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"abstract": "Intracerebroventricular (ICV) administration of opioids for control of intractable cancer pain has been used since 1982. We present here our experience of intracerebroventricular administration of pain treatments including ziconotide associated with morphine and ropivacaine for patients resistant to a conventional approach, with nociceptive, neuropathic, or mixed pain. These clinical cases were conducted with patients suffering from refractory pain, more than 6/10 on a numerical pain rating scale (NPRS) while on high-dose medical treatment and/or intolerance with significant side effects from oral medication. The baseline study visit included a physical examination and an assessment of pain intensity on a NPRS. Under general anesthesia, a neuronavigation device was used to place the catheter on the floor of the third ventricle, supported by an endoscope. Then, drugs were injected in the cerebroventricular system, through a pump (external or subcutaneous). The primary objective was to measure pain evaluation with ICV treatment after a complete withdrawal of other medications.Four patients were enrolled: 3 with intractable cancer pain and one with central neuropathic pain. The median NPRS at baseline was 9.5 [8.5; 19]. The mean NPRS after one month was 3.5 [3; 4.5]. Ziconotide was initiated at 0.48 µg/d and up to a median of 1.2 µg/d [1.0; 1.56]. The median dose of morphine and ropivacaine used initially was respectively 0.36 mg/d [0.24; 0.66] up to 0.6 mg/d [0.45; 4.63] and 1.2 mg/d [0; 2.4] up to 2.23 mg/d [1.2; 3.35]. Minor side effects were initially observed but transiently. One psychiatric agitation required discontinuation of ziconotide infusion. For intractable pain, using ziconotide by intracerebroventricular infusion seems safe and efficient, specifically for chronic neoplastic pain of cervicocephalic, thoracic, or diffuse origin and also for pain arising from a central neuropathic mechanism.",
"affiliations": "Hopital Beaujon, Neurochirurgie, Clichy la Garenne, France, CHU d'Angers, Angers, France.;Anesthesia and Pain Department, Institut de cancérologie de l'ouest - Paul Papin, Angers, France.;Neurosurgery, CHU Angers, France.;Neurosurgery, CHU Angers, France.",
"authors": "Staquet|Héléne|H|;Dupoiron|Denis|D|;Nader|Edmond|E|;Menei|Philippe|P|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid; D020960:omega-Conotoxins; D009020:Morphine; C078452:ziconotide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "19(6)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000368:Aged; D000700:Analgesics; D000701:Analgesics, Opioid; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine; D059408:Pain Management; D010148:Pain, Intractable; D020960:omega-Conotoxins",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "E905-15",
"pmc": null,
"pmid": "27454282",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intracerebroventricular Pain Treatment with Analgesic Mixtures including Ziconotide for Intractable Pain.",
"title_normalized": "intracerebroventricular pain treatment with analgesic mixtures including ziconotide for intractable pain"
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"companynumb": "FR-MYLANLABS-2016M1034637",
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"activesubstancename": "ZICONOTIDE"
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"abstract": "BACKGROUND\nAtypical femoral fracture is an uncommon complication of prolonged use of bisphosphonates, mainly occurring in the femoral shaft. We report a case of an atraumatic insufficiency fracture of femoral neck after four years of treatment with a bisphosphonate.\n\n\nMETHODS\nA 71-year-old female presented with history of pain on Lt. hip and difficulty in walking. Although there was no fracture on the radiographs, diagnosis could be made early using magnetic resonance imaging (MRI) scans. She was treated by internal fixation using cannulated screws.\n\n\nCONCLUSIONS\nBecause bisphosphonate prevents bone healing and remodeling, it is difficult to accomplish the bony union despite of proper treatment in patients who have fractured after long-term use of bisphosphonate.\n\n\nCONCLUSIONS\nA high suspicion index and early diagnosis through the use of MRI are essential for the successful treatment of these fractures.",
"affiliations": "Department of Orthopaedic Surgery, Dongeui Medical Center, 62 Yangjung-ro, Jin-gu, Busan, 47227, South Korea.;Department of Orthopaedic Surgery, Dongeui Medical Center, 62 Yangjung-ro, Jin-gu, Busan, 47227, South Korea.;Department of Orthopaedic Surgery, Dongeui Medical Center, 62 Yangjung-ro, Jin-gu, Busan, 47227, South Korea. Electronic address: wonro@hanmail.net.",
"authors": "Seong|Yoon Jae|YJ|;Shin|Jong Ki|JK|;Park|Won Ro|WR|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.04.003",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30195-4\n10.1016/j.ijscr.2020.04.003\nArticle\nEarly detected femoral neck insufficiency fracture in a patient treated with long-term bisphosphonate therapy for osteoporosis: A need for MRI\nSeong Yoon Jae Shin Jong Ki Park Won Ro wonro@hanmail.netwonro0908@naver.com⁎ Department of Orthopaedic Surgery, Dongeui Medical Center, 62 Yangjung-ro, Jin-gu, Busan, 47227, South Korea\n⁎ Corresponding author. wonro@hanmail.netwonro0908@naver.com\n07 5 2020 \n2020 \n07 5 2020 \n70 213 215\n17 12 2019 23 3 2020 1 4 2020 © 2020 The Author(s)2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• If long term bisphosphonate users complain of non-traumatic hip pain, medical examination should be taken with care.\n\n• Even though no fractures are identified in their radiographs, it is recommended to check an MRI.\n\n• If the fracture can be identified before cortical breakage, the treatment success rate for the fracture will be high.\n\n\n\nIntroduction\nAtypical femoral fracture is an uncommon complication of prolonged use of bisphosphonates, mainly occurring in the femoral shaft. We report a case of an atraumatic insufficiency fracture of femoral neck after four years of treatment with a bisphosphonate.\n\nPresentation of case\nA 71-year-old female presented with history of pain on Lt. hip and difficulty in walking. Although there was no fracture on the radiographs, diagnosis could be made early using magnetic resonance imaging (MRI) scans. She was treated by internal fixation using cannulated screws.\n\nDiscussion\nBecause bisphosphonate prevents bone healing and remodeling, it is difficult to accomplish the bony union despite of proper treatment in patients who have fractured after long-term use of bisphosphonate.\n\nConclusion\nA high suspicion index and early diagnosis through the use of MRI are essential for the successful treatment of these fractures.\n\nKeywords\nInsufficiency fractureFemoral neckBisphosphonateMagnetic resonance imaging\n==== Body\n1 Introduction\nOsteoporosis is a disorder characterized by low bone density and impaired bone strength which is an important risk factor for fracture in older adults [1]. Bisphosphonate is one of the medicines for osteoporosis and has been used for many years to reduce bone loss and prevent fractures. Many studies have been reported that bisphosphonate elevates the bone mineral density of osteoporosis patients and is effective in preventing fractures [2,3]. However, as a result of long-term follow-up of patients using bisphosphonate, two major complications, osteonecrosis of jaw and atypical femoral fracture, were identified [4]. In addition, femoral neck insufficiency fracture has been reported in several studies, those studies indicated difficulties in treating femoral neck insufficiency fracture after prolonged use of bisphosphonate [[5], [6], [7], [8]]. We accordingly report a case of early diagnosis and successful treatment of patients with femoral neck insufficiency fracture after prolonged use of bisphosphonate. The work has been reported in line with the SCARE criteria [9].\n\n2 Presentation of case\nA 71-year-old female presented to our hospital with history of pain on Lt. hip and difficulty in walking for the past few days. There was no definite history of significant trauma like falls. Clinical examination revealed no deformities of both legs and severe pain on passive movement of Lt. hip. And a positive Patrick’s test result on the Lt. hip. Radiographs of her pelvis showed no evidence of fractures on Lt. hip (Fig. 1). According to her medical history, she had been diagnosed as having osteoporosis (T-score −3.0 at spine and −2.0 at femoral neck), and had received treatment with the risedronate (Actonel EC) 35 mg once a week through oral administration for 4 years. She was admitted in to ward for pain control. A magnetic resonance imaging (MRI) scan of the pelvis including both hips was carried out to find the cause of on-going pain and also to rule out insufficiency femoral fractures. The MRI scan showed the incomplete linear fracture of the femoral neck (Fig. 2). The patient underwent internal fixation using 3 cannulated screws, and the postoperative radiograph was satisfactory (Fig. 3). The patient was recommended to walk using crutches for 1month, and the postoperative period was uneventful. Six weeks after surgery, she could ambulate independently without pain. At 3 months follow up, she could still ambulate well without Lt. hip pain.Fig. 1 Radiographs of patient’s pelvis showed no evidence of fractures on Lt. hip.\n\nFig. 1Fig. 2 The MRI scan showed the incomplete linear fracture of the Lt. femoral neck.\n\nFig. 2Fig. 3 The patient underwent internal fixation using 3 cannulated screws.\n\nFig. 3\n\n3 Discussion\nWe report a case of femoral neck insufficiency fracture without trauma in a patient treated with long term bisphosphonate. Insufficiency fractures are a type of stress fracture, which are the result of normal stresses on abnormal bone. Insufficiency fracture is defined as an injury that occurs when minimal stress is applied to abnormal bone characterized by decreased elastic resistance [10]. They occur in elderly patients or in postmenopausal women with osteoporotic bone. Insufficiency fractures occur most frequently in the weight bearing bones like sacrum, tibia [10]. As with our report, there have been several studies that report insufficiency fractures in the femoral neck after long term treatment of bisphosphonate [[5], [6], [7], [8]].\n\nAntiresorptive drugs such as bisphosphonate increase bone mass by inhibiting osteoclast activity and reducing bone resorption. This mechanism increases the bone mineral density (BMD) and reduces the chance of fracture. Although several factors such as bone structure, bone remodeling, bone quality are related to fractures, BMD is a strong predictor of fracture [11].\n\nBisphosphonates interfere with osteoclast activity and thus decrease the rate of bone resorption.\n\nAt the same time, bisphosphonate also plays a role in inhibiting osteoblast activity. As a result, bone resorption and bone formation decrease simultaneously. With regard to fractures, a decrease in bone resorption increases bone mass and prevents fractures. On the other hand, new bone formation is reduced, the bone quality worsens. This changed bone like osteopetrosis is easily broken to stress. Whyte et al. described bisphosphonate-induced osteopetrosis (marble bone disease) in a 12-year-old boy [12]. Prolonged treatment with high doses of pamidronate resulted in findings characteristic of osteopetrosis, including increased bone density and defective remodeling. Increased BMD following bisphosphonate use reduces the overall incidence of fractures in patients with osteoporosis. However, changed bony conditions increase the incidence of nonspecific fractures like atypical femoral shaft fracturs and femoral neck insufficiency fractures [4].\n\nThere is a difference in the rate of uptake between trabecular and cortical bones [13]. Differential uptake by trabecular and cortical sites depends on delivery via blood and may depend on the relative bone affinity of each bisphosphonates [14]. Previous work on skeletal distribution has predominantly focused on trabecular bone as this is where bisphosphonates produce their most prominent skeletal effect [13]. Although bisphosphonates also significantly affect cortical bone by reducing porosity through suppression of intracortical remodeling, the effects and side effects of using bisphosphonate will be more prominent in the trabecular bone than the cortical bone.\n\nFemoral neck area can be stressed due to the morphological characteristics of the bone structure in stance loading conditions [15]. When stance loading is applied to the femoral neck, bending force is used repeatedly. Thus, the femoral neck area is more easily broken by minor trauma in osteoporotic state. In patients treated with long term bisphosphonate, bone conditions altered by the mechanism described above cause atypical fractures in the femoral neck area. In cases that have been reported femoral neck insufficient fractures to long term bisphosphonate users, most of the fracture site was superior cortex of the femoral neck [[5], [6], [7], [8]]. Human femurs have thinner superior than inferior cortices at the mid-femoral neck region. In addition, elderly femurs have marked thinning in the superior regions but have thicker cortices compared with young femurs [16]. Although this case did not progress to cortical breakage, we could confirm the cancellous bone fracture by MRI.\n\nSeveral cases of insufficiency femoral fracture have been reported in patients with osteoporosis medications other than bisphosphonate. Among them, denosumab is an antiresorptive drug that can replace bisphosphonate and has been used in several years. Paparodis et al. reported an unusual, nontraumatic subtrochanteric insufficiency fracture in a patient treated with the antiresorptive agent denosumab [17].\n\nFractures are usually diagnosed only by radiographs. However, it is impossible to diagnose a fracture by radiographs if the cortical bone breakage has not progressed like in femoral neck insufficiency fracture. MRI can diagnose femoral neck insufficiency fracture that has not progressed to cortical bone breakage and can be identified by low signal intensity lines on T1 images. Considering the possibility of insufficiency femoral neck fracture, an early MRI test is necessary for the long-term bisphosphonate patients complaining of hip pain.\n\nBisphosphonate has produced sustained reduction of bone remodeling and osteogenesis, and this may have negative effect on bony union of fracture site [2]. Odvina et al. found a lack of bone formation and a delay of bone union in an iliac crest examination of nine cases for which patients were prescribed long-term treatment with alendronate and experienced abnormal stress fractures. Many studies have described the difficulty of treating bisphosphonate induced femoral neck insufficiency fracture [[5], [6], [7], [8]]. Femoral neck insufficiency fracture which progressed to cortical bone breakage, is difficult to obtain an union even after proper internal fixation surgery in long-term bisphosphonate users. Persistent pain due to nonunion of the fracture site will require artificial joint replacement surgery in the future.\n\nThrough this case and previous reports, the authors propose the following methods to improve the success rate of femoral neck insufficiency fracture treatment in the long-term bisphosphonate users. If long term bisphosphonate users complain of non-traumatic hip pain, medical examination should be taken with care. Even though no fractures are identified in their radiographs, it is recommended to check an MRI. If the fracture can be identified before cortical breakage, the treatment success rate for the fracture will be high. It should be noted that the success rate of internal fixation using screws generally decreases in the case of femoral neck insufficiency fracture that have been confirmed to cortical breakage. In some cases of cortical breakage, joint replacement surgery may need to be considered as a primary treatment option. In case of screw fixation surgery, use of osteogenic agents such as teriparatide and romosozumab may be considered.\n\n4 Conclusion\nThe diagnosis of femoral neck insufficiency fracture can be missed easily by simple radiographs alone. If patients treated by long-term bisphosphonate have hip pain that persists without a history of significant trauma or unusual increase in daily activity, femoral neck insufficiency fractures should be considered. And an immediate MRI assessment will be needed for an early diagnosis and better clinical outcome.\n\nDeclaration of Competing of Interest\nThe authors declare no conflict of interest.\n\nSources of funding\nWe have nothing to declare.\n\nEthical approval\nThis is exempt from ethnical approval in our institution.\n\nConsent\nInformed consent was obtained from the patient for publication of this case report and accompanying figures.\n\nAuthors contribution\nYoon Jae Seong: Conception and design the study, analysis and interpretation of data.\n\nJong Ki Shin: Acquisition of data, drafting the article.\n\nWon Ro Park: Performing the surgery, Conception and design the study, Final approval of the version to be submitted.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nWon Ro Park.\n\nProvenance and peer review\nEditorially reviewed, not externally peer-reviewed.\n==== Refs\nReferences\n1 McClung M.R. The relationship between bone mineral density and fracture risk Curr. Osteoporos. Rep. 3 2005 57 63 16036103 \n2 Bone H.G. Hosking D. Devogelaer J.P. Tucci J.R. Emkey R.D. Tonino R.P. Ten years’ experience with alendronate for osteoporosis in postmenopausal women N. Engl. J. Med. 350 2004 1189 1199 15028823 \n3 Reid I.R. Short-term and long-term effects of osteoporosis therapies Nat. Rev. Endocrinol. 11 2015 418 428 25963272 \n4 McClung M. Harris S.T. Miller P.D. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday Am. J. Med. 126 2013 13 20 23177553 \n5 Kim Dh Lee Ec Kang Sk. Insufficiency fracture of ipsilateral femur neck in patient treated with long term bisphosphonate treatment - a case report J. Bone Metab. 19 2012 159 162 24524048 \n6 Ahn D.K. Kim J.H. Lee J.I. Kim J.W. Bilateral femoral neck insufficiency fractures after use of a long-term anti-resorptive drug therapy for osteoporosis: a case report Hip Pelvis 27 2015 115 119 27536613 \n7 Khan S.K. Savaridas T. Hemers J.S. Maarouf Z. Orgee J.M. Orr M.M. Atraumatic intracapsular neck of femur fractures after prolonged bisphosphonate treatment: a new atypical variant? Clin. Cases Miner. Bone Metab. 13 2016 38 41 27252743 \n8 Suh Y.S. Jang B.W. Nho J.H. Won S.H. Lee W.S. Atypical incomplete femoral neck fracture in patients taking long-term bisphosphonate: case report, a report of 2 cases Medicine (Baltimore) 98 2019 e14701 30817607 \n9 (a) Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 (b) Pentecost R.L. Murray R.A. Brindley H.H. Fatigue, insufficiency, and pathologic fractures JAMA 28 1964 1001 1004 \n10 Rivadeneira F. Zillikens M.C. De Laet C.E. Hofman A. Uitterlinden A.G. Beck T.J. Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam Study J. Bone Miner. Res. 22 2007 1781 1790 17638578 \n11 Whyte M.P. Wenkert D. Clements K.L. McAlister W.H. Mumm S. Bisphosphonate-induced osteopetrosis N. Engl. J. Med. 349 2003 457 463 12890844 \n12 Turek J. Ebetino F.H. Lundy M.W. Sun S. Kashemirov B.A. McKenna C.E. Bisphosphonate binding affinity affects drug distribution in both intracortical and trabecular bone of rabbits Calcif. Tissue Int. 90 2012 202 210 22249525 \n13 Russell R.G. Watts N.B. Ebetino F.H. Rogers M.J. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy Osteoporos. Int. 19 2008 733 759 18214569 \n14 Schileo E. Balistreri L. Grassi L. Cristofolini L. Taddei F. To what extent can linear finite element models of human femora predict failure under stance and fall loading configurations? J. Biomech. 47 2014 3531 3538 25261321 \n15 Poole K.E. Mayhew P.M. Rose C.M. Brown J.K. Bearcroft P.J. Loveridge N. Changing structure of the femoral neck across the adult female lifespan J. Bone Miner. Res. 25 2010 482 491 19594320 \n16 Paparodis R. Buehring B. Pelley Em Binkley N. A case of an unusual subtrochanteric fracture in a patient receiving denosumab Endocr. Pract. 19 2013 e64 e68 23337161 \n17 Odvina C.V. Zerwekh J.E. Rao D.S. Maalouf N. Gottschalk F.A. Pak C.Y. Severely suppressed bone turnover: a potential complication of alendronate therapy J. Clin. Endocrinol. Metab. 90 2005 1294 1301 15598694\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "70()",
"journal": "International journal of surgery case reports",
"keywords": "Bisphosphonate; Femoral neck; Insufficiency fracture; Magnetic resonance imaging",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "213-215",
"pmc": null,
"pmid": "32417741",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12890844;15598694;27252743;24524048;17638578;27536613;18214569;23177553;30817607;22249525;14102934;15028823;25963272;16036103;25261321;30342279;23337161;19594320",
"title": "Early detected femoral neck insufficiency fracture in a patient treated with long-term bisphosphonate therapy for osteoporosis: A need for MRI.",
"title_normalized": "early detected femoral neck insufficiency fracture in a patient treated with long term bisphosphonate therapy for osteoporosis a need for mri"
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"companynumb": "KR-TEVA-2020-KR-1826949",
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"activesubstancename": "RISEDRONATE SODIUM"
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"abstract": "The World Health Organization HIV guidelines recommend either infant zidovudine (ZDV) or nevirapine (NVP) prophylaxis for the prevention of intrapartum mother-to-child HIV transmission (MTCT) among formula-fed infants. No study has evaluated the comparative efficacy of infant prophylaxis with twice daily ZDV versus once daily NVP in exclusively formula-fed HIV-exposed infants.\nUsing data from the Mpepu Study, a Botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, retrospective analyses of MTCT events and Division of AIDS (DAIDS) Grade 3 or Grade 4 occurrences of anaemia or neutropenia were performed among infants born full-term (≥ 37 weeks gestation), with a birth weight ≥ 2500 g and who were formula-fed from birth. ZDV infant prophylaxis was used from Mpepu Study inception. A protocol modification mid-way through the study led to the subsequent use of NVP infant prophylaxis.\nAmong infants qualifying for this secondary retrospective analysis, a total of 695 (52%) infants received ZDV, while 646 (48%) received NVP from birth for at least 25 days but no more than 35 days. Confirmed intrapartum HIV infection occurred in two (0.29%) ZDV recipients and three (0.46%) NVP recipients (p = 0.68). Anaemia occurred in 19 (2.7%) ZDV versus 12 (1.9%) NVP (p = 0.36) recipients. Neutropenia occurred in 28 (4.0%) ZDV versus 21 (3.3%) NVP recipients (p = 0.47).\nBoth ZDV and NVP resulted in low intrapartum transmission rates and no significant differences in severe infant haematologic toxicity (DAIDS Grade 3 or Grade 4) among formula-fed full-term infants with a birthweight ≥ 2500 g.",
"affiliations": "Massachusetts General Hospital, Departments of Medicine and Pediatrics, United States.;Harvard T. H. Chan School of Public Health, Department of Immunology and Infectious Diseases, United States.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Harvard T. H. Chan School of Public Health, Department of Immunology and Infectious Diseases, United States.;Bennett Statistical Consulting, Inc, Ballston Lake, United States.;Goodtables Data Consulting, Norman, United States.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Ministry of Health, Gaborone, Botswana.;Ministry of Health, Gaborone, Botswana.;Division of Infectious Diseases, Boston Children's Hospital, United States.;Harvard T. H. Chan School of Public Health, Department of Immunology and Infectious Diseases, United States.;Harvard T. H. Chan School of Public Health, Department of Immunology and Infectious Diseases, United States.",
"authors": "Powis|Kathleen M|KM|0000-0002-4478-4471;Lockman|Shahin|S|0000-0002-5384-9716;Ajibola|Gbolahan|G|0000-0002-5408-4823;Hughes|Michael D|MD|;Bennett|Kara|K|0000-0002-9465-8983;Leidner|Jean|J|0000-0002-4707-3747;Batlang|Oganne|O|0000-0003-1186-2979;Botebele|Kerapetse|K|0000-0003-3821-4592;Moyo|Sikhulile|S|;van Widenfelt|Erik|E|;Makhema|Joseph|J|0000-0003-0017-2438;Petlo|Chipo|C|;Jibril|Haruna B|HB|0000-0002-1764-0712;McIntosh|Kenneth|K|;Essex|Max|M|;Shapiro|Roger L|RL|",
"chemical_list": null,
"country": "South Africa",
"delete": false,
"doi": "10.4102/sajhivmed.v19i1.751",
"fulltext": "\n==== Front\nSouth Afr J HIV MedSouth Afr J HIV MedHIVMEDSouthern African Journal of HIV Medicine1608-96932078-6751AOSIS HIVMED-19-75110.4102/sajhivmed.v19i1.751Original ResearchSimilar HIV protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in Botswana http://orcid.org/0000-0002-4478-4471Powis Kathleen M. 123http://orcid.org/0000-0002-5384-9716Lockman Shahin 234http://orcid.org/0000-0002-5408-4823Ajibola Gbolahan 3Hughes Michael D. 2http://orcid.org/0000-0002-9465-8983Bennett Kara 5http://orcid.org/0000-0002-4707-3747Leidner Jean 6http://orcid.org/0000-0003-1186-2979Batlang Oganne 3http://orcid.org/0000-0003-3821-4592Botebele Kerapetse 3Moyo Sikhulile 3van Widenfelt Erik 3http://orcid.org/0000-0003-0017-2438Makhema Joseph 3Petlo Chipo 7http://orcid.org/0000-0002-1764-0712Jibril Haruna B. 7McIntosh Kenneth 8Essex Max 23Shapiro Roger L. 231 Massachusetts General Hospital, Departments of Medicine and Pediatrics, United States2 Harvard T. H. Chan School of Public Health, Department of Immunology and Infectious Diseases, United States3 Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana4 Brigham and Women’s Hospital, Infectious Disease Division, United States5 Bennett Statistical Consulting, Inc, Ballston Lake, United States6 Goodtables Data Consulting, Norman, United States7 Ministry of Health, Gaborone, Botswana8 Division of Infectious Diseases, Boston Children’s Hospital, United StatesCorresponding author: Kathleen M. Powis, kpowis@mgh.harvard.edu28 3 2018 2018 19 1 75121 3 2017 30 10 2017 © 2018. The Authors2018Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.Background\nThe World Health Organization HIV guidelines recommend either infant zidovudine (ZDV) or nevirapine (NVP) prophylaxis for the prevention of intrapartum mother-to-child HIV transmission (MTCT) among formula-fed infants. No study has evaluated the comparative efficacy of infant prophylaxis with twice daily ZDV versus once daily NVP in exclusively formula-fed HIV-exposed infants.\n\nMethods\nUsing data from the Mpepu Study, a Botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, retrospective analyses of MTCT events and Division of AIDS (DAIDS) Grade 3 or Grade 4 occurrences of anaemia or neutropenia were performed among infants born full-term (≥ 37 weeks gestation), with a birth weight ≥ 2500 g and who were formula-fed from birth. ZDV infant prophylaxis was used from Mpepu Study inception. A protocol modification mid-way through the study led to the subsequent use of NVP infant prophylaxis.\n\nResults\nAmong infants qualifying for this secondary retrospective analysis, a total of 695 (52%) infants received ZDV, while 646 (48%) received NVP from birth for at least 25 days but no more than 35 days. Confirmed intrapartum HIV infection occurred in two (0.29%) ZDV recipients and three (0.46%) NVP recipients (p = 0.68). Anaemia occurred in 19 (2.7%) ZDV versus 12 (1.9%) NVP (p = 0.36) recipients. Neutropenia occurred in 28 (4.0%) ZDV versus 21 (3.3%) NVP recipients (p = 0.47).\n\nConclusions\nBoth ZDV and NVP resulted in low intrapartum transmission rates and no significant differences in severe infant haematologic toxicity (DAIDS Grade 3 or Grade 4) among formula-fed full-term infants with a birthweight ≥ 2500 g.\n==== Body\nIntroduction\nPrevious studies have demonstrated that infant antiretroviral (ARV) prophylaxis with zidovudine (ZDV) or nevirapine (NVP), or both combined, have been efficacious in preventing intrapartum mother-to-child HIV transmission (PMTCT).1,2,3,4,5 Recent work has shown that infant NVP prophylaxis provides additional protection against mother-to-child HIV transmission (MTCT) during breastfeeding.4,5 Currently, the World Health Organization (WHO) recommends NVP prophylaxis for all HIV-exposed infants, but WHO guidelines do not preferentially support either ZDV or NVP in formula-fed HIV-exposed infants.6,7 In fact, the strength of the recommendation for use of daily NVP or twice daily ZDV from birth for 4–6 weeks among breastfed HIV-exposed infants was categorised as ‘strong’ based on ‘moderate’ evidence.6 However, the WHO prophylaxis recommendation for formula-fed HIV-exposed infants from birth was categorised as a ‘conditional’ recommendation with ‘low’ evidence, suggesting the need for data-driven evidence.6\n\nFormula feeding is an alternative to breastfeeding in lower infant-mortality settings where formula feeding is available and can be safely prepared; when breastfeeding cannot occur; and among those who wish to maximally reduce the risk of late HIV transmission. At present, formula feeding is widely practiced as a PMTCT strategy throughout Europe and the Americas, and in some areas of Asia and Africa.8,9,10,11\n\nThe Mpepu Study, conducted in Botswana from May 2011 through June 2015, permitted comparison of four weeks of infant prophylaxis consisting of either single-dose NVP (sdNVP) and ZDV twice daily or NVP once daily among formula-fed HIV-exposed infants. The majority of infants born to women who consented prior to February 2013 received sdNVP and ZDV prophylaxis. Thereafter, most infants received NVP prophylaxis as a single-drug regimen. We performed a retrospective analysis evaluating MTCT rates and haematologic safety of ARV prophylaxis for full-term, normal birthweight, formula-fed infants who received 4 weeks of sdNVP plus ZDV versus NVP.\n\nStudy population and methods\nStudy population and monitoring\nThis retrospective study was conducted in Botswana, a middle-income country with high HIV prevalence, estimated at 21.9% among persons aged 15–49 as of 2016.12 Botswana was among the first countries with high HIV prevalence to promote PMTCT, offering free antiretroviral treatment (ART) to pregnant women living with HIV who qualified for treatment for their own health as early as 2002, while providing ZDV monotherapy to pregnant women living with HIV if they did not yet qualify for HIV treatment. In 2012, Botswana national HIV treatment guidelines were updated to recommend triple ARV use among all pregnant women living with HIV, regardless of their HIV disease state.13 As of 2016, more than 95% of pregnant women living with HIV in Botswana accessed ART.14 This has contributed to significant reductions in MTCT with a rate of 1.8%, despite the fact that HIV prevalence among pregnant women remains high at over 25%.15 Up until 2016, Botswana has promoted exclusive formula feeding in the first six months-of-life for HIV-exposed infants.13,16 In 2016, this policy changed to encourage breastfeeding of HIV-exposed uninfected (HEU) infants so long as the mother is taking ART and is virally suppressed.17 Despite this policy change, the practice of providing free infant formula-fed during the first year of life to HIV-exposed infants remains an option. Use of formula feeding for HIV-exposed infants has been widely adopted, with nearly 80% of women living with HIV in Botswana opting to formula feed their infant. In this context, data were analysed retrospectively from the Mpepu Study to evaluate comparative efficacy of four weeks of sdNVP with ZDV versus NVP.\n\nThe Mpepu Study, a double-blinded randomised controlled trial, investigated prophylactic co-trimoxazole (CTX) versus placebo from 2 weeks to 15 months of age in HEU infants, studying health outcomes including diarrhoeal illness, pneumonia and death (NCT01229761). This study has previously been described.18 In brief, HIV-infected women were eligible for enrolment between 26 weeks gestation and 35 days postpartum. Infants were enrolled from birth to 35 days-of-life. The study opened for enrolment in May 2011 and was conducted in the capital city (Gaborone), the rural village of Molepolole, located approximately 56 km from the capital city, and the peri-urban town of Lobatse located approximately 67 km from the capital city. Consistent with Botswana’s PMTCT guidelines,19 the initial study protocol followed government dosing of sdNVP (6 mg) within 72 h of birth and ZDV [4 mg/kg twice daily for full-term infants (37 weeks) with a birth weight ≥ 2500 g] for four weeks. Randomisation to CTX or placebo took place between 28 and 35 days-of-life. From February 2013, the protocol was amended to allow randomisation to CTX or placebo as early as 14 days-of-life for infants born full-term and weighing ≥ 2500 g. To avoid the possibility of overlapping haematologic toxicity from CTX with ZDV with this protocol change, study infants were offered NVP (15 mg once daily for four weeks from birth). Of note, the prevailing prophylaxis under national guidelines remained sdNVP with four weeks of ZDV.20 Therefore, some infants enrolled in the study after the protocol amendment received sdNVP and ZDV initiated by government nursing staff at maternity wards where they were born.\n\nData were collected on the initiation and stop dates of infant ARV prophylaxis. At infant enrolment and randomisation study visits, infant HIV-1 testing was performed using qualitative polymerase chain reaction (PCR) DNA assay (Amplicor HIV-1, Roche Diagnostic Systems, New Jersey, USA) for infants at the birth (enrolment) and randomisation study visits. Over 95% of infant enrolment DNA PCRs were collected in the first 72 h after infant birth. If an infant enrolment PCR was not available and a subsequent HIV-1 PCR test was negative, the enrolment PCR was imputed as negative. Additional infant HIV DNA PCR testing was performed at six weeks of life in government-run health facilities in accordance with Botswana national PMTCT guidelines with results documented in Mpepu Study records and by Mpepu Study clinicians at any visit where an infant was noted to have significant interim or current illness or insufficient weight gain. Infants attending the 18-month study visit were retested for HIV status using enzyme-linked immunosorbent assay (ELISA). A full blood count was drawn at randomisation (between 14 and 35 days-of-life), and 3- and 6-month visits and included haemoglobin and absolute neutrophil count. Infant haemoglobin and absolute neutrophil count (ANC) values were graded using the Division of AIDS (DAIDS) Table for Grading and Severity of Adult and Paediatric Events, Version 1.0, December 2004; Clarification August 2009.21 Haemoglobin or absolute neutrophil count results corresponding to DAIDS Grade 3 or Grade 4 values were classified as anaemia or neutropenia.\n\nMaternal verbal reports and clinical records were used to ascertain maternal ARV use; all maternal ARVs were provided through the government’s Infectious Disease Care Clinics. At Mpepu Study inception, the national policy endorsed triple ARV for all HIV-infected women for PMTCT (Option B),19 transitioning from a policy where only women with CD4+ cell counts of < 350 cells/µL were eligible for triple ARVs.20 However, Option B was not fully operationalised until January 2013.22\n\nStudy inclusion and exclusion criteria\nInfants were eligible for this secondary analysis if they were born full-term (≥ 37 weeks gestation) with a birth weight ≥ 2500 g, received 25–35 days of ZDV twice daily or NVP once daily and were exclusively formula-fed in the first 35 days-of-life based on maternal verbal report. Where mixed feeding was reported, infants were excluded. National guidelines endorsed sdNVP within 72 h of birth for all infants receiving ZDV prophylaxis. Gestational age and birth weight restrictions were employed to avoid study-specific sources of bias in this secondary analysis, because preterm and low-birth-weight infants in the later study period were more likely to have received ZDV prophylaxis.\n\nStatistical methods\nSAS, version 9.3 (SAS Institute, Cary, North Carolina, USA) was used for statistical analyses. Maternal and infant characteristics were compared by infant ARV prophylaxis group. Continuous variables were compared using Wilcoxon rank sum test. Fisher’s exact testing was used for comparison of non-continuous variables and to assess MTCT prevalence by infant HIV DNA PCR results obtained between 14 and 35 days-of-life. Exact (Clopper–Pearson) methods for binomial proportions were used to estimate the MTCT confidence limits. Time to first occurrence of infant anaemia or neutropenia in the first six months-of-life by ARV prophylaxis group was compared using Cox proportional hazard models, stratified by infant randomisation arm (CTX or placebo). All testing used a significance level of 0.05, with two-sided hypothesis testing.\n\nEthical consideration\nThe Health Research Development Committee of Botswana and the Office of Human Research Administration at the Harvard T.H. Chan School of Public Health approved the study protocol and amendments. Women signed a written consent form approved by the ethical review boards for their and their infants’ participation.\n\nProject research number: Clinical Trials.gov Registration Number: NCT01229761.\n\nResults\nOf 3164 infants enrolled in the Mpepu Study, 1823 (58%) infants were excluded from this secondary analysis: 930 born preterm and/or with a birth weight < 2500 g, 203 evaluated only at birth, 420 breastfed infants, 69 without ARV prophylaxis documentation, 95 with documentation of < 25 days of prophylaxis, 55 with extended prophylaxis (> 35 days) and 51 given dual ZDV and NVP prophylaxis (Figure 1). Of the remaining 1341 (42%) infants, 695 received ZDV prophylaxis for a median of 28 [interquartile range (IQR) 27–30] days, with 665 (95.7%) of the infants receiving ZDV prophylaxis also having documentation of sdNVP dosing within 72 h of delivery. The remaining 646 infants received NVP for a median of 29 days (IQR 28–30). Before the protocol change in February 2013, 2 (0.3%) infants received NVP prophylaxis, whereas 644 (86.6%) infants received NVP prophylaxis after the change.\n\nFIGURE 1 Consort diagram.\n\nCharacteristics of mother–infant pairs by prophylaxis regimen are presented in Table 1. A significantly higher proportion of mothers of NVP recipients received triple ARVs during pregnancy, as 99% of all NVP recipients were born after Botswana’s National HIV Treatment Guidelines transitioned to Option B. Only 1.3% of mothers of NVP recipients received ZDV monotherapy in pregnancy versus 21.4% of mothers of ZDV recipients. The median days to HIV DNA PCR testing at parent study randomisation (visit for initiation of CTX/placebo) was 29 days-of-life for ZDV infants and 15 days-of-life for NVP infants, reflecting the earlier age at randomisation for NVP recipients after the protocol change. Early closure of the Lobatse site led to a higher proportion of Lobatse enrolled infants receiving ZDV. In all other respects, characteristics between groups were similar.\n\nTABLE 1 Comparison of mother–infant characteristic by infant antiretroviral prophylaxis.\n\nMaternal or infant characteristics\tMothers† of infants with ZDV prophylaxis‡ (n = 693)\tMothers† of infants with NVP prophylaxis (n = 642)\t\nMedian maternal age (years) [IQR]\t30.9 [ 26.9–34.8]\t31.6 [ 26.8–36.0]\t\nGravida including current pregnancy (n, %)\t\n1\t88 (12.7%)\t93 (14.5%)\t\n2\t172 (24.8%)\t136 (21.2%)\t\n3\t187 (27.0%)\t171 (26.6%)\t\n4 or more\t246 (35.5%)\t242 (37.7%)\t\nMedian enrollment CD4+ count (cells/µL) [IQR]\t476 [348–629]\t508 [352–674]\t\nEnrollment CD4+ < 200 cells/µL (n, %)\t35 (5.0%)\t35 (5.6%)\t\nMaternal ARV regimen\t\n Triple ARVs initiated before conception\t247 (35.6%)\t313 (48.8%)\t\n Triple ARVs initiated in pregnancy\t269 (38.8%)\t299 (46.6%)\t\n ZDV monotherapy\t148 (21.4%)\t8 (1.2%)\t\n No ARVs\t29 (4.2%)\t22 (3.4%)\t\nEnrollment site (n, %)§\t\n Molepolole (Village)\t238 (34.3%)\t246 (38.3%)\t\n Lobatse (Town)\t104 (15.0%)\t2 (0.3%)\t\n Gaborone (City)\t351 (50.7%)\t394 (61.4%)\t\nMarital status (n, % )\t\n Single\t548 (79.2%)\t533 (83.0%)\t\n Married/Cohabitating\t134 (19.4%)\t105 (16.4%)\t\n Widowed/Divorced\t10 (1.4%)\t4 (0.6%)\t\nEducation (n, %)\t\n None or Primary\t117 (18.3%)\t91 (15.7%)\t\n Secondary\t388 (60.7%)\t370 (63.9%)\t\n University\t134 (21.0%)\t118 (20.4%)\t\nInfant characteristics\tInfants with ZDV prophylaxis (n = 695)\tInfants with NVP prophylaxis (N = 646)\t\nInfant sex (n, %)\t\n Male\t354 (50.9%)\t322 (49.8%)\t\n Female\t341 (49.1%)\t324 (50.2%)\t\nMedian gestational age in weeks at delivery [IQR]\t39 [38–40]\t39 [38–40]\t\nMedian anthropometric measures\t\n Birth weight (kg) [IQR]\t\n Male infants\t3.12 [2.87–3.40]\t3.10 [2.85–3.36]\t\n Female infants\t3.00 [2.80–3.25]\t2.98 [2.78–3.20]\t\n Length (cm) [IQR]\t\n Male infants\t51 [49–53]\t51 [49–52]\t\n Female infants\t50 [49–52]\t50 [49–51]\t\nMedian days of ZDV or NVP prophylaxis [IQR]\t28 [27–30]\t29 [28–30]\t\nMpepu Study randomisation arm (n, %)\t\n Co-trimoxazole\t359 (51.7%)\t309 (47.8%)\t\n Placebo\t336 (48.3%)\t337 (52.2%)\t\nMedian days to HIV DNA PCR testing [IQR]\t29 [28–30]\t15 [14–16]\t\nARVs, antiretrovirals; IQR, interquartile range; NVP, nevirapine; ZDV, zidovudine; cm, centimeters; kg, kilograms.\n\n† , Of the 1335 women in this sub-study, 6 women delivered twins of which both infants met study eligibility criteria.\n\n‡ , Among infants receiving ZDV prophylaxis, 95.7% had documentation of single-dose NVP receipt within 72 h of delivery.\n\n§ , The Lobatse study site closed to accrual in August 2012, prior to study protocol change to use NVP infant prophylaxis.\n\nOf the 1341 formula-fed infants, 9 (0.67%) represented potential intrapartum infections (HIV infection acquired during labour or delivery), having a first positive HIV DNA PCR result > 72 h after delivery; 6 [0.86%; 95% confidence interval (CI): 0.32% – 1.87%] ZDV recipients and 3 (0.46%; 95% CI: 0.10% – 1.35%) NVP recipients (p = 0.51). Among these nine potential intrapartum infections, five were confirmed intrapartum infections, having documentation of an initial negative HIV DNA PCR prior to a positive test result on a second HIV DNA PCR test, two (0.29%; 95% CI: 0.04% – 1.04%) infants receiving ZDV and three (0.46%; 95% CI: 0.04% – 1.12%) receiving NVP (p = 0.68). The remaining four infants, all receiving ZDV prophylaxis (one without sdNVP dosing documentation), had their first HIV DNA PCR test between 6 and 29 days-of-life, and it was positive. For these infants, the possibility of in utero transmission cannot be excluded.\n\nA total of 201 (15%) of the 1341 mother–infant pairs were at higher risk for vertical transmission, defined as no or < 28 days of maternal ARV use during pregnancy, or maternal enrolment CD4+ cell count < 250 cells/µL. Of these, 110 infants received ZDV and 91 received NVP. Four (2.0%) potential intrapartum transmission events occurred among high-risk infants; three (2.73%; 95% CI: 0.57% – 7.76%) ZDV recipients and one (1.10%; 95% CI: 0.03% – 5.97%) NVP recipient (p = 0.63). Two of the high-risk ZDV recipients (one without sdNVP dosing documentation) were not confirmed intrapartum transmissions, as their first HIV DNA PCR test was positive but was not drawn until more than two weeks after delivery.\n\nA total of 31 (2.3%) infants experienced at least one episode of anaemia, by DAIDS Grade 3 or Grade 4 criteria, in the first six months: 19 (2.7%) ZDV recipients and 12 (1.9%) NVP recipients (p = 0.36). Because the parent study involved infant randomisation to CTX or placebo, and CTX can cause bone marrow suppression,23 Cox proportional hazard models were used to evaluate time to first occurrence of anaemia or neutropenia by infant prophylaxis with stratification by infant randomisation arm (CTX or placebo). The adjusted hazard ratio for the time to first episode of anaemia among ZDV recipients did not differ significantly from NVP recipients [aHR 1.51 (95% CI: 0.73–3.14), p = 0.26] after stratification. DAIDS Grade 3 or Grade 4 neutropenia occurred more frequently than anaemia, with 49 (3.7%) infants experiencing at least one episode in the first six months; 28 (4.0%) ZDV recipients and 21 (3.3%) NVP recipients (p = 0.47). Time to first episode of neutropenia did not differ significantly for ZDV recipients compared with NVP recipients [aHR 1.04 (95% CI 0.57–1.91), p = 0.90] after stratification by CTX versus placebo.\n\nDiscussion\nUsing data from the Mpepu Study, we provide the first comparative evaluation of vertical transmission and haematologic safety among full-term, normal birthweight, formula-fed HIV-exposed infants, analysing infant prophylactic regimens of sdNVP and ZDV twice daily versus NVP once daily. Whether including confirmed or potential intrapartum transmissions, the intrapartum MTCT incidence was low in this cohort where over 80% of all women received triple ARVs during pregnancy. Reassuringly, vertical transmission was low for both infant prophylaxis regimens. Even among mother–infant pairs at highest risk for MTCT, both infant prophylaxis regimens achieved low vertical transmission outcomes. DAIDS Grade 3 and Grade 4 anaemia and neutropenia events were each noted in fewer than 5% of infants, with no significant difference between prophylaxis groups in the first six months-of-life.\n\nThis study reduced bias by reporting confirmed and potential intrapartum transmissions and utilising very similar comparison groups from each study era. However, the study design imposed some limitations to this secondary analysis. First, preterm and low-birth-weight infants in the Mpepu Study were more likely to receive ZDV. Unfortunately, this precluded analysis of transmission outcomes and haematologic safety among infants born at < 37 weeks gestational age or with a birth weight < 2500 g, excluding nearly 30% of the infants in the Mpepu Study. Second, it is possible that some false-negative HIV DNA PCR results may have occurred, because testing was performed at the time the infant was taking prophylaxis or within days of discontinuing prophylaxis. However, in a study conducted by Burgard and colleagues evaluating the sensitivity of HIV DNA PCR performed between 15 and 45 days-of-life among 1293 formula-fed HIV-exposed infants, the sensitivity of HIV DNA PCR during this window when infants were taking or had recently completed ARV prophylaxis was quite high (88%).24 Mpepu Study infants were referred for HIV DNA PCR testing at six weeks of age under Botswana’s national programme, with no positive tests known to the study team. Furthermore, 48% of formula-fed children had an 18-month ELISA through the study (the remaining 52% were not followed to 18 months owing to early closure of the study for futility, at the recommendation of the Data Safety and Monitoring Board); all but one of these children had a negative ELISA at 18 months-of-life (the one infant with a positive ELISA had documentation of a negative HIV DNA PCR at three months-of-life, suggesting HIV acquisition from a source other than intrapartum HIV transmission, such as undisclosed breastfeeding). Third, this analysis involved comparison of infants from two consecutive time periods. As such, temporal confounders may be present. For example, less extensive maternal ART coverage in the earlier study era may explain the non-significant increase in overall (but not confirmed) intrapartum transmission events with ZDV (6 vs. 3). In terms of haematological toxicity, we acknowledge that the Mpepu testing schedule with a full blood count obtained between 14 and 35 days-of-life with follow-up at 3- and 6 months-of-life may have missed the occurrence of anaemia or neutropenia shortly after the infant discontinued ARV prophylaxis but before the 3-month visit. Lastly, this is a retrospective analysis of a study specifically designed for other purposes. As such, it was not powered to detect prophylaxis efficacy between the two infant regimens. Although a larger study with more complete birth PCR testing might have provided better discrimination between NVP and ZDV, the very low overall occurrence of MTCT in the Mpepu Study suggests that clinically meaningful differences in transmission were not missed.\n\nIn conclusion, while formula feeding of HIV-exposed infants in resource-limited settings remains the exception, our study findings provide reassuring evidence that a 4-week infant prophylaxis regimen of either sdNVP plus ZDV or ongoing NVP was similarly efficacious for PMTCT among formula-fed, full-term, normal birthweight infants in the context of extensive maternal ART use, without significant differences in haematologic adverse consequences. Prior to this study, the WHO recommendation for the use of sdNVP plus ZDV versus NVP was categorised as ‘conditional’ and based upon low evidence. Our comparative analysis strengthens the evidence, supporting current WHO recommendations for use of either ZDV or NVP as prophylaxis among HIV-exposed full-term infants in the first month of life to prevent intrapartum HIV acquisition.\n\nAcknowledgements\nThe Mpepu Study was supported by funding from the National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases (R01 HD061265). K.M.P. received salary support from the National Institute of Child Health and Human Development (K23HD070774).\n\nCompeting interests\nThe authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article.\n\nAuthors’ contributions\nR.L.S. and S.L. were the principal investigators of the parent study, Mpepu, and K.M.P. and G.A. were the study coordinators for the Mpepu Study. O.B. and K.B. (Botswana Harvard AIDS Institute Partnership) were Mpepu Study clinicians and K.M.P., G.A., O.B. and K.B. routinely interacted with women and infants enrolled in this study to collect data and specimens. E.v.W is the information technology manager at Botswana–Harvard AIDS Institute Partnership (BHP). He designed the electronic data capture systems for the Mpepu Study. Both E.v.W. and J.L. assisted in the preparation of data sets for the secondary analysis presented in this manuscript. S.M. is the lab director at BHP and processed and resulted all the specimens or lab tests presented in the manuscript. K.M.P. designed the study and performed the primary statistical analyses for the manuscript, with K.B. (Bennett Statistical Consulting, Inc.) and M.D.H. providing validation of the statistical code and outcomes reported in the manuscript. K.M.P. wrote the first draft of the manuscript, with first draft editing support from R.L.S. and S.L. All co-authors of the manuscript, including J.M., C.P., H.B.J., K.M. and M.E. reviewed the final draft and provided meaningful edits to the final version of the manuscript submitted.\n\nHow to cite this article: Powis KM, Lockman S, Ajibola G, et al. Similar HIV protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in Botswana. S Afr J HIV Med. 2018;19(1), a751. http://doi.org/10.4102/sajhivmed.v19i1.751\n\nNote: Presented in part: 2016 Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, United States, 22–25 February (Abstract 16-1677).\n==== Refs\nReferences\n1. Connor EM , Sperling RS , Gelber R , et al \nReduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group . N Engl J Med . 1994 ;331 (18 ):1173 –1180 . https://doi.org/10.1056/NEJM199411033311801 7935654 \n2. 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J Pediatr . 2012 ;160 (1 ):60 –66.e1 . https://doi.org/10.1016/j.jpeds.2011.06.053 21868029\n\n",
