 84.9 to 96.8). Virtually all patients (98%) experienced at least 1 significant late effect. Most (83.3%) experienced 2 or more late effects, and more than half of the patients (64.7%) experienced 3 or more late effects. The most commonly observed late effects included dental problems (92.2%), short stature (55.9%), cognitive deficits (53.6%), pulmonary dysfunction (18.6%), and abnormal pubertal development (27.9%). This is the first report of late effects of Bu-based conditioning in a cohort of very young patients at the time of transplant. These results will inform clinical care guidelines for long-term follow-up and add to the growing information regarding outcomes of hematopoietic stem cell transplantation.",
"affiliations": "Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina. Electronic address: heather.allewelt@dm.duke.edu.;The EMMES Corporation, Rockville, Maryland.;The EMMES Corporation, Rockville, Maryland.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.",
"authors": "Allewelt|Heather|H|;El-Khorazaty|Jill|J|;Mendizabal|Adam|A|;Taskindoust|Mahsa|M|;Martin|Paul L|PL|;Prasad|Vinod|V|;Page|Kristin|K|;Sanders|Jean|J|;Kurtzberg|Joanne|J|",
"chemical_list": "D019653:Myeloablative Agonists; D002066:Busulfan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2016.05.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "22(9)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Busulfan; Late effects; Myeloablative conditioning; Umbilical cord blood transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D002066:Busulfan; D064419:Chemically-Induced Disorders; D002675:Child, Preschool; D036101:Cord Blood Stem Cell Transplantation; D064420:Drug-Related Side Effects and Adverse Reactions; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D000069451:Long Term Adverse Effects; D019653:Myeloablative Agonists; D016019:Survival Analysis; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1627-1635",
"pmc": null,
"pmid": "27264632",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning.",
"title_normalized": "late effects after umbilical cord blood transplantation in very young children after busulfan based myeloablative conditioning"
} | [
{
"companynumb": "US-OTSUKA-2016_025474",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "Liposomal doxorubicin is used for the treatment of various cancers like epithelial ovarian cancers, multiple myeloma and sarcomas. We report the first case of anaphylaxis to pegylated liposomal doxorubicin.",
"affiliations": "Cancer Centre and Blood Institute, St Joseph Regional Medical Centre, Lewiston, Idaho, USA.;Cancer Centre and Blood Institute, St Joseph Regional Medical Centre, Lewiston, Idaho, USA.;Cancer Centre and Blood Institute, St Joseph Regional Medical Centre, Lewiston, Idaho, USA; 1250 Idaho Street, Lewiston, Idaho 83501, USA. binay.shah@gmail.com.",
"authors": "Sharma|L R|LR|;Subedi|A|A|;Shah|B K|BK|",
"chemical_list": null,
"country": "Jamaica",
"delete": false,
"doi": "10.7727/wimj.2013.270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-3144",
"issue": "63(4)",
"journal": "The West Indian medical journal",
"keywords": null,
"medline_ta": "West Indian Med J",
"mesh_terms": null,
"nlm_unique_id": "0417410",
"other_id": null,
"pages": "376-7",
"pmc": null,
"pmid": "25429486",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": "12604051;12954584;11072960;18281662;6237897",
"title": "Anaphylaxis to pegylated liposomal Doxorubicin: a case report.",
"title_normalized": "anaphylaxis to pegylated liposomal doxorubicin a case report"
} | [
{
"companynumb": "US-PFIZER INC-2016526209",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "A 19-year-old-woman experienced severe burning pain in the lower extremities with erythema and swelling. She was diagnosed with primary erythromelalgia (PE). The pain was unresponsive to medications but relieved by immersing her feet in cold water. We performed a multilevel lumbar sympathetic ganglion block (LSGB) with 5% phenol at second lumbar vertebra (L2) and third lumbar vertebra (L3), and additional fourth lumbar vertebra (L4) levels. An epidural block was intermittently combined. The pain and skin lesions dramatically improved after the procedures, and she no longer needed medications or to soak her feet in cold water. This case demonstrated that extensive LSGB may be a therapeutic option for intractable PE.",
"affiliations": "From the Departments of Pain Management and Palliative Care Medicine.;Anesthesiology.;Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;From the Departments of Pain Management and Palliative Care Medicine.",
"authors": "Ogawa|Satoru|S|;Ueno|Hiroshi|H|;Maruyama|Ayano|A|;Amaya|Fumimasa|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001325",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "14(12)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D001340:Autonomic Nerve Block; D004916:Erythromelalgia; D005260:Female; D005728:Ganglia, Sympathetic; D006801:Humans; D010146:Pain; D055815:Young Adult",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01325",
"pmc": null,
"pmid": "33031105",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extensive Lumbar Sympathetic Ganglion Block Combined With Epidural Block for Primary Erythromelalgia: A Case Report.",
"title_normalized": "extensive lumbar sympathetic ganglion block combined with epidural block for primary erythromelalgia a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1064723",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe optimal management of major bleeding associated with vitamin K antagonists remains unclear.\n\n\nOBJECTIVE\nThe aim of the study was to assess the determinants of outcome of vitamin K antagonists-associated major bleeding and the outcome of bleeding in relation with the therapeutic management.\n\n\nMETHODS\nPatients hospitalized for major bleeding while on vitamin K antagonists were included in a prospective, cohort study. Major bleeding was defined according to the criteria of the International Society of Thrombosis Haemostasis. The primary study outcome was death at 30days from major bleeding.\n\n\nRESULTS\n544 patients were included in this study, of which 282 with intracranial hemorrhage. Prothrombin complex concentrates were used in 51% and in 23% of patients with intracranial hemorrhage or non-intracranial major bleeding, respectively (p<0.001); fresh frozen plasma was used in 7% and in 17% of patients with intracranial hemorrhage or non-intracranial major bleeding (p<0.001). Death at 30days occurred in 100 patients (18%), 72 patients with intracranial hemorrhage and 28 patients with non-intracranial major bleeding. Age over 85years, low Glasgow Coma Scale score and shock were independent predictors of death at 30days. Invasive procedures were associated with decreased risk of death.\n\n\nCONCLUSIONS\nAmong the patients hospitalized for major bleeding while on vitamin K antagonists, the risk for death is substantial. The risk for death is associated with the clinical severity of major bleeding as assessed by the GCS score and by the presence of shock more than with the initial localization of major bleeding (ICH vs other sites).",
"affiliations": "Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Italy. Electronic address: cecilia.becattini@unipg.it.;Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Italy.;Internal Medicine, Santa Maria Nuova Hospital, Firenze, Italy.;Emergency Medicine, Ospedali Riuniti Umberto I - Lancisi - Salesi, Ancona, Italy.;Emergency Medicine, Ospedale Cattinara, Trieste, Italy.;Internal Medicine, University of Siena, Italy.;Emergency Medicine, Policlinico Maggiore, Milano, Italy.;Emergency Medicine, Santa Maria della Misericordia Hospital, Udine, Italy.;Internal Medicine, Santa Croce Hospital, Cuneo, Italy.;Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Italy.",
"authors": "Becattini|C|C|;Franco|L|L|;Masotti|L|L|;Nitti|C|C|;Cattinelli|S|S|;Cappelli|R|R|;Manina|G|G|;Sbrojavacca|R|R|;Pomero|F|F|;Agnelli|G|G|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents; D014812:Vitamin K; C025667:prothrombin complex concentrates; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "33()",
"journal": "European journal of internal medicine",
"keywords": "Anticoagulants; Hemorrhage; Prognosis; Stroke; Warfarin",
"medline_ta": "Eur J Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001779:Blood Coagulation Factors; D019468:Disease Management; D005260:Female; D005343:Fibrinolytic Agents; D015600:Glasgow Coma Scale; D006801:Humans; D019934:International Normalized Ratio; D020300:Intracranial Hemorrhages; D007558:Italy; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010949:Plasma; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "47-54",
"pmc": null,
"pmid": "27289494",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Clinical management and outcome of major bleeding in patients on treatment with vitamin K antagonists.",
"title_normalized": "clinical management and outcome of major bleeding in patients on treatment with vitamin k antagonists"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT07688",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
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"drugadditional": null,
... |
{
"abstract": "Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce.\n\n\n\nProspective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed.\n\n\n\nOf 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively.\n\n\n\nPrimary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified.\n\n\n\nChildhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.",
"affiliations": "Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria katja.von-hoff@charite.de martin.benesch@klinikum-graz.at.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Hopp Children's Cancer Center (KiTZ), Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, Heidelberg, Germany.;Institute of Diagnostic and Interventional Neuroradiology, University Hospital Würzburg, Würzburg, Germany.;Institute of Neuropathology, Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy (DGNN), University of Bonn, Bonn, Germany.;Institute of Diagnostic and Interventional Neuroradiology, University Hospital Würzburg, Würzburg, Germany.;Hopp Children's Cancer Center (KiTZ), Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, Heidelberg, Germany.;Hopp Children's Cancer Center (KiTZ), Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, Heidelberg, Germany.;Hopp Children's Cancer Center (KiTZ), Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, Heidelberg, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Pediatric Hematology and Oncology, Pediatrics III, University Children's Hospital of Essen, Essen, Germany.;Pediatric Hematology and Oncology, Pediatrics III, University Children's Hospital of Essen, Essen, Germany.;Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.;Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.;Department of Pediatric Hematology/Oncology, University Otto von Guericke Magdeburg, Magdeburg, Germany.;Department of Pediatric Hematology/Oncology, Medical School Hannover, Hanover, Germany.;University Children's Hospital, Rostock, Germany.;Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, (corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health), Berlin, Germany.;Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.;Zentrum für Kinder- und Jugendmedizin, Helios Klinikum Krefeld, Krefeld, Germany.;Pediatric Hematology and Oncology Unit, Department of Pediatrics, Helios Klinikum Erfurt, Erfurt, Germany.;Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany katja.von-hoff@charite.de martin.benesch@klinikum-graz.at.",
"authors": "Benesch|Martin|M|;Mynarek|Martin|M|0000-0003-3302-2719;Witt|Hendrik|H|;Warmuth-Metz|Monika|M|;Pietsch|Torsten|T|;Bison|Brigitte|B|;Pfister|Stefan M|SM|;Pajtler|Kristian W|KW|;Kool|Marcel|M|;Schüller|Ulrich|U|;Pietschmann|Klaus|K|;Juhnke|Björn-Ole|BO|;Tippelt|Stephan|S|;Fleischhack|Gudrun|G|;Schmid|Irene|I|;Kramm|Christof M|CM|;Vorwerk|Peter|P|;Beilken|Andreas|A|;Classen|Carl Friedrich|CF|;Hernáiz Driever|Pablo|P|;Kropshofer|Gabriele|G|;Imschweiler|Thomas|T|;Lemmer|Andreas|A|;Kortmann|Rolf-Dieter|RD|;Rutkowski|Stefan|S|;von Hoff|Katja|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(9)",
"journal": "The oncologist",
"keywords": "Children; Intracranial ependymoma; Metastases; Molecular subgroups; Therapy",
"medline_ta": "Oncologist",
"mesh_terms": "D000293:Adolescent; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D004806:Ependymoma; D005260:Female; D006801:Humans; D015192:Infratentorial Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D011379:Prognosis; D000077982:Progression-Free Survival; D011446:Prospective Studies; D011878:Radiotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e921-e929",
"pmc": null,
"pmid": "30850560",
"pubdate": "2019-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10661334;11230470;12466129;14991260;15050308;16200565;16226707;16234523;16300848;16609018;16919771;17610266;18698591;19061350;19274783;19360417;19362789;20463607;20516456;20646868;21038109;21627842;21636711;21840481;22338015;22526017;22851561;23223339;24553141;24553142;24562983;24969797;25965575;27157931;27194148;27269943;27556362;27858204;27863192;29258295;29350470;29539639;29909548;8276653;8559293;9732252",
"title": "Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.",
"title_normalized": "newly diagnosed metastatic intracranial ependymoma in children frequency molecular characteristics treatment and outcome in the prospective hit series"
} | [
{
"companynumb": "AT-MYLANLABS-2020M1022265",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPityriasis rubra pilaris (PRP) is a rare papulosquamous dermatosis. We evaluated evaluate co-morbidities, complications, and outcome of treatment regimens.\n\n\nMETHODS\nThis is a retrospective study at an academic teaching hospital. We analyzed all patients with the definite diagnosis of PRP seen since 2001. Epidemiologic data, co-morbidities, response to and course during treatment were investigated.\n\n\nRESULTS\nWe identified 10 PRP-patients (6 men, 4 women), mean age 56.4 years, with type I (n = 9) and type IV (n = 1). Three patients had internal co-morbidities (atrial fibrillation with cardiac insufficiency, dilated cardiomyopathy, diabetes mellitus). Two patients needed psychiatric treatment because of depression. PRP caused ectropium (2 x), diffuse effluvium (1 x), and stenosis of the outer ear canal (1 x). We did not observe a spontaneous remission. Among 9 patients with PRP type I, five were treated with acitretin (two of them as Re-PUVA), and two with methotrexate (in one patient combined with fumaric acids). Systemic corticosteroids were not effective. One patient was treated with infliximab i.v., 5 mg/kg body weight. Starting with the first application, inflammatory activity decreased and erythema got paler. The treatment was well tolerated.\n\n\nCONCLUSIONS\nPRP type I is a severe, chronic inflammatory dermatosis responding hesitantly to classic systemic therapies. Tumor necrosis factor-alpha antagonists are an effective treatment option for difficult cases.",
"affiliations": "Department of Dermatology and Allergology, Dresden-Friedrichstadt Hospital, Dresden, Germany.",
"authors": "Gemmeke|Astrid|A|;Schönlebe|Jaqueline|J|;Koch|André|A|;Wollina|Uwe|U|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1111/j.1610-0387.2010.07338.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1610-0379",
"issue": "8(6)",
"journal": "Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG",
"keywords": null,
"medline_ta": "J Dtsch Dermatol Ges",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015897:Comorbidity; D003863:Depression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010916:Pityriasis Rubra Pilaris; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101164708",
"other_id": null,
"pages": "439-44",
"pmc": null,
"pmid": "20202046",
"pubdate": "2010-06",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": null,
"title": "Pityriasis rubra pilaris--a retrospective single center analysis over eight years.",
"title_normalized": "pityriasis rubra pilaris a retrospective single center analysis over eight years"
} | [
{
"companynumb": "DE-TEVA-2020-DE-1222561",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Campylobacter fetus is an opportunist Gram-negative bacillus. The most frequent clinical manifestation is bacteriemia but it can also be responsable for soft tissue infections, endovascular infections, meningitis, peritonitis and thrombophlebitis. Campylobacter fetus cellulitis has been described, but rarely identified in subcutaneous puncture samples. We report a case of an immunocompromised patient with Campylobacter fetus bacteriemia associated with a soft tissue infection whose subcutaneous puncture also revealed the bacteria.",
"affiliations": "Department of internal medicine, infectious and tropical diseases, Saint Luc University hospital, Bruxelles.",
"authors": "Ausselet|N|N|;Huang|D|D|;Vandercam|B|B|;Yombi|J C|JC|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1179/acb.2009.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "64(4)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002169:Campylobacter Infections; D002168:Campylobacter fetus; D002481:Cellulitis; D006801:Humans; D016867:Immunocompromised Host; D008297:Male",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "346-8",
"pmc": null,
"pmid": "19810424",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Campylobacter fetus cellulitis in an immunocompromised patient: case report and review of the literature.",
"title_normalized": "campylobacter fetus cellulitis in an immunocompromised patient case report and review of the literature"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-267513",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"dr... |
{
"abstract": "In this study, we report the follow-up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).\n\n\n\nNewly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2 , or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, radiotherapy (RT) including reduced-dose CSRT (23.4 or 30.6 Gy), four cycles of post-RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.\n\n\n\nIn all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5-year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5-year CI. Taken together, the 5-year event-free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.\n\n\n\nThe strategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.",
"affiliations": "Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.",
"authors": "Lee|Ji Won|JW|0000-0003-0084-1304;Lim|Do Hoon|DH|0000-0002-5426-0604;Sung|Ki Woong|KW|0000-0001-5989-4772;Cho|Hee Won|HW|0000-0002-0440-645X;Ju|Hee Young|HY|0000-0001-6744-0412;Hyun|Ju Kyung|JK|0000-0001-9371-3808;Yoo|Keon Hee|KH|0000-0002-5980-7912;Koo|Hong Hoe|HH|0000-0001-8082-1412;Suh|Yeon-Lim|YL|0000-0001-5809-2401;Joung|Yoo-Sook|YS|0000-0002-9225-4643;Shin|Hyung Jin|HJ|0000-0003-0856-7098",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.3199",
"fulltext": "\n==== Front\nCancer Med\nCancer Med\n10.1002/(ISSN)2045-7634\nCAM4\nCancer Medicine\n2045-7634 John Wiley and Sons Inc. Hoboken \n\n10.1002/cam4.3199\nCAM43199\nOriginal Research\nClinical Cancer Research\nOriginal Research\nPromising survival rate but high incidence of treatment‐related mortality after reduced‐dose craniospinal radiotherapy and tandem high‐dose chemotherapy in patients with high‐risk medulloblastoma\nLEE et al.Lee Ji Won https://orcid.org/0000-0003-0084-1304\n1\n Lim Do Hoon https://orcid.org/0000-0002-5426-0604\n2\n Sung Ki Woong https://orcid.org/0000-0001-5989-4772\n1\nkwsped@skku.edu Cho Hee Won https://orcid.org/0000-0002-0440-645X\n1\n Ju Hee Young https://orcid.org/0000-0001-6744-0412\n1\n Hyun Ju Kyung https://orcid.org/0000-0001-9371-3808\n1\n Yoo Keon Hee https://orcid.org/0000-0002-5980-7912\n1\n Koo Hong Hoe https://orcid.org/0000-0001-8082-1412\n1\n Suh Yeon‐Lim https://orcid.org/0000-0001-5809-2401\n3\nylsuh76@skku.edu Joung Yoo‐Sook https://orcid.org/0000-0002-9225-4643\n4\n Shin Hyung Jin https://orcid.org/0000-0003-0856-7098\n5\n \n1 \nDepartment of Pediatrics\nSamsung Medical Center\nSungkyunkwan University School of Medicine\nSeoul\nRepublic of Korea\n\n\n2 \nDepartment of Radiation Oncology\nSamsung Medical Center\nSungkyunkwan University School of Medicine\nSeoul\nRepublic of Korea\n\n\n3 \nDepartment of Pathology\nSamsung Medical Center\nSungkyunkwan University School of Medicine\nSeoul\nRepublic of Korea\n\n\n4 \nDepartment of Psychiatry\nSamsung Medical Center\nSungkyunkwan University School of Medicine\nSeoul\nRepublic of Korea\n\n\n5 \nDepartment of Neurosurgery\nSamsung Medical Center\nSungkyunkwan University School of Medicine\nSeoul\nRepublic of Korea\n\n* Correspondence\n\nKi Woong Sung, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon‐ro, Gangnam‐gu, Seoul 06351, Korea.\n\nEmail: kwsped@skku.edu\n\nYeon‐Lim Suh, Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon‐ro, Gangnam‐gu, Seoul 06351, Korea.\n\nEmail: ylsuh76@skku.edu\n\n30 6 2020 \n8 2020 \n9 16 10.1002/cam4.v9.165807 5818\n11 11 2019 20 5 2020 20 5 2020 © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nIn this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB).\n\nMethods\nNewly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.\n\nResults\nIn all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.\n\nConclusions\nThe strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.\n\nTandem high‐dose chemotherapy (HDCT) after reduced‐dose craniospinal radiotherapy resulted in a low progression rate in high‐risk medulloblastoma. However, the high treatment‐related mortality rate indicates the need to modify the HDCT regimen and carefully select patients who may benefit from HDCT.\n\n\ncraniospinal radiotherapyhigh‐dose chemotherapylong‐term follow‐upmedulloblastomatreatment‐related mortalityMinistry of Health and Welfare15202101720270 source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.6 mode:remove_FC converted:18.08.2020\n\n\nLee \nJW \n, \nLim \nDH \n, \nSung \nKW \n, et al. Promising survival rate but high incidence of treatment‐related mortality after reduced‐dose craniospinal radiotherapy and tandem high‐dose chemotherapy in patients with high‐risk medulloblastoma\n. Cancer Med . 2020 ;9 :5807 –5818\n. 10.1002/cam4.3199 \n\n\n\nJi Won Lee and Do Hoon Lim contributed equally to this work.\n==== Body\n1 INTRODUCTION\nMedulloblastoma (MB) is the most common malignant brain tumor of childhood accounting for 20% of CNS tumors in the pediatric population.\n1\n Standard treatment of MB consisted of maximal surgical resection followed by risk‐adaptive craniospinal radiotherapy (CSRT) and adjuvant chemotherapy. The current clinical risk stratification divides MB into standard risk and high risk according to age, presence of metastasis, extent of postsurgical residual disease, and histology.\n2\n In patients over 3 years old, patients who had subtotal resection, metastatic disease, and/or anaplastic histology are considered as high risk. Current treatment protocols for high‐risk MB generally use 36.0‐39.6 Gy CSRT followed by a tumor bed boost to 54.0‐55.8 Gy of total dose.\n2\n, \n3\n With this approach, the 5‐year event‐free survival (EFS) in high‐risk MB has been reported as 60%‐70%.\n4\n, \n5\n\n\n\nHowever, radiotherapy (RT), especially CSRT, can cause several serious late sequelae such as neurocognitive dysfunction, endocrine dysfunction, growth disturbances, and secondary malignancy.\n6\n High‐dose chemotherapy (HDCT) with autologous stem cell rescue has been investigated in infant brain tumors including MB to reduce, defer, or omit RT to minimize the risk of irreversible sequelae of RT, particularly CSRT, and this approach showed success in some studies.\n7\n, \n8\n Also, some studies have suggested that further dose‐escalation using tandem HDCT might further improve outcomes in the treatment of recurrent or high‐risk brain tumors.\n9\n, \n10\n With this background, we hypothesized that the dose of CSRT might be reduced without jeopardizing survival rate if chemotherapy is intensified with tandem HDCT in high‐risk MB.\n\nFrom 2005, we performed reduced‐dose CSRT followed by tandem HDCT in patients with high‐risk MB, and reported early results of this study in 2012 with 20 patients.\n11\n However, the previous report had its limitations in terms of small number of patients, short follow‐up duration, and lack of molecular study. Therefore, we reported the results of longer follow‐ups with a larger number of enrolled patients. Molecular studies were also performed to investigate the effect of molecular subgroups on the clinical outcome in patients using this treatment strategy.\n\n2 METHODS\n2.1 Patients\nNewly diagnosed high‐risk MB patients over 3 years of age were enrolled in this study from October 2005 to April 2018. High‐risk MB was defined as MB with metastatic disease (M+), postoperative residual tumor > 1.5 cm2 (R+), or large cell/anaplastic histology. This study was approved by the Institutional Review Board of our center, and written informed consent was obtained from the parents or guardians of each patient.\n\n2.2 Treatment\nDetailed information of treatment was described in the previous report.\n11\n Briefly, two cycles of pre‐RT chemotherapy were given before RT, and four cycles post‐RT chemotherapy were given with reduced dose by 25% before tandem HDCT. A cisplatin‐etoposide‐cyclophosphamide‐vincristine regimen and a carboplatin‐etoposide‐ifosfamide‐vincristine regimen were used in alternation. Peripheral blood stem cells (PBSCs) were collected during the recovery phase after the first chemotherapy cycle.\n\nRadiation dose was initially 23.4 Gy of CSRT, 30.6 Gy of primary site RT, and 21.6 Gy of boost to gross seeding nodule for all patients. After experiencing three relapses from nine M+ patients during the early study period (from October 2005 through December 2007), CSRT dose was increased to 30.6 Gy for M+ patients over 6 years of age or for patients with anaplastic MB. RT was administered at 1.8 Gy/d for 5 d/wk. All patients were treated with three‐dimensional photon beams until December 2015; thereafter, patients were treated with proton beams.\n\nCTE (carboplatin, thiotepa, and etoposide) and CyM (cyclophosphamide and melphalan) regimens were used for the first and second HDCT, respectively. In 2014, we published a paper studying the toxicity during tandem HDCT using CTE/CyM regimen in brain tumor. In this paper, age younger than 8 years was a significant predictor of hepatic veno‐occlusive disease (VOD), and all six patients who died from treatment‐related mortality (TRM) during the second HDCT were younger than 9 years of age.\n12\n With these results, we reduced the dose of tandem HDCT for young children: 90% for children aged ≥6‐9 years and 80% for ≥3‐6 years. As a result, 3 out of 6 patients aged ≥3‐6 years received 80% dose and 7 out of 12 patients aged ≥6‐9 years received 90% dose. Patients received heparin at a dose of 100 IU/kg/d and lipo‐prostaglandin E1 (Alprostadil, Eglandin; Mitsubishi Tanabe Pharma Co.) at a dose of 1 mg/kg/d through continuous infusion for prophylaxis of VOD. We allowed an approximate 12‐week interval without treatment between the first and second HDCT.\n\n2.3 Surveillance of late complications\nLate effects were evaluated annually after the second HDCT. Endocrine, ophthalmologic, auditory, cardiac, and respiratory problems were evaluated along with cognitive function. The diagnosis of growth hormone deficiency was based on a declining growth rate, and it was confirmed by biochemical testing. Hypothyroidism was diagnosed by elevated thyrotropin levels. Adrenal insufficiency was diagnosed on the basis of the failure to increase cortisol levels after corticotropin‐releasing hormone administration.\n\nCognitive function was evaluated using the Korean version of the Wechsler Intelligence Scales of Children (K‐WISC) and Korean version of Wechsler Adult Intelligence Scale (K‐WAIS). Korean version of the Wechsler Intelligence Scales of Children‐III and K‐WAIS‐III were used until 2011, and thereafter, K‐WISC‐IV and K‐WAIS‐IV were used. Korean version of the Wechsler Intelligence Scales of Children‐III/K‐WAIS‐III used 10 subtests to calculate the Verbal intelligence quotient (IQ) Scale and Performance IQ scale score; 5 subtests (Information, Similarities, Arithmetic, Vocabulary, and Comprehension in K‐WISC‐III/Information, Similarities, Arithmetic, Vocabulary, and Digit span in K‐WAIS‐III) for Verbal IQ and 5 (Picture Completion, Coding, Picture Arrangement, Block Design, and Object Assembly in K‐WISC‐III and Block Design, Matrix Reasoning, Visual Puzzles, Symbol Search, and Coding in K‐WAIS‐III) for Performance IQ. Full‐Scale IQ (FSIQ) is a composite of the Verbal and Performance scores. In the K‐WISC‐IV and K‐WAIS‐IV, 10 core subtests are used to create 4‐factor index scores, and FSIQ is computed from all 10 core subtests.\n\n2.4 Molecular study\nFormalin‐fixed, paraffin‐embedded tissues were used, and all tumor specimens were reviewed by a pathologist to determine the percentage of viable tumor and their adequacy for molecular tests. For molecular subgrouping, the nCounter® system (NanoString Technologies) was used according to the methods proposed by Northcott et al in 2012.\n13\n All procedures were performed according to the manufacturer's instructions. A customized cancer panel, designed to cover the exonic DNA sequences of 351 cancer genes was used for DNA sequencing. DNA preparation, panel sequencing, and bioinformatics analysis were performed as previously published.\n14\n\n\n\n2.5 Statistics\nDifferences in continuous variables were calculated using Mann‐Whitney U test. EFS rate and overall survival (OS) rate were estimated using the Kaplan‐Meier method, and the difference of the survival curve was compared with the log‐rank test. Cumulative incidences (CI) of relapse/progression and TRM were estimated with competing risk methods.\n15\n Relapse/progression and TRM were regarded as competing risks with each other.\n\n3 RESULTS\n3.1 Patients characteristics\nFrom October 2005 to April 2018, 40 patients (23 males and 17 females) were enrolled in this study. The median age at diagnosis was 8.5 years (range, 3.8‐31.5 years). Nineteen (47.5%) patients had gross residual tumor > 1.5 cm2 after surgery, and 28 (70.0%) patients had metastatic disease at initial diagnosis. M stages were M1 in 1 patient, M2 in 8, M3 in 18 patients, and M4 in 1 patient. Histologically, 26 patients had classic types, 3 had desmoplastic/nodular types, and 11 had anaplastic types.\n\n3.2 Molecular subgroup\nAmong the 40 patients, tissues at diagnosis were available for 25 patients. The results of NanoString assay and Next‐generation Sequencing (NGS) study are summarized in Table 1. After RNA extraction, three RNA samples were excluded because they did not meet the quality standard. NanoString assay of samples of the remaining 22 patients successfully classified 19 patients into 1 wingless (WNT), 2 sonic hedgehog (SHH), 8 Group 3, and 8 Group 4. The remaining three patients were not classifiable with the NanoString method because the results after class prediction analysis did not fit any subtype. Panel sequencing of DNA could be performed in 17 patients. It revealed CTNNB1 mutations (1 S33P and 1 S33F) with loss of chromosome 6 in two patients (one WNT and one unclassifiable in NanoString assay). One patient who was not classifiable with NanoString method had stopgain (S733*, VAF 37.27%) and frameshift (L431fs, VAF 4.14%) mutation of PTCH1. TP53 mutation (R158H) was found in only one WNT patient. No MYCN amplification was observed in these patients. Taking the NanoString assay and panel sequencing results together, we could classify 21 patients into subgroup; 2 WNT, 3 SHH, 8 Group 3, and 8 group 4. Figure 1 illustrates the molecular subgroup along with their clinical and pathological features.\n\nTABLE 1 Results of molecular study\n\nPatients no\tNanoString assay\tPanel sequencing\na\n\n\tSubgroup\t\n2\tGroup 3\tN‐S\tGroup 3\t\n4\tFail\tFail\tfail\t\n5\tUnclassifiable\tFail\tUnclassifiable\t\n7\tFail\tFail\tfail\t\n8\tGroup 3\tFail\tGroup 3\t\n10\tGroup 4\tN‐S\tGroup 4\t\n11\tSHH\tFail\tSHH\t\n12\tWNT\t\nCTNNB1 S33F, Chr 6 loss, TP53 R158H\tWNT\t\n13\tGroup 4\tFail\tGroup 4\t\n14\tGroup 4\tFail\tGroup 4\t\n16\tGroup 3\t\nBRCA2 1858_1859 del\tGroup 3\t\n19\tUnclassifiable\tN‐S\tUnclassifiable\t\n21\tGroup 4\tN‐S\tGroup 4\t\n22\tSHH\tFail\tSHH\t\n23\tGroup 4\tN‐S\tGroup 4\t\n25\tFail\t\nCTNNB1 S33P, Chr 6 loss\tWNT\t\n27\tGroup 3\tN‐S\tGroup 3\t\n28\tGroup 3\tN‐S\tGroup 3\t\n29\tGroup 4\tN‐S\tGroup 4\t\n30\tGroup 4\tN‐S\tGroup 4\t\n32\tGroup 4\tN‐S\tGroup 4\t\n34\tGroup 3\t\nTSC1 G389*, CDKN2A/2B del\tGroup 3\t\n37\tUnclassifiable\t\nPTCH1 S733*, PTCH1 L431fs, PIK3CA E542K\tSHH\t\n39\tGroup 3\tN‐S\tGroup 3\t\n40\tGroup 3\t\nSMARCA4 T910M\tGroup 3\t\nAbbreviations: del, deletion; fs, frameshift mutation; N‐S, no significant alteration; SHH, sonic hedgehog; WNT, wingless.\n\na Only pathogenic or likely pathogenic variants were illustrated.\n\nJohn Wiley & Sons, LtdFIGURE 1 Molecular subgroups of patients. Molecular subgroups incorporating the results of NanoString and DNA sequencing are illustrated along with the clinical features and outcomes. CSRT, craniospinal radiotherapy; TRM, treatment‐related mortality\n\n3.3 Treatment of patients\nFigure 2 shows the flow of enrolled patients. All enrolled patients including two patients who showed progression during the post‐RT chemotherapy underwent the first HDCT. The two patients who experienced progression during post‐RT chemotherapy received additional RT and salvage chemotherapy with topotecan/cyclophosphamide. One patient showed a partial response after salvage treatment, but the other patient showed progression. Both of them proceeded to tandem HDCT. Second HDCT was administered to all patients except one patient who refused to proceed to second HDCT. One patient who experienced relapse after the first HDCT also proceeded to the second HDCT as salvage treatment.\n\nFIGURE 2 Flow of patients. Treatment courses of enrolled patients are summarized. All enrolled patients including two patients who showed progression during the induction chemotherapy underwent the first HDCT. Second HDCT was given to all patients except 1 patient who refused to proceed to second HDCT. CCR, continuous complete remission; HDCT, high‐dose chemotherapy; PD, progressive disease; TRM, treatment‐related mortality\n\nCraniospinal radiotherapy dose was 23.4 Gy in 20 patients (6 M0, 14 M+) and 30.6 Gy in 20 patients (6 M0, 14 M+). Craniospinal radiotherapy dose according to the M stage and histology is illustrated in Figure 3. In nine patients, boost RT was administered to a gross metastatic nodule. Proton beam therapy was administered to 11 patients.\n\nFIGURE 3 Relapse according to M stage, histology, and CSRT dose. Treatment outcome according to the M stage, histology, and CSRT dose is illustrated. The numbers in parentheses indicate the number of patients in each group. CSRT, craniospinal radiotherapy\n\nDuring the tandem HDCT, the median numbers of infused CD34+ cells were 35.4 (10.9‐98.0) × 106/kg in the first HDCT and 35.6 (7.6‐157.0) × 106/kg in the second HDCT. The median number of days required to reach an Absolute Neutrophil Count of more than 0.5 × 109/L was 8 days (7‐10 days) in the first HDCT and 9 days (7‐12 days) in the second HDCT. Platelet recovery more than 20 × 109/L required a median 19 days (13‐99 days) in the first HDCT and 22.5 days (13‐294 days) in the second HDCT. Among 15 patients who underwent HDCT after 2015, the dose of HDCT was reduced in 10 patients under 9 years of age; 90% in 7 patients and 80% in 3 patients. Acute toxicities ≥ Common Terminology Criteria for Adverse Events grade 3 during the tandem HDCT are summarized according to the study period in Table 2. The frequencies of stomatitis, diarrhea, liver enzyme elevation, and hypokalemia were higher in the first HDCT. Hepatic VOD occurred in nine patients (23.1%) during the second HDCT; four of them recovered with conservative management, and the other five received intensive care management including continuous renal replacement therapy and ventilator care.