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"abstract": "BACKGROUND\nPersistent Genital Arousal Disorder (PGAD) is defined as \"spontaneous, intrusive, and unwanted genital arousal (tingling, throbbing, pulsating) in the absence of sexual interest and desire\" and traditionally causes marked distress, embarrassment and shame. PGAD may be caused by starting, discontinuing, or making adjustments in certain antidepressants or other medications.\n\n\nOBJECTIVE\nTo report the case of a 36- year- old woman with PGAD, likely due to changes in her psychiatric medications, who was treated with pramipexole and experienced improvement in her PGAD symptoms.\n\n\nMETHODS\nPatient self-report and literature review. Written informed consent was obtained from the patient.\n\n\nMETHODS\nImprovement in PGAD symptoms.\n\n\nRESULTS\nPatient reported improvement in her symptoms by \"90%\" on a low dose of pramipexole, although higher doses exacerbated her symptoms.\n\n\nCONCLUSIONS\nIt is likely that an effective treatment window exists for the treatment of PGAD with drugs that possess the ability to exert their control of dopaminergic transmission. This includes direct acting receptor agonists like pramipexole, which produce feedback inhibition. Limitations to their efficacy then involve co-treatments that counteract their ability to exert a dampening effect on hyperstimulated dopamine transmission. It is recommended that clinicians be aware of drugs taken by patients to treat psychiatric disorders that could induce PGAD symptoms, drugs recently discontinued where a rebound effect could lead to PGAD symptoms, and drug mechanisms that could counteract the effect of treatments for PGAD. Lynn BK, Grabenhorst C, Komisaruk BR, et al. The Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report. Sex Med 2021;9:100372.",
"affiliations": "Saint Louis University School of Medicine, OBGYN, Saint Louis, MO, USA; Evora Women's Health, Chesterfield, MO, USA. Electronic address: evoramedllc@gmail.com.;Evora Women's Health, Chesterfield, MO, USA.;Rutgers University, Psychology, Newark, NJ, USA.;Sexual Medicine. Alvarado Hospital, Alvarado Hospital, Sexual Medicine, San Diego, CA, USA.;Universidad Veracruzana, Centro de Investidaciones Cerebrales, Veracruz, MX.",
"authors": "Lynn|Becky Kaufman|BK|;Grabenhorst|Chloe|C|;Komisaruk|Barry R|BR|;Goldstein|Irwin|I|;Pfaus|Jim|J|",
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"fulltext": "\n==== Front\nSex Med\nSex Med\nSexual Medicine\n2050-1161\nElsevier\n\nS2050-1161(21)00052-0\n10.1016/j.esxm.2021.100372\n100372\nCase Report\nThe Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report\nLynn Becky Kaufman MD, MBA evoramedllc@gmail.com\n12⁎\nGrabenhorst Chloe MS 2\nKomisaruk Barry R. PhD 3\nGoldstein Irwin MD 4\nPfaus Jim PhD 5\n1 Saint Louis University School of Medicine, OBGYN, Saint Louis, MO, USA\n2 Evora Women's Health, Chesterfield, MO, USA\n3 Rutgers University, Psychology, Newark, NJ, USA\n4 Sexual Medicine. Alvarado Hospital, Alvarado Hospital, Sexual Medicine, San Diego, CA, USA\n5 Universidad Veracruzana, Centro de Investidaciones Cerebrales, Veracruz, MX\n⁎ Corresponding Author: Becky Kaufman Lynn, MD, MBA, OBGYN, Saint Louis University School of Medicine, 6420 Clayton Road, Saint Louis, MO 63117, USA. Tel.: 314-934-0551 evoramedllc@gmail.com\n11 6 2021\n8 2021\n11 6 2021\n9 4 1003725 12 2020\n29 3 2021\nCopyright © 2021 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine.\n2021\nThe Authors\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/).\nIntroduction\n\nPersistent Genital Arousal Disorder (PGAD) is defined as “spontaneous, intrusive, and unwanted genital arousal (tingling, throbbing, pulsating) in the absence of sexual interest and desire” and traditionally causes marked distress, embarrassment and shame. PGAD may be caused by starting, discontinuing, or making adjustments in certain antidepressants or other medications.\n\nAim\n\nTo report the case of a 36- year- old woman with PGAD, likely due to changes in her psychiatric medications, who was treated with pramipexole and experienced improvement in her PGAD symptoms.\n\nMethods\n\nPatient self-report and literature review. Written informed consent was obtained from the patient.\n\nMain Outcome Measure\n\nImprovement in PGAD symptoms.\n\nResults\n\nPatient reported improvement in her symptoms by “90%” on a low dose of pramipexole, although higher doses exacerbated her symptoms.\n\nConclusions\n\nIt is likely that an effective treatment window exists for the treatment of PGAD with drugs that possess the ability to exert their control of dopaminergic transmission. This includes direct acting receptor agonists like pramipexole, which produce feedback inhibition. Limitations to their efficacy then involve co-treatments that counteract their ability to exert a dampening effect on hyperstimulated dopamine transmission. It is recommended that clinicians be aware of drugs taken by patients to treat psychiatric disorders that could induce PGAD symptoms, drugs recently discontinued where a rebound effect could lead to PGAD symptoms, and drug mechanisms that could counteract the effect of treatments for PGAD. Lynn BK, Grabenhorst C, Komisaruk BR, et al. The Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report. Sex Med 2021;9:100372.\n\nKey Words\n\nPersistent genital arousal disorder, Restless genital syndrome, Pramipexole, Dopamine\n==== Body\nPersistent Genital Arousal Disorder (PGAD) is defined as “spontaneous, intrusive, and unwanted genital arousal (tingling, throbbing, pulsating) in the absence of sexual interest and desire” and causes marked distress, embarrassment and shame according to a consensus statement from the Fourth International Consultation on Sexual Medicine.1 It is unrelieved or worsened by orgasm and may have severe psychological consequences including isolation or suicidal ideation. PGAD is different from hypersexuality in that it occurs in the absence of desire whereas hypersexuality is characterized by high desire for sexual activity. Despite a sensation of engorgement, physical engorgement is usually not visualized. In addition, some women experience spontaneous orgasms, not related to sexual activity, that they find “disturbing, distracting and uncomfortable”. Symptoms may be worsened by stress, anxiety, visual stimuli or physical stimuli. Physical stimuli may be sexual or nonsexual, like the vibrations felt when riding in a car (See Goldstein et al. for a comprehensive review).2\n\nPGAD was first recognized as a condition in 2001. Leiblum & Nathan first reported on a series of 5 women with the disorder and named it persistent sexual arousal syndrome.2 The name was changed to persistent genital arousal disorder to reflect that the arousal is confined to the genitals in the absence of subjective arousal. Based on limited data, PGAD is thought to occur in approximately 1% of women.\n\nETIOLOGY\n\nThe etiology of PGAD is unclear. It may be the end result of a variety of different conditions, psychological and/or physiological. Physiologically, it may be central or peripheral. Peripherally, PGAD may be due to neuropathy or radiculopathy. It has been linked to meningeal cysts, especially Tarlov cysts, which irritate the pudendal and pelvic nerve root components of the cauda equina.2 Disc impingements, annular tears, facet cysts and spinal stenosis have also been implicated in its development.3,4,5 Women with pudendal neuropathy may have symptoms of PGAD.2 Several case reports have linked PGAD to starting or discontinuing selective serotonin reuptake inhibitors (SSRIs) or SNRIs.2 It has also been linked to the use of trazodone, amitriptyline, pramipexole and lamotrigine. Psychologically, anxiety, and stress seem to worsen PGAD.2\n\nWe present here a case report of a 36 year old woman who developed PGAD symptoms related to adjustments in her antidepressant/antianxiety medications. Her symptoms ultimately improved with the use of pramipexole, a dopamine D3-preferring receptor agonist typically used to treat Parkinson's Disease and Restless Leg Syndrome. Pramipexole has been used in the past to treat PGAD.6 Raj et al report on a case of PGAD that was successfully treated with a combination of pramipexole and leuprolide. Pramipexole has also been reported to be associated with the development of PGAD in another case report in a woman with Parkinson's syndrome.7\n\nCASE REPORT\n\nA 36 year old female presented to a sexual medicine clinic with symptoms of PGAD in March of 2018. Informed consent was obtained from the patient for this case report. She described feeling arousal in the genital area that was so severe that sometimes she couldn't walk. She also described urinary urgency, frequency and nocturia. Her symptoms had started one year prior after she was discharged from the hospital following an admission for adjustment of her psychiatric medicines including weaning her off alprazolam, which she took for anxiety. Before her admission, she had been on multiple psychiatric medications including fluoxetine, buproprion, venlafaxine, trazodone, amitriptyline and vilazodone. Her psychiatrist felt it was important to stop the multiple medications to “start fresh regarding her medications”. The patient thinks she may have been taking other medications that she could not recall. She specifically noticed arousal symptoms after stopping fluoxetine and vilazodone.\n\nDuring her admission, she was started on lurasidone 20 mg and titrated up to 40 mg. She was discharged on this medication. After hospitalization, she was placed on quetiapine which was ultimately discontinued, and she was started on desvenlafaxine.\n\nShe initially sought treatment for arousal symptoms with her gynecologist who started her on ethinyl estradiol and/or etonorgestrel ring and a topical estrogen cream. The ring worsened her symptoms “times 20” and the cream did nothing for her symptoms. She then presented to a sexual medicine clinic. At that time, her PGAD symptoms seemed to be the most intense at night. She did not experience any lower back or extremity pain, numbness, tingling, or weakness. She denied a history of trauma or motor vehicle accidents. She had had a c-section 9 years ago. She was taking trazodone and tramadol. The tramadol provided some relief. Her exam showed no abnormal findings. She was weaned off the trazodone, continued on tramadol, referred to pelvic floor physical therapy, to urogynecology for urinary symptoms, and an MRI was ordered.\n\nIn April of 2018 she returned with improvement of urinary symptoms at night while using tramadol. Physical therapy did not alleviate her symptoms, although it helped with her urgency and frequency. A bilateral pudendal block was performed in the office. The pudendal block did not alleviate her symptoms.\n\nIn June of 2018 the patient returned after starting levomilnacipran for her anxiety that seemed to worsen her PGAD symptoms “by five times”. She was switched to sertraline and she discontinued the tramadol because it was no longer effective. She tried varenicline and zolpidem and neither alleviated her symptoms.\n\nIn July of 2018 she saw the urogynecologist and was started on mirabegron.\n\nIn March of 2019, an x-ray of the abdomen pelvis was unremarkable. Her MRI showed degenerative disc and joint disease at L3-4 and L4-5 with possible hemangiomas seen at L2 and L3. No Tarlov cysts, annular tears or bulging discs were seen.\n\nIn April of 2019 the patient saw a pain specialist who performed a right pudendal nerve block. She returned about 8 weeks later without improvement and the pain specialist performed a bilateral pudendal nerve block. In September of 2019 she underwent a fluoroscopically guided caudal epidural steroid injection with no improvement.\n\nShe returned to the sexual medicine clinic in November of 2019. Her husband had found an article in which PGAD had been successfully treated with pramipexole. She was started on pramipexole at a dose of 0.125 mg TID. In January of 2020, she reported that pramipexole had slightly improved her symptoms. Her pramipexole was increased to 0.125 mg BID with 0.250 mg at night. At this dose her symptoms worsened, so she returned to 0.125 mg TID.\n\nThe patient followed up in the sexual medicine clinic in May of 2020. After being on the pramipexole for 6-7 months, she reported that her symptoms were “so much better” and her feelings of arousal had decreased by 90%. There was no change in the quality of her sensations. Prior to starting the pramipexole she rated her symptoms as a 5 during the day and 10 at night. After starting pramipexole, she rated her symptoms as 0-2 during the day and 4 at night. She was not sexually active because she was worried that it would trigger her symptoms or worsen them. The patient reports that in 2021, the pramipexole is still alleviating her symptoms.\n\nDISCUSSION\n\nThis case report illustrates the complications that polypharmacy can have in both the etiology and treatment of PGAD. The patient was on a number of drugs to treat depression and anxiety, many of which have neurochemical side effects that involve hypothalamic mechanisms that control genital blood flow.\n\nPramipexole is a selective agonist of the dopamine D2, D3, and D4 receptors8 with a longer sustained action at these receptors relative to other dopamine agonists. At first glance, it seems paradoxical that a dopamine agonist should reduce PGAD symptoms, given the role of dopamine in the medial preoptic area and elsewhere in mediating genital blood flow and linking it to subjective sexual arousal and desire.9 However, subchronic treatment with pramipexole reduces both phasic dopamine release in mesolimbic terminals (e.g., nucleus accumbens) and reduces dopamine cell firing by 40%,8,10 due to inhibitory feedback caused by direct agonist action that is sustained. The net effect is reminiscent of the “takeover” of dopamine cell firing with varenicline via actions at cholinergic receptors.11 In both cases, the disruption of phasic dopamine cell firing and release may reduce or eliminate the feelings of PGAD.\n\nSo why was varenicline not effective in this patient? It is likely that the timing of her other treatments played a role. Her PGAD symptoms emerged when she discontinued SSRI treatment with fluoxetine and vilazodone. Discontinuance of SSRI treatment releases brain dopamine systems from chronic inhibition by serotonin,9 which in some individuals causes an increase in phasic dopamine release in the medial preoptic area that either induces genital blood flow or results in PGAD-like feelings of genital engorgement.12 Although varenicline may have worked at that time, we note that she was subsequently on levomilnacipran at the time she tried varenicline. Levomilnacipran is a selective serotonin and noradrenaline reuptake blocker (SNRI) that elevates both serotonin and noradrenaline concentrations in the central nervous system, but also leads to an increase in dopamine concentrations due to its inhibition of noradrenaline reuptake.13 This may have counteracted the effect of varenicline. We note that the patient was taken off levomilnacipran before pramipexole was prescribed, which is likely why it worked.\n\nCONCLUSIONS\n\nIt is likely that an effective treatment window exists for the treatment of PGAD with drugs that possess the ability to exert their own control of dopaminergic transmission. This includes varenicline, which promotes a lower but sustained release of dopamine from axon terminals, and direct acting receptor agonists like pramipexole, which produce feedback inhibition. Limitations to their efficacy then involve co-treatments that counteract their ability to exert a dampening effect on hyperstimulated dopamine transmission. It is recommended that clinicians be aware of drugs taken by patients to treat psychiatric disorders that could induce PGAD symptoms, drugs recently discontinued in which a rebound effect could lead to PGAD symptoms, and drug mechanisms that could counteract the effect of treatments for PGAD.\n\nSTATEMENT OF AUTHORSHIP\n\nConceptualization, BKL; Writing- Original Draft, BKL, CG, and JP; Writing-Review and Editing, IG and BK.\n\nConflict of Interest: The author report no conflicts of interest.\n\nFunding: None.\n==== Refs\nREFERENCES\n\n1 McCabe M Sharlip I Atalla E Definitions of sexual dysfunctions in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015 J Sex Med 6 2009 1479 1486 19228278\n2 Goldstein I Komisaruk BR Pukall CF International society for the study of women’s sexual health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dysesthesia (PGAD/GPD) J Sex Med 8 2021 665 697\n3 Yue JJ Telles C Schlösser TP Do presence and location of annular tear influence clinical outcome after lumbar total disc arthroplasty? A prospective 1-year follow-up study Int J Spine Surg 6 2012 13 17 25694865\n4 Soldatos T Chalian M Thawait S Spectrum of magnetic resonance imaging findings in congenital lumbar spinal stenosis World J Clin Cases 2 2014 883 887 25516864\n5 Gu YT Cui Z Shao HW Percutaneous transforaminal endoscopic surgery (PTES) for symptomatic lumbar disc herniation: a surgical technique, outcome, and complications in 209 consecutive cases J Orthop Surg Res 12 2017 25 28178992\n6 Raj R Bhagat N. Pramipexole with leuprolide: a treatment strategy for PGAD Int J Basic Clin Pharmacol 6 2017 1828 1832\n7 Elkins G Ramsey D Yu Y Hypnotherapy for persistent genital arousal disorder: a case study Int J Clin Exp Hypn 62 2014 215 223 24568327\n8 Chernoloz O El Mansari M Blier P Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain Neuropsychopharmacology 34 2009 651 661 18688211\n9 Pfaus JG. Pathways of sexual desire J Sex Med 6 2009 1506 1533 19453889\n10 Pes R Godar SC Fox AT Pramipexole enhances disadvantageous decision-making: lack of relation to changes in phasic dopamine release Neuropharmacology 114 2017 77 87 27889491\n11 Korda JB Pfaus JG Goldstein I. Persistent genital arousal disorder: a case report in a woman with lifelong PGAD where serendipitous administration of varenicline tartrate resulted in symptomatic improvement J Sex Med 6 2009 1479 1486 19228278\n12 Goldstein I, Komisaruk BR, Pukall CF, et al. International society for the study of women's sexual health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dysesthesia (PGAD/GPD) J Sex Med, submitted.\n13 Asnis GM Henderson MA. Levomilnacipran for the treatment of major depressive disorder: a review Neuropsychiatric Dis Treat 11 2015 125 135\n\n",
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"keywords": "Persistent genital arousal disorder, Restless genital syndrome, Pramipexole, Dopamine",
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"abstract": "BACKGROUND\nCerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early.\n\n\nMETHODS\nWe present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia.\n\n\nCONCLUSIONS\nParaneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.",
"affiliations": "Department of Neurology, University Hospital of Gießen and Marburg, Marburg, Germany. philipp.loehrer@uk-gm.de.;Department of Neurology, University Hospital of Gießen and Marburg, Marburg, Germany.;Institute of Pathology, University Hospital of Gießen and Marburg, Marburg, Germany.;Laboratory Krone, Bad Salzuflen, Germany.;Department of Nuclear Medicine, University Hospital of Gießen and Marburg, Marburg, Germany.;Department of Neurology, University Hospital of Gießen and Marburg, Marburg, Germany.",
"authors": "Loehrer|Philipp A|PA|http://orcid.org/0000-0002-5279-2156;Timmermann|Lars|L|;Pehl|Anika|A|;Bien|Corinna I|CI|;Pfestroff|Andreas|A|;Pedrosa|David J|DJ|",
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"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1788\n10.1186/s12883-020-01788-z\nCase Report\nRhombencephalitis associated with isolated Zic4-antibodies in Paraneoplastic cerebellar degeneration: a case report\nhttp://orcid.org/0000-0002-5279-2156Loehrer Philipp A. philipp.loehrer@uk-gm.de 1 Timmermann Lars 1 Pehl Anika 2 Bien Corinna I. 3 Pfestroff Andreas 4 Pedrosa David J. 1 1 grid.411067.50000 0000 8584 9230Department of Neurology, University Hospital of Gießen and Marburg, Marburg, Germany \n2 grid.411067.50000 0000 8584 9230Institute of Pathology, University Hospital of Gießen and Marburg, Marburg, Germany \n3 Laboratory Krone, Bad Salzuflen, Germany \n4 grid.411067.50000 0000 8584 9230Department of Nuclear Medicine, University Hospital of Gießen and Marburg, Marburg, Germany \n25 5 2020 \n25 5 2020 \n2020 \n20 20814 2 2020 14 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nCerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early.\n\nCase presentation\nWe present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia.\n\nConclusion\nParaneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.\n\nKeywords\nParaneoplastic Cerebellar DegenerationZic4Paraneoplastic SyndromesAutoimmune EncephalitisCase Reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nParaneoplastic cerebellar degeneration (PCD) is one of the most frequent paraneoplastic presentations [1]. It is characterized by a subacute onset of symmetrical limb and truncal ataxia, dysarthria, and nystagmus. The symptoms can be preceded by a prodromal phase including fever, headache, nausea, and vomiting, whereby progression to pancerebellar dysfunction occurs within weeks [1]. Symptoms of PCD can antecede tumor diagnosis in more than 50% of the patients depending on the tumor and associated antibody [2, 3]. Initial brain imaging is usually normal, whereas cerebrospinal fluid (CSF) shows pleocytosis, elevated protein levels, and intrathecal IgG synthesis [4]. Malignancies commonly associated with PCD are small cell lung cancer (SCLC, 33%), ovarian carcinoma (25%), and Hodgkin lymphoma (15%) [4].\n\nThe pathogenesis of PCD is attributed to an autoimmune response elicited by the underlying malignancy when proteins restricted to immune privileged neurons are presented by the tumor [4]. In 60% of the cases, onconeuronal antibodies (targeting intracellular proteins) are identified, although associations with antibodies to cell surface proteins like voltage-gated calcium channels (VGCC) have been described [4]. Identifying the respective antibody is important, since presence of a well-characterized antibody helps to establish the diagnosis of PCD and specific associations between antibody and cancer type exist. Among the most prevalent antibodies in PCD are anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. Anti-Yo antibodies (also known as anti-Purkinje cell antibody 1) are directed against Purkinje-cells and typically associate with breast or ovarian cancer as well as a primarily isolated cerebellar syndrome. Anti-Hu antibodies (also known as antineuronal nuclear antibody-type 1, ANNA-1) are attributed to SCLC and the clinical presentation of an encephalomyelitis. Anti-Tr/DNER (delta/notch-like epidermal growth factor-related receptor) antibodies associate with Hodgkin lymphoma and conduct to an isolated cerebellar syndrome.\n\nIn the last decades, multiple antibodies have been linked with PCD including Zinc-finger protein 4 (Zic4) antibodies [4, 5]. Zic4 antibodies are considered onconeuronal antibodies with the zinc finger domain of the intracellular transcription factor Zic4 as the target antigen [6]. Due to the intracellular location of Zic4, antibody associated autoimmunity is potentially T-cell mediated, although exact mechanisms are unknown [5]. Zic4 antibodies hence serve as a biomarker for the syndrome and underlying tumor (see below). The zinc-finger protein of the cerebellum (ZIC) family comprise five transcription factors involved in cerebellar development and maturation [7]. Each factor consists of five Cys2His2 zinc-finger domains and is encoded by one of five ZIC-genes, all of which remained highly conserved throughout evolution [7]. Aberrant ZIC-gene expression during embryogenesis may entail Dandy-Walker malformation (Zic1 and Zic4), neural tube defects (Zic2), holoprosencephaly (Zic2), and heterotaxy syndrome (Zic5) [7]. In adults, contrarily, ZIC-protein family alterations primarily manifest as cerebellar dysfunction.\n\nPatients harboring Zic4 antibodies commonly develop PCD and 92% have SCLC [6]. However, most patients with Zic4 antibodies have concomitant anti-Hu or CRMP5 (collapsin response mediator protein 5) antibodies and present with various additional paraneoplastic syndromes, obscuring the clinical significance of Zic4 antibodies [6, 8]. Isolated Zic4 antibodies, contrarily, appear to be associated with benign paraneoplastic syndromes when treated early. Here, we present the first case of isolated Zic4 antibodies associated with PCD and rhombencephalitis, which subsequently led to fatal dysautonomia, adding important information on how this particular antibody can affect the central nervous system.\n\nCase presentation\nA 67-year-old woman with no relevant past medical or family history was admitted to our emergency department due to progressive staggering vertigo. Ten days prior to admission, the patient had noted unsteadiness of gait and inadequate coordination of her extremities along with truncal instability. In the neurological examination on admission, the patient presented with bilateral dysmetria but especially severe truncal ataxia disabling her to walk. Examination of vertical eye movements revealed upbeat nystagmus, whereas pupillary function, horizontal smooth pursuit, and the vestibulo-ocular reflex were unremarkable. Further neurologic examination was normal, as were the initial laboratory results.\n\nMagnetic resonance imaging (MRI) of the head, including contrast enhanced scans, revealed no pathological findings beyond minor nonspecific vascular white matter hyperintensities on fluid attenuated inversion recovery (FLAIR) sequences. Especially no abnormalities in the brainstem or the cerebellum were present. Cerebrospinal fluid (CSF) showed a pleocytosis (97/mm3) with positive oligoclonal bands. Consecutive serum and CSF analyses were negative for active infectious or systemic autoimmune causes. An immunoblot for intraneuronal antibodies revealed Zic4 antibodies in serum and CSF (coverage: Table 1 and Fig. 1). A combined positron-emission tomography and computed tomography (PET-CT) revealed substantial 18F-fluorodeoxyglucose (FDG) uptake in the right upper pulmonary lobe consistent with lung cancer (Fig. 2.A). Subsequent immunohistochemistry after lobectomy confirmed small cell lung carcinoma (SCLC, Fig. 2.B-E), insofar as that TTF-1 (thyroid transcription factor-1) evidenced a pulmonary origin (Fig. 2.E) and Synaptophysin-staining demonstrated neuroendocrine differentiation (Fig. 2.C). Moreover, a fraction of about 70% of Ki67-positive cells were indicative of high proliferation rates in this tumor (Fig. 2.D). The patient had previously admitted history of long-term cigarette smoking.\nTable 1 Antibodies assessed in this Case\n\nImmunoblot\tCell-based assays\tRadioimmunoassay\t\nAmphiphysin\tGAD65\tVGCC\t\nCV2/CRMP5\tNMDAR\t\t\nMa2/Ta\tGABABR\t\t\nRi\tIgLON5\t\t\nYo\tAMPAR2\t\t\nHu\tDPPX\t\t\nRecoverin\tLGI1\t\t\nSox1\tCASPR2\t\t\nTitin\tGlycinereceptor\t\t\nZic4\tmGluR5\t\t\nDNER/Tr\tmGluR1\t\t\nFig. 1 Immunoblot and Immunofluorescence Test on Mouse Cerebellum. Demonstration of Zic4 antibodies in serum (the same results were obtained with cerebrospinal fluid, not shown). a On an immunoblot, 1:100 diluted patient serum produces on the right lane a band with Zic4 only (arrow and insert), not with any other antigen (Euroline DL 1111–1601-4 G, Euroimmun, Lübeck, Germany). The left lane was incubated with a control serum. b Incubation of patient serum, diluted 1:20, with unfixed mouse cerebellum (Euroimmun, Lübeck, Germany). Patient’s immunoglobulin G (IgG) binds in a Zic-4-typical pattern to the cerebellar granular cells (cf. Fig. 1 in Bataller et al., 2002 [5]). Bound antibodies are visualized by an anti-human-IgG antibody coupled to a red fluorochrome. Original magnification × 100. Bar: 100 μm. The area in the rectangle is shown in (C). c Original magnification × 400. Bar: 25 μm. Zic-4 IgG-antibodies bind to the nuclei of the granular layer and spare the nucleoli. Nuclear counterstaining with Hoechst 33342 1:10.000 in blue. ML = molecular layer; Pu = Purkinje cell layer; GL = granular layer; WM = white matter\n\nFig. 2 18F-FDG-PET Findings and SCLC Histology. a FDG-avid lesion in the right upper pulmonary lobe (red arrow) and non-specific uptake in cervical lymph nodes as a consequence of a mild inflammation. b Hematoxylin and eosin (HE) staining (magnification × 200), shows the tumor with typical basophil small cells with sparse cytoplasm and irregular nuclei. c Immunohistochemical (IH) staining for Synaptophysin (magnification × 200). Tumor tissue stains positive (brown), confirming neuroendocrine differentiation. d IH staining for Ki67 (magnification × 200) marks proliferating cells in a tumor. Proliferation rate was up to 70% in this case. e IH staining for TTF-1 (magnification × 200), shows the typical nuclear staining of cells of pulmonary origin\n\n\n\nUnder the diagnosis of a paraneoplastic cerebellar degeneration (PCD), intravenous methylprednisolone 1000 mg q.d. was administered over five days, followed by five sessions of plasma exchange. In consequence of increasing respiratory distress and incapacitating opsoclonus-myoclonus syndrome, we had come to an agreement with the patient before to initiate sedation and mechanical ventilation not least because of the pending lobectomy.\n\nAfter tumor resection, clinical presentation remained unchanged, so that intravenous immunoglobulin (IVIG) were administered for five additional days and cyclophosphamide therapy was started. The patient was discharged to rehabilitation in a cardiopulmonary stable but reduced overall state requiring mechanical ventilation. Regrettably, she deceased six weeks later due to cardiac arrest.\n\nDiscussion and conclusions\nThis is the first report of isolated Zic4 antibodies associated with rhombencephalitis leading to fatal dysautonomia. In reviewing the literature, a Medline search returned only 14 cases with isolated Zic4 antibodies (Table 2). In the majority of these reports early immunomodulatory treatment conduced to a benign clinical course. Only a single case reported a similarly rapid and clinically severe affection based on coincident spontaneous Creutzfeldt-Jacob disease (CJD) [9]. The authors thereby speculated about autonomic dysfunction and respiratory failure in CJD due to prion deposition in respiratory nuclei. In our patient, however, CJD was ruled out and early immunomodulatory treatment resulted in limited clinical improvement over the entire course. Particularly autonomic dysfunction with cardiac instability and respiratory insufficiency were defiant. In contempt of numerous interdisciplinary tertiary hospital diagnostics and considerable therapeutic efforts, no other pathology was traceable, indicating exclusive paraneoplastic cause. Nevertheless, we acknowledge that presence of other, yet unidentified antibodies cannot be ruled out. In this context, we refer to a recent report describing autoantibodies against Kelch-like-protein-11 (KLHL11-ab) causing a paraneoplastic brainstem and cerebellar syndrome resembling the clinical appearance of our patient [13]. Despite an unavailable specific test to-date, tissue-based assays were not indicative of the presence of KLHL11-ab in our case.\nTable 2 Summary of Case Reports of isolated Zic4-Antibodies \n\nAuthor\tAge/Sex\tAssociated Tumor\tPrimary syndrome at Diagnosis\tSymptoms\tTreatment\tTreatment response\t\nCurrent Study\t67/F\tSCLC\tBrainstem, PCD\tOpsoclonus-Myoclonus Syndrome, Dysautonomia\tMethylprednisolone, Plasmapheresis, IVIG, Lobectomy, Cyclophosphamide\tnone\t\nSalazar et al. 2018 [9]\t70/M\tNone, sCJD\tBrainstem, PCD\tDementia, Ataxia, Myoclonus, Dysautonomia\tMethylprednisolone\tnone\t\nEye et al. 2018 [10]\t94/F\tDLBCL,\n\nSMM\n\n\tPCD\tDownbeat Nystagmus, alternating Skew Deviation, Gait Ataxia\tChemotherapy,\n\nRituximab\n\n\tImprovement but persisting symptoms\t\nAydin et al. 2018 [11]\t40/F\tDuctal breast cancer\tSSN\tPain, Asymmetric Numbness\tn/a\tImprovement but persisting symptoms\t\nKerasnoudis et al. 2011 [12]\t60/F\tOvarian adenocarcinoma\tPCD\tProgressive Gait Ataxia, Dysarthria\tMethylprednisolone,\n\nOvariectomy, Chemotherapy\n\n\tComplete clinical remission\t\nSabater et al. 2008 [8]\tn/a\tSCLC\tPCD\tn/a\tn/a\tn/a\t\nBataller et al. 2004 [6]\t67a/\n\n8: M, 1: F\n\n\t8: SCLC\n\n1: no tumor\n\n\t7: PCD\n\n1: PCD + LE\n\n1: LEMS\n\n\tCerebellar Ataxia\n\nCerebellar Ataxia, Cognitive Dysfunction\n\nMyasthenia\n\n\tn/a\tn/a\t\namedian age\n\n\n\nIrrespective of the divergent clinical course, our case is conforming to previous reports suggesting a link between PCD and Zic4 antibodies. Their presence has most frequently been attributed to SCLC as in our patient [6, 8]. Nevertheless, a source of uncertainty as for the clinical manifestation related to these antibodies may be the co-occurrence with other antibodies like Anti-Hu- or CRMP5-antibodies [6]. Hence, in the first comprehensive case series, Bataller et al. indicated that in 215 patients with paraneoplastic neurologic disorders, 49 showed Zic4 antibodies but only nine patients its exclusive manifestation [6].\n\nIn conclusion, we present a rapidly progressive Zic4 antibody related PCD resulting from local SCLC. Despite considerable therapeutic efforts, the patient passed away within few weeks after symptom-onset on autonomic dysfunction. This underlines the significance of isolated Zic4 antibody associated paraneoplastic syndrome and illustrates how this particular autoimmune disorder can affect the central nervous system.\n\nAbbreviations\nAMPAR2α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor\n\nANNA-1antineuronal nuclear antibody-type 1\n\nCASPR2Contactin-associated protein 2\n\nCRMP5collapsing response mediator protein 5\n\nCSFcerebrospinal fluid\n\nCV2/CRMP5collapsin response mediator protein 5\n\nDLBCLdiffuse large B-cell lymphoma\n\nDNERDelta/notch-like epidermal growth factor-related receptor\n\nDPPXDipeptidyl-Peptidase-like Protein-6\n\nFDGfluorodeoxyglucose\n\nFLAIRfluid attenuated inversion recovery\n\nGABABRγ-aminobutyric acid-B receptor\n\nGAD65glutamic acid decarboxylase 65 kDa\n\nGLgranular layer\n\nHEhematoxylin and eosin\n\nIgGImmunoglobulin protein, subclass G\n\nIgLON5immunoglobulin-like cell adhesion molecule 5\n\nIHimmunohistochemical\n\nIVIGintravenous immunoglobulin\n\nLElimbic encephalitis\n\nLEMSLambert-Eaton myasthenic syndrome\n\nLGI1Leucine-rich, glioma inactivated 1\n\nmGluR1/5metabotropic glutamate receptor 1/5\n\nMLmolecular layer\n\nmm3cubic millimeter\n\nNMDARN-methyl-D-aspartate receptor\n\nPCDparaneoplastic cerebellar degeneration\n\nPET-CTcombined positron-emission tomography and computed tomography\n\nPuPurkinje cell layer\n\nq.d.quaque die\n\nRiNova 1 or ANNA-2 (anti-neuron-specific cell nuclear antibodies)\n\n(s)CJD(spontaneous) Creutzfeldt-Jacob disease\n\nSCLCsmall cell lung cancer\n\nSMMsmoldering multiple myeloma\n\nSox1anti-glia nuclear antibody\n\nSSNsubacute sensory neuropathy\n\nTTF-1thyroid transcription factor-1\n\nVGCCvoltage-gated calcium channel\n\nYoanti-PCA-1 (Purkinje cell antigen 1)\n\nZICzinc-finger protein of the cerebellum\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank Christian G. Bien, M.D., Bielefeld and Bad Salzuflen, Germany, for providing Fig. 1 and critical discussion of the manuscript.\n\nAuthors’ contributions\nPAL conceptualized and designed the study and analyzed and interpreted the patient data. LT conceptualized and designed the study and analyzed and interpreted the patient data. AP1 contributed to the design of the study and analyzed and interpreted the patient data regarding the SCLC histology. CIB contributed to the design of the study and analyzed and interpreted the patient data regarding the immunoblot and immunofluorescence test on mouse cerebellum. AP2 contributed to the design of the study and analyzed and interpreted the patient data regarding the 18F-FDG-PET findings. DJP conceptualized and designed the study and analyzed and interpreted the patient data. The first draft of the manuscript was written by PAL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors declare that they have not received funding to support the presented work.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nEthical approval was waived by the local Ethics Committee of University of Marburg in view of the retrospective nature of the short report and all the procedures being performed were part of the routine care.\n\nConsent for publication\nWritten informed consent for publication was obtained from nearest to kin (niece) and is available to the journal in German (a translation can be provided on request).\n\nCompeting interests\nThe authors declare that they have no conflict of interest related to the presented work.\n\nLT reports grants, personal fees and non-financial support from SAPIENS Steering Brain Stimulation, Medtronic, Boston Scientific and St. Jude medical and has received payments from Bayer Healthcare, UCB Schwarz Pharma, and Archimedes Pharma and also honoraria as a speaker on symposia sponsored by Teva Pharma, Lundbeck Pharma, Bracco, Gianni PR, Medas Pharma, UCB Schwarz Pharma, Desitin Pharma, Boehringer Ingelheim, GSK, Eumecom, Orion Pharma, Medtronic, Boston Scientific, Cephalon, Abbott, GE Medical, Archimedes, and Bayer.\n==== Refs\nReferences\n1. Dalmau J Rosenfeld MR Paraneoplastic syndromes of the CNS The Lancet Neurology 2008 7 4 327 340 10.1016/S1474-4422(08)70060-7 18339348 \n2. Peterson K Rosenblum MK Kotanides H Posner JB Paraneoplastic cerebellar degeneration. I. a clinical analysis of 55 anti-Yo antibody-positive patients Neurology 1992 42 10 1931 1937 10.1212/WNL.42.10.1931 1407575 \n3. Graus F Keime-Guibert F Rene R Benyahia B Ribalta T Ascaso C Escaramis G Delattre JY Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients Brain : a journal of neurology 2001 124 Pt 6 1138 1148 10.1093/brain/124.6.1138 11353730 \n4. Hoftberger R Rosenfeld MR Dalmau J Update on neurological paraneoplastic syndromes Curr Opin Oncol 2015 27 6 489 495 10.1097/CCO.0000000000000222 26335665 \n5. Bataller L Wade DF Fuller GN Rosenfeld MR Dalmau J Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum Neurology 2002 59 12 1985 1987 10.1212/01.WNL.0000038352.01415.CE 12499499 \n6. Bataller L Wade DF Graus F Stacey HD Rosenfeld MR Dalmau J Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer Neurology 2004 62 5 778 782 10.1212/01.WNL.0000113749.77217.01 15007130 \n7. Grinberg I Millen KJ The ZIC gene family in development and disease Clin Genet 2005 67 4 290 296 10.1111/j.1399-0004.2005.00418.x 15733262 \n8. Sabater L Bataller L Suarez-Calvet M Saiz A Dalmau J Graus F ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer J Neuroimmunol 2008 201-202 163 165 10.1016/j.jneuroim.2008.01.018 18639938 \n9. Salazar R Atypical presentation of probable Creutzfeldt-Jakob disease associated with anti-Zic4 antibody: literature review of neuronal antibodies in Creutzfeldt-Jakob disease Clin Neurol Neurosurg 2018 168 72 76 10.1016/j.clineuro.2018.02.043 29525731 \n10. Eye Philip George Wang Bin Keung Elaine S. Tagg Nathan Troy Anti-ZIC4 associated paraneoplastic cerebellar degeneration in a patient with both diffuse large B-cell lymphoma and incidental smoldering multiple myeloma Journal of the Neurological Sciences 2018 384 36 37 10.1016/j.jns.2017.11.005 29249374 \n11. Aydin C, Celik SY, Icoz S, Ulusoy C, Gunduz T, Demir GA, Kurtuncu M, Tuzun E. Prognostic factors in anti-neuronal antibody positive patients. Noro psikiyatri arsivi. 2018;55(2):189–94.\n12. Kerasnoudis A. Isolated ZIC4 antibodies in paraneoplastic cerebellar syndrome with an underlying ovarian tumor. Arch Neurol. 2011;68(8):1073.\n13. Maudes E, Landa J, Munoz-Lopetegi A, Armangue T, Alba M, Saiz A, Graus F, Dalmau J, Sabater L. Clinical significance of Kelch-like protein 11 antibodies. Neurology(R) neuroimmunology & neuroinflammation. 2020;7(3).\n\n",
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"issn_linking": "1471-2377",
"issue": "20(1)",
"journal": "BMC neurology",
"keywords": "Autoimmune Encephalitis; Case Report; Paraneoplastic Cerebellar Degeneration; Paraneoplastic Syndromes; Zic4",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D004660:Encephalitis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009419:Nerve Tissue Proteins; D020362:Paraneoplastic Cerebellar Degeneration; D054969:Primary Dysautonomias; D012249:Rhombencephalon; D055752:Small Cell Lung Carcinoma; D014157:Transcription Factors",
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"title": "Rhombencephalitis associated with isolated Zic4-antibodies in Paraneoplastic cerebellar degeneration: a case report.",
"title_normalized": "rhombencephalitis associated with isolated zic4 antibodies in paraneoplastic cerebellar degeneration a case report"
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"abstract": "There is evidence of a slight increase in malignant lymphoma among rheumatoid arthritis(RA)patients receiving methotrexate( MTX). Increased rates of lymphoma have been attributed to reactivation of the Epstein-Barr virus(EBV). A 72-yearold woman was admitted to our hospital for generalized lymph adenopathy. She suffered from RA and has been treated with MTX for 7 years; the total amount of MTX received was around 2, 700 mg. The cervical lymph node revealed a diffuse proliferation of large atypical lymphocytes. An immunophenotype revealed CD10+, CD19+, CD20+, and k+. The chromosome analysis showed a complex abnormality containing t(14;18)(q32;q21). The tumor cells were positive for EBV sequences by in situ hybridization(ISH). A rituximab containing regimen was effective, but a systemic relapse occurred 4 years later. The biopsied sample was diagnosed as diffuse large B-cell lymphoma. FISH analysis revealed positive for t(14;18)(q32;q21), however, EBV was negative using ISH. In general, the concurrence of t(14;18)(q32;q21)and EBV in the B-cell lymphoma is rare. In addition, the negative change in EBV in the relapsed lymphoma cells revealed a quite rare phenomenon.",
"affiliations": "Dept. of Internal Medicine, Matsuyama Red Cross Hospital.",
"authors": "Nakanishi|Hidehiro|H|;Muta|Tsuyoshi|T|;Oshiro|Yumi|Y|;Hida|Akira|A|;Mizuno|Yosuke|Y|;Yasunaga|Megumi|M|;Ueda|Yoko|Y|;Fujisaki|Tomoaki|T|",
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"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016393:Lymphoma, B-Cell; D008727:Methotrexate",
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"references": null,
"title": "B-cell lymphoma possessing t(14;18)(q32;q21)in a patient with rheumatoid arthritis receiving methotrexate treatment.",
"title_normalized": "b cell lymphoma possessing t 14 18 q32 q21 in a patient with rheumatoid arthritis receiving methotrexate treatment"
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"abstract": "Status asthmaticus is a severe asthma exacerbation with persistent airway obstruction despite standard therapy. Use of extracorporeal membrane oxygenation (ECMO) as rescue therapy in pregnancy is exceedingly rare. We describe a case of ECMO for treatment of status asthmaticus in woman with a periviable pregnancy culminating in a term delivery.\n\n\n\nThe patient was a 33-year-old woman, gravida 3 para 1, admitted at 23 2/7 weeks of gestation with respiratory failure secondary to status asthmaticus. Venovenous ECMO was initiated and continued for 6 days. After hospital discharge, she had no further respiratory issues. She ultimately developed fetal growth restriction and gestational hypertension and underwent a repeat cesarean delivery at 38 weeks of gestation.\n\n\n\nVenovenous ECMO can be used successfully for status asthmaticus during a periviable pregnancy and enable delivery at term.",
"affiliations": "Department of Obstetrics and Gynecology and the Division of Maternal-Fetal Medicine, Tufts Medical Center, Boston, Massachusetts.",
"authors": "Clifford|Caitlin|C|;Mhatre|Mohak|M|;Craigo|Sabrina|S|",
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"mesh_terms": "D000328:Adult; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D013224:Status Asthmaticus",
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"pubdate": "2018-10",
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"references": null,
"title": "Successful Use of Extracorporeal Membrane Oxygenation for Status Asthmaticus in a Woman With a Periviable Pregnancy.",
"title_normalized": "successful use of extracorporeal membrane oxygenation for status asthmaticus in a woman with a periviable pregnancy"
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"abstract": "Belatacept is a novel immunosuppressive agent that may be used as an alternative to calcineurin inhibitors (CNI) in immunosuppression (IS) regimens. We report two cases of pancreas transplant that were switched from tacrolimus (TAC) to belatacept. Case 1: 38-year-old female with pancreas transplant alone maintained on TAC-based IS regimen whose serum creatinine (SCr) slowly deteriorated from 0.6 mg/dL at baseline to 2.2 mg/dL, 16 months posttransplant. A native kidney biopsy performed showed CNI toxicity. The patient was started on belatacept and TAC was eliminated. Case 2: 49-year-old female with simultaneous pancreas-kidney transplant, maintained on TAC-based regimen where the SCr worsened over an initial 3-month period from a baseline of 1.0 to 3.0 mg/dL. Belatacept was started and TAC was lowered. Due to persistent graft dysfunction and kidney transplant biopsy still showing changes consistent with CNI toxicity, the TAC was then discontinued. At >1 year postbelatacept and off TAC follow-up, kidney function as measured by SCr remains stable at 1.0±0.2 mg/dL in both recipients. Neither patient developed rejection following the switch, and pancreas allograft function remains stable in both recipients.",
"affiliations": "Division of Nephrology and Transplant, Indiana University School of Medicine, Indianapolis, IN.",
"authors": "Mujtaba|M A|MA|;Sharfuddin|A A|AA|;Taber|T|T|;Chen|J|J|;Phillips|C L|CL|;Goble|M|M|;Fridell|J A|JA|",
"chemical_list": "D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D016559:Tacrolimus",
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"issue": "14(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; immunosuppression/immune modulation; kidney transplantation/nephrology; off-label drug use; pancreas/simultaneous pancreas-kidney transplantation; patient safety",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D018450:Disease Progression; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D016035:Pancreas Transplantation; D016559:Tacrolimus",
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"title": "Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients.",
"title_normalized": "conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation case report of two patients"
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"abstract": "Musical hallucinations remain a poorly understood clinical phenomenon, possibly because these types of hallucination have multiple causes and are rarely the focus of published reports. Here, the case of a 51-year-old female patient with a hearing impairment who developed musical hallucinations during treatment with ceftazidime, a third-generation cephalosporin, is presented. She responded to the discontinuation of ceftazidime and the initiation of low-dose olanzapine treatment. Musical hallucinations associated with ceftazidime are very rare, and the mechanisms underlying its occurrence remain unknown. Further studies will be necessary to determine the pathophysiology of adverse psychiatric reactions associated with ceftazidime.",
"affiliations": "Department of Otorhinolaryngology, Yonsei University College of Medicine.;Department of Psychiatry, Jeju National University School of Medicine.",
"authors": "Song|Chan Il|CI|;Jung|Young-Eun|YE|",
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"doi": "10.9758/cpn.2019.17.2.326",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 3090513510.9758/cpn.2019.17.2.326cpn-17-326Case ReportMusical Hallucination Caused by Ceftazidime in a Woman with a Hearing Impairment Song Chan Il 1Jung Young-Eun 2\n1 Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, \nKorea\n2 Department of Psychiatry, Jeju National University School of Medicine, Jeju, \nKoreaAddress for correspondence: Young-Eun Jung, MD, PhD, Department of Psychiatry, Jeju National University School of Medicine, 15 Aran 13-gil, Jeju 63241, Korea, Tel: +82-64-717-1850, Fax: +82-64-717-1849, E-mail: jyejye77@daum.net, ORCID: https://orcid.org/0000-0001-7608-00093 2019 30 4 2019 17 2 326 328 10 7 2017 31 7 2017 01 8 2017 Copyright © 2019, Korean College of Neuropsychopharmacology2019This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Musical hallucinations remain a poorly understood clinical phenomenon, possibly because these types of hallucination have multiple causes and are rarely the focus of published reports. Here, the case of a 51-year-old female patient with a hearing impairment who developed musical hallucinations during treatment with ceftazidime, a third-generation cephalosporin, is presented. She responded to the discontinuation of ceftazidime and the initiation of low-dose olanzapine treatment. Musical hallucinations associated with ceftazidime are very rare, and the mechanisms underlying its occurrence remain unknown. Further studies will be necessary to determine the pathophysiology of adverse psychiatric reactions associated with ceftazidime.\n\nCeftazidimeMusical hallucinationAdverse drug reactionHearing impairment\n==== Body\nINTRODUCTION\nMusical hallucinations, which are also known as musical hallucinosis or musical-ear syndrome, are characterized by songs, tunes, harmonics, rhythms, and/or timbers.1) The exact prevalence of musical hallucinations is unknown, although estimates as high as 2.5% have been reported in older patients with hearing impairments.2) Various types of dysfunction within an extensive network of interconnected brain areas are thought to be the potential causes of musical hallucinations, but most cases are likely due to multifactorial etiologies. The etiology of musical hallucinations can be divided into five groups: secondary to auditory deprivation, focal cerebral lesions, psychiatric pathology, epilepsy, and secondary to pharmaceuticals or metabotoxic causes.3–7)\n\nHere, the case of a patient with no personal or family history of psychiatric disorders who complained of musical hallucinations associated with the administration of ceftazidime is presented. Ceftazidime is a third-generation cephalosporin that belongs to a group of beta-lactam antibiotics used for the treatment of severe infections, particularly ciprofloxacin-resistant Pseudomonas aeruginosa infections. Ceftazidime is associated with several adverse reactions within the central nervous system, including headaches, dizziness, convulsions, manic episodes, and hallucinations.8–12) To our knowledge, this is the first report of musical hallucinations associated with ceftazidime in the absence of other neurological or psychiatric symptoms.\n\nCASE\nA 51-year-old woman presented for a consultation for bilateral otorrhea at our otorhinolaryngology department. The patient had tympanic membrane perforations and active pus discharge in both ears; a bacterial culture of the otorrhea samples showed ciprofloxacin-resistant P. aeruginosa. Computed tomography (CT) scans of the temporal bone revealed chronic otitis media in both ears. Although the patient had hearing impairments in both ears, it was possible to appropriately communicate with her because she had speech discrimination scores of 96% for both ears without hearing aids on a speech audiometry exam. Her condition was diagnosed as bilateral chronic otitis media; thus, surgery and administration of antibacterial agents were recommended as treatment. However, the patient did not want to undergo surgery and was treated only with intravenous administrations of ceftazidime (2 g/day), which is a third-generation cephalosporin effective against ciprofloxacin-resistant P. aeruginosa. The patient complained of auditory hallucinations that began 1 to 2 days after administration of ceftazidime. She had suddenly begun hearing songs with lyrics that repeated themselves indefinitely before changing into different pieces of music. In the beginning, the music was soft and did not interfere with her daily life, but the loudness of the music eventually increased, and the musical hallucinations were present from the moment she awoke until late at night.\n\nThe patient was thoroughly assessed, but neurological examinations and a brain CT scan revealed no significant abnormalities. Blood examinations, including a hemogram and liver function, kidney function, serum electrolyte, and thyroid function tests, were all within normal limits; there was no individual or family history of any psychiatric or medical illness in the index patient, and no history of substance abuse was present. A psychiatric interview and examination were unable to identify any factors responsible for the musical hallucinations other than ceftazidime. Thus, administration of ceftazidime was discontinued after 2 weeks. However, the musical hallucinations persisted, and the patient began treatment with olanzapine tablets (2.5 mg/day). During subsequent follow-up visits, the sounds decreased in intensity and did not interfere with her daily life, but were not completely resolved. As a result, the olanzapine dose was increased to 5 mg/day; but, due to increased sedation, it had to be decreased to 2.5 mg/day again. The patient was followed for approximately 6 months and she maintained improvements.\n\nDISCUSSION\nMusical hallucinations are associated with being female, hearing impairments, brain diseases affecting the non-dominant hemisphere, temporal lobe lesions, and mental disorders such as depression, schizophrenia, and obsessive-compulsive disorder.1) In the present case, the musical hallucinations were associated with moderately severe-to-severe hearing loss in the absence of other neuropsychiatric conditions. Keshavan and Schooler13) suggested that musical hallucinations derive from memory tracts, which is a concept they refer to as “parasitic memory.” It has also been suggested that musical hallucinations are the result of sensory deprivation and may be similar to the effects of sensory deprivation in patients with phantom limbs.14)\n\nPrevious studies have reported occurrences of ceftazidime-induced encephalopathy with or without hallucinations.9,10,15) The central nervous system effects associated with ceftazidime manifest primarily in elderly patients (over 60 years of age) and in patients with impaired renal function in whom the dose of ceftazidime is not appropriately adjusted. Because ceftazidime is not metabolized and is exclusively excreted by the kidney, great care should be exercised when administering ceftazidime to patients with renal disease.15) A previous report described the case of a 62-year-old woman with auditory and visual hallucinations in the absence of other psychiatric symptoms. The occurrence of hallucinations in this elderly patient was presumed to be due to the prolonged half-life of the drug attributable to impaired renal clearance.8) Compared to that case, the present patient was relatively young and did not have a renal disease. Jackson and Berkovic10) suggested that ceftazidime toxicity may result in disturbances to deep midline gray matter which, in turn, cause transient toxic peduncular hallucinosis. The patient in that case experienced vivid visual and auditory hallucinations that closely resembled the nature of peduncular hallucinosis, which is usually associated with lesions involving the deep midline gray matter of the midbrain, hypothalamus, or thalamus. Their hypothesis may not be applicable to the present case of persistent musical hallucinations that likely arose from other underlying mechanisms. However, it was impossible to determine whether the patient had any anatomical or functional lesions because she refused further evaluations with magnetic resonance imaging or an electroencephalogram.\n\nThe persistent musical hallucinations in the present patient may be attributed to delays in identifying the adverse drug reaction to ceftazidime. Although the musical hallucinations began just 1 or 2 days after administration of ceftazidime, the possible cause of the symptoms was not identified for 2 weeks, and administration of ceftazidime was continued during this time. Previous case reports determined that when ceftazidime administration was discontinued immediately after symptoms began, hallucinations subsided after several days.8–10)\n\nGeneral recommendations for the treatment of musical hallucinations have yet to be established, but a variety of therapeutic options have been tried in case reports and small case series.1) Treatments are aimed the underlying cause, if it is known, but not all patients require treatment, as musical hallucinations may be self-limiting and reassurance is often sufficient in patients with low levels of distress.1) All pharmacological treatments for idiopathic musical hallucinations are off-label, and it has been shown that some antipsychotics or acetylcholinesterase inhibitors have an effect on musical hallucinations.1,16,17)\n\nIn conclusion, it is emphasized that although musical hallucinations are very rare, clinicians should try to evaluate their existence and consider multiple pathologies. The majority of cases in which treatment has been effective depended on the resolution of the underlying cause such as suspending the responsible pharmaceuticals. However, treating musical hallucinations remains a challenge as there is currently no curative treatment. Further studies will be necessary to determine the pathophysiology, natural course, and treatment results of musical hallucinations.\n==== Refs\nREFERENCES\n1 Coebergh JA Lauw RF Bots R Sommer IE Blom JD Musical hallucinations: review of treatment effects Front Psychol 2015 6 814 10.3389/fpsyg.2015.00814 26136708 \n2 Cole MG Dowson L Dendukuri N Belzile E The prevalence and phenomenology of auditory hallucinations among elderly subjects attending an audiology clinic Int J Geriatr Psychiatry 2002 17 444 452 10.1002/gps.618 11994933 \n3 Sanchez TG Rocha SC Knobel KA Kii MA Santos RM Pereira CB Musical hallucination associated with hearing loss Arq Neuropsiquiatr 2011 69 395 400 10.1590/S0004-282X2011000300024 21625772 \n4 Golden EC Josephs KA Minds on replay: musical hallucinations and their relationship to neurological disease Brain 2015 138 3793 3802 10.1093/brain/awv286 26446167 \n5 Schielke E Reuter U Hoffmann O Weber JR Musical hallucinations with dorsal pontine lesions Neurology 2000 55 454 455 10.1212/WNL.55.3.454 10932294 \n6 Evers S Musical hallucinations Curr Psychiatry Rep 2006 8 205 210 10.1007/s11920-006-0024-0 19817070 \n7 Tomar A Cheung G Musical hallucinations induced by drugs Int Psychogeriatr 2007 19 1169 1172 10.1017/S1041610207005820 17845733 \n8 al-Zahawi MF Sprott MS Hendrick DJ Hallucinations in association with ceftazidime BMJ 1988 297 858 10.1136/bmj.297.6652.858-a 3140957 \n9 Douglas MA Quandt CM Stanley DA Ceftazidime-induced encephalopathy in a patient with renal impairment Arch Neurol 1988 45 936 937 10.1001/archneur.1988.00520330010002 3046579 \n10 Jackson GD Berkovic SF Ceftazidime encephalopathy: absence status and toxic hallucinations J Neurol Neurosurg Psychiatry 1992 55 333 334 10.1136/jnnp.55.4.333 1583528 \n11 Quandt-Herrera P Suarez-Jesus J Yelmo-Cruz S Antibiomania: Secondary mania associated with ceftazidime J Clin Psychopharmacol 2015 35 619 621 10.1097/JCP.0000000000000380 26270201 \n12 Slaker RA Danielson B Neurotoxicity associated with ceftazidime therapy in geriatric patients with renal dysfunction Pharmacotherapy 1991 11 351 352 1923920 \n13 Keshavan MS Schooler NR First-episode studies in schizophrenia: criteria and characterization Schizophr Bull 1992 18 491 513 10.1093/schbul/18.3.491 1411336 \n14 Auffarth IS Kropp S Musical hallucination in a patient after cochlear implantation J Neuropsychiatry Clin Neurosci 2009 21 230 231 10.1176/jnp.2009.21.2.230 19622701 \n15 Joseph J Vimala A Ceftazidime-induced myoclonus and encephalopathy in hemodialysis patient Indian J Nephrol 2015 25 61 62 10.4103/0971-4065.144426 25684877 \n16 Blom JD Coebergh JA Lauw R Sommer IE Musical hallucinations treated with acetylcholinesterase inhibitors Front Psychiatry 2015 6 46 10.3389/fpsyt.2015.00046 25904872 \n17 Mansoor D Ganzini L Musical hallucinations successfully treated with antipsychotic medications: three case reports Psychosomatics 2014 55 191 193 10.1016/j.psym.2013.02.004 23756119\n\n",
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"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Adverse drug reaction; Ceftazidime; Hearing impairment; Musical hallucination",
"medline_ta": "Clin Psychopharmacol Neurosci",
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"pages": "326-328",
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"title": "Musical Hallucination Caused by Ceftazidime in a Woman with a Hearing Impairment.",
"title_normalized": "musical hallucination caused by ceftazidime in a woman with a hearing impairment"
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"abstract": "Despite the efficacy of tyrosine kinase inhibitors (TKIs) across multiple cancers, side effects including treatment-related diarrhea can impede a patient's ability to reach therapeutic doses or stay on therapy. Below, we present the case of a 72-year-old patient with metastatic papillary renal cell carcinoma recurrent despite nephrectomy. Over the course of treatment, the patient received multiple different tyrosine kinase inhibitors with varying efficacy. Treatment with the TKI cabozantinib after failure of two prior TKIs resulted in a clinical response with shrinkage of his nodal metastatic disease. However, the severe treatment-related diarrhea refractory to conventional management required both dose holds and dose reductions of cabozantinib. Off-label administration of crofelemer, a novel FDA-approved antidiarrheal agent, successfully controlled the treatment-related diarrhea and allowed resumption and partial dose increase of cabozantinib. This case suggests that crofelemer could be a viable therapeutic strategy to address TKI-induced diarrhea.",
"affiliations": "Division of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.;Division of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. terence.friedlander@ucsf.edu.",
"authors": "Greene|Claire|C|;Barlesi|Brigid|B|;Tarroza-David|Sigrid|S|;Friedlander|Terence|T|http://orcid.org/0000-0002-3630-4941",
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"doi": "10.1007/s40487-021-00147-3",
"fulltext": "\n==== Front\nOncol Ther\nOncol Ther\nOncology and Therapy\n2366-1070\n2366-1089\nSpringer Healthcare Cheshire\n\n33826111\n147\n10.1007/s40487-021-00147-3\nCase Report\nImproved Control of Tyrosine Kinase Inhibitor-Induced Diarrhea with a Novel Chloride Channel Modulator: A Case Report\nGreene Claire 1\nBarlesi Brigid 2\nTarroza-David Sigrid 2\nhttp://orcid.org/0000-0002-3630-4941\nFriedlander Terence terence.friedlander@ucsf.edu\n\n1\n1 grid.266102.1 0000 0001 2297 6811 Division of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California USA\n2 grid.266102.1 0000 0001 2297 6811 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California USA\n7 4 2021\n7 4 2021\n6 2021\n9 1 247253\n15 1 2021\n6 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nDespite the efficacy of tyrosine kinase inhibitors (TKIs) across multiple cancers, side effects including treatment-related diarrhea can impede a patient’s ability to reach therapeutic doses or stay on therapy. Below, we present the case of a 72-year-old patient with metastatic papillary renal cell carcinoma recurrent despite nephrectomy. Over the course of treatment, the patient received multiple different tyrosine kinase inhibitors with varying efficacy. Treatment with the TKI cabozantinib after failure of two prior TKIs resulted in a clinical response with shrinkage of his nodal metastatic disease. However, the severe treatment-related diarrhea refractory to conventional management required both dose holds and dose reductions of cabozantinib. Off-label administration of crofelemer, a novel FDA-approved antidiarrheal agent, successfully controlled the treatment-related diarrhea and allowed resumption and partial dose increase of cabozantinib. This case suggests that crofelemer could be a viable therapeutic strategy to address TKI-induced diarrhea.\n\nKeywords\n\nCrofelemer\nDiarrhea\nRenal cell carcinoma\nTargeted therapy-induced diarrhea\nTyrosine kinase inhibitor\nNapo Pharmaissue-copyright-statement© The Author(s) 2021\n==== Body\nKey Summary Points\n\nWhy carry out this study?\t\nIn cancer patients, diarrhea is a common problem that can result from cancer itself or as a side effect of treatment, and can often impede the ability to achieve therapeutic doses of therapy.\t\nDespite the efficacy of tyrosine kinase inhibitors (TKIs) for the treatment of a range of cancers, side effects including treatment-related diarrhea can impede a patient’s ability to reach therapeutic doses or stay on therapy.\t\nIn this case study, we investigated the outcomes of using crofelemer, a treatment approved for symptomatic relief of noninfectious diarrhea in adult patients living with HIV/AIDS receiving antiretroviral therapy, to treat TKI-induced diarrhea in a 72-year-old male patient with papillary renal cell carcinoma (pRCC).\t\nWhat was learned from the study?\t\nIn this case study, we present a 72-year-old male patient with papillary renal cell carcinoma (pRCC) who experienced TKI-induced diarrhea that was successfully treated crofelemer, a treatment approved for use in patients with HIV-related diarrhea.\t\nThis case provides initial evidence that crofelemer can help control diarrhea in pRCC patients receiving cabozantinib.\t\nGoing forward, further studies, ideally using a randomized, controlled design, will be required to best ascertain the role of crofelemer in treating targeted therapy-induced diarrhea (TTID) in cancer patients receiving TKIs.\t\n\nDigital Features\n\nThis article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.14170604.\n\nCase Presentation\n\nA 72-year-old man was incidentally found to have renal insufficiency during a primary care visit. Computerized tomography revealed a right renal mass and bulky retroperitoneal and mediastinal lymphadenopathy suggestive of metastatic renal cell carcinoma (RCC). A right radical nephrectomy revealed a 12.1 cm, Fuhrman grade 3 papillary RCC (pRCC) with perirenal and sinus fat invasion.\n\nTwo months after surgery, the patient started pazopanib 800 mg daily, a tyrosine kinase inhibitor (TKI) approved for the first-line treatment of metastatic RCC (Fig. 1). This was discontinued after 2 months due to unexpected acute renal failure that required temporary hemodialysis. Second-line treatment with axitinib 5 mg BID was poorly tolerated, with persistent diarrhea, somnolence, cough, difficult-to-control hypertension and worsening renal function. Therefore, axitinib treatment was halted after 1 month. A CT scan 1 month later showed disease progression in the retroperitoneum, mediastinum, and cervical lymph nodes.Fig. 1 Timeline showing the patient’s course of TKI and diarrhea-related treatment\n\nHe then received the anti-PD-1 antibody nivolumab 240 mg every 2 weeks starting 2 months after axitinib cessation. Though this treatment was well tolerated for 3 months, it had limited efficacy, with disease progression on positron emission tomography/computed tomography (PET/CT), and fine needle aspiration of a new soft tissue mass in the nasopharynx showed progressive pRCC.\n\nTwo months after cessation of nivolumab, the patient was started on the TKI cabozantinib at a dose of 60 mg daily. However, in less than 2 months, the treatment had to be halted due to grade 3 diarrhea that was refractory to both loperamide and atropine-diphenoxylate treatment. Cabozantinib was restarted at full dose 5 days later, but was halted again less than a month later due to diarrhea. Despite the poor tolerance of cabozantinib, restaging PET/CT approximately 5 months after the initiation of therapy showed interval decrease in some of the lymph nodes. Consequently, cabozantinib was restarted at a lower dose of 40 mg daily; however, persistent diarrhea necessitated a further dose reduction to 20 mg daily. PET/CT after a month showed interval decrease in size and hypermetabolism of the metastatic disease (Fig. 2). Four months later, however, new hypermetabolic lymphadenopathy developed, and the cabozantinib dose was raised to 40 mg daily. A month later, the cabozantinib was halted once again due to recurrence of grade 2 diarrhea.Fig. 2 a PET/CT scan conducted on June 2016 showed significant hypermetabolism with a metastatic mass (yellow arrow) measuring 59.0 mm. b PET/CT scan conducted on September 2016 displayed reduced hypermetabolism and the metastatic mass measuring 56.8 mm\n\nTreatment cessation for 2 days improved diarrhea, but shortly thereafter the patient’s condition worsened. Despite being administered diphenoxylate/atropine and tincture of opium (up to 6 mg daily as needed), the patient had episodes of emesis and required hospitalization for dehydration. Workup showed no evidence of clostridium difficile infection, and stool studies including an ova and parasite analysis were negative.\n\nAt this point, the providers discussed starting the antidiarrheal crofelemer, given its approval for patients with HIV-related diarrhea. The patient started taking 125 mg BID crofelemer and, within 1 week, his diarrhea ceased and bowel function normalized. Concurrent with crofelemer, the cabozantinib dose was increased to 40 mg daily, which the patient tolerated with normal stools. After 2 weeks on crofelemer, the patient was well-nourished, reported feeling better, and had no acute distress. Given the excellent control of diarrhea with crofelemer, cabozantinib was increased to the original 60 mg daily dose. Although the patient had to occasionally skip cabozantinib doses and supplement with diphenoxylate/atropine or tincture of opium, the diarrhea was overall better controlled. Due to breakthrough diarrhea after 4 months, the cabozantinib dose was decreased to 40 mg daily. One month later, new bony lesions and abdominal carcinomatosis were found on CT, and both cabozantinib and crofelemer were discontinued due to disease progression. Despite subsequent systemic therapy including erlotinib and bevacizumab, the disease worsened, and 3 months later the patient passed away.\n\nAfter his passing, his next of kin provided consent for publication of this case, and this reporting is in compliance with UCSF Institutional Review Board guidelines for case reporting.\n\nDiscussion\n\nPapillary RCC is a relatively uncommon cancer for which the optimal therapy is not known. Given the significant clinical activity of TKIs for clear-cell RCC, a number of studies have shown that some pRCC patients benefit from TKI therapy [1–3]. Consistent treatment with uninterrupted therapeutic doses is essential to optimize patient outcomes. In addition, studies have shown that maximizing TKI doses may confer better anti-tumor activity, although may cause more side effects. For example, in a randomized study of 112 RCC patients, increasing the axitinib dose from 5 to 7 mg BID resulted in both a higher response rate, but more treatment-related toxicity [4].\n\nDiarrhea is a common side effect of many TKIs; however, it is not well understood and is thought to be due to their impact on the bowel epithelium as a result of their vascular endothelial growth factor receptor/epidermal growth factor receptor (VEGFR/EGFR) inhibition, poor intestinal epithelial healing leading to mucosal atrophy [5], alteration of chloride secretion, upregulation of inflammation, and other factors [6, 7] (Fig. 3). Diarrhea occurs in 50–80% of patients [8] and can be subdivided into chemotherapy-induced diarrhea (CID), radiotherapy-induced diarrhea (RID) and targeted therapy-induced diarrhea (TTID) [8, 9]. TTID caused by targeted agents such as epidermal growth factor or tyrosine kinase inhibitors impacts the patient’s health overall and their ability to get anticancer treatment [8] and can often impede the ability to achieve effective doses of therapy, either by requiring treatment holidays or dose reductions [10]. In one study of patients with colorectal cancer, treatment-related diarrhea led to dose reduction in 9.5% of the patients [11]. Additionally, a change in regimen and chemotherapy cessation were required in 15.9% and 34.2% of patients, respectively [11].Fig. 3 a Chloride ion channels in the intestinal lumen (CFTR and CACC) help to regulate the fluid and electrolyte balance in the GI tract. b Tyrosine kinase inhibitors can inhibit EGFR, and activate both basolateral membrane potassium (K+) channels and apical membrane CFTR channels in intestinal epithelia, leading to an imbalance of fluid and electrolytes in the GI tract and causing diarrhea. c Crofelemer regulates CFTR and CACC channels to normalize the balance of fluid and electrolytes, resolving symptoms of TKI-induced diarrhea\n\nPharmacological strategies to manage TTID include the use of loperamide or tincture of opium as a first-line treatment and octreotide as second line [10]. Loperamide and tincture of opium are both opioids that reduce diarrhea by impeding gastrointestinal (GI) motility to delay gastric emptying time [10]. Unfortunately, opioids have high addiction liability [12], and their impact on GI motility can lead to constipation [13]. Second-line octreotide increases intestinal transit time by reducing the secretion of vasoactive intestinal peptide [12]. Octreotide requires TID injections, so both cost and administration logistics are not insignificant [14]. Given the limitations of these current treatment options and the profound impact on cancer treatment, TTID represents a major unmet need.\n\nCrofelemer is a Food and Drug Administration (FDA)-approved drug for symptomatic relief of noninfectious diarrhea in adult patients living with HIV/AIDS receiving antiretroviral therapy [15]. Unlike other medications used for diarrhea, crofelemer exerts its antisecretory effects by negatively modulating the CFTR chloride channel and calcium-activated chloride channel at the luminal membrane of enterocytes [16] (Fig. 3). This novel mechanism of action helps restore the fluid and electrolyte balance in the GI tract, leading to symptomatic relief of noninfectious chronic diarrhea in adult HIV/AIDS patients and avoids the development of constipation often observed with opioids. Crofelemer also has negligible oral bioavailability, thus keeping the drug localized to the GI tract and minimizing any significant drug–drug interactions [15].\n\nOur case study presents the off-label use of crofelemer in a 72-year-old patient with metastatic pRCC. We were unable to treat him with cabozantinib at the maximal recommended doses due to treatment-related diarrhea refractory to standard measures including loperamide, tincture of opium and diphenoxylate/atropine. With the administration of crofelemer, bowel function normalized and the cabozantinib dose was able to be increased to the daily recommended dose of 60 mg daily. While ultimately still difficult to control, it is important for clinicians to be aware of this agent when facing difficult choices in treating patients with TKI therapy.\n\nTo date, there are over 40 protein kinase inhibitors approved by the FDA for oncological indications [2]. With the increasing frequency of use of kinase inhibitors in cancer treatment, crofelemer may have the potential for wider antidiarrheal applicability in other malignancies being treated with targeted therapies. With fewer interruptions to anticancer treatment regimens due to diarrhea, better clinical outcomes may be possible. This case provides initial evidence that crofelemer can help control diarrhea in pRCC patients with TTID, including those receiving cabozantinib. Going forward, further studies, ideally using a randomized, controlled design, will be required to best ascertain the role of crofelemer in treating TTID in cancer patients receiving TKIs.\n\nAcknowledgements\n\nWe thank the family of the patient for providing consent to report the history here.\n\nFunding\n\nThis case study was supported by Napo Pharmaceuticals, Inc., including funding of the Journal’s Rapid Service Fee.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nThe authors (CG, BM, STD, and TF) have no personal, financial, commercial or academic conflicts of interest to disclose.\n\nCompliance with Ethics Guidelines\n\nThe use of crofelemer was consistent with medical treatment as per FDA guidelines, and was not considered clinical research; therefore, IRB approval was not required. The patient’s next of kin provided consent for publication of this case after his passing and prior to manuscript preparation. The data reported here comply with UCSF Institutional Guidelines for decedent case reporting without protected health information.\n==== Refs\nReferences\n\n1. Campbell MT Bilen MA Shah AY Lemke E Jonasch E Venkatesan AM Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis Eur J Cancer 2018 104 188 194 10.1016/j.ejca.2018.08.014 30380460\n2. Ciccarese C Iacovelli R Brunelli M Massari F Bimbatti D Fantinel E Addressing the best treatment for non-clear cell renal cell carcinoma: A meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies Eur J Cancer 2017 83 237 246 10.1016/j.ejca.2017.06.030 28756136\n3. Martínez Chanzá N Xie W Asim Bilen M Dzimitrowicz H Burkart J Geynisman DM Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study Lancet Oncol 2019 20 4 581 590 10.1016/S1470-2045(18)30907-0 30827746\n4. Rini BI Melichar B Ueda T Grünwald V Fishman MN Arranz JA Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial Lancet Oncol 2013 14 12 1233 1242 10.1016/S1470-2045(13)70464-9 24140184\n5. Bowen JM Mechanisms of TKI-induced diarrhea in cancer patients Curr Opin Support Palliat Care 2013 7 2 162 167 10.1097/SPC.0b013e32835ec861 23399616\n6. Hirsh V Blais N Burkes R Verma S Croitoru K Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors Curr Oncol 2014 21 6 329 336 10.3747/co.21.2241 25489260\n7. Secombe KR Van Sebille YZA Mayo BJ Coller JK Gibson RJ Bowen JM Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome Integr Cancer Ther 2020 10.1177/1534735420928493 32493068\n8. Cherny NI Evaluation and management of treatment-related diarrhea in patients with advanced cancer: a review J Pain Symptom Manage 2008 36 4 413 423 10.1016/j.jpainsymman.2007.10.007 18411014\n9. Benson AB Ajani JA Catalano RB Engelking C Kornblau SM Martenson JA Recommended guidelines for the treatment of cancer treatment-induced diarrhea J Clin Oncol 2004 22 14 2918 2926 10.1200/JCO.2004.04.132 15254061\n10. Ippoliti C Antidiarrheal agents for the management of treatment-related diarrhea in cancer patients Am J Health Syst Pharm 1998 55 15 1573 1580 10.1093/ajhp/55.15.1573 9706182\n11. Maroun JA Anthony LB Blais N Burkes R Dowden SD Dranitsaris G Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea Curr Oncol 2007 14 1 13 20 10.3747/co.2007.96 17576459\n12. Volkow ND Jones EB Einstein EB Wargo EM Prevention and Treatment of Opioid Misuse and Addiction: A Review JAMA Psychiatry 2019 76 2 208 216 10.1001/jamapsychiatry.2018.3126 30516809\n13. McQuade RM Stojanovska V Abalo R Bornstein JC Nurgali K Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments Front Pharmacol 2016 3 7 414\n14. Stein A Voigt W Jordan K Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management Ther Adv Med Oncol 2010 2 1 51 63 10.1177/1758834009355164 21789126\n15. Patel TS Crutchley RD Tucker AM Cottreau J Garey KW Crofelemer for the treatment of chronic diarrhea in patients living with HIV/AIDS HIV AIDS (Auckl) 2013 15 5 153 162\n16. Tradtrantip L Namkung W Verkman AS Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels Mol Pharmacol 2010 77 1 69 78 10.1124/mol.109.061051 19808995\n\n",
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"title": "Improved Control of Tyrosine Kinase Inhibitor-Induced Diarrhea with a Novel Chloride Channel Modulator: A Case Report.",
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"abstract": "Anterocollis is a type of cervical dystonia characterized by simultaneous and repetitive antagonist muscles contractions, resulting in abnormal neck flexion. It was described with a frequency of 6.8% from 399 patients with diagnosis of cervical dystonia and usually coexists with torticollis and/or laterocollis, as mixed cervical dystonia patterns. Botulinum toxin is usually a practical and effective treatment for cervical dystonia. The target muscles to inject in anterocollis are usually sternocleidomastoid and scalene muscles. There is also a case report suggesting longus collis involvement. Nevertheless, the dosage of the medication in anterocollis is limited by frequent side effects of dysphagia. We described 2 cases of refractory anterocollis. They did not benefit from conventional bilateral upper portion of sternocleidomastoid muscle injections with OnabotulinumtoxinA, but notably improved their symptoms and clinical global impression after switching to injections into bilateral lower portion of sternocleidomastoid muscles, without significant side effects.",
"affiliations": "*Department of Neurology, Center for Movement Disorders & Neurorestoration, Gainesville, FL †ATIX Foundation ‡Faculty of Medicine, University for Development, Las Condes, Santiago, Chile.",
"authors": "Peng-Chen|Zhongxing|Z|;Thompson|Amanda|A|;Rodriguez|Ramon L|RL|",
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"title": "Bilateral Lower Sternocleidomastoid Botulinum Toxin Injections to Address Refractory Anterocollis.",
"title_normalized": "bilateral lower sternocleidomastoid botulinum toxin injections to address refractory anterocollis"
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"abstract": "Hepatitis C virus (HCV) infection is a major public health concern worldwide, raising important medical and economic issues. HCV-related end-stage liver disease is one of the most common indications for hepatic transplantation. Chronic hepatitis C is also assimilated to a systemic disease because of multiple extrahepatic manifestations, including lymphoproliferative disorders. The revolution of HCV treatment with the advent of direct-acting antivirals has significantly improved the management with high antiviral efficacy and good safety profile compared with old regimens, thus allowing good outcomes on hepatic and extrahepatic symptoms. However, with the widespread use of these new agents, controversial concerns about unexpected increasing cases of hepatocellular carcinoma were reported. We now report the case of a patient presenting with HCV-related cirrhosis, treated with direct-antiviral therapy and diagnosed with primary hepatic lymphoma shortly after the end of the treatment.",
"affiliations": "Hepato-gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia.;Hepato-gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia ayari.myriam@hotmail.fr.;Radiology, Charles Nicolle Hospital, Tunis, Tunisia.;Medical Oncology, Institut Salah-Azaïz, Tunis, Tunisia.;Hepato-gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia.;Hepato-gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia.;Radiology, Charles Nicolle Hospital, Tunis, Tunisia.",
"authors": "Zaimi|Yosra|Y|;Ayari|Myriam|M|0000-0001-7361-8248;Cherifi|Walid|W|;Letaief Ksontini|Feryel|F|;Ayadi|Shema|S|;Bel Hadj Mabrouk|Emna|E|;Jrad|Myriam|M|",