\n\nTABLE 2 Acute toxicities after HDCT\n\nParameters\tHDCT1 (n = 40)\tHDCT2 (n = 39)\t\nUntil 2014 (n = 25)\tAfter 2015 (n = 15)\tUntil 2014 (n = 25)\tAfter 2015 (n = 14)\t\nHematologic toxicity\t\nCD34+ cells (×106/kg)\na\n\n\t42.5 (11.1‐98.0)\t28.1 (10.9‐57.5)\t37.1 (9.5‐157.0)\t33.1 (7.6‐97.3)\t\nDays to reach an ANC 500/μL\na \n, \n\nb\n\n\n\t8 (7‐10)\t8 (7‐10)\t9 (8‐12)\t8 (7‐9)\t\nDays to reach a PLT count 20 000/μL\na \n, \n\nc\n\n\n\t18 (13‐35)\t21 (14‐99)\t22 (13‐294)\t24 (15‐88)\t\nDays of BT ≥ 38.0°C, d (range)\na\n\n\t5 (0‐10)\t2 (0‐6)\t2 (0‐7)\t0 (0‐3)\t\nPositive blood culture, no. (%)\t2 (8.0)\t2 (13.3)\t4 (16.0)\t2 (14.3)\t\nNon‐hematologic toxicity\t\nStomatitis, no. (%)\t21 (84.0)*\n\t7 (46.7)*\n\t2 (8.0)\t0 (0.0)\t\nVomiting, no. (%)\t4 (16.0)\t1 (6.7)\t2 (8.0)\t2 (14.3)\t\nDiarrhea, no. (%)\t10 (40.0)\t3 (20.0)\t6 (24.0)\t5 (35.7)\t\nElevation of liver enzyme, no. (%)\t15 (60.0)\t9 (60.0)\t1 (4.0)\t0 (0.0)\t\nHyperbilirubinemia, no. (%)\t1 (4.0)\t1 (6.7)\t2 (8.0)\t0 (0.0)\t\nRenal insufficiency, no. (%)\t0 (0.0)\t0 (0.0)\t2 (8.0)\t0 (0.0)\t\nHypokalemia, no. (%)\t13 (52.0)\t4 (26.7)\t10 (40.0)*\n\t0 (0.0)*\n\t\nHyperkalemia, no. (%)\t2 (8.0)\t1 (6.7)\t2 (8.0)\t0 (0.0)\t\nHyponatremia, no. (%)\t0 (0.0)\t0 (0.0)\t2 (8.0)\t1 (7.1)\t\nHypernatremia, no. (%)\t1 (4.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nHepatic VOD, no. (%)\t0 (0.0)\t1 (6.7)\t7 (28.0)\t2 (14.3)\t\nMyocarditis, no. (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nAbbreviations: ANC, absolute neutrophil count; BT, body temperature; HDCT, high‐dose chemotherapy; PLT, platelet; VOD, veno‐occlusive disease.\n\na Median (range).\n\nb The first day ANC exceeded 500 neutrophils/mL for 3 consecutive days.\n\nc The first day PLT count exceeded 20 000 platelets/mL without transfusion for 7 d.\n\n* \nP < .05\n\nJohn Wiley & Sons, Ltd3.4 Events and survival\nTreatment‐related mortality occurred in six patients (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Four patients died from acute TRM during the second HDCT. Three of them died from hepatic VOD and multi‐organ failure (MOF) at 1.9, 2.3, and 3.3 months after the second HDCT. All of them were under 9 years at the time of second HDCT, and two of them underwent HDCT after 2016 and received reduced dose (90%) of HDCT. Another patient with acute TRM died of RSV pneumonia 1.1 months after the second HDCT. Two patients died from late TRMs. One of them had severe VOD and acute renal failure during the second HDCT, which progressed to chronic renal failure. The patient admitted to the hospital with Influenza A viral pneumonia and died of progressive interstitial lung disease and acute respiratory distress syndrome (ARDS) at 30 months after the HDCT. The other patient had been suffering from recurrent infections such as pneumonia, urinary tract infection, peritonitis, and ventro‐peritoneal shunt infection after the HDCT, and died from pneumonia/ARDS at 46 months after the second HDCT.\n\nRelapse/progression occurred in four patients (three at the spinal cord and one at the primary site) with 10.4 ± 0.3% of 5‐year CI; two during the induction chemotherapy, one after the first HDCT, and one after the second HDCT. After the change of RT strategy from 2008 (increased CSRT dose to 30.6 Gy for M+ patients over 6 years or for patients with anaplastic MB), only one patient with R+/M0 and anaplastic histology experienced relapse. Relapse/progression according to the M stage, histology, and CSRT dose is illustrated in Figure 3. Of 12 M0 patients, only one patient who had an anaplastic tumor and had a significant postoperative residual tumor experienced relapse at the primary site within the local RT field after receiving 30.6 Gy of CSRT/23.4 Gy of local RT. No recurrence was observed in six patients with M0/classic histology who received 23.4 Gy of CSRT. Among 14 M+ patients who received 23.4 Gy of CSRT, three experienced relapses and all of them were metastatic relapses at the spinal cord. All 14 M+ patients who received 30.6 Gy of CSRT remain progression free regardless of histology. According to the molecular subgroup, one patient with SHH MB and one patient with Group 3 MB had relapse/progression (Figure 1). All of the four patients who experienced relapse/progression eventually died despite salvage treatments, and as a result, the 5‐year EFS and OS of all patients were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. There were no differences in EFS and OS according to the M stage (Figure 4).\n\nFIGURE 4 Survival of patients. Event‐free survival and overall survival of all patients and the differences according to the M stage are analyzed\n\n3.5 Late effects and long‐term outcome\nLate effects were evaluated in 25 patients including 6 patients who were treated with proton beams. Late effect evaluations were performed periodically, and the results of last evaluation for each patient were used for the analysis. Median age of patients at the evaluation was 19.2 years (range, 7.6‐36.5) years, and median time after the second HDCT was 7.5 years (range, 1.2‐12.3 years). Summary of late effects is illustrated in Table 3. High‐tone hearing loss was the most prevalent late effect, but only two patients needed hearing aids. Endocrine problems and dyslipidemia were also common. Five patients developed grade 1 chronic kidney disease (median estimated glomerular filtration rate 74.5 mL/min/1.73 m2, range 72.3‐84.0 mL/min/1.73 m2), and none of these patients experienced VOD during the tandem HDCT. One patient who received 23.4 Gy of CSRT developed meningioma on the anterior falx at 13 years after initial diagnosis. Vertical growth was evaluated excluding the five patients who were diagnosed after 18 years of age (Figure 5A). Median Z‐score at 5 years after the second HDCT was −2.66 (range, 5.31‐1.33). Patients who received 23.4 Gy of CSRT seemed to have better results in the growth retardation, but there was no statistical significance (Figure 5B).\n\nTABLE 3 Late complications\n\nLate complications\tUntil 2014 (n = 17)\tAfter 2015 (n = 8)\t\nNo.\t%\tNo.\t%\t\nEndocrine\t\nHypothyroidism\t9\t52.9\t1\t12.5\t\nGrowth hormone deficiency\t10\t58.8\t2\t25.0\t\nGlucocorticoid deficiency\t2\t11.8\t0\t0.0\t\nSex hormone deficiency\na\n\n\t7\t41.2\t2 (n=3)\t66.7\t\nPrecocious puberty\t1\t5.9\t1\t12.5\t\nDyslipidemia\t7 (2)\nb\n\n\t41.2\t1\t12.5\t\nHearing loss\t11 (2)\nb\n\n\t64.7\t7\t87.5\t\nOpthalmologic\t\nCataract\t2\t11.8\t0\t0.0\t\nOptic neuropathy\t0\t0.0\t1\t12.5\t\nChronic lung disease\t0\t0.0\t0\t0.0\t\nRenal\t\nChronic kidney disease\t3\t17.6\t2\t25.0\t\nCardiac\t0\t0.0\t0\t0.0\t\nHeart dysfunction\t0\t0.0\t0\t0.0\t\nArrhythmia\t1 (1)\nb\n\n\t5.9\t0\t0.0\t\nOthers\t\nMeningioma\t1\t5.9\t0\t0.0\t\nSMA syndrome\t0\t0.0\t1\t12.5\t\nBarrett esophagus\t1\t5.9\t0\t0.0\t\nNAFLD\t1\t5.9\t0\t0.0\t\nGenu valgum\t1\t5.9\t0\t0.0\t\nSpastic hand deformity\t1\t5.9\t0\t0.0\t\na Sex hormone deficiency was evaluated in patients who reached puberty.\n\nb The numbers in parenthesis indicate the number of patients with CTCAE grade 3 or higher.\n\nJohn Wiley & Sons, LtdFIGURE 5 Late effects. A, Annual Z‐score of heights of each patient are plotted. B, Patients who received 23.4 Gy of CSRT seemed to have better results in the growth retardation, but there was no statistical significance. C, Z‐score of FSIQ and 4‐factor index score of K‐WISC‐IV or K‐WAIS‐IV are plotted. CSRT, craniospinal radiotherapy; FSIQ, Full‐Scale intelligence quotient; PRI, perceptual reasoning index; PSI, processing speed index; VCI, verbal comprehension index; WMI, working memory index\n\nCognitive function test was performed at median 4.8 (range, 0.9‐10.1) years after the second HDCT. Korean version of the Wechsler Intelligence Scales of Children‐III or K‐WAIS‐III were used in 2 patients, and K‐WISC‐IV or K‐WAIS‐IV were used in the remaining 23 patients. Median values for FSIQ were 71 (range, 47‐108); ≤69 in 8 patients, 70‐79 in 9 patients, and ≥80 in 8 patients. The detailed results of patients who had K‐WISC‐IV or K‐WAIS‐IV are illustrated in Table 4 and Figure 5C.\n\nTABLE 4 Cognitive function test\n\nK‐WISC‐IV (N = 11)\tMean\tSD\tRange\tK‐WAIS‐IV (N = 12)\tMean\tSD\tRange\t\n\nVerbal comprehension index\n\t\nVerbal comprehension index\n\t\nSimilarities\t4.8\t3.5\t1‐11\tSimilarities\t9.1\t2.8\t4‐13\t\nVocabulary\t6.5\t2.5\t2‐10\tVocabulary\t7.4\t3.0\t3‐12\t\nComprehension\t5.4\t3.0\t1‐10\tInformation\t8.6\t2.6\t5‐14\t\n\nPerceptual reasoning index\n\t\nPerceptual reasoning index\n\t\nBlock design\t7.1\t4.3\t1‐13\tBlock design\t6.0\t3.5\t3‐13\t\nPicture concepts\t6.0\t3.8\t1‐11\tMatrix reasoning\t8.3\t2.9\t3‐12\t\nMatrix reasoning\t6.4\t4.7\t1‐13\tVisual puzzle\t6.9\t2.3\t3‐12\t\n\nWorking memory index\n\t\nWorking memory index\n\t\nDigit span\t5.5\t3.0\t1‐9\tDigit span\t6.7\t4.0\t1‐12\t\nLetter‐number sequencing\t6.5\t2.7\t2‐10\tArithmetic\t7.3\t2.2\t2‐10\t\n\nProcessing speed index\n\t\nProcessing speed index\n\t\nCoding\t3.2\t2.0\t1‐8\tSymbol search\t4.7\t2.5\t1‐9\t\nSymbol search\t4.5\t3.7\t1‐11\tCoding\t5.5\t3.7\t1‐12\t\nAbbreviations: K‐WAIS, Korean version of Wechsler Adult Intelligence Scale; K‐WISC, Korean version of Wechsler Intelligence Scales of Children; SD, standard deviation.\n\nJohn Wiley & Sons, LtdThere was no significant difference in the long‐term outcome including endocrinologic problems, height, and cognitive function according to the RT modalities. With respect to educational attainment and employment, among the 14 patients currently over 18 years of age (two patients were diagnosed at adult age), 10 entered university after the end of treatment. Among five patients over 23 years of age, three had jobs.\n\n4 DISCUSSION\nIn this study, tandem HDCT was performed to reduce the CSRT dose to 23.4 or 30.6 Gy in high‐risk MB patients. This approach resulted in promising survival rate showing 10.4% of CI of relapse/progression and 71.1% of 5‐year EFS, and the EFS was not different according to the presence of metastasis. EFS of high‐risk MB remained less than 50% in the earlier studies until 1990.\n16\n, \n17\n, \n18\n Many different strategies, including HDCT, hyperfractionated accelerated radiotherapy, or concurrent chemotherapy during CSRT, have been employed to overcome the poor outcome in the last decades.\n4\n, \n10\n, \n19\n, \n20\n In the HIT 2000 trial with metastatic MB incorporating 40.0 Gy of hyperfractionated CSRT showed 5‐year EFS and OS were 62% and 74%, respectively.\n4\n Children's Oncology Group (COG) studied concurrent carboplatin during 36 Gy of CSRT as a radiosensitizer in metastatic MB, and 5‐year EFS and OS were reported as 78% and 71%, respectively.\n20\n In a study by Gajjar et al, 48 patients with high‐risk MB were treated with CSRT (36‐39.6 Gy) followed by four cycles of HDCT and autologous stem cell rescue, and the 5‐year EFS rate was 70%.\n10\n Considering that the CSRT dose of the previous studies was 36‐40 Gy, it is meaningful that our study showed similar EFS using 23.4‐30.6 Gy of CSRT. These findings suggest that, in patients with high‐risk MB, dose‐intense chemotherapy may reduce the necessary dose of CSRT. In our study, all of the six patients with M0/classic histology (who were classified into high‐risk MB due to the presence of residual tumor) were progression free with 23.4 Gy of CSRT. Also, all 14 M+ patients who received 30.6 Gy of CSRT remain progression free. These results can suggest that CSRT dose could be reduced to 30.6 Gy if tandem HDCT is combined even in M+ patients.\n\nHowever, the biggest problem of the study was the high incidence of TRM. Especially, hepatic VOD was the main cause of TRM. During the second HDCT, hepatic VOD occurred in nine (23.1%) patients, and three of them died of progressive hepatic VOD and MOF. Tandem HDCT is associated with greater toxicity and a higher TRM rate than single HDCT, particularly during the second HDCT. The variable intensity of tandem HDCT regimens could result in different outcomes and toxicity profiles.\n10\n, \n19\n A more intensive tandem HDCT regimen is associated with a higher TRM rate but also might be associated with a lower relapse/progression rate. The optimal combination of regimens for tandem HDCT has not yet been determined. In our institution, the CTE/CyM regimen has been used since 2005 after these two regimens have separately shown efficacy in pediatric high‐risk or recurrent brain tumors.\n21\n, \n22\n In our previous study reporting the toxicity during tandem HDCT using CTE/CyM regimen, age younger than 8 years was the significant predictor for hepatic VOD, and all six patients who died from toxicity during the second HDCT were younger than 9 years of age.\n12\n Due to these results, we reduced the dose of HDCT according to the age at HDCT during the late study period. Despite the dose reduction strategy, two young patients still developed hepatic VOD and died. This high rate of TRM cannot be accepted even considering the severity of the patient's disease. Therefore, further study is needed to determine the optimal dose of HDCT especially in young children. In this study, infused stem cell doses were higher than the usual dose because stem cells were collected during the first cycle of chemotherapy. However, it is unlikely that the higher stem cell dose had an effect on the high TRM considering the stem cell dose of patients with TRM.\n\nIn this study, three patients showed disease progression while on treatment (two during the post‐RT chemotherapy and one before the second HDCT). All of them eventually died of disease progression even after the tandem HDCT. A patient who achieved PR after salvage treatment and underwent tandem HDCT remained progression free for 18 months after the second HDCT, but the other two patients died shortly after the second HDCT. Given the high toxicity of HDCT and the results of such treatment, HDCT should be carefully considered in patients who progressed during treatment, especially in patients who did not respond to the salvage treatment.\n\nGene expression profiling in MB by several study groups identified discrete molecular subgroups within MB, and consensus for MB subgroups was established in 2012 proposing four subgroup designations: WNT, SHH, Group 3, and Group 4.\n23\n It is known that the four molecular subgroups differ in many aspects such as genetics, demographics, clinical features, and prognosis.\n24\n Risk stratification of non‐infant, childhood MB (age: 3‐17 years) in the context of subgroups was further refined at the consensus conference in 2015,\n25\n and the most recent clinical trials in MB have incorporated molecular risk stratification into the trial design.\n3\n In the present study, we retrospectively performed NanoString and DNA sequencing with archival tissues to investigate the effect of molecular subgroups on the clinical outcome of this study. NanoString assay successfully classified 19 patients into subgroups, and two additional patients could be classified into WNT and SHH subgroups, respectively, because of the pathogenic mutation of pathognomonic genes of each subgroup such as CTNNB1 or PTCH1. There were insufficient number of patients in each subgroup, and a few patients had relapses; thus, the number of patients was insufficient to tell the difference according to the molecular subgroups. Two patients with WNT MB were allocated in the high‐risk group due to the presence of residual tumor. Considering the good prognosis with standard treatment in WNT MB, this group of patients needs to be excluded in our future trial. Also, real‐time molecular study and prospective risk stratification will be needed for the future clinical trial.\n\nIn the late effect evaluation, endocrine dysfunction and high‐tone hearing loss were frequent, but grade 3‐4 toxicity was not common. There was no patient who developed secondary neoplasm except one patient who had meningioma. Cognitive function after pediatric brain tumor treatment has been one of the main concerns. It has been known that adult pediatric brain tumor survivors exhibited progressive decline in IQ scores because of the slow rate of acquisition of new information and skills.\n26\n A conceptual model suggested that core cognitive abilities (such as working memory, information processing speed, and attention) underlie poor intellectual outcomes and academic achievements in pediatric medulloblastoma survivors,\n26\n, \n27\n and this theoretical model was empirically evaluated in a recent study.\n28\n The cognitive function in our study showed similar results in terms of IQ score compared to the previous studies despite reducing the CSRT dose,\n29\n, \n30\n and this can be partly because HDCT can also negatively affect the cognitive outcome.\n30\n In particular, among the four indices of the cognitive function test, the z‐score of the processing speed index (PSI) was lower than the other 3 index scores, in our study. Considering the results of King et al\n28\n that processing speed was the core cognitive skill most widely associated with neurodevelopmental risk factors, future studies will need to carefully evaluate changes in the PSI to predict prognosis of cognitive function. For the potential future direction, germline genomics of the host could be one of the predictive markers of individual variation in neurocognitive morbidity after the treatment of pediatric brain tumor.\n31\n In this study, there were no significant differences in late effects according to the RT modalities, but a longer follow‐up duration is needed in patients who were treated with proton beams.\n\nIn the present study, HDCT was effective in reducing progression rate while using lower CSRT dose, but it also showed severe toxicities. In the next phase, it is necessary to balance the efficacy and toxicity of HDCT. Reducing the intensity of HDCT may contribute to decrease not only the TRM but also the late effects. However, there are also concerns about how this strategy will affect survival. Another strategy that can be used is to consider the introduction of intrathecal (IT) methotrexate. Intraventricular or intravenous methotrexate has been used in some protocols showing promising results.\n32\n, \n33\n In the German HIT 2000 trial of non‐metastatic MB patients younger than 4 years, intraventricular and high‐dose intravenous methotrexate were combined with conventional chemotherapy resulting in 80 ± 6% of 5‐year OS.\n32\n HIT 2000 trial including children and young adolescents also showed that a higher cumulative dose of intraventricular methotrexate was associated with better survival although there were frequent infectious complications associated with reservoir.\n33\n Because there is still a problem with late sequelae even after the reduced‐dose RT, introduction of IT methotrexate could be considered as an alternative option to further reduce the RT dose.\n\nIn conclusion, strategy using tandem HDCT following reduced‐dose CSRT was successful in terms of low progression rate. However, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in future studies.\n\nETHIC STATEMENT\nThis study was approved by the Institutional Review Board of our center (IRB No. 2005‐12‐009 and No. 2015‐11‐053) and written informed consent was obtained from the parents or guardians of each patient.\n\nCONFLICT OF INTEREST\nThe authors declare that they have no competing interests.\n\nAUTHORS' CONTRIBUTION\nStudy design: KWS, DHL, and HJS; clinical data collection and analysis: JWL, KWS, HWC, HYJ, JKH, KHY, HHK, and YSJ; genomic data collection and analysis: JWL and Y.S; article writing: JWL, KWS, and DHL; review the data and article: KWS, DHL, YS, and HJS.\n\nACKNOWLEDGMENT\nThis study was supported by grants from the National R & D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (no. 1520210 and no. 1720270). We thank Miss So Yeon Lee for her research assistance.\n\nDATA AVAILABILITY STATEMENT\nAll data used in the production of this manuscript are available on request.\n==== Refs\nREFERENCES\n1 \n\nOstrom \nQT \n, \nGittleman \nH \n, \nLiao \nP \n, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007‐2011\n. Neuro Oncol . 2014 ;16 (suppl 4 ):iv1 ‐iv63\n.25304271 \n2 \n\nThomas \nA \n, \nNoel \nG \n. Medulloblastoma: optimizing care with a multidisciplinary approach\n. J Multidiscip Healthc . 2019 ;12 :335 ‐347\n.31118657 \n3 \n\nNorthcott \nPA \n, \nRobinson \nGW \n, \nKratz \nCP \n, et al. Medulloblastoma\n. Nat Rev Dis Primers . 2019 ;5 :11 .30765705 \n4 \n\nvon Bueren \nAO \n, \nKortmann \nR‐D \n, \nvon Hoff \nK \n, et al. Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters\n. J Clin Oncol . 2016 ;34 :4151 ‐4160\n.27863192 \n5 \n\nEsbenshade \nAJ \n, \nKocak \nM \n, \nHershon \nL \n, et al. A phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high‐risk medulloblastoma (protocol POG 9631): a report from the Children's Oncology Group\n. Pediatr Blood Cancer . 2017 ;64 .\n6 \n\nMoxon‐Emre \nI \n, \nBouffet \nE \n, \nTaylor \nMD \n, et al. Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients with medulloblastoma\n. J Clin Oncol . 2014 ;32 :1760 ‐1768\n.24516024 \n7 \n\nGuerra \nJA \n, \nDhall \nG \n, \nMarachelian \nA \n, et al. Marrow‐ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation in pediatric patients with malignant brain tumors\n. Bone Marrow Transplant . 2017 ;52 :1543 ‐1548\n.28783147 \n8 \n\nLafay‐Cousin \nL \n, \nSmith \nA \n, \nChi \nSN \n, et al. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high‐dose chemotherapy\n. Pediatr Blood Cancer . 2016 ;63 :1527 ‐1534\n.27145464 \n9 \n\nSung \nKW \n, \nYoo \nKH \n, \nCho \nEJ \n, et al. High‐dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high‐risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor\n. Pediatr Blood Cancer . 2007 ;48 :408 ‐415\n.17066462 \n10 \n\nGajjar \nA \n, \nChintagumpala \nM \n, \nAshley \nD \n, et al. Risk‐adapted craniospinal radiotherapy followed by high‐dose chemotherapy and stem‐cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma‐96): long‐term results from a prospective, multicentre trial\n. Lancet Oncol . 2006 ;7 :813 ‐820\n.17012043 \n11 \n\nSung \nKW \n, \nLim \nDH \n, \nSon \nMH \n, et al. Reduced‐dose craniospinal radiotherapy followed by tandem high‐dose chemotherapy and autologous stem cell transplantation in patients with high‐risk medulloblastoma\n. Neuro Oncol . 2013 ;15 :352 ‐359\n.23258845 \n12 \n\nLee \nSH \n, \nSon \nMH \n, \nSung \nKW \n, et al. Toxicity of tandem high‐dose chemotherapy and autologous stem cell transplantation using carboplatin‐thiotepa‐etoposide and cyclophosphamide‐melphalan regimens for malignant brain tumors in children and young adults\n. J Neurooncol . 2014 ;120 :507 ‐513\n.25108776 \n13 \n\nNorthcott \nPA \n, \nShih \nDJH \n, \nRemke \nM \n, et al. Rapid, reliable, and reproducible molecular sub‐grouping of clinical medulloblastoma samples\n. Acta Neuropathol . 2012 ;123 :615 ‐626\n.22057785 \n14 \n\nLee \nB \n, \nLee \nJW \n, \nShim \nJH \n, et al. Clinical relevance of genomic changes in recurrent pediatric solid tumors\n. Transl Oncol . 2018 ;11 :1390 ‐1397\n.30216764 \n15 \n\nKim \nHT \n. Cumulative incidence in competing risks data and competing risks regression analysis\n. Clin Cancer Res . 2007 ;13 :559 ‐565\n.17255278 \n16 \n\nZeltzer \nPM \n, \nBoyett \nJM \n, \nFinlay \nJL \n, et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study\n. J Clin Oncol . 1999 ;17 :832 ‐845\n.10071274 \n17 \n\nTaylor \nRE \n, \nBailey \nCC \n, \nRobinson \nKJ \n, et al. Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET‐3 chemotherapy\n. Eur J Cancer . 2005 ;41 :727 ‐734\n.15763649 \n18 \n\nKortmann \nR‐D \n, \nKühl \nJ \n, \nTimmermann \nB \n, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91\n. Int J Radiat Oncol Biol Phys . 2000 ;46 :269 ‐279\n.10661332 \n19 \n\nDufour \nC \n, \nKieffer \nV \n, \nVarlet \nP \n, et al. Tandem high‐dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high‐risk medulloblastoma or supratentorial primitive neuro‐ectodermic tumors\n. Pediatr Blood Cancer . 2014 ;61 :1398 ‐1402\n.24664937 \n20 \n\nJakacki \nRI \n, \nBurger \nPC \n, \nZhou \nT \n, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group phase I/II study\n. J Clin Oncol . 2012 ;30 :2648 ‐2653\n.22665539 \n21 \n\nGraham \nML \n, \nHerndon \nJE \n, \nCasey \nJR \n, et al. High‐dose chemotherapy with autologous stem‐cell rescue in patients with recurrent and high‐risk pediatric brain tumors\n. J Clin Oncol . 1997 ;15 :1814 ‐1823\n.9164190 \n22 \n\nDunkel \nIJ \n, \nBoyett \nJM \n, \nYates \nA \n, et al. High‐dose carboplatin, thiotepa, and etoposide with autologous stem‐cell rescue for patients with recurrent medulloblastoma Children's Cancer Group\n. J Clin Oncol . 1998 ;16 :222 ‐228\n.9440746 \n23 \n\nTaylor \nMD \n, \nNorthcott \nPA \n, \nKorshunov \nA \n, et al. Molecular subgroups of medulloblastoma: the current consensus\n. Acta Neuropathol . 2012 ;123 :465 ‐472\n.22134537 \n24 \n\nKool \nM \n, \nKorshunov \nA \n, \nRemke \nM \n, et al. Molecular subgroups of medulloblastoma: an international meta‐analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas\n. Acta Neuropathol . 2012 ;123 :473 ‐484\n.22358457 \n25 \n\nRamaswamy \nV \n, \nRemke \nM \n, \nBouffet \nE \n, et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus\n. Acta Neuropathol . 2016 ;131 :821 ‐831\n.27040285 \n26 \n\nPalmer \nSL \n. Neurodevelopmental impact on children treated for medulloblastoma: a review and proposed conceptual model\n. Dev Disabil Res Rev . 2008 ;14 :203 ‐210\n.18924159 \n27 \n\nWolfe \nKR \n, \nMadan‐Swain \nA \n, \nKana \nRK \n. Executive dysfunction in pediatric posterior fossa tumor survivors: a systematic literature review of neurocognitive deficits and interventions\n. Dev Neuropsychol . 2012 ;37 :153 ‐175\n.22339228 \n28 \n\nKing \nTZ \n, \nAilion \nAS \n, \nFox \nME \n, \nHufstetler \nSM \n. Neurodevelopmental model of long‐term outcomes of adult survivors of childhood brain tumors\n. Child Neuropsychol . 2019 ;25 :1 ‐21\n.28956496 \n29 \n\nYoo \nHJ \n, \nKim \nH \n, \nPark \nHJ \n, \nKim \nDS \n, \nRa \nYS \n, \nShin \nHY \n. Neurocognitive function and health‐related quality of life in pediatric Korean survivors of medulloblastoma\n. J Korean Med Sci . 2016 ;31 :1726 ‐1734\n.27709849 \n30 \n\nSzentes \nA \n, \nErős \nN \n, \nKekecs \nZ \n, et al. Cognitive deficits and psychopathological symptoms among children with medulloblastoma\n. Eur J Cancer Care (Engl) . 2018 ;27 :e12912.30204287 \n31 \n\nSiegel \nBI \n, \nKing \nTZ \n, \nRupji \nM \n, et al. Host genome variation is associated with neurocognitive outcome in survivors of pediatric medulloblastoma\n. Transl Oncol . 2019 ;12 :908 ‐916\n.31078964 \n32 \n\nvon Bueren \nAO \n, \nvon Hoff \nK \n, \nPietsch \nT \n, et al. Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology\n. Neuro Oncol . 2011 ;13 :669 ‐679\n.21636711 \n33 \n\nPompe \nRS \n, \nvon Bueren \nAO \n, \nMynarek \nM \n, et al. Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: feasibility, acute toxicity and evidence for efficacy\n. Eur J Cancer . 2015 ;51 :2634 ‐2642\n.26346136\n\n",
"fulltext_license": "CC BY",
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"journal": "Cancer medicine",
"keywords": "craniospinal radiotherapy; high-dose chemotherapy; long-term follow-up; medulloblastoma; treatment-related mortality",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D061888:Craniospinal Irradiation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D060828:Induction Chemotherapy; D008297:Male; D008527:Medulloblastoma; D009364:Neoplasm Recurrence, Local; D000077982:Progression-Free Survival; D011879:Radiotherapy Dosage; D015996:Survival Rate; D055815:Young Adult",
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"title": "Promising survival rate but high incidence of treatment-related mortality after reduced-dose craniospinal radiotherapy and tandem high-dose chemotherapy in patients with high-risk medulloblastoma.",
"title_normalized": "promising survival rate but high incidence of treatment related mortality after reduced dose craniospinal radiotherapy and tandem high dose chemotherapy in patients with high risk medulloblastoma"
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"abstract": "Immunologic alterations, such as cryoglobulinemia, have been described in the acute phase of primary cytomegalovirus (CMV) infections in immunocompetent patients. There are few references about these influences of a primary CMV infection in an at-risk kidney transplant recipient (donor positive/recipient negative-D(+)/R(-)). Herein we have described the case of a 46-year-old man, who was naive for CMV and underwent renal transplantation from a CMV+ cadaveric donor, thereby at high risk for disease transmission. The immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and steroids. The recipient was not treated with CMV prophylaxis, but rather regularly screened for possible pre-emptive treatment. At 35 days after transplantation, he was admitted because of deep vein thrombosis (DVT) in the transplant ipsilateral lower limb accompanied by oliguria, fever, and epigastric pain accompanied by type II cryoglobulinemia and acute CMV infection. The direct antiglobulin test (DAT) for C3d was positive. The cryoglobulins displayed anti-red blood cell specificity, with maximum activity at 4°C. The DVT was successfully treated with locoregional thrombolysis in combination with anticoagulant therapy. The DAT improved with CMV treatment and increased steroid therapy. The urine output and renal function tests improved with resolution of the thrombosis, achieving complete recovery without sequelae. Our hypothesis was that CMV infection triggered cryoglobulinemia. The blood disorder caused hyperviscosity, inducing DVT. This case, of CMV infection showed associated cryoglobulinemia presenting with antierythrocyte specificity in a kidney transplant recipient.",
"affiliations": "U.O.C. Chirurgia dei Trapianti, Fondazione Policlinico Tor Vergata, University of Rome \"Tor Vergata\", Rome, Italy.",
"authors": "Sforza|D|D|;Iaria|G|G|;Tariciotti|L|L|;Manuelli|M|M|;Anselmo|A|A|;Ciano|P|P|;Manzia|T M|TM|;Toti|L|L|;Tisone|G|G|",
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"issn_linking": "0041-1345",
"issue": "45(7)",
"journal": "Transplantation proceedings",
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"mesh_terms": "D000918:Antibody Specificity; D003449:Cryoglobulinemia; D003586:Cytomegalovirus Infections; D004912:Erythrocytes; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020246:Venous Thrombosis",
"nlm_unique_id": "0243532",
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"title": "Deep vein thrombosis as debut of cytomegalovirus infection associated with type II cryoglobulinemia, with antierythrocyte specificity in a kidney transplant recipient: a case report.",
"title_normalized": "deep vein thrombosis as debut of cytomegalovirus infection associated with type ii cryoglobulinemia with antierythrocyte specificity in a kidney transplant recipient a case report"
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"abstract": "In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.",
"affiliations": "Anesthesiology, Moffitt Cancer Center, Tampa, USA.;Anesthesiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, USA.;Physical Medicine and Rehabilitation, AT Still University, Arizona, USA.;Anesthesiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, USA.;Anesthesiology/Pain Medicine, H Lee Moffitt Cancer Center and Research Institute, Tampa, USA.",
"authors": "Muncey|Aaron R|AR|;Aldawoodi|Nasrin N|NN|;Chitneni|Ahish|A|;Hoffman|Jamie P|JP|;Escher|Allan R|AR|",
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"doi": "10.7759/cureus.13653",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.13653\nAnesthesiology\nOncology\nHematology\nIntraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy\nMuacevic Alexander Adler John R Muncey Aaron R 1 Aldawoodi Nasrin N 2 Chitneni Ahish 3 Hoffman Jamie P 2 Escher Allan R Jr.4 \n1 \nAnesthesiology, Moffitt Cancer Center, Tampa, USA \n\n2 \nAnesthesiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, USA \n\n3 \nPhysical Medicine and Rehabilitation, AT Still University, Arizona, USA \n\n4 \nAnesthesiology/Pain Medicine, H Lee Moffitt Cancer Center and Research Institute, Tampa, USA \n\nAllan R. Escher Jr. allan.escher@moffitt.org\n2 3 2021 \n3 2021 \n13 3 e136532 3 2021 Copyright © 2021, Muncey et al.2021Muncey 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/45220-intraoperative-hypotension-in-a-patient-with-antithrombin-deficiency-bilateral-pulmonary-emboli-and-cefazolin-allergyIn medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.\n\nantithrombin iiipulmonary embolifollicular neoplasmallergy and anaphylaxisthyroid neoplasmantithrombin deficiencyhypercoagulable statemottlingtryptasestanford emergency manualThe 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\nEmergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.\n\nAT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].\n\nAT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].\n\nTwo different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].\n\nPerioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].\n\nCase presentation\nA 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.\n\nThe patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.\n\nAt this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.\n\nThe operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy. \n\nA serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).\n\nFigure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.\nCTA, computed tomography angiogram; POD, postoperative day\n\nLower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).\n\nFigure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks\nUS, ultrasound; DVT, deep venous thrombosis\n\nFigure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.\nDVT, deep venous thrombosis\n\nDoppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).\n\nFigure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses\nMR, magnetic resonance\n\nThe patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.\n\nDiscussion\nThis case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.\n\nAccording to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.\n\nThere was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.\n\nFortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.\n\nThis case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.\n\nThe patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.\n\nConclusions\nThis complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n\nWe thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures.\n==== Refs\nReferences\n1 Inherited antithrombin deficiency: a review Haemophilia Patnaik MM Moll S 1229 1239 14 2008 19141163 \n2 Management of antithrombin deficiency: an update for clinicians Expert Rev Hematol Bravo-Perez C Vicente V Corral J 397 405 12 2019 31116611 \n3 Epidemiology of perioperative anaphylaxis Presse Med Mertes PM Volcheck GW Garvey LH Takazawa T Platt PR Guttormsen AB Tacquard C 758 767 45 2016 27181074 \n4 Perioperative anaphylaxis Immunol Allergy Clin North Am Mertes PM Lambert M Gueant-Rodriguez RM 429 451 29 2009 19563990 \n5 Epinephrine and its use in anaphylaxis: current issues Curr Opin Allergy Clin Immunol Simons KJ Simons FE 354 361 10 2010 20543673 \n6 Identification and management of perioperative anaphylaxis J Allergy Clin Immunol Pract Volcheck GW Hepner DL 2134 2142 7 2019 31154032 \n7 Stanford Anesthesia Cognitive Aid Program*. Emergency Manual. Cognitive aids for perioperative critical events 1 2021 Stanford Anesthesia Cognitive Aid Program: Howard SK CL Goldhaber-Fiebert SN Gaba DM Harrison TK: Emergency Manual: Cognitive aids for perioperative critical events. Creative Commons BY-NC-ND 2016 http://emergencymanual.stanford.edu \n8 Acute pulmonary embolism. Aggressive therapy with anticoagulants and thrombolytics Postgrad Med Handler JA Feied CF 61 62 97 1995 https://www.tandfonline.com/doi/abs/10.1080/00325481.1995.11945946?journalCode=ipgm20 \n9 Effect of epinephrine on platelet-activating factor-stimulated human vascular smooth muscle cells J Allergy Clin Immunol Vadas P Perelman B 1329 1333 129 2012 22460068 \n10 Practical guidelines for perioperative hypersensitivity reactions J Investig Allergol Clin Immunol Laguna JJ Archilla J Dona I 216 232 28 2018 \n11 Using baseline and peak serum tryptase levels to diagnose anaphylaxis: a review Clin Rev Allergy Immunol Passia E Jandus P 366 376 58 2020 32034676 \n12 Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase Clin Exp Immunol Krishna MT York M Chin T 399 404 178 2014 25070464 \n13 The serum tryptase test: an emerging robust biomarker in clinical hematology Expert Rev Hematol Valent P Sperr WR Sotlar K 683 690 7 2014 25169217\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "allergy and anaphylaxis; antithrombin deficiency; antithrombin iii; follicular neoplasm; hypercoagulable state; mottling; pulmonary emboli; stanford emergency manual; thyroid neoplasm; tryptase",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13653",
"pmc": null,
"pmid": "33665061",
"pubdate": "2021-03-02",
"publication_types": "D002363:Case Reports",
"references": "19563990;25070464;20543673;31154032;27181074;25169217;19141163;31116611;29411702;7816717;32034676;22460068",
"title": "Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.",
"title_normalized": "intraoperative hypotension in a patient with antithrombin deficiency bilateral pulmonary emboli and cefazolin allergy"