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"fulltext": "\n==== Front\nBMJ Open Gastroenterol\nBMJ Open Gastroenterol\nbmjgast\nbmjgast\nBMJ Open Gastroenterology\n2054-4774\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbmjgast-2021-000721\n10.1136/bmjgast-2021-000721\nHepatology\n1506\nPrimary hepatic large B-cell lymphoma following direct-acting antiviral treatment for hepatitis C\nZaimi Yosra 1\nhttp://orcid.org/0000-0001-7361-8248\nAyari Myriam 1\nCherifi Walid 2\nLetaief Ksontini Feryel 3\nAyadi Shema 1\nBel Hadj Mabrouk Emna 1\nJrad Myriam 2\n1 Hepato-gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia\n2 Radiology, Charles Nicolle Hospital, Tunis, Tunisia\n3 Medical Oncology, Institut Salah-Azaïz, Tunis, Tunisia\nCorrespondence to Dr Myriam Ayari; ayari.myriam@hotmail.fr\n2021\n16 8 2021\n8 1 e00072108 6 2021\n01 8 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nHepatitis C virus (HCV) infection is a major public health concern worldwide, raising important medical and economic issues. HCV-related end-stage liver disease is one of the most common indications for hepatic transplantation. Chronic hepatitis C is also assimilated to a systemic disease because of multiple extrahepatic manifestations, including lymphoproliferative disorders. The revolution of HCV treatment with the advent of direct-acting antivirals has significantly improved the management with high antiviral efficacy and good safety profile compared with old regimens, thus allowing good outcomes on hepatic and extrahepatic symptoms. However, with the widespread use of these new agents, controversial concerns about unexpected increasing cases of hepatocellular carcinoma were reported. We now report the case of a patient presenting with HCV-related cirrhosis, treated with direct-antiviral therapy and diagnosed with primary hepatic lymphoma shortly after the end of the treatment.\n\nHCV\nantiviral therapy\nlymphoma\ncirrhosis\nspecial-featureunlocked\n==== Body\nIntroduction\n\nHepatitis C virus (HCV) is a lymphotropic, hepatotropic virus and one of the major causes of chronic liver disease. In addition to the risk of progression to cirrhosis and its related complications, HCV exposes also to extrahepatic manifestations such as lymphoproliferative disorders ranging from benign to aggressive lymphoma, leading to significant morbidity and mortality. Currently, there is no effective vaccine against HCV. Nevertheless, the development of direct-acting antivirals (DAAs) has revolutionised the treatment of hepatitis C with sustained virological response (SVR) rates >90% in all genotypes. Viral eradication can prevent, stabilise or even regress liver fibrosis lesions and portal hypertension, thus reducing chronic liver disease complications. Besides, antiviral treatment may allow the regression of extrahepatic manifestations related to HCV. This revolution in the management of patients with chronic hepatitis C has nurtured, consequently, the hope that hepatic carcinogenesis risk would significantly decrease. Yet, concerns were expressed, noting increasing reported cases of hepatocellular carcinoma (HCC) after antiviral treatment, thus generating a long debate these recent years. However, there are very scant reports regarding hepatic lymphoma, an uncommon liver tumour, occurring after viral clearance with DAAs. Herein, we report a case of patient with HCV-related cirrhosis, treated successfully with sofosbuvir/ribavirin regimen and developing a primary hepatic lymphoma shortly thereafter.\n\nCase presentation\n\nA 58-year-old Caucasian man was diagnosed with Child A5 cirrhosis secondary to chronic hepatitis C genotype 2 infection in August 2019. Medical history included only epilepsy well controlled with lamotrigine. Family medical history was irrelevant. The patient did not take any other medications and did not consume any alcohol, herbs or toxics. Laboratory findings showed normal haemoglobin of 136 g/L, normal platelet level, normal albumin level and hypocholesterolaemia of 3.65 mmol/L. Hepatic tests indicated only elevated transaminases—aspartate aminotransferase of 60 U/L and alanine aminotransferase of 490 U/L—and slightly elevated international normalised ratio of 1.3 (normal range 0.8–1.2). There was no cholestasis. Laboratory blood analysis results are summarised in table 1. His fibroscan showed a median of 13 kPa, correlating to a fibrosis score of F4. On upper endoscopy, the patient presented grade 2 oesophageal varices and gastric varices GOV II. Primary prophylaxis of variceal bleeding was initiated with propranolol. The viral load (HCV RNA) was 1.7×105 UI/mL. Abdominal ultrasound performed just before antiviral therapy showed dysmorphic liver without focal lesions and collateral circulation. DAA therapy based on 24 weeks of sofosbuvir and ribavirin regimen was initiated on August 2019. Serum HCV RNA levels rapidly decreased, and SVR was successfully achieved without any adverse events. As part of HCC screening, ultrasound was repeated by the end of January 2020, shortly after the end of antiviral treatment, revealing many hypoechogenic nodules mainly in the right liver lobe. The patient was asymptomatic. On physical examination, there was only hepatomegaly without evidence of ascites, and peripheral lymph nodes were not enlarged. Multifocal HCC or hepatic metastases were suspected and thoraco-abdomino-pelvic CT scan was performed, detecting multiple lesions (figure 1) arising from the right hepatic lobe, of which the largest was in segment VII measuring 42.5×35 mm. Enhancement of these lesions was heterogeneous after contrast injection without arterial hypervacularisation or washout. There was no evidence of any primary tumour, adenopathies or other pathological findings. The patient, then, underwent a contrast MRI of the abdomen, confirming the presence of multiple nodules mainly in the right lobe. These lesions were hyperintense in T2‐weighted imaging and hypointense in T1‐weighted imaging without contrast enhancement on the arterial phase and with hypointense appearance on the portal phases (figure 2). These features ruled out HCC typical behaviour. Upper endoscopy and colonoscopy done while investigating malignancy showed no potential digestive tumour. Tests for serum tumour markers including alpha-fetoprotein, carcinoembryonic antigen and cancer antigen 19‐9 showed normal values. As imaging, laboratory and endoscopic work-up were unremarkable, it was decided to perform ultrasound-guided biopsy. After a first attempt showing only fibroinflammatory lesions suggesting pseudo-inflammatory tumour, percutaneous core-needle biopsy was repeated a second time. Histological examination with immunohistochemical study concluded a large B-cell lymphoma with positive CD20 staining and negative CD5 and CD3 (figure 3). The proliferation factor measured by Ki67 was very high. Gene mutation study indicated non-double-hit profile (BCL2+/MYC−). Position emission tomography scan could not be performed due to difficulties in accessibility and being unavailable in our institution. As part of the disease assessment, bone marrow biopsy and lumbar punction were performed and excluded bone marrow and central nervous system affection. Serological markers of Epstein-Barr virus, herpes simplex virus and HIV were negative. The patient presented with good performance status (PS1) and thus received six cycles of immunochemotherapy with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone). Follow-up imaging after treatment has shown partial response of the disease according to the CHESON criteria, characterised by a decrease in the target tumour volume estimated at 77% with appearance of a large amount of ascites. There was no newly appearing suspicious lesion.\n\nFigure 1 Abdominal CT scan views showing dysmorphic liver with lobulated contours and multiple nodular hepatic lesions of different sizes (arrows).\n\nFigure 2 MRI axial sequences centred on the largest lesion. Nodule straddling segments VI and VII of the liver showing heterogeneous hypersignal on T2-weighted image (A) and spontaneous hyposignal on T1-weighted image (B) without washin at the arterial time (C) or washout at the portal time (D).\n\nFigure 3 Liver tumour histopathology. H&E examination at ×200 magnification showing dense B-cell lymphoepithelial infiltration of hepatic parenchyma (A). Immunochemistry staining revealing positive CD20 (B) and negative CD5 (C).\n\nTable 1 Laboratory blood test results\n\nBlood test\tResult\tReference range\t\nWhite blood cell count (/mm³)\t4300\t4000–10 000\t\nNeutrophils (/mm³)\t1849\t1500–7000\t\nLymphocytes (/mm³)\t2150\t1500–4000\t\nMonocytes (/mm³)\t172\t200–800\t\nEosinophils (/mm³)\t129\t<400\t\nBasophils (/mm³)\t0\t<100\t\nRed blood cell count (millions/mm³)\t4.3\t4.2–5.7\t\nHaemoglobin (g/L)\t139\t13–17\t\nHaematocrit (%)\t41\t40–52\t\nPlatelets (billion/L)\t169\t150–400\t\nLactate dehydrogenase (U/L)\t150\t140–280\t\nAlbumin (g/dl)\t36\t35–45\t\nTotal protein (g/L)\t72\t60–80\t\nCholesterol (mmol/L)\t3.65\t4.14–5.18\t\nProthrombin time (%)\t60\t70–100\t\nAspartate aminotransferase (U/L)\t60\t<40\t\nAlanine aminotransferase (U/L)\t490\t<40\t\nGamma-glutamyl transpeptidase (U/L)\t41\t10–50\t\nAlkaline phosphatase (IU/L)\t92\t40–130\t\nTotal bilirubin (mg/dL)\t10\t0.3–1.2\t\n\nDiscussion\n\nHepatitis C is a major public health concern throughout the world, exposing the patient to possible complications related to portal hypertension and liver failure, as well as to the risk of malignancy and extrahepatic manifestations. Recently, the development of new direct antiviral molecules directed against the three major HCV targets (NS3/4A protein, NS5B protein and NS5A protein) has significantly improved the management of chronic hepatitis C with short ‘interferon-free’ treatment regimens that provide an SVR of up to 90%–100% and few adverse effects.\n\nPrimary hepatic lymphoma (PHL) occurring after antiviral therapy is rather uncommon and only discussed in minimal previous reports in the literature. PHL is a very rare malignancy and reported as case reports in the literature, mostly corresponding to large B-cell type. There are even few available data on PHL occurring after DAA therapy, and to the best of our knowledge, there are only two cases reporting this association in the literature.1 2 The issues raised about HCC following DAA therapy, which led to an avalanche of studies with contradictory findings, make these anecdotal observations more disquieting.\n\nThe suppression of HCV viral replication would allow, in most cases, a regression of HCV-related extrahepatic symptoms, and thus antiviral treatment should be considered without delay in patients with clinically significant extrahepatic manifrstations. However, as to the effect of antiviral therapy on lymphoproliferative disorders, data are still quite contradictory. Although treatment with interferon regimen was reported to reduce the risk of lymphoma, El-Serag et al have recently shown in a large cohort that successful DAA treatment resulting in SVR was not associated with significant risk reductions in non-Hodgkin’s lymphoma.3 Moreover, in terms of immune response, data showed that DAA treatment can be effective as to reducing the frequency of pathological B cells in the peripheral blood of HCV seropositive patients, but monoclonal populations can persist after viral eradication.4 Hence, this suggests that DAAs might have a lower antilymphoma activity than interferon therapy, which acts as an immunological modulator, explaining that the development of malignant lymphomas may occur after HCV clearance with the new drugs.\n\nBesides, escaping from immune surveillance due to a decrease in virus-induced inflammation, as it has been hypothesised with HCC after DAA use, may lead to uncontrolled proliferation of malignant clone. Lymphomagenesis could be initiated by the relief of lymphoma cell inhibition from sustained HVC signal stimulation after viral clearance.\n\nMoreover, DAA administration was associated with increased serum vascular endothelial growth factor (VEFG), and consequently, this may cause imbalance of the antitumor surveillance of the host.5 Interestingly, VEFG is also found to be overexpressed and to play a role in the progression of non-Hodgkin’s lymphoma.6 This mechanism could be a rational of lymphomagenesis.\n\nIn our case, the diagnosis made immediately at the end of the treatment could be considered as a very short period for the development of hepatic lymphoma and may suggest unrecognised lymphoma. However, the fact that the patient was in a good condition and that there was no evidence of hepatic mass or malignancy on ultrasound just before the therapy suggests that hepatic lymphoma may be linked to the prescribed antiviral therapy. Currently, there is no clear evidence supporting the relationship between PHL and DAAs due to its rarity, and the possible mechanisms mentioned should be evoked and investigated in further studies.\n\nRegarding the diagnosis of PHL, it may be challenging as it is not only an extremely rare tumour but also often misdiagnosed. Careful work-up and follow-up are mandatory to exclude primary disease elsewhere. Clinical manifestations, laboratory findings and imaging features are usually non-specific, making it difficult to distinguish from other more common hepatic tumours such as HCC, especially in a context of cirrhosis treated by DAAs, or metastatic disease when presenting with multiple nodules, as it is in our case. Thus, definitive diagnosis requires liver biopsy with immunohistochemical staining, which is essential for subtype determination, and this should be repeated if the first attempt is unremarkable.\n\nIn conclusion, we reported an extremely rare case of PHL occurring in patient with HCV-related cirrhosis shortly after viral clearance with sofosvubir and ribavirin. This report raises the issue about the possible development of hepatic lymphoid malignancy despite successful HCV treatment with DAAs. There is currently no clear evidence of the role of interferon-free antiviral treatment on hepatic lymphomagenesis; therefore, caution is needed before drawing final conclusions. Nevertheless, physicians should be aware of the risk during and after direct antiviral therapy for better monitoring, rapid diagnosis and early management.\n\nWe express our gratitude to the staff at Charles Nicolle Hospital who were involved in the patient care.\n\nData availability statement\n\nAll data relevant to the study are included in the article or uploaded as supplementary information. All data are available as part of the article and no additional source data are required.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nTwitter: @Myriam__Ayari\n\nContributors: YZ and MA gathered the information, was involved in the definition of intellectual content and literature search, and wrote the manuscript. WC and MJ extracted and interpreted radiological data. FLK assisted in the preparation of the manuscript. SA and EBHM contributed to the critical review of the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nEthics statements: Written consent was obtained from the patient.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 AndradeXA, PazLH, NassarMo''ath, et al . Primary liver diffuse large B-cell lymphoma following complete response for hepatitis C infection after direct antiviral therapy. Acta Haematol 2018;139 :77–80. 10.1159/000484653 29393087\n2 ShimagakiT, MaedaT, KinjoN, et al . Primary hepatic follicular lymphoma 5 years post sustained virological response from hepatitis C viral infection. J Clin Pathol 2021;74 :e3. 10.1136/jclinpath-2020-206469 32792415\n3 El-SeragHB, ChristieIC, PuenpatomA, et al . The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection. Aliment Pharmacol Ther 2019;49 :1442–7. 10.1111/apt.15240 30932218\n4 SchiavinatoA, ZanettoA, PantanoG, et al . Polyclonal and monoclonal B lymphocytes response in HCV-infected patients treated with direct-acting antiviral agents. J Viral Hepat 2017;24 :1168–76. 10.1111/jvh.12746 28643451\n5 VillaniR, FacciorussoA, BellantiF, et al . DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for tumor risk during anti-HCV treatment. PLoS One 2016;11 :e0167934. 10.1371/journal.pone.0167934 27997563\n6 YangJ, LiW, HeX, et al . Vegf overexpression is a valuable prognostic factor for non-Hodgkin's lymphoma evidence from a systemic meta-analysis. Dis Markers 2015;2015 :1–9. 10.1155/2015/786790\n\n",
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"mesh_terms": "D000998:Antiviral Agents; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008113:Liver Neoplasms; D016403:Lymphoma, Large B-Cell, Diffuse",
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"title": "Primary hepatic large B-cell lymphoma following direct-acting antiviral treatment for hepatitis C.",
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"abstract": "The death of a female anaesthesiologist is reported. Although the situation at the scene indicated propofol overdose-related death, self-administration of such high doses of propofol was unlikely, given the pharmacological properties of this drug. The analysis of the situation at the scene and the toxicological analysis in which the blood and liver propofol concentrations were 2.40microg/ml and 0.56microg/g, respectively, supported the conclusion that the death was a consequence of propofol self-administration at therapeutic doses from a person who used the drug on chronic basis seeking to its euphoric effects. However, because the toxic concentrations of propofol in non-intubated patients may be different from those intubated and fully supported in the operating room or in the intensive care unit, a mere interpretation of the blood and tissue concentrations of propofol in the toxicological analysis can confirm the drug intake but it may be of limited diagnostic significance without taking into account this difference.",
"affiliations": "Department of Forensic Sciences, Medical School, University of Crete 71110, Heraklion, Greece.",
"authors": "Kranioti|Elena F|EF|;Mavroforou|Anna|A|;Mylonakis|Panagiotis|P|;Michalodimitrakis|Manolis|M|",
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... |
{
"abstract": "Although transient hypocalcemia following kidney transplantation can occur, severe refractory hypocalcemia is uncommon. We report a case of a 31-yr-old highly sensitized man with end-stage renal disease caused by reflux nephropathy, who received an expanded criteria deceased donor kidney transplant. The post-transplant course was significant for profound hypocalcemia despite treatment with large doses of calcium and vitamin D, in the setting of severe hypoparathyroidism following a subtotal parathyroidectomy three yr prior to the transplant. His course was also complicated by suboptimal allograft function with significant new vascular changes seen in the allograft biopsy by seven wk post-transplant. Teriparatide (recombinant parathyroid hormone) injections were initiated (up to three times daily) with improvement in the vascular changes and a decrease in calcium phosphate calcification in biopsy, as well as reduction in hypercalciuria, restoration of calcium phosphate homeostasis and stabilization of allograft function. We describe six other cases of post-transplant hypoparathyroidism, with five of six having decreased allograft function and three of those five demonstrating significant accelerated vascular changes on biopsy. We discuss the use of teriparatide injections for the treatment of renal transplant recipients with impaired renal function in the setting of hypoparathyroidism.",
"affiliations": "Renal Division, Transplant Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;Renal Division, Transplant Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;Renal Division, Transplant Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.",
"authors": "Hod|Tammy|T|;Riella|Leonardo V|LV|;Chandraker|Anil|A|",
"chemical_list": "D050071:Bone Density Conservation Agents; D011994:Recombinant Proteins; D019379:Teriparatide",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.12622",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "29(11)",
"journal": "Clinical transplantation",
"keywords": "hypocalcemia; hypoparathyroidism; kidney; parathyroid hormone; transplantation",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D050071:Bone Density Conservation Agents; D006801:Humans; D007011:Hypoparathyroidism; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D016105:Parathyroidectomy; D011994:Recombinant Proteins; D019379:Teriparatide",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "951-7",
"pmc": null,
"pmid": "26331695",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Recombinant PTH therapy for severe hypoparathyroidism after kidney transplantation in pre-transplant parathyroidectomized patients: review of the literature and a case report.",
"title_normalized": "recombinant pth therapy for severe hypoparathyroidism after kidney transplantation in pre transplant parathyroidectomized patients review of the literature and a case report"
} | [
{
"companynumb": "US-ASTELLAS-2015US044488",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BELATACEPT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRecreational use of Synthetic Cannabinoid Receptors Agonists (SCRAs) has become increasingly common in many countries and may cause severe toxic effects.\n\n\nOBJECTIVE\nTo describe the clinical features of toxicity in seven men after analytically confirmed exposure to MDMB-CHMICA, a recently described indole-based SCRA.\n\n\nMETHODS\nClinical information and biological samples (blood, urine) were collected from patients with severe toxicity after suspected use of novel psychoactive substances. Samples were analyzed by data-independent liquid chromatography-tandem mass spectrometry (LC-MS/MS).\n\n\nMETHODS\nAll seven cases were men who presented to hospitals in England between July and October 2015; six reported smoking \"legal high\" products. In all cases, MDMB-CHMICA was identified in blood samples taken on admission to hospital. Other substances were identified in four cases (methadone 1, methiopropamine 1, other SCRAs 2). Clinical features in all seven cases and in the three exposed to MDMB-CHIMICA alone included acidosis (7/7 and 3/3) which was respiratory (3/7 and 3/3), metabolic (3/7 and 0/3) or mixed (1/7, 0/3), reduced level of consciousness (6/7 and 3/3), mydriasis (5/7 and 3/3), tachycardia (5/7 and 2/3), bradycardia (2/7 and 1/3), tonic-clonic convulsions (2/7 and 1/3) and agitation (3/7 and 1/3). Recovery occurred within 24 h in all cases except one male also exposed to methiopropamine.\n\n\nCONCLUSIONS\nAnalytically confirmed exposure to MDMB-CHMICA was associated with acidosis (often of respiratory origin), reduced level of consciousness, mydriasis, heart rate disturbances and convulsions.",
"affiliations": "a National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Medical Toxicology Centre, Newcastle University , Newcastle , UK ;;b Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary , Newcastle , UK ;;a National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Medical Toxicology Centre, Newcastle University , Newcastle , UK ;;c Royal Liverpool University Hospital , Liverpool , UK ;;d Acute Medical Unit , North Manchester General Hospital , Manchester , UK ;;e Emergency Department , Royal London Hospital , London , UK.;a National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Medical Toxicology Centre, Newcastle University , Newcastle , UK ;;a National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Medical Toxicology Centre, Newcastle University , Newcastle , UK ;",
"authors": "Hill|Simon L|SL|;Najafi|Javad|J|;Dunn|Michael|M|;Acheampong|Paul|P|;Kamour|Ashraf|A|;Grundlingh|Johann|J|;Blain|Peter G|PG|;Thomas|Simon H L|SH|",
"chemical_list": "D063386:Cannabinoid Receptor Agonists; D013287:Illicit Drugs; D007211:Indoles; D011619:Psychotropic Drugs; C000610109:methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2016.1190980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "MDMB-CHMICA; methiopropamine; synthetic cannabinoid receptor agonist; toxicity",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D063386:Cannabinoid Receptor Agonists; D002853:Chromatography, Liquid; D006801:Humans; D013287:Illicit Drugs; D007211:Indoles; D008297:Male; D008875:Middle Aged; D011619:Psychotropic Drugs; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry; D006113:United Kingdom; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "638-43",
"pmc": null,
"pmid": "27251903",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical toxicity following analytically confirmed use of the synthetic cannabinoid receptor agonist MDMB-CHMICA. A report from the Identification Of Novel psychoActive substances (IONA) study.",
"title_normalized": "clinical toxicity following analytically confirmed use of the synthetic cannabinoid receptor agonist mdmb chmica a report from the identification of novel psychoactive substances iona study"
} | [
{
"companynumb": "PHHY2016GB125464",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "OBJECTIVE\nTo detail a diagnostic dilemma of intentional hand amputation in a man with a history of substance misuse and associated psychosis, depression and traumatic brain injury and to highlight issues in joint psychiatric and surgical management of such a complex patient in a general hospital setting.\n\n\nCONCLUSIONS\nDeliberate limb self-amputation is a rare event with the majority of reported cases occurring during an episode of psychosis. This case illustrates the diagnostic utility of the literature supporting that a person who has self-inflicted amputation of a limb should be treated as psychotic until proven otherwise. The presence of a traumatic brain injury, with associated cognitive and psychosocial sequelae, affected diagnosis and management. Early and ongoing involvement of consultation-liaison psychiatry collaborating with a multidisciplinary general hospital team may improve mental and physical health outcomes for such patients.",
"affiliations": "Trainee in Psychiatry, South Eastern Sydney Local Health District, NSW, Australia.;Staff Specialist Psychiatrist, Consultation-Liaison Psychiatry and Conjoint Senior Lecturer, South Eastern Sydney Local Health District, NSW, and; Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia a.wand@unsw.edu.au.;Staff Specialist Psychiatrist, Consultation-Liaison Psychiatry and Conjoint Lecturer, South Eastern Sydney Local Health District, NSW, and; Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia.",
"authors": "Crawford|Alison|A|;Wand|Anne Pf|AP|;Smith|Michelle A|MA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1039856215604479",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "24(2)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "amputation; consultation-liaison; psychosis; self-mutilation; traumatic brain injury",
"medline_ta": "Australas Psychiatry",
"mesh_terms": "D000671:Amputation; D019468:Disease Management; D006769:Hospitals, General; D006801:Humans; D008297:Male; D011618:Psychotic Disorders; D012017:Referral and Consultation; D016728:Self-Injurious Behavior; D055815:Young Adult",
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "173-5",
"pmc": null,
"pmid": "26400454",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Self-amputation of the hand: issues in diagnosis and general hospital management.",
"title_normalized": "self amputation of the hand issues in diagnosis and general hospital management"
} | [
{
"companynumb": "AU-JNJFOC-20151001383",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": nul... |
{
"abstract": "We report a case of metastatic renal cell carcinoma in the native kidney of a renal transplant recipient. The patient was a 57-year-old man in whom a tumor in the native kidney and bone metastasis were found incidentally on imaging, 10 years after cadaveric renal transplantation. Interferon-alpha was administered after nephrectomy and following palliative irradiation of the metastasis, but could not be continued because of allograft dysfunction. Subsequent administration of zoledronic acid and sorafenib stabilized the disease for 18 months after nephrectomy. This is the first reported case of sorafenib administration to a renal transplant recipient with metastatic renal cell carcinoma.",
"affiliations": "Department of Urology, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku, Hiroshima, Japan. yasuhase@hiroshima-u.ac.jp",
"authors": "Hasegawa|Yasuhisa|Y|;Mita|Koji|K|;Matsubara|Akio|A|;Ohdan|Hideki|H|",
"chemical_list": "D001557:Benzenesulfonates; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077211:Zoledronic Acid; D000077157:Sorafenib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-008-0868-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "14(5)",
"journal": "International journal of clinical oncology",
"keywords": null,
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001557:Benzenesulfonates; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D002292:Carcinoma, Renal Cell; D004164:Diphosphonates; D006801:Humans; D007093:Imidazoles; D007166:Immunosuppressive Agents; D033162:Incidental Findings; D016898:Interferon-alpha; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018714:Radiotherapy, Adjuvant; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "465-7",
"pmc": null,
"pmid": "19856059",
"pubdate": "2009-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17382145;8051761;12631097;9199039;9186319;16879668;14568274;12118559;7613790;17215530;15466206;6183119;15593084;17470685;12915606;12942563;17408850;9734490",
"title": "Multidisciplinary treatment including sorafenib stabilized the bone metastases of renal cell carcinoma in an immunosuppressed renal transplant recipient.",
"title_normalized": "multidisciplinary treatment including sorafenib stabilized the bone metastases of renal cell carcinoma in an immunosuppressed renal transplant recipient"
} | [
{
"companynumb": "JP-BAYER-2015-050413",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "Silent brain lesions might be associated with overt cerebrovascular accident over time in beta thalassemia major (BTM) and intermediate (BTI). Aspirin may be protective in these patients. We evaluated brain magnetic resonance imaging (MRI) in thalassemia patients to see whether aspirin is protective or not. A historical cohort study was conducted on 35 thalassemia patients, 22 BTI, and 13 BTM patients at Shiraz Hematology Research Center in 2018. Median age of the patients was 32 years and ranged from 8 to 42 years. Twenty-four patients (68.6%) were females. Overall frequency of white matter lesions (WMLs) in the first MRI was 10 patients (28.6%). After 3 years, 3 patients developed new lesions and the frequency of WMLs was 13 patients (37.1%) in the second MRI. Moreover, in 3 patients, number of WMLs increased. Patients with new lesions or more lesions compared to the baseline were significantly older than the other group (median age 36.5 years vs. 31 years, P = 0.046). Regarding aspirin consumption, only 1 patient (16.7%) of patients with new lesions was using aspirin compared to 10 (34.5%) of the other group (P = 0.640). The high-risk patients with thrombocytosis, splenectomy, severe iron overload, and older age (> 30 years) should be under close follow-up and evaluated on a regular periodic basis as well as brain MRI at least once every 3 years. Aspirin could be protective against new or progressive brain lesions so that low-dose aspirin is recommended in high-risk thalassemia patients.",
"affiliations": "Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. mkarimi820@gmail.com.;Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.",
"authors": "Karimi|Mehran|M|http://orcid.org/0000-0001-8555-1001;Haghpanah|Sezaneh|S|;Pishdad|Parisa|P|;Zahedi|Zohreh|Z|;Parand|Shirin|S|;Safaei|Sanaz|S|",
"chemical_list": "D001241:Aspirin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03765-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "98(10)",
"journal": "Annals of hematology",
"keywords": "Aspirin; Beta thalassemia; Silent brain lesions",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001241:Aspirin; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012307:Risk Factors; D020521:Stroke; D017086:beta-Thalassemia",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2267-2271",
"pmc": null,
"pmid": "31388698",
"pubdate": "2019-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Frequency of silent brain lesions and aspirin protection evaluation over 3 years follow-up in beta thalassemia patients.",
"title_normalized": "frequency of silent brain lesions and aspirin protection evaluation over 3 years follow up in beta thalassemia patients"
} | [
{
"companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-226126",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "BACKGROUND\nThe signs and symptoms of Lassa fever are initially indistinguishable from other febrile illnesses common in the tropics and complications of pregnancy. Surviving Lassa fever during pregnancy is rare. Only few cases have been documented. The antiviral drug of choice is ribavirin.\n\n\nMETHODS\nA 25-year-old multigravida farmer with fever who was initially thought to have malaria in pregnancy at 29 weeks gestation. Further changes in her clinical state and laboratory tests led to a confirmation of Lassa fever. The Liver enzymes were markedly deranged and the packed cell volume was 27%. She commenced on ribavirin and subsequently was delivered of a live male neonate who was RT PCR negative for Lassa fever virus. Her clinical state improved, repeat RT PCR on day 15 was negative and she made full recovery.\n\n\nCONCLUSIONS\nThe case reported had similar clinical features of fever and abdominal pain and resulted in the initial diagnoses of Malaria in pregnancy. When she failed to respond to antimalarial and antibiotics treatments, a strong suspicion of viral hemorrhagic fever was made. At this time the patient was in advanced stage of the disease with bleeding from vagina and puncture sites. On the third day of admission she was delivered of a live male neonate who remained negative after 2 consecutive RT PCR tests for Lassa fever virus. Lassa fever carries a high risk of death to the fetus throughout pregnancy and to the mother in the third trimester. Mothers with Lassa fever improved rapidly after evacuation of the uterus by spontaneous abortion, or normal delivery. She was clinically stable following delivery. Her laboratory investigations were essentially normal. Throughout her management transmission based precautions were observed. None of the six close contacts developed symptoms after been followed up for 21 days.\n\n\nCONCLUSIONS\nThis report adds to the body of literature that individuals can survive Lassa fever during pregnancy with good maternal and fetal outcome.",
"affiliations": "Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria. Electronic address: jagboeze@gmail.com.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Alex-Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi State, Nigeria.;Medecins sans Frontieres Nigeria, Nigeria.;Medecins sans Frontieres Nigeria, Nigeria.;Medecins sans Frontieres Nigeria, Nigeria.;Medecins sans Frontieres Nigeria, Nigeria.",
"authors": "Agboeze|Joseph|J|;Nwali|Matthew Igwe|MI|;Nwakpakpa|Ebenezer|E|;Ogah|Onwe Emeka|OE|;Onoh|Robinson|R|;Eze|Justus|J|;Ukaegbe|Chukwuemeka|C|;Ajayi|Nnennaya|N|;Nnadozie|Uzodimma Ugochukwu|UU|;Orji|Maria-Lauretta|ML|;Ojide|Kingsley Chiedozie|KC|;Unigwe|Sunday Uche|SU|;Chika-Igwenyi|Nneka|N|;Nwidi|Demian Ugonna|DU|;Clement|Chukwunenye Ugochukwu|CU|;Kalombo|Charles|C|;Makwe|Catherine|C|;Tshiang|Jacques|J|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2019.08.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "89()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Abakaliki; Lassa fever; Pregnancy",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D005334:Fever; D006801:Humans; D007231:Infant, Newborn; D007835:Lassa Fever; D007836:Lassa virus; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012254:Ribavirin",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "84-86",
"pmc": null,
"pmid": "31465848",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lassa fever in pregnancy with a positive maternal and fetal outcome: A case report.",
"title_normalized": "lassa fever in pregnancy with a positive maternal and fetal outcome a case report"
} | [
{
"companynumb": "NVSC2020NG001017",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Children with refractory or relapsed Burkitt lymphoma (BL) or Burkitt leukemia (B-AL) have a poor chance to survive. We describe characteristics, outcome, reinduction, and transplantation approaches and evaluate risk factors among children with progression of a BL/B-AL included in Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster studies between 1986 and 2016. Treatment recommendation was reinduction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5 ± 3%. Survival significantly improved from 11 ± 3% before to 27 ± 5% after 2000 (P < .001), allowing for risk factor analyses among the latter 75 patients. Survival of 14 patients with relapse after initial therapy for low-risk disease (R1/R2) was 50 ± 13% compared with 21 ± 5% for 61 patients progressing after R3/R4 therapy (P < .02). A total of 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during reinduction, 15 of 16 not reaching a complete remission (CR) before transplantation, 9 of 10 treated with rituximab front-line, and all 13 patients not receiving rituximab during reinduction died. Forty-six patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67 ± 12% compared with 18 ± 5% for all other regimen and transplantations (P = .003). Patients with relapsed BL/B-AL have a poor chance to survive after current effective front-line therapies. Progression during initial or reinduction chemotherapy and initial high-risk disease are risk factors in relapse. Time-condensed continuous-infusion reinduction followed by stem cell transplantation forms the basis for testing new drugs.",
"affiliations": "Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) Study Center and Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.;NHL-BFM Study Center and Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.;Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) Study Center and Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts-University, Kiel, Germany.;Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts-University, Kiel, Germany.;Pediatric Hematology and Oncology, University Hospital Zurich, Zurich, Switzerland.;Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic; and.;Pediatric Hematology and Oncology, St. Anna Children´s Hospital, Vienna, Austria.;Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.;NHL-BFM Study Center and Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.",
"authors": "Woessmann|Wilhelm|W|;Zimmermann|Martin|M|;Meinhardt|Andrea|A|;Müller|Stephanie|S|;Hauch|Holger|H|;Knörr|Fabian|F|;Oschlies|Ilske|I|;Klapper|Wolfram|W|;Niggli|Felix|F|;Kabickova|Edita|E|;Attarbaschi|Andishe|A|;Reiter|Alfred|A|;Burkhardt|Birgit|B|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019003591",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "135(14)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000074322:Antineoplastic Agents, Immunological; D002051:Burkitt Lymphoma; D002648:Child; D018450:Disease Progression; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D000069283:Rituximab; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1124-1132",
"pmc": null,
"pmid": "31961927",
"pubdate": "2020-04-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Progressive or relapsed Burkitt lymphoma or leukemia in children and adolescents after BFM-type first-line therapy.",
"title_normalized": "progressive or relapsed burkitt lymphoma or leukemia in children and adolescents after bfm type first line therapy"
} | [
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{
"abstract": "Causalgia, the post-traumatic pain syndrome remains one of the most poorly understood and frequently misdiagnosed entities encountered in clinical practice. Ablation of the upper thoracic sympathetic trunk has been used for over a century with variable success for a variety of conditions. Endoscopic transthoracic techniques of ablation of the sympathetic trunk have the advantage of a minimally invasive approach with excellent visualization of the sympathetic trunk and rapid postoperative recovery. We discuss a case of causalgia in a 35 years old man with 15 years duration of symptoms (stage 2 Drucker) in whom nonoperative therapy has consisted of drug therapy (phenytion, amitriptyline, carbamazepine, beclofen, ibuprofen and diclofenac Na), intermittent sympathetic blocks and physiotherapy failed, but full degree of pain relief was achieved by thoracic T2-T3 sympathectomy endoscopically without any major complication. Endoscopic transthoracic techniques for sympathectomy are a major technical advance in the management of causalgia and pancreatic pain. The operation is safe, effective and well tolerated and leads to a high level of patient satisfaction. Further applications of this technique are inevitable and are likely to replace conventional open procedures.",
"affiliations": "Department of Surgery, Shahid Rahnemoon Hospital, Shahid Sadoogi University of Medical Science, Yazd, Iran. saeedkargar@go.com",
"authors": "Kargar|S|S|;Parizi|F S|FS|",
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"country": "Finland",
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"issn_linking": "0355-9521",
"issue": "90(3)",
"journal": "Annales chirurgiae et gynaecologiae",
"keywords": null,
"medline_ta": "Ann Chir Gynaecol",
"mesh_terms": "D000328:Adult; D002422:Causalgia; D006801:Humans; D008297:Male; D013562:Sympathectomy; D013906:Thoracoscopy",
"nlm_unique_id": "7609767",
"other_id": null,
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"pmc": null,
"pmid": "11695793",
"pubdate": "2001",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thoracoscopic sympathectomy in causalgia.",
"title_normalized": "thoracoscopic sympathectomy in causalgia"
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"companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2014R1-91305",
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"abstract": "Individuals with HIV may present to the emergency department with HIV-related or HIV-unrelated conditions, toxicity associated with antiretroviral therapy or primary HIV infection (seroconversion). In individuals with HIV infection, central nervous system toxoplasmosis occurs from reactivation of disease, especially when the CD4+ count is <100 cells/μL, whereas in those taking immunosuppressive therapy, this can be either due to newly acquired or reactivated latent infection. It is a rare occurrence in immune-competent patients. Vertical transmission during pregnancy can manifest as congenital toxoplasmosis in the neonate and is often asymptomatic until the second or third decade of life when ocular lesions develop. Toxoplasmosis is an infection caused by the intracellular protozoan parasite Toxoplasma gondii and causes zoonotic infection. It can cause focal or disseminated brain lesions leading to neurological deficit, coma and death. Typical radiological findings are multiple ring-enhancing lesions. Histopathological examination demonstrating tachyzoites of T. gondii and the presence of nucleic material in the spinal cerebrospinal fluid (CSF) confirms the diagnosis. The authors present the case of a 52-year-old male UK resident, born in sub-Saharan Africa, with a 3-week history of visual hallucinations. He attended the emergency department on three occasions. Laboratory investigations and a CT head were unremarkable. He was referred to psychological medicine for further evaluation. On his third presentation, 2 months later, a CT head showed widespread lesions suggestive of cerebral metastasis. Dexamethasone was initiated and he developed rigours. An MRI head showed multiple ring-enhancing lesions disseminated throughout his brain parenchyma. CSF analysis and serology confirmed the diagnosis of HIV and toxoplasmosis, respectively. His CD4 count was 10 and his viral load (VL) was 1 245 003. He was then initiated on Biktarvy 50 mg/200 mg/25 mg, one tablet daily, which contains 50 mg of bictegravir, 200 mg of emtricitabine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide. After 3 months of antiretroviral therapy, his HIV VL reduced to 42. However, his abbreviated mental test remained at 2/10. Despite presenting with neurocognitive impairment and being born in a HIV prevalent region, an HIV test was not offered. This case highlights missed opportunities to request HIV serology and raises awareness that cerebral toxoplasmosis can occur as the first manifestation of HIV. Prompt diagnosis and early initiation of antiretroviral therapy reduces morbidity and mortality in this patient cohort.",
"affiliations": "Department of Acute Medicine, Royal Berkshire NHS Foundation Trust, Reading, UK Louise.Dunphy@doctors.org.uk.;Department of HIV Medicine, Royal Berkshire Hospital, Reading, UK.;Department of HIV Medicine, The Royal Berkshire NHS Foundation Trust, Reading, UK.;Department of Rheumatology, The Royal Berkshire NHS Foundation Trust, Reading, UK.",
"authors": "Dunphy|Louise|L|http://orcid.org/0000-0001-5499-415X;Palmer|Bret|B|;Chen|Fabian|F|;Kitchen|Joanne|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237120",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "HIV / AIDS; infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D016781:Toxoplasmosis, Cerebral",
"nlm_unique_id": "101526291",
"other_id": null,
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"pmid": "33462006",
"pubdate": "2021-01-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant diffuse cerebral toxoplasmosis as the first manifestation of HIV infection.",
"title_normalized": "fulminant diffuse cerebral toxoplasmosis as the first manifestation of hiv infection"
} | [
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"companynumb": "GB-TEVA-2021-GB-1887601",
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{
"abstract": "OBJECTIVE\nDrug-induced immune-mediated thrombocytopenia is a rare adverse event that remains a diagnostic challenge, especially in the critically ill population. There are only two previously reported cases of rapid and profound thrombocytopenia after administration of piperacillin/tazobactam.\n\n\nMETHODS\nA 64-year-old man experienced several episodes of isolated thrombocytopenia after receiving piperacillin/tazobactam. Interestingly, the degree of thrombocytopenia varied with the amount of corticosteroid therapy the patient was receiving. Due to the complexity of thrombocytopenia in critically ill patients, other potential causes were extensively worked up and ruled out.\n\n\nCONCLUSIONS\nWe describe the first case of piperacillin/tazobactam-induced immune-mediated thrombocytopenia that was mitigated by the administration of corticosteroid therapy. This case highlights the importance of identifying potential drug-related causes of isolated thrombocytopenia.",
"affiliations": "Department of Critical Care and Department of Pharmacy Services, Surrey Memorial Hospital, Surrey, BC, Canada.;Department of Critical Care and Department of Pharmacy Services, Surrey Memorial Hospital, Surrey, BC, Canada.;Department of Critical Care and Department of Pharmacy Services, Surrey Memorial Hospital, Surrey, BC, Canada. Sarah.Stabler@fraserhealth.ca.",
"authors": "Boyce|K|K|;Brar|H|H|;Stabler|S N|SN|http://orcid.org/0000-0001-5296-3261",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "41(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "immune; piperacillin/tazobactam; thrombocytopenia",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000900:Anti-Bacterial Agents; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D013921:Thrombocytopenia",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "730-732",
"pmc": null,
"pmid": "27670947",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Piperacillin/tazobactam-induced immune-mediated thrombocytopenia in the intensive care unit.",
"title_normalized": "piperacillin tazobactam induced immune mediated thrombocytopenia in the intensive care unit"
} | [
{
"companynumb": "CA-PFIZER INC-2016514839",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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... |
{
"abstract": "Stent thrombosis is a potentially life threatening condition caused by several factors or a combination factors, such as resistance to platelet agents and type of anticoagulation used as well as stent types. We report a case of acute thrombosis and discuss potential areas of intervention with literature review.",
"affiliations": "NYMC, Metropolitan Hospital Center, Department of Emergency Medicine, United States; NYU Langone Hospital Brooklyn, Department of Emergency Medicine, United States. Electronic address: Getawworku.Hassen@nychhc.org.;Mount Sinai St. Luke's Hospital, Department of Cardiology, United States.;NYU Langone Hospital Brooklyn, Department of Medicine, Division of Cardiology, United States.;Johns Hopkins University, Department of Biomedical Engineering, United States.;Columbia University Postbaccalaureate Premedical Program, United States.;NYU Langone Hospital Brooklyn, Department of Medicine, United States.;NYMC, Metropolitan Hospital Center, Department of Emergency Medicine, United States.",
"authors": "Hassen|Getaw Worku|GW|;Talebi|Soheila|S|;Alhadad|Basel|B|;Azhir|Alaleh|A|;Jennings|Catherine Ann|CA|;Zavaro|Doris|D|;Kalantari|Hossein|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2018.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "36(8)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D003328:Coronary Thrombosis; D054855:Drug-Eluting Stents; D004554:Electric Countershock; D004632:Emergency Medical Services; D006801:Humans; D008297:Male; D062645:Percutaneous Coronary Intervention; D000072657:ST Elevation Myocardial Infarction; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D014693:Ventricular Fibrillation",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1526.e1-1526.e4",
"pmc": null,
"pmid": "29776823",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute stent thrombosis: Should preventative measures start in the emergency department?",
"title_normalized": "acute stent thrombosis should preventative measures start in the emergency department"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0112064",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
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{
"abstract": "BACKGROUND\nWe describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels.\n\n\nMETHODS\nA 37 year old man was admitted with neuroglycopenia (plasma-glucose 1.6mmol/l) 18 months after RYGB, with normal 72h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels.\n\n\nRESULTS\nPlasma-glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463pmol/l. A decrease of plasma-glucose followed: 2.2, 3.0, 3.9 and 2.9mmol/l respectively and insulin levels were suppressed at 150min: 45, 22, 21 and 14pmol/l, respectively. GLP-1 levels increased in the PO test (60min: 122pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12-23pmol/l at 60min).\n\n\nCONCLUSIONS\nReduction of plasma-glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.",
"affiliations": "Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway. Electronic address: elisabeth.qvigstad@ous-hf.no.;Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway.;Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway.;Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland.;Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway.;Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway.;Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway.",
"authors": "Qvigstad|E|E|;Gulseth|H L|HL|;Risstad|H|H|;le Roux|C W|CW|;Berg|T J|TJ|;Mala|T|T|;Kristinsson|J A|JA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)00080-810.1016/j.ijscr.2016.02.033Case ReportA novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report Qvigstad E. elisabeth.qvigstad@ous-hf.noe_qvigstad@hotmail.coma⁎Gulseth H.L. aRisstad H. able Roux C.W. cBerg T.J. abMala T. aKristinsson J.A. aa Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norwayb Faculty of Medicine, University of Oslo, Norwayc Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland⁎ Corresponding author at: Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, P.O. Box 4959 Nydalen, N-0424 Oslo, Norway. Fax: +47 22894250.Department of EndocrinologyMorbid Obesity and Preventive MedicineOslo University HospitalNorway elisabeth.qvigstad@ous-hf.noe_qvigstad@hotmail.com27 2 2016 2016 27 2 2016 21 91 94 30 10 2015 19 2 2016 19 2 2016 © 2016 Published by Elsevier Ltd. on behalf of IJS Publishing Group Ltd.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Postprandial hypoglycemia may be a serious adverse effect following Roux-en-Y gastric bypass surgery.\n\n• Most patient can be treated with diet and pharmacological agents, but some patients need surgical reversals.\n\n• This Roux-en-Y gastric bypass reversal alleviates severe postprandial hyperinsulinaemic hypoglycaemia.\n\n• The technique retains some component of rapid transit of food into a shorter alimentary limb in an attempt to reduce weight regain.\n\n• This new surgical procedure also attenuates s-GLP-1 and s-insulin responses along with improved p-glucose.\n\n\n\nBackground\nWe describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels.\n\nCase summary\nA 37 year old man was admitted with neuroglycopenia (plasma–glucose 1.6 mmol/l) 18 months after RYGB, with normal 72 h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels.\n\nResults\nPlasma–glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8 mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463 pmol/l. A decrease of plasma–glucose followed: 2.2, 3.0, 3.9 and 2.9 mmol/l respectively and insulin levels were suppressed at 150 min: 45, 22, 21 and 14 pmol/l, respectively. GLP-1 levels increased in the PO test (60 min: 122 pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12–23 pmol/l at 60 min).\n\nConclusions\nReduction of plasma–glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.\n\nKeywords\nRoux-en-Y gastric bypassHypoglycaemiaGastric bypass reversalObesityPostprandial hyperinsulinemic hypoglycaemiaGLP-1Case report\n==== Body\n1 Background\nRoux-en-Y gastric bypass (RYGB) is widely used to treat morbid obesity (Fig. 1a). Postprandial hyperinsulinemic hypoglycaemia (PHH) can be a complication after RYGB and potentially difficult to treat [1], [2]. The mechanisms for PHH are not fully understood, but exaggerated incretin responses play a role [3], [4]. A small subgroup of patients does not respond to dietary changes and medical therapy. For these patients, surgical reversal or pancreatectomy have been proposed although the optimal surgical treatment has not been defined [5], [6].\n\nWe describe a patient with severe PHH unresponsive to non-surgical treatment. A novel surgical approach of partial reversal of the RYGB was successfully used. Here we describe the pre- and postoperative physiological responses demonstrating the resolution of PHH.\n\n2 Patient and methods\nA 37-year-old man (weight 183 kg, height 185 cm, BMI 53.5 kg/m2) with known bradycardia, asthma and gout, but no diabetes, had a laparoscopic RYGB with a 150 cm (antecolic) alimentary and a 50 cm bilio–pancreatic limb (Fig. 1a). One year after surgery he had lost 88 kg (48% total weight loss) and his BMI was reduced to 27.7 kg/m2.\n\nEighteen months after surgery the patient was admitted to hospital with neuroglycopenic symptoms relieved by consumption of carbohydrates and plasma–glucose of 1.6 mmol/l. He used standard nutritional supplements, but no drugs and rarely alcohol. Serum–cortisol, thyroid function tests, cerebral- and abdominal CT scans, cardiac evaluation and plasma–glucose after a 72 h fast were normal. Despite dietary modifications and self-monitoring of blood–glucose the hypoglycaemic episodes and hospital admissions increased in frequency. Acarbose was attempted but not tolerated due to gastrointestinal side effects. Diazoxide up to 600 mg daily had little effect and was discontinued due to dyspnea. Verapamil was not considered as the patient had bradycardia. Subcutaneous injection of octreotide (50 mcg 3 times daily) resulted in less severe PHH for some weeks, but the effect gradually attenuated and his alanine transaminase and aspartate transaminase increased.\n\nSevere symptomatic hypoglycaemia occurred on a daily basis resulting in hospital admission for glucose infusions. In an attempt to alleviate the symptoms, feeding through a gastrostomy tube into the remnant stomach was started. The laparascopic positioning of the gastrostomy tube was complicated by subileus and the patient was reoperated. To evaluate if feeding through the gastrostomy tube would decrease the PHH a standard mixed meal test was performed orally before the gastrostomy tube placement (PO), and via the tube at 1 week (GT1) and 4 weeks (GT2) after the tube placement. The test meal; 200 ml of Fresubin 2 kcal™ (400 kcal, 45 g carbohydrates, 20 g protein and 15.6 g fat) was ingested or infused through the gastric tube over 12 min. During the tests, the Edinburgh symptom scale for hypoglycaemia [8] was used to evaluate hypoglycaemic symptoms every 15 min, in parallel with pulse and BP measurements. Plasma–glucose, serum–insulin and plasma–GLP-1 were measured every 15 min during the first hour, and then every 30 min until the end of the test.\n\nFour weeks after the last test the patient developed recurrent abdominal pain, especially after ingestion of oral fiber-rich foods, and became dependent on continuous parenteral glucose infusions to prevent hypoglycemia. He developed signs of hypoglycaemia unawareness. Reduced oral feeding did not prevent the hypoglycaemia, in spite of gradually increased nutrition (250 ml × 3 Diaben™) through the gastric tube.\n\nRYGB reversal: Due to prolonged hospitalization, the need for continuous glucose infusions and the development of hypoglycaemic unawareness surgery was considered. The patient was finally offered a modified reversal of the RYGB (Fig. 1b).\n\nDuring laparoscopy the gastrostomy tube was removed and the alimentary limb was transected 6 cm below the gastro–jejunostomy (Fig. 1b). A side-to-side anastomosis was created between the highest part of the remnant stomach on the minor side and the small bowel 6 cm below the original RYGB pouch. The bilio–pancreatic limb was divided at the entero–entero anastomosis and a new side-to-side entero–entero anastomosis was created between the previously divided alimentary limb and the bilio–pancreatic limb.\n\nThe same mixed meal was given orally 4 weeks after the RYGB reversal (POr).\n\nBiochemical analysis: Plasma–glucose was analyzed every 5 min by a glucose oxidase method (YSI Inc., Yellow Springs, Ohio, USA.). Serum–insulin was analyzed at the Hormone Laboratory (ECLIA, Roche diagnostic Inc.). Plasma–GLP-1 samples were centrifuged and frozen at −80° and analyzed later in one run by an EMD Millipore ELISA kit (CV 8%).\n\nThe present case report is compliant with the CARE Guidelines [7].\n\n3 Results\nDuring the mixed meal testing pre-intervention, Serum–insulin levels increased rapidly during the first 30 min in parallel with glucose levels, and were later suppressed. Plasma–glucose decreased from 30 to 90 min. Plasma–GLP-1 levels demonstrated exaggerated responses during the first two tests (PO, GT1), but was attenuated at both the GT2 and the POr tests (Fig. 2a–c).\n\nSymptoms and signs during both the PO and GT1 tests included palpitations, abdominal pain, nausea, sleepiness and redness. These symptoms were attenuated after gastric tube adaptation (GT2). Postoperatively (POr), the patient experienced neither symptoms of hypoglycaemia, nor episodes of abdominal pain. The patient had one episode of constipation successfully corrected by a barium enema.\n\nThe patient was reviewed two months after the RYGB reversal and reported no hypoglycaemic symptoms. His body weight was 87.3 kg. Three months after the partial reversal of RYGB, continuous glucose monitoring demonstrated plasma–glucose levels around 5 mmol/l, and no report of hypoglycaemic symptoms in spite of provocations with high glycaemic meals. At 10 months post operatively he weighed 94 kg, reported some dyspepsia, but had a normal upper endoscopy and infrequent low blood glucose levels (lowest at 2.7 mmol/l), but no hypoglycaemic symptoms.\n\n4 Discussion\nIn our patient the symptoms of PHH resolved after partial reversal of the RYGB and he returned to work 6 weeks after surgery. We found a reduction in hypoglycaemia and symptoms three weeks after gastric tube feeding was started, with further improvement after RYGB reversal. The attenuation of plasma–GLP-1 and insulin responses were associated with improved plasma–glucose and symptoms during to the two latter meal tests (GT2 and POr).\n\nThe exaggerated plasma–GLP-1 response at the GT1 visit, which involved feeding through the gastrostomy tube, suggests that the duodenum and jejunum in the bilio–pancreatic limb had an exacerbated response to the mixed meal. The subsequent attenuated GLP-1 response during GT2 and POr tests, suggests small bowel adaptation, resulting in a diminutive response triggered by the mixed meals.\n\nThe optimal surgical approach to patients with post-RYGB hypoglycaemia not responding to diet and/or pharmacotherapy has not been defined [6]. A gastrostomy tube has been used by some authors to test the potential effects of RYGB reversal. Our findings suggest time to pass for an enteral adaptation to nutrition by the gastric tube, prior to testing the effect of tube feeding on plasma–glucose levels and symptoms of hypoglycaemia.\n\nPancreatic resection and reversal have both been used in an attempt to relieve PHH [6]. To prevent weight regain a sleeve gastrectomy has been performed together with the RYGB reversal [5]. We describe a technically easier reversal while potentially retaining some component of nutritional restriction as the original gastric pouch is preserved. This may reduce the risk of weight regain. This approach has to our knowledge, not previously been described in the context of surgical treatment to PHH after RYGB. Our short-term findings indicate that the procedure alleviates the symptoms of hypoglycaemia. Further study of long-term outcome is necessary for evaluation of the clinical applicability of this technique of RYGB reversal.\n\nConflict of interest\nThe authors declare that they have no conflicts of interests.\n\nFunding\nThe authors declare that they have no sources of funding for the research.\n\nEthical approval\nThis is an observational case report. No ethical approval is required.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nAuthors’ contributions\nEQ, TM, HR and JAK performed the clinical work-up, EQ and HLG planned and performed the tests, TM and JAK planned and performed the surgical procedures. CLR analyzed the GLP-1 samples. EQ, HLG, HR, CLR, TJB, TM and JAK interpreted the test results and wrote the manuscript.\n\nGuarantor\nEQ, JAK.\n\nFig. 1 Panel a depicts the entero–entero anastomosis (OEE) and the gastro–jejunostomy after Roux-en-Y gastric bypass. Panel b demonstrates the division of the alimentary limb 6 cm below the gastro–jejunostomy and the anastomosis of the proximal part of the alimentary limb to the gastric remnant. A new entero–entero anastomosis is made between the former alimentary and bilio–pancreatic limb following transection of the original entero–entero anastomosis at the bilio–pancreatic limb side. A is previously published in D. Hofsø et al.: Follow-up after bariatric surgery, in the Journal of the Norwegian Medical Association, 2011, by permission from K. Toverud, CMI. B was produced for our paper by K. Toverud, CMI. The images are not covered by the terms of the Creative Commons licence of this publication. For permission to reuse, please contact the rights holder (K. Toverud, CMI).\n\nFig. 1Fig. 2 Panel a–c respectively: Plasma–glucose, serum–insulin and plasma–GLP-1 levels during tests (peroral □), gastric tube unadapted (GT1 +), gastric tube adapted (GT2 ×), peroral after reversion (POr ♦). # indicates the point where the PO test was stopped due to a serious episode of hypoglycaemia (2,0 mmol/l), necessitating iv. glucose injection.\n\nFig. 2\n==== Refs\nReferences\n1 Marsk R. Jonas E. Rasmussen F. Naslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5040 patients undergoing surgery for obesity in 1986–2006 in Sweden Diabetologia 53 2010 2307 2311 20495972 \n2 Foster-Schubert K.E. Hypoglycemia complicating bariatric surgery: incidence and mechanisms Curr. Opin. Endocrinol. Diabetes Obes. 18 2011 129 133 21297468 \n3 Dirksen C. Hansen D.L. Madsbad S. Hvolris L.E. Naver L.S. Holst J.J. Worm D. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report Diabetes Care 33 2010 375 377 19918005 \n4 Patti M.E. Li P. Goldfine A.B. Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass Obesity 23 2015 798 807 25755084 \n5 Vilallonga R. van de Vrande S. Himpens J. Laparoscopic reversal of Roux-en-Y gastric bypass into normal anatomy with or without sleeve gastrectomy Surg. Endosc. 27 2013 4640 4648 23860610 \n6 Mala T. Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment Surg. Obes. Relat. Dis. 10 2014 1220 1225 25002326 \n7 www.care-statement.org.\n8 Geddes J. Wright R.J. Zammitt N.N. Deary I.J. Frier B.M. An evaluation of methods of assessing impaired awareness of hypoglycemia in type 1 diabetes Diabetes Care 30 2007 1868 1870 17416785\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "21()",
"journal": "International journal of surgery case reports",
"keywords": "Case report; GLP-1; Gastric bypass reversal; Hypoglycaemia; Obesity; Postprandial hyperinsulinemic hypoglycaemia; Roux-en-Y gastric bypass",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "91-4",
"pmc": null,
"pmid": "26957187",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "19918005;21297468;25002326;25755084;20495972;23860610;17416785",
"title": "A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report.",
"title_normalized": "a novel technique of roux en y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia a case report"
} | [
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"companynumb": "NO-MYLANLABS-2016M1018020",
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{
"abstract": "Thrombotic microangiopathy (TMA) is devastating for renal transplantation (RT) causing graft/ patient loss. We present 5-year experience of TMA in RT in retrospective study of indicated renal allograft biopsies with TMA. Patient-donor demographics and associated histological findings with respect to transplants under tolerance induction protocol (Group 1) were compared with patients transplanted under triple immunosuppression (Group 2). Statistical analysis was performed using IBM SPSS Statistics version 20. Sixty-one (4.1%) of 1520 biopsies [Group 1:17 (1.9%)/882, Group 2:44 (6.9%)/638] revealed TMA. Tacrolimus trough levels were normal. There was no evidence of systemic involvement in any patient. Mean age was 36.8 years with 70.6% males, HLA-match, 2.6/6, and the most common original disease unknown (41.2%) in Group 1, and 35.9 years with 86.4% males, HLA-match, 2.1/6, and the most common original disease unknown (50%) in Group 2. Biopsies were performed at mean 5.1-year posttransplant in Group 1 and 2.3 years in Group 2. Acute TMA constituted 47% Group 1 and 43.2% Group 2 biopsies; of these, antibody-mediated rejections were observed in 58.8%, T-cell mediated rejections in 11.8%, tacrolimus toxicity in 76.5%, and other findings in 35.3% Group 1; and 61.4%, 25%, 50%, and 18.2%, respectively, in Group 2 biopsies. Higher rejection activity scores were more in Group 2. Postbiopsy 1- and 5- year patient survival was 94.1%, 86.9% in Group 1 and 92.1%, 88.3% in Group 2; 1- and 4-year graft survival was 52.9%, 15.9% in Group 1 and 20.3%, 5.4% in Group 2. TMA was poor prognosticator for RT, especially under triple immunosuppression. Antibody- mediated rejection and tacrolimus toxicity were more prone to TMA.",
"affiliations": "Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology; Department of Stem Cell Therapy and Regenerative Medicine, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Stem Cell Therapy and Regenerative Medicine, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.;Department of Biostatistics, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital-Medicity Campus, Asarwa, Ahmedabad, India.",
"authors": "Vanikar|Aruna V|AV|;Kanodia|Kamal V|KV|;Suthar|Kamlesh S|KS|;Nigam|Lovelesh A|LA|;Patel|Rashmi D|RD|;Thakkar|Umang G|UG|;Mehta|Aanal H|AH|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.308342",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "31(6)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D064591:Allografts; D001706:Biopsy; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate; D016559:Tacrolimus; D057049:Thrombotic Microangiopathies; D023001:Transplantation Tolerance; D055815:Young Adult",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "1331-1343",
"pmc": null,
"pmid": "33565445",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombotic microangiopathy in a renal allograft: Single-center five-year experience.",
"title_normalized": "thrombotic microangiopathy in a renal allograft single center five year experience"
} | [
{
"companynumb": "IN-ASTELLAS-2021US006109",
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"occurcountry": "IN",
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"activesubstancename": "PREDNISONE"
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"abstract": "BACKGROUND\nLeft atrial (LA) reentrant tachycardias are not uncommon in regions where rheumatic heart disease is prevalent. Some of these arrhythmias may be curable by radiofrequency ablation (RFA). However, there are limited data pertaining to this in existing literature.\n\n\nMETHODS\nThree patients who had rheumatic mitral valve disease with past history of surgical-/catheter-based intervention and having no significant residual disease had symptomatic atrial flutter despite optimal medical management. An electrophysiological study confirmed an LA focal/micro-reentrant mechanism in all. There was patchy scarring of the LA, and successful RFA of these arrhythmias could be achieved.\n\n\nCONCLUSIONS\nThe focal nature of the scar in these patients may suggest that the rheumatic involvement of the atrium or the hemodynamic consequence of the vulvar lesion causes nonuniform insult to the atrial tissue and limited scar. At least in some patients with limited scarring, early RFA may help in the maintenance of sinus rhythm.",
"affiliations": "Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.",
"authors": "Prabhu|Mukund A|MA|;Thajudeen|Anees|A|;Vk|Ajit Kumar|AK|;J|Tharakan|T|;B V|Prasad Srinivas|PS|;Namboodiri|Narayanan|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pace.12912",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-8389",
"issue": "40(1)",
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": "ablation; left atrial; reentrant; rheumatic; tachycardia",
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": "D000328:Adult; D017115:Catheter Ablation; D005260:Female; D006325:Heart Atria; D006329:Heart Conduction System; D006349:Heart Valve Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve; D012214:Rheumatic Heart Disease; D013611:Tachycardia, Atrioventricular Nodal Reentry; D016896:Treatment Outcome",
"nlm_unique_id": "7803944",
"other_id": null,
"pages": "97-103",
"pmc": null,
"pmid": "27346449",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Radiofrequency Ablation of Left Atrial Reentrant Tachycardias in Rheumatic Mitral Valve Disease: A Case Series.",
"title_normalized": "radiofrequency ablation of left atrial reentrant tachycardias in rheumatic mitral valve disease a case series"
} | [
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"companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2017VAL000368",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL TARTRATE"
},
... |
{
"abstract": "OBJECTIVE\nPsoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform eruptions after initiation of dupilumab in children.\n\n\nMETHODS\nRecords of patients ≤18 years of age with atopic dermatitis who developed psoriasiform dermatitis during treatment with dupilumab were reviewed retrospectively.\n\n\nRESULTS\nSix children, 4-18 years of age, on dupilumab for severe atopic dermatitis developed new-onset psoriasiform dermatitis at a median duration of 8 months (range, 6-12 months) after dupilumab initiation. Typical locations of psoriasis were involved (face, scalp, trunk, and extensor extremities). The majority showed clearance or near clearance with the use of medium-strength to potent topical corticosteroid ointments and 83% continued use of the dupilumab. A 7th patient had psoriasis, in addition to severe atopic dermatitis, and the psoriasis was unmasked by its failure to respond to dupilumab.\n\n\nCONCLUSIONS\nAlthough unusual, psoriasiform lesions can appear during effective treatment with dupilumab for atopic dermatitis, potentially reflecting a shift toward cutaneous IL-23/TH 17 pathway activation with dupilumab-induced suppression of type 2 immunity.",
"affiliations": "Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.;Departments of Pediatrics and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Dermatology, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Dermatology, University of Miami Miller School of Medicine, Miami, FL, USA.;Departments of Pediatrics and Medicine, University of Calgary, Calgary, AB, USA.;Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.",
"authors": "Parker|Jennifer J|JJ|https://orcid.org/0000-0001-7797-1460;Sugarman|Jeffrey L|JL|;Silverberg|Nanette B|NB|https://orcid.org/0000-0002-4274-7597;Gonzalez|Mercedes Elena|ME|;Ramien|Michele L|ML|;Teng|Joyce M C|JMC|;Paller|Amy S|AS|https://orcid.org/0000-0001-6187-6549",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": null,
"journal": "Pediatric dermatology",
"keywords": "atopic dermatitis; children; dupilumab; psoriasiform; psoriasis",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8406799",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34647354",
"pubdate": "2021-10-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Psoriasiform dermatitis during dupilumab treatment for moderate-to-severe atopic dermatitis in children.",
"title_normalized": "psoriasiform dermatitis during dupilumab treatment for moderate to severe atopic dermatitis in children"
} | [
{
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE DIPROPIONATE"
},
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{
"abstract": "BACKGROUND\nHepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA).\n\n\nMETHODS\nA 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy.\n\n\nCONCLUSIONS\nIn immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended--as in our case--if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.",
"affiliations": "Center of Laboratory Medicine, Frohbergstrasse 3, 9001, St. Gallen, Switzerland. detlev.schultze@zlmsg.ch.;Center of Laboratory Medicine, Frohbergstrasse 3, 9001, St. Gallen, Switzerland. bernhard.mani@zlmsg.ch.;Center of Laboratory Medicine, Frohbergstrasse 3, 9001, St. Gallen, Switzerland. guenter.dollenmaier@zlmsg.ch.;Institute of Microbiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 48, 1011, Lausanne, Switzerland. roland.sahli@chuv.ch.;Institute of Medical Virology, Winterthurerstrasse 190, 8057, Zürich, Switzerland. zbinden.andrea@virology.uzh.ch.;Spital Linth, Gasterstrasse 25, 8730, Uznach, Switzerland. pierre-alexandre.krayenbuehl@spital-linth.ch.",
"authors": "Schultze|Detlev|D|;Mani|Bernhard|B|;Dollenmaier|Günter|G|;Sahli|Roland|R|;Zbinden|Andrea|A|;Krayenbühl|Pierre Alexandre|PA|",
"chemical_list": "D006508:Hepatitis Antibodies; D007166:Immunosuppressive Agents; D012254:Ribavirin",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-015-1146-y",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 114610.1186/s12879-015-1146-yCase ReportAcute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report Schultze Detlev detlev.schultze@zlmsg.ch Mani Bernhard bernhard.mani@zlmsg.ch Dollenmaier Günter guenter.dollenmaier@zlmsg.ch Sahli Roland roland.sahli@chuv.ch Zbinden Andrea zbinden.andrea@virology.uzh.ch Krayenbühl Pierre Alexandre pierre-alexandre.krayenbuehl@spital-linth.ch Center of Laboratory Medicine, Frohbergstrasse 3, 9001 St. Gallen, Switzerland Institute of Microbiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland Institute of Medical Virology, Winterthurerstrasse 190, 8057 Zürich, Switzerland Spital Linth, Gasterstrasse 25, 8730 Uznach, Switzerland 29 10 2015 29 10 2015 2015 15 4744 8 2015 24 9 2015 © Schultze et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA).\n\nCase presentation\nA 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy.\n\nConclusions\nIn immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression.\n\nAlthough anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended – as in our case - if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.\n\nKeywords\nHepatitis E virusEpstein-Barr virusImmunosuppressionRheumatoid arthritisMethotrexateissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHepatitis E virus (HEV) is a non-enveloped single-stranded RNA virus approximately 27–34 nm in diameter belonging to the genus Hepevirus in the Hepeviridae family.\n\nIt is the most recently discovered of the hepatotropic viruses, with four different HEV genotypes (GT) that represents a single serotype able to infect humans [1]. Though humans are traditionally regarded the only reservoir for GT1 (Asia and North Africa) and GT2, there are reports of GT1 circulating in pigs as well. This zoonotic potential is well-demonstrated for GT3 in the Americas, Europe and Asia, and for GT4 in Asia, where they are also found in pigs and wild animals [2]. It has recently become obvious that HEV is endemic in industrialized countries, and that more infections are autochthonous (locally acquired) than travel-associated [3]. HEV infection has to be considered as a zoonosis and viral transmission from animals (pigs, wild animals) occurs through food or direct contact [1]. In high-income countries of North America and Europe, in Japan and Australia, autochthonous transmission of HEV causes both asymptomatic infections in healthy individuals as well as fulminant hepatitis in mostly immunocompromised patients [4]. Although it is now considered to be an emerging disease, HEV infection is yet not a notifiable disease in Switzerland [5].\n\nWe present a unique case of autochthonous HEV infection in a Swiss woman with coincident reactivation of Epstein-Barr virus (EBV) infection under immunosuppression of her RA.\n\nCase presentation\nOn April 22nd 2015 a 68-year-old Swiss woman complained about nausea, headache and fever. She had slightly elevated transaminases and elevated C-reactive protein. The general practitioner interpreted the abnormal liver function tests as complication of MTX therapy she had received for treatment of RA since 2002. As transaminases increased over the following eight days to values above upper limit in point-of-care testing, the patient was admitted with preliminary diagnosis of MTX-induced liver injury [6]. On admission the patient complained of nausea, pain below right rib cage and in lower extremities and buttocks. She was afebrile, showed no jaundice and further physical examination was unremarkable. Abdominal ultrasound showed slight liver steatosis. Liver magnetic resonance imaging revealed no further abnormalities. The low-dose MTX therapy (10 mg/week) for erosive RA (positive for anti-cyclic citrullinated peptide-antibody) and the weekly prednisolon dosis (5mg) that she had received for treatment of chronic obstructive lung disease were stopped. The therapy with bronchodilators (ipratropium bromide, budenoside, albuterol) was continued.\n\nLiver transaminases, alkaline phosphatase, gamma-glutamyl transferase, and acute phase proteins (C-reactive protein, ferritin, haptoglobin) were elevated (Table 1). Leukocytes and platelets were slightly above normal reference limit. Bilirubin, prothrombin time, and activated partial thromboplastin time laid within normal ranges. Serology for hepatotropic viruses and parasites (Hepatitis A virus, Hepatitis C virus, Cytomegalo-virus (CMV), Echinococcus alveolaris, Echinococcus granulosus, Toxoplasma gondii) and anti-mitochondrial-antibody as well as markers for autoimmune hepatitis (anti-liver kidney microsome type 1-, anti-smooth muscle-, anti-soluble liver antigen- antibody) were negative.Table 1 Evolution of laboratory parameters and discontinuation of therapy\n\nParameter (Reference or limit of detection)\tDay after onset of illness\t\n\t8\t9\t12\t21\t40\t75\t\nAST (<40 U/l)\t1920\t1787\t578\t53\t31\t26\t\nALT(<55 U/l)\t1743\t1650\t1021\t122\t27\t25\t\nyGT(<35 U/l)\t265\t226\t221\t102\t35\t20\t\nALP (42–98 U/l)\t352\t296\t302\t150\t70\t58\t\nBilirubin (<20 umol/l)\t15\t15\t13\t16\t\t\t\nCRP(<5 mg/l)\t41\t35\t14\t37\t12\t4\t\nCMV IgG (neg)\tNeg\t\t\t\t\t\t\nCMV IgM (neg)\tNeg\t\t\t\t\t\t\nHepatitis A IgM (neg)\tNeg\t\t\t\t\t\t\nHBs Antigen (neg)\tNeg\t\t\t\t\t\t\nHBc Ig (neg)\t\tPos\t\t\tNeg\t\t\nHBc IgM (neg)\t\tPos\t\t\tNeg\t\t\nHBe Ig (neg)\t\tNeg\t\t\tNeg\t\t\nHBe Antigen (neg)\t\tNeg\t\t\t\t\t\nHBs Ig (neg)\t\tNeg\t\t\t\t\t\nHBV DNA (<9 IU/ml)\t\t\t<9\t\t\t\t\nHepatitis C Ig (neg)\tNeg\t\t\t\t\t\t\nEBV VCA IgG (neg)\t\tPos\t\t\t\t\t\nEBV NA1 IgG (neg)\t\tPos\t\t\t\t\t\nEBV VCA IgM (neg)\t\tPos\t\t\tPos\t\t\nEBV DNA (<122 IU/ml)\t\t\t566\t\t<122\t<122\t\nHeterophile IM (neg)\tNeg\t\t\t\t\t\t\nHEV IgG (neg); Diapro\t\tPos\t\t\t\t\t\nHEV IgM (neg); Diapro\t\tPos\t\t\t\t\t\nHEV IgG (<1.0 index); Wantai\t5.3\t\t\t\t19.4\t19.5\t\nHEV IgM (<1.0 index); Wantai\t10.4\t\t\t\t10.6\t10.6\t\nHEV RNA (<1000 cc/ml)\t\t\t\t8959\t<1000\t<1000\t\nStop (\\) and reinitiation (/) of\t\t\t\t\t\t\t\n- Prednisolon therapy\t8 \\\t\t\t\t\t/ 48\t\n- Methotrexate therapy\t8 \\\t\t\t\t\t/ 63\t\n\n\nTo note, tests for specific IgM-antibody against EBV viral capsid antigen (VCA), Hepatitis B-Virus (HBV)-core-antigen (Architect®, Abbott, Wiesbaden, Germany), and HEV (Diapro, Milan, Italy) were positive, indicating a recent infection with three different viruses. Subsequent viral load testing revealed low copy numbers of EBV DNA (928 copies/ml corresponding to 566 IU/ml calibrated to World Health Organisation EBV standard; TaqMan real-time PCR assay according to Berger et al. [7] with modified primers) and HEV RNA (8959 copies/ml; Real-time reverse transcriptase (RT)--PCR assay according to Jothikumar et al. [8] with minor primer modifications to account for HEV genotypic diversity). No HBV DNA could be detected in plasma (COBAS AmpliPrep-COBAS TaqMan 48 HBV Test, Version 2.0, Roche, Switzerland). Additional HEV IgG- and IgM-specific ELISA tests (Beijing Wantai Biological Pharmacy Enterprise), retrospectively done on a serum sample from day 8 of illness confirmed positive results.\n\nOne month follow-up showed clearing of both Hepatitis E- and Epstein-Barr viral load and seroreversion of anti-HB core-IgM and anti-HB core-Ig antibody, with significant increase of HEV IgG index. Results of blood tests are shown in Table 1.\n\nThe patient fully recovered after 40 days and suffered no relapse after reinitiation of MTX and prednisolon therapy, in the following five weeks.\n\nDiscussion\nAlthough HEV infection is often asymptomatic and only occasionally induces a self-limited acute hepatitis with low mortality, it can, however, be more severe in immune-suppressed individuals [4]. Acute HEV infection can be diagnosed either directly by detecting the viral genome in biologic specimens (e.g. stools, liver biopsy) or indirectly by detecting specific IgM and IgG antibodies against the virus [2]. In plasma, HEV RNA may be detected at low levels with onset of illness, persisting for up to 4 weeks. In immunosuppressed patients, HEV diagnosis by detection of HEV RNA is recommended, as testing for antibodies may give false negative results due to immunosuppression [2]. The detection of HEV specific-IgG and -IgM can be delayed in immunosuppressed patients e.g. after liver transplantation, with a diagnostic window of several weeks between the first detection of HEV RNA and the detection of HEV-specific antibodies [9]. In blood samples of 35 immunosuppressed solid-organ transplant patients and five haematological patients, drawn at the time of first elevation of the ALT activity and positive for HEV RNA, Abravanel F et al. [10] reported a sensitivity of 85 % (95 % CI: 70.2-94.3) for detection of HEV specific-IgM antibodies (ELISA Kit, Beijing Wantai Biological Pharmacy Enterprise). The authors concluded, that well validated anti-HEV-IgM assays can be used as first line virological tool in immunosuppressed patients, but molecular detection of HEV RNA is essential, if anti-HEV IgM tests turn out negative.\n\nFurthermore, serological testing is hindered either by the potential inability to detect anti-HEV IgM or by false positive HEV-IgM results that have been reported to occur in infections by other hepatotropic viruses like EBV and CMV. In the latter case, false positive HEV-IgM antibodies may appear, e.g., as a consequence of polyclonal B-cell stimulation by EBV infection or – rarely - crossreactive EBV-specific IgM antibodies. Since liver involvement is not rare in both viruses, acute hepatitis may be incorrectly diagnosed as being due to HEV infection or (vice versa) to EBV or CMV infection, respectively, if the diagnosis is not confirmed by molecular tests [11, 12].\n\nAlthough the classical presentation of acute HEV infection is with general malaise, fever, jaundice accompanied by pale stools, darkened urine and gastrointestinal symptoms, this phenotype is rarely seen with HEV GT3 and 4 in high income countries [2]. Our patient had mild gastrointestinal symptoms, lacking jaundice. In such atypical cases, liver enzyme elevations especially elevated aspartate transaminase (AST) and alanine transaminase (ALT) are the clue for the correct diagnosis, but may be incorrectly ascribed to other acute hepatic diseases such as drug-induced liver injury [2]. In our patient, elevated liver enzymes were initially interpreted as complication of MTX therapy, despite folic acid supplementation that lowers frequency of liver function abnormalities. Although low-dose MTX therapy is considered immunosuppressive, it does not increase infection risk in patients with RA, that per se have a higher rate of infection when compared with a healthy control population [13]. A french retrospective multicenter study [14] demonstrated that HEV infection should be suspected in patients with RA and elevated liver enzyme levels. Among RA patients in this study, HEV infection had been treated by discontinuation of immunosuppressive therapy to allow restoration of T cell responses against the virus and by ribavirin therapy when liver enzyme levels were particularly elevated and/or when the activity of the inflammatory arthritis required immunosuppressive drugs. Nearly half of all patients including other inflammatory rheumatic diseases reported in this study by Bauer et al. were totally asymptomatic, emphasizing the need to specifically look for HEV in the checkup of elevated liver enzymes, regardless of the symptoms [14].\n\nHEV GT3 infection in immunocompromised patients may become chronic, defined as HEV RNA detectable for more than 6 months, leading to chronic hepatic inflammation and rapidly progressive cirrhosis, as in patients chronically infected with hepatitis C virus [2].\n\nIn our patient, discontinuation of MTX and prednisolone therapy during one month, i.e., time from hospital admission (day 8) and the day of the first negative PCR result for HEV RNA (day 40), was sufficient to clear both HEV RNA and EBV DNA. This is in the range of the french study [14], in which 9 of 12 patients with RA (7 females; median 61 yr , range 44–72 yr ) received MTX, partially in combination with a biologic (e.g.Rituximab), corticosteroid and/or disease-modifying drug (Leflunomide). After discontinuation of immunosuppressive therapy, the median time of HEV RNA positivity in 10 of these patients was 7 weeks (range 4–10.5 weeks). One 68-year-old man on MTX and Rituximab received ribavirin for 3 months and the HEV load disappeared within 8 weeks. In contrast to our patient, no reactivation of latent EBV infection was noted. In accordance with the study patients, the course of acute HEV in our patient was found to be cytolytic rather than cholestatic, with a duration of liver cytolysis of <40 days, compared to <3 months in study patients. Additionally, our patient experienced no flare of its rheumatic disease after discontinuation of immunosuppression, whereas it occurred in half of the study patients at a median of 4 weeks (range 1 day −10 weeks).\n\nEBV persists as a latent infection with episomal DNA in a very small number of memory B cells, and it is difficult to detect EBV in the plasma of healthy individuals [15, 16], whereas in patients with RA there is a 10-fold systemic EBV overload in peripheral blood mononuclear cells (PBMCs) due to an impaired immune response to EBV [17]. MTX therapy of patients with RA may reactivate EBV production [15] by differentiation of memory B cells into plasma cells that undergo lytic infection and produce virus [16]. In our patient, concomitantly positive EBV VCA-IgG, EBV VCA-IgM, and EBNA-1 IgG antibodies were measured. Although this reflects a past EBV infection in most cases, it may also correspond to an EBV reactivation episode, a state of polyclonal stimulation by a heterologous infectious agent or to a relatively recent EBV-related primary infection [18]. In our patient, the low viral load of EBV and a negative test for heterophile antibodies (Clearview IM; Inverness Medical, UK) pointed against primary EBV infection and rather indicated a reactivation of latent EBV [19]. The negative HBs antigen, anti-HBs-Ig, and anti-HBe-IgG were a hint to falsely positive anti-HB core-IgM and anti-HB core-Ig antibody, confirmed by seroreversion one month later. Taken together, microbiological tests indicated a recent HEV infection with coincident reactivation of the patient’s latent EBV infection.\n\nOne month after discontinuation of MTX and prednisolon therapy, neither HEV RNA nor EBV DNA was detectable in the patient’s plasma. Thus, reactivation of the patient’s EBV-infection might have been triggered by the HEV infection.\n\nMost HEV transmissions occur by the fecal-oral (GT1 and GT2) and food-borne routes (GT3 and GT4). HEV has been documented in pig products in the human food chain across Europe, and shellfish, such as bivalve mollusks, have been shown to act as reservoirs [2] Other transmission routes, including human to human transfer [20], vertical transmissions and infection through blood transfusion have also been described [3]. Environmental presence of HEV has been demonstrated in sewage samples of developed countries, where sporadic, locally acquired infections of HEV genotypes 3 and 4 have been reported during the past decade. These autochthonous zoonotic infections have been linked to ingestion of raw or undercooked meat especially from pigs, wild boar, and deer [2]. In several western European countries including Switzerland, seroepidemiological studies suggest that domestic pigs and wild boars are the main reservoirs for human HEV. A significantly lower seroprevalence in domestics pigs in Switzerland was observed in 2011 than in 2006, possibly due to the ban in 2008 on using sewage sludge from water treatment plants as fertilizer in agriculture [21].\n\nAs our patient had not left Switzerland for many years, she must have acquired an autochthonous infection, possibly due to consumption of pork spare ribs four weeks prior to onset of symptoms. Genotyping of the HEV was not feasible, due to the low viral load that hampered amplification of cDNA to detectable levels.\n\nConclusions\nIn immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, NAAT for detection of HEV RNA are recommended – as in our case - if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this Journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nDS wrote the manuscript and supervised part of the microbiological analyses, BMa, GD, RS, AZ each supervised part of the microbiological analyses, PAK diagnosed and treated the patient. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe are grateful to the patient for permission to publish this case report.\n\nThe Center of Laboratory Medicine, St. Gallen, Switzerland partly funded the microbiological analyses as part of the quality improvement program. No other, especially no commercial funding was received for the study.\n==== Refs\nReferences\n1. Purcell RH Emerson SU Hepatitis E: An emerging awareness of an old disease J Hepatol 2008 48 3 494 503 10.1016/j.jhep.2007.12.008 18192058 \n2. Arends JE Ghisetti V Irving W Dalton HR Izopet J Hoepelman AIM Salmon D Hepatitis E - An emerging infection in high income countries J Clin Virol 2014 59 81 88 10.1016/j.jcv.2013.11.013 24388207 \n3. Dreier J Juhl D Autochthonous Hepatitis E Virus Infections: A New Transfusion- Associated Risk? Transfus Med Hemother 2014 41 29 39 10.1159/000357098 24659945 \n4. Dalton HR Bendall R Ijaz S Banks M Hepatitis E: an emerging infection in developed countries Lancet Infect Dis 2008 8 698 709 10.1016/S1473-3099(08)70255-X 18992406 \n5. Federal Public Health Office, Berne, Switzerland; Meldung Infektionskrankheiten: http://www.bag.admin.ch/k_m_meldesystem/00733/00804/index.html?lang=de; accessed June 3ed, 2015.\n6. Chalasani NP Hayashi PH Bonkovsky HL Navarro VJ Lee WM Fontana RJ on behalf of the Practice Parameters Committee of the American College of Gastroenterology ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury Am J Gastroenterol 2014 109 950 966 10.1038/ajg.2014.131 24935270 \n7. Berger C Day P Meier G Zingg W Bossart W Nadal D Dynamics of Epstein-Barr virus DNA levels in serum during EBV-associated disease J Med Virol 2001 64 4 505 512 10.1002/jmv.1078 11468736 \n8. Jothikumar N Cromeans TL Robertson BH Meng XJ Hill VR A broadly reactive one-step real-time RT-PCR assay for rapid and sensitive detection of hepatitis E virus J Virol Methods 2006 131 65 71 10.1016/j.jviromet.2005.07.004 16125257 \n9. Pischke S Suneetha PV Baechlein C Barg-Hock H Heim A Kamar N Schlue J Strassburg CP Lehner F Raupach R Bremer B Magerstedt P Cornberg M Seehusen F Baumgaertner W Klempnauer J Izopet J Manns MP Grummer B Wedemeier H Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients Liver Transpl 2010 16 74 82 10.1002/lt.21958 19866448 \n10. Abravanel F Chapuy-Regaud S Lhomme S Miedougé M Peron JM Alric L Rostaing L Kamar N Izopet J Performance of anti-HEV assays for diagnosing acute hepatitis E in immunocompromised patients J Clin Virol 2013 58 624 8 10.1016/j.jcv.2013.10.003 24183927 \n11. Fogeda M de Ory F Avellon A Echevarria JM Differential diagnosis of hepatitis E virus, cytomegalovirus and Epstein-Barr virus infection in patients with suspected hepatitis E J Clin Virol 2009 45 259 261 10.1016/j.jcv.2009.05.022 19505848 \n12. Hyams C Mabayoje DA Copping R Maranao D Patel M Labbett W Haque T Webster DP Serological Cross Reactivity to CMV and EBV causes problems in the Diagnosis of Acute Hepatitis E Virus Infection J Med Virol 2014 86 478 483 10.1002/jmv.23827 24402843 \n13. McLean-Tooke A Aldridge C Waugh S Spickett GP Kay L Methotrexate, rheumatoid arthritis and infection risk - what is the evidence? Rheumatology 2009 48 867 871 10.1093/rheumatology/kep101 19447771 \n14. Bauer H Luxembourger C Gottenberg JE Fournier S Abravanel F Cantagrel A Chatelus E Claudepierre P Hudry C Izopet J Fabre S Lefevre G Marguerie L Martin A Messer L Molto A Pallo-Prades B Pers YM Roque-Afonso AM Roux C Sordet C Soubrier M Veissier C Wendling D Péron JM Siblia J on behalf fo the Club Rhumatismes et Inflammation, a section of the French Society of Rheumatology Outcome of Hepatitis E Virus Infection in Patients With Inflammatory Arthritides Treated With Immunosuppressants – A French Retrospective Multicenter Study Medicine 2015 94 1 6 10.1097/MD.0000000000000675 \n15. Feng WH Cohen JI Fischer S Li L Sneller M Goldbach-Mansky R Raab-Traub N Delecluse HJ Kenney SC Reactivation of Latent Epstein-Barr Virus by Methotrexate: A Potential Contributor to Methotrexate-Associated Lymphomas J Natl Cancer Inst 2004 96 22 1691 1702 10.1093/jnci/djh313 15547182 \n16. Kimura H Ito Y Suzuki R Nishiyama Y Measuring Epstein–Barr virus (EBV) load: the significance and application for each EBV-associated disease Rev Med Virol 2008 18 305 319 10.1002/rmv.582 18494041 \n17. Balandraud N Guis S Meynard JP Auger I Roudier J Roudier C Long-Term Treatment With Methotrexate or Tumor Necrosis Factor alpha Inhibitors Does Not Increase Epstein-Barr Virus Load in Patients With Rheumatoid Arthritis Arthritis & Rheumatism 2007 57 5 762 767 10.1002/art.22783 17530675 \n18. Corrales I Giménez E Navarro D Evaluation of the Architect Epstein-Barr Virus (EBV) Viral Capsid Antigen (VCA) IgG, VCA IgM, and EBV Nuclear Antigen 1 IgG Chemiluminescent Immunoassays for Detection of EBV Antibodies and Categorization of EBV Infection Status Using Immunofluorescence Assays as the Reference Method Clin Vaccine Immunol 2014 21 5 684 688 10.1128/CVI.00104-14 24623623 \n19. Nystad TW Myrmel H Prevalence of primary versus reactivated Epstein-Barr virus infection in patients with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis J Clin Virol 2007 38 4 292 7 10.1016/j.jcv.2007.01.006 17336144 \n20. Mansuy JM Huynh A Abravanel F Recher C Peron JM Izopet J Molecular evidence of patient-to-patient transmission of hepatitis E virus in a hematology ward Clin Infect Dis 2009 48 373 374 10.1086/595893 19128164 \n21. Burri C Vial F Ryser-Degiorgis MP Schwermer H Darling K Reist M Wu N Beerli O Schöning J Cavassini M Waldvogel A Seroprevalence of Hepatitis E Virus in Domestic Pigs and Wild Boars in Switzerland Zoonoses Public Health 2014 61 537 544 24499160\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "15()",