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"abstract": "In 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes.\nAt the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy.\nData were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk.\nData were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12-6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3-37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14-1.31; p < 0.001]).\nNo association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.",
"affiliations": "Centre for Infectious Disease Epidemiology and Research (CIDER), School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.;South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa.;Maternal and Adolescent Child Health Systems (MatCH), School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.;Maternal and Adolescent Child Health Systems (MatCH), School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.;KwaZulu-Natal Department of Health, Pietermaritzburg, South Africa.;Prince Mshiyeni Memorial Hospital, Durban, South Africa.;Prince Mshiyeni Memorial Hospital, Durban, South Africa.;Division of Human Genetics, Department of Medicine, University of Cape Town, Cape Town, South Africa.;Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.;VP Health Systems, KwaZulu-Natal, Durban, South Africa.;South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa.;Programmatic Pharmacovigilance Unit, National Department of Health, Pretoria, South Africa.;National Department of Health, Pretoria, South Africa.;KwaZulu-Natal Department of Health, Pietermaritzburg, South Africa.",
"authors": "Mehta|Ushma C|UC|https://orcid.org/0000-0002-0032-3171;van Schalkwyk|Cari|C|https://orcid.org/0000-0001-5154-1390;Naidoo|Prineetha|P|https://orcid.org/0000-0002-6025-5393;Ramkissoon|Arthi|A|https://orcid.org/0000-0003-4061-6320;Mhlongo|Otty|O|https://orcid.org/0000-0002-4263-8040;Maharaj|Niren R|NR|https://orcid.org/0000-0002-9210-9913;Naidoo|Niree|N|https://orcid.org/0000-0003-3912-8258;Fieggen|Karen|K|https://orcid.org/0000-0002-2910-6306;Urban|Michael F|MF|https://orcid.org/0000-0001-9150-3620;Krog|Shaun|S|https://orcid.org/0000-0002-0985-9474;Welte|Alex|A|https://orcid.org/0000-0001-7139-7509;Dheda|Mukesh|M|https://orcid.org/0000-0002-9355-5405;Pillay|Yogan|Y|https://orcid.org/0000-0003-3366-0892;Moran|Neil F|NF|https://orcid.org/0000-0002-6498-8762",
"chemical_list": null,
"country": "South Africa",
"delete": false,
"doi": "10.4102/sajhivmed.v20i1.971",
"fulltext": "\n==== Front\nSouth Afr J HIV MedSouth Afr J HIV MedHIVMEDSouthern African Journal of HIV Medicine1608-96932078-6751AOSIS HIVMED-20-97110.4102/sajhivmed.v20i1.971Original ResearchBirth outcomes following antiretroviral exposure during pregnancy: Initial results from a pregnancy exposure registry in South Africa https://orcid.org/0000-0002-0032-3171Mehta Ushma C. 1https://orcid.org/0000-0001-5154-1390van Schalkwyk Cari 2https://orcid.org/0000-0002-6025-5393Naidoo Prineetha 3https://orcid.org/0000-0003-4061-6320Ramkissoon Arthi 3https://orcid.org/0000-0002-4263-8040Mhlongo Otty 4https://orcid.org/0000-0002-9210-9913Maharaj Niren R. 5https://orcid.org/0000-0003-3912-8258Naidoo Niree 5https://orcid.org/0000-0002-2910-6306Fieggen Karen 6https://orcid.org/0000-0001-9150-3620Urban Michael F. 7https://orcid.org/0000-0002-0985-9474Krog Shaun 8https://orcid.org/0000-0001-7139-7509Welte Alex 2https://orcid.org/0000-0002-9355-5405Dheda Mukesh 9https://orcid.org/0000-0003-3366-0892Pillay Yogan 10https://orcid.org/0000-0002-6498-8762Moran Neil F. 41 Centre for Infectious Disease Epidemiology and Research (CIDER), School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa2 South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa3 Maternal and Adolescent Child Health Systems (MatCH), School of Public Health, University of the Witwatersrand, Johannesburg, South Africa4 KwaZulu-Natal Department of Health, Pietermaritzburg, South Africa5 Prince Mshiyeni Memorial Hospital, Durban, South Africa6 Division of Human Genetics, Department of Medicine, University of Cape Town, Cape Town, South Africa7 Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa8 VP Health Systems, KwaZulu-Natal, Durban, South Africa9 Programmatic Pharmacovigilance Unit, National Department of Health, Pretoria, South Africa10 National Department of Health, Pretoria, South AfricaCorresponding author: Ushma Mehta, ushma.mehta@uct.ac.za30 9 2019 2019 20 1 97119 3 2019 04 5 2019 © 2019. The Authors2019Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.Background\nIn 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes.\n\nObjectives\nAt the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy.\n\nMethod\nData were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk.\n\nResults\nData were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12–6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3–37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14–1.31; p < 0.001]).\n\nConclusion\nNo association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.\n\npharmacovigilanceantiretroviralspregnancybirth outcomessafetybirth defectcongenital malformationssurveillance\n==== Body\nIntroduction\nDespite improvements in recent years, maternal and infant mortality rates in South Africa remain unacceptably high. HIV/AIDS (complicated by Tuberculosis and pneumonia), haemorrhage and hypertension account for more than two-thirds of the avoidable maternal deaths.1 The early initiation of antiretroviral therapy (ART) in pregnant women and women of child-bearing age has well-described benefits and has become standard practice in South Africa.2 In 2013, the World Health Organization (WHO) recommended the initiation of lifelong antiretroviral treatment for pregnant women diagnosed with HIV during pregnancy, regardless of CD4 cell count or clinical stage (Option B+).3 This approach was adopted by the South African National Department of Health (NDoH) in April in the same year.4 However, various reports have suggested that antiretroviral therapy may increase the risk of adverse birth outcomes (ABOs), including preterm delivery (PTD),5,6 low birth weight (LBW),7,8 small for gestational age (SGA),9,10 stillbirth (SB),9,11 neonatal death (NND)9,11 and, according to some reports, congenital malformations (CM).12,13,14 In most of these situations, the contribution of the underlying HIV infection and other maternal risk factors is difficult to rule out.15 Further studies have investigated the relative safety of different ART regimens,16,17 while others have assessed whether the timing of the initiation of ART, in relation to conception, influences the risk of ABOs.6,7,8,18\n\nQuestions persist about the risk of ABOs associated with exposure to specific antiretrovirals such as nevirapine (NVP) and protease inhibitors (PIs).16,19 Most recently, concerns about the safety in pregnancy of dolutegravir (DTG), a long-anticipated agent with an improved efficacy and safety profile, have been raised by early signals of higher rates of neural tube defects in infants exposed in utero at the time of conception compared to efavirenz (EFV).12\n\nA robust meta-analysis of data from the outcomes of 2026 live births of women exposed to EFV during the first trimester found only one case of a neural tube defect, and the rate of CM was not higher than in infants exposed to non-EFV-containing first-trimester regimens.20 In preclinical primate and clinical studies, in utero exposure to tenofovir (TDF) has been associated with growth restriction, bone mineral content reduction and bone toxicity.21,22 However, the Antiretroviral Pregnancy Registry (APR), based in the United States, concluded that a doubling and 1.5-fold increase in risk of CMs, with EFV and TDF, respectively, could be ruled out based on the American background CM rate of 2.7%.23 Similarly, no increase in the risk of CM has been observed with NVP to date.24\n\nGiven the relative rarity of CMs, lack of available data on baseline rates of CM from low- and middle-income countries and the great number of exposures in HIV-affected settings like South Africa, Ford and others have recommended ongoing prospective birth outcomes surveillance.20,25,26,27 Concerns about the safety of ART in the unborn child, applicable to millions of women who are and will be receiving ART during pregnancy in the coming years, will persist in the absence of controlled studies that are able to quantify the risk of potential CMs and other ABOs such as LBW, PTD, NND, SB and SGA. Hence, in 2013, the South African NDoH implemented a pregnancy exposure registry (PER) and birth defect surveillance (BDS) system at selected sentinel sites to assess the association of medicines commonly used in pregnant women, initially focusing on antiretrovirals, with ABOs. In partnership with the KwaZulu-Natal (KZN) Provincial Department of Health and other supporting partners, the project was launched on 07 October 2013.\n\nWe describe the findings of the first 12 months of this project, focusing on the risk of CM at birth and other ABOs (pregnancy losses, NND, SGA, PTD and LBW) in infants born to mothers with confirmed exposure to specific antiretroviral regimens. Two separate analyses were conducted for CM (where the risk of teratogenic exposure is highest in the first trimester when organogenesis occurs) and for other ABOs where the risk period of exposure is less well defined and more likely to be continuous.\n\nMethods\nSetting\nThe birth defect (referred to as ‘congenital malformations’ [CM] in this article) surveillance was carried out at Prince Mshiyeni Memorial Hospital (PMMH) in the KwaZulu-Natal province of South Africa, where approximately 14 000 deliveries occur each year. HIV prevalence among pregnant women in this province at the time of the study was steadily increasing from approximately 37.4% (95% CI 35.8% – 39.0%) in 2011 to 44.4% (95% CI 42.5% – 46.3%) in 2015,28 with antenatal ART initiation rates increasing from 85.4% in 2013 and 2014 to 97.2% in 2015 and 2016.29\n\nSurveillance method\nFive surveillance nurses surveyed the hospital’s maternity wards and labour ward registers to identify women who had recently delivered. The surveillance nurses collected information on demographics, health and health-seeking behaviour during pregnancy, obstetric and neonatal history, HIV status, medical conditions, medicine use including folate, calcium and iron supplementation, and labour/delivery information. As they only worked from Monday to Friday during office hours, there was incomplete coverage of deliveries during this initial pilot period. The women’s maternity case records (MCRs) were used to confirm and expand on what was reported during a brief interview. A systematic neonatal surface examination, recommended by the WHO, was performed on all live infants and stillbirths (whenever feasible) by the trained surveillance nurses.30 Birth weight, length, head circumference and reported gestational age at birth were collected from the MCR. Gestational age at birth is routinely documented by nursing staff based on the estimated date of delivery calculated during antenatal care based on the last menstrual period (LMP) reported at the first antenatal visit, and confirmed by ultrasound, when available. Major CMs identified at birth were recorded on the surveillance system’s case record form. In the case of infants in the nursery who were premature, febrile, ill, or too fragile to be unnecessarily handled, the surveillance nurses did not physically examine the infant themselves but rather referred to the clinical notes to complete the form.\n\nIn the case of major CMs, digital photographs were taken if consent was obtained from the mother. A CM confirmation form was completed and signed by a neonatologist or senior clinician in the nursery ward designated to support the surveillance system. A CM review panel comprising medical geneticists, paediatricians and neonatologists confirmed diagnoses of CMs by viewing photographs, the results of any chromosomal tests, and the assessment of the clinician at the time of the event. The panel classified CMs as major (i.e. structural changes that have significant medical, social or cosmetic consequences for the affected individual, and typically require medical intervention), or minor, and advised on inclusion in the risk factor analyses. We were guided by the example of Holmes;31 in that single minor anomalies, normal variations, birth marks, chromosomal or genetic anomalies/disorders, positional deformities, features of prematurity and physiological abnormalities were excluded from the analysis of teratogenic potential.\n\nNeonates born in surrounding clinics or other health facilities but admitted to PMMH were not included in this analysis. Babies born at home, in the community or en-route to the PMMH who were brought directly to the hospital without first attending any other health facility were included. CMs diagnosed after discharge were not identified or reported in this analysis.\n\nMiscarriages and terminations of pregnancy (TOPs) were not systematically captured, as they are not managed in the maternity wards. Complicated congenital anomalies detected on ultrasound may sometimes have been referred to Inkosi Albert Luthuli Central Hospital and delivered there, especially if neonatal surgery was anticipated. Early medical or curettage-based TOPs that did not require foeticide of the baby (i.e. before 24 weeks gestational age or a lethal foetal anomaly) would have been conducted at PMMH but might not have been captured in the maternity registers depending on the gestation.\n\nA concurrent prospective pregnancy exposure registry project involving the recruitment of pregnant women at their first antenatal visit was implemented at 3 midwife-run obstetric units (MOUs) within the PMMH catchment area. However, as the data for this cohort were not available at the time of the analysis, we are unable to report on this prospective cohort.\n\nRisk analyses\nWe conducted two separate risk analyses for ART exposure:\n\nAnalysis A (see 2.3.4.): Risk factors for major CM detected at birth. As the critical exposures are likely to be during organogenesis (T1), we compared exposure ‘during the entire first trimester’ with no exposure during any part of the first trimester. Women for whom the timing of ART was uncertain in relation to the first trimester were excluded from this analysis.\n\nAnalysis B (see 2.3.5.): Risk factors for a composite of other ABOs, which included:\n■ Pregnancy losses: Birth of a dead foetus.\n\n■ Neonatal deaths (included deaths before 28 days post-delivery which occurred prior to hospital discharge).\n\n■ Small for gestational age (live births with birth weight below the 10th percentile using WHO criteria).\n\n■ Preterm delivery (live births born at gestational age less than 37 weeks).\n\n■ Low birth weight (live births born at weight < 2500 g)\n\n\n\nAs these outcomes could be linked to a broader range of exposure timings than just T1, we compared any ART exposure during pregnancy to a comparator group with no HIV/ART exposure (i.e. HIV-uninfected women).\n\nExclusions from analyses\nMaternal deaths whose medical records were not accessible for review or where there was no delivery of a foetus were excluded from the analysis. Maternal deaths are systematically reviewed for causes through other national procedures.1 A central register of deliveries housed at the hospital was used to establish the rate of capture of deliveries through the surveillance system. Women who switched from a NVP-based regimen to an EFV-based regimen or vice versa, were excluded from all drug-specific and time-period-specific (‘entire first trimester’ vs. ‘any part of pregnancy’) analyses. Pregnancies were excluded from all risk analyses (though not from the overall demographic and ART exposure breakdown) if:\n\nHIV status was unknown.\n\nHIV status was recorded as positive but there was no record of ART (as this constitutes sub-standard care in the local context and is associated with substantially worse outcomes).\n\nBirth outcomes were unknown (alive or dead).\n\nMultiple births were recorded (as multiple births are known to have higher complication rates and higher rates of CMs).\n\nFigure 1 below provides a breakdown of the cohort of pregnant women (deliveries) and their birth outcomes primarily by HIV exposure and ART exposure.\n\nFIGURE 1 Birth outcomes by HIV/ART exposure status among pregnant women in the cohort.\n\nAntiretroviral therapy exposures\nThe present analysis is based on 1 year of data from an ongoing surveillance system – approximately 18 months after first-line therapy was being changed from TDF/lamivudine (3TC)/NVP to TDF/emtricitabine (FTC)/EFV. Exposures to (second-line) PIs, as well as non-standard regimens, were limited. Given the a priori concern about non-nucleoside reverse transcriptase inhibitors (NNRTIs), risk factor analysis was confined to assessing the effects of (1) any ART regimen, (2) EFV-based regimens and (3) NVP-based regimens.\n\nTo verify the timings of exposures reported in the MCR, women were also explicitly asked, after delivery, whether ART had been initiated ‘before’ or ‘during’ the pregnancy.\n\nRisk analysis A – Major congenital malformations detected at birth\nFor consideration of major CM, risk factor timing is critical because the period of pregnancy when maternal drug exposure has the greatest teratogenic potential is the embryonic phase during which organ differentiation is completed. In addition, this analysis of 1 year of data was not adequately powered to conduct finely differentiated pregnancy-stage-specific analyses, and the routinely collected data on LMP, gestational age at birth and the timing of treatment initiation were often missing or poorly captured and could lead to misclassification of exposure timing. Hence, we prefer a conservative approach of only classifying birth outcomes as exposed if ART was initiated at least 2 weeks before LMP. However, as a significant number of ART initiations appear to be during the first trimester, we also considered a broader exposure category in which ART initiations within 15 weeks post LMP are included. These exposed groups were compared to an unexposed group defined as all HIV-unexposed births as well those exposed to HIV and ART beginning more than 15 weeks after LMP (see Table 3).\n\nRisk analysis B – Composite of other adverse birth outcomes\nIn the risk analysis for the composite endpoint of ABOs, known singleton birth outcomes among HIV-uninfected women were used as the comparator group. Studies about the effect of ART initiation in relation to the pregnancy have elicited conflicting findings on birth outcomes.5,6,7,17,32 Therefore, exposure groups assessed included any ART, EFV-based and NVP-based regimens initiated a) at any time before birth; b) before pregnancy (defined conservatively as 2 weeks before LMP); and c) after onset of pregnancy (defined as LMP plus 2 weeks). A 2-week exclusion window period around LMP was used to reduce the likelihood of misclassification in this analysis.\n\nStatistical analyses\nData were analysed with STATA 12 (StataCorp LP, College Station, TX, USA). For Analysis B, covariates included (in a multivariable binomial regression) included maternal age category (< 18, 18–35 or > 35 years), parity (0 = nulliparous; 1 = parous) and educational completion (none or primary vs. secondary or higher). Multivariable risk factor analysis was deemed inappropriate for Analysis A given the limited number of CMs detected. A p-value of < 0.05, conducted using a 2-sided t-test, was deemed to indicate statistical significance.\n\nEthical considerations\nApproval for this surveillance system was obtained from the South African Medical Research Council’s ethics committee (protocol EC015-7/2013 approved on 30 July 2013). As the PER/BDS system is mooted to become a national sentinel surveillance system, consent for routine data gathering was not required, but the digital photography of infants with CMs, as well as stillbirths, which is not routine, required explicit consent.\n\nResults\nOver 12 months (07 October 2013 to 06 October 2014), 10 417 (71.4%) of a total of 14 587 deliveries at PMMH were captured representing 10 517 birth outcomes, including 98 twin births and 1 triplet birth.\n\nMaternal demographics\nTable 1 provides a summary of maternal characteristics, stratified by HIV status. Of the 27 maternal deaths reported during the study period, 12 (44.4%) died prior to childbirth. Only 2 of the remaining 15 (13.3%) maternal deaths were captured by the surveillance team during the reporting year due to restricted access to these medical records at the time of data collection.\n\nTABLE 1 Maternal characteristics by HIV infection status.\n\nVariable\tTotal\tHIV uninfected\tHIV infected\tHIV status unknown\tHIV status association p‡\t\nN\t%\tIQR†\tN\t%\tIQR†\tN\t%\tIQR†\tN\t%\tIQR†\t\nNumber of mothers\t10 417\t-\t-\t6280\t60.3\t-\t4013\t38.5\t-\t124\t1.2\t-\t-\t\nMaternal age\t< 0.001\t\n< 18 years\t704\t6.8\t-\t620\t9.9\t-\t73\t1.8\t-\t11\t8.9\t-\t-\t\n18–35 years\t8596\t82.5\t-\t5197\t82.8\t-\t3299\t82.2\t-\t100\t80.6\t-\t-\t\n> 35 years\t1106\t10.6\t-\t463\t7.4\t-\t640\t15.9\t-\t3\t2.4\t-\t-\t\nUnknown\t11\t0.1\t-\t0\t0\t-\t1\t0.0\t-\t10\t8.1\t-\t-\t\nMedian\t25\t-\t21–30\t23\t-\t20–27\t28\t-\t23–32\t22\t-\t19–26\t< 0.001\t\nEducation\t0.214\t\nNone/primary\t808\t7.76\t-\t471\t7.5\t-\t328\t8.2\t-\t9\t7.3\t-\t-\t\nSecondary/Tertiary\t9538\t91.6\t-\t5773\t91.9\t-\t3665\t91.3\t-\t97\t78.2\t-\t-\t\nUnknown\t71\t0.7\t-\t33\t0.5\t-\t20\t0.5\t-\t18\t14.5\t-\t-\t\nCurrently employed\t1393\t13.4\t-\t696\t11.1\t-\t689\t17.2\t-\t8\t6.5\t\t< 0.001\t\nGravidity\t< 0.001\t\n1\t4060\t39.0\t-\t3127\t49.8\t-\t889\t22.2\t-\t44\t35.5\t-\t-\t\n2\t3509\t33.7\t-\t1857\t29.6\t-\t1610\t40.1\t-\t42\t33.9\t-\t-\t\n> 3\t2807\t27.0\t-\t1283\t20.4\t-\t1500\t37.4\t-\t24\t19.4\t-\t-\t\nUnknown\t41\t0.4\t-\t13\t0.2\t-\t14\t0.4\t-\t14\t11.3\t-\t-\t\nMedian\t2\t-\t1–3\t2\t-\t1–2\t2\t-\t2–3\t2\t-\t1–2\t< 0.001\t\nParity\t< 0.001\t\n0\t4309\t41.4\t-\t3265\t52.0\t-\t998\t24.9\t-\t46\t37.1\t-\t-\t\n1–2\t5285\t50.7\t-\t2602\t41.4\t-\t2613\t65.1\t-\t60\t48.4\t-\t-\t\n> 2\t809\t7.8\t-\t409\t6.5\t-\t396\t9.9\t-\t4\t3.2\t-\t-\t\nUnknown\t24\t0.2\t-\t4\t0.1\t-\t6\t0.1\t-\t14\t11.3\t-\t-\t\nAlcohol use during pregnancy\t< 0.001\t\nNon-user\t9352\t89.8\t-\t5724\t91.1\t-\t3542\t88.3\t-\t86\t69.4\t-\t-\t\nPast user\t786\t7.6\t-\t407\t6.5\t-\t370\t9.2\t-\t9\t7.3\t-\t-\t\nUser\t23\t0.2\t-\t9\t0.1\t-\t13\t0.3\t-\t1\t0.8\t-\t-\t\nUnknown\t256\t2.5\t-\t140\t2.2\t-\t88\t2.2\t-\t28\t22.6\t-\t-\t\nTobacco use during pregnancy\t0.003\t\nNon-user\t9766\t93.75\t-\t593\t94.4\t-\t3744\t93.3\t-\t91\t73.4\t-\t-\t\nPast user\t370\t3.55\t-\t192\t3.1\t-\t174\t4.3\t-\t4\t3.2\t-\t-\t\nUser\t9\t0.09\t-\t5\t0.1\t-\t4\t0.1\t-\t0\t0.0\t-\t-\t\nUnknown\t272\t2.61\t-\t152\t2.4\t-\t91\t2.3\t-\t23\t4.0\t-\t-\t\nIllicit substance use during pregnancy\t0.003\t\nNon-user\t9770\t93.8\t-\t5930\t94.4\t-\t3748\t93.4\t-\t92\t74.2\t-\t-\t\nPast user\t364\t3.5\t-\t192\t3.1\t-\t168\t4.2\t-\t4\t3.2\t-\t-\t\nUser\t4\t0.04\t-\t1\t0.0\t-\t3\t0.1\t-\t0\t0.0\t-\t-\t\nUnknown\t279\t2.7\t-\t157\t2.5\t-\t94\t2.3\t-\t28\t22.6\t-\t-\t\nGestational age at first ANC\t< 0.001\t\n< 12 weeks\t500\t4.8\t-\t275\t4.4\t-\t224\t5.6\t-\t1\t0.8\t-\t-\t\n12 to 20 weeks\t4057\t39.0\t-\t2415\t38.5\t-\t1632\t40.7\t-\t10\t8.1\t-\t-\t\n21 to 28 weeks\t3399\t32.6\t-\t2145\t34.2\t-\t1240\t30.9\t-\t14\t11.3\t-\t-\t\n> 28 weeks\t1092\t10.9\t-\t681\t10.8\t-\t405\t10.1\t-\t6\t4.8\t-\t-\t\nUnknown\t1369\t13.1\t-\t764\t12.2\t-\t512\t12.8\t-\t93\t75\t-\t-\t\nMedian age\t20\t-\t16-26\t21\t-\t16-26\t20\t-\t16-25\t24\t-\t18-28\t< 0.001\t\nNumber of ANC visits during current pregnancy\t< 0.001\t\n0–3 ANC visits\t2658\t25.52\t-\t1715\t27.3\t-\t932\t23.2\t-\t17\t13.7\t-\t-\t\n> 4 ANC visits\t7341\t70.47\t-\t4381\t69.8\t-\t2944\t73.4\t-\t16\t12.9\t-\t-\t\nUnknown\t418\t4.01\t-\t190\t3.0\t-\t137\t3.4\t-\t91\t73.4\t-\t-\t\nMedian\t5\t-\t3-6\t5\t-\t3-6\t5\t-\t4-7\t3\t-\t2-6\t< 0.001\t\nReported previous adverse pregnancy outcomes (N = 6316)§\t344\t5.4\t-\t151\t2.4\t-\t192\t4.8\t-\t1\t0.8\t-\t0.05\t\nMedical conditions\t\nPre-existing diabetes\t34\t0.3\t-\t26\t0.4\t-\t8\t0.2\t-\t0\t0.0\t-\t0.077\t\nEpilepsy\t53\t0.5\t-\t28\t0.4\t-\t24\t0.6\t-\t1\t0.8\t-\t0.217\t\nTuberculosis (TB)\t202\t1.9\t-\t53\t0.8\t-\t148\t3.7\t-\t1\t0.8\t-\t< 0.001\t\nSyphilis\t177\t1.7\t-\t81\t1.3\t-\t96\t2.4\t-\t0\t0.0\t-\t< 0.001\t\n† , IQR – Interquartile Range; ANC – Antenatal Care.\n\n‡ , The hypothesis in each case is that there is no association between known HIV-status and the characteristic described. At a 5% level of significance, a p-value of less than 0.05 can be interpreted as a significant association between HIV status and the given characteristic.\n\n§ , Analysis excludes primagravidae.\n\nMost of the 10 417 women (10 293, 98.8%) had a known HIV status, of whom 4013 (38.5%) were HIV-positive. The HIV-positive women had 4063 babies (live or stillborn). HIV-infected women tended to be older than HIV-uninfected women; teenage pregnancies in the HIV-uninfected group were 5 times more common than the HIV-infected cohort (9.9% vs. 1.8%). Self-reported use of alcohol, tobacco and illicit substances was higher among HIV-infected women.\n\nOnly 195 women (1.9%) did not seek any antenatal care before delivery. More than two-thirds (70.5%) of the cohort had four or more antenatal visits. However, almost half (43.1%) first sought care after 20 weeks of gestation. The prevalence of previous ABOs was reported for multigravidae (n = 6316) with only six women (0.1%) reporting previously giving birth to infants with CMs.\n\nHIV prevalence increased with age, reaching 58.3% (640/1106) in women over 35 years of age. The prevalence in multigravidae (49.2%) was more than twice that in primigravid women (21.9%). Women who reported being currently employed had a higher prevalence of HIV than unemployed women. Both TB and syphilis were more commonly reported in HIV-infected women.\n\nBirth outcomes\nAmong the birth outcomes reflected in Table 2, 10 197 were live births, 275 (2.6%) pregnancy losses, 85 (0.8%) NND, 852 (8.1%) SGA and 56 (0.5%) new-borns with CMs detected at birth (Supplementary Table 1). Thirty-seven of the CMs were eligible for inclusion in the teratogenicity analysis (Analysis A), of which 11 (29.7%) occurred in women on ART during pregnancy (described in Table 4). The other 19 CMs were excluded from the analysis based on Holmes’s criteria noted earlier. Extra two CMs were excluded from the risk analysis as they occurred among women whose ART exposure time was uncertain or who switched ART regimens during critical or uncertain times.\n\nTABLE 2 Birth outcome by HIV infection status.\n\nBirth outcome\tTotal\tHIV negative\tHIV positive\tHIV status unknown\tp†\t\nN\t%\tN\t%\tN\t%\tN\t%\t\nNumber of birth outcomes‡\t10 517\t-\t6330\t60.2\t4063\t38.6\t124\t1.2\t-\t\nLive births (incl. NND)\t10 197\t97.0\t6162\t97.3\t3941\t97.0\t94\t75.8\t0.249\t\nPregnancy losses (Stillbirths + Abortions)\t275\t2.6\t149\t2.4\t109\t2.7\t17\t13.7\t0.081\t\nNeonatal Death (NND)\t85\t0.8\t44\t0.7\t39\t1.0\t2\t2.4\t0.139\t\nCongenital malformations\t56\t0.5\t36\t0.6\t20\t0.5\t0\t0.0\t0.603\t\nCongenital malformations (included only)§\t37\t0.4\t26\t0.4\t11\t0.3\t0\t0.0\t0.242\t\nUnknown birth outcome\t45\t0.4\t10\t0.3\t13\t0.3\t13\t10.5\t-\t\nBirth weight in kg (Mean + s.d.)\t3.0\t0.6\t3.0\t0.6\t3.0\t0.7\t2.7\t0.9\t< 0.001\t\nSmall for gestational age (SGA) (< 10th percentile)\t852\t8.1\t482\t7.6\t364\t9.0\t6\t4.8\t0.011\t\nLow birth weight (LBW) (< 2500 g)\t1287\t12.2\t685\t10.8\t587\t14.4\t15\t12.1\t< 0.001\t\nBirth weight unknown\t34\t0.3\t18\t0.3\t15\t0.4\t1\t0.8\t-\t\nTwins/ triplets (1 set)\t199\t1.9\t99\t1.6\t100\t2.5\t0\t0.0\t0.001\t\nMale\t5288\t50.3\t3191\t50.4\t2043\t50.3\t54\t43.5\t0.383\t\nGestational age at birth\t-\t-\t-\t-\t-\t-\t-\t-\t< 0.001\t\nPreterm < 37 weeks\t2285\t21.7\t1281\t20.2\t970\t23.9\t34\t27.4\t-\t\nTerm delivery 37–40 weeks\t7578\t72.1\t4652\t73.5\t2874\t70.7\t52\t41.9\t-\t\nPost term > 40 weeks\t488\t4.6\t326\t5.2\t160\t3.9\t2\t1.6\t-\t\nUnknown\t166\t1.6\t71\t1.1\t59\t1.5\t36\t29.0\t-\t\n† , The hypothesis in each case is that there is no association between known HIV-status and the characteristic described. At a 5% level of significance, a p-value of less than 0.05 can be interpreted as a significant association between HIV status and the given characteristic.\n\n‡ , Denominator includes 98 twins and 1 set of triplets = 100 more infants than number of pregnant women.\n\n§ , Included cases are congenital malformations that could be influenced by environmental exposures and therefore included in teratogenicity analysis. Decision on whether or not to include cases are made by the congenital malformation review panel.\n\nOf the 3632 ART-exposed singleton births, the vast majority of births (3391, 93.4%) reported being on the recommended first-line adult ART regimen, TDF-FTC-EFV. There were only 96 singleton births (2.6%) exposed to NVP-based regimens during pregnancy, at least 58 (60.4%) of whom were already on treatment before pregnancy. In total, there were 3465 (95.4%) births exposed to an EFV-based ART regimen, of which 306 (8.8%) were initiated before the pregnancy and an additional 641 (18.5%) were initiated during the first trimester.\n\nAntiretroviral therapy during pregnancy\nTable 3 describes the in-utero antiretroviral exposures during the course of pregnancy. 3932 infants were exposed to ART during pregnancy (96.8% of HIV-exposed infants). Twin births and births exposed to more than one ART regimen during pregnancy were excluded from the risk analysis. Uncertain timing of exposures due to the uncertainty of the temporal ordering of LMP and ART initiation resulted in almost a third (30.4%) of all singleton births being excluded from analysis (1105 of 3632). Of the remaining births, 380 (10.4%) were exposed from conception, and 653 (18.0%) initiated treatment some time during the first trimester. In 56 cases, ART exposure was classified as having occurred prior to pregnancy based only on self-reported timing in the absence of a reported LMP.\n\nTABLE 3 Births with antiretroviral therapy exposure during pregnancy in HIV infected women.\n\nVariable\tTotal ever exposed in utero\tDefinitive and entire first trimester exposure\tAmbiguous/partial first trimester exposure\tFirst trimester non-exposure\tUnknown/uncertain exposure time (Excluded)\tSelf-reported as ‘Before pregnancy’ without exposure dates\t\nN\t%*\tN\t%†\tN\t%‡\tN\t%§\tN\t%¶\tN\t%††\t\nTotal births in HIV-infected women\t4063\t-\t-\t-\t-\t-\t-\t-\t-\t-\t-\t-\t\nNo ART exposure reported\t131\t3.2\t-\t-\t-\t-\t-\t-\t-\t-\t-\t-\t\nNumber exposed to ART regimen\t3932*\t96.8\t486\t12.4\t667\t17.0\t1541\t39.2\t1238\t31.5\t74\t1.9\t\nART regimens switched during pregnancy\t219\t5.4‡‡\t-\t-\t-\t-\t-\t-\t-\t-\t-\t-\t\nTwin babies exposed to ART regimen\t85\t2.1\t-\t-\t-\t-\t-\t-\t-\t-\t-\t-\t\nNumber exposed to ART regimen (excluding those who switched and excluding twin births)\t3632\t89.4\t380\t10.4\t653\t18.0\t1494\t41.1\t1105\t30.4\t56\t1.5\t\nRegimens (excluding those who switched and twin births)\t\nTDF/FTC/EFV\t3391\t-\t261\t7.7\t641\t18.9\t1473\t43.4\t1016\t30.0\t43\t1.3\t\nTDF/3TC/EFV\t57\t-\t30\t52.6\t0\t0.0\t3\t5.3\t24\t42.1\t1\t1.8\t\nTDF/FTC/NVP\t75\t-\t45\t60.0\t4\t5.3\t5\t6.7\t21\t29.0\t3\t4.0\t\nD4T/3TC/NVP\t8\t-\t5\t62.5\t0\t0.0\t0\t0.0\t3\t37.5\t1\t12.5\t\nOther EFV-based regimens**\t17\t-\t15\t88.2\t0\t0.0\t1\t5.9\t1\t5.9\t3\t17.6\t\nOther NVP-based regimens***\t13\t-\t8\t61.5\t1\t7.7\t0\t0.0\t4\t30.8\t2\t15.4\t\nPI-based regimens****\t30\t-\t7\t46.7\t4\t13.3\t4\t13.3\t15\t50.0\t0\t0.0\t\nMissing/Unknown regimens\t41\t-\t9\t22.0\t3\t7.3\t8\t19.5\t21\t51.2\t3\t7.3\t\n† , ART initiated before reported LMP and continued on the specific regimen throughout the first 15 weeks of pregnancy; in the absence of known LMP, ART initiated at least 12 months before delivery or in the absence of any dates, exposure self-reported by the woman as being initiated before pregnancy (i.e. last column: ‘Self-reported as ‘Before pregnancy’ without exposure dates’).\n\n‡ , Cases excluded from birth risk analysis because date of ART onset was reported to be between 2 weeks prior to LMP and LMP+15 weeks.\n\n§ , First trimester unexposed birth outcomes where ART was initiated at least 15 weeks after first date of the last menstrual period.\n\n¶ , Cases excluded: where date of ART onset was unknown; LMP date was unknown (and ART onset was reported as < 12 months prior to infant’s date of birth) or where there was discordance between reported dates of exposure and woman’s reporting of whether treatment was initiated before or during the pregnancy.\n\n†† , Cases that were classified as ‘Exposed’ based on the woman’s self-reported timing of ART exposure as being ‘before pregnancy’ but where LMP or onset date was not reported. These cases are included as Definitive and entire first trimester exposures.\n\n‡‡ , Regimen was switched in 2 twin pregnancies.\n\n* , Of 4063 HIV-exposed births, 3932 were exposed to ART in utero;\n\n** D4T/3TC/EFV or AZT/3TC/EFV;\n\n*** AZT/3TC/NVP or NVP/3TC/TDF;\n\n**** TDF/3TC/LPV/r; TDF/FTC/LPV/r; AZT/3TC/LPV/r; TDF/3TC/ATV/r; AZT/3TC/ATV/r; TDF/FTC/ATV/r.\n\nCongenital malformations at birth among HIV-exposed birth outcomes\nHIV infection in the mothers was reported in 11 of the 37 (29.7%) included CM cases (Table 2), all of whom received ART at some time during pregnancy as described in Table 4. Five of these infants were exposed to ART continuously from conception throughout T1. One of these had a regimen change to TDF/FTC/EFV during the second trimester of pregnancy; two were initiated on ART at some time during the first trimester, and four were initiated during the second trimester.\n\nTABLE 4 Summary of congenital malformations reported in HIV-infected women on antiretroviral treatment.\n\nNumber\tART regimen exposure/s\tOnset of ART regimen in relation to LMP†\tCongenital malformations\t\nDefinitive and Entire First Trimester Exposure\t\n1‡\tD4T/3TC/NVP\t5 years pre-LMP\tMicrocephaly, flat nasal bridge, short neck, left club foot\t\n2\tTDF/3TC/NVP\t3 years pre-LMP\tHydrocephalus\t\n3\tTDF/3TC/EFV\t4.3 years pre-LMP\tUnilateral hypoplastic thumb\t\n4§\tTDF/FTC/EFV\tSelf-reported as starting before pregnancy but start date recorded as 6 months post LMP\tTalipes equinovarus, and low set ears\t\nAmbiguous/Partial Exposure – First Trimester Initiation\t\n5¶\tTDF/3TC/NVP - switched to TDF/FTC/EFV in second trimester\tInitiated NVP-based regimen in first trimester\tLumbar Myelomeningocele\t\n6††\tTDF/FTC/EFV\t57 days post-LMP\tMyelomeningocele\t\n7\tTDF/FTC/EFV\t12 weeks post-LMP\tCleft Lip and Palate\t\nSecond Trimester ART Initiation\t\n8‡‡\tAZT/3TC/LPV/r\t4 months post-LMP\tHypospadias\t\n9\tTDF/FTC/EFV\t4 months post-LMP\tDysmorphic facial features, micrognathia, unilateral preaxial polydactyly\t\n10\tTDF/FTC/EFV\t4 months post-LMP\tExomphalos\t\n11\tTDF/FTC/EFV\t6 months post-LMP\tHypospadias\t\nART, antiretroviral therapy; LMP, last menstrual period; NVP, Nevirapine.\n\n† , LMP = First date of last menstrual period.\n\n‡ , Mother reported use of alcohol before pregnancy.\n\n§ , Case excluded from risk analysis due to uncertain timing of initiation in relation to pregnancy.\n\n¶ , Neonatal death post discharge.\n\n†† , Baby born at 3100 g 2 months before the estimated due date suggesting inaccurate LMP.\n\n‡‡ , Unusual regimen as mother was part of a clinical trial (no record of prior exposures to first line treatments).\n\nIn addition to the 2 neural tube defects reported among infants of the women on ART, a case of anencephaly was reported in an HIV-unexposed infant.\n\nRisk analyses\nThe numbers in Table 3 may not directly match with those in Tables 5 and 6 because cases with missing values for the outcomes concerned were excluded from the denominators in Tables 5 and 6.\n\nTABLE 5 Risk of congenital malformations detected at birth: Analysis A.\n\nVariable\tNumber of CM\tN\tUnadjusted Risk ratio\tp\t\nN\t%\tRisk ratio\t95% CI\t\nPrimary risk analysis\t\nRisk in HIV-negative pregnancies + HIV-positive late initiation pregnancies\t29\t0.4\t7532\t1.00\t-\t-\t\nART initiated before pregnancy\t3\t0.8\t368\t2.11\t0.65–6.92\t0.214\t\nEFV-based regimen initiated before pregnancy\t1\t0.3\t297\t0.87\t0.12–6.40\t0.895\t\nNVP-based regimen initiated before pregnancy\t2\t3.5\t56\t9.28\t2.27–37.94\t0.002\t\nSensitivity Analysis (including initiation during first 15 weeks post LMP)\t\nART initiated before LMP + during T1\t6\t0.6\t998\t1.56\t0.65–3.75\t0.319\t\nEFV-based regimen initiated before LMP + during T1\t3\t0.3\t915\t0.85\t0.26–2.79\t0.791\t\nNVP-based regimen initiated before LMP + during T1\t2\t3.2\t61\t8.52\t2.08–34.90\t0.003\t\nNVP, Nevirapine; LMP, last menstrual period; CI, confidence interval.\n\nRisk Analysis B, comparing the risk of the composite endpoint of other ABOs with ART initiation (1) at any time during pregnancy, (2) before and (3) during pregnancy is reflected in Table 6.\n\nTABLE 6 Risk of other adverse birth outcomes:† Analysis B.\n\nRisk analyses\tNumber of ABOs\tN\tUnadjusted risk ratio\tp\tAdjusted risk ratio\tp\t\nN\t%\tRisk ratio\t95% CI\tRisk ratio\t95% CI\t\nSingleton births to HIV negative women\t1597\t26.0\t6134\t1.00\t\t\t\t\t\t\nART initiated any time during or before pregnancy\t1069\t29.9\t3577\t1.15\t1.08–1.23\t< 0.001\t1.23\t1.14–1.31\t< 0.001\t\nART initiated before conception\t118\t31.2\t378\t1.20\t1.03–1.40\t0.022\t1.34\t1.14–1.58\t0.001\t\nART initiated during pregnancy\t617\t29.2\t2112\t1.12\t1.04–1.21\t0.004\t1.20\t1.11–1.30\t< 0.001\t\nEFV-based regimen initiated any time during or before pregnancy\t1015\t29.8\t3411\t1.14\t1.07–1.22\t< 0.001\t1.22\t1.14–1.31\t< 0.001\t\nEFV-based regimen initiated before conception\t93\t30.6\t304\t1.18\t0.99–1.40\t0.07\t1.31\t1.09–1.57\t0.004\t\nEFV-based regimen initiated during pregnancy\t608\t29.2\t2083\t1.12\t1.04–1.21\t0.005\t1.20\t1.11–1.30\t< 0.001\t\nNVP-based regimen initiated any time during or before pregnancy\t32\t33.3\t96\t1.28\t0.96–1.70\t0.09\t1.46\t1.10–1.95\t0.01\t\nNVP-based regimen initiated before conception\t20\t34.5\t58\t1.32\t0.93–1.89\t0.123\t1.54\t1.07–2.20\t0.019\t\nNVP-based regimen initiated during pregnancy\t3\t30.0\t10\t1.15\t0.45–2.97\t0.769\t1.29\t0.50–3.32\t0.6\t\nART initiated before conception\t118\t31.2\t378\t1.00\t-\t-\t-\t-\t-\t\nART initiated during pregnancy\t617\t29.2\t2112\t0.94\t0.79–1.10\t0.427\t0.90\t0.76–1.07\t0.237\t\nEFV-based regimen initiated before conception\t93\t30.6\t304\t1.00\t-\t-\t-\t-\t-\t\nEFV-based regimen initiated during pregnancy\t608\t29.2\t2083\t0.95\t0.80–1.14\t0.613\t0.93\t0.77–1.12\t0.42\t\nNVP-based regimen initiated before conception\t20\t34.5\t58\t1.00\t-\t-\t-\t-\t-\t\nNVP-based regimen initiated during pregnancy\t3\t30.0\t10\t0.87\t0.32–2.39\t0.787\t0.57\t0.17–1.98\t0.379\t\nEFV-based regimen initiated before conception\t93\t30.6\t304\t1.00\t-\t-\t-\t-\t-\t\nNVP-based regimen initiated before conception\t20\t34.5\t58\t0.89\t0.60–1.31\t0.551\t0.80\t0.54–1.19\t0.267\t\nABOs, adverse birth outcomes; ART, antiretroviral treatment; EFV, Efavirenz; NVP, Nevirapine; CI, confidence interval.\n\n† , Other ABOs include pregnancy losses, early neonatal deaths, preterm delivery and small for gestational age.\n\nThere was no significant difference in risk of CM in births exposed to ART during the first trimester compared to HIV-unexposed births and HIV-exposed births only exposed to ART beyond T1 (2.11 [95% CI 0.65–6.92; p = 0.214]; Table 5).\n\nThe first-trimester exposure to the EFV-based treatment (0.87 [95% CI 0.12–6.40]) was not associated with an increased risk compared to births not exposed to ART in the first trimester. However, there was a higher risk of CMs in births with pre-pregnancy initiation of NVP-based ART (9.28 [95% CI 2.27–37.94; p = 0.002]) compared to births not exposed to ART in the first trimester. Similar findings were obtained when a sensitivity analysis was conducted including cases with first-trimester ART initiation.\n\nAfter adjusting for age category, parity and education, ART and EFV-based ART initiation regardless of the timing was associated with a higher rate of ABOs compared to HIV-uninfected women (adjusted: 1.23 95% CI 1.23–1.31; p < 0.001; 1.22 95% CI 1.14–1.31; p = 0.001). There was a tendency towards higher risk ratios when ART-, EFV- and NVP-based regimens were initiated before conception compared to initiation after conception (Table 6).\n\nHowever, no difference in ABOs was noted when comparing ART initiation before pregnancy against ART initiated after conception 0.90 (95% CI 0.76–1.07; p = 0.237). This was also the case when the timing of the initiation of EFV- and NVP-based regimens was assessed (EFV 0.93 (95% CI 0.77–1.12; p = 0.42; NVP 0.57 (95% CI 0.17–1.98; p = 0.379). Moreover, there was no significant difference between the risk of ABOs when comparing pre-pregnancy initiation of EFV-based ART with pre-pregnancy initiation of NVP-based ART (adjusted risk ratio: 0.80 95% CI 0.54–1.19; p = 0.267).\n\nDiscussion\nThese data represent the findings of the first year of a drug safety surveillance system aimed at improving our understanding of the safety of medicines commonly used by both HIV-infected and HIV-uninfected pregnant women in South Africa. A substantial proportion of the women (4013, 38.5%) were HIV-infected, the majority of whom were on ART (3932, 96.8%) and of whom 3467 (93.4%) were receiving the recommended first-line regimen of TDF/FTC/EFV according to SA NDoH guidelines. Only 96 women were on a NVP-based regimen during the pregnancy, mostly initiated prior to conception (Table 3). The very small number of women (40) receiving PI-containing regimens precludes the assessment of their association with primary outcomes.\n\nRisk analysis was conducted only on the subset of CM (‘included CM’) which could plausibly have been caused by teratogenic exposures, as assessed by clinical geneticists using predefined criteria.31 Reassuringly, and in line with previous studies and review,16,17,22,23,24,33 we did not find an increased risk of CM among infants exposed to EFV in the first trimester. The two CMs reported (hypoplastic thumb and club foot) in two infants with first trimester exposure are unlike previously reported CM associated with EFV.13,14 It is unlikely that the reported myelomeningocele (a neural tube defect) in an infant exposed to TDF/FTC/EFV later in the first trimester was causally linked to the treatment given during the late onset of treatment initiation in the pregnancy.34\n\nThere was a significant statistical association between first trimester exposure to NVP-based regimens and the occurrence of congenital malformations. This statistical association will require accrual of further evidence over time (preferably prospectively collected data). Note: (1) the lack of a postulated common mechanism for these defects; (2) the small number of cases (3 cases) and (3) potential confounders such as maternal age, underlying disease severity, nutritional state, evidence of alcohol and illicit substance abuse and other potential teratogenic exposures which should be explored.\n\nOur findings of an increased risk of other ABOs in HIV-exposed infants compared to HIV-unexposed infants assessed in Analysis B (Table 6) are well described.6,7,10,16,17,35 Given the exclusion of HIV-positive untreated pregnancies (noted above as representative of substandard access to care and a particularly vulnerable population), it is not possible to make a direct comparison between treated and untreated HIV-positive mothers. As there is no particular suspicion of association between HIV status and CMs, this is probably not a major limitation of the ‘Analysis A’. For ‘Analysis B’ which deals with composite ABOs, this shows that differences observed between HIV-exposed and HIV-unexposed birth outcomes are composed of mitigation of HIV infection by ART, possible adverse effects of ART and residual confounding. The effect size appeared to be bigger with NVP-based regimens than with EFV-based regimens, although a head-to-head comparison between EFV-based and NVP-based regimens in the first trimester yielded no significant difference in ABOs. Our findings of the lack of effect of timing of exposure on ABOs as a composite endpoint supports similar findings by Malaba6 and others.7,32\n\nDue to pragmatic challenges with implementation during the first year of surveillance, coverage rates for neonatal death (53.1%) at the hospital were found to be lower than the total coverage for all deliveries (71.4%), suggesting an under-representation of these outcomes and a diminished chance of assessing risk factor associations.\n\nThe overall detection rate for CMs identifiable by surface examination was lower (0.5%) compared to 0.67% reported in other LMIC settings35 as only malformations identified through a surface examination conducted at the time of birth were identified and included in the analysis. The incomplete coverage of stillbirths that were cremated or taken home by the family prior to a surface examination being performed by the surveillance nurses could have contributed to under-detection, as well as exclusion of serious CMs requiring urgent referral to other institutions, either prenatally for termination or delivery or postnatally for additional care. Medical termination of pregnancies, miscarriages and early stillbirths were also not captured in this cohort, as these admissions were not seen in the labour wards.\n\nWe have no evidence to suggest that the HIV status of the women influenced the coverage in a way that would introduce a bias into the analysis, although it is possible that the under-ascertainment of CMs would make detection of an increased birth prevalence of CMs related to ART more difficult. Improved capacity for the detection and assessment of CMs, including the capture of terminations of pregnancies, was identified as a priority measure for refining the surveillance system at the site.\n\nThe surveillance programme was initiated approximately 18 months after NVP-based first-line regimen was replaced by the EFV-based regimen. Therefore, the cohort of women on NVP-based treatment had been initiated on treatment before the new guidelines were implemented and, therefore, probably on ART treatment for longer than those on the EFV-based regimens. As most women have likely been switched from NVP-based regimens to an EFV-based regimen as the cohort expands, it is unlikely that South African sites alone will generate adequate first-trimester NVP exposures to further explore this association. Previous international reports have not found an association between NVP-based ART exposure and the risk of CMs but with other ABOs such as stillbirths.16,36,37\n\nData on early exposure to TDF, FTC and EFV will dominate future analyses, facilitating improved quantification of risks of ABOs. Similarly, information on the safety of second-line regimens will grow. The recent safety signal of an association between dolutegravir-based ART and the risk of neural tube defects in Botswana is already delaying the use of this effective regimen in women with child-bearing potential. This has highlighted the importance of ongoing pregnancy exposure surveillance in African settings where the burden of HIV and other communicable diseases is high, given a growing pipeline of new medicines, including vaccines, targeting pregnant women.\n\nThe conservative inclusion of only cases with a definite timing of exposure into the risk factor analysis meant that a significant proportion (30.4%) of the cohort of ART-exposed birth outcomes were excluded from the analyses. However, we found no difference between the cohort that was included in the risk analysis and the excluded group in terms of age category, parity and educational status, and believe that the exclusion of these cases is unlikely to bias our findings. As the surveillance system matures, we also expect improved data on ART exposures from record linkage between maternal and child health services and the data captured in the national electronic ART registration system (Tier.Net). Reported LMP dates will be augmented with data on gestational age from routine early ultrasound scans to better characterise the timing of exposures. Nevertheless, the low rates of SGA and PTD reported in this study suggest that the estimations of gestational age at birth may not be accurate. This can be attributed to the low reporting of LMP, late presentation of prenatal ultrasound and lack of a standardised assessment used for assessing prematurity at birth in labour ward. In future analyses, low birth weight, albeit crude, may be a more reliable endpoint to measure instead of SGA and PTD.\n\nThe background rates of common malformations detectable at birth will be more reliably observed as capacity development activities at this sentinel surveillance site are expanded, including systematic assessment of stillbirths and improved access to clinical genetic expertise at the site for better characterisation and diagnosis of CMs detected at the time of birth. The surveillance system is currently only able to detect external visible malformations detectable immediately after delivery. As the surveillance system matures and the ABOs under scrutiny accumulate, multivariable analyses incorporating the data collected on other risk factors and exposures, including the use of herbal and traditional medicines, illicit drugs, tobacco and alcohol, can be incorporated into the risk analyses as can calendar time.\n\nConclusion\nWe found no association between first-trimester exposure to EFV-based treatments and risk of congenital malformations. The risk of other ABOs is greater among HIV-exposed versus HIV-unexposed infants. However, the timing of initiation of EFV and NVP-based ART regimens, in relation to conception, did not affect the risk of ABOs. While reassuring, the data are not yet sufficient to completely exclude relevant drug-related risks associated with the components of the current first-line ART regimen for pregnant women in South Africa, and surveillance should be continued. The unexpected statistically significant associations, found between T1 exposure to NVP and CMs, demonstrate the need to continue to monitor the safety of medicines in pregnancy even in the absence of previous animal and human evidence of teratogenic risk. These initial signals of statistical association need to be reassessed using multivariable analysis as the surveillance system expands. The overall low rate of CMs in women on the current first-line ART regimen (TDF/FTC/EFV) for pregnant women in South Africa is reassuring and supported by similar work in Botswana.12,16,17,38\n\nThis PER/BDS surveillance system, having produced significant unexpected, albeit crude, associations in its first year, is clearly creating a rich resource of data. This will be critical for monitoring potential risk, for mothers and their infants, for widely used medicines and for addressing potential concerns with formal measures of low risks.\n\nAcknowledgements\nThe cooperation of the women who provided information after delivery and the efforts of the surveillance nurses, data capturers and hospital staff who continue to work on this novel surveillance project is gratefully acknowledged. Louisa Bhengu, Engela Honey and Thirona Naicker served as members of the CM review panel. Dr Augustin Ntilivamunda and Dr Francois Renaud from WHO provided technical and administrative support throughout the project.\n\nCompeting interests\nThe authors have no conflict of interests.\n\nAuthors’ contributions\nAll listed authors contributed to the drafting and/or editing of this manuscript. U.C.M. developed the protocol and procedures, provided technical oversight throughout the development of the surveillance system, developed the analysis plan together with C.v.S. and A.W. and drafted the report in collaboration and consultation with all co-authors. C.v.S. assisted in data cleaning and conducted the statistical analysis of the data. O.M. served as the chairperson of the project steering committee, N.R.M. and N.N. provided clinical support for surveillance staff at the facilities. A.R. and P.N. were responsible for obtaining project funding, as well as oversight of surveillance, data capture and quality improvement activities at the sites and served as members of the project steering committee. A.N. and F.R. provided technical and administrative support to the National Department of Health for surveillance activities. N.F.M. served as a member of the steering committee, providing technical support throughout the project. K.F. and M.F.U. served as members of the U.C.M. review panel. M.F.U. assisted with the development of the data collection tools, and K.F. provided further technical support during data analysis. S.K. served as the data manager and assisted with data analysis. M.D. and Y.P. serve as the national co-ordinators of this surveillance system and provided technical, administrative and policy support for this surveillance system.\n\nFunding\nThe surveillance system is supported by financial contributions from PEPFAR (United States President’s Emergency Plan for AIDS Relief), the World Health Organization and the South African National Department of Health. This publication was made possible through the support provided by the US Agency for International Development to MatCH (Maternal, Adolescent and Child Health) under the terms of Contract No. AID-674-A-12-00019. The opinions expressed herein are those of the authors and do not necessarily reflect the views of the US Agency for International Development.\n\nData availability statement\nData sharing is not applicable to this article as no new data were created or analysed in this study.\n\nDisclaimer\nThe views expressed in the article are those of the authors and not an official position of the institution or funder.\n\nHow to cite this article: Mehta UC, Van Schalkwyk C, Naidoo P, et al. Birth outcomes following antiretroviral exposure during pregnancy: Initial results from a pregnancy exposure registry in South Africa. S Afr J HIV Med. 2019;20(1), a971. https://doi.org/10.4102/sajhivmed.v20i1.971\n==== Refs\nReferences\n1. Moodley J , Fawcus S , Pattinson R \nImprovements in maternal mortality in South Africa . SAMJ . 2018 ;3 (suppl1 ):S4 –S8 .\n2. Govender T , Coovadia H \nEliminating mother to child transmission of HIV-1 and keeping mothers alive . J Infect . 2014 ;68 (1 ):S57 –S62 . 10.1016/j.jinf.2013.09.015 24139190 \n3. WHO \nConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach [homepage on the Internet] . 2013 [cited 2018 Oct 3]. Available from: https://apps.who.int/iris/bitstream/handle/10665/85321/9789241505727_eng.pdf \n4. National Department of Health, South Africa \nNational Consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents, and adults [homepage on the Internet] . 2013 [cited 2019 Apr 27]. Available from: https://sahivsoc.org/Files/ART%20Guidelines%2015052015.pdf \n5. Powis KM , Kitch D , Ogwu A , et al \nIncreased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy . J Infect Dis . 2011 ;204 (4 ):506 –514 . 10.1093/infdis/jir307 21791651 \n6. Malaba TR , Phillips T , Le Roux S , et al \nAntiretroviral therapy use during pregnancy and adverse birth outcomes in South African women . Int J Epidemiol . 2017 ;46 (5 ):1 –12 . 10.1093/ije/dyx136 28338818 \n7. Ramokolo V , Goga A , Lombard C , et al \nIn utero ART exposure and birth and early growth outcomes among HIV-exposed uninfected infants attending immunization services: Results from national PMTCT surveillance . Open Forum Infect Dis . 2017 ;4 (4 ):ofx187 \n10.1093/ofid/ofx187 29062860 \n8. Bengtson AM , Chibwesha CJ , Westreich D , et al \nDuration of cART before delivery and low infant birthweight among HIV-infected women in Lusaka, Zambia . J Acquir Immune Defic Syndr . 2016 ;71 (5 ):563 –569 . 10.1097/QAI.0000000000000909 26627103 \n9. Li N , Sando MM , Spiegelman D , et al \nAntiretroviral therapy in relation to birth outcomes among HIV-infected women: A cohort study . J of Infect Dis . 2016 ;213 (7 ):1057 –1064 . 10.1093/infdis/jiv389 26265780 \n10. Chen JY , Ribaudo HJ , Souda S , et al \nHighly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana . J Infect Dis . 2012 ;206 (11 ):1695 –1705 . 10.1093/infdis/jis553 23066160 \n11. Siemieniuk RA , Foroutan F , Mizra R , et al \nAntiretroviral therapy for pregnant women living with HIV or Hepatitis B: A systematic review and meta-analysis . BMJ Open . 2017 ;7 (9 ):e019022 \n10.1136/bmjopen-2017-019022 \n12. Zash R , Makhema J , Shapiro RL \nNeural-tube defects with dolutegravir treatment from the time of conception . N. Engl J Med . 2018 ;379 (10 ):979 –981 . 10.1056/NEJMc1807653 30037297 \n13. Sibiude J , Mandelbrot L , Blanche S , et al \nAssociation between prenatal exposure to antiretroviral therapy and birth defects: An analysis of the French perinatal cohort study (ANRS CO1/CO11) . PLoS Med . 2014 ;11 (4 ):e1001635 \n10.1371/journal.pmed.1001635 24781315 \n14. Knapp KM , Brogly SB , Muenz DG , et al \nPrevalence of congenital anomalies in utero exposure to antiretrovirals . Pediatr Infect Dis J . 2012 ;31 (2 ):164 –170 . 10.1097/INF.0b013e318235c7aa 21983213 \n15. Conroy AL , McDonald CR , Gamble JL , et al \nAltered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV . Am J Obs Gyn . 2017 ;217 (6 ):684 e1 –14 . 10.1016/j.ajog.2017.10.003 \n16. Zash R , Jacobson DL , Diseko M , et al \nComparative safety of antiretroviral treatment regimens in pregnancy . JAMA Paed . 2017 ;171 (10 ):e172222 \n10.1001/jamapediatrics.2017.2222 \n17. Zash R , Souda S , Chen JY , et al \nReassuring birth outcomes with tenofovir/emtricitabine/efavirenz used for prevention of mother-to-child transmission of HIV in Botswana . J Acquir Immune Defic Syndr . 2016 ;71 (4 ):428 –436 . 10.1097/QAI.0000000000000847 26379069 \n18. Uthman OA , Nachega JB , Anderson J , et al \nTiming of initiation of antiretroviral therapy and adverse pregnancy outcomes: A systematic review and meta-analysis . Lancet . 2017 ;4 (1 ):e21 –e30 . 10.1016/S2352-3018(16)30195-3 \n19. Papp E , Mohammadi H , Loutfy MR , et al \nHIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction . J Infect Dis . 2015 ;211 (1 ):10 –18 . 10.1093/infdis/jiu393 25030058 \n20. Ford N , Mofenson L , Shubber Z , et al \nSafety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis . AIDS . 2014 (Suppl 2 ):S123 –S131 . 10.1097/QAD.0000000000000231 24849471 \n21. Siberry GK , Williams PL , Mendez H , et al \nSafety of tenofovir use during pregnancy: Early growth outcomes in HIV-exposed uninfected infants . AIDS . 2012 ;26 (9 ):1151 –1159 . 10.1097/QAD.0b013e328352d135 22382151 \n22. Van Dyke RB , Chadwick EG , Hazra R , et al \nThe PHACS SMARTT Study: Assessment of the safety of in utero exposure to antiretroviral drugs . Front Immunol . 2016 \n10.3389/fimmu.2016.00199 \n23. Antiretroviral Pregnancy Registry Steering Committee, Antiretroviral pregnancy registry international interim report for 1 January 1989 through 31 January 2018 [homepage on the Internet] . [cited 2018 Oct 23]. Wilmington, NC : Registry Coordinating Centre \nAvailable from: www.apregistry.com \n24. US Department of Health and Human Services, AIDSinfo: Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States [cited 2019 Apr 27] . Available from: https://aidsinfo.nih.gov/guidelines/html/3/perinatal/204/nevirapine--viramune--nvp- \n25. Zash RM , Williams P , Holmes LB \nWhat is the risk of major congenital abnormalities among women on antiretroviral therapy? \nAIDS . 2018 ;32 (3 ):403 –404 . 10.1097/QAD.0000000000001711 29309347 \n26. Prestes-Carneiro LE \nAntiretroviral therapy, pregnancy, and birth defects: A discussion on the updated data . HIV AIDS . 2013 ;5 :181 –189 . 10.2147/HIV.S15542 \n27. Siberry GK , Jacobson DL , Kalkwarf HJ , et al \nLower newborn bone mineral content associated with maternal use of tenofovir disoproxil fumarate during pregnancy . Clin Infect Dis . 2015 ;61 (6 ):996 –1003 . 10.1093/cid/civ437 26060285 \n28. The 2015 National Antenatal Sentinel HIV and Herpes Simplex type-2 prevalence Survey [homepage on the Internet] . South Africa : National Department of Health [cited 2018 Oct 23]. Available from: http://www.health.gov.za/index.php/shortcodes/2015-03-29-10-42-47/2015-04-30-08-18-10/2015-04-30-08-21-56?download=2584:2015-national-antenatal-hiv-prevalence-survey-final-23oct17 \n29. Massyn N , Padarath A , Peer N , et al., editors \nDistrict Health Barometer 2016/17 [homepage on the Internet] . Durban : Health Systems Trust ; 2017 [cited 2018 Oct 23]. Chapter 5, p. 77 \nAvailable from: http://www.hst.org.za/publications/District%20Health%20Barometers/5%20(Section%20A)%20PMTCT.pdf \n30. World Health Organization/Centers for Disease Control and Prevention/International Clearinghouse for Birth Defects Surveillance and Research (WHO/CDC/ICBDSR) \nBirth defects surveillance: A manual for programme managers [homepage on the Internet] . Geneva : World Health Organization ; 2014 [cited 2018 Oct 23]. Available from: https://www.who.int/nutrition/publications/birthdefects_manual/en/. \n31. Holmes LB , Westgate MN \nInclusion and exclusion criteria for malformations in newborn infants exposed to potential teratogens . Birth Defects Res A Clin Mol Teratol . 2011 ;91 (9 ):807 –812 . 10.1002/bdra.20842 21800414 \n32. Stoner MCD , Cole SR , Price J , et al \nTiming of initiation of antiretroviral therapy and risk of preterm birth in studies of HIV-infected pregnant women: The role of selection bias . Epidemiology . 2018 ;29 (2 ):224 –229 . 10.1097/EDE.0000000000000772 29045283 \n33. Liu KC , Farahani M , Mashamba T , et al \nPregnancy outcomes and birth defects from an antiretroviral drug safety study of women in South Africa and Zambia . AIDS . 2014 ;28 (15 ):2259 –2268 . 10.1097/QAD.0000000000000394 25115319 \n34. Holmes LB \nCommon malformations . New York : Oxford University Press ; 2012 .\n35. Macdonald EM , Ng R , Bayoumi AM , et al \nAdverse neonatal outcomes among women living with HIV: A population-based study . J Obstet Gynaecol Can . 2015 ;37 (4 ):302 –309 . 10.1016/S1701-2163(15)30279-6 26001682 \n36. Dellicour S , Sevene E , McGready R , et al \nFirst trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies . PLoS Med . 14 (5 ):e1002290 \n10.1371/journal.pmed.1002290 \n37. Veroniki AA , Antony J , Straus SE , et al \nComparative safety and effectiveness of perinatal antiretroviral therapies for HIV-infected women and their children: Systematic review and network meta-analysis including different study designs . PLoS One . 2018 ;13 (6 ):e0198447 \n10.1371/journal.pone.0198447 29912896 \n38. Caniglia EC , Zash R , Jacobson DL , et al \nEmulating a target trial of antiretroviral therapy regimens started before conception and risk of adverse birth outcomes . AIDS . 2018 ;32 (1 ):113 –120 . 10.1097/QAD.0000000000001673 29112066\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1608-9693",
"issue": "20(1)",
"journal": "Southern African journal of HIV medicine",
"keywords": "antiretrovirals; birth defect; birth outcomes; congenital malformations; pharmacovigilance; pregnancy; safety; surveillance",
"medline_ta": "South Afr J HIV Med",
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"title": "Birth outcomes following antiretroviral exposure during pregnancy: Initial results from a pregnancy exposure registry in South Africa.",
"title_normalized": "birth outcomes following antiretroviral exposure during pregnancy initial results from a pregnancy exposure registry in south africa"
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"companynumb": "ZA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-008052",
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"abstract": "BACKGROUND\nThe SARS-CoV-2 pandemic brought challenges to all areas of medicine. In pediatric bone marrow transplant (BMT), one of the biggest challenges was determining how and when to transplant patients infected with SARS-CoV-2 while mitigating the risks of COVID-related complications.\n\n\nMETHODS\nOur joint adult and pediatric BMT program developed protocols for performing BMT during the pandemic, including guidelines for screening and isolation. For patients who tested positive for SARS-CoV-2, the general recommendation was to delay BMT for at least 14 days from the start of infection and until symptoms improved and the patient twice tested negative by polymerase chain reaction (PCR). However, delaying BMT in patients with malignancy increases the risk of relapse.\n\n\nRESULTS\nWe opted to transplant two SARS-CoV-2 persistently PCR positive patients with leukemia at high risk of relapse. One patient passed away early post-BMT of a transplant-related complication. The other patient is currently in remission and doing well.\n\n\nCONCLUSIONS\nThese cases demonstrate that when the risk associated with delaying BMT is high, it may be reasonable to proceed to transplant in pediatric leukemia patients infected with SARS-CoV-2.",
"affiliations": "Pediatric Blood and Marrow Transplantation, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Hematology & Oncology, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Infectious Diseases, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Hematology & Oncology, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Blood and Marrow Transplantation, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Blood and Marrow Transplantation, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Blood and Marrow Transplantation, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Pediatric Blood and Marrow Transplantation, Hackensack University Medical Center, Hackensack, New Jersey, USA.",
"authors": "Krajewski|Jennifer|J|https://orcid.org/0000-0002-6226-965X;Chen|Jing|J|;Motiani|Juhi|J|;Baer|Aryeh|A|;Appel|Burton|B|;Zakrzewski|Johannes|J|;Hankewycz|Melanie|M|;Durning|Nancy|N|;Gillio|Alfred|A|",
"chemical_list": null,
"country": "Denmark",
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"doi": "10.1111/petr.14179",
"fulltext": null,
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"issn_linking": "1397-3142",
"issue": null,
"journal": "Pediatric transplantation",
"keywords": "\nHSCT\n; allogeneic stem cell transplantation; bone marrow transplantation; hematopoietic stem cell transplantation; infectious risk; pediatrics",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e14179",
"pmc": null,
"pmid": "34708505",
"pubdate": "2021-10-27",
"publication_types": "D002363:Case Reports",
"references": "32598831;29728694;32736007;32404975;26369984;34708505;33482113;33277976;33549624;32790663",
"title": "Hematopoietic stem cell transplant in two pediatric patients testing positive for SARS-CoV-2: A case report.",
"title_normalized": "hematopoietic stem cell transplant in two pediatric patients testing positive for sars cov 2 a case report"
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"abstract": "From asymptomatic patients to severe acute respiratory distress syndrome, COVID-19 has a wide range of clinical presentations, and venous thromboembolism has emerged as a critical and frequent complication.\nWe present a case of a 69-year-old man with a clinical presentation of massive-like pulmonary embolism (PE) overlapping with severe COVID-19 pneumonia. The diagnosis was made based on hypotension, severe oxygen desaturation (33%), and right ventricular dysfunction (RVD). We used alteplase and low-molecular-weight heparin, obtaining immediate clinical improvement. Also, we identified an extremely elevated D-dimer (31.2 mcg/mL), and computed tomography pulmonary angiography (CTPA) revealed an unexpected low thrombus burden and a crazy-paving pattern. Considering this, we decided to discontinue the alteplase. Therefore, the mechanisms of pulmonary hypertension and RVD could be multifactorial. Despite the patient's respiratory status worsening and ongoing mechanical ventilation, biomarkers kept lowering to normal ranges. It appears a favourable outcome was related to early PE diagnosis and a multimodal therapeutic approach.\nPhysicians in the ER should be warned about extremely high D-dimer measurements and severe oxygen desaturation as possible markers of severe COVID-19 pneumonia in patients with high-clinical suspicion of PE. Although ESC guidelines recommend immediate reperfusion in cardiogenic shock secondary to PE, we suggest initial CTPA in patients with high-clinical suspicion of severe COVID-19.",
"affiliations": "Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico.;Hospital Zambrano Hellion, TecSalud, San Pedro Garza García, Nuevo Leon, Mexico.;Hospital Zambrano Hellion, TecSalud, San Pedro Garza García, Nuevo Leon, Mexico.",