"journal": "BMC infectious diseases",
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"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D060085:Coinfection; D020031:Epstein-Barr Virus Infections; D005260:Female; D006508:Hepatitis Antibodies; D006515:Hepatitis B virus; D016751:Hepatitis E; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D012254:Ribavirin",
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"pubdate": "2015-10-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18494041;19447771;17530675;24402843;15547182;24659945;19505848;24935270;18192058;24499160;24623623;11468736;19866448;18992406;16125257;17336144;24388207;24183927;25860212;19128164",
"title": "Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report.",
"title_normalized": "acute hepatitis e virus infection with coincident reactivation of epstein barr virus infection in an immunosuppressed patient with rheumatoid arthritis a case report"
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"abstract": "Penetrating head trauma (PHT) includes any traumatic injury where an object pierces the skull and breaches the dural membrane surrounding the brain. PHTs are less prevalent than blunt head injuries. However, they often have more complex damage, worse prognosis, and higher rates of morbidity and mortality. An 83-year-old man fell at his home and hit his head on the right side toward a shoji (a Japanese-style paper sliding door). He reported to the emergency room the following day with his family. He had a small wound before the right ear, which was sutured in the emergency room. A CT scan demonstrated tiny pieces of bone fragments inside the brain, as well as right temporal subcortical hemorrhage and pneumocephalus. He was admitted to the hospital and received intensive prophylaxis with antibiotics. He developed life-threatening skin disease and subsequent acute kidney disease requiring hemodialysis. He fully recovered from his life-threatening condition. Here, we report an unprecedented case of a penetrating head injury of an older adult caused by a shoji.",
"affiliations": "Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.;Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.;Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.;Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.;Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.;Department of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan.",
"authors": "Okura|Hidehiro|H|;Takaki|Yuki|Y|;Makino|Kensaku|K|;Nonaka|Senshu|S|;Tsutsumi|Satoshi|S|;Ishii|Hisato|H|",
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"doi": "10.1016/j.tcr.2021.100533",
"fulltext": "\n==== Front\nTrauma Case Rep\nTrauma Case Rep\nTrauma Case Reports\n2352-6440\nElsevier\n\nS2352-6440(21)00138-2\n10.1016/j.tcr.2021.100533\n100533\nCase Report\nAn unprecedented case of penetrating head trauma caused by shoji (a Japanese-style paper sliding door)\nOkura Hidehiro hohkura@juntendo.ac.jp\n⁎\nTakaki Yuki\nMakino Kensaku\nNonaka Senshu\nTsutsumi Satoshi\nIshii Hisato\nDepartment of Neurosurgery, Juntendo Urayasu Hospital, 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan\n⁎ Corresponding author at: 2-1-1 Tomioka, Urayasu-city, Chiba 279-0021, Japan. hohkura@juntendo.ac.jp\n10 9 2021\n12 2021\n10 9 2021\n36 1005336 9 2021\n© 2021 The Authors\n2021\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/).\nPenetrating head trauma (PHT) includes any traumatic injury where an object pierces the skull and breaches the dural membrane surrounding the brain. PHTs are less prevalent than blunt head injuries. However, they often have more complex damage, worse prognosis, and higher rates of morbidity and mortality. An 83-year-old man fell at his home and hit his head on the right side toward a shoji (a Japanese-style paper sliding door). He reported to the emergency room the following day with his family. He had a small wound before the right ear, which was sutured in the emergency room. A CT scan demonstrated tiny pieces of bone fragments inside the brain, as well as right temporal subcortical hemorrhage and pneumocephalus. He was admitted to the hospital and received intensive prophylaxis with antibiotics. He developed life-threatening skin disease and subsequent acute kidney disease requiring hemodialysis. He fully recovered from his life-threatening condition. Here, we report an unprecedented case of a penetrating head injury of an older adult caused by a shoji.\n\nKeywords\n\nPenetrating\nHead trauma\nHead injury\nOlder adults\nShoji\n==== Body\npmcIntroduction\n\nPenetrating head trauma (PHT) includes any traumatic injury where an object pierces the skull and breaches the dural membrane surrounding the brain. PHTs are less prevalent than blunt head injuries, and they represent approximately 0.4% of injuries; however, they often have more complex damage, worse prognosis, and higher rates of morbidity and mortality [1]. Bullets are the most common foreign bodies attributed to PHT; however, chopsticks, toothbrushes, nails, and knives have also been reported [1].\n\nShoji is a Japanese-style room divider consisting of translucent thin paper sheets on wooden lattice frames. It is lightweight, fragile, and usually easily broken by light impact. A broken edge of a lattice frame can pierce people after falls and cause PHT. Here, we report an unprecedented case of penetrating head trauma caused by shoji that was successfully treated, and the life-threatening comorbidities associated with intensive prophylactic antibiotics were controlled.\n\nCase report\n\nAn 83-year-old man with hypertension fell in his home and hit his head on the right side toward a shoji (a Japanese-style paper sliding door) (Fig. 1A). The patient had a small laceration and bleeding that stopped spontaneously. He reported to the emergency room the following day with his family complaining of mild midline occipitalgia. He was awake and alert. He had full strength in all extremities. He did not present any other neurological manifestations. He had a small wound in front of the right ear, which was sutured in the emergency room (Fig. 1B). Computed tomography (CT) at presentation revealed tiny pieces of bone fragments inside the brain, as well as right temporal subcortical hemorrhage and pneumocephalus (Fig. 2). According to his family, the lattice frame of the shoji broke and penetrated his temple just in front of the right ear. The family lost the broken lattice frame after withdrawing it. He was admitted to the hospital for further treatment. Conservative management was initiated with intensive prophylaxis with antibiotics, including vancomycin (VCM) and ceftriaxone (CTX). He developed a skin rash seemingly caused by the antibiotics. VCM and CTX were changed to meropenem (MEPM). His skin rash significantly deteriorated. A dermatology service was also involved. He was diagnosed with acute generalized exanthematous pustulosis. MEPM had to be discontinued. However, his systemic skin rash continued to worsen. He was diagnosed with generalized pustular psoriasis (GPP) and developed a subsequent acute kidney injury. Along with steroid administration, granulocyte monocyte apheresis in combination with hemodialysis was initiated. MEPM was resumed since the GPP was considered unrelated to MEMP by the dermatology service. MEMP was continued for six weeks after the diagnosis of GPP. Periodically repeated magnetic resonance imaging (MRI) showed no evidence of abscess development during treatment (Fig. 3). He fully recovered from the life-threatening skin disease and was neurologically stable. He was transferred to a rehabilitation hospital because of disuse syndrome.Fig. 1 (A) A broken shoji (a Japanese-style paper sliding door) missing a fragment of a lattice frame. (B) A small wound in front of the right ear.\n\nFig. 1\n\nFig. 2 (A) Head CT without contrast at presentation demonstrating tiny pieces of bone fragments inside the brain, as well as (B) right temporal subcortical hemorrhage and pneumocephalus. (C) 3D-CT bone image demonstrating penetrating bone fracture in the right temporal bone.\n\nFig. 2\n\nFig. 3 Brain MRI two months after the injury. FLAIR (A) and DWI (B) showing a high-intensity signal in the right temporal lobe that remained the same during the illness.\n\nFig. 3\n\nDiscussion\n\nPHT is a rare but lethal disease [1]. Foreign bodies in the brain can cause immediate complications, such as pneumocephalus, intracerebral hemorrhage, and brain contusions, which can lead to abscesses, meningitis, and encephalitis [1]. The incidence of infections, including intra- and extra-cranial infections, range from 5% to 23% [2]. In the present case, the patient pulled out a fragment of the lattice frame after the fall and threw it away. However, wooden foreign bodies are very infectious because porous organic materials provide good culture conditions for bacterial agents [3]. In addition, injection in the brain can be associated with high morbidity and mortality rates [4]. Although Staphylococcus aureus is the most frequently associated organism, gram-negative bacteria frequently cause intracranial infections after PHT [5]. We did not perform a culture test. Therefore, we immediately initiated broad-spectrum prophylactic intravenous antibiotics.\n\nCerebral abscesses have a reported incidence of 2–3%, and they are the most severe intracranial infections with a mortality rate above 50% [6]. Brain abscesses are more likely to form around retained fragments, generally developing 2–4 weeks after the initial trauma, although they may rarely develop years later [6]. While the patient no longer had a lattice frame in his brain at presentation, the potentially contaminating bony fragments were observed beneath the entry site on the initial CT scan. This may have to the development of brain abscess.\n\nDiffusion-weighted imaging (DWI) is one of the most useful for evaluating and predicting the development of brain abscesses. DWI shows a high-intensity signal for hypoxia, edema, hemorrhage, or brain abscess. This case showed a sustained high DWI signal during the illness. We did not perform gadolinium (Gd)-enhanced MRI due to acute kidney failure. We needed to carefully decide on the timing of antibiotic discontinuation. There have been several previous reports on the duration of use of antibiotics in patients with PHT [7]. There is no clear consensus on the duration of the disease. Esposito and Walker recommended the use of intravenous ceftriaxone, metronidazole, and vancomycin for a minimum of six weeks for PHT patients [8]. Kazim et al. recommended that prophylactic antibiotics should be maintained for at least 7–14 days. In this case, we temporarily interrupted the administration of antibiotics due to the skin rash. The blood tests showed continuous elevation of white blood cell (WBC) and C-reactive protein (CRP) levels. We eventually continued antibiotic treatment for six weeks after his WBC and CRP levels had returned to normal.\n\nSeveral penetrating brain injuries are caused by soft and metal materials. However, we are unaware of any previous reports of PHT caused by a broken lattice frame. Older adults are likely to fall due to their wobbling gaits or feelings of faintness. Adults with PHT who are 50 or more years have higher mortality risks [5]. Older adults also generally have functional deterioration, including declines in gait and balance, increased fall risks, and loss of independence [9]. Age-related physiological changes affect drug pharmacokinetics and pharmacodynamics, meaning that older adults are sensitive to various medications [10].\n\nThis case serves as a reminder that supposedly trivial brain injuries caused by a fragile lattice frame can be complicated by life-threatening systemic reactions caused by intensive antibiotic therapy. Given the rapidly aging society, the number of older adults with wobbling gait has been on the rise. Care needs to be exercised, especially for older adults, to prevent this type of PHT.\n\nDeclaration of competing interest\n\nAll authors report no conflict of interest.\n\nAcknowledgments\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n==== Refs\nReferences\n\n1 Temple N. Donald C. Skora A. Reed W. Neuroimaging in adult penetrating brain injury: a guide for radiographers J. Med. Radiat. Sci. 62 2 2015 122 131 26229677\n2 Vakil M.T. Singh A.K. A review of penetrating brain trauma: epidemiology, pathophysiology, imaging assessment, complications, and treatment Emerg. Radiol. 24 3 2017 301 309 28091809\n3 Miller C.F. Brodkey J.S. Colombi B.J. The danger of intracranial wood Surg. Neurol. 7 2 1977 95 103 835079\n4 Antibiotic prophylaxis for penetrating brain injury J. Trauma 51 2 Suppl 2001 S34 S40 11505198\n5 Kazim S.F. Shamim M.S. Tahir M.Z. Enam S.A. Waheed S. Management of penetrating brain injury J. Emerg. Trauma Shock 4 3 2011 395 402 21887033\n6 Kim P.E. Go J.L. Zee C.S. Radiographic assessment of cranial gunshot wounds Neuroimaging Clin. N. Am. 12 2 2002 229 248 12391634\n7 Sunshine K. Penuela M. Defta D. Antibiotic prophylaxis in penetrating brain injury: a systematic review of the literature Neurosurgery 67 2020 145\n8 Esposito D.P. Walker J.B. Contemporary management of penetrating brain injury Neurosurg. Q. 19 4 2009 249 254\n9 Yu J. The etiology and exercise implications of sarcopenia in the elderly Int. J. Nurs. Sci. 2 2 2015 199 203\n10 Lavan A.H. Gallagher P. Predicting risk of adverse drug reactions in older adults Ther. Adv. Drug Saf. 7 1 2016 11 22 26834959\n\n",
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"issue": "36()",
"journal": "Trauma case reports",
"keywords": "Head injury; Head trauma; Older adults; Penetrating; Shoji",
"medline_ta": "Trauma Case Rep",
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"publication_types": "D002363:Case Reports",
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"title": "An unprecedented case of penetrating head trauma caused by shoji (a Japanese-style paper sliding door).",
"title_normalized": "an unprecedented case of penetrating head trauma caused by shoji a japanese style paper sliding door"
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"abstract": "We report a patient with HIV-associated multicentric Castleman's disease who had recurrent human herpesvirus-8 viremia associated with intermittent febrile exanthema and lymphadenopathy. Although the patient relapsed after single-agent treatment with liposomal doxorubicin, weekly infusions of rituximab led to complete remission even though the reactivation of the Kaposi's sarcoma was unfortunately observed. Rituximab could not only eliminate the accumulation of HHV-8 load but also play a part in the modulation of dysregulated CD20-positive B cells in HIV-associated multicentric Castleman's disease.",
"affiliations": "Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan; Department of Microbiology, Saitama Medical University, Saitama, Japan. Electronic address: t_maeda@saitama-med.ac.jp.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.",
"authors": "Osa|Morichika|M|;Maeda|Takuya|T|;Misawa|Kazuhisa|K|;Imai|Kazuo|K|;Fujikura|Yuji|Y|;Kawana|Akihiko|A|",
"chemical_list": "C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069283:Rituximab; D004317:Doxorubicin",
"country": "Netherlands",
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"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "HHV-8; HIV; Liposomal doxorubicin; Multicentric Castleman's disease; Rituximab",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D005871:Castleman Disease; D004317:Doxorubicin; D015658:HIV Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols; D000069283:Rituximab",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "804-807",
"pmc": null,
"pmid": "27373909",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical response to liposomal doxorubicin and rituximab in HHV-8-associated multicentric Castleman's disease in an HIV-positive patient.",
"title_normalized": "clinical response to liposomal doxorubicin and rituximab in hhv 8 associated multicentric castleman s disease in an hiv positive patient"
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"abstract": "OBJECTIVE\nTo evaluate the efficacy and safety of intensive immunosupressive therapy (IST) with antithymocyte/antilymphocyte globulin plus cyclosporine A in the treatment of older patients (≥60 years) with severe aplastic anemia (SAA).\n\n\nMETHODS\nThe hematologic response and safety of sixteen older SAA patients treated with IST regimen in our hospital were retrospectively analyzed , and the factors affecting response were also explored.\n\n\nRESULTS\nA total of 16 older SAA patients were involved, the median age was 63.5 (60-79) years. Among them, 7 were VSAA and 9 were SAA; 9 patients received Rabbit anti- human thymocyte globulin (rATG), and 7 patients porcine anti- human lymphocyte globulin (pALG). Two patients died within 3 months after IST; at the 6 months after IST, 9 patients achieved hematology response and 5 patients had no response; overall response rate was 56.3%. Two (22%) of the 9 patients treated with rATG achieved hematology response; However, all 7 patients (100.0%) treated with pALG achieved hematology response. rATG/pALG associated adverse reactions were mild and easily managed.\n\n\nCONCLUSIONS\nThe older patients with SAA could still benefit from IST consisting of standard dose rATG/pALG with CsA, and the patients with VSAA had worse prognosis, pALG was inferior to rATG as a first treatment for SAA.",
"affiliations": "Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China.",
"authors": "Li|J P|JP|;Yang|W R|WR|;Li|Y|Y|;Ye|L|L|;Zhou|K|K|;Jing|L P|LP|;Li|Y|Y|;Peng|G X|GX|;Song|L|L|;Zhang|F K|FK|;Zhang|L|L|",
"chemical_list": "D000961:Antilymphocyte Serum; D016572:Cyclosporine",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2016.07.013",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n27535863\ncjh-37-07-607\n10.3760/cma.j.issn.0253-2727.2016.07.013\n论著\nATG/ALG联合环孢素A治疗老年重型再生障碍性贫血16例疗效及安全性评估\nAntithymocyte/Antilymphocyte globulin plus cyclosporine A therapy for the treatment of older patients with severe aplastic anemia 李 建平 Li Jianping 杨 文睿 Yang Wenrui 李 园 Li Yuan 叶 蕾 Ye Lei 周 康 Zhou Kang 井 丽萍 Jing Liping 李 洋 Li Yang 彭 广新 Peng Guangxin 宋 琳 Song Lin 张 凤奎 Zhang Fengkui 张 莉 Zhang Li 300020 天津，中国医学科学院、北京协和医学院血液学研究所、血液病医院Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China\n刘 爽 通信作者：张莉(Zhang Li)，Email：choli@medmail.com.cn\n7 2016 \n37 7 607 610\n21 1 2016 2016年版权归中华医学会所有Copyright © 2016 by Chinese Medical Association2016This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n评估老年（≥60岁）重型再生障碍性贫血（SAA）患者接受兔抗人胸腺细胞球蛋白（rATG）／猪抗人淋巴细胞球蛋白（pALG）联合环孢素A(CsA）的强烈免疫抑制治疗（IST）方案的疗效和安全性。\n\n方法\n回顾性分析16例老年SAA患者接受rATG/pALG+CsA治疗的血液学反应率和安全性，分析影响疗效的相关因素。\n\n结果\n16例患者男13例，女3例，中位年龄63.5(60~79）岁，其中60~69岁13例，≥70岁3例；SAA患者9例，极重型AA(VSAA）患者7例；9例患者接受rATG治疗，7例患者接受pALG治疗。16例患者均顺利完成rATG/pALG治疗，治疗后早期死亡2例（12.5%），均为VSAA患者（2/7, 28.6%）；IST后6个月9例（56.3%）患者获得血液学反应，5例无治疗反应。9例应用rATG的患者有2例获得血液学反应，7例应用pALG患者全部获得血液学反应，差异有统计学意义（22.2％对100.0%，P=0.003）。rATG/pALG+CsA相关不良反应轻微，经对症治疗好转。\n\n结论\n老年SAA接受rATG/pALG联合CsA的IST方案仍可获较好血液学反应；VSAA患者早期死亡率高，治疗风险大；pALG治疗老年SAA疗效可能优于rATG。\n\nObjective\nTo evaluate the efficacy and safety of intensive immunosupressive therapy (IST) with antithymocyte/antilymphocyte globulin plus cyclosporine A in the treatment of older patients (≥60 years) with severe aplastic anemia (SAA).\n\nMethods\nThe hematologic response and safety of sixteen older SAA patients treated with IST regimen in our hospital were retrospectively analyzed, and the factors affecting response were also explored.\n\nResults\nA total of 16 older SAA patients were involved, the median age was 63.5 (60–79) years. Among them, 7 were VSAA and 9 were SAA; 9 patients received Rabbit anti-human thymocyte globulin (rATG), and 7 patients porcine anti-human lymphocyte globulin (pALG). Two patients died within 3 months after IST; at the 6 months after IST, 9 patients achieved hematology response and 5 patients had no response; overall response rate was 56.3%. Two (22%) of the 9 patients treated with rATG achieved hematology response; However, all 7 patients (100.0%) treated with pALG achieved hematology response. rATG/pALG associated adverse reactions were mild and easily managed.\n\nConclusion\nThe older patients with SAA could still benefit from IST consisting of standard dose rATG/pALG with CsA, and the patients with VSAA had worse prognosis, pALG was inferior to rATG as a first treatment for SAA.\n\n贫血，再生障碍性老年人免疫抑制法Anemia, aplasticOlderImmunosupressive therapy\n==== Body\n重型再生障碍性贫血（Severe aplastic anemia，SAA）临床表现为重度全血细胞减少和骨髓造血衰竭，若不能给予积极有效的治疗，大多数患者会在诊断后的1~2年内死于出血或感染并发症。抗胸腺／淋巴细胞球蛋白（ATG/ALG）联合环孢素A (CsA）是目前公认的不适合行造血干细胞移植（HSCT）的SAA患者的一线强烈免疫抑制治疗（IST）方案。ATG/ALG+CsA治疗可以使60%~80%的SAA患者恢复三系造血。与HSCT不同，年龄本身不是IST的禁忌因素，其实施不受年龄限制[1]，国外报道行IST SAA患者最大年龄为89岁[2]。然而国内对老年SAA患者行IST相对保守，缺少应用经验。为了解老年SAA患者行IST的有效性和安全性，我们回顾性总结了我院2006年10月至2014年10月16例接受IST的老年SAA患者的临床特征、IST的耐受性和疗效，初步分析了影响疗效的预后因素，以期对老年SAA患者的治疗提供临床依据。\n\n病例与方法\n1．病例：初治老年（年龄≥60岁）SAA/极重型AA(VSAA）患者16例，均为2006年10月至2014年10月我中心住院治疗患者。AA诊断依据1987年国际粒细胞减少和AA诊断标准[3]，严重程度分型参照Camitta标准[4]。所有患者均行染色体检查、外周血细胞流式细胞术CD55、CD59或嗜水气单胞菌溶素变异体（Flaer）检测排除低增生性骨髓增生异常综合征（MDS）及阵发性睡眠性血红蛋白尿症（PNH）。所有患者均无重要脏器功能严重异常。\n\n2．IST方案：兔抗人ATG (rATG，美国健赞公司产品）1.75~3.50 mg·kg−1·d−1或猪抗人ALG(pALG，武汉生物制品研究所产品）20 mg·kg−1·d−1静脉输注，连用5 d；同时给予泼尼松1 mg·kg−1·d−1预防即刻不良反应和血清病反应，2周后泼尼松开始减量，3周停药。出现血清病反应者给予氢化可的松100 mg/d静脉滴注。患者疾病诊断明确后即开始CsA口服，以3 mg·kg−1·d−1分两次口服起始，1周后检测血药浓度，调整CsA剂量维持全血谷浓度200~400 µg/L。口服CsA至少6个月，当达到最佳血液学反应并血液学参数稳定至少3个月后开始缓慢减量，每3个月约减量1 mg·kg−1·d−1。口服CsA治疗共2~3年。\n\n3．支持治疗：ANC <0.5 × 109/L时采用G-CSF 300 µg/d皮下注射，HGB<70 g/L及PLT<10×109/L时分别给予红细胞、血小板输注支持治疗。\n\n4．随访及疗效判定：随访截止日期为2015年4月30日。所有患者分别于IST后3、6、9、12个月进行随访，此后每年随访1次，观察包括外周血和骨髓细胞形态学及组织活检、PNH克隆、脏器功能、免疫指标等以评估血液学反应和不良反应。治疗后3个月内死亡定义为早期死亡，纳入治疗相关不良反应及疗效评价分析。疗效判定采用Camitta标准[4]。脱离红细胞和血小板输注，HGB≥100 g/L、ANC≥ 1.5×109/L且PLT≥100×109/L判定为完全治疗反应（CR）；脱离红细胞和血小板输注，ANC>0.5×109/L，实验室检查不再符合SAA标准而未达CR标准者判定为部分治疗反应（PR）；未达PR标准者为无治疗反应（NR）。生存时间定义为开始IST至患者死亡或随访终点。\n\n5．统计学处理：使用SPSS 19.0软件进行统计学分析，计量资料组间比较采用非参数检验，不同组间6个月血液学反应率的单因素分析采用卡方检验。P<0.05为差异有统计学意义。\n\n结果\n1．患者基本特征：16例初诊的老年SAA/VSAA患者，男13例，女3例，中位年龄63.5（60~79）岁；其中60~69岁13例，≥70岁3例。中位ANC 0.41 (0.02~2.60）×109/L，中位网织红细胞绝对值（ARC）14.9（2.8~32.0）× 109/L，中位PLT 15（6~18）× 109/L；AA发病至开始IST中位时间为43（29~390）d；VSAA患者7例，SAA患者9例。所有患者IST前均进行PNH筛查，其中3例患者存在微小PNH克隆，无临床溶血表现和生化检查溶血证据；2例患者染色体核型为45,X,-Y，其余患者为正常核型；1例患者AA发病前2年诊断胃癌并行胃大部切除术。9例患者接受rATG治疗，7例患者接受pALG治疗。\n\n2．早期死亡：16例患者中2例（12.5%）在治疗后3个月内死亡，均为VSAA患者（2/7, 28.6%），死亡原因亦均为重症感染。\n\n3．血液学反应：IST后6个月9例患者获得血液学反应，其中5例CR，4例PR；5例NR，总体血液学反应率56.3%。获得血液学反应的9例患者，脱离红细胞输注中位时间33(0~85) d，脱离血小板输注中位时间36(0~94) d。\n\n4．影响疗效的因素：单因素分析结果显示性别、年龄、发病至开始IST的时间、初始PLT及ARC等对IST后6个月血液学反应无明显影响。分析骨髓造血衰竭严重程度对疗效的影响，VSAA患者7例，早期死亡2例（28.6%），3例获得血液学反应，2例NR；SAA患者9例，无早期死亡，6例获得血液学反应，3例NR，血液学反应率分别为42.8％和66.7%（P=0.615）。分析免疫抑制剂类型对疗效的影响，9例应用rATG患者中，2例早期死亡（22.2%），2例PR（分别于治疗后12个月和24个月达CR），5例NR，总体血液学反应率为22.2%；7例应用pALG患者中，无一例早期死亡，5例CR，2例PR，总血液学反应率为100.0%（7/7），明显高于应用rATG患者（P=0.003）。13例60~69岁患者，1例早期死亡，9例获得血液学反应，3例NR；3例≥70岁患者，1例早期死亡，2例NR（P=0.063）。\n\n5．IST后淋巴细胞恢复：rATG/pALG两组患者IST前后淋巴细胞绝对值（ALC）变化见图1，结果显示rATG与pALG治疗后患者外周血ALC均明显降低，而以rATG治疗后下降更为明显，ALC低下维持时间更长、恢复更慢，至治疗后12周仍未能恢复到治疗前水平。\n\n图1 16例老年再生障碍性贫血患者不同免疫抑制剂类型治疗后淋巴细胞绝对值变化\n6．不良反应：IST期间药物相关不良反应包括：药物性发热3例，糖皮质激素致血压升高2例、血糖升高3例，停药后症状消失；血清病反应7例，经对症治疗好转。9例患者合并感染，早期死亡2例，1例于IST后12个月死于反复感染，其余患者经治疗后好转。未出现严重出血和肝肾功能损害，无心脑血管意外发生。无严重不良反应发生。\n\n排除早期死亡2例，剩余14例患者中，2例不能耐受，CsA剂量未达治疗标准（CsA血药浓度持续低于200 µg/L）；12例CsA血药浓度浓度达到200~250 µg/L，其中6例在治疗后6~24个月出现肾功能异常（其中3例发生于CsA血药浓度300~450 µg/L时），血肌酐最高者为152 µmol/L，CsA减量后肌酐恢复正常水平，减量后CsA浓度在150 µg/L左右，其中5例获得血液学反应，另6例治疗全程中无肾功能异常。\n\n7．异常克隆转归：合并微小PNH克隆患者3例，治疗后NR、PR、CR各1例，微小PNH克隆均持续存在，无一例发生溶血。−Y患者2例，1例NR，异常克隆持续存在；1例CR，异常克隆于治疗后6个月消失。\n\n8．生存及随访结果：16例患者中位随访18(3~75）个月，2例早期死亡；1例IST后12个月死于反复感染；1例在IST后6个月失访；3例治疗无效患者持续输血依赖；另9例患者生存状况良好无复发，12个月累积生存率为77.8%。2例患者在IST后3个月出现新发克隆性染色体异常，分别为−Y和t(1;13），随访期内2例患者骨髓象无血细胞发育异常形态改变，血常规检查提示持续CR；1例染色体正常核型NR患者IST后20个月转化为典型MDS-难治性贫血伴原始细胞过多，持续输血依赖。2例患者IST后6个月出现新发PNH克隆，无溶血表现。1例既往胃癌患者无肿瘤复发迹象，病情稳定。\n\n讨论\nAA可发生于任何年龄段，而10~20岁和≥60岁为两个发病高峰[5]。随着对疾病认识和临床研究的进展，HSCT和IST已经成为SAA患者标准的可选择方案。鉴于年龄>50岁的患者移植相关死亡率大大增高[6]，而行IST仍可有60％左右的生存率[7]，因此欧洲血液学标准委员会推荐年龄>50岁的患者首选ATG联合CsA的强烈IST。在国内，老年SAA患者治疗方案选择更为保守，行ATG/ALG联合CsA者甚少，资料缺乏。因此我们总结了我中心行IST的老年患者的疗效及安全性，以提高对老年SAA治疗和预后的认识。\n\n本组16例患者年龄大，造血衰竭严重，其中7例患者符合VSAA标准，但身体状况尚好，无重大基础疾病。治疗后6个月的总体血液学反应率为56.3%，其中大部分为良好血液学反应，生存质量得到改善，其血液学反应率与国际报道相当。Tichelli等[2]研究显示≥60岁AA患者IST疗效约为52%，与20~49岁和50~59岁年龄组比较差异无统计学意义（P=0.055），提示SAA患者IST疗效并不依赖于年龄。考虑到标准治疗剂量ATG本身的不良反应和可能增加老年患者的病死率，也有研究者应用低强度免疫抑制剂以提高长期生存率，Killick等[8]单独应用低剂量（1/3标准剂量）马ATG，纳入了14例老年SAA患者，无一例发生治疗相关死亡，12例可评价疗效患者中仅1例有效，提示低剂量ATG耐受性较好，但疗效不佳，并不支持老年AA患者应用低剂量ATG，推荐应用标准剂量IST。\n\n老年患者行IST较年轻患者出现严重感染和出血的风险大，Tichelli等[2]的研究显示，接受IST 3个年龄组AA患者中≥60岁组5年生存率最低，为50%（P<0.01）；病死率最高，为32%（P=0.029）。2008年Kao等[9]的研究显示24例老年AA患者中，6例应用标准剂量的ATG＋CsA治疗，13例应用减低剂量ATG＋CsA治疗。结果显示标准剂量组早期死亡率为43%，减低剂量组为18%（P=0.4）；而标准剂量组血液学反应率为43%，减低剂量组为53%（P=0.4）。影响死亡的原因包括疾病严重程度、感染及伴随疾病（冠心病、心力衰竭、肝硬化、脑血管疾病等）。提示此类患者适度减低IST强度仍可获得疗效，或可能减少早期死亡，而治疗前对患者疾病及身体状况评估非常重要。本组16例患者除了2例ATG减量，大部分均应用常规剂量rATG/pALG，输注过程均顺利，无严重不良反应发生。IST后有2例早期死亡，12个月累积生存率为77.8%，表明老年患者对药物的耐受较好，治疗相关死亡率并不高。这可能与本组患者基础身体状况较好有关。\n\n老年患者长期应用CsA引起的肾功能异常需要重视。本组患者中57%（8/14）出现肾功能异常，调整CsA剂量后肾功能均获得好转，尽管减量后CsA血药谷浓度达不到200~400 µg/L，仅在150 µg/L的水平，也未明显影响疗效。因此，针对老年人的最佳CsA血药谷浓度还需要进一步摸索。\n\n本组VSAA与SAA患者疗效差异无统计学意义，但早期死亡患者均为VSAA患者（2/7, 28.6%）。另一个可能影响疗效的因素为免疫抑制剂类型，从血液学反应率看pALG组明显优于rATG组（P= 0.003）。Scheinberg等[10]的随机对照研究显示马与兔ATG 6个月血液学反应率分别为68％对37%（P< 0.01），但相关研究显示，rATG较马ATG有更强的免疫抑制作用，提示更强的IST并不意味着更好的疗效[11]–[13]。但是，这些研究纳入患者中位年龄多在20~40岁，≥60岁患者相关研究较少。在我们的研究中rATG组IST血液学反应率较低（22.2%，2/9）；而pALG组血液学反应率达100.0%（7/7）。同时，两组患者强烈IST前后ALC变化的统计分析显示，rATG组较pALG组ALC下降更多，恢复更慢；rATG较pALG有更强的免疫抑制作用，可能导致更多的感染、早期死亡，从而导致IST总体疗效不佳。但由于本组患者病例数较少，且为单中心回顾性分析，这些初步发现尚需前瞻性、多中心研究来加以确认。\n\n综上，老年SAA患者进行ATG/ALG+CsA方案的IST耐受性较好，疗效也与60岁以下患者相当；但老年VSAA患者由于造血衰竭重于SAA患者，早期死亡率高，治疗风险较大。\n==== Refs\nReferences\n1 Scheinberg P Young NS How I treat acquired aplastic anemia[J] Blood 2012 120 6 1185 1196 10.1182/blood-2011-12-274019 22517900 \n2 Tichelli A Socié G Henry-Amar M Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party[J] Ann Intern Med 1999 130 3 193 201 10049197 \n3 Incidence of aplastic anemia: the relevance of diagnostic criteria. By the International Agranulocytosis and Aplastic Anemia Study[J] Blood 1987 70 6 1718 1721 3676511 \n4 Camitta BM Thomas ED Nathan DG Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality[J] Blood 1976 48 1 63 70 779871 \n5 Montané E Ibáñez L Vidal X Epidemiology of aplastic anemia: a prospective multicenter study[J] Haematologica 2008 93 4 518 523 10.3324/haematol.12020 18322256 \n6 Gupta V Eapen M Brazauskas R Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors[J] Haematologica 2010 95 12 2119 2125 10.3324/haematol.2010.026682 20851870 \n7 Tichelli A Schrezenmeier H Socié G A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation[J] Blood 2011 117 17 4434 4441 10.1182/blood-2010-08-304071 21233311 \n8 Killick SB Cavenagh JD Davies JK Low dose antithymocyte globulin for the treatment of older patients with aplastic anaemia[J] Leuk Res 2006 30 12 1517 1520 10.1016/j.leukres.2006.02.003 16530266 \n9 Kao SY Xu W Brandwein JM Outcomes of older patients (> or = 60 years) with acquired aplastic anaemia treated with immunosuppressive therapy[J] Br J Haematol 2008 143 5 738 743 19062343 \n10 Scheinberg P Nunez O Weinstein B Horse versus rabbit antithymocyte globulin in acquired aplastic anemia[J] N Engl J Med 2011 365 5 430 438 10.1056/NEJMoa1103975 21812672 \n11 Scheinberg P Nunez O Wu C Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil[J] Br J Haematol 2006 133 6 606 611 10.1111/j.1365-2141.2006.06085.x 16704434 \n12 Scheinberg P Wu CO Nunez O Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study[J] Haematologica 2009 94 3 348 354 10.3324/haematol.13829 19181786 \n13 Scheinberg P Nunez O Weinstein B Activity of alemtu-zumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia[J] Blood 2012 119 2 345 354 10.1182/blood-2011-05-352328 22067384\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-2727",
"issue": "37(7)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": null,
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D000368:Aged; D000741:Anemia, Aplastic; D000818:Animals; D000961:Antilymphocyte Serum; D016572:Cyclosporine; D006801:Humans; D011817:Rabbits; D012189:Retrospective Studies; D013552:Swine; D016896:Treatment Outcome",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "607-10",
"pmc": null,
"pmid": "27535863",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "20851870;16704434;22517900;22067384;21233311;3676511;16530266;21812672;19062343;779871;19181786;10049197;18322256",
"title": "Antithymocyte/Antilymphocyte globulin plus cyclosporine A therapy for the treatment of older patients with severe aplastic anemia.",
"title_normalized": "antithymocyte antilymphocyte globulin plus cyclosporine a therapy for the treatment of older patients with severe aplastic anemia"
} | [
{
"companynumb": "PHHY2017CN061322",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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{
"abstract": "Introduction: Diffuse alveolar hemorrhage (DAH) is an early pulmonary complication of hematopoietic cell transplantation (HCT) associated with severe hypoxemic respiratory failure and mortality. Extracorporeal membrane oxygenation (ECMO) support is often used for respiratory failure refractory to conventional interventions; however, its use has been limited in HCT patients with DAH due to potential for worsening alveolar hemorrhage and reported high mortality. Case Presentation: We report two cases of DAH following HCT who developed refractory hypoxemic respiratory failure despite cessation of bleeding and were successfully supported with ECMO. Conclusion: DAH after HCT should not automatically preclude ECMO support; rather, these patients must be evaluated individually for ECMO within the context of their overall clinical picture.",
"affiliations": "Division of Pediatric Critical Care, University of Tennessee Health Science Center, Memphis, TN, United States.;Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.;Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States.;Division of Solid Tumor, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.;Department of Bone Marrow Transplant, St. Jude Children's Research Hospital, Memphis, TN, United States.;Division of Pediatric Critical Care, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, United States.;Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States.;Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States.;Division of Pediatric Critical Care, University of Tennessee Health Science Center, Memphis, TN, United States.;Division of Pediatric Critical Care, University of Tennessee Health Science Center, Memphis, TN, United States.;Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States.",
"authors": "Fan|Kimberly|K|;Hurley|Caitlin|C|;McNeil|Michael J|MJ|;Agulnik|Asya|A|;Federico|Sara|S|;Qudeimat|Amr|A|;Saini|Arun|A|;McArthur|Jennifer|J|;Morrison|Ronald Ray|RR|;Sandhu|Hitesh|H|;Shah|Samir|S|;Ghafoor|Saad|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2020.587601",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360 Frontiers Media S.A. \n\n10.3389/fped.2020.587601\nPediatrics\nCase Report\nCase Report: Management Approach and Use of Extracorporeal Membrane Oxygenation for Diffuse Alveolar Hemorrhage After Pediatric Hematopoietic Cell Transplant\nFan Kimberly 1† Hurley Caitlin 2† McNeil Michael J. 3 Agulnik Asya 2 Federico Sara 4 Qudeimat Amr 5 Saini Arun 6 McArthur Jennifer 2 Morrison Ronald Ray 2 Sandhu Hitesh 1 Shah Samir 1 Ghafoor Saad 2* 1Division of Pediatric Critical Care, University of Tennessee Health Science Center, Memphis, TN, United States\n2Division of Critical Care, St. Jude Children's Research Hospital, Memphis, TN, United States\n3Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States\n4Division of Solid Tumor, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States\n5Department of Bone Marrow Transplant, St. Jude Children's Research Hospital, Memphis, TN, United States\n6Division of Pediatric Critical Care, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, United States\nEdited by: James Donald Fortenberry, Emory University, United States\n\nReviewed by: Timothy M. Maul, Nemours Children's Hospital, United States; Ravi R. Thiagarajan, Boston Children's Hospital and Harvard Medical School, United States\n\n*Correspondence: Saad Ghafoor saad.ghafoor@stjude.orgThis article was submitted to Pediatric Critical Care, a section of the journal Frontiers in Pediatrics\n\n†These authors have contributed equally to this work and share first authorship\n\n\n13 1 2021 \n2020 \n8 58760107 8 2020 14 12 2020 Copyright © 2021 Fan, Hurley, McNeil, Agulnik, Federico, Qudeimat, Saini, McArthur, Morrison, Sandhu, Shah and Ghafoor.2021Fan, Hurley, McNeil, Agulnik, Federico, Qudeimat, Saini, McArthur, Morrison, Sandhu, Shah and GhafoorThis 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.Introduction: Diffuse alveolar hemorrhage (DAH) is an early pulmonary complication of hematopoietic cell transplantation (HCT) associated with severe hypoxemic respiratory failure and mortality. Extracorporeal membrane oxygenation (ECMO) support is often used for respiratory failure refractory to conventional interventions; however, its use has been limited in HCT patients with DAH due to potential for worsening alveolar hemorrhage and reported high mortality.\n\nCase Presentation: We report two cases of DAH following HCT who developed refractory hypoxemic respiratory failure despite cessation of bleeding and were successfully supported with ECMO.\n\nConclusion: DAH after HCT should not automatically preclude ECMO support; rather, these patients must be evaluated individually for ECMO within the context of their overall clinical picture.\n\ndiffuse alveolar hemorrhage (DAH)hematopoitic stem cell transplantationextracorporeal mebrane oxygenationextracorporeal life support (ECLS)pediatric acute respiratory distress syndrome\n==== Body\nIntroduction\nDiffuse alveolar hemorrhage (DAH) is a known pulmonary complication following hematopoietic cell transplant (HCT). It usually occurs within the first 30 days following HCT and is diagnosed clinically by a constellation of hypoxemic respiratory failure, diffuse pulmonary infiltrates on chest radiography and progressively bloody bronchoalveolar lavage return on bronchoscopy (1–3). The pathogenesis of DAH is not clearly understood, but it is thought to develop from a combination of intrinsic lung injury, dysregulated inflammation, and cytokine release (1). It is classically considered a non-infectious process, although it may be precipitated by occult infections (3, 4). While systemic glucocorticoids are considered the mainstay of therapy, there is high variability in dosing, duration of therapy, and a reported mortality over 40% within the pediatric population (2, 3). More recently, cohorts of pediatric HCT patients treated with newer therapeutic agents, such as nebulized tranexamic acid (TXA) and intrapulmonary recombinant activated human factor VII (IP-rFVIIa), have demonstrated improved survival to over 65% (5, 6). Interventions such as extracorporeal membrane oxygenation (ECMO) have been used in non-HCT DAH (7, 8). HCT has historically been considered a contraindication for ECMO by some centers; therefore, its use has been limited (9). To our knowledge, there has only been one case report in the literature of ECMO use for DAH following HCT in pediatrics (10). We report two cases of pulmonary hemorrhage following HCT successfully supported with ECMO and present our approach to the management of these unique and complex patients.\n\nCase 1\nCase Presentation\nAn 18-year old female with Diamond-Blackfan anemia underwent a 10/10 matched unrelated donor (MUD) HCT, following a conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, thiotepa, and rabbit anti-thymoglobulin. The initial post-transplant course was complicated by fungal sepsis with Candida parapsilosis and a large right atrial thrombus for which she underwent open thrombectomy on cardiopulmonary bypass.\n\nOn HCT day 60 (Figure 1), she developed respiratory distress with bilateral pulmonary infiltrates on chest radiography. She was transferred to the intensive care unit (ICU) with worsening hypoxemia progressing to endotracheal intubation and mechanical ventilation. Bronchoscopy demonstrated many red blood cells and hemosiderin-laden macrophages consistent with DAH but no active hemorrhage. Bronchoalveolar lavage revealed positive aspergillus antigen, for which she was continued on antifungal therapy for probable pulmonary aspergillosis. She improved with supportive management and was extubated to non-invasive positive pressure support. However, on HCT day 69, she developed new bilateral infiltrates on chest radiography requiring reintubation (Figure 2). A repeat bronchoscopy showed persistence of hemosiderin-laden macrophages without evidence of active bleeding.\n\nFigure 1 Timeline of Events for Case 1. HCT, hematopoietic cell transplant; ICU, intensive care unit; ECMO, extracorporeal membrane oxygenation; CD, cluster of differentiation; G-CSF, granulocyte-colony stimulating factor.\n\nFigure 2 Serial chest radiographs for Case 1 demonstrating the progression and subsequent improvement of diffuse bilateral interstitial and alveolar opacities. (A) Initial decline prompting transfer to the ICU, (B) Mild respiratory improvement, (C) Worsening ARDS leading to transfer for ECMO evaluation, (D) ECMO–Cannulation, (E) Pre-decannulation.\n\nBy HCT day 76, she progressed to severe acute respiratory distress syndrome (ARDS) with a peak oxygenation index (OI) of 40. Given her acute deterioration, poor organ reserve, and high mortality risk, she was transferred to the regional pediatric ECMO program at Le Bonheur Children's Hospital and emergently cannulated onto Veno-Venous (VV) ECMO with placement of two-21 French Biomedicus (Medtronic, Minneapolis, MN, USA) cannulas in the right femoral and right internal jugular veins. She was adequately supported with initial flows of 2.16 liters per minute (LPM), ~40 ml/kg/min, and sweep gas flow of 3 LPM using the Maquet Rotaflow centrifugal pump and Quadrox-iD adult oxygenator (Maquet, Harlingen, Germany). She was anticoagulated on our institution's bleeding protocol with unfractionated heparin targeting an activated clotting time (ACT) of 180–200 s and transfused with packed red blood cells (PRBC) and platelets to keep hematocrit > 35% and platelet count > 75 × 109/L, respectively. She was treated with intravenous methylprednisolone 2 mg/kg/day for 7 days followed by a 6 week wean. She was successfully decannulated after 7 days of VV ECMO support. There was no recurrence of pulmonary hemorrhage on ECMO and she was transferred back to the referring institution 3 days after decannulation.\n\nAfter decannulation, she had multiple pulmonary hemorrhage episodes treated with methylprednisolone, aminocaproic acid, and IP-rFVIIa. A lung biopsy on HCT day 90 was indicative of recent and remote alveolar hemorrhages. Due to her recurrent pulmonary hemorrhages and evolving practice for early tracheostomy placement at that time, her tracheostomy was delayed for more than 60 days following her initial respiratory failure. She was considered a higher risk for early tracheostomy due to secondary graft insufficiency. She received a CD34+ cell boost on HCT day 259. After extensive inpatient rehabilitation, she was liberated from her tracheostomy and is successfully surviving 4 years after HCT.