"authors": "Betancourt-Del Campo|Hector|H|0000-0003-2530-9779;Jerjes-Sanchez|Carlos|C|0000-0003-3222-7405;Castillo-Perez|Mauricio|M|0000-0003-1881-9471;López-de la Garza|Hector|H|0000-0001-9162-8634;Paredes-Vázquez|José Gildardo|JG|0000-0002-6895-8026;Flores-Sayavedra|Yoezer Z|YZ|0000-0001-9148-639X;Moreno-Abril Hoyos|Francisco|F|;Ibarra-Flores|Marcos|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa448",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa448\nytaa448\nGrand Round\nOther\nAcademicSubjects/MED00200\nSystemic thrombolysis and anticoagulation improved biomarker measurements in massive-like pulmonary embolism and severe COVID-19 pneumonia: a case report\nhttp://orcid.org/0000-0003-2530-9779Betancourt-del Campo Hector 12 http://orcid.org/0000-0003-3222-7405Jerjes-Sanchez Carlos 12 http://orcid.org/0000-0003-1881-9471Castillo-Perez Mauricio 1 http://orcid.org/0000-0001-9162-8634López-de la Garza Hector 12 http://orcid.org/0000-0002-6895-8026Paredes-Vázquez José Gildardo 12 http://orcid.org/0000-0001-9148-639XFlores-Sayavedra Yoezer Z 1 Moreno-Abril Hoyos Francisco 3 Ibarra-Flores Marcos 3 1 \nTecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, Nuevo Leon, Mexico\n2 \nInstituto de Cardiología y Medicina Vascular, TecSalud, San Pedro Garza García, Nuevo Leon, Mexico\n3 \nHospital Zambrano Hellion, TecSalud, San Pedro Garza García, Nuevo Leon, Mexico\nBernstein Brett Sydney Editor Dejan Milasinovic Handling Editor Eshtehardi Parham Editor Cankovic Milenko Zoran Editor D'Amario Domenico Editor Vishal Shahil Mehta Editor Corresponding author. Tel: +528188880464. Email: jerjes@prodigy.net.mx, carlos.jerjes@udicem.org.mx, carlos.jerjes@medicos.tecsalud.mx\n12 2020 \n13 12 2020 \n13 12 2020 \n4 6 1 8\n21 7 2020 4 11 2020 01 7 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nFrom asymptomatic patients to severe acute respiratory distress syndrome, COVID-19 has a wide range of clinical presentations, and venous thromboembolism has emerged as a critical and frequent complication.\n\nCase summary\nWe present a case of a 69-year-old man with a clinical presentation of massive-like pulmonary embolism (PE) overlapping with severe COVID-19 pneumonia. The diagnosis was made based on hypotension, severe oxygen desaturation (33%), and right ventricular dysfunction (RVD). We used alteplase and low-molecular-weight heparin, obtaining immediate clinical improvement. Also, we identified an extremely elevated D-dimer (31.2 mcg/mL), and computed tomography pulmonary angiography (CTPA) revealed an unexpected low thrombus burden and a crazy-paving pattern. Considering this, we decided to discontinue the alteplase. Therefore, the mechanisms of pulmonary hypertension and RVD could be multifactorial. Despite the patient’s respiratory status worsening and ongoing mechanical ventilation, biomarkers kept lowering to normal ranges. It appears a favourable outcome was related to early PE diagnosis and a multimodal therapeutic approach.\n\nDiscussion\nPhysicians in the ER should be warned about extremely high D-dimer measurements and severe oxygen desaturation as possible markers of severe COVID-19 pneumonia in patients with high-clinical suspicion of PE. Although ESC guidelines recommend immediate reperfusion in cardiogenic shock secondary to PE, we suggest initial CTPA in patients with high-clinical suspicion of severe COVID-19.\n\nCase reportCOVID-19SARS-CoV-2Pulmonary embolismThrombolysis\n==== Body\nPrimary Specialties involved other than cardiology\nCardiology, Pneumology and Critical Care Medicine, Infectology\n\n\nLearning points\nOverlapping severe COVID-19 pneumonia and pulmonary embolism (PE) is a challenge, extremely D-dimer measurements and severe oxygen desaturation are possible markers of severity.\n\nBedside echocardiogram and biomarker measurements are critical elements in the assessment of COVID-19 and PE patients.\n\nAlthough ESC guidelines recommend the same thrombolytic regimes for COVID-19 patients, the ideal regime remains unknown.\n\n\n\n\nIntroduction\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in Wuhan, China, in late 2019, and coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, rapidly evolved into a global pandemic. COVID-19 is characterized by high mortality predominantly in male patients secondary to severe acute respiratory distress syndrome.1 However, among common complications observed in deceased patients with COVID-19 disease, venous thromboembolism has emerged as a critical and frequent complication. Currently, most of the data regarding this clinical association has been derived from hospitalized patients. Data on the clinical presentation, therapeutic approach, and biomarkers behaviour in outpatients are scarce.2 Here we present the case of a 69-year-old man with a clinical presentation of massive-like pulmonary embolism (PE) overlapped with severe COVID-19 pneumonia in whom we observed immediate clinical improvement using a reduced alteplase dose. Additionally, we identified an unusual D-dimer (DD) measurement, multifactorial mechanisms of pulmonary hypertension, and upon admission, despite severe right ventricular dysfunction, a borderline B-type natriuretic peptide (BNP) value.\n\nTimeline\nTime\tEvents\t\nMedical history\tHypertension, chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea, arthritis, morbid obesity\t\n27 days prior to admission\tContact with SARS-CoV-2 (+) son\t\n\nInitial presentation\n\t\t\nOn arrival to the ER\tClinical instability, oxygen desaturation (33%)\t\nElectrocardiogram: sinus tachycardia, S1Q3T3, qR, ST-elevation in V1 and aVR\t\nChest X-ray: bilateral ground-glass opacity\t\nTransthoracic echocardiogram: severe right ventricular dysfunction\t\n\tBiomarkers: D-dimer 31.2 mcg/mL, B-type natriuretic peptide (BNP) 101 pg/mL, hs-cTnI 49.7 mcg/L\t\n\tComputed tomography pulmonary angiography: interlobar and segmental thrombi; extensive bilateral ground-glass opacity\t\n\tRecombinant tissue plasminogen activator 10 mg and enoxaparin 80 mg BID\t\nDay 1\tInfluenza A and B negative\t\n\tIsolated intensive critical care (ICU) with telepresence robot for interaction\t\n\tHydroxychloroquine, azithromycin, lopinavir/ritonavir\t\nDay 2\tHemodynamic stability\t\n\tHs-cTnI and BNP increased, D-dimer decreased\t\n\tReal-time reverse transcription-polymerase chain reaction (rRT-PCR): SARS-CoV-2 (+)\t\nDay 3\tInvasive mechanical ventilation due to respiratory failure\t\n\tParadoxical improvement of biomarkers\t\n\tHydroxychloroquine suspended (prolonged QTc)\nTocilizumab is started\t\nDay 5–8\tDaily dose of hyperimmune plasma\t\n\tImproved ventilatory support\t\nDay 9\tAzythromicin discontinued\t\nDay 14\tLopinavir/ritonavir discontinued\t\nDay 20\tWeaned off from mechanical ventilation\t\n\tHospital-acquired pneumonia\t\n\tNegative antiphospholipid antibodies\t\n\tSwitched enoxaparin 80 mg BID to rivaroxaban 20 mg QD\t\nDay 29\trRT-PCR: SARS-CoV-2 (-)\t\n\tDischarged with rivaroxaban 20 mg QD\t\nFollow-up\t\t\nAt 15 days by telemedicine\tAsymptomatic and undergoing physical rehabilitation\t\nCase presentation\nA 69-year-old man presented to the Emergency room (ER) with a 2-h history of stabbing pain in the right lower limb, associated with sudden dyspnoea, plus severe chest pain 6/10, presyncope, and profuse diaphoresis. His past medical history included former smoking, hypertension (valsartan, hydrochlorothiazide, and atenolol), chronic obstructive pulmonary disease (non-specified treatment), obstructive sleep apnoea syndrome treated with continuous positive airway pressure (CPAP), undifferentiated arthritis (sulfasalazine and acemetacin), and morbid obesity. Additionally, his son had been recently diagnosed with severe COVID-19 after a recent trip to Vail, Colorado, 31 days ago, and they had contact in Mexico City 27 days before his admission. On arrival at the ER, the patient was afebrile, with clinical instability, hypotension (80/50 mmHg), tachycardia (140 b.p.m.), respiratory failure (30 b.p.m.), and severe oxygen desaturation (33%). The physical examination revealed a stuporous patient with pallor, diaphoresis, loud S2, bilateral lung crackles, swollen feet, and a body mass index (BMI) of 42.1 kg/m2. We started oxygen with a reservoir mask at 10 L/min, improving consciousness state, oxygen saturation (73%), and heart rate (HR) (110 b.p.m.).\n\nThe initial electrocardiogram (ECG) showed sinus tachycardia at 110 b.p.m., right axis deviation, QTc 471 ms, S1Q3T3, qR, ST-elevation in aVR and V1, and right ventricular overload (Figure 1A). A chest X-ray showed bilateral ground-glass opacity, and pulmonary infiltrates (Figure 2). A transthoracic echocardiogram revealed severe right ventricular dysfunction and hypokinesis, left ventricular ejection fraction (LVEF) of 80% by the Teicholz method, tricuspid annular plane systolic excursion (TAPSE) 9 mm, tricuspid regurgitation gradient of 28 mmHg, and pulmonary artery systolic pressure (PASP) of 48 mmHg (Video 1). Blood tests showed haemoglobin 14.6 g/dL (13.2–18.0 g/dL), 11.6 × 103/µL leucocytosis (4.5–11.0 × 103/µL), lymphocytes 700 per mm3 (1000–4000 per mm3), platelets 323 × 103/µL (150–420 × 103/µL), glucose 242 mg/dL (60–100 mg/dL), creatinine 1.3 mg/dL (0.7–1.3 mg/dL), hypoalbuminaemia 2.6 g/dL (3.5–5 g/dL), lactate dehydrogenase (LDH) 528 U/L (125–243 U/L), sodium 139 mEq/L (136–145 mEq/L), potassium 3.7 mEq/L (3.5–5.1 mEq/L), chloride 98.2 mEq/L (98–107 mEq/L), and fibrinogen 551 mg/dL (238–498 mg/dL).\n\nFigure 1 (A) Initial electrocardiogram with sinus tachycardia (110 b.p.m.), right axis deviation, QTc 471 ms, S1Q3T3 pattern, presence of qR, ST-elevation in V1 and aVR, inferior pseudonecrosis, and right ventricular systolic overload. (B) Follow-up electrocardiogram on Day 3, with prolonged QTc 560 ms. There is improvement of RV ischaemia and systolic overload.\n\nFigure 2 Chest X-ray that shows bilateral ground-glass opacity and pulmonary infiltrates.\n\nBiomarkers revealed a DD of 31.2 mcg/mL (<0.5 mcg/mL), BNP 101 pg/mL (<100 pg/mL), high-sensitivity troponin I (hs-cTnI) 49.7 ng/L (<2 ng/L) (Figure 5), high-sensitivity protein C 22.68 mg/dl (0.00–0.50 mg/dL), ferritin 304 ng/mL (20–250 ng/mL), and procalcitonin 0.55 ng/mL (<0.5 ng/mL). Based on risk factors, clinical presentation, a very high-risk pulmonary embolism severity index (PESI) score (239 points), and high-risk sPESI score (3 points), chest X-ray, biomarkers, and echocardiographic findings, we established a high-clinical suspicion of massive PE and community-acquired pneumonia.\n\nWe decided to commence treatment using alteplase with a 10 mg bolus, followed by 40 mg in 2 h and enoxaparin 80 mg BID. The computed tomography pulmonary angiography (CTPA) revealed a dilated main pulmonary artery (34 mm) and the presence of thrombus located in the right interlobar artery and the segmental branches of the superior left lobe and inferior left and right lobes (Figure 3). Unexpectedly, the lung parenchyma revealed a crazy-paving pattern, highly suggestive of severe COVID-19 pneumonia (Figure 4). Immediately after the 10 mg alteplase bolus, consciousness state, blood pressure (120/85 mmHg), HR (100 b.p.m.), and respiratory rate (25 b.p.m.) improved. Severe oxygen desaturation remained low (75%) despite using a reservoir oxygen mask at 10 l/min. Considering the thrombus burden and severe pneumonia, we decided to discontinue the 40 mg alteplase infusion and transfer the patient to the COVID-19 isolated ICU. To protect the patients and healthcare workers, we used a telepresence robot for daily interaction. The rapid nucleic acid amplification test for influenza A and B was negative. We collected samples following Center for Disease Control and Prevention (CDC) guidance (serum, and nasopharyngeal and oropharyngeal swab specimens). The patient received enoxaparin 80 mg BID, oral hydroxychloroquine 200 mg thrice in a day (TID), azithromycin 500 mg QD, IV ceftaroline 1 g QD, oral lopinavir/ritonavir 200/50 mg BID, and IV paracetamol 1 g TID.\n\nFigure 3 Computed tomography pulmonary angiogram. (A) An axial view with main pulmonary artery dilation with a diameter of 34 mm and the presence of thrombus located in the right interlobar artery. (B) A coronal view with thrombus in the segmental branches of the superior and inferior left lobe. (C, D) A coronal view with thrombus in the right interlobar artery and thrombus in segmental branches of the inferior right lobe, respectively.\n\nFigure 4 Chest computed tomography. (A) A classic crazy-paving pattern, with extensive bilateral ground-glass opacities in middle and lower lobes. Upper lobes extension of the aforementioned opacities is depicted in (B).\n\nOn Day 2, the patient remained mostly stable. Upon follow-up examination, hs-cTnI and BNP increased, and D-dimer decreased (Figure 5). A chest X-ray reported a slight improvement of bilateral ground-glass opacity and pulmonary infiltrates. The nasopharyngeal and oropharyngeal swabs tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay.\n\nFigure 5 Biomarker values on admission and their immediate reduction following anticoagulation and thrombolytic treatment. We also demonstrate biomarkers in-hospital follow-up, the IL-6 behaviour, and the therapeutic approach during the in-hospital stay. D-dimer red line, B-type natriuretic peptide blue line, Hs-cTnI yellow line, and IL-6 purple line. HCQ, hydroxychloroquine; LMWH, low-molecular-weight heparin; rtPA, recombinant tissue plasminogen activator; TCL, tocilizumab.\n\nOn Day 3, due to respiratory failure and diagnosis of acute respiratory distress syndrome (ARDS) we started invasive mechanical ventilation (FiO2 70%, PEEP 16, and Kirby index of 105). The patient had hypotension as a side effect of sedation, which required transient inotropic support (norepinephrine). For the mechanical ventilation, we used A/C mode, with lung-protective ventilation using tidal volumes of 6 mL/kg predicted body weight and inspiratory pressure of 12 cmH2O. We maintained an initial respiratory rate (RR) 16 b.p.m., I:E relation of 1:1.5, and a constant PEEP of 16 cmH2O with decremental titration. We provided prone ventilation, and we did not use recruitment manoeuvres. Despite clinical worsening, the biomarkers continued to improve (Figure 5). We stopped hydroxychloroquine due to abnormal QTc (up to 560 ms) on follow-up ECG (Figure 1B). We administered three doses of tocilizumab 800 mg TID and continued full anticoagulation with enoxaparin. We maintained the norepinephrine support intermittently for nine days.\n\nOn Days 5 through 8, due to clinical worsening and the high viral load, we administered three doses of hyperimmune plasma each day, with improvement in ventilatory support (Kirby index of 187). On Day 9, we discontinued azithromycin, and after 14 days lopinavir/ritonavir.\n\nOn Day 15, the patient had a fever, and we suspected a ventilator-associated pneumonia. We obtained a tracheal aspirate culture, which showed Klebsiella pneumoniae, and we started meropenem for 7 days. After 20 days, clinical, ventilatory, and laboratory parameters improved (Figure 5), and we successfully removed the patient from mechanical ventilation.\n\nThe patient remained in hospital with episodes of delirium and intermittent dry cough, with oxygen saturation of 98% and ongoing enoxaparin 80 mg BID. A repeat rt-PCR swab was negative for SARS-CoV-2 and negative anti-cardiolipin IgM, IgG, Beta-2-glycoprotein antibodies, and phosphatidylserine IgA, IgM, and IgG were reported. We did not perform lower limb ultrasound and further CTPA due to critical illness.\n\nAfter 29 days, the patient was discharged with propranolol 10 mg TID, losartan 50 mg BID, amlodipine 5 mg QD, and rivaroxaban 20 mg QD. In a telemedicine follow-up office visit 15 days later, the patient remained asymptomatic and was undergoing physical rehabilitation. A follow-up echocardiogram performed four months after initial presentation showed improvement in right ventricular size and function, with a TAPSE of 23 mm (Video 2).\n\nDiscussion\nThe main observations of this case were as follows: firstly, after thrombolysis and anticoagulation, DD measurements improved. Secondly, upon admission BNP was discordantly low despite severe right ventricular dysfunction, likely related to a short time between the onset of symptoms and admission to hospital; in the next 24 h BNP correlated with the presence and degree of right ventricular dysfunction and higher hs-cTnI measurements, suggesting type 2 myocardial infarction3 (Figure 5). Thirdly, this case was a clinical challenge because acute PE and COVID-19 pneumonia overlapped. Finally, this case represents—to our knowledge—the first description of biomarkers (DD, BNP, hs-cTnI) in scenarios involving COVID-19 pneumonia and PE.\n\nSince the first clinical description,4 abnormal DD measurements and age have been related to increased mortality and a high prevalence of thrombotic events in COVID-19.5,6 Patients with severe COVID-19 disease are at high-risk of thromboinflammation since they have proinflammatory risk factors and cardiopulmonary comorbidities related to inflammation.7 The SARS-CoV-2 infection leads to a cytokine storm, inducing endothelial activation, cell damage, increased platelet aggregation, thrombi sensitivity, arterial inflammation, as well as disruption of vulnerable plaques.8,9 Interleukin-6 (IL-6) induces the expression of several prothrombotic factors and dysregulation of antithrombin III, protein S, and thrombomodulin.9,10 Additionally, it could activate immunothrombosis, another thrombosis mechanism.10 All these mechanisms can induce diffuse microangiopathy with micro and macro thrombosis.11 Also, SARS-CoV-2 may predispose to both venous and arterial thrombosis secondary to antiphospholipid antibodies,12,13 hypoxia, immobilization, and diffuse intravascular coagulation.14\n\nAmong the common complications observed in deceased patients with severe COVID-19,7 venous thromboembolism (VTE) has emerged as a critical and frequent complication.9 Currently, we do not have strong evidence of the overall incidence and recommendations for in-hospital anticoagulation in patients with PE.9,11,15 However, the available evidence suggests a frequency of 25% to 27% in ICU patients14,16 and imaging has demonstrated both unilateral and bilateral thrombus (small branches, segmental, lobar, and main pulmonary artery).5,17,18 DD measurements seem to be an available test to identify high-risk groups of VTE14,18 and patients that need different doses of enoxaparin [low (0.6 mg/kg/12 h)18 or standard treatment17].\n\nIn this complicated case with overlapping severe COVID-19 pneumonia and PE, the clinical presentation suggesting massive PE drove the decision to use systemic thrombolysis. We supported the high-clinical suspicion of massive PE based on sudden dyspnoea, chest pain, presyncope, a fall in blood pressure, ECG changes, echocardiographic findings, as well as signs of deep venous thrombosis. We decided to interrupt the alteplase infusion based on thrombus burden, which was lower than expected considering the clinical presentation of massive PE, a high rate of bleeding (16%) in populations with respiratory failure15 and lacking recommendations in severe COVID-19 disease.9,15 A relevant observation is that after the alteplase bolus, an immediate significant clinical improvement suggesting reperfusion appeared. This result could represent the effectiveness and safety of 10 mg or 5 mg alteplase bolus to initiate fibrinolysis in ST-elevation myocardial infarction19 and left atrial thrombus, respectively.20 Also, another low dose of alteplase (30 mg) was safe and effective in submassive PE patients,21 and an alteplase bolus of 10 mg followed by a 2-h 40 mg infusion in ARDS22 and pulmonary vascular phenotype COVID-19 patients.23\n\nAfter thrombolysis, in the first 96 h, enoxaparin achieved a significant decrease in DD measurements (Figure 5). Considering the clinical condition, the evidence suggesting prophylactic anticoagulation failure,24 and the high risk of recurrence (individual, COVID-19, ICU, and hospital stay), we sustained the subcutaneous therapeutic anticoagulation without bleeding complications during the in-hospital stay. At admission, the exceptionally high DD levels observed suggested hyper-inflammation, hypercoagulability, and an actual thrombotic disease, possibly induced by cellular activation triggered by the virus,25 and resemble the extremely high values encountered in COVID-19 related acute or pulmonale,26 as well as thrombotic events in cerebral27 and coronary circulation.28 Additionally, we should never ignore abnormal or extremely elevated DD levels29 in COVID-19, since it is the expression of the coagulation system and fibrinolysis activity, suggesting high-risk of acute thrombosis.29 Although, in our case, the extremely elevated DD levels could be explained by the association of severe COVID-19 and VTE, we cannot exclude the possibility of subclinical cancer.30 After anticoagulation therapy, reduced DD levels suggest anticoagulation effectiveness16 (Figure 5). Preliminary evidence suggests mortality benefit from anticoagulation in severe COVID-19 disease,31 including anti-inflammatory mechanisms.32 Upon admission, the measurement of hs-cTnI suggested myocardial injury with a subsequent increase (likely due to type 2 myocardial infarction) still detectable until 96 h later33 (Figure 5), similar to the behaviour observed in PE patients.33 The initial therapeutic approach decreased the expression of hs-cTnI, which is historically related to poor in-hospital outcomes in COVID-1915 and non-COVID-19 patients.3 Another interesting finding was the initial borderline BNP measurements despite severe RVD. B-type natriuretic peptide concentration might seem discordantly low in flash pulmonary oedema (1 h), acute pulmonary oedema secondary to acute mitral regurgitation, immunologic myopericarditis with predominantly right ventricular involvement34 and submassive PE.35 In these settings, BNP gene expression may have had insufficient time between the initial trigger of increased ventricular wall stress and the measurement of BNP concentrations, since the half-life of BNP is 23 min and 2 h are required for its full expression.35 The mechanism of massive PE and initial almost normal BNP value was the immediate patient presentation after symptom onset.35 This case identifies another clinical condition characterized by severe ventricular dysfunction and discordantly low BNP. BNP measurements in the next 24 h correlated with the right ventricular dysfunction stage and reperfusion,36 and serial measurements were useful in assessing the success of thrombolysis and anticoagulation.36 Despite worsening respiratory effects and mechanical ventilation, BNP remained below 50 pg/mL until discharge (Figure 5).\n\nNon-COVID-19 pneumonia and PE have a frequent association (65.6%) that increases mortality.37 This patient with risk factors for PE and risk factors for severe COVID-19 disease had both acute events at home. Current evidence regarding COVID-19 pneumonia and PE comes from in-hospital series and case reports.5,14,17,18,26,38–40 Therefore, the clinical presentation of an acute PE in the setting of severe COVID-19 pneumonia in an outpatient is not clear. Recently, in a case series of PE patients with risk factors, the clinical presentation was characterized by persistence or worsening of respiratory symptoms with increasing oxygen requirements. Besides, DD levels were several-fold higher than the normal upper threshold.2 Recently, systemic thrombolysis in one massive PE patient with COVID-19 induced bleeding complications as the cause of mortality;2 however, the thrombolytic regimen and the bleeding complication were not described. Initial clinical behaviour in this case was similar to that observed in non-COVID-19 submassive and massive PE patients.41,42 Considering CTPA findings, the mechanisms of pulmonary hypertension and right ventricular dysfunction could be multifactorial, including pulmonary thrombi, hypoxic pulmonary vasoconstriction,43 and possible pulmonary microthrombi.23,44 Also, SARS-CoV-2 direct down-regulation of ACE2 may result in unopposed angiotensin II accumulation and local renin-angiotensin-aldosterone system (RAAS) activation, increasing pulmonary vasoconstriction.45 Finally, the favourable outcome was related to early PE diagnosis and a multimodal therapeutic approach, including respiratory support, fibrinolysis activation, coagulation system inhibition, antivirals, antibiotics, a monoclonal antibody, and hyperimmune plasma (Figure 5). We also need current and robust evidence to identify if we need a different thrombolytic regimen to those currently recommended.26,46\n\nConclusion\nPhysicians in the ER should be warned about high or extremely elevated DD measurements and severe oxygen desaturation, as possible risk markers of severe COVID-19 pneumonia in patients with high-clinical suspicion of PE. Also, they should be aware of this 2-h lag period before the onset of BNP increase to avoid underdiagnosing right ventricular dysfunction.35 Finally, we suggest CTPA before starting immediate reperfusion in a severe COVID-19 patient with high-clinical suspicion of massive PE.46\n\nLead author biography\nHéctor Betancourt del Campo is a Cardiology Fellow in training and has an Internal Medicine PhD. He actually practices echocardiography, heart failure, haemodynamics, and electrophysiology in Zambrano Hellion Hospital, TecSalud of Tecnologico de Monterrey. He is interested in becoming an Electrophysiology Fellow next year.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidelines.\n\n\nConflict of interest: none declared.\n\n\nFunding: none declared.\n\nSupplementary Material\nytaa448_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n1 \n\nEllinghaus \nD \n, Degenhardt F , Bujanda L , Buti M , Albillos A , Invernizzi P \net al\nGenomewide association study of severe Covid-19 with respiratory failure\n. N Engl J Med 2020 .\n2 \n\nFaggiano \nP \n, Bonelli A , Paris S , Milesi G , Bisegna S , Bernardi N \net al\nAcute pulmonary embolism in COVID-19 disease: preliminary report on seven patients\n. Int J Cardiol 2020 ;313 :129 –131\n.32471650 \n3 \n\nJanuzzi \nJL \n, Mahler SA , Christenson RH , Rymer J , Newby LK , Body R \net al\nRecommendations for institutions transitioning to high-sensitivity troponin testing\n. J Am Coll Cardiol 2019 ;73 :1059 –1077\n.30798981 \n4 \n\nZhou \nF \n, Yu T , Du R , Fan G , Liu Y , Liu Z \net al\nClinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study\n. Lancet 2020 ;395 :1054 –1062\n.32171076 \n5 \n\nDanzi \nGB \n, Loffi M , Galeazzi G , Gherbesi E. \nAcute pulmonary embolism and COVID-19 pneumonia: a random association?\n\nEur Heart J \n2020 ;41 :1858 –1858\n. ehaa32227120 \n6 \n\nXie \nY \n, Wang X , Yang P , Zhang S. \nCOVID-19 complicated by acute pulmonary embolism\n. Radiology 2020 ;2 :e200067 .\n7 \n\nChen \nT \n, Wu D , Chen H , Yan W , Yang D , Chen G \net al\nClinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study\n. BMJ 2020 ;386 :1091 .\n8 \n\nMusher \nDM \n, Abers MS , Corrales-Medina VF. \nAcute infection and myocardial infarction\n. N Engl J Med 2019 ;380 :171 –176\n.30625066 \n9 \n\nAtri \nD \n, Siddiqi HK , Lang J , Nauffal V , Morrow DA , Bohula EA. \nCOVID-19 for the cardiologist: a current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies\n. JACC: Basic Transl Sci 2020 ;5 :518 –536\n.32292848 \n10 \n\nVazquez-Garza \nE \n, Jerjes-Sanchez C , Navarrete A , Joya-Harrison J , Rodriguez D. \nVenous thromboembolism: thrombosis, inflammation, and immunothrombosis for clinicians\n. J Thromb Thrombolysis 2017 ;44 :377 –385\n.28730407 \n11 \n\nLiu \nPP \n, Blet A , Smyth D , Li H. \nThe science underlying COVID-19: implications for the cardiovascular system\n. Circulation 2020 ;142 :68 –78\n.32293910 \n12 \n\nZhang \nY \n, Xiao M , Zhang S , Xia P , Cao W , Jiang W \net al\nCoagulopathy and antiphospholipid antibodies in patients with Covid-19\n. N Engl J Med 2020 ;382 :e38 .32268022 \n13 \n\nBowles \nL \n, Platton S , Yartey N , Dave M , Lee K , Hart DP \net al\nLupus anticoagulant and abnormal coagulation tests in patients with Covid-19\n. N Engl J Med 2020 ;383 :288 –290\n.32369280 \n14 \n\nKlok \nFA \n, Kruip MJHA , van der Meer NJM , Arbous MS , Gommers D , Kant KM \net al\nIncidence of thrombotic complications in critically ill ICU patients with COVID-19\n. Thromb Res 2020 ;191 :148 –150\n.32381264 \n15 \n\nBikdeli \nB \n, Madhavan MV , Jimenez D , Chuich T , Dreyfus I , Driggin E \net al\nCOVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up\n. J Am Coll Cardiol 2020 ;75 :2950 –2973\n.32311448 \n16 \n\nCui \nS \n, Chen S , Li X , Liu S , Wang F. \nPrevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia\n. J Thromb Haemost 2020 ;18 :1421 –1424\n.32271988 \n17 \n\nUllah \nW \n, Saeed R , Sarwar U , Patel R , Fischman DL. \nCOVID-19 complicated by acute pulmonary embolism and right-sided heart failure\n. JACC: Case Rep 2020 ;2 :1379 –1382\n.32313884 \n18 \n\nChen \nJ \n, Wang X , Zhang S , Liu B , Wu X , Wang Y \net al\nFindings of acute pulmonary embolism in COVID-19 patients\n. SSRN J 2020 .\n19 \n\nGurewich \nV. \n \nTherapeutic fibrinolysis\n. J Am Coll Cardiol 2016 ;68 :2099 –2106\n.27810050 \n20 \n\nWolff \nG \n, Kelm M , Westenfeld R , Horn P. \nLow-dose thrombolysis for the management of left atrial thrombus formation during percutaneous mitral valve repair\n. JACC: Cardiovasc Interv 2019 ;12 :e9–10 –e10\n. 30594509 \nReferences 21 to 46 are available in Supplementary material online.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "4(6)",
"journal": "European heart journal. Case reports",
"keywords": "COVID-19; Case report; Pulmonary embolism; SARS-CoV-2; Thrombolysis",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "33634226",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "32313884;32369280;32471650;30798981;32227120;32381264;32293910;30625066;27810050;32217556;28730407;32292848;32268022;32171076;32271988;32311448;30594509",
"title": "Systemic thrombolysis and anticoagulation improved biomarker measurements in massive-like pulmonary embolism and severe COVID-19 pneumonia: a case report.",
"title_normalized": "systemic thrombolysis and anticoagulation improved biomarker measurements in massive like pulmonary embolism and severe covid 19 pneumonia a case report"
} | [
{
"companynumb": "MX-LUPIN PHARMACEUTICALS INC.-2021-18476",
"fulfillexpeditecriteria": "2",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "Drug resistant idiopathic nephrotic syndrome (DRNS) remains a therapeutic dilemma. In this pilot study, the efficacy of the new fully humanised, anti-CD20 monoclonal antibody ofatumumab was tested in 4 children with persistence of proteinuria for at least 12 months in spite of a full drug approach (including rituximab). We used a low-dose 2-infusion ofatumumab model (300+700 mg/1.73 m(2) 2 weeks apart) using specified premedication. Transient normalisation of proteinuria (persisting for 2 months) was achieved in 1 child while another presented stable remission after 12 months; both had normal renal function. The outcome was not modified in the remaining 2 children presenting an impaired renal function. These results demonstrate that low-dose ofatumumab may induce remittance of proteinuria in children with a long story of DRNS and normal renal function. Further studies are needed to test whether higher doses of ofatumumab can also modify proteinuria in patients with impaired renal function.",
"affiliations": "Division of Nephrology Dialysis and Transplantation, Istituto G Gaslini, Genoa, Italy.;Division of Nephrology Dialysis and Transplantation, Istituto G Gaslini, Genoa, Italy.;Division of Nephrology and Dialysis, Ospedale San Martino, Oristano, Italy.;Division of Nephrology Dialysis and Transplantation, Istituto G Gaslini, Genoa, Italy.",
"authors": "Bonanni|Alice|A|;Rossi|Roberta|R|;Murtas|Corrado|C|;Ghiggeri|Gian Marco|GM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D000069283:Rituximab; D016572:Cyclosporine; D009173:Mycophenolic Acid; C527517:ofatumumab; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D016572:Cyclosporine; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D007262:Infusions, Intravenous; D008297:Male; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D010865:Pilot Projects; D000069283:Rituximab; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26376698",
"pubdate": "2015-09-16",
"publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15531003;23739238;24480824;8203357;22581994;15172969;24670185;8315953;20506254;18465150;21566104;25592855;21859685;19427037;20798255;24965823;2857421",
"title": "Low-dose ofatumumab for rituximab-resistant nephrotic syndrome.",
"title_normalized": "low dose ofatumumab for rituximab resistant nephrotic syndrome"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1002370",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies.\n\n\n\nThe study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs).\n\n\n\nNine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response.\n\n\n\nYS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.",
"affiliations": "Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address: takeda_m@med.kindai.ac.jp.;Department of Thoracic Oncology, National Cancer Center Hospital, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, Japan.;Department of Thoracic Oncology, NHO Kyushu Cancer Center, Japan.;Department of Thoracic Oncology, NHO Kyushu Cancer Center, Japan.;Research & Training Center for Asbestos-Related Diseases, Japan.;Kissei Pharmaceutical Co. Ltd., Japan.;Kissei Pharmaceutical Co. Ltd., Japan.;Y's AC Co. Ltd., Japan.;Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Japan.;Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.",
"authors": "Takeda|Masayuki|M|;Ohe|Yuichiro|Y|;Horinouchi|Hidehito|H|;Hida|Toyoaki|T|;Shimizu|Junichi|J|;Seto|Takashi|T|;Nosaki|Kaname|K|;Kishimoto|Takumi|T|;Miyashita|Itaru|I|;Yamada|Masayuki|M|;Kaneko|Yutaro|Y|;Morimoto|Chikao|C|;Nakagawa|Kazuhiko|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; C000621698:YS110 monoclonal antibody; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2019.09.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "137()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "CD26; Japanese; Malignant mesothelioma; Phase I; YS110",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D015331:Cohort Studies; D018819:Dipeptidyl Peptidase 4; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009367:Neoplasm Staging; D010997:Pleural Neoplasms; D011379:Prognosis; D066066:Response Evaluation Criteria in Solid Tumors; D014018:Tissue Distribution; D055815:Young Adult",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "64-70",
"pmc": null,
"pmid": "31557561",
"pubdate": "2019-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma.",
"title_normalized": "phase i study of ys110 a recombinant humanized monoclonal antibody to cd26 in japanese patients with advanced malignant pleural mesothelioma"
} | [
{
"companynumb": "JP-PFIZER INC-2019427026",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "The prognosis of children with acute lymphoblastic leukemia can be improved with the use of monoclonal antibodies such as blinatumomab. Many studies discuss the management and treatment of symptoms; however, none of them describe practical complications related to the continuous infusion of blinatumomab, especially during home-based therapy. The purpose of this study is to describe the experience gained over 4 years in the management of pediatric patients undergoing therapy with blinatumomab in an Italian tertiary hospital. The establishment of a nursing program dedicated to improving infusion pump management, patient support, quality of care, and patient safety will be discussed.",
"affiliations": "Bambino Gesù Children's Research Hospital Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sant'Onofrio Square, Rome, Italy.;Bambino Gesù Children's Research Hospital Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sant'Onofrio Square, Rome, Italy.",
"authors": "Amicucci|Matteo|M|;Ciaralli|Italo|I|",
"chemical_list": "D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C510808:blinatumomab",
"country": "United States",
"delete": false,
"doi": "10.1097/NAN.0000000000000409",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-1458",
"issue": "44(1)",
"journal": "Journal of infusion nursing : the official publication of the Infusion Nurses Society",
"keywords": null,
"medline_ta": "J Infus Nurs",
"mesh_terms": "D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002648:Child; D006699:Home Care Services; D006801:Humans; D007558:Italy; D009722:Nurse Practitioners; D061214:Patient Safety; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016730:Program Development; D011787:Quality of Health Care",
"nlm_unique_id": "101124170",
"other_id": null,
"pages": "34-40",
"pmc": null,
"pmid": "33394872",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nurse Practitioner Management of a Blinatumomab Infusion Program: Impact on Patient Safety and Quality of Care.",
"title_normalized": "nurse practitioner management of a blinatumomab infusion program impact on patient safety and quality of care"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021017281",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Few cases of hepatocellular carcinoma (HCC) have been described during the course of acute leukemia. The chemotherapy given may be responsible for the development of HCC in such cases. Associated hepatitis may also be responsible. Usually, cancer is a multistep process in which multiple genetic alterations must occur to have a cumulative effect on the control of cell differentiation, cell division, and growth control. This usually takes place over the span of years. Here, we present a case of a patient with acute myeloblastic leukemia who developed HCC of a short malignant transformation time, which does not seem to be related to associated hepatitis or to the chemotherapy given. This may draw attention to the possible contributory role of certain products secreted by the myeloid leukemic cells such as the hepatocyte growth factor (HGF) in increasing the risk of developing HCC.",
"affiliations": "Hematology and Medical Oncology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt. mohmabed@mans.edu.eg",
"authors": "Mabed|M|M|;Aref|S|S|;Aladle|D A|DA|",
"chemical_list": "D006133:Growth Substances",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-003-0653-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "82(5)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D002471:Cell Transformation, Neoplastic; D056486:Chemical and Drug Induced Liver Injury; D006133:Growth Substances; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D013997:Time Factors",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "318-20",
"pmc": null,
"pmid": "12709828",
"pubdate": "2003-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatocellular carcinoma of a short malignant transformation time in a patient with acute myeloblastic leukemia.",
"title_normalized": "hepatocellular carcinoma of a short malignant transformation time in a patient with acute myeloblastic leukemia"
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"abstract": "Antibiotic-associated diarrhea is a relatively common problem, and the main bacterial cause is Clostridioides difficile followed by Staphylococcus aureus and other pathogens. The diagnostic procedure for methicillin-resistant S. aureus enteritis is not well established. Phagocytosis is a key antimicrobial process involved in host defense. Phagocytosed bacteria identified by Gram staining are one marker to identify causative microorganisms and select subsequent treatment strategies. However, there are few reports on fecal Gram staining using phagocytosed bacteria as a target for diarrhea treatment. We report the successful use of fecal Gram staining to diagnose and treat methicillin-resistant S. aureus enteritis.",
"affiliations": "Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. Electronic address: shimiken@hp-emerg.med.osaka-u.ac.jp.;Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.;Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address: daisukem@gen-info.osaka-u.ac.jp.;Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address: nshota@gen-info.osaka-u.ac.jp.;Division of Infection Control and Prevention, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. Electronic address: tomono@hp-infect.med.osaka-u.ac.jp.;Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. Electronic address: ogura@hp-emerg.med.osaka-u.ac.jp.;Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. Electronic address: shimazu@hp-emerg.med.osaka-u.ac.jp.",
"authors": "Shimizu|Kentaro|K|;Takahashi|Ayumi|A|;Motooka|Daisuke|D|;Nakamura|Shota|S|;Tomono|Kazunori|K|;Ogura|Hiroshi|H|;Shimazu|Takeshi|T|",
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"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Diarrhea; Feces; Gram staining; Intensive care unit; Phagocytosis; Staphylococcus aureus",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D010587:Phagocytosis; D013194:Staining and Labeling; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "9608375",
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"title": "Fecal Gram staining of phagocytosed bacteria to differentiate methicillin-resistant Staphylococcus aureus: A case report.",
"title_normalized": "fecal gram staining of phagocytosed bacteria to differentiate methicillin resistant staphylococcus aureus a case report"
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"abstract": "During the last years several synthetic opioids have been introduced on Internet sites selling new psychoactive substances (NPS). One of these, called MT-45, a piperazine derivative originally synthesized as a therapeutic drug candidate in the 1970s, has recently been detected in 21 deaths, according to unpublished data from the Swedish National Board of Forensic Medicine. We present clinical data from 12 analytically confirmed hospital cases of MT-45 poisoning. The cases demonstrate that MT-45, like other opioids, can induce potentially life threatening respiratory depression and loss of consciousness in users and that symptoms are usually reversed by standard doses of the opioid receptor antagonist naloxone. Significant auditory symptoms with transient tinnitus and hearing loss occurred in two cases and a pronounced sensorineural hearing loss still present at two weeks follow-up in one case. This indicates that MT-45 may be an ototoxic substance, illustrating the ubiquitous risk of unintended adverse effects NPSs pose to users.",
"affiliations": "Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden.;Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden.;- Stockholm, Sweden - Stockholm, Sweden.;Karolinska Institutet - Labmed Stockholm, Sweden Karolinska Institutet - Labmed Stockholm, Sweden.",
"authors": "Lindeman|Erik|E|;Bäckberg|Matilda|M|;Personne|Mark|M|;Helander|Anders|A|",
"chemical_list": "D000701:Analgesics, Opioid; D015198:Designer Drugs; D013287:Illicit Drugs; D009292:Narcotic Antagonists; D010879:Piperazines; D011619:Psychotropic Drugs; D009270:Naloxone",
"country": "Sweden",
"delete": false,
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"issn_linking": "0023-7205",
"issue": "111(40)",
"journal": "Lakartidningen",
"keywords": null,
"medline_ta": "Lakartidningen",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D015198:Designer Drugs; D006319:Hearing Loss, Sensorineural; D006801:Humans; D013287:Illicit Drugs; D020407:Internet; D008297:Male; D009270:Naloxone; D009292:Narcotic Antagonists; D010879:Piperazines; D011039:Poison Control Centers; D011619:Psychotropic Drugs; D012131:Respiratory Insufficiency; D055815:Young Adult",
"nlm_unique_id": "0027707",
"other_id": null,
"pages": "1712-5",
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"pmid": "25253604",
"pubdate": "2014-09-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "MT-45--a dangerous and potentially ototoxic internet drug.",
"title_normalized": "mt 45 a dangerous and potentially ototoxic internet drug"
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"abstract": "Reported is a case of a 39-year-old male who was diagnosed with exercise-induced anaphylaxis (EIA). He was initially treated prophylactically with fexofenadine, montelukast, and ranitidine. He also used an epinephrine autoinjector as needed. He was refractory to these medications and continued to have episodes of EIA. He was then started on a trial of omalizumab, an immunoglobulin E monoclonal antibody, and had resolution of the EIA episodes. After discontinuation of the omalizumab, the EIA episodes returned. He was restarted on omalizumab and since that time, has had 5 years free of EIA episodes and can now exercise without any symptoms. To our knowledge, this is only the third case in the literature of successful treatment of EIA by using omalizumab. This case was unique because it provided successful long-term use of omalizumab for EIA. Further studies are recommended for the use of omalizumab in the treatment of EIA.",
"affiliations": "From the Department of Allergy and Immunology, Wilford Hall Abulatory Surgical Center, Lackland AFB, San Antonio, Texas.;From the Department of Allergy and Immunology, Wilford Hall Abulatory Surgical Center, Lackland AFB, San Antonio, Texas.",
"authors": "Peterson|Mark R|MR|;Coop|Christopher A|CA|",
"chemical_list": null,
"country": "United States",
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"doi": "10.2500/ar.2017.8.0204",
"fulltext": "\n==== Front\nAllergy Rhinol (Providence)Allergy Rhinol (Providence)arAllergy & Rhinology2152-65752152-6567OceanSide Publications, Inc. Providence, RIUSA AR077-1610.2500/ar.2017.8.0204ArticlesLong-term omalizumab use in the treatment of exercise-induced anaphylaxis Peterson Mark R. D.O.Coop Christopher A. M.D.From the Department of Allergy and Immunology, Wilford Hall Abulatory Surgical Center, Lackland AFB, San Antonio, TexasAddress correspondence to Mark Peterson, D.O., U.S. Air Force Medical Corp, 655 Seventh Street, Bldg 700, Robins AFB, Warner Robins, GA 31098 E-mail address: mark.peterson.26@us.af.mil10 2017 8 3 e170 e172 Copyright © 2017, OceanSide Publications, Inc., U.S.A.2017This work is published and licensed by OceanSide Publications, Inc. The full terms of this license are available at https://www.allergyandrhinology.com, and incorporate the Creative Commons License Deed: Attribution – Non-Commercial 4.0 Unported (CC BY-NC 4.0). By accessing the work you hereby accept the terms. Non-commercial uses of the work are permitted without any further permission from OceanSide Publications, Inc., provided the work is properly attributed. Any use of the work other then as authorized under this license or copyright law is prohibited.Reported is a case of a 39-year-old male who was diagnosed with exercise-induced anaphylaxis (EIA). He was initially treated prophylactically with fexofenadine, montelukast, and ranitidine. He also used an epinephrine autoinjector as needed. He was refractory to these medications and continued to have episodes of EIA. He was then started on a trial of omalizumab, an immunoglobulin E monoclonal antibody, and had resolution of the EIA episodes. After discontinuation of the omalizumab, the EIA episodes returned. He was restarted on omalizumab and since that time, has had 5 years free of EIA episodes and can now exercise without any symptoms. To our knowledge, this is only the third case in the literature of successful treatment of EIA by using omalizumab. This case was unique because it provided successful long-term use of omalizumab for EIA. Further studies are recommended for the use of omalizumab in the treatment of EIA.\n\nAnaphylaxisangioedemaepinephrineexercise-induced anaphylaxisfood dependent exercise-induced anaphylaxisgliadinmast cell activationOmalizumaburticaria\n==== Body\nOmalizumab is an immunoglobulin E (IgE) monoclonal antibody that is approved for allergic asthma and chronic idiopathic asthma. Omalizumab has also been used successfully in the treatment of idiopathic anaphylaxis, systemic mastocytosis, and venom-induced anaphylaxis.1–6 We are aware of two other reported cases of successful use of omalizumab in treating exercise-induced anaphylaxis (EIA).1,2 We present a case of EIA successfully treated with omalizumab with long-term follow-up.\n\nCASE PRESENTATION\nA 39-year-old male referred to the allergy clinic due to an episode of diffuse urticaria, periorbital edema, and a globus sensation, 15 minutes after running 2 miles on the treadmill. He was seen in the emergency department for the episode and received intramuscular epinephrine, intravenous steroids and diphenhydramine, which resolved his symptoms within 1 hour. Over the previous 3 months, he had reported many episodes of lightheadedness and patches of urticaria, with chest tightness that happened either with or shortly after exercise. With these episodes, he would also have associated rhinitis and, at times, dysphagia and throat tightness. The dysphagia would also happen without exercise. He did have a history of allergic rhinitis and was on cetirizine. He had normal spirometry results, negative methacholine challenge and vortex stimulation results.\n\nDue to the dysphagia, the patient had a skin-prick test for many foods and had positive results for almond, carrot, celery, egg white, egg yolk, peanut, pistachio, shrimp, soybean, black walnut, whole wheat, orange, potato, and, by history, for gluten and chickpea. He did not have any history of anaphylactic episodes with eating these foods. It was presumed that he had an episode of EIA and, in addition, dysphagia, which was separate. It was thought that, with the positive skin-prick test results to many foods, these may have contributed to the episode of EIA. The patient was given an epinephrine autoinjector, fexofenadine, montelukast, and ranitidine. These medications helped with the throat and chest tightness with exercise, but did not completely resolve his symptoms to include the dysphagia without exercise. He continued to have urticaria and some chest tightness with occasional throat tightness, only associated with exercise for at least 15 minutes. He was later diagnosed with eosinophilic esophagitis via biopsy as the cause of his dysphagia. He was lost to follow-up for awhile.\n\nFour years later, the patient returned to the allergy clinic and reported every 3 months, he would have one to two episodes of urticaria with shortness of breath, periorbital edema, and a globus sensation. All episodes required epinephrine use and one required hospitalization. The patient was a physician and, due to a previous concern for possible food-induced EIA and his diagnosis of eosinophilic esophagitis, he had been avoiding wheat and, later, all food for up to 12 hours before exercise, which helped with the throat tightness, but not the frequency of EIA symptoms and the need for epinephrine. The episodes mostly occurred with running, with one episode with walking and another with cycling.\n\nThe patient's laboratory evaluation included a normal complete blood cell count, a tryptase level of 4 ng/mL, and a serum IgE level of 393.8 IU/mL. The tryptase level was not assessed during an acute episode due to either not being seen or having gone to the emergency department. Discussed completing exercise testing with and without food challenge in a controlled setting to see if EIA could be induced, but the patient declined; he felt that he had already challenged himself. Levocetirizine was added in place of fexofenadine to his medications listed earlier, but he continued with more-frequent episodes of urticaria and difficulty breathing, and these episodes were becoming more severe as well, requiring epinephrine nearly every time he exercised. Because of worsening episodes despite treatment and wanting to continue to exercise due to being in the military, he wanted to try something more. There was literature that indicated success with the use of omalizumab in treating EIA, but this was off-label use. The patient signed a consent form and elected to start a trial of omalizumab.\n\nThe patient was started on omalizumab injections of 300 mg every 2 weeks, with the dose being based on weight and total IgE levels, as done for asthma. There were no food restrictions given during this time. At a 3-month follow-up, the patient reported marked improvement. He had been exercising three times a week and had one episode of mild urticaria, but it happened when he had missed one of his omalizumab injections. There were no episodes of anaphylaxis. He had been able to tolerate eating normally even just before exercise. Omalizumab helped reduce his dysphagia as well. To determine if the omalizumab was what was truly helping reduce his symptoms, omalizumab was discontinued and he continued on levocetirizine, fluticasone propionate, and montelukast sodium for his allergic rhinitis.\n\nThe patient returned to the clinic after 4 months off omalizumab and reported that at just 1 month off, he started with episodes of urticaria, markedly increased chest tightness, and periorbital edema after at least 15 minutes of exercise. His dysphagia symptoms also increased, as did his throat tightness with exercise. He ultimately had an episode of anaphylaxis with urticaria, difficulty breathing, and facial swelling that required epinephrine, steroids, diphenhydramine, ranitidine, and intravenous fluids in the emergency department. After this episode, omalizumab was restarted at the same doses and intervals. Five years later, the patient continues on omalizumab with no further episodes of anaphylaxis and has been able to return to full activity level with no restrictions. He will continue to be followed up monthly and exercise normally, reporting any symptoms that he has.\n\nDISCUSSION\nEIA is a rare, but potentially life-threatening syndrome. There are a variety of symptoms that present during or shortly after exercise. These symptoms include but are not limited to pruritus, urticaria, wheezing, chest tightness, nausea, diarrhea, angioedema, and ultimately, airway compromise and circulatory collapse.7–9 It can happen independently, but there also is a food-dependent EIA (FdEIA). In this type of EIA, ingestion of certain foods before exercise induces the anaphylactic episodes. It has been seen in most cases that symptoms occurred when food was consumed between a few minutes to 2 hours before exercise, with a few cases occurring up to 6 hours after exercise.10 Typically, if the food is avoided for 4–6 hours before exercise, the symptoms do not occur, which is the treatment of choice for FdEIA. Many patients will have positive skin-prick test results or IgE immunoassays to the triggering foods. Some triggers include wheat, seafood, nuts, seeds, alcohol, and some vegetables and fruits. Wheat has been found to be one of the most prevalent triggers and best studied cause of FdEIA.11 It was found that omega-5 gliadin, which is a major protein of wheat, is a contributing factor in >80% of patients with wheat allergy that caused FdEIA.12,13\n\nThe pathophysiology of EIA and FdEIA is not fully understood, but is thought to be mediated by mast cell activation and subsequent histamine release.14 Other theories regarding the pathophysiology are exercise-induced antigen release and changes in blood flow and pH. Increased gut permeability is also a proposed mechanism because gastrin is released with exercise and is a known mast cell secretagogue. The increased gut permeability may also increase the absorption of food allergens into the circulation and cause a higher antigen load, which results in symptoms.8,15 Prophylactic therapies that have been tried include histamine blockers, leukotriene inhibitors, oral steroids, epinephrine, and the cessation of activity as soon as symptoms begin to occur. There also has been the successful use of omalizumab.\n\nOur patient was thought to have FdEIA and thus was counseled to avoid food 4–6 hours before exercise and to remove foods from his diet to which he had tested positive, which included wheat. He did this and extended to 12 hours with no food consumption before exercise by not eating at night and exercising in the morning, but the symptoms continued. He was prophylactically taking a H1 and H2 antihistamine and a leukotriene inhibitor, and continued with no change in frequency or severity of symptoms. Due to exhausting all recommended therapies with no success, it was conjointly determined by the patient and physician that a trial of omalizumab should be taken because there was one reported successful case.1 Omalizumab offered relief of all of his symptoms, which provided a second successful case with long-term follow up.\n\nOmalizumab does not treat or block all of the proposed pathways that could cause EIA. It is thought that mast cell stabilization plays a key role. There also is a case that showed improvement in symptoms of EIA with montelukast, a leukotriene inhibitor, which would decrease the stimulation and subsequent degranulation of mast cells.16 With these methods, there is a decreasing rate of mast cell degranulation, and this is a presumed pathway involved in EIA. The European Academy of Allergy and Clinical Immunology released a position statement stating that the proposed mechanisms of EIA that are popular today lack validity.17 More research is needed to better understand the pathophysiology of EIA and to offer better diagnostic and treatment options. Our patient also had resolution of his dysphagia symptoms as well after starting on the omalizumab. There is a recent study that demonstrated improvement in the symptoms of eosinophilic esophagitis,18 which seems to have been the case in our patient.\n\nCONCLUSION\nWe concluded that omalizumab was helpful in the resolution of EIA symptoms. This case provided evidence of the successful use of omalizumab over a long period of time. We suggest that mast cell stabilization may be the main contributing factor in reducing the symptoms of EIA, but more research needs to be done to validate this presumption. We also recommend further clinical studies of treatment of EIA with omalizumab.\n\nNo external funding sources reported\n\nThe authors have no conflicts of interest to declare pertaining to this article\n==== Refs\nREFERENCES\n1. \nJones JD Marney SR JrFahrenholz JM \nIdiopathic anaphylaxis successfully treated with omalizumab . Ann Allergy Asthma Immunol \n101 :550 –551 , 2008 .19055211 \n2. \nChristensen MJ Bindslev-Jensen C \nSuccessful treatment with omalizumab in challenge confirmed exercise-induced anaphylaxis . J Allergy Clin Immunol Pract \n5 :204 –206 , 2017 .27839749 \n3. \nWarrier P Casale TB \nOmalizumab in idiopathic anaphylaxis . Ann Allergy Asthma Immunol \n102 :257 –258 , 2009 .19354075 \n4. \nCarter MC Robyn JA Bressler PB \nOmalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis . J Allergy Clin Immunol \n119 :1550 –1551 , 2007 .17481708 \n5. \nTartibi HM Majmundar AR Khan DA \nSuccessful use of omalizumab for prevention of fire ant anaphylaxis . J Allergy Clin Immunol \n126 :664 –665 , 2010 .20673977 \n6. \nSchulze J Rose M Zielen S \nBeekeepers anaphylaxis: Successful immunotherapy covered by omalizumab . Allergy \n62 :963 –964 , 2007 .17484729 \n7. \nSheffer AL Austen KF \nExercise-induced anaphylaxis . J Allergy Clin Immunol \n73 :699 –703 , 1984 .6715733 \n8. \nBarg W Medrala W Wolanczyk-Medrala A \nExercise-induced anaphylaxis: An update on diagnosis and treatment . Curr Allergy Asthma Rep \n11 :45 –51 , 2011 .20922508 \n9. \nRobson-Ansley P Toit GD \nPathophysiology, diagnosis and management of exercise-induced anaphylaxis . Curr Opin Allergy Clin Immunol \n10 :312 –317 , 2010 .20543674 \n10. \nEggleston PA Kagey-Sobotka A Proud D \nDisassociation of the release of histamine and arachidonic acid metabolites from osmotically activated basophils and human lung mast cells . Am Rev Respir Dis \n141 (pt. 1 ):960 –964 , 1990 .1691604 \n11. \nRomano A Di Fonso M Giuffreda F \nFood-dependent exercise-induced anaphylaxis: Clinical and laboratory findings in 54 subjects . Int Arch Allergy Immunol \n125 :264 –272 , 2001 .11490160 \n12. \nPalosuo K Alenius H Varjonen E \nA novel wheat gliadin as a cause of exercise- induced anaphylaxis . J Allergy Clin Immunol \n103 (pt. 1 ):912 –917 , 1999 .10329828 \n13. \nZogaj D Ibranji A Hoxha M \nExercise-induced anaphylaxis: The role of cofactors . Mater Sociomed \n26 :401 –404 , 2014 .25685088 \n14. \nBray SM Fajt ML Petrov AA \nSuccessful treatment of exercise-induced anaphylaxis with omalizumab . Ann Allergy Asthma Immunol \n109 :281 –282 , 2012 .23010237 \n15. \nTharp MD Thirlby R Sullivan TJ \nGastrin induces histamine release from human cutaneous mast cells . J Allergy Clin Immunol \n74 :159 –165 , 1984 .6205035 \n16. \nGajbhiye S Agrawal RP Atal S \nExercise-induced anaphylaxis and antileukotriene montelukast . J Pharmacol Pharmacother \n6 :163 –165 , 2015 .26312002 \n17. \nAnsley L Bonini M Delgado L \nPathophysiological mechanisms of exercise-induced anaphylaxis: An EAACI position statement . Allergy \n70 :1212 –1221 , 2015 .26100553 \n18. \nLoizou D Enav B Komlodi-Pasztor E \nA pilot study of omalizumab in eosinophilic esophagitis . PLoS One \n10 :e0113483 , 2015 .25789989\n\n",
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"title": "Long-term omalizumab use in the treatment of exercise-induced anaphylaxis.",
"title_normalized": "long term omalizumab use in the treatment of exercise induced anaphylaxis"
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"abstract": "Tuberculosis (TB) is still an endemic disease in Malaysia. Cystic lung disease in post primary tuberculosis is not common. It can occur before, during or after completion of anti-TB treatment. Clinical history and review of serial chest radiograph is paramount to make the diagnosis. This case report highlights an interesting case of a young female patient who developed extensive cystic lung disease during the course of anti-TB treatment and the importance of recognizing this unusual manifestation.",
"affiliations": "Hospital Taiping, Department of Radiology, Perak, Malaysia. lingsze_78@yahoo.com.;Hospital Taiping, Department of Radiology, Perak, Malaysia.",
"authors": "Tan|L S|LS|;Tan|S|S|",
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"title": "Acquired lung cysts in post primary tuberculosis: An uncommon radiological finding in a common disease.",
"title_normalized": "acquired lung cysts in post primary tuberculosis an uncommon radiological finding in a common disease"
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"abstract": "Medication-related osteonecrosis of the jaw (MRONJ) is developed even in the patients who are edentulous and treated with short-term bisphosphonate therapy and oral administration. It sometimes causes lethal sepsis in patients who have multiple health problems such as diabetes, cirrhosis, steroid use for interstitial pneumonia, sepsis, and spinal disk herniation.",
"affiliations": "Department of Pathophysiology-Periodontal Science Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 2-5-1 Shikata-cho Kita-ku Okayama 700-8525 Japan.;Department of Oral and Maxillofacial Surgery Hiroshima City Hiroshima Citizens Hospital 7-33 Motomachi Naka-ku Hiroshima 730-0011 Japan.;Department of Oral and Maxillofacial Surgery Hiroshima City Hiroshima Citizens Hospital 7-33 Motomachi Naka-ku Hiroshima 730-0011 Japan.;Department of Oral and Maxillofacial Surgery Hiroshima City Hiroshima Citizens Hospital 7-33 Motomachi Naka-ku Hiroshima 730-0011 Japan.;Department of Oral and Maxillofacial Surgery Hiroshima City Hiroshima Citizens Hospital 7-33 Motomachi Naka-ku Hiroshima 730-0011 Japan.;Department of Oral and Maxillofacial Surgery Hiroshima City Hiroshima Citizens Hospital 7-33 Motomachi Naka-ku Hiroshima 730-0011 Japan.;Department of Oral and Maxillofacial Reconstructive Surgery Okayama University Hospital 2-5-1 Shikata-cho Kita-ku Okayama 700-8525 Japan.;Department of Oral and Maxillofacial Reconstructive Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences 2-5-1 Shikata-cho Kita-ku Okayama 700-8525 Japan.;Department of Pathophysiology-Periodontal Science Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 2-5-1 Shikata-cho Kita-ku Okayama 700-8525 Japan.",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.751CCR3751Case ReportCase ReportsMedication‐related osteonecrosis of the jaws caused lethal sepsis in an edentulous patient with multiple systemic factors K. Yamashiro et al.Yamashiro Keisuke \n1\nSato Aki \n2\nOkazaki Fumihiko \n2\nNakano Makoto \n2\nSawaki Koichi \n2\nHirata Yasuhisa \n2\nYamachika Eiki \n3\nIida Seiji \n4\nTakashiba Shogo stakashi@okayama-u.ac.jp \n1\n1 Department of Pathophysiology‐Periodontal ScienceOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences2‐5‐1 Shikata‐choKita‐kuOkayama700‐8525Japan2 Department of Oral and Maxillofacial SurgeryHiroshima City Hiroshima Citizens Hospital7‐33 MotomachiNaka‐kuHiroshima730‐0011Japan3 Department of Oral and Maxillofacial Reconstructive SurgeryOkayama University Hospital2‐5‐1 Shikata‐choKita‐kuOkayama700‐8525Japan4 Department of Oral and Maxillofacial Reconstructive SurgeryOkayama University Graduate School of MedicineDentistry and Pharmaceutical Sciences2‐5‐1 Shikata‐choKita‐kuOkayama700‐8525Japan* Correspondence\n\nShogo Takashiba, Department of Pathophysiology‐Periodontal Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2‐5‐1 Shikata‐cho, Kita‐ku, Okayama 700‐8525, Japan. Tel: 81‐86‐235‐6675; Fax: 81‐86‐235‐6679; E‐mail: stakashi@okayama-u.ac.jp\n30 12 2016 2 2017 5 2 10.1002/ccr3.2017.5.issue-297 103 22 4 2016 13 10 2016 03 11 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nMedication‐related osteonecrosis of the jaw (MRONJ) is developed even in the patients who are edentulous and treated with short‐term bisphosphonate therapy and oral administration. It sometimes causes lethal sepsis in patients who have multiple health problems such as diabetes, cirrhosis, steroid use for interstitial pneumonia, sepsis, and spinal disk herniation.\n\nAntiangiogenic medicationsantiresorptive agentsbisphosphonatebisphosphonate‐related osteonecrosis of the jawmedication‐related osteonecrosis of the jawsystemic factors source-schema-version-number2.0component-idccr3751cover-dateFebruary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.4 mode:remove_FC converted:03.02.2017\n==== Body\nIntroduction\nBisphosphonates are the most commonly prescribed drugs for osteoporosis treatment 1. They are also used to treat multiple myeloma, bone metastases, and calcium disorders 2. These patients reportedly often develop bisphosphonate‐related osteonecrosis of the jaw (BRONJ) that is caused by subsequent dental surgery 3, 4. In general, it is thought that nitrogen‐containing bisphosphonates are much high risk of osteonecrosis than nitrogen not‐containing bisphosphonates. It is also thought that intravenous bisphosphonates are much high risk than oral bisphosphonates. Thus, medications for cancer, such as Zoledronate (Zometa®), are thought to have much high risk of osteonecrosis than medications for osteoporosis, such as Alendronate (Bonalon®) 5. In addition, it is considered that long‐term bisphosphonates therapy tends to cause osteonecrosis. Besides bisphosphonates, other antiresorptive agents such as denosumab and antiangiogenic medications also cause osteonecrosis 6. Thus, the American Association of Oral and Maxillofacial Surgeons position paper published in 2014 and the committee recommended changing the nomenclature of BRONJ to the term “medication‐related osteonecrosis of the jaw” (MRONJ) to accommodate the growing number of jaw osteonecrosis cases associated with other antiresorptive and antiangiogenic therapies 7. According to the position paper, there are three categories of risk factors for MRONJ: (1) medication‐related risk factors (e.g., bisphosphonate use), (2) local factors (e.g., dental surgery), and (3) demographic and systemic factors and other medication factors.\n\nIn this case report, the patient developed MRONJ and died of sepsis, although he received short‐term oral bisphosphonate therapy and had not received any dental surgical treatment because he was completely edentulous. However, he had many systemic factors such as diabetes, cirrhosis, and steroid use for interstitial pneumonia. The presence of multiple systemic factors can be a very high risk for MRONJ, even though there are few medication‐related factors and local factors 8, 9, 10.\n\nCase Report\nThe patient was a 59‐year‐old man with a history of smoking and drinking, insulin use for diabetes, cirrhosis associated with chronic hepatitis C, steroid use for interstitial pneumonia, sepsis, and spinal disk herniation. This study was conducted according to the guidelines of Hiroshima City Hiroshima Citizens Hospital, and a written informed consent was obtained from this patient. He was suddenly hospitalized with interstitial pneumonia. At that time of admission, white blood cell count (WBC) was 7800/μL and C‐reactive protein (CRP) level was 15.523 mg/L. He was treated for 2 months before developing MRONJ. During the treatment period, he was treated with intravenous steroids (i.e., methylprednisolone sodium succinate 1000 mg/day for 3 days, prednisolone sodium succinate 20 mg twice daily for 4 days, and methylprednisolone sodium succinate 1000 mg/day for 3 days). This regimen was followed by oral steroids (i.e., prednisolone 60 mg/day for 2 months). To prevent steroid‐induced osteoporosis, he was treated with oral bisphosphonate (i.e., alendronate 35 mg/week for 7 weeks). However, the administration of these drugs was stopped because of a right buccal space infection. A physician consulted us and referred the patient to our department. The patient had severe swelling from the right buccal area to the infraorbital region, hypesthesia, and tenderness, but no spontaneous pain (Fig. 1A). He was edentulous and usually used complete dentures. There were ulcerations and exposed bone on the alveolar part of the right incisor and molar (Fig. 1B and C). A pus discharge was observed in that area. The orthopantomogram did not show any bone resorption on the right mandible (Fig. 2A). Computer tomography (CT) scanning with a radio‐contrast agent showed swelling in the right buccal area, but showed no mandibular bone resorption (Fig. 2B). Magnetic resonance imaging (MRI) demonstrated an abnormal signal (e.g., low signal on T1‐weighted [T1W1] MRI and high signal on T2‐weighted [T2W1] MRI) in the bone marrow of the right mandibular angle (Fig. 2C), which suggested the presence of osteomyelitis in that area. Multiple‐drug‐resistant Enterococcus faecalis was detected by bacteriological identification (Table 1). Based on these results, the patient was diagnosed as having right mandibular cellulitis, sepsis, and disseminated intravascular coagulation (DIC). Treatment was started. We administered intravenous antibiotic treatment and irrigated part of the exposed bone with povidone–iodine every weekday. At 3 days after the first visit, sequestrectomy and drainage were administered (Fig. 1B). The pathologic findings showed extracted bone‐like sequestrum. During the treatment, the patient developed acute inflammation. Therefore, we changed the antibiotics from meropenem hydrate (Meropen; Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan) alone to meropenem hydrate and ampicillin/sulbactam (Unasyn S; Pfizer Inc., New York, USA) (Fig. 3). One month after the first visit, swelling from right buccal area had nearly disappeared (Fig. 4A) and there was fistulation in the right region (Fig. 4B). Exposed bone remained on the alveolar portion of the right mandibular molar and pus discharge was present (Fig. 4C and D). Antibiotic‐resistant bacteria (Gram‐positive bacilli) were detected at that time (Table 1). Therefore, we changed the antibiotics to sitafloxacin (Gracevit; Daiichi Sankyo, Tokyo, Japan) (Fig. 3). Seven weeks after the first visit, his condition had taken a turn for the worse. We treated him with ceftriaxone (Rocephin; Hoffman–La Roche, Basel, Switzerland) (Fig. 3). Eight weeks after the first visit, he died of multiorgan failure. Finally, we diagnosed this patient as MRONJ. His multiple systematic factors and MRONJ caused lethal sepsis because it fulfilled the diagnostic criteria: previous treatment with bisphosphonate, exposed bone in the maxillofacial region that has persisted for 8 weeks and no history of radiation therapy to the jaws.\n\nFigure 1 (A) Severe swelling from the right buccal area to the infraorbital region. (B) Bisphosphonate‐related exposed necrotic bone in the right posterior mandibular (during drainage). (C) Exposed bone on the alveolar part of the right incisor.\n\nFigure 2 (A) No bone resorption is present on the right part of the mandibula in orthopantomogram analysis. (B, C) Right buccal swelling is apparent, but there is no bone resorption of the mandibula, based on computer tomography (CT) analysis. (D, E) Abnormal signal (i.e., a low signal on T1‐weighted imaging [TIWI] and a high signal on T2‐weighted imaging [T2W1]) of the bone marrow on the right angle part of the mandibula.\n\nTable 1 Bacterial identification and microbial sensitivity test\n\nBacterial identification\tFirst visit\t18 days from first visit\t\nEnterococcus faecalis\tGram‐positive Bacillus\t\nAntibiotic Reagents (trade name)\tMIC\tMIC\t\nAminobenzyl Penicillin (Viccillin)\t2\t>8\t\nSulbactam/Ampicillin Unasyn S\t<8\t>16\t\nAmoxicillin/Clavulanate (Augmentin)\t<2\t>4\t\nBenzylpenicillin (Penicillin G)\t2\t>8\t\nCefditoren pivoxil (Meiact)\t>2\t>2\t\nCefazolin (Cefamezin)\t2\t>2\t\nCefpirome (Broact)\t16\t>16\t\nCefotiam (Pansporin)\t>16\t>16\t\nCefozopran (Firstein)\t16\t>16\t\nFlomoxef (Flumarin)\t>16\t>16\t\nImipenem/Cilastatin (Tienam)\t<1\t>8\t\nMeropenem (Meropen)\t2\t>8\t\nGentamicin (Gentacin)\t8>\t8\t\nClarithromycin\t–\t4\t\nErythromycin (Erythrosine)\t4\t>4\t\nMinocycline (Minomycin)\t<1\t8\t\nLevofloxacin (Cravit)\t2\t>4\t\nClindamycin (Dalacin)\t>2\t>2\t\nFosfomycin (Fosmicin)\t16\t>16\t\nSulfamethoxazole/Trimethoprim (Baktar)\t<0.5\t2\t\nJohn Wiley & Sons, LtdFigure 3 The transition in the laboratory test values for the white blood cell count (WBC) and the C‐reactive protein (CRP) level, and the use of several antibiotics for cellulitis and medication‐related osteonecrosis of the jaws (MRONJ).\n\nFigure 4 (A) Disappearance of swelling from the right buccal area to the infraorbital region. (B) Fistulation in the right region. (C) Discharge of pus by exposed bone on the alveolar part of the right mandibular molar. (D) Exposed bone on the alveolar part of the mandibular right molar.\n\nDiscussion\nIn recently years, there have been many reports on osteonecrosis of the jaw (ONJ) caused by bisphosphonates and by other antiresorptive and antiangiogenic therapies 6, 11, 12. The investigators of these reports accordingly recommended changing the term of this disease from “bisphosphonate‐related osteonecrosis of the jaw” to “medication‐related osteonecrosis of the jaw” 7. Denosumab, a RANK ligand inhibitor, is an antiresorptive agent and used to treat osteoporosis, multiple myeloma, and giant cell tumor 13. This agent inhibits bone resorption by a different mechanism than that of bisphosphonate. The manufacturer reports that the frequency of ONJ with denosumab is nearly the same as the frequency with zoledronic acid treatment 14. Thus, it may be that the development of ONJ is associated with the inhibition of bone resorption, rather than the use of a certain type of drug. However, it is considered that careful attention is required for the use of bisphosphonates in the present case due to the frequent use for the treatment of osteoporosis, osteopenia, and other diseases.\n\nMany reports indicate that the incidence of ONJ is significantly higher with the use of intravenous (IV) bisphosphonates such as zoledronic acid (Zometa; Novartis, Basel, Switzerland) than by the use of oral bisphosphonate 3, 15. The incidence of ONJ because of the use oral bisphosphonates was higher in Japan than in Europe and America 16. The period of drug use is also important, and long‐term use is considered a high risk for the development of ONJ.\n\nIn our patient, the period of oral bisphosphonates use was only 7 weeks, but it caused severe symptoms. It may be that these symptoms were because of his multiple systemic factors. In this case, bisphosphonate was used as preventive administration for steroidal osteoporosis. Thus, it is thought that there were another option not to use bisphosphonate for such a high‐risk patient or at least before administration we had to perform a risk assessment for MRONJ enough.\n\nGlucocorticoides are associated with an increased risk for MRONJ 17. He received steroid pulse therapies and oral steroids for interstitial pneumonia. Diabetes is also a risk factor for MRONJ 8. His glycemic control was extremely poor. In addition, the presence of comorbid condition such as obesity, alcohol use, and smoking was a risk factor for MRONJ 9.\n\nLocal factors are also important in the development of MRONJ. Dentoalveolar surgery such as tooth extraction is a major risk factor. Poor oral hygiene and oral infection such as periodontal disease are also risk factors 18, 19. The patient did not receive any dental surgery or radiation therapy. However, there were some ulcerations caused by the use of ill‐fitting dentures. The dentures were possibly contaminated with oral bacteria. In this case, we do not know whether the dentures were ill‐fitting and there were denture‐related traumatic ulcers because he already had ulcerations and exposed bone when we first saw him. However, we think denture‐related traumatic ulcers might have promoted a MRONJ. Osteonecrosis of the jaw has also been reported in patients with no history of surgery or in edentulous regions of the jaw 20. Physicians have to be careful with the use of bisphosphonates or other bone resorption inhibitors in patients, regardless of the presence or absence of teeth or surgical history.\n\nThe most important thing to prevent MRONJ is to perform a risk assessment enough before drug administration. It required cooperation among physicians, nurses, dentists, dental hygienists, pharmacists, and other medical staff 7. Physicians who prescribe bisphosphonates or other bone resorption inhibitors have to provide a detailed explanation to patients of the risk of MRONJ and consult dentists if a patient has even a small risk factor. To prevent MRONJ, dentists and dental hygienists have to explain sufficiently to patients the importance of oral hygiene, and perform oral care and dental treatments before patients use these drugs.