\n\nCase 2\nCase Presentation\nA 4-year-old male with metastatic neuroblastoma underwent his second tandem autologous HCT following a conditioning regimen of melphalan, etoposide, and carboplatin. His medical history was notable for acute kidney injury secondary to cisplatin with non-functioning right kidney on imaging. His transplant course was complicated by fever and severe mucositis and mild sinusoidal obstructive syndrome (SOS). On HCT day 4 (Figure 3), he was transferred to the ICU with systemic inflammatory response and worsening respiratory distress and was found to have Lactobacillus rhamnosus sepsis and mastoiditis. Despite treatment with broad-spectrum antibiotics and methylprednisolone 1 mg/kg/day, he had worsening respiratory distress requiring endotracheal intubation on HCT day 6. He subsequently developed bloody secretions in his endotracheal tube (ETT) which led to the discontinuation of defibrotide. Bronchoscopy showed copious mucopurulent secretions in the right lower lobe which became bloody with the second aliquot on BAL and were positive for Aspergillus. He was therefore treated for presumed fungal pneumonia. Methylprednisolone 1 mg/kg/day for 4 days and nebulized TXA (n-TXA) 250 mg were used for pulmonary hemorrhage control. In addition, a mean airway pressure (MAP) > 15 cm H2O was targeted to tamponade the bleed. He was transfused to maintain a hemoglobin > 7 gram/dL and a platelet count over 100 × 109/L, respectively. Hemostasis was achieved, however, he developed severe ARDS with a peak OI of 25. The ECMO liaison team initiated early joint discussions regarding ECMO candidacy at this time. The patient developed renal failure and fluid overload necessitating continuous renal replacement therapy (CRRT). Further, he had a rising lactate dehydrogenase, refractory hypertension and thrombocytopenia, he was treated with eculizumab for suspicion of transplant-associated thrombotic microangiopathy (TA-TMA).\n\nFigure 3 Timeline of Events for Case 2. HCT, hematopoietic cell transplant; ICU, intensive care unit; ETT, endotracheal tube; BAL, bronchoalveolar lavage; ECMO, extracorporeal membrane oxygenation; CRRT, continuous renal replacement therapy; TA-TMA, transplant-associated thrombotic microangiopathy.\n\nOn HCT day 24, he had an acute hypoxemic event with copious bloody secretions in his ETT. Chest radiography showed increased pulmonary opacities (Figure 4). Coagulation factors at that time included a platelet count of 97 × 109/L, and normal PT, INR, aPTT and fibrinogen levels. He was treated with intravenous TXA 1,000 mg bolus followed by 10 mg/kg/hr infusion, nebulized TXA 250 mg, and 3 doses of intrapulmonary rFVIIa (IP-rFVIIa) 50 μg/kg. Despite achieving hemostasis following IP-rFVIIa and escalation of his respiratory support to HFOV, he had progressive hypoxemia with an OI of 68. All infectious studies were negative. The added risk of mortality with multiorgan failure and SOS were discussed between the clinical and ECMO liaison teams but he was considered a candidate for ECMO due to the reversibility of his organ dysfunction. Due to his clinical acuity and high risk of death on the current support, he was transferred to the regional ECMO program. Upon arrival at the referral center, he was placed on HFOV while awaiting cannulation. Due to his small size and the presence of a femoral vascath, he was cannulated onto VA ECMO with a 14 French arterial cannula in the right carotid artery and a 15 French venous canula in the right internal jugular vein (BioMedicus Medtronic, Minneapolis, MN, USA). He was supported with initial flows of 1.3 liters per minute (LPM), ~110 ml/kg/min, and sweep gas flow of 0.6 LPM using the Maquet CardioHelp centrifugal pump and HLS Set Advanced 7.0 Oxygenator (Maquet, Rastatt, Germany). For anticoagulation, he was placed on a bivalirudin infusion per institutional preference, titrated to maintain aPTT of 40–60 s. Given the need for systemic anticoagulation, he was treated with three additional doses of nebulized IP-rFVIIa 50 μg/kg and received IV methylprednisolone 2 mg/kg/day and n-TXA 250 mg every 6 h throughout his ECMO course. He had no further episodes of DAH or thromboembolic complications. CRRT was continued for fluid overload. He was maintained on higher MAP during the course of his ECMO stay. He was decannulated after 10 days of ECMO support and transferred back to the referring institution the following day.\n\nFigure 4 Serial chest radiographs for Case 2 demonstrating the progression and subsequent improvement of diffuse bilateral interstitial and alveolar opacities (A) Following intubation, (B) Prior to transfer for ECMO evaluation, (C) Following ECMO cannulation, (D) Prior to ECMO decannulation, (E) Post-transfer back to referring center.\n\nFollowing return of renal function, CRRT was discontinued. He underwent tracheostomy placement 11 days following ECMO decannulation to allow gradual weaning of mean airway pressure and facilitate rehabilitation. He was weaned off mechanical ventilation support, transferred to the general medical floor under the care of the oncology team for continued radiation and chemotherapy, and successfully discharged to outpatient care on HCT day 109. He remains well 6 months following hospital discharge.\n\nFamily Perspectives\nWe asked the families to share their thoughts and experiences through the course of their children's illness and hospital course. As expected, the families' found the process stressful but were ultimately relieved and grateful for the outcome.\n\nPerspective From the Mother of Patient 1\n“There are things I remember so vividly about my daughter's experience on ECMO, and things that I think my mind has chosen to forget out of self-protection. I remember listening through the glass doors in the ICU, [the intensivist] arguing for why my daughter should be [an ECMO candidate]. I remember watching the team wheel her out [for transfer to the ECMO referral center], and the look on their faces is what sticks with me the most. They were trying so hard to be brave for us, but everyone knew […] that she may not come back. I was simply in survival mode at that point. My daughter doesn't remember much about ECMO, which is a blessing considering how difficult the experience was, both clinically and emotionally. I am forever grateful to everyone that played a part in saving my daughter's life, and my sanity during such trying times.”\n\nPerspective From the Mother of Patient 2\nWhen describing the experience, our patient's mother's first response was that of shock. It was difficult for her to recall specific emotions or thoughts during this distressing experience. She expressed appreciation for the support she received from the medical team. She was particularly grateful for the careful and thoughtful approach from team members when making difficult medical decisions. She recognized it was not one individual deciding her son's care but a collaborative expert medical team. One statement she felt was unhelpful but heard repeatedly was “things will get worse before they get better.” She knew it was valuable information but hearing it continually became exasperating. She understood that once her son was on ECMO the only thing worse would be losing him. She is extremely grateful that he is better and doing well-today.\n\nDiscussion\nDiagnosis and Evaluation\nDAH is a known pulmonary complication of HCT with a historically high mortality rate (2, 3). While there is no standardized laboratory or radiographic feature pathognomonic for DAH, it is clinically diagnosed by respiratory failure, diffuse infiltrates on chest radiography, and restrictive lung disease. It is confirmed with progressively bloodier BAL on bronchoscopy or ≥20% hemosiderin-laden alveolar macrophages (1). The use of newer, more specific agents, such as n-TXA and IP-rFVIIa (5, 6), have improved survival over the last decade, DAH still carries significant morbidity and mortality. Therefore, we recommend a holistic, multidisciplinary team approach. At our institution, treatment of DAH is guided by the principles of early recognition and diagnosis, achieving hemostasis, decreasing inflammation, and ultimately allowing for endothelial healing. Post-HCT, patients are monitored closely in the transplant unit for changes in respiratory status or new findings on chest radiography. If these are detected, prompt bronchoscopy is performed to identify and treat potential infectious sources. As most patients with DAH eventually develop respiratory failure and require intensive care (2, 3, 11), patients are transferred to the ICU early for continued monitoring if DAH is suspected. Additional evaluation including computed tomography of the chest and early lung biopsy is considered. Our management plan rests on the hypothesis that endothelial damage underlies many complications of HCT (12). The diagnosis of TA-TMA is pursued early and eculizumab given when indicated. We provide supportive treatment to allow time for the endothelium to heal.\n\nActive Bleeding\nOnce DAH is diagnosed, our standardized treatment protocol includes systemic glucocorticoids and nebulized TXA, with the addition of IP-rFVIIa if there is refractory hemorrhage. Initially, methylprednisolone is dosed at 2 mg/kg/day with an accelerated taper over 4–8 weeks, particularly if there is concern for disseminated viral infection. We strongly consider the use of pulse dose glucocorticoids, methylprednisolone 15–30 mg/kg/day or dexamethasone 4-5 mg/kg/day, for 2–3 days followed by a taper over 4–8 weeks to maximize the genomic and non-genomic anti-inflammatory effects of glucocorticoids (13, 14). Nebulized TXA is given every 6 h over the first 18–24 h. If the bleeding continues, then IP-rFVIIa 50 μg/kg is added. IP-rFVIIa is initially administered every 15–30 min until hemostasis is achieved and subsequently continued every 4–6 h for a maximum of 3 days. Respiratory failure is managed with early endotracheal intubation and mechanical ventilation with MAP > 15 cmH2O to tamponade the bleeding. Continuous renal replacement therapy is considered early to manage fluid overload. During active bleeding, PRBC and platelet transfusions are used to maintain hemoglobin over 7 gram/dl and a platelet count over 50 × 109/L respectively. Rotational thromboelastometry (ROTEM) is used to further guide therapy.\n\nDAH has been described in the setting of TA-TMA (15), a subset of thrombotic microangiopathies characterized by the presence of schistocytes, elevated serum LDH, renal, and neurologic dysfunction (16). In the setting of TA-TMA, DAH has a reported mortality rate of up to 100% (15). Eculizumab is a complement inhibitor that is promising in the treatment of TA-TMA (17). Therefore, if there is suspicion of TA-TMA as in our second case, the addition of eculizumab is considered in collaboration with the transplant team. As occult infections have later been identified in patients with DAH despite initial negative cultures, we empirically start patients on broad spectrum antimicrobials and continue treatment for at least 48 h. A second bronchoscopy is frequently performed 2 to 5 days after the development of symptoms for repeat cultures.\n\nIdiopathic pneumonia syndrome (IPS) is another non-infectious pulmonary complication of HCT and shares many clinical features with DAH. It is characterized by elevated levels of specific cytokines, including tumor necrosis factor receptor-1 (TNFR1), a marker for tumor necrosis factor- alpha (TNF-α). IPS is treated with glucocorticoids and etanercept, a TNF-α binding protein (18). Thus, if no infectious process is identified and IPS is of concern, treatment with etanercept is considered. For refractory hypoxemic respiratory failure despite cessation of bleeding, use of ECMO is considered as discussed below.\n\nRecurrent Bleeding\nIn cases of recurrent bleeding, in addition to the above treatments, we consider early tracheostomy with the goals of maintaining a high mean airway pressure with mechanical ventilation for >4 weeks while endothelial healing occurs and allowing for early mobilization and rehabilitation.\n\nECMO Decision\nThe medical complexity of HCT care inherently raises the PICU mortality when compared to the general population (19). As such, underlying malignancy and HCT are considered contraindications for ECMO support by most centers. In a review of the Extracorporeal Life Support Organization (ELSO) database, Gow et al. identified 107 patients with underlying malignancies supported with ECMO from 1994 to 2007. Of these, 42% survived to ECMO decannulation and 35% survived to hospital discharge, suggesting that ECMO use may be a reasonable support modality in this patient population (20). Unfortunately, ECMO outcomes in HCT patients have been worse. In another review of the ELSO database from 1991 to 2004, Gow et al. reported a 21% and 5% survival to ECMO decannulation and hospital discharge, respectively, in HCT patients (9). In 2014, DiNardo et al. published an extended review of ECMO support post-HCT from the ELSO database from 1991 to 2012 and found that 21% survived to decannulation and 10% survived to hospital discharge (21). However, since these publications, there have been significant advancements in HCT care, including conditioning regimens, donor cell source selection, HLA matching, preparation and supportive care (22). Likewise, technological advances in ECMO support and improvements in the management of mechanical ventilated patients have resulted in improved ECMO outcomes (23, 24). Zinter et al. found a 22% PICU survival in HCT patients supported with ECMO from 2009 to 2014 (19). Most recently, in a review of HCT patients supported with ECMO from 2011 to 2018, Steppan et al. found that 4 out of 8 patients survived to hospital discharge (25). Additionally, successful ECMO after HCT cases not included in aforementioned reviews have been reported. Williams et al. reported a 18 month old patient with acute respiratory failure from rhinovirus infection and aspiration pneumonia after autologous HCT for neuroblastoma who was successfully supported with VV ECMO (26). Potratz et al. reported a 14 year old allogeneic HCT patient with acute respiratory failure secondary to engraftment syndrome successfully supported on VV ECMO (27). Morris et al. reported the successful use of ECMO for diffuse alveolar hemorrhage post-HCT in a single pediatric patient (10). Together with our patients, there are now 3 pediatric patients successfully supported for post-HCT DAH with ECMO support.\n\nChoosing which HCT patient has a reasonable chance of recovery with ECMO support is challenging. In collaboration with our regional pediatric ECMO program at Le Bonheur Children's Hospital, we have developed a liaison team to assess ECMO candidacy with the goals of arranging timely transfer for ECMO evaluation and early ECMO initiation to limit significant ventilator-induced lung injury. This ECMO liaison team was instrumental in the process of case discussion and patient advocacy for transfer and early initiation of extracorporeal therapy in the cases reported here. The liaison teams consist of intensivists at both institutions and garners input from oncologists, HCT physicians and other specialties as needed on a case by case basis. We also review the indications, risks, and benefits of ECMO with the patient's family to allow them to make an informed decision regarding transfer for ECMO evaluation during these initial discussions. We begin ECMO candidacy discussions early—ideally days before the patient requires transfer for ECMO evaluation. In general, the criteria for ECMO initiation is similar to that which is used for our general pediatric population, with a few considerations specific to oncologic and HCT patients. HCT patients represent a heterogenous population with various underlying diseases, conditioning regimens, cell sources and post HCT comorbidities. These patients must be individually evaluated for the potential of ECMO benefit. The ECMO liaison team is invaluable for teasing out the nuances of individual patient factors.\n\nOur report is limited by an inherent selection bias for HCT ECMO survivors who had cessation of pulmonary hemorrhage prior to ECMO initiation since active bleeding not controlled with medical management is considered an institutional contraindication for ECMO at this time. As such, we do not include patients with DAH who were not considered ECMO candidates in this case series. A concern in the HCT population has been that while ECMO supports the lungs, it may worsen other organ dysfunction and increase infection risk. This concern has limited the use of ECMO in the HCT population. Our cases highlight that HCT and DAH should not absolutely preclude patients from ECMO candidacy. HCT patients should be evaluated within the context of their overall clinical picture.\n\nConclusion\nECMO support has historically been considered contraindicated in HCT patients given the complexity of their disease. Through the development of a multidisciplinary approach in treatment of DAH post-HCT, as well as an expert ECMO liaison team to evaluate ECMO candidacy, we successfully supported two patients with respiratory failure secondary to DAH refractory with ECMO. Over the last decade, there have been significant advances made in ECMO technology as well as the field of HCT, we argue that ECMO use should be considered in select HCT patients.\n\nData Availability Statement\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\nWritten 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\nKF provided substantial contribution to the conception, literature search, and drafting of the manuscript. CH provided substantial contribution to the drafting and critical revisions of the manuscript. MM and SF obtained informed consent for publication of the second case, contributed to writing the family perspective, and provided critical revisions of the content. AA, AQ, AS, JM, RM, HS, and SS provided critical intellectual revisions of the manuscript content. SG provided substantial contribution to the conception, literature search, intellectual content, critical revision, approval of the final version of the manuscript, and agrees to be accountable for all aspects of the work related to accuracy and integrity. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\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\nWe would like to thank Ashlea Anderson, NP for obtaining informed consent for publication and the family perspective for case 1. We would like to thank the ICU team at St. Jude Children's Research Hospital, the ICU team, ECMO coordinators and specialists at Le Bonheur Children's Hospital for their management and family support during ECMO.\n==== Refs\nReferences\n1. Afessa B Tefferi A Litzow MR Krowka MJ Wylam ME Peters SG \nDiffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients\n. Am J Respir Crit Care Med. (2002 ) 166 :641 –5\n. 10.1164/rccm.200112-141CC 12204858 \n2. Ben-Abraham R Paret G Cohen R Szold O Cividalli G Toren A \nDiffuse alveolar hemorrhage following allogeneic bone marrow transplantation in children\n. Chest. (2003 ) 124 :660 –4\n. 10.1378/chest.124.2.660 12907557 \n3. Heggen J West C Olson E Olson T Teague G Fortenberry J \nDiffuse alveolar hemorrhage in pediatric hematopoietic cell transplant patients\n. Pediatrics. (2002 ) 109 :965 –71\n. 10.1542/peds.109.5.965 11986464 \n4. Agusti C Ramirez J Picado C Xaubet A Carreras E Ballester E . 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Comprehensive prognostication in critically ill pediatric hematopoietic cell transplant patients: results from merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) registries\n. Biol Blood Marrow Transplant. (2020 ) 26 :333 –42\n. 10.1016/j.bbmt.2019.09.027 31563573 \n20. Gow KW Heiss KF Wulkan ML Katzenstein HM Rosenberg ES Heard ML \nExtracorporeal life support for support of children with malignancy and respiratory or cardiac failure: the extracorporeal life support experience\n. Crit Care Med. (2009 ) 37 :1308 –16\n. 10.1097/CCM.0b013e31819cf01a 19242331 \n21. Di Nardo M Locatelli F Palmer K Amodeo A Lorusso R Belliato M . Extracorporeal membrane oxygenation in pediatric recipients of hematopoietic stem cell transplantation: an updated analysis of the extracorporeal life support organization experience\n. Intensive Care Med. (2014 ) 40 :754 –6\n. 10.1007/s00134-014-3240-9 24556913 \n22. McDonald GB Sandmaier BM Mielcarek M Sorror M Pergam SA Cheng GS . Nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: comparing 2003-2007 versus 2013-2017 cohorts\n. Ann Intern Med. (2020 ) 172 :229 –39\n. 10.7326/M19-2936 31958813 \n23. Bartlett RH \nECMO: the next ten years\n. Egypt J Critic Care Med . (2016 ) 4 :7 –10\n. 10.1016/j.ejccm.2016.01.003 \n24. Solé A Jordan I Bobillo S Moreno J Balaguer M Hernández-Platero L . Venoarterial extracorporeal membrane oxygenation support for neonatal and pediatric refractory septic shock: more than 15 years of learning\n. Eur J Pediatr. (2018 ) 177 :1191 –200\n. 10.1007/s00431-018-3174-2 29799085 \n25. Steppan DA Coleman RD Viamonte HK Hanson SJ Carroll MK Klein OR . Outcomes of pediatric patients with oncologic disease or following hematopoietic stem cell transplant supported on extracorporeal membrane oxygenation: The PEDECOR experience\n. Pediatric Blood Cancer . (2020 ) 67 :e28403 . 10.1002/pbc.28403 32519430 \n26. Williams FZ Vats A Cash T Fortenberry JD \nSuccessful use of extracorporeal life support in a hematopoietic stem cell transplant patient with neuroblastoma\n. J Extra Corpor Technol. (2018 ) 50 :61 –4\n.29559757 \n27. Potratz J Ahlmann M Rössig C Omran H Masjosthusmann K . Successful extracorporeal life support in a pediatric hematopoietic stem cell transplant recipient with periengraftment respiratory failure\n. J Pediatr Hematol Oncol. (2018 ) 40 :e256 –9\n. 10.1097/MPH.0000000000000929 28816799\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "8()",
"journal": "Frontiers in pediatrics",
"keywords": "diffuse alveolar hemorrhage (DAH); extracorporeal life support (ECLS); extracorporeal mebrane oxygenation; hematopoitic stem cell transplantation; pediatric acute respiratory distress syndrome",
"medline_ta": "Front Pediatr",
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"nlm_unique_id": "101615492",
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"title": "Case Report: Management Approach and Use of Extracorporeal Membrane Oxygenation for Diffuse Alveolar Hemorrhage After Pediatric Hematopoietic Cell Transplant.",
"title_normalized": "case report management approach and use of extracorporeal membrane oxygenation for diffuse alveolar hemorrhage after pediatric hematopoietic cell transplant"
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"abstract": "Background. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), are associated with gastrointestinal toxicity. MTX inhibits dihydrofolate reductase, but it is unclear if polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene predict toxicity. Case. We describe a 33-year-old male with polyarticular rheumatoid arthritis who developed sigmoid diverticular perforation while receiving methotrexate, folic acid, prednisone, and naproxen. He tested heterozygous for the C677T allele MTHFR gene. Discussion. Rheumatoid arthritis and its treatments are associated with increased risk of gastrointestinal disease. In one study, perforation was highest among individuals with concomitant exposure to NSAIDs, nonbiologic DMARDs, and glucocorticoids. Multiple mutations of the MTHFR gene have been identified, but their association with MTX toxicity is unclear. This case adds to a growing body of literature that could help inform the treatment of others in the future.",
"affiliations": "Department of Medicine, Michigan State University, East Lansing, MI 48824, USA ; EW Sparrow Hospital, Lansing, MI 48912, USA.;Department of Medicine, Michigan State University, East Lansing, MI 48824, USA ; Arthritis Care, PC, Lansing, MI 48906, USA.;Department of Medicine, Michigan State University, East Lansing, MI 48824, USA ; EW Sparrow Hospital, Lansing, MI 48912, USA.",
"authors": "Chang|Ian|I|;Guggenheim|Carla|C|;Laird-Fick|Heather|H|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/617268Case ReportA Case of Diverticular Perforation in a Young Patient with Rheumatoid Arthritis on Methotrexate Chang Ian \n1\n\n2\n\n*\nGuggenheim Carla \n1\n\n3\nLaird-Fick Heather \n1\n\n2\n1Department of Medicine, Michigan State University, East Lansing, MI 48824, USA2EW Sparrow Hospital, Lansing, MI 48912, USA3Arthritis Care, PC, Lansing, MI 48906, USA*Ian Chang: ian.chang@hc.msu.eduAcademic Editor: Remo Panaccione\n\n2015 29 4 2015 2015 61726821 1 2015 14 4 2015 Copyright © 2015 Ian Chang et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), are associated with gastrointestinal toxicity. MTX inhibits dihydrofolate reductase, but it is unclear if polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene predict toxicity. Case. We describe a 33-year-old male with polyarticular rheumatoid arthritis who developed sigmoid diverticular perforation while receiving methotrexate, folic acid, prednisone, and naproxen. He tested heterozygous for the C677T allele MTHFR gene. Discussion. Rheumatoid arthritis and its treatments are associated with increased risk of gastrointestinal disease. In one study, perforation was highest among individuals with concomitant exposure to NSAIDs, nonbiologic DMARDs, and glucocorticoids. Multiple mutations of the MTHFR gene have been identified, but their association with MTX toxicity is unclear. This case adds to a growing body of literature that could help inform the treatment of others in the future.\n==== Body\n1. Introduction\nRheumatoid arthritis (RA) is a chronic inflammatory disorder affecting symmetric small and large joints associated with bone deformity and destruction. Common symptoms include pain, morning stiffness, and joint swelling. The clinical diagnosis is supported by elevated serum rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA). Pulmonary, cardiovascular, renal, gastrointestinal (GI), and dermatologic involvement may be associated with disease progression or iatrogenically induced during medical management. RA treatment seeks to mitigate symptoms, prevent joint damage, and improve quality of life. Definitive treatment for rheumatoid arthritis begins with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX). However, methotrexate has significant adverse side effects including pulmonary and hepatic toxicity. In addition, methotrexate treatment causes increased mucosal turnover and oral ulcerations which may increase the risk of GI complications [1]. We herein present a case where methotrexate may have been responsible for colonic perforation in a patient with RA.\n\n2. Case\nA 33-year-old nonsmoking Caucasian male with family history of RA and lupus, but no diverticulosis, presented to the clinic with complaints of symmetric hand, foot, neck, shoulder, knee, and ankle pain. He had morning stiffness and pain lasting several hours and denied ocular irritation, melena, skin rash, or history of sexually transmitted disease. He had some difficulty dressing himself including closing shirt buttons and tying shoes. He was diagnosed with polyarticular, RF positive, ACPA positive rheumatoid arthritis. He was started on methotrexate 17.5 mg orally weekly, folic acid, and prednisone. He used naproxen as needed. His symptoms did not improve, so he was started on sulfasalazine and hydroxychloroquine. Approximately eight months later, his arthritis was well controlled with methotrexate, low-dose oral prednisone (2 mg daily), and naproxen as needed; both sulfasalazine and hydroxychloroquine were discontinued.\n\nOne day he developed sudden, severe abdominal pain. X-rays in the emergency department identified mildly prominent loops of small bowel and a few scattered air-fluid levels, consistent with mild ileus. CT abdomen/pelvis without contrast showed perforated solitary sigmoid colonic diverticula with pneumoperitoneum; there was no abscess (Figure 1). He underwent urgent partial colectomy with diverting colostomy. Pathology revealed a lesion with hemorrhagic and granular mucosa, consistent with diverticulitis. There were no other diverticula. Over the next year, he underwent a colostomy take-down and reanastomosis with loop ileostomy and then finally ileostomy reversal. Additional testing revealed that he was heterozygous for the C677T allele methylenetetrahydrofolate reductase (MTHFR) gene mutation. He recovered well following his surgeries and has been off methotrexate since, declining to ever use it again. He subsequently did well on hydroxychloroquine and etanercept.\n\n3. Discussion\nRheumatoid arthritis is associated with increased risk of upper and lower GI disease [2]. Although the incidence of upper GI disease, such as ulcers and bleeding, has decreased with newer therapeutic regimens, there has been no change in the incidence of lower GI complications (i.e., diverticulitis, colitis, and perforation).\n\nMpofu et al. showed that corticosteroids, independent of rheumatic diagnoses, are associated with increased risk of sigmoid diverticular abscess perforation (SDAP) [3]. Glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) in combination further increase the risk of GI bleed and perforation in older patients with diverticulosis [4]. Gastrointestinal perforation is most frequent among patients treated with NSAIDs, nonbiologic DMARDs, and glucocorticoids. Prior studies have shown that exposure to DMARDs alone does not increase risk for bowel perforation [5]. Similarly, biologic agents generally do not increase the risk of perforation either. One exception is tocilizumab, a humanized anti-human interleukin-6 receptor antibody, which may cause intestinal perforation; it is contraindicated in older patients and patients with history of diverticulitis [5].\n\nIn this unusual case, our otherwise healthy young man on methotrexate, subphysiologic prednisone, and nondaily naproxen for RA suffered perforation of solitary, uninfected diverticula. His pathology was inconsistent with hereditary diverticulosis. The precise contributions of MTX, prednisone, and naproxen to his perforation are unclear, but a recent meta-analysis has suggested that polymorphisms of the MTHFR gene, such as the one our patient had, may contribute to methotrexate toxicity in patients with RA [6].\n\nMore investigation and clinical vigilance regarding the safety of methotrexate, NSAIDs, and corticosteroids alone or in combination will likely be beneficial. Furthermore, analysis of the potential association of MTHFR gene mutations (either heterozygous or homozygous) and methotrexate toxicity may prove to be crucial in preventing serious morbidity and mortality.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Wall thickening and inflammatory changes involving the sigmoid colon with multifocal pneumoperitoneum. Scattered hypodense collections in the abdomen and pelvis without obvious well-defined, rim-enhancing abscess.\n==== Refs\n1 Hoekstra M. van Ede A. E. Haagsma C. J. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis Annals of the Rheumatic Diseases 2003 62 5 423 426 2-s2.0-0037404893 10.1136/ard.62.5.423 12695153 \n2 Myasoedova E. Matteson E. L. Talley N. J. Crowson C. S. Increased incidence and impact of upper and lower gastrointestinal events in patients with rheumatoid arthritis in Olmsted County, Minnesota: a longitudinal population-based study The Journal of Rheumatology 2012 39 7 1355 1362 2-s2.0-84863529243 10.3899/jrheum.111311 22467929 \n3 Mpofu S. Mpofu C. M. A. Hutchinson D. Maier A. E. Dodd S. R. Moots R. J. Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions Annals of the Rheumatic Diseases 2004 63 5 588 590 10.1136/ard.2003.010355 2-s2.0-1942468044 15082493 \n4 Curtis J. R. Lanas A. John A. Johnson D. A. Schulman K. L. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis Arthritis Care and Research 2012 64 12 1819 1828 10.1002/acr.21764 2-s2.0-84870529267 22730417 \n5 Závada J. Lunt M. Davies R. Clinical and epidemiological research concise report: the risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA Annals of the Rheumatic Diseases 2014 73 1 252 255 23644671 \n6 Song G. G. Bae S.-C. Lee Y. H. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis Clinical Rheumatology 2014 33 12 1715 1724 10.1007/s10067-014-2645-8 2-s2.0-84901730610 24794492\n\n",
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"title": "A Case of Diverticular Perforation in a Young Patient with Rheumatoid Arthritis on Methotrexate.",
"title_normalized": "a case of diverticular perforation in a young patient with rheumatoid arthritis on methotrexate"
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"abstract": "Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma.\n\n\n\nA 62-year-old man was treated with nivolumab for papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy showed focal segmental glomerulosclerosis. Treatment with high-dose corticosteroids had insufficient effect, but the addition of mycophenolate mofetil resulted in remission of the nephrotic syndrome and recovery of renal function. Proteinuria subsequently relapsed during corticosteroid tapering.\n\n\n\nThe time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication.",
"affiliations": "Departments of *Internal Medicine †Nephrology ‡Medical Oncology §Pathology, Radboud university medical center, Nijmegen, The Netherlands.",
"authors": "Daanen|Robin A|RA|;Maas|Rutger J H|RJH|;Koornstra|Rutger H T|RHT|;Steenbergen|Eric J|EJ|;van Herpen|Carla M L|CML|;Willemsen|Annelieke E C A B|AECAB|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; D009173:Mycophenolic Acid",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D020127:Recovery of Function; D012008:Recurrence",
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"title": "Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report.",
"title_normalized": "nivolumab associated nephrotic syndrome in a patient with renal cell carcinoma a case report"
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"abstract": "Patients on systemic glucocorticoids for GVHD after hematopoietic cell transplant are susceptible to invasive fungal infections (IFI), which greatly contribute to morbidity and mortality. We evaluated the efficacy of prophylactic treatment options (voriconazole or fluconazole vs itraconazole) for IFI by performing a retrospective review of patients on glucocorticoids for GVHD who were administered voriconazole (n=97), fluconazole (n=36) or itraconazole (n=36). IFI developed in 7/72 (10%) patients on fluconazole/itraconazole vs 2/97 (2%) on voriconazole (P=0.03) within the first 100 days of glucocorticoids. Five (7%) patients developed Aspergillus IFI on fluconazole/itraconazole, compared with none on voriconazole (0%) (P=0.008); Aspergillus IFI resulted in death in all five patients. We found that IFI occurred in patients who received an initial dose of at least 2 mg/kg/day of prednisone or equivalent; when the analysis was restricted to these patients, the hazard ratio (0.39; 95% confidence interval: 0.08-1.86) was consistent with a protective effect of voriconazole compared with fluconazole/itraconazole, although this subset analysis did not reach significance. OS at 100 days after start of glucocorticoids was 77% in patients administered fluconazole/itraconazole and 85% in those administered voriconazole (P=0.22). Our results suggest that voriconazole is more effective than fluconazole/itraconazole in preventing IFI, especially aspergillosis, in patients receiving glucocorticoids post transplant.",
"affiliations": "Department of Medicine, Weill Cornell Medical College, New York, NY, USA.",
"authors": "Gergis|U|U|;Markey|K|K|;Greene|J|J|;Kharfan-Dabaja|M|M|;Field|T|T|;Wetzstein|G|G|;Schell|M J|MJ|;Huang|Y|Y|;Anasetti|C|C|;Perkins|J|J|",
"chemical_list": "D000935:Antifungal Agents; D005938:Glucocorticoids; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D015725:Fluconazole; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2009.210",
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"issn_linking": "0268-3369",
"issue": "45(4)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D018890:Chemoprevention; D005260:Female; D015725:Fluconazole; D005938:Glucocorticoids; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D011743:Pyrimidines; D012189:Retrospective Studies; D014230:Triazoles; D065819:Voriconazole",
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"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
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"title": "Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD.",
"title_normalized": "voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for gvhd"
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"abstract": "We report the virological monitoring and the antiviral therapy adopted for the treatment of a patient affected by chronic B lymphocytic leukemia, who experienced a severe pneumonia with long-term shedding of influenza virus A(H1N1)pdm09, characterized by an early development of oseltamivir resistance.",
"affiliations": "Department of Molecular Medicine, University of Padova, Padova, Italy; Microbiology and Virology Unit, Azienda Ospedaliera di Padova, Padova, Italy.;Division of Infectious Diseases, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy; Microbiology and Virology Unit, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy.;Division of Infectious Diseases, Azienda Ospedaliera di Padova, Padova, Italy.;Division of Infectious Diseases, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy; Microbiology and Virology Unit, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy; Microbiology and Virology Unit, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy.;Department of Molecular Medicine, University of Padova, Padova, Italy; Microbiology and Virology Unit, Azienda Ospedaliera di Padova, Padova, Italy. Electronic address: giorgio.palu@unipd.it.",
"authors": "Salata|Cristiano|C|;Sgarabotto|Dino|D|;Del Vecchio|Claudia|C|;Solimbergo|Erica|E|;Marini|Giulia|G|;Nicolè|Stefano|S|;Franchin|Elisa|E|;Parolin|Cristina|C|;Calistri|Arianna|A|;Palù|Giorgio|G|",
"chemical_list": "D000998:Antiviral Agents; D053139:Oseltamivir; D053243:Zanamivir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.11.008",
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"issue": "25(7)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "A(H1N1)pdm09; Chronic lymphocytic leukemia; Influenza virus; Oseltamivir resistance; Triple-combination antiviral drug therapy (TCAD); Zanamivir",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D053139:Oseltamivir; D011024:Pneumonia, Viral; D016896:Treatment Outcome; D017201:Virus Shedding; D053243:Zanamivir",
"nlm_unique_id": "9608375",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antiviral treatment and virological monitoring of oseltamivir-resistant influenza virus A(H1N1)pdm09 in a patient with chronic B lymphocytic leukemia.",
"title_normalized": "antiviral treatment and virological monitoring of oseltamivir resistant influenza virus a h1n1 pdm09 in a patient with chronic b lymphocytic leukemia"
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"abstract": "We herein describe the case of a 63-year-old man who died from relapsed epidermal growth factor receptor gene (EGFR) exon 19 deletion lung adenocarcinoma treated with erlotinib. According to the autopsy results, he was confirmed to have small cell carcinoma without the EGFR T790M mutation in his pancreas and left kidney metastatic specimens, while the adenocarcinoma metastatic lesion in his right kidney had the EGFR T790M mutation; both retained the somatic EGFR exon 19 deletion. We herein report an autopsy case of resistance to an EGFR tyrosine kinase inhibitor via small cell carcinoma transformation and the EGFRT790M mutation in separate metastatic organs.",
"affiliations": "Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases (The First Department of Internal Medicine), Faculty of Medicine, University of the Ryukyus, Japan.",
"authors": "Furugen|Makoto|M|;Uechi|Kayoko|K|;Hirai|Jun|J|;Aoyama|Hajime|H|;Saio|Masanao|M|;Yoshimi|Naoki|N|;Kinjo|Takeshi|T|;Miyagi|Kazuya|K|;Haranaga|Shusaku|S|;Higa|Futoshi|F|;Tateyama|Masao|M|;Fujita|Jiro|J|",
"chemical_list": "D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors",
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"delete": false,
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"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents; D001344:Autopsy; D018288:Carcinoma, Small Cell; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D017353:Gene Deletion; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation",
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"title": "An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation.",
"title_normalized": "an autopsy case of two distinct acquired drug resistance mechanisms in epidermal growth factor receptor mutant lung adenocarcinoma small cell carcinoma transformation and epidermal growth factor receptor t790m mutation"
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"abstract": "BACKGROUND Serotonin syndrome is a life-threatening condition that can lead to neurologic complications and is associated with the use of serotonergic medications. As the use of antidepressant medications has increased, the incidence of perioperative serotonin syndrome has transitioned from a rare diagnosis to one that should be considered as a differential diagnosis for any patient displaying signs of neuroexcitation. CASE REPORT A 70-year-old man (ASA 2) with a history of vestibular migraines (treated with venlafaxine), gastroesophageal reflux disease, and benign prostatic hyperplasia presented to our institution for photoselective vaporization of the prostate. Upon review of prior anesthetic records, his medical chart was found to list a propofol allergy. In discussion with the patient, he stated the reaction was rigidity. The anesthesiologist and patient agreed this was not an allergy. Thus, the patient was induced with propofol and given ketamine and fentanyl boluses throughout the procedure. During emergence, the patient exhibited myoclonic jerks in the upper and lower extremities. He was given intravenous meperidine for postoperative shivering; minutes after administration, the myoclonic jerks and rigidity worsened. The anesthesia team raised concern about serotonin syndrome. Intravenous midazolam improved the patient's myoclonic jerks and rigidity. CONCLUSIONS Patients with a history of rigidity/movement disorders during the perioperative period may have experienced serotonin toxicity. It is possible, as in our case, for this history to have been labelled as an allergy to a perioperative medication. Clinicians should remain vigilant for patients at risk of developing serotonin syndrome, such as those taking outpatient medications that increase neuronal serotonin.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Smischney|Nathan J|NJ|;Pollard|Emily M|EM|;Nookala|Asha U|AU|;Olatoye|Oludare O|OO|",