\n\nConclusion\nThere is a tendency to believe that MRONJ is caused by long‐term bisphosphonate use (especially intravenous bisphosphonate) and dental surgery. We found that multiple systemic factors can be a worse risk factor for MRONJ because it may cause lethal disease such as sepsis.\n\nPhysicians have to be careful when administering bisphosphonate, other antiresorptive agents, and antiangiogenic medications for patients with multiple systemic factors, even if the patients seem to have no problems in the oral cavity.\n\nConflict of Interest\nThe authors have no conflict of interests to disclose.\n\nAuthorship\nKY: involved in study conception, design, and drafting manuscript; AS: involved in study conception, design, and is the chief doctor for the patient; FO: is one of the main doctors for the patient and performed data acquisition; MN: is supervisor and main doctor for the patient; KS and EY: performed analysis and interpretation of data; YH: is one of the main doctors for the patient and performed data acquisition; SI: made critical revision for this report; ST: made critical revision and is the corresponding author.\n\nAcknowledgments\nThe authors would like to thank all staff members of the Department of Oral and Maxillofacial Surgery in Hiroshima City Hiroshima Citizens Hospital and Department of Pathophysiology–Periodontal Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Hiroshima, Japan. We would like to thank Editage (www.editage.jp) for English language editing.\n==== Refs\nReferences\n1 \n\nRussell , R. G. \n, \nZ. \nXia \n, \nJ. E. \nDunford \n, \nU. \nOppermann \n, \nA. \nKwaasi \n, \nP. A. \nHulley \n, et al. 2007 \nBisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy . Ann. N. Y. Acad. Sci. \n1117 :209 –257 .18056045 \n2 \n\nBeuselinck , B. \n, \nP. \nWolter \n, \nA. \nKaradimou \n, \nR. \nElaidi \n, \nH. \nDumez \n, \nA. \nRogiers \n, et al. 2012 \nConcomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases . Br. J. Cancer \n107 :1665 –1671 .23132391 \n3 \n\nMavrokokki , T. \n, \nA. \nCheng \n, \nB. \nStein \n, and \nA. \nGoss \n. 2007 \nNature and frequency of bisphosphonate‐associated osteonecrosis of the jaws in Australia . J. Oral Maxillofac. Surg. \n65 :415 –423 .17307586 \n4 \n\nRuggiero , S. L. \n\n2009 \nBisphosphonate‐related osteonecrosis of the jaw (BRONJ): initial discovery and subsequent development . J. Oral Maxillofac. Surg. \n67 (Suppl. 5 ):13 –18 .\n5 \n\nKumar , V. \n, and \nA. K. \nShahi \n. 2014 \nNitrogen containing bisphosphonates associated osteonecrosis of the jaws: a review for past 10 year literature . Dent. Res. J. (Isfahan) \n11 :147 –153 .24932183 \n6 \n\nTaylor , K. H. \n, \nL. S. \nMiddlefell \n, and \nK. D. \nMizen \n. 2010 \nOsteonecrosis of the jaws induced by anti‐RANK ligand therapy . Br. J. Oral Maxillofac. Surg. \n48 :221 –223 .19836866 \n7 \n\nRuggiero , S. L. \n, \nT. B. \nDodson \n, \nJ. \nFantasia \n, \nR. \nGoodday \n, \nT. \nAghaloo \n, \nB. \nMehrotra \n, et al. 2014 \nAmerican Association of Oral and Maxillofacial Surgeons position paper on medication‐related osteonecrosis of the jaw–2014 update . J. Oral Maxillofac. Surg. \n72 :1938 –1956 .25234529 \n8 \n\nKhamaisi , M. \n, \nE. \nRegev \n, \nN. \nYarom \n, \nB. \nAvni \n, \nE. \nLeitersdorf \n, \nI. \nRaz \n, et al. 2007 \nPossible association between diabetes and bisphosphonate‐related jaw osteonecrosis . J. Clin. Endocrinol. Metab. \n92 :1172 –1175 .17179196 \n9 \n\nAbu‐Id , M. H. \n, \nP. H. \nWarnke \n, \nJ. \nGottschalk \n, \nI. \nSpringer \n, \nJ. \nWiltfang \n, \nY. \nAcil \n, et al. 2008 \n“Bis‐phossy jaws” ‐ high and low risk factors for bisphosphonate‐induced osteonecrosis of the jaw . J. Craniomaxillofac. Surg. \n36 :95 –103 .18234504 \n10 \n\nWessel , J. H. \n, \nT. B. \nDodson \n, and \nA. I. \nZavras \n. 2008 \nZoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case‐control study . J. Oral Maxillofac. Surg. \n66 :625 –631 .18355585 \n11 \n\nFrancini , F. \n, \nA. \nPascucci \n, \nE. \nFrancini \n, \nS. T. \nMiano \n, \nG. \nBargagli \n, \nG. \nRuggiero \n, et al. 2011 \nOsteonecrosis of the jaw in patients with cancer who received zoledronic acid and bevacizumab . J. Am. Dent. Assoc. \n142 :506 –513 .21531932 \n12 \n\nKatsarelis , H. \n, \nN. P. \nShah \n, \nD. K. \nDhariwal \n, and \nM. \nPazianas \n. 2015 \nInfection and Medication‐related Osteonecrosis of the Jaw . J. Dent. Res. \n94 :534 –539 .25710950 \n13 \n\nBurkiewicz , J. S. \n, \nS. L. \nScarpace \n, and \nS. P. \nBruce \n. 2009 \nDenosumab in osteoporosis and oncology . Ann. Pharmacother. \n43 :1445 –1455 .19622756 \n14 \nAmgen 2009 Annual Report , 2009 pp. 35 –48 \n\n15 \n\nKim , J. H. \n, \nY. J. \nKo \n, \nJ. Y. \nKim \n, \nY. \nOh \n, \nJ. \nHwang \n, \nS. \nHan \n, et al. 2015 \nGenetic investigation of bisphosphonate‐related osteonecrosis of jaw (BRONJ) via whole exome sequencing and bioinformatics . PLoS ONE \n10 :e0118084 .25668207 \n16 \n\nUrade , M. \n, \nN. \nTanaka \n, \nK. \nFurusawa \n, \nJ. \nShimada \n, \nT. \nShibata \n, \nT. \nKirita \n, et al. 2011 \nNationwide survey for bisphosphonate‐related osteonecrosis of the jaws in Japan . J. Oral Maxillofac. Surg. \n69 :e364 –e371 .21782307 \n17 \n\nWeinstein , R. S. \n\n2012 \nGlucocorticoid‐induced osteonecrosis . Endocrine \n41 :183 –190 .22169965 \n18 \n\nOteri , G. \n, \nE. \nBramanti \n, \nV. \nNigrone \n, and \nM. \nCicciù \n. 2013 \nDecayed, missing, and filled teeth index and periodontal health in osteoporotic patients affected by BRONJ: an observational study . J. Osteoporos. \n2013 :231289 .24455411 \n19 \n\nThumbigere‐Math , V. \n, \nB. S. \nMichalowicz \n, \nJ. S. \nHodges \n, \nM. L. \nTsai \n, \nK. K. \nSwenson \n, \nL. \nRockwell \n, et al. 2014 \nPeriodontal disease as a risk factor for bisphosphonate‐related osteonecrosis of the jaw . J. Periodontol. \n85 :226 –233 .23786404 \n20 \n\nRuggiero , S. L. \n\n2007 \nGuidelines for the diagnosis of bisphosphonate‐related osteonecrosis of the jaw (BRONJ) . Clin. Cases Miner. Bone Metab. \n4 :37 –42 .22460751\n\n",
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"keywords": "Antiangiogenic medications; antiresorptive agents; bisphosphonate; bisphosphonate‐related osteonecrosis of the jaw; medication‐related osteonecrosis of the jaw; systemic factors",
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"title": "Medication-related osteonecrosis of the jaws caused lethal sepsis in an edentulous patient with multiple systemic factors.",
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"abstract": "Background: The burden of the people living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) is largely borne by communities in Sub-Saharan Africa. The rate of kidney disease is increasing amongst HIV patients and occurs more often in patients with advanced stage of the disease with lower CD4 counts and associated with a high rate of morbidity and mortality. The objective of this study is to determine the prevalence and predictors of chronic kidney disease (CKD) amongst HIV patients on highly active antiretroviral therapy (HAART) at the University of Calabar Teaching Hospital, Calabar. Materials and methods: This was a cross-sectional study that was carried out over a 4-month period from May to August 2018. In all, a total of 118 patients with HIV on HAART were recruited into the study in a consecutive manner and their serum creatinine measured with the calculation of estimated glomerular filtration rate (eGFR). Other data collected were sex, age, weight, height, body mass index (BMI), waist hip ratio (WHR), packed cell volume, CD4 count etcetera. Data collected were inputted and analyzed with SPSS version 18, and statistical significance was taken to be p<0.05. Results: There were more females (69.5%) amongst the HIV participants and the prevalence of CKD was 15.3%. The risk factors seen to be associated with CKD were lower levels of CD4 count below 200 cells/µl, lower PCV, weight, BMI, and eGFR. Also, higher levels of WHR and creatinine were associated with CKD. Factors directly correlated with CKD were weight, BMI and CD4 count levels, while creatinine level was inversely correlated with CKD. However, a logistic regression model showed only creatinine to be a predictor of CKD. Conclusion: HIV patients on antiretroviral therapy, mainly the highly active antiretroviral therapy (HAART) have a relatively high prevalence of CKD of 15.3% and high level of serum creatinine was predictive of CKD in the logistic regression model in our study.",
"affiliations": "Renal Unit, Department of Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria.;Department of Family Medicine, University of Calabar, Calabar and University of Calabar Teaching Hospital, Calabar, Nigeria.;Department of Internal Medicine, University of Calabar, Calabar, Nigeria.;Renal Unit, Department of Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria.;Department of Family Medicine, University of Calabar, Calabar and University of Calabar Teaching Hospital, Calabar, Nigeria.;Institute of Community Health, University of Houston, Texas Medical Center, Houston, TX, USA.",
"authors": "Okpa|Henry Ohem|HO|;Bisong|Elvis Mbu|EM|;Enang|Ofem Egbe|OE|;Effa|Emmanuel Edet|EE|;Monjok|Emmanuel|E|;Essien|Ekere James|EJ|",
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"fulltext": "\n==== Front\nHIV AIDS (Auckl)HIV AIDS (Auckl)HIVhivHIV/AIDS (Auckland, N.Z.)1179-1373Dove 18980210.2147/HIV.S189802Original ResearchPredictors of chronic kidney disease among HIV–infected patients on highly active antiretroviral therapy at the University of Calabar Teaching Hospital, Calabar, South-South Nigeria Okpa et alOkpa et alOkpa Henry Ohem 12Bisong Elvis Mbu 3Enang Ofem Egbe 24Effa Emmanuel Edet 12Monjok Emmanuel 35Essien Ekere James 51 Renal Unit, Department of Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria2 Department of Internal Medicine, University of Calabar, Calabar, Nigeria3 Department of Family Medicine, University of Calabar, Calabar and University of Calabar Teaching Hospital, Calabar, Nigeria4 Endocrine and Metabolism Unit, University of Calabar Teaching Hospital, Calabar, Nigeria5 Institute of Community Health, University of Houston, Texas Medical Center, Houston, TX, USACorrespondence: Henry Ohem OkpaDepartment of Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria, 540242Tel +234 803 718 3400 Email henohmsy2k@yahoo.com05 4 2019 2019 11 61 67 05 10 2018 18 2 2019 © 2019 Okpa et al.2019Okpa 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).Background: The burden of the people living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) is largely borne by communities in Sub-Saharan Africa. The rate of kidney disease is increasing amongst HIV patients and occurs more often in patients with advanced stage of the disease with lower CD4 counts and associated with a high rate of morbidity and mortality. The objective of this study is to determine the prevalence and predictors of chronic kidney disease (CKD) amongst HIV patients on highly active antiretroviral therapy (HAART) at the University of Calabar Teaching Hospital, Calabar.\n\nMaterials and methods: This was a cross-sectional study that was carried out over a 4-month period from May to August 2018. In all, a total of 118 patients with HIV on HAART were recruited into the study in a consecutive manner and their serum creatinine measured with the calculation of estimated glomerular filtration rate (eGFR). Other data collected were sex, age, weight, height, body mass index (BMI), waist hip ratio (WHR), packed cell volume, CD4 count etcetera. Data collected were inputted and analyzed with SPSS version 18, and statistical significance was taken to be p<0.05.\n\nResults: There were more females (69.5%) amongst the HIV participants and the prevalence of CKD was 15.3%. The risk factors seen to be associated with CKD were lower levels of CD4 count below 200 cells/µl, lower PCV, weight, BMI, and eGFR. Also, higher levels of WHR and creatinine were associated with CKD. Factors directly correlated with CKD were weight, BMI and CD4 count levels, while creatinine level was inversely correlated with CKD. However, a logistic regression model showed only creatinine to be a predictor of CKD.\n\nConclusion: HIV patients on antiretroviral therapy, mainly the highly active antiretroviral therapy (HAART) have a relatively high prevalence of CKD of 15.3% and high level of serum creatinine was predictive of CKD in the logistic regression model in our study.\n\nKeywords\npredictorschronic kidney diseaseHIVSouth – SouthNigeria\n==== Body\nIntroduction\nThe burden of the people living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) is largely borne by communities in Sub-Saharan Africa1 in which Nigeria is included.\n\nKidney disease is an important complication in HIV patients with an increasing rate in its prevalence. This kidney-related disease tends to occur more often in patients with advanced stage of the HIV infection with lower CD4 counts and is associated with a high rate of morbidity and mortality.2\n\nRelevant comorbid conditions such as chronic kidney disease (CKD) and end-stage renal disease (ESRD) are found in HIV-infected individuals.3 Also, the risk of ESRD as shown by the United States renal data system is said to be 50-fold higher in African Americans living with HIV than in HIV-infected white patients.4\n\nAbout 30% of HIV-infected patients have been shown to have abnormal kidney function, with HIV-related kidney disease becoming a main cause of ESRD requiring dialytic intervention, with subsequent progression of kidney disease to AIDS and ultimately death.5\n\nIn Nigeria, the overall prevalence of renal disorders among HIV-infected patients is not known. A study from Ile–Ife reported a prevalence of 38% for HIV-associated nephropathy (HIVAN),6 while another study in Jos showed a prevalence of 51.8% for renal disease in HIV-infected patients.7 Other studies done in South-East and South-West Nigeria showed prevalences of 22.9%8 and 23.5%9 respectively.\n\nA study in Baltimore, USA showed that, in a kidney biopsy report amongst some CKD patients of African American descent, there was a 3-fold higher rate in the risk of progression to ESRD with HIVAN than in those with other forms of renal histopathologic lesions.10\n\nThe pathologic characteristics of HIV-associated CKD is varied in nature, with biopsy and autopsy series showing a wide range of pathologic lesions during analysis of the tissues.11–14 However, among the African descendants, mostly found is the collapsing variant of focal segmental glomerulosclerosis, termed “HIVAN,”11,14,15 which has been reported to have a more aggressive downward course and rapid progression to ESRD.16,17\n\nThe increased availability and usage of HAART by HIV-infected patients has influenced the rise of kidney diseases, as most HIV patients now live longer to develop such complications associated with the kidneys.18 However, there is an appreciable reduction in the risk of developing ESRD by 40–60%, mainly due to the slower clinical course of kidney disease among HIV patients, with an attendant increase from 25% to 75% in the 1-year survival rate while undergoing dialysis and renal transplantation is a successful treatment option.19,20\n\nKidney disease and its associated risk factors are frequently found among HIV-infected patients, irrespective of the improvements with the use of HAART, and it remains a cause of morbidity and mortality.21 The associated risk factors for kidney in this population include black race, older age, hypertension, diabetes, low CD4 cell count, and high viral load.21\n\nAlso, acute or chronic kidney disease has been shown to be associated with the use of antiretroviral regimens.21 Drugs such as tenofovir and some protease inhibitors have been implicated as a cause of severe renal impairment.22\n\nThere are still very few studies in Nigeria, particularly in the South-South region of the country where our institution is located that conducted a study on the prevalence and predictors of CKD among HIV patients on HAART.\n\nThese findings prompted us to undertake this study in order to determine the prevalence and risk factors associated with CKD in HIV patients on HAART at the University of Calabar Teaching Hospital, Calabar.\n\nMaterials and methods\nStudy design, settings, and population\nThis was a cross-sectional study that was conducted in the special treatment clinic for HIV patients at the University of Calabar Teaching Hospital (UCTH), Calabar over a 4 month period from May to August, 2018.\n\nA total of 118 HIV patients on HAART attending the special treatment clinic were consecutively recruited after meeting the study criteria and all participants provided written informed consent.This study was conducted in accordance with the Declaration of Helsinki.\n\nAll subjects underwent interview by using a structured questionnaire.\n\nInformation regarding patients’ age, sex, occupation, religion, and educational status were obtained. Moreso, information on the family history of hypertension and history suggestive of renal disease were obtained. All subjects were fully examined and anthropometric measurements such as weight and height were taken by the investigators. Body mass index (BMI) was calculated from these. Subjects in the study had their blood pressures measured using a mercury sphygmomanometer and a standard sized cuff using the usual methods with the patient sitting quietly. The mean of two readings taken at least 2 minutes apart after the patient had rested in a relaxed sitting position for 5 minutes in a quiet room was recorded as the blood pressure.\n\nHypertension was defined as systolic blood pressure (SBP) 140 mmHg at least and/or diastolic blood pressure (DBP) 90 mmHg at least, using the Joint National Committee 7 (JNC 7) guideline or history of hypertension with the use of antihypertensive medications.\n\nSamples for urine and blood were obtained from the participants at first contact with the investigators during the clinic visits of the HIV patients.\n\nUrinalysis with multistix (combi – 9) were carried out on all participants for the presence of overt proteinuria. Serum creatinine value was measured using alkaline picrate method while the creatinine clearance was calculated using the cockcroft and Gault formula for predicting glomerular filtration rate (GFR) as follows:\n 140−Ageinyear×weightkg×0.85forwomen72×serumcreatininemg/dl. \n\nThis formula is readily preferred due to its simplicity and good predictive ability of GFR in HIV – positive patients.23\n\nThe subjects were classified using the GFR according to the National Kidney Foundation using the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines as follows:24\n\nStage 1 (Normal or increased eGFR) ≥90 mL/min/1.73 m2\n\nStage 2 (Mildly decreased eGFR) =60–89 mL/min/1.73 m2\n\nStage 3 (Moderately decreased eGFR) =30–59 mL/min/1.73 m2\n\nStage 4 (Severely decreased eGFR) =15–29 mL/min/1.73 m2\n\nStage 5 (Kidney failure) <15 mL/min/1.73 m2\n\nChronic kidney disease was therefore defined based on either of the two criteria. First, on the eGFR of <60 mL/min24 and secondly on elevated plasma creatinine levels using values for the classification of chronic progressive renal disease:25\n\nReduced renal reserve (88.4–221 mmol/L)\n\nRenal insufficiency (221–530.4 mmol/L)\n\nRenal failure (486.2–972.4 mmol/L)\n\nESRD (>707.2 mmol/L)\n\nInclusion criteria\nPatients confirmed to have been diagnosed with HIV and on HAART at UCTH.\n\nHIV patients aged 18 years and above.\n\nHIV patients that consent to the study.\n\n\n\n\nExclusion criteria\nHIV patients with comorbid conditions such as diabetes and liver cirrhosis.\n\nHIV patients below 18 years of age.\n\nHIV patients that do not give consent.\n\n\n\n\nData analysis\nThe data obtained were inputted and analyzed using Statistical Package for Social Sciences (SPSS) version 18. Continuous variables and categorical variables were expressed as means ± SD and percentages respectively. Comparison of means was done using Independent sample Student t-test and ANOVA; and Bivariate Correlation and Binary Logistic regression were used to determine the predictors of CKD. Other statistical tests were used as appropriate. p<0.05 was accepted to be significant.\n\nEthical consideration\nEthical approval was duly applied for and subsequently obtained from the Health Research Ethical Committee (HREC) of the University of Calabar Teaching Hospital, Calabar.\n\nResults\nTable 1 shows more female participants (69.5%) with about 58.3% of the patients below the age of 41 years and 15.3% of the participants having eGFR below 60 mls/min. The majority of the participants were married (54.2%), had secondary education (40.7%), were mainly business persons (62.7%) and resided in the urban region (73.7%). About half of the participants were on tenofovir-based combination ARV.\nTable 1 Clinical and demographic characteristics of participants\n\nVariables\tFrequency (%), N=118\t\nGender\t\t\nFemale\t82 (69.5%)\t\nMale\t36 (30.5%)\t\nAge category (years)\t\t\n18–30\t20 (16.9%)\t\n31–40\t50 (42.4%)\t\n41–50\t31 (26.3%)\t\n51–60\t12 (10.2%)\t\nAbove 60\t5 (5.2%)\t\neGFR category (mls/min)\t\t\n≥90\t46 (39.0%)\t\n60–89\t34 (45.7%)\t\n30–59\t16 (13.6%)\t\n15–29\t2 (1.7%)\t\n˂15\t0 (0.0%)\t\nMarital status\t\t\nSingle\t37 (31.4%)\t\nMarried\t64 (54.2%)\t\nDivorced\t4 (3.4%)\t\nWidow\t13 (11.0%)\t\nEducational level\t\t\nNo formal education\t2 (1.7%)\t\nPrimary\t21 (17.8%)\t\nSecondary\t48 (40.7%)\t\nTertiary\t47 (39.8%)\t\nOccupation\t\t\nStudent\t4 (3.4%)\t\nCivil servant\t26 (22.0%)\t\nPublic servant\t14 (11.9%)\t\nBusiness (artisans, traders)\t74 (62.7)\t\nPlace of residence\t\t\nUrban\t87 (73.7%)\t\nRural\t31 (26.3%)\t\nEthnic group\t\t\nEfik\t37 (31.4%)\t\nEjagham\t19 (16.1%)\t\nIbibio\t47 (38.8%)\t\nAnang\t9 (7.6%)\t\nOthers (Igbo, Hausa, Yoruba)\t6 (5.1%)\t\nARV therapy\t\t\nABC/AZT/EFV\t1 (0.8%)\t\n3TC/AZT/NVP\t42 (35.6%)\t\nTDF/AZT/EFV\t8 (6.8%)\t\nABC/3TC/EFV\t15 (12.7%)\t\nTDF/3TC/EFV\t37 (31.4%)\t\nTDF/3TC/LPVr\t15 (12.7%)\t\nAbbreviations: ARV, antiretroviral; ABC, abacavir; AZT, zidovudine; EFV, efavirenz; 3TC, lamivudine; NVP, nevirapine; TDF, tenofovir; LPVr, lopinavir-retonavir.\n\n\n\n\nTable 2 showed that participants with a CD4 count ≤200 and those on TDF/3TC/EFV ARV therapy are more likely to develop CKD with significant values of 0.006 and 0.038 respectively.\nTable 2 Cross tabulation of clinical and biochemical parameters\n\nVariables\tCKD present (eGFR <60 mL/min), N=18, (%)\tCKD absent (eGFR >60 mL/min), N=100, (%)\tp-value\t\nAge category (years)\t\t\t\t\n18–30\t2 (11.1)\t18 (18.0)\t0.481*\t\n31–40\t6 (33.3)\t44 (44.0)\t\t\n41–50\t5 (27.8)\t26 (26.0)\t\t\n51–60\t3 (16.7)\t9 (9.0)\t\t\n>60\t2 (11.1)\t3 (3.0)\t\t\nGender\t\t\t\t\nFemale\t11 (61.1)\t71 (71.0)\t0.402\t\nMale\t7 (38.9)\t29 (29.0)\t\t\nHIV duration (months)\t\t\t\t\n≤60 months\t12 (66.7)\t48 (48.0)\t0.145\t\n>60 months\t6 (33.3)\t52 (52.0)\t\t\nCD4count (cells/µL)\t\t\t\t\n≤200\t8 (44.4)\t16 (16.0)\t0.006\t\n>200\t10 (55.6)\t84 (84.0)\t\t\nARV therapy\t\t\t\t\nABC/AZT/EFV\t0 (0.0)\t1 (1.0)\t0.038*\t\n3TC/AZT/NVP\t2 (11.1)\t40 (40.0)\t\t\nTDF/AZT/EFV\t3 (16.7)\t5 (5.0)\t\t\nABC/3TC/EFV\t5 27.8)\t10 (10.0)\t\t\nTDF/3TC/EFV\t7 (38.9)\t30 (30.0)\t\t\nTDF/3TC/LPVr\t1 (5.6)\t14 (14.0)\t\t\nHypertension\t\t\t\t\nYes\t6 (33.3)\t25 (25.0)\t0.46\t\nNo\t12 (66.7)\t75 (75.0)\t\t\nNote: *Fisher’s exact test.\n\nAbbreviations: ARV, antiretroviral; ABC, abacavir; AZT, zidovudine; EFV, efavirenz; 3TC, lamivudine; NVP, nevirapine; TDF, tenofovir; LPVr, lopinavir-retonavir.\n\n\n\n\nIn Table 3, the mean WHR and creatinine levels are significantly higher in subjects with CKD (p<0.05) while the mean weight, BMI, eGFR and CD4 count levels are significantly lower in subjects with CKD (p<0.05).\nTable 3 Relationship between CKD and some selected variables\n\nVariables\tCKD present (eGFR <60 mL/min), N=18\tCKD absent (eGFR >60 mL/min), N=100\tp-value\t\nAge (years)\t44.17±11.87\t39.22±9.65\t0.109\t\nHIV duration (months)\t50.78±48.44\t70.71±45.58\t0.119\t\nSBP\t114.44±21.48\t113.10±19.05\t0.806\t\nDBP\t70.56±16.62\t70.00±13.48\t0.895\t\nWeight (kg)\t59.89±12.29\t68.72±13.06\t0.010\t\nBMI (kg/m2)\t23.47±4.76\t26.01±4.37\t0.046\t\nWHR\t0.93±0.03\t0.91±0.05\t0.020\t\nPCV (%)\t29.10±5.37\t31.73±5.69\t0.070\t\nCreatinine (µmoL/L)\t133.13±46.06\t85.73±19.13\t0.001\t\neGFR (mL/min)\t50.59±11.28\t90.67±20.78\t0.001\t\nCD4 count (cells/µL)\t293.11±235.42\t446.73±242.06\t0.018\t\nARV duration (months)\t46.72±47.88\t65.35±43.73\t0.138\t\nAbbreviations: HIV, human immunodeficiency virus; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; WHR, waist hip ratio; PCV, packed cell volume; eGFR, estimated glomerular filtration rate; ARV, antiretroviral.\n\n\n\n\nTable 4 shows that the weight, BMI, PCV and CD4 count levels are directly correlated with eGFR, while creatinine levels are inversely correlated.\nTable 4 Correlation of eGFR and some selected variables\n\nVariables\tCorrelation coefficient\tp-value\t\nAge years)\t−0.177\t0.056\t\nHIV duration (months)\t0.137\t0.140\t\nSBP\t−0.018\t0.843\t\nDBP\t0.019\t0.835\t\nWeight (kg)\t0.36**\t0.0001\t\nBMI (kg/m2)\t0.327**\t0.0001\t\nWHR\t−0.108\t0.246\t\nPCV (%)\t0.319**\t0.0001\t\nCreatinine (µmol/L)\t−0.678**\t0.0001\t\nCD4 count (cells/µL)\t0.216*\t0.019\t\nARV duration (months)\t0.148\t0.110\t\nNote:*Shows the level of correlation, where * indicates weakly correlated while ** and above indicates strongly correlated.\n\nAbbreviations: HIV, human immunodeficiency virus; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; WHR, waist hip ratio; PCV, packed cell volume; eGFR, estimated glomerular filtration rate; ARV, antiretroviral.\n\n\n\n\nIn the logistic regression model in Table 5, when the risk factors that were significantly correlated in Table 4 were put into the model, creatinine levels were the main predictor of CKD.\nTable 5 Logistic regression analysis of risk factors for CKD\n\nVariables\tExp. B\t95% CI/Odds Ratio\tp-value\t\nWeight (kg)\t1.083\t0.982–1.194\t0.109\t\nBMI (kg/m2)\t0.945\t0.712–1.254\t0.693\t\nPCV (%)\t1.033\t0.936–1.140\t0.517\t\nCD4 count (µmol/l)\t1.002\t0.999–1.005\t0.116\t\nCreatinine (µmol/l)\t0.933\t0.903–0.964\t0.0001\t\nARV Type 1 (3TC/AZT/NVP)\t1.548\t0.000\t1.000\t\nARV Type 2 (TDF/AZT/EFV)\t1.429\t0.120–16.998\t0.778\t\nARV Type 3 (ABC/3TC/EFV)\t0.119\t0.010–1.426\t0.093\t\nARV Type 4 (TDF/3TC/EFV)\t0.143\t0.014–1.418\t0.097\t\nARV Type 5 (TDF/3TC/LPVr)\t0.306\t0.034–2.733\t0.098\t\nAbbreviations: BMI, body mass index; WHR, waist hip ratio; PCV, packed cell volume; eGFR, estimated glomerular filtration rate; EFV, efavirenz; 3TC, lamivudine; AZT, zidovudine; NVP, nevirapine; ARV, antiretroviral; LPVr, lopinavir-retonavir.\n\n\n\n\nDiscussion\nOur study showed that 15.3% of the HIV subjects had CKD, and the risk factors associated with the development of CKD were lower levels of CD4 count below 200 cells/µL, lower PCV, weight, BMI and eGFR. Also, higher levels of WHR and creatinine were associated with CKD. Factors directly correlated with CKD were weight; BMI and CD4 count levels, while the creatinine levels were inversely correlated. However, a logistic regression model showed only creatinine to be a predictor of CKD.\n\nThe prevalence of 15.3% in our study is lower than that obtained from some Nigerian studies with a range of 22–51%,6–9 but has similarity with the studies in USA with a range of 2–15.5%.26–28 The difference noted in the prevalence of CKD in our study and the former reports may be adduced to the differences in sample size and HAART combination, as our study had protease inhibitor-based combination while the former reports were mainly nucleoside and nucleotide reverse transcriptase inhibitors combination.\n\nThis study showed that lower CD4 count is a risk factor for CKD, and lower CD4 count has also been shown to be associated with advanced HIV disease.2 This finding in our study is in contrast with another study8 but in keeping with other studies where lower CD4 count was a predictor of CKD.6,29\n\nAlso, studies have shown low BMI and hemoglobin to be predictors of CKD,8,30 but our study showed these parameters to be associated with CKD as risk factors as they were not significant in the logistic regression model.\n\nIn this study, tenofovir-based combination ARV therapy was associated with CKD in HIV patients; TDF/3TC/EFV combination was also a major implication.\n\nResearch has shown that tenofovir has been demonstrated to contribute to severe renal impairment in HIV-infected patients.22 There appears to be a consistent slight drop (up to 10%) in eGFR with the use of TDF, across some studies,31–33 and appears to be more marked during the first years of exposure. However a study suggested that this decrease was largely irreversible,30 but the difference was of doubtful clinical significance. Studies have been conducted on patients who have initiated TDF in the presence of renal dysfunction and have shown that while the majority of patients did not deteriorate during study follow-up, those with pre-existing stage 2 (eGFR between 60 mL/min/1.73 m2 and 89 mL/min/1.73 m2) and stage 3 (30–59 mL/min/1.73 m2) renal disease were associated with progression to renal failure on TDF,34,35 although one study actually demonstrated improvement on TDF in patients with severe (<30 mL/min/1.73 m2) renal failure\n\nHigh levels of serum creatinine were found to be predictive of CKD in HIV patients in our study which is in keeping with earlier studies.6,8 Surprisingly, creatinine-based estimated GFR which is a more reliable tool in assessing renal function was associated with CKD but not predictive.36\n\nOur study did not demonstrate any association between gender and CKD in HIV patients, in contrast with a study that found female sex to be associated with CKD and another study which is in keeping with our findings.8,37\n\nAccording to a report by Agbaji et al,37 older age was associated with and a predictor of CKD in HIV patients. However, our study did not show such relationship, despite almost the same mean age of the subjects in their study and ours.\n\nThis study did not report any association between SBP, DBP, and CKD. This is in agreement with an earlier mentioned study.8 In contrast, some other studies reported SBP and DBP to be predictors of CKD.6,38 The difference with the later reports may be due to difference in study design.\n\nConclusion\nIn conclusion therefore, the prevalence of CKD reported among HIV subjects in this study was 15.3% and the risk factors associated with CKD in HIV subjects on HAART were lower levels of CD4 count below 200 cells/µL, lower PCV, weight, BMI, and eGFR. Also, higher creatinine was associated and predictive of CKD in HIV subjects.\n\nLimitations of the study\nIt was a cross-sectional study carried out in one center which may not give a true prevalence of CKD in HIV patients in the South-South region of Nigeria, a multicenter study wwould be very helpful.\n\nAlso, other investigations that would have contributed to the risk factors and predictors of CKD were not measured; these include renal biopsy, HIV viral load, Hepatitis B and C, and lipid profile.\n\nAcknowledgment\nThe authors acknowledge the University of Calabar Teaching Hospital HIV special clinic staff for their unreserved support during the study.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. UNAIDS Report on the Global AIDS Epidemic 2013 . UNAIDS ; 2013 \nAvailable from : http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013\n2. Szczech \nLA , Hoover \nDR , Feldman \nJG , et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy . Clin Infect Dis . 2004 ;39 (8 ):1199 –1206 . doi:10.1086/424013 15486845 \n3. Schwartz \nEJ , Szczech \nLA , Ross \nMJ , Klotman \nME , Winston \nJA , Klotman \nPE . Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease . J Am Soc Nephrol . 2005 ;16 :2412 –2420 . doi:10.1681/ASN.2005040340 15987747 \n4. Eggers \nPW , Kimmel \nPL . Is there an epidemic of HIV infection in the US ESRD program? \nJ Am Soc Nephrol . 2004 ;15 :2477 –2485 . doi:10.1097/01.ASN.0000138546.53152.A7 15339998 \n5. Gupta \nSK , Eustace \nJA , Winston \nJA , et al. Guidelines for the management of chronic kidney disease in HIV infected patients: recommendations of the HIV Medicine Association of the Infectious Disease Society of America . Clin Infect Dis . 2005 ;40 :1559 –1585 . doi:10.1086/430257 15889353 \n6. Emem-Chioma \nP , Arogundade \nFA , Sanusi \nAA , Wokoma \nFS , Akinsola \nA . Renal disease in HIV-seropositive patients in Nigeria: an assessment of prevalence, clinical features and risk factors . Nephrol Dial Transplant . 2008 ;23 :741 –746 . doi:10.1093/ndt/gfm836 18065807 \n7. Agaba \nEI , Agaba \nPA , Sirisena \nND , Anteyi \nEA , Idoko \nJA . Renal disease in the acquired immunodeficiency syndrome in North Central Nigeria . Niger J Med . 2003 ;12 :120 –125 .14737980 \n8. Anyabolu \nEN , Chukwuonye \nII , Arodiwe \nE , Ijoma \nCK , Ulasi \nI . Prevalence and predictors of chronic kidney disease in newly diagnosed human immunodeficiency virus patients in Owerri, Nigeria . Ind J Nephrol . 2016 ;26 (1 ):10 –15 . doi:10.4103/0971-4065.156115 \n9. Umeizudike \nT , Mabayoje \nM , Okany \nC , Abdulkareem \nF , Adeyomoye \nA , Okubadejo \nN . Okpechi prevalence of chronic kidney disease in HIV positive patients in Lagos, South-west Nigeria . Nephrol Rev . 2012 ;4 :22 –26 . doi:10.4081/nr.2012.e5 \n10. Lucas \nGM , Lau \nB , Atta \nMG , Fine \nDM , Keruly \nJ , Moore \nRD . Chronic kidney disease incidence, and progression to end-stage renal disease, in HIV-infected individuals: a tale of two races . J Infect Dis . 2008 ;197 (11 ):1548 –1557 . doi:10.1086/587994 18422458 \n11. Szczech \nLA , Gupta \nSK , Habash \nR , et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection . Kidney Int . 2004 ;66 :1145 –1152 . doi:10.1111/j.1523-1755.2004.00865.x 15327410 \n12. Gerntholtz \nTE , Goetsch \nSJ , Katz \nI . HIV-related nephropathy: a South African perspective . Kidney Int . 2006 ;69 :1885 –1891 . doi:10.1038/sj.ki.5000351 16625149 \n13. Estrella \nM , Fine \nDM , Gallant \nJE , et al. HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients . Clin Infect Dis . 2006 ;43 :377 –3380 . doi:10.1086/505497 16804855 \n14. Shahinian \nV , Rajaraman \nS , Borucki \nM , Grady \nJ , Hollander \nWM , Ahuja \nTS . Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients . Am J Kidney Dis . 2000 ;35 :884 –888 . doi:10.1016/S0272-6386(00)70259-9 10793023 \n15. D’Agati \nV , Suh \nJI , Carbone \nL , Cheng \nJT , Appel \nG . Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study . Kidney Int . 1989 ;35 :1358 –1370 . doi:10.1038/ki.1989.135 2770114 \n16. Rao \nTK , Friedman \nEA , Nicastri \nAD . The types of renal disease in the acquired immunodeficiency syndrome . N Engl J Med . 1987 ;316 :1062 –1068 . doi:10.1056/NEJM198704233161705 3561458 \n17. Laradi \nA , Mallet \nA , Beaufils \nH , Allouache \nM , Martinez \nF . HIV-associated nephropathy: outcome and prognosis factors. Groupe d’ Etudes Nephrologiques d’Ile de France . J Am Soc Nephrol . 1998 ;9 :2327 –2335 .9848787 \n18. US Renal Data System . USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States . Bethesda (MD) : National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases ; 2007 .\n19. Ahuja \nTS , Grady \nJ , Khan \nS . Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States . J Am Soc Nephrol . 2002 ;13 :1889 –1893 .12089385 \n20. Lucas \nGM , Eustace \nJA , Sozio \nS , Mentari \nEK , Appiah \nKA , Moore \nRD . Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study . Aids . 2004 ;18 :541 –546 .15090808 \n21. Winston \nJ , Deray \nG , Hawkins \nT , Szczech \nL , Wyatt \nC , Young \nB . Kidney disease in patients with HIV infection and AIDS . Clin Infect Dis . 2008 ;47 :1449 –1457 . doi:10.1086/593099 18947327 \n22. Röling \nJ , Schmid \nH , Fischereder \nM , Draenert \nR , Goebel \nF . HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy . Clin Infect Dis . 2006 ;42 :1488 –1495 . doi:10.1086/503566 16619164 \n23. Ravasi \nG , Lauriola \nM , Tinelic \nC , Brandolini \nM , Uglietti \nA , Maserati \nR . Comparism of glomerulae filtration rate estimate vs. 24-h creatinine clearance in HIV-positive patients . HIV Med . 2009 ;10 (4 ):219 –228 . doi:10.1111/j.1468-1293.2008.00673.x 19187174 \n24. National Kidney Foundation . K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification . Am J Kidney Dis . 2002 ;39 :S1 –S266 .11904577 \n25. Adedeji \nTA , Adedeji \nON , Adebisi \nSA , Idowu \nAA , Fawale \nMB , Jimoh \nKA . Prevalence and pattern of chronic kidney disease in antiretroviral-naive patients with HIV/AIDS . J Int Assoc Provid AIDS Care . 2015 ;14 (5 ):434 –440 . doi:10.1177/2325957415587570 26013249 \n26. Mocroft \nA , Kirk \nO , Gatell \nJ , et al. Chronic renal failure among HIV-1-infected patients . Aids . 2007 ;21 :1119 –1127 . doi:10.1097/QAD.0b013e3280f774ee 17502722 \n27. Crum-Cianflone \nN , Ganesan \nA , Teneza-Mora \nN , et al. Prevalence and factors associated with renal dysfunction among HIV-infected patients . AIDS Patient Care STDS . 2010 ;24 :353 –360 . doi:10.1089/apc.2009.0326 20515419 \n28. Overton \nET , Nurutdinova \nD , Freeman \nJ , Seyfried \nW , Mondy \nKE . Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy . HIV Med . 2009 ;10 :343 –350 . doi:10.1111/j.1468-1293.2009.00693.x 19490182 \n29. Szczech \nLA , Gange \nSJ , van der Horst \nC , et al. Predictors of proteinuria and renal failure among women with HIV infection . Kidney Int . 2002 ;61 :195 –202 . doi:10.1046/j.1523-1755.2002.00094.x 11786101 \n30. Reid \nA , Stöhr \nW , Walker \nAS , et al. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy . Clin Infect Dis . 2008 ;46 :1271 –1281 . doi:10.1086/533468 18444867 \n31. Fux \nCA , Simcock \nM , Wolbers \nM , et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study . Antivir Ther . 2007 ;12 (8 ):1165 –1173 .18240857 \n32. Horberg \nM , Tang \nB , Towner \nW , et al. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients . J Acquir Immune Defic Syndr . 2010 ;53 (1 ):62 –69 . doi:10.1097/QAI.0b013e3181be6be2 19838127 \n33. Laprise \nC , Baril \nJ-G , Dufresne \nS , Trottier \nH . Association between tenofovir exposure and reduced kidney function in a cohort of HIV-positive patients: results from 10 years of follow-up . Clin Infect Dis . 2013 ;56 (4 ):567 –575 . doi:10.1093/cid/cis937 23143096 \n34. Brennan \nA , Evans \nD , Maskew \nM , et al. Relationship between renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir . Aids . 2011 ;25 (13 ):1603 –1609 . doi:10.1097/QAD.0b013e328343443b 21646902 \n35. Mulenga \nL , Musonda \nP , Mwango \nA , et al. Effect of baseline renal function on tenofovir-containing antiretroviral therapy outcomes in Zambia . Clin Infect Dis . 2014 ;58 (10 ):1473 –1480 . doi:10.1093/cid/ciu117 24585558 \n36. Shemesh \nO , Golbetz \nH , Kriss \nJP , Myers \nBD . Limitations of creatinine as a filtration marker in glomerulopathic patients . Kidney Int . 1985 ;28 :830 –838 . doi:10.1038/ki.1985.205 2418254 \n37. Agbaji \nOO , Onu \nA , Agaba \nPE , Muazu \nMA , Falang \nKD , Idoko \nJA . Predictors of impaired renal function among HIV infected patients commencing highly active antiretroviral therapy in Jos, Nigeria . Niger Med J . 2011 ;52 :182 –185 .22083208 \n38. Cheung \nCY , Wong \nKM , Lee \nMP , et al. Prevalence of chronic kidney disease in Chinese HIV-infected patients . Nephrol Dial Transplant . 2007 ;22 :3186 –3190 . doi:10.1093/ndt/gfm350 17575315\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1373",
"issue": "11()",
"journal": "HIV/AIDS (Auckland, N.Z.)",
"keywords": "HIV; Nigeria; South – South; chronic kidney disease; predictors",
"medline_ta": "HIV AIDS (Auckl)",
"mesh_terms": null,
"nlm_unique_id": "101515943",
"other_id": null,
"pages": "61-67",
"pmc": null,
"pmid": "31118824",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10793023;11786101;11904577;12089385;14737980;15090808;15327410;15339998;15486845;15889353;15987747;16619164;16625149;16804855;17502722;17575315;18065807;18240857;18422458;18444867;18947327;19187174;19490182;19838127;20515419;21646902;22083208;23143096;2418254;24585558;26013249;26937072;2770114;3561458;9848787",
"title": "Predictors of chronic kidney disease among HIV-infected patients on highly active antiretroviral therapy at the University of Calabar Teaching Hospital, Calabar, South-South Nigeria.",
"title_normalized": "predictors of chronic kidney disease among hiv infected patients on highly active antiretroviral therapy at the university of calabar teaching hospital calabar south south nigeria"
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"abstract": "BACKGROUND\nTreatment of solid malignancies has been revolutionized with the introduction of immune checkpoint inhibitors (ICIs) and their use is being expanded in therapy of different cancers. However, immune related adverse events (IRAEs) can occur during treatment. These side effects occur due to stimulation of the innate and adaptive immune system and can lead to serious complications. Recently, acral ischemia has been reported in some cases during treatment with programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors. Here, we discuss a case in which acral necrosis developed after initiation of a PD-1 inhibitor. We offer a review of the existing literature on the pathophysiology, clinical course and treatment outcomes.\n\n\nMETHODS\nA 68-year-old female was diagnosed with stage IV non-small cell lung adenocarcinoma and was started on pembrolizumab. The patient developed sudden onset numbness and discoloration of fingertips bilaterally at week 25 after initiation of ICI treatment. Extensive workup to rule out hypercoagulable, autoimmune and vascular disease was unremarkable except for mild elevation of ANA and ESR. The symptoms quickly progressed into dry gangrene within four weeks and did not respond to medical or surgical treatment. Pembrolizumab was subsequently discontinued due to progression of metastatic disease. The patient refused further interventions and transitioned to hospice care where she expired after two months.\n\n\nCONCLUSIONS\nAcral ischemia can develop during treatment of malignancies. This complication, although uncommon, canresult in digital amputation. Physicians should be aware of the possible progression of acral vascular necrosis when Raynaud's like symptoms develop. Larger studies are needed to confirm the role of ICIs in the pathogenesis of acral vascular necrosis.",
"affiliations": "Rosalind Franklin University of Medicine and Science, 915 Armistead Lane, McHenry, Chicago, IL, 60050, USA. Karam.khaddour@gmail.com.;North Western Medicine Centegra Healthcare System, Chicago, USA.;Rosalind Franklin University of Medicine and Science, 915 Armistead Lane, McHenry, Chicago, IL, 60050, USA.",
"authors": "Khaddour|Karam|K|http://orcid.org/0000-0001-6697-3516;Singh|Veerpal|V|;Shayuk|Maryna|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "England",
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"doi": "10.1186/s12885-019-5661-x",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 566110.1186/s12885-019-5661-xCase ReportAcral vascular necrosis associated with immune-check point inhibitors: case report with literature review http://orcid.org/0000-0001-6697-3516Khaddour Karam Karam.khaddour@gmail.com 1Singh Veerpal drveerpalsing@yahoo.com 2Shayuk Maryna mshayuk@centegra.com 11 0000 0004 0388 7807grid.262641.5Rosalind Franklin University of Medicine and Science, 915 Armistead Lane, McHenry, Chicago, IL 60050 USA 2 North Western Medicine Centegra Healthcare System, Chicago, USA 14 5 2019 14 5 2019 2019 19 4493 12 2018 30 4 2019 © The Author(s). 2019Open 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\nTreatment of solid malignancies has been revolutionized with the introduction of immune checkpoint inhibitors (ICIs) and their use is being expanded in therapy of different cancers. However, immune related adverse events (IRAEs) can occur during treatment. These side effects occur due to stimulation of the innate and adaptive immune system and can lead to serious complications. Recently, acral ischemia has been reported in some cases during treatment with programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors. Here, we discuss a case in which acral necrosis developed after initiation of a PD-1 inhibitor. We offer a review of the existing literature on the pathophysiology, clinical course and treatment outcomes.\n\nCase presentation\nA 68-year-old female was diagnosed with stage IV non-small cell lung adenocarcinoma and was started on pembrolizumab. The patient developed sudden onset numbness and discoloration of fingertips bilaterally at week 25 after initiation of ICI treatment. Extensive workup to rule out hypercoagulable, autoimmune and vascular disease was unremarkable except for mild elevation of ANA and ESR. The symptoms quickly progressed into dry gangrene within four weeks and did not respond to medical or surgical treatment. Pembrolizumab was subsequently discontinued due to progression of metastatic disease. The patient refused further interventions and transitioned to hospice care where she expired after two months.\n\nConclusion\nAcral ischemia can develop during treatment of malignancies. This complication, although uncommon, canresult in digital amputation. Physicians should be aware of the possible progression of acral vascular necrosis when Raynaud’s like symptoms develop. Larger studies are needed to confirm the role of ICIs in the pathogenesis of acral vascular necrosis.\n\nKeywords\nAcral ischemiaNecrosisCase reportsSmall vessel vasculitisImmunotherapyImmune related adverse events (IRAEs)issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nIn May 2017, BMC Cancer Journal published a case report by Gambichler et al. describing development of paraneoplastic acral vascular necrosis in association with CTLA-4 and PD-1 inhibitors during treatment of metastatic melanoma [1]. Other reports described similar findings under different diagnostic terms including small vessel vasculitis and digital ischemia. This newly observed adverse event although not reported in phase I/II trials appears to be significant should necrosis progresses requiring surgical amputation. Immune checkpoint inhibitors (ICIs) enhance the immune system through blockage of costimulatory signal receptors that are present on normal and cancer cells, which facilitate tumor evasion by inducing tolerance and anergy. The resultant adverse events of hyperstimulation of the immune system during treatment with ICIs are termed immune related adverse events (IRAEs). These side effects can have a wide spectrum of manifestations such as acute hypophysitits, colitis, pneumonitis and rarely myocarditis. Moreover, vasculitis has been described to occur during treatment mostly in large and medium size vessels. Recently, some reports suggested an association between ICIs and small vessel vasculitis, which might lead to digital ischemia and necrosis.\n\nCase presentation\nA 68-year-old Caucasian female presented to our hospital with shortness of breath and unintentional weight loss of 30 pounds three months prior. The patient was an active smoker and her past medical history included well controlled type 2 diabetes mellitus (Hemoglobin A1C 6.0%) and non-obstructive coronary artery disease. Her medication included insulin, aspirin and metoprolol succinate. Thoracic computed tomography showed an interlobular mass in the medial right upper lobe with extension into the right hilum (Fig. 1). Tissue biopsy was performed and histopathology was consistent with non-small cell adenocarcinoma with negative EGFR mutation, ALK and ROS-1. Programmed Death Ligand-1 (PD-L1) expression by immunohistochemistry was 70%. The clinical staging with Positron Emission Tomography- Computed Tomography (PET-CT) scan showed mediastinal metastatic lymph nodes and scattered osseous metastases in the axial and proximal appendicular skeleton (Stage IV; T4, N3, M1b). Given the high expression of PD-L1 > 50%, immunotherapy with pembrolizumab was started at (200 mg) intravenously once every three weeks per KEYNOTE-024 protocol [2]. Subsequent surveillance with CT showed a significant decrease in the size of the primary tumor in the lungs from 8.5 × 5.5 cm to 2.7 × 0.9 cm with a decrease in the size of bone metastases. In addition, patient’s Eastern Cooperative Oncology Group performance status (ECOG) improved from 2 prior to therapy to 0. After week 25 of pembrolizumab, she developed Raynaud’s like symptoms in both hands with mild non-purpuric erythema, pain and paresthesia at the fingertips bilaterally aggravated by cold weather. A thorough history revealed no prior autoimmune disease, recent trauma or similar symptoms in the past. The patient was started on nifedipine 30 mg extended release orally once daily due to potential vasospasm demonstrated by the triad of pallor, cyanosis and hyperemia. There was no improvement of symptoms on 1 week follow up and nifedipine dose could not be increased due to labile blood pressure. The mild intermittent discoloration progressed to persistent periungual blue discoloration over the course of 2 weeks in the digits bilaterally. The patient was started on oral prednisone 30 mg daily (0.5 mg per kg daily) in conjunction with nifedipine. An autoimmune panel revealed anti-nuclear antibodies (ANA) of 1:80 with a homogenous pattern; erythrocyte sedimentation rate (ESR) of 70 mm/hr. Further testing, including ANCA-c, ANCA-p was negative. Complement levels were within normal limits in our lab reference range. Simple nailfold capillaroscopy did not yield any abnormalities. Additional work up did not reveal a septic source, hypercoagulable disease, hyperviscosity related immunoglobulinopathies, lymphoproliferative disorders or vascular occlusion as shown in Table 1. The patient continued on pembrolizumab given the significant interval tumor response. Over the course of 2 weeks, the patient experienced progression of the discoloration into dry gangrene, ulceration with necrosis involving all fingertips and extending to the proximal phalanges in right digits (1st, 2nd, 3rd, 4th) and (1st, 2nd, 3rd, 5th) digits in the left (Fig. 2). Arterial Doppler ultrasound showed normal arterial waveforms through the upper extremity arteries with peak systolic velocity ratios within normal limits. There were no signs of stenosis, atherosclerotic disease or occlusion. CT angiography showed a normal appearance of the arterial branch up to the palmar arch artery without evidence of saccular aneurysm formation, stenosis or occlusion; digital arteries were not adequately visualized. The patient underwent sympathectomy given the rapid progression of necrosis with no response to calcium channel blockers or glucocorticoids. The decision of amputation was deferred until necrotic tissue would have clear demarcation (Table 2 shows course of progression).Fig. 1 Coronal PET-CT Demonstrating the Primary Lung Tumor. Legends: Coronal PET-CT indicating right upper lobular mass (white arrow) measuring 8.5 × 5.5 in the biaxial diameter\n\nTable 1 Laboratory and imaging tests performed after development of acral ischemia\n\n\tTests Performed\tResults\t\nInfection\tCBC, CRP\nBlood cultures\nEchocardiography\nHBV, HCV\tNormal\nNegative\nNo vegetation or myxoma\nNegative\t\nHypercoagulable state\tProtein C\nProtein S\nAnti- thrombin 3\nPlatelet\nPT/aPTT/INT\t131% (Normal)\n73% (Normal)\nNormal\n280 10 × 3/uL (Normal)\nNormal\t\nLymphoproliferative disease\tKappa/Lambda Ratio\nBeta-2 microglobulin (B2M)\nLDH\nSPEP/IFE\t1.37 (Normal)\n3 mg/L (Mildly elevated)\n138 U/L (Normal)\nNormal\t\nTumor invasion\tCT Chest\nCT Angiography\tNo invasion of sympathetic nervous plexus\nNo vascular occlusion, saccular aneurysm or stenosis up to the palmar arch arteries\t\nAutoimmune and inflammatory disease / Thromboangiitis obliterans\tANA\nESR\nCH50\nANCA-c, ANCA-p\nCryoglobulin\nAPL ab, Anti-Scl-70 Ab, Anti-dsDNA ab, Anti-U1 RNP Ab, Anti-Sm ab, Anti-Ro/SSA ab\nNailfold videocapillaroscopy\nSkin biopsy\t\n1:80 Homogeneous\n\n\n70 mm/hr\n\n170 CAE Units (elevated)\n(Acute phase reactant)\nNormal\nNegative (Normal)\nNot performed\nNot performed\nNot performed\t\nAb: antibodies, APL: antiphospholipid, Anti-Scl-70: topoisomerase I, ANCA-c: Central anti-neutrophil cytoplasmic antibodies, ANCA-p: perinuclear anti- neutrophil cytoplasmic antibodies, Anti-Sm: anti smith antibodies, Anti-Ro/SSA: anti sjögren’s syndrome related antigen A, SPEP: serum protein electrophoresis, IFE: immunofixation electrophoresis\n\nFig. 2 Development of acral necrosis at week 33 of treatment with PD-1 inhibitors. Legends: Varying degree of extension of necrosis and ulceration involving the proximal phalanges in right (1st, 2nd, 3rd, 4th) and (1st, 2nd, 3rd, 5th) digits in the left hand. There is no presence of calcinosis or involvement of the bone protuberants\n\nTable 2 Timeline of progression of acral necrosis since administration of PD-1 inhibitor\n\nTimeline from Treatment\tClinical Progression\t\nDay 0\t1st dose of pembrolizumab (No symptoms)\t\nAt 25 weeks\tRaynaud’s like symptoms (Patient started on nifedipine)\t\nAt 27 weeks\tNo resolution of Raynaud’s symptoms and persistence of cyanosis (Patient started on prednisone)\t\nAt 29 weeks\tDevelopment of dry gangrene at fingertips bilaterally\t\nAt 33 weeks\tExtension of necrosis and development of ulceration. Patient still on pembrolizumab. Sympathectomy performed (patient still on nifedipine and glucocorticoids)\t\nAt 37 weeks\tTumor progression (pembrolizumab stopped). Extension of the necrosis stopped after week 37\t\n\n\nPembrolizumab was stopped later (week 37) due to tumor progression and it was noted that the involved necrotic area in the digits did not progress further after discontinuation of PD-1 inhibitor. Unfortunately, the patient transferred to hospice care and expired two months after.\n\nDiscussion and conclusion\nAcral necrosis has not been documented to occur as an immune related adverse event (IRAEs) during phase I/II trials of CTLA-4 and PD-1 inhibitors [3, 4]. However, a recent French prospective multicenter study (REISAMIC) was conducted to assess the development of connective tissue disease after treatment with PD-1/PD-L1 inhibitors [5]. This study found the incidence to be low with only three of 447 patients who developed connective tissue disease. Interestingly, one of the three patients had small vessel vasculitis involving the digits, which was secondary to cryoglobulinemia and was associated with an elevated ANA (1:160) and anti-SSA antibodies [5]. The most common type of vasculitis that develops as an (IRAEs) involves large and medium vessels as was demonstrated in a case series by Daxini et al. [6]. This systematic review reported 20 cases of vasculitis associated with treatment with ICIs of which three were small vessel vasculitis one of them being digital ischemia [6]. There have been more cases reported in the last two years describing progression of acral necrosis, which might represent small vessel vasculitis during treatment with ICIs.\n\nThe time onset of acral ischemia developing after initiation of ICI treatment varies in the different cases reported between 3 and 26 weeks as noted in Table 3. Similar results of previous case series have reported duration of 1.2 to 6 months before development of vasculitis after initiating treatment with ICIs [6]. Vascular risk factors such as diabetes and smoking have been reported in some patients who developed digital ischemia during treatment with ICIs. None of the patients reported in the literature had a preexisting autoimmune disease prior to initiating immunotherapy treatment. A comprehensive work up is recommended to identify the etiology of the acral ischemia which can dictate treatment strategy (Table 1 illustrates some of the tests that could help establishing a diagnosis). History and physical exam remain essential as they can guide with diagnostic work up for acral necrosis, which should consider all possible etiologies. Optimal treatment of acral necrosis in association with ICIs remains unknown given the low number of observations and multidisciplinary approach is warranted. The use of calcium channel blockers, prostaglandins and sympathectomy reported in different cases have all been unsuccessful [1, 7]. Glucocorticoids showed variable outcomes from complete resolution of the ischemia to partial or no response [1, 8]. Rituximab was reported to be beneficial in one case and to halt the progression of acral necrosis, but the patient required digital amputation eventually [7].Table 3 Summary of case reports of digital ischemia and small vessel vasculitis with immune-check point inhibitors use\n\nCase\tAge /Gender\tVascular Risk Factors\tMalignancy\tMedication\tSymptoms\tDuration before onset of symptoms\tTreatment\tFinal Outcome\t\nGambichler et al. [1]\t60/ Male\tNone\tMetastatic Melanoma\nBRAF V600E Mutated\tIpilimumab + Nivolumab\tSubungal necrosis followed by gangrene\t3 weeks\tProstacycline, methylprednisolone (50 mg in tapering dose), methylprednisolone 500 mg\tSurgical amputation\t\nPadda et al. [7]\t52/ Female\tNone\tMetastatic Melanoma\tIpilimumab\tDigital Necrosis\t3 weeks\tAmlodipine, Aspirin, Prednisone (60 mg), methyl prednisolone 500 mg, epoprostenol, Normal Saline, Rituximab\tSurgical amputation\t\nThoreau et al. [12]\t73/ Male\tDiabetes\tMetastatic Melanoma\tPembrolizumab\tAcute ischemia of the left toes\t26 weeks\tIloprost, anticoagulation, amputation, aspirin, fogarty arterial embolectomy\tSurgical amputation\t\nComont et al. [8]\t66/ Male\tSmoker\tUrothelial Bladder Cancer\tTremelimumab\n+ durvalumab/Chemotherapya\tPeriungal skin necrosis bilaterally\t20 weeks\tPrednisone 1 mg/kg\nImmunotherapy discontinuation\tComplete resolution\t\nLeburel et al. [5]\t60/Male\tNot available\tMelanoma\tPD-L1 inhibitor+ BRAF and MEK inhibitors\tCyanosis of fingers, necrosis of 3 fingers and the heels, arthralgia, dry mouth, paresthesia of feet and interstitial pneumonia\t8.5 weeks\tICI withdrawal, prednisone 1 mg/kg, CCB, iloprost and ASA\tPartial resolution\t\naMethotrexate, vinblastine, doxorubicin and cisplatin\n\nASA acetylsalicylic acid, CCB calcium channel blockers\n\n\n\nWe postulate two hypotheses to explain the pathophysiology for development of acral necrosis during treatment with ICIs. The first hypothesis is based on the anecdotal reports and the mechanism of action of ICIs that leads to alteration of the immunological homeostasis. This could lead to either activation of T cell population or antibody formation against self-antigens (endothelial cells in this case) which theoretically could cause vasculitis related syndromes. Zhang et al. examined the role of PD-1/PD-L1 inhibition on the development of vasculitis specifically giant cell arteritis and concluded that blockade of the coninhibitory ligand can initiate T cell infiltration of the vascular endothelium and exacerbate an inflammatory response that leads to vasculitis [9]. However, Zhang’s study involved giant cell arteritis, which is a medium/ large vessel vasculitis. Moreover, PD-1 receptor impairment has been described to induce autoantibodies against shared antigens between the tumor and normal tissue knock-out mice models leading to lupus-like syndrome [10]. Some literature regarding digital ischemia favors autoimmune involvement during treatment with ICIs. As an example, Comont et al. described a case of acral necrosis during combined treatment with CTLA-4 and PD-L1 inhibitors that was associated with increased titers of ANA (1:5200) which would support an autoimmune etiology [8]. In this case, there was a complete reversal of the acral ischemia with high suppressive dose of prednisone (1 mg/kg daily) [8]. However, the patient of the previous study received chemotherapy prior to ICI includeding methotrexate, vinblastine, doxorubicin and cisplatin which could be culprits in acral necrosis. Similarly, a patient who developed digital ischemia in (REISAMIC) study had high ANA titers (160, speckled pattern) and responded well to steroids with partial resolution of ischemic symptoms [5]. In our patient, there was a weak evidence of an autoimmune process due to borderline ANA and elevated ESR which were nonspecific for a definitive diagnosis for autoimmune conditions as they can be elevated in various non-immunologic conditions and our patient did not have a good response to prednisone (received prednisone0.5 mg/kg/day). In addition, Gambichler et al. performed a tissue biopsy from the area of acral necrosis in their patient, which did not reveal any evidence of T cell infiltration or immune complex precipitation that might represent leuococytoclastic vasculitis [1].\n\nThe second hypothesis for the development of acral necrosis with ICIs treatment is the proinflammatory effect causing vascular damage. The endothelial insult could induce either atherosclerotic lesions or a procoagulable state, which might lead to vascular (arterial) thrombosis. Mice models that lacked PD-1 receptors due to PD-1 blockade had more abundant T cell inflammatory infiltrate in atherosclerotic lesions compared to control mice models suggesting that PD-1 impairment can lead to proatherogenic state [11]. In our search of the literature there was one case that involved acral ischemia of left toes with the use of PD-1 inhibitors. The patient was later found to have arterial thrombosis, which was removed with fogarty thrombectomy and was believed to be secondary to PD-1 inhibitor. However, the patient had diabetes mellitus with diabetic ketoacidosis, which also could induce endothelial inflammatory damage under oxidative stress leading to arterial thrombosis [12].\n\nHistorically, the observed phenomenon of acral ischemia was described early in the literature in association with malignancy and was considered a manifestation of a paraneoplastic syndrome [13]. The pathophysiology of paraneoplastic acral vascular syndrome (PAVS) is not well established. Many cases described development of acral ischemia with specific chemotherapies including gemcitabine and carboplatin leading to think that medication could be a culprit in the development of acral ischemia [14, 15]. Older generation immunotherapies like interferon may potentially cause acral ischemia as noted in a case series by Sharpai et al. which identified Raynaud’s like syndrome and acral arterial occlusion in 12 patients of 24 who were treated with interferon [16]. Other studies have emphasized these findings and have showed interferon alpha/beta to cause endothelial injury in the microvasculature leading to impaired subcutaneous tumor blood flow in mice models [17]. Paraneoplastic acral vascular necrosis is more frequently encountered in association with adenocarcinoma followed by squamous cell carcinoma and hematologic malignancies from a cohort of 100 patients who were hospitalized due to digital ischemia [18]. This study found an incidence of 15% of malignancy associated with digital ischemia [18].\n\nTo our knowledge, our report is the first to describe development of acral necrosis with the use of pembrolizumab, which is a humanized monoclonal antibody against programmed death 1 receptors [19].\n\nAcral vascular necrosis can develop in association with malignancies and during treatment. It is controversial whether this complication represents an immune related adverse event to the use of ICIs. Physicians should have a high index of suspicion when Raynaud’s like symptoms occur during treatment of malignancy and monitor closely for development of digital ischemia and necrosis. Larger studies are needed to identify the etiology of this complication.\n\nAbbreviations\nANAAntinuclear antibodies\n\nCTLA-4Cytotoxic T lymphocyte antigen-4\n\nICIsImmune-check point inhibitors\n\nIRAEsImmune related adverse events\n\nPAVSParaneoplastic acral vascular syndrome\n\nPD-1/PD-L1Programmed death-1/ programmed death- ligand 1\n\nAcknowledgements\nThe authors would like to thank Dr. Preston B Cannady for reviewing of the manuscript.\n\nFunding\nNo sources of funding were utilized in the preparation of this report.\n\nAvailability of data and materials\nAll data generated or analyzed during this case study are included in this published article.\n\nAuthors’ contributions\nKK “corresponding author” contributed to the production of the case report, conceptualization of the discussion along with literature review and providing the images and tables. VS and MS contributed to reviewing the manuscript production. All authors have read and approved the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of the clinical details and clinical images was obtained from the patient’s medical power of attorney. A copy of the written consent is available for review by the editor of the journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Gambichler T Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade BMC Cancer 2017 17 327 10.1186/s12885-017-3313-6 28499411 \n2. Reck M Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer N Engl J Med 2016 375 19 1823 1833 10.1056/NEJMoa1606774 27718847 \n3. Brahmer JR Tykodi SS Chow LQM Hwu W-J Safety and activity of anti-PD-L1 antibody in patients with advanced cancer N Engl J Med 2012 366 2455 2465 10.1056/NEJMoa1200694 22658128 \n4. Wolchok JD Neyns B Linette G Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study Lancet Oncol 2010 11 155 164 10.1016/S1470-2045(09)70334-1 20004617 \n5. Le Burel S Champiat S Routier E Aspeslagh S Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy Ann Rheum Dis 2018 77 468 470 10.1136/annrheumdis-2016-210820 28242618 \n6. Daxini A Cronin K Sreih AG Vasculitits associated with immune checkpoint inhibitors-a systematic review Clin Rheumatol 2018 37 2579 2584 10.1007/s10067-018-4177-0 29923081 \n7. Padda A Ipilimumab induced digital vasculitis J Immunother Cancer 2018 6 12 10.1186/s40425-018-0321-2 29433584 \n8. Comont T Sibaud V Mourey L Cougoul P Beyne-Rauzy O Immune checkpoint inhibitor-related acral vasculitis J Immunother Cancer 2018 16 6 120 10.1186/s40425-018-0443-6 \n9. Zhang H Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis Proc Natl Acad Sci U S A 2017 114 6 E970 E979 10.1073/pnas.1616848114 28115719 \n10. Okazaki T Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice Nat Med 2003 9 1477 1483 10.1038/nm955 14595408 \n11. Bu D Tarrio M Maganto-Garcia E Stavrakis G Tajima G Lederer J Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation Arterioscler Thromb Vasc Biol 2011 31 5 1100 1107 10.1161/ATVBAHA.111.224709 21393583 \n12. Thoreau B Gouaillier-Vulcain F Machet L Acute lower limb Ischaemia and diabetes in a patient treated with anti-PD1 monoclonal antibody for metastatic melanoma Acta Derm Venereol 2017 10 97 408 409 10.2340/00015555-2504 \n13. Hawley PR Johnston AW Rankin JT Association between digital ischaemia Br Med J 1967 3 208 212 10.1136/bmj.3.5559.208 6028467 \n14. Dasanu CA Gemcitabine: vascular toxicity and prothrombotic potential Expert Opin Drug Saf 2008 7 703 716 10.1517/14740330802374262 18983217 \n15. Staff S Lagerstedt E Seppänen J Acute digital ischemia complicating gemcitabine and carboplatin combination chemotherapy for ovarian cancer Acta Obstet Gynecol Scand 2011 90 1296 1297 10.1111/j.1600-0412.2011.01259.x 21880022 \n16. Schapira D Nahir AM Hadad N Interferon-induced Raynaud’s syndrome Semin Arthritis Rheum 2002 32 157 162 10.1053/sarh.2002.34606 12528080 \n17. Dvorak HF Gresser I Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice J Natl Cancer Inst 1989 5 81 497 502 10.1093/jnci/81.7.497 \n18. Le Besnerais M Miranda S Digital Ischemia Associated with Cancer Results from a Cohort Study Medicine (Baltimore) 2014 93 e47 10.1097/MD.0000000000000047 25170929 \n19. Fessas P A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab Semin Oncol 2017 44 136 140 10.1053/j.seminoncol.2017.06.002 28923212\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "19(1)",
"journal": "BMC cancer",
"keywords": "Acral ischemia; Case reports; Immune related adverse events (IRAEs); Immunotherapy; Necrosis; Small vessel vasculitis",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D005385:Fingers; D005734:Gangrene; D006801:Humans; D008175:Lung Neoplasms",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "449",
"pmc": null,
"pmid": "31088420",
"pubdate": "2019-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12528080;14595408;18983217;20004617;21393583;21880022;22658128;25170929;27377178;27718847;28115719;28242618;28499411;28923212;2921774;29433584;29923081;30446009;6028467",
"title": "Acral vascular necrosis associated with immune-check point inhibitors: case report with literature review.",
"title_normalized": "acral vascular necrosis associated with immune check point inhibitors case report with literature review"
} | [
{
"companynumb": "US-009507513-1905USA014126",
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... |
{
"abstract": "Baclofen withdrawal syndrome is a rare and potentially life-threatening condition manifesting with autonomic dysreflexia, high fevers, spasticity, seizures, and multiorgan failure. Reversible cardiomyopathy due to this condition is extremely rare. A high level of suspicion is needed to recognize this condition and start an early intervention to improve patient outcome. Electrocardiographic ST-segment elevation in lead aVR was previously described in association with left main, left anterior descending, and triple-vessel coronary artery disease as well as Takotsubo cardiomyopathy. In this article we present a rare case of reversible cardiomyopathy due to baclofen withdrawal syndrome associated with diffuse ST-segment depressions and ST-segment elevation in lead aVR.",
"affiliations": "State University of New York at Buffalo, NY, USA. dimonk5@yahoo.com",
"authors": "Kireyev|Dmitriy|D|;Poh|Kian-Keong|KK|",
"chemical_list": "D058786:GABA-B Receptor Agonists; D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.15420/ahhj.2010.8.1.52",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1541-9215",
"issue": "8(1)",
"journal": "The American heart hospital journal",
"keywords": null,
"medline_ta": "Am Heart Hosp J",
"mesh_terms": "D000328:Adult; D020211:Autonomic Dysreflexia; D001418:Baclofen; D002037:Bundle-Branch Block; D004562:Electrocardiography; D005334:Fever; D058786:GABA-B Receptor Agonists; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central; D009128:Muscle Spasticity; D013375:Substance Withdrawal Syndrome; D013577:Syndrome; D013616:Tachycardia, Sinus; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101156064",
"other_id": null,
"pages": "52-4",
"pmc": null,
"pmid": "21194052",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible electrocardiogram changes and cardiomyopathy secondary to baclofen withdrawal syndrome.",
"title_normalized": "reversible electrocardiogram changes and cardiomyopathy secondary to baclofen withdrawal syndrome"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-12SUNBA24P",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACLOFEN"
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"drugaddit... |
{
"abstract": "Itacitinib in combination with nab-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.\n\n\n\nCytokine-mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer.\n\n\n\nThis phase Ib/II dose-optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel plus gemcitabine in adults with treatment-naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab-paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony-stimulating factor, de-escalations of itacitinib to 300 mg once daily (QD), nab-paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2.\n\n\n\nAmong 55 patients in Part 1, 6 developed seven hematologic dose-limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de-escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%).\n\n\n\nItacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.",
"affiliations": "Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA gregory.beatty@uphs.upenn.edu.;Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, USA.;Hematology/Oncology, Highlands Oncology Group, Fayetteville, Arkansas, USA.;Department of Medicine, NYU Langone Arena Oncology, Lake Success, New York, USA.;Medical Oncology and Hematology Division, Jefferson Health/Abington Memorial Hospital, Abington, Pennsylvania, USA.;Division of Medical Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Hematology/Oncology, Beverly Hills Cancer Center, Beverly Hills, California, USA.;Oncology Drug Development, Incyte Corporation, Wilmington, Delaware, USA.;Clinical Research, Incyte Corporation, Wilmington, Delaware, USA.;Biostatistics, Incyte Corporation, Wilmington, Delaware, USA.;Molecular Medicine Division, Translational Genomics Research Institute (TGen), Scottsdale, Arizona, USA.",
"authors": "Beatty|Gregory L|GL|;Shahda|Safi|S|;Beck|Thaddeus|T|;Uppal|Nikhil|N|;Cohen|Steven J|SJ|;Donehower|Ross|R|;Gabayan|Afshin Eli|AE|;Assad|Albert|A|;Switzky|Julie|J|;Zhen|Huiling|H|;Von Hoff|Daniel D|DD|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D053613:Janus Kinase 1",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0665",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(1)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D053613:Janus Kinase 1; D008297:Male; D009369:Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "14-e10",
"pmc": null,
"pmid": "30115734",
"pubdate": "2019-01",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25638248;21472137;15526319;9271387;29508247;20008249;18516298;14698135;24959088;23720768;20871233;10823417;28611107;26769332;19097774;9558006;24131140",
"title": "A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors.",
"title_normalized": "a phase ib ii study of the jak1 inhibitor itacitinib plus nab paclitaxel and gemcitabine in advanced solid tumors"
} | [
{
"companynumb": "US-PFIZER INC-2018343302",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
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