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"doi": "10.12659/AJCR.909497",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3000846710.12659/AJCR.909497909497ArticlesSerotonin Syndrome in the Perioperative Setting Smischney Nathan J. ABCDEFGPollard Emily M. BDEFNookala Asha U. BDEFOlatoye Oludare O. BDEFDepartment of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, U.S.A.Authors’ 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\nCorresponding Author: Nathan J. Smischney, e-mail: smischney.nathan@mayo.edu2018 16 7 2018 19 833 835 13 2 2018 08 5 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 70\n\nFinal Diagnosis: Serotonin syndrome\n\nSymptoms: Myoclonus • rigidity\n\nMedication: —\n\nClinical Procedure: Photoseletive vaporization of prostate\n\nSpecialty: Anasthesiology\n\nObjective:\nMistake in diagnosis\n\nBackground:\nSerotonin syndrome is a life-threatening condition that can lead to neurologic complications and is associated with the use of serotonergic medications. As the use of antidepressant medications has increased, the incidence of perioperative serotonin syndrome has transitioned from a rare diagnosis to one that should be considered as a differential diagnosis for any patient displaying signs of neuroexcitation.\n\nCase Report:\nA 70-year-old man (ASA 2) with a history of vestibular migraines (treated with venlafaxine), gastroesophageal reflux disease, and benign prostatic hyperplasia presented to our institution for photoselective vaporization of the prostate. Upon review of prior anesthetic records, his medical chart was found to list a propofol allergy. In discussion with the patient, he stated the reaction was rigidity. The anesthesiologist and patient agreed this was not an allergy. Thus, the patient was induced with propofol and given ketamine and fentanyl boluses throughout the procedure. During emergence, the patient exhibited myoclonic jerks in the upper and lower extremities. He was given intravenous meperidine for postoperative shivering; minutes after administration, the myoclonic jerks and rigidity worsened. The anesthesia team raised concern about serotonin syndrome. Intravenous midazolam improved the patient’s myoclonic jerks and rigidity.\n\nConclusions:\nPatients with a history of rigidity/movement disorders during the perioperative period may have experienced serotonin toxicity. It is possible, as in our case, for this history to have been labelled as an allergy to a perioperative medication. Clinicians should remain vigilant for patients at risk of developing serotonin syndrome, such as those taking outpatient medications that increase neuronal serotonin.\n\nMeSH Keywords:\nAnesthesiaMuscle RigidityMyoclonusPropofolSerotonin Syndrome\n==== Body\nBackground\nSerotonin syndrome manifests as a wide spectrum of clinical presentations, which can range from self-limiting to life-threatening. Symptoms include agitation, clonus, tremor, hypertonia, and diaphoresis. The number of cases of serotonin syndrome reported has increased over the past several years, likely due to both the increased use of serotonergic agents and increased diagnosis of the syndrome [1,2].\n\nCase Report\nA 70-year-old man (ASA 2) with a history of benign prostatic hyperplasia, vestibular migraines (treated with high-dose venlafaxine), and gastroesophageal reflux disease presented to the outpatient surgery center for a planned green-light photoselective vaporization of the prostate. Review of his medical chart prior to anesthesia revealed a listed allergy to propofol. It was determined the allergy was listed after 2 prior anesthetics when he woke up with shaking in the post-anesthesia care unit (PACU) at outside facilities. After discussion about his prior anesthetic history, the anesthesiologist and patient agreed this was not an allergy to propofol, but more likely an adverse effect of propofol, an adverse effect of another medication given during the perioperative period, or possibly not related to medication administration at all. The patient was subsequently induced with propofol 200 mg and was given ketamine 20 mg and fentanyl boluses for a total of 225 mcg throughout the 2-hour procedure. He had no complications during the anesthetization or procedure.\n\nUpon awakening after the procedure, it was noted he had myoclonic jerks in bilateral upper and lower extremities. To treat for possible postoperative shivering, meperidine 25 mg was administered intravenously. The myoclonic jerks became worse, and hypertonia increased after receiving meperidine. The anesthesia team raised suspicion of serotonin syndrome at this time due to the patient’s outpatient regimen of venlafaxine and the intraoperative administration of fentanyl. The most commonly used diagnostic tool for serotonin syndrome is the Hunter Criteria. The anesthesia team felt confident diagnosing the patient’s symptoms as serotonin syndrome secondary to fulfilling the Hunter Criteria. The patient exhibited both spontaneous clonus and diaphoresis in the setting of having multiple serotonergic medications.\n\nSubsequently, he was administered 4 mg intravenous midazolam. The myoclonic jerks and muscle rigidity improved shortly thereafter. After the patient returned to baseline, the anesthesiologist discussed these events with the patient, and it was felt that his prior episodes of perioperative shaking and rigidity were likely similar in nature to what we witnessed.\n\nDiscussion\nSerotonin syndrome remains a diagnostic conundrum. Its presentation varies widely in severity [1]. The triad of symptoms commonly associated with serotonin syndrome includes autonomic hyperactivity, neuromuscular abnormalities, and altered mental status [1,2]. Due to numerous factors, this triad is difficult to recognize both intraoperatively and postoperatively. While several medications, including selective serotonin reuptake inhibitors (SSRIs), tramadol, meperidine, and fentanyl, have a well-established association with serotonin syndrome, there are other drug classes that can potentially result in the syndrome [3,4]. We present a case report of postoperative serotonin syndrome in the setting of propofol allergy reported as rigidity. While the patient did have a listed propofol allergy documented at an outside hospital, there was no record of the reaction type or severity prior to the procedure. Despite the lack of intraoperative hemodynamic changes following induction with propofol, the presence of myoclonic-like movements in the PACU was highly suggestive of serotonin syndrome. To the best of our knowledge, there is only 1 reported case of serotonin syndrome related to propofol administration [5]. While that case noted intraoperative clonus, we noted myoclonus in the postoperative period as the patient emerged from anesthesia.\n\nA recent meta-analysis by Werneke et al. highlights the difficulties associated with making the diagnosis of serotonin syndrome [1]. For example, common teachings about serotonin syndrome include hyperthermia as a presenting symptom and that onset of serotonin syndrome is quicker than that of neuroleptic malignant syndrome [3]. However, most of these findings are based on very small sample sizes. Additionally, there are 3 diagnostic criteria systems (Hunter, Sternbach, and Radomski classifications), which can cause conflicting results when applied to a case [1,6]. Furthermore, diffuse body movements in the intraoperative and postoperative setting could easily be confused with other conditions such as malignant hyperthermia, shivering, seizures, or propofol-induced movement disorder [5]. For these reasons, clinicians must maintain an open mind about the potential for serotonin toxicity, even if diagnostic criteria are not met [1].\n\nGiven the diagnostic challenges of serotonin syndrome, there is a risk of unknowingly administering a medication that could potentially exacerbate the condition. Serotonin toxicity in our patient manifested as myoclonic jerks in bilateral upper and lower legs. This could easily be mistaken for shivering, a common finding in the postoperative period. This patient was given meperidine to treat what was hypothesized as shivering upon arrival to the PACU, which intensified the myoclonic jerks.\n\nOver the past 20 years, an increasing number of patients in the United States have been prescribed antidepressant medications.\n\nIn 1999, 6.8% of adults in the U.S. were prescribed an antidepressant and by 2012 that had increased to 13% of the adult population [7]. Selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are commonly prescribed modern antidepressants that both cause increased serotonin at the synaptic cleft. As these medications become more prevalent, perioperative physicians will see an increasing number of patients who present for surgery with elevated serotonin. It is plausible that these patients who are tolerating outpatient therapy without symptoms will receive additional medications during the perioperative period and begin to show signs of increased neuro-transmission manifesting as serotonin syndrome (Table 1) [8]. It is important to remember that taking multiple serotonergic medications produces a compounding effect that can cause serotonin syndrome. Serotonin syndrome can also present later on in the perioperative course if the patient has been given large doses of benzodiazepines that mask the physical symptoms such as rigidity. In patients for whom the risk of serotonin syndrome is high, it may be beneficial to monitor them for longer periods of time in the Post-anesthesia Recovery Unit [9].\n\nThis case highlights 2 critical points: patients with a history of perioperative rigidity or movement disorders may, in fact, be experiencing serotonin syndrome. Gathering this history in a patient taking serotonergic medications should alert the clinician to consider minimizing agents that will further increase serotonin. For at-risk patients, it is important to maintain a high index of suspicion in order to diagnose serotonin syndrome in patients taking serotonergic medications. Despite the increasing number of patients taking serotonergic medications, most notably SSRIs, many clinicians are not aware of serotonin syndrome. In 1999, 85% of general practitioners were not aware of serotonin syndrome [2]. As polypharmacy increases in aging patient populations, it is important to consider serotonin syndrome in patient taking proserotonergic agents, especially in the perioperative setting, with a documented history of propofol allergy described as rigidity/movement disorder. If high-risk patients could be identified pre-operatively, they could be more safely managed by avoiding the addition of other serotonergic medications [6].\n\nConclusions\nIn summary, serotonin syndrome can be manifested as a wide variety of neurologic symptoms, agitation, and autonomic dysfunction. The diagnosis is entirely clinical, and the Hunter Criteria can be applied to assist with accurate diagnosis. Timely and supportive therapy, removal of offending agents, and cyproheptadine are mainstays of treatment. In the perioperative period, as in our case, the offending agents were likely fentanyl plus long-term venlafaxine outpatient therapy. Fortunately, fentanyl is short-acting and our patient’s serotonergic toxicity was short-lived.\n\nStatement\n\nThis work was supported by the Department of Anesthesiology and Perioperative Medicine with no direct financial support.\n\nTable 1. Medications that can be associated with serotonin syndrome.\n\nSelective serotonin reuptake inhibitors (SSRIs)\tSerotonin-norepinephrine reuptake inhibitor (SNRIs)\tOpioids\tAnti-emetics\tMiscellaneous\t\nCitalopram\tParoxetine\tFentanyl\tGranisetron\tTrazadone\t\nFluoxetine\tVenlafaxine\tTramadol\tOndansetron\tMirtazapine\t\nSertraline\tDuloxetine\tMeperidine\tMetoclopramide\tBuspirone\t\nEscitalopram\t\tMethadone\n==== Refs\nReferences:\n1. Werneke U Jamshidi F Taylor DM Ott M Conundrums in neurology: Dagnosing serotonin syndrome – a meta-analysis of cases BMC Neurology 2016 16 97 106 27406219 \n2. MacKay FJ Dunn NR Mann RD Antidepressants and the serotonin syndrome in general practice Br J Gen Pract 1999 49 871 74 10818650 \n3. Volpi-Abadie J Kaye AM Kaye AD Serotonin syndrome Ochsner J 2013 13 533 40 24358002 \n4. Gollapudy S Kumar V Dhamee MS A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion J Clin Anesth 2012 24 251 52 22537574 \n5. Davis JJ Buck NS Swenson JD Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil J Clin Anesth 2013 25 52 54 23391344 \n6. Boyer EW Serotonin syndrome (serotonin toxicity). Traub SJ Grayzel J UpToDate Waltham, MA 2010 \n7. Kantor ED Rehm CD Haas JS Trends in prescription drug use among adults in the United States from 1999–2012 JAMA 2015 314 1818 31 26529160 \n8. Pedavally S Fugate JE Rabinstein AA Serotonin syndrome in the Intensive Care Unit: Clinical presentation and precipitating medications Neurocrit Care 2014 21 108 13 24052457 \n9. Warner ME Naranjo J Pollard EM Serotonergic medications, herbal supplements, and perioperative serotonin syndrome Can J Anaesth 2017 64 940 46 28667541\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
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"mesh_terms": "D000368:Aged; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008874:Midazolam; D011468:Prostatectomy; D011470:Prostatic Hyperplasia; D012701:Serotonin; D020230:Serotonin Syndrome; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
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"pubdate": "2018-07-16",
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"title": "Serotonin Syndrome in the Perioperative Setting.",
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"abstract": "Immune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented.\n\n\n\nA 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively.\n\n\n\nThe patient's symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient's hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient's clinical course of hypoparathyroidism. CaSR antibodies purified from the patient's serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1.\n\n\n\nThe etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.",
"affiliations": "Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Oncology and Metabolism, The University of Sheffield, Sheffield, South Yorkshire, UK.;Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas, USA.;Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA htawbi@mdanderson.org.",
"authors": "Dadu|Ramona|R|;Rodgers|Theresa E|TE|;Trinh|Van A|VA|;Kemp|Elizabeth Helen|EH|;Cubb|Trisha D|TD|;Patel|Sapna|S|0000-0003-1339-1517;Simon|Julie M|JM|;Burton|Elizabeth M|EM|;Tawbi|Hussein|H|",
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"doi": "10.1136/jitc-2020-000687",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32581059\njitc-2020-000687\n10.1136/jitc-2020-000687\nCase Report\n1506\n2518\nCalcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up\nDadu Ramona 1 Rodgers Theresa E 2 Trinh Van A 2 Kemp Elizabeth Helen 3 Cubb Trisha D 4 http://orcid.org/0000-0003-1339-1517Patel Sapna 2 Simon Julie M 5 Burton Elizabeth M 5 Tawbi Hussein 2 \n1 \nEndocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\n\n\n2 \nMelanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\n\n\n3 \nOncology and Metabolism, The University of Sheffield, Sheffield, South Yorkshire, UK\n\n\n4 \nEndocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas, USA\n\n\n5 \nSurgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\n\nCorrespondence to Hussein Tawbi; htawbi@mdanderson.org\n2020 \n24 6 2020 \n8 1 e00068707 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nImmune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented.\n\nCase and methods\nA 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively.\n\nResults\nThe patient’s symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient’s hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient’s clinical course of hypoparathyroidism. CaSR antibodies purified from the patient’s serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1.\n\nConclusion\nThe etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.\n\nantigensimmunity, humoralimmunotherapymelanomaepitope mappingspecial-featureunlocked\n==== Body\nBackground\nMonoclonal antibodies that inhibit immune checkpoint proteins such as the cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 receptor (PD-1) have revolutionized the treatment approach to many solid tumors.1 2 Furthermore, the combination of ipilimumab, an anti-CTLA-4 antibody, and nivolumab, a PD-1 inhibitor, has demonstrated synergistic antitumor activities, significantly improving objective response rates and overall survival in patients with advanced melanoma or renal cell carcinoma.3 4 Given these results, we expect the number of emerging indications for immune checkpoint inhibitors (ICIs) to continue to grow. However, these novel agents can cause life-threatening immune-related adverse events (irAEs) since checkpoint blockade can lead to unrestrained immune attack on healthy tissues.5 In addition to the skin and the gastrointestinal tract, the endocrine system is one of the most commonly affected organs.5 6\n\n\nThyroid dysfunction and hypophysitis have the highest incidence among the endocrine irAEs of ICIs.5 6 Thyroid disorders are more common with the anti-PD-1/programmed cell death receptor ligand 1 antibodies, either as monotherapy or in combination with an anti-CTLA-4 antibody.7 8 Hypophysitis is more frequently observed with ipilimumab as single agent or in combination with other ICIs.5 Rare cases of type 1 diabetes, Graves’ ophthalmopathy, and autoimmune adrenalitis have been observed.5 6 Hypoparathyroidism is exceedingly rare.9–11\n\n\nHere, we describe the long-term follow-up of a patient who developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab combination for the treatment of metastatic melanoma. A possible autoimmune etiology of the patient’s hypoparathyroidism was investigated. The patient’s serum samples were tested for: (1) Calcium-sensing receptor (CaSR) antibodies, as they can be present in patients with hypoparathyroidism.12–14 (2) NACHT leucine-rich repeat protein 5 (NALP5) antibodies, as they can be indicative of hypoparathyroidism in the context of autoimmune polyendocrine syndrome type 1 (APS1).15 (3) Cytokine antibodies to confirm or deny a diagnosis of APS1 of which hypoparathyroidism is a key manifestation.16 The effect of the patient’s CaSR antibodies on CaSR activity was also tested.\n\nCase presentation\nA 73-year-old man with widely metastatic BRAF V600K mutated melanoma was treated in the frontline setting with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg combination therapy intravenously every 3 weeks. One week after his second cycle, he presented to the emergency department with increased fatigue, dizziness, difficulty maintaining balance, and abdominal bloating and discomfort. His wife also noticed slowing of speech and change in facial expression. Review of systems was positive for perioral numbness, paresthesia in both hands and feet, and numbness over his left abdomen. Physical exam was remarkable for marked ataxia when walking.\n\nLaboratory tests at presentation revealed a low total calcium of 5 mg/dL (normal range: 8.4–10.2 mg/dL), low ionized calcium of 0.67 mmol/L (normal range: 1.13–1.32 mmol/L), high phosphate of 6.6 mg/dL (normal range: 2.5–4.5 mg/dL), low magnesium of 1.5 mg/dL (normal range: 1.8–2.9 mg/dL), and undetectable intact parathyroid hormone (PTH) at <1 pg/mL (normal range: 15–65 pg/mL) (figure 1). In addition, the patient had normal albumin of 4.1 g/dL (normal range: 3.5–5.2 g/dL), normal creatinine of 0.9 mg/dL (normal range: 0.67–1.17 mg/dL), but a high urinary calcium of 266.6 mg/24 hours. The patient also had low 25-hydroxyvitamin D of 18 ng/mL (normal range: 30–100 ng/mL) and normal 1,25-dihydroxyvitamin D of 29 pg/mL (normal range: 18–64 pg/mL). The 1,25-dihydroxyvitamin D level would be expected to be low because of severely reduced PTH. It is likely that the hypoparathyroidism event was acute such that 1,25 dihydroxyvitamin D was still normal, although low, at the point of presentation. The laboratory analyses led to a diagnosis of severe symptomatic hypocalcemia due to primary hypoparathyroidism.\n\nFigure 1 Time course of biochemical tests. The results of biochemical tests are shown for corrected calcium (normal range: 8.4–10.2 mg/dL), phosphate (normal range: 2.5–4.5 mg/dL), ionized calcium (normal range: 1.13–1.32 mmol/L), magnesium (normal range: 1.8–2.9 mg/dL), and intact parathyroid hormone (PTH) (normal range: 15–65 pg/mL) from the start of acute hypocalcemia to the most recent follow-up visit.\n\nThe patient was initiated on a calcium gluconate drip (5000 mg/500 mL calcium gluconate with 5% dextrose at an infusion rate of 50 mL/hour), oral calcium carbonate supplement (equivalent to 1500 mg of elemental calcium three times daily), calcitriol (0.5 µg twice daily), and ergocalciferol (50 000 IU daily for 5 days and weekly, thereafter). Mild hypomagnesemia was corrected (figure 1). Despite normalization of calcium and magnesium levels, PTH remained undetectable (figure 1). Nevertheless, the patient’s symptoms improved in parallel with serum calcium normalization. He was discharged 4 days later on calcium carbonate (equivalent of 1000 mg elemental calcium twice daily), calcitriol (0.25 µg twice daily) and ergocalciferol (50 000 IU weekly).\n\nThe patient received cycle 3 of ipilimumab and nivolumab therapy 3 weeks later. Additional irAEs emerged including thyroiditis with a thyrotoxicosis phase (free T4 of 4.52 ng/mL, normal range: 0.93–1.70 ng/mL; thyroid-stimulating hormone (TSH) of <0.02 µU/mL, normal range: 0.27–4.20 µU/mL; total T3 of 226 ng/dL, normal range 80–200 ng/dL; thyroid peroxidase antibody-negative, and TSH receptor antibody-negative), and hepatitis (alanine aminotransferase of 706 U/L, normal range: 7–56 U/L; aspartate aminotransferase of 447 U/L, normal range: 14–46 U/L) requiring high doses of steroids and permanent discontinuation of ICI therapy 4 weeks after the hypoparathyroidism diagnosis.\n\nDespite his toxicities, the patient achieved a complete response to treatment with disappearance of all his metastatic tumors and remains in remission and asymptomatic from his previous irAEs almost 2 years later (figure 2). His calcium level continued to be stable, between 8.0 mg/dL and 8.5 mg/dL (figure 1) with low doses of calcium (equivalent of 1000 mg elemental calcium per day), calcitriol (0.25 µg daily) and ergocalciferol (50 000 IU weekly). PTH remained undetectable (<0.1 pg/mL) for over 2 years (figure 1). However, 2 years and 3 months since this sentinel event, his PTH level was 12.8 pg/mL with a corrected calcium of 8.2 mg/dL (figure 1). A trial of calcium and calcitriol discontinuation was attempted, however, the patient developed recurrent symptoms of hypocalcemia and, therefore, was given calcium and calcitriol. At his last follow-up at 3 years and 3 months, his PTH was again inappropriately low at 7.6 pg/mL.\n\nFigure 2 Response of the patient to ipilimumab plus nivolumab treatment. Positron emission tomography (PET) scans showing the patient prior to treatment (left-hand panel) and the complete response to treatment (right-hand panel) with disappearance of all the patient’s cancer lesions 2 years after the start of immune checkpoint inhibitor (ICI) therapy.\n\nWith respect to the etiology of the patient’s hypoparathyroidism, he denied a history of past radiation to the neck or prior surgery to thyroid and parathyroid glands which could have damaged the organs prior to ICI treatment. No familial hypocalcemic disorders were present. The patient had no history of autoimmune disease or parathyroid inflammation. In addition, the patient’s total calcium level prior to immunotherapy initiation was normal at 9.2 mg/dL. This information excluded the possibility that he had a primary parathyroid dysfunction prior to treatment with ICIs. The patient’s hypoparathyroidism was therefore considered to be related to his treatment with ipilimumab and nivolumab and that it maybe autoimmune in etiology as irAEs against endocrine organs often are.\n\nAutoimmune hypoparathyroidism can occur in isolation or as part of Autoimmune Polyglandular Syndrome Type 1 (APS1).12 14 Initially, to eliminate APS1 as the disease context for the patient’s hypoparathyroidism, serial archived serum samples from the patient were evaluated in ELISAs for cytokine antibodies against interleukin (IL) 22, IL-17F, IL-17A, interferon (IFN)-ω, IFN-α2A, and IFN-λ1.16 These are disease markers for APS1. The patient was negative for all cytokine antibodies tested, indicating that the patient was unlikely to have APS1. In addition, serum samples were investigated using radioligand binding assays for the APS1 hypoparathyroidism markers, NALP5 antibodies.15 However, NALP5 antibody serology was negative at all time points (figure 3).\n\nFigure 3 Calcium-sensing receptor (Casr) and NACHT leucine-rich repeat protein 5 (NALP5) antibody tests. The upper limit of healthy control sera in the CaSR antibody assay was a CaSR antibody index of 2.69. The upper limit of healthy control sera in the NALP5 antibody assay was an NALP5 antibody index of 1.73. The upper limit for each assay is shown by a dotted line.\n\nAntibodies against the CaSR have been detected in patients with autoimmune hypoparathyroidism with and without the context of APS1.12–14 17 In the present case, CaSR antibodies were detected at multiple time points, with time at positivity correlating with the patient’s clinical course of hypoparathyroidism (figure 3). His serum samples were negative for CaSR antibodies at two time points prior to hypoparathyroidism diagnosis, and increased at the time of hypoparathyroidism diagnosis and remained high during follow-up.\n\nPatient serum samples post-ICI therapy were analyzed in ELISAs using CaSR peptides spanning amino acids 41–69, 75–115, 114–126, 138–170, 171–195, 214–238, 260–340, 344–358, and 374–391 as the target antigens.13 The results indicated that the patient’s CaSR antibodies were against the CaSR peptide 114–126, an epitope previously identified.13 No other CaSR antibody-binding specificities were detected (figure 4A). Subsequently, peptide affinity chromatography13 was used to purify CaSR antibodies against CaSR peptide 114–126 from the patient’s serum.\n\nFigure 4 Characterization of the patient’s calcium-sensing receptor (CaSR) antibodies. (A) Epitope identification. Patient post-treatment serum samples and sera from 10 healthy controls were evaluated at a dilution of 1:100 in ELISAs for antibodies against CaSR peptides 41–69, 75–115, 114–126, 138–170, 171–195, 214–238, 260–340, 344–358, and 374–391. The CaSR antibody index (mean±SD) is shown for three experiments. (B) Effect of the patient’s CaSR antibodies on CaSR activity. Changes in inositol-1-phosphate (IP1) accumulation were measured in response to Ca2+ in human embryonic kidney 293 cells expressing the receptor (HEK293-CaSR) cells preincubated with the patient’s purified CaSR antibody against CaSR peptide 114–126 at a 1:100 dilution prior to stimulation with Ca2+ at a final concentration of 1.5 mM. HEK293-CaSR cells without preincubation with antibody and preincubated with IgG from a healthy individual were included as controls. Intracellular IP1 accumulation was measured using a IP-One ELISA. The mean (±SD) IP1 accumulation is shown for three experiments.\n\nIn some cases, CaSR antibodies have been shown to modulate the receptor’s function such that its response to calcium is adversely affected.14 17 To determine the effects of the patient’s CaSR antibodies on CaSR function, human embryonic kidney 293 cells expressing the receptor (HEK293-CaSR) were preincubated with the patient’s purified CaSR antibodies prior to measurement of Ca2+-induced inositol-1-phosphate (IP1) accumulation in an IP-One ELISA.17 The results showed that preincubation of HEK293-CaSR cells with the patient’s CaSR antibody significantly increased the levels of IP1 accumulation when compared with Ca2+-stimulation of HEK293-CaSR cells that were not preincubated with CaSR antibody (figure 4B). The results indicated that the patient’s CaSR antibodies were able to stimulate the receptor so that even at lower than optimum calcium levels PTH secretion from the parathyroids would be reduced leading to hypocalcemia.\n\nDiscussion\nChronic hypoparathyroidism is a rare endocrinopathy.18 Surgical intervention to the neck is responsible for 75% of cases with the remainder occurring secondary to autoimmune, genetic, or infiltrative etiologies.18 19 Autoimmune hypoparathyroidism is more commonly seen as part of APS1, but can arise as an isolated disease.19 20 It can be caused by immune-mediated damage to the parathyroid gland or by functional hypoparathyroidism due to antibody-induced activation of parathyroid function.14 17 20 Such activating antibodies are directed towards the CaSR.14 By decreasing the receptor’s set point, PTH is not released at lower than optimum blood calcium concentrations resulting in hypocalcemia.14 20 Although rare, autoimmune hypoparathyroidism can also manifest following the use of ICIs for the treatment of cancer.9–11\n\n\nHere, we report a patient with metastatic melanoma who developed hypocalcemia resulting from autoimmune hypoparathyroidism following ICI treatment. The case described demonstrates a cause of hypoparathyroidism that is likely immune-mediated secondary to ICIs, given the temporal proximity of hypoparathyroidism to the initiation of treatment without other mechanism for acute injury to the parathyroid glands. The detection of CaSR-activating antibodies matching the patient’s clinical course further supports a diagnosis of autoimmune hypoparathyroidism caused by the development of CaSR antibodies that could inhibit PTH release from the parathyroid even at below optimum levels of blood calcium.14\n\n\nA similar case of hypoparathyroidism in the setting of ICIs has been reported. Piranavan et al described a case with similar clinical presentation and development of CaSR antibodies.10 In that case also, antibody-activation of the CaSR was demonstrated by increased intracellular IP1 levels in a CaSR-expressing cell line following treatment with the patient’s IgG. In our case, we were able to confirm that the patient had negative CaSR antibodies before their hypoparathyroidism diagnosis and to demonstrate that the patient became CaSR antibody-positive at the time of hypoparathyroidism diagnosis and remained so with long-term follow-up. Hypoparathyroidism appears to be a long-term sequela, however, so continuous follow-up is needed to assess possible recovery, although this is challenging for patients with advanced malignancies who have received ICIs late in their disease course.\n\nWhile T cell-mediated immune destruction of healthy tissue is typically considered the overarching mechanism for irAEs associated with ICIs,21 22 it is increasingly appreciated that humoral immunity may play a role in their development. Some irAEs such as hypothyroidism, bullous pemphigoid, myasthenia gravis, and nephritis have been observed with similar autoantibody profiles traditionally associated with their autoimmune disease counterparts.7 23–25\n\n\nSeronegative antibody-mediated irAEs have also been described with ICIs. Wilson et al reported novel IgG and IgM reacting to relevant tissue preparations in a patient with seronegative transverse myelitis secondary to pembrolizumab and another with seronegative myasthenia gravis due to ipilimumab-nivolumab administration,26 suggesting that ICIs uncover previously unrecognized autoreactive antibodies. This is corroborated by Gowen et al, demonstrating that patients who later developed severe irAEs to ICIs possessed a distinct pretreatment antibody pattern extending beyond the known autoantibodies, such as antinuclear, antismooth muscle, and antithyroid antibodies.27\n\n\nRecently, Das et al showed that combined ICIs led to a decrease in circulating B cells, an increase in CD21 B cells, and an increase in plasmablasts after the first cycle of therapy.28 More importantly, the magnitude of early B cell changes correlated with both the time to onset and the grade of subsequent irAEs, and the patient cohort with early B cell changes had much higher rates of grade 3 or higher irAEs at 6 months. The use of anti-CD20 antibodies in the management of irAEs from ICIs has also been reported.29 Altogether, this evidence supports the notion of a B cell-mediated mechanism for irAEs that exists alongside the T cell-dependent model. It remains unclear whether B cell and antibody changes represent the direct impact of ICIs or the indirect effect of self-tolerance dysregulation secondary to ICIs or both.\n\nIn conclusion, hypoparathyroidism is a rare but life-threatening endocrinopathy associated with ICIs. Thus, calcium levels should be monitored during treatment. The underlying mechanism of ICI-related hypoparathyroidism likely involves the formation of CaSR-activating antibodies. Investigation into the B cell compartment may allow for a better understanding of irAEs pathophysiology and open new avenues for identifying patient subsets at high risk for irAEs and for developing novel treatment options for these.\n\nThe authors thank the patient for allowing their case to be researched.\n\nTwitter: @DrSapnaPatel\n\nContributors: EHK: Collected and analyzed data, created figures, edited and approved the final manuscript; EMB: Collected data, edited and approved the final manuscript; HAT: Collected data, critically appraised, edited and approved the manuscript; JMS: Collected data, edited and approved the final manuscript; RD: Developed the concept, collected data, critically appraised, edited and approved the final manuscript; SPP: Collected data, edited and approved the final manuscript; TDC: Collected data, edited and approved the final manuscript; TER: Created figures, was involved with case presentation, edited and approved the final manuscript; VAT: Collected data, edited and approved the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nEthics approval: The patient’s serum samples were collected longitudinally under an Institutional Review Board approved protocol. The patient gave informed consent for their samples to be collected and their case to be researched.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nHodi FS , O'Day SJ , McDermott DF , et al \nImproved survival with ipilimumab in patients with metastatic melanoma\n. N Engl J Med \n2010 ;363 :711 –23\n. 10.1056/NEJMoa1003466 \n20525992 \n2 \nGandhi L , Rodríguez-Abreu D , Gadgeel S , et al \nPembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer\n. N Engl J Med \n2018 ;378 :2078 –92\n. 10.1056/NEJMoa1801005 \n29658856 \n3 \nWolchok JD , Chiarion-Sileni V , Gonzalez R , et al \nOverall survival with combined nivolumab and ipilimumab in advanced melanoma\n. N Engl J Med \n2017 ;377 :1345 –56\n. 10.1056/NEJMoa1709684 \n28889792 \n4 \nMotzer RJ , Tannir NM , McDermott DF , et al \nNivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma\n. N Engl J Med \n2018 ;378 :1277 –90\n. 10.1056/NEJMoa1712126 \n29562145 \n5 \nHaanen JBAG , Carbonnel F , Robert C , et al \nManagement of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up\n. Annals of Oncology \n2017 ;28 :iv119 –42\n. 10.1093/annonc/mdx225 \n\n6 \nBarroso-Sousa R , Barry WT , Garrido-Castro AC , et al \nIncidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis\n. JAMA Oncol \n2018 ;4 :173 –82\n. 10.1001/jamaoncol.2017.3064 \n28973656 \n7 \nOsorio JC , Ni A , Chaft JE , et al \nAntibody-Mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer\n. Ann Oncol \n2017 ;28 :583 –9\n. 10.1093/annonc/mdw640 \n27998967 \n8 \nIyer PC , Cabanillas ME , Waguespack SG , et al \nImmune-Related thyroiditis with immune checkpoint inhibitors\n. Thyroid \n2018 ;28 :1243 –51\n. 10.1089/thy.2018.0116 \n30132401 \n9 \nWin MA , Thein KZ , Qdaisat A , et al \nAcute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism\n. Am J Emerg Med \n2017 ;35 :1039.e5 –1039.e7\n. 10.1016/j.ajem.2017.02.048 \n\n10 \nPiranavan P , Li Y , Brown E , et al \nImmune checkpoint inhibitor-induced hypoparathyroidism associated with calcium-sensing receptor-activating autoantibodies\n. J Clin Endocrinol Metab \n2019 ;104 :550 –6\n. 10.1210/jc.2018-01151 \n30252069 \n11 \nUmeguchi Takenoshita H H , Takenoshita H , Inoue H , et al \nAutoimmune-related primary hypoparathyroidism possibly induced by the administration of pembrolizumab: a case report\n. J Oncol Pract \n2018 ;14 :449 –51\n. 10.1200/JOP.18.00076 \n29906213 \n12 \nGavalas NG , Kemp EH , Krohn KJE , et al \nThe calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1\n. J Clin Endocrinol Metab \n2007 ;92 :2107 –14\n. 10.1210/jc.2006-2466 \n17374709 \n13 \nHabibullah M , Porter JA , Kluger N , et al \nCalcium-Sensing receptor autoantibodies in patients with autoimmune polyendocrine syndrome type 1: epitopes, specificity, functional affinity, IgG subclass, and effects on receptor activity\n. J Immunol \n2018 ;201 :3175 –83\n. 10.4049/jimmunol.1701527 \n30381479 \n14 \nKifor O , McElduff A , LeBoff MS , et al \nActivating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism\n. J Clin Endocrinol Metab \n2004 ;89 :548 –56\n. 10.1210/jc.2003-031054 \n14764760 \n15 \nAlimohammadi M , Björklund P , Hallgren A , et al \nAutoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen\n. N Engl J Med \n2008 ;358 :1018 –28\n. 10.1056/NEJMoa0706487 \n18322283 \n16 \nMeager A , Visvalingam K , Peterson P , et al \nAnti-Interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1\n. PLoS Med \n2006 ;3 :e289. 10.1371/journal.pmed.0030289 \n16784312 \n17 \nKemp EH , Gavalas NG , Krohn KJE , et al \nActivating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1\n. J Clin Endocrinol Metab \n2009 ;94 :4749 –56\n. 10.1210/jc.2009-1080 \n19837919 \n18 \nBrandi ML , Bilezikian JP , Shoback D , et al \nManagement of hypoparathyroidism: summary statement and guidelines\n. J Clin Endocrinol Metab \n2016 ;101 :2273 –83\n. 10.1210/jc.2015-3907 \n26943719 \n19 \nShoback DM , Bilezikian JP , Costa AG , et al \nPresentation of hypoparathyroidism: etiologies and clinical features\n. J Clin Endocrinol Metab \n2016 ;101 :2300 –12\n. 10.1210/jc.2015-3909 \n26943721 \n20 \nBetterle C , Garelli S , Presotto F \nDiagnosis and classification of autoimmune parathyroid disease\n. Autoimmun Rev \n2014 ;13 :417 –22\n. 10.1016/j.autrev.2014.01.044 \n24424178 \n21 \nPhan GQ , Yang JC , Sherry RM , et al \nCancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma\n. Proc Natl Acad Sci U S A \n2003 ;100 :8372 –7\n. 10.1073/pnas.1533209100 \n12826605 \n22 \nJohnson DB , Balko JM , Compton ML , et al \nFulminant myocarditis with combination immune checkpoint blockade\n. N Engl J Med \n2016 ;375 :1749 –55\n. 10.1056/NEJMoa1609214 \n27806233 \n23 \nNaidoo J , Schindler K , Querfeld C , et al \nAutoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1\n. Cancer Immunol Res \n2016 ;4 :383 –9\n. 10.1158/2326-6066.CIR-15-0123 \n26928461 \n24 \nMakarious D , Horwood K , Coward JIG \nMyasthenia gravis: an emerging toxicity of immune checkpoint inhibitors\n. Eur J Cancer \n2017 ;82 :128 –36\n. 10.1016/j.ejca.2017.05.041 \n28666240 \n25 \nKishi S , Minato M , Saijo A , et al \nIga nephropathy after nivolumab therapy for postoperative recurrence of lung squamous cell carcinoma\n. Intern Med \n2018 ;57 :1259 –63\n. 10.2169/internalmedicine.9814-17 \n29279511 \n26 \nWilson R , Menassa DA , Davies AJ , et al \nSeronegative antibody-mediated neurology after immune checkpoint inhibitors\n. Ann Clin Transl Neurol \n2018 ;5 :640 –5\n. 10.1002/acn3.547 \n29761126 \n27 \nGowen MF , Giles KM , Simpson D , et al \nBaseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors\n. J Transl Med \n2018 ;16 :82. 10.1186/s12967-018-1452-4 \n29606147 \n28 \nDas R , Bar N , Ferreira M , et al \nEarly B cell changes predict autoimmunity following combination immune checkpoint blockade\n. J Clin Invest \n2018 ;128 :715 –20\n. 10.1172/JCI96798 \n29309048 \n29 \nMajem M , García-Martínez E , Martinez M , et al \nSEOM clinical guideline for the management of immune-related adverse events in patients treated with immune checkpoint inhibitors (2019)\n. Clin Transl Oncol \n2020 ;22 :213 –22\n. 10.1007/s12094-019-02273-x \n31993963\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "antigens; epitope mapping; immunity, humoral; immunotherapy; melanoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001323:Autoantibodies; D005500:Follow-Up Studies; D006801:Humans; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D000077594:Nivolumab; D011379:Prognosis; D044169:Receptors, Calcium-Sensing",
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"title": "Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up.",
"title_normalized": "calcium sensing receptor autoantibody mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy diagnosis and long term follow up"
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"abstract": "Apixaban, a direct factor Xa inhibitor, is a novel oral anticoagulant (NOAC) indicated for prevention of embolic events in patients with nonvalvular atrial fibrillation. The agent is associated with a lower risk of bleeding compared with vitamin K antagonists such as warfarin. Hemopericardium is a life-threatening bleeding event that is rarely caused by anticoagulants. We describe the case of a 76-year-old woman who was diagnosed with nonvalvular atrial fibrillation and treated with apixaban. Six weeks later, she was hospitalized after complaints of weakness and dizziness, and a chest radiograph revealed cardiomegaly. Further imaging, including a computed tomography scan and transthoracic echocardiogram, confirmed a diagnosis of hemopericardium. To our knowledge, this is the first case report of hemopericardium associated with apixaban therapy. This report, along with two previous cases reports of hemopericardium associated with dabigatran and rivaroxaban, emphasizes the need for careful use of NOACs and for further research to identify an antidote or other method for controlling hemorrhage secondary to NOACs in an acute setting. Furthermore, clinicians should consider hemopericardium in the differential diagnosis of patients treated with anticoagulants, including NOACs, who present with cardiomegaly.",
"affiliations": "Internal Medicine D, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.;affiliated with Sackler Faculty of Medicine, Tel-Aviv University, Israel.;Internal Medicine D, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.;Internal Medicine D, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.",
"authors": "Sigawy|Chen|C|;Apter|Sara|S|;Vine|Jacob|J|;Grossman|Ehud|E|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
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"issue": "35(7)",
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"keywords": "anticoagulation; atrial fibrillation; bleeding",
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"mesh_terms": "D000368:Aged; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D010490:Pericardial Effusion; D011720:Pyrazoles; D011728:Pyridones",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous Hemopericardium in a Patient Receiving Apixaban Therapy: First Case Report.",
"title_normalized": "spontaneous hemopericardium in a patient receiving apixaban therapy first case report"
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"abstract": "We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.",
"affiliations": "David Geffen School of Medicine, University of California, Los Angeles, CA, USA.",
"authors": "Reddy|S M|SM|;Winston|D J|DJ|;Territo|M C|MC|;Schiller|G J|GJ|",
"chemical_list": null,
"country": "England",
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"doi": "10.1038/bmt.2010.35",
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"issn_linking": "0268-3369",
"issue": "45(6)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D002494:Central Nervous System Infections; D003586:Cytomegalovirus Infections; D004351:Drug Resistance; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D009894:Opportunistic Infections",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "979-84",
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"pmid": "20190836",
"pubdate": "2010-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency.",
"title_normalized": "cmv central nervous system disease in stem cell transplant recipients an increasing complication of drug resistant cmv infection and protracted immunodeficiency"
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"companynumb": "US-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-E2B_00005602",
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"abstract": "A 59-year-old man with a history of giant cell myocarditis was admitted to our hospital with recurrent giant cell myocarditis triggered by a 1 mg/day taper in his prednisolone dose. During the initial episode, he had undergone rescue implantation of a temporary left ventricular assist device followed by the administration of dual immunosuppressive therapy with prednisolone and concomitant cyclosporine. Triple combination immunosuppressive therapy maintained with additional mycophenolate mofetil successfully controlled recurrent myocarditis, enabled a reduction in the prednisolone dose, and achieved the functional recovery of the left ventricle.",
"affiliations": "Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Japan.;Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.",
"authors": "Akita|Tomomi|T|;Mori|Shumpei|S|;Onishi|Akira|A|;Hara|Shigeo|S|;Yamada|Haruhi|H|;Nagasawa|Akira|A|;Imada|Hiroshi|H|;Shimoura|Hiroyuki|H|;Ooka|Junichi|J|;Tanaka|Hidekazu|H|;Hirata|Ken-Ichi|KI|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2471-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3091819310.2169/internalmedicine.2471-18Case ReportSuccessful Triple Combination Immunosuppressive Therapy with Prednisolone, Cyclosporine, and Mycophenolate Mofetil to Treat Recurrent Giant Cell Myocarditis Akita Tomomi 1Mori Shumpei 1Onishi Akira 2Hara Shigeo 3Yamada Haruhi 1Nagasawa Akira 1Imada Hiroshi 1Shimoura Hiroyuki 1Ooka Junichi 1Tanaka Hidekazu 1Hirata Ken-ichi 1\n1 Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan\n2 Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Japan\n3 Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, JapanCorrespondence to Dr. Shumpei Mori, shumpei_8@hotmail.com\n\n28 3 2019 15 7 2019 58 14 2035 2039 3 12 2018 10 1 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 59-year-old man with a history of giant cell myocarditis was admitted to our hospital with recurrent giant cell myocarditis triggered by a 1 mg/day taper in his prednisolone dose. During the initial episode, he had undergone rescue implantation of a temporary left ventricular assist device followed by the administration of dual immunosuppressive therapy with prednisolone and concomitant cyclosporine. Triple combination immunosuppressive therapy maintained with additional mycophenolate mofetil successfully controlled recurrent myocarditis, enabled a reduction in the prednisolone dose, and achieved the functional recovery of the left ventricle. \n\ncyclosporinegiant cell myocarditismycophenolate mofetilprednisolonerecurrence\n==== Body\nIntroduction\nHistorically, giant cell myocarditis is a fulminant and fatal form of myocarditis commonly associated with progressive congestive heart failure, refractory ventricular arrhythmias, and cardiogenic shock, and consequently an unfavorable prognosis (1, 2). Approximately 20% of all cases are associated with autoimmune disorders, including inflammatory bowel disease (8%), as well as thyroiditis, and thymoma (1, 2). Previous studies have shown that combination immunosuppressive therapy improves survival (3-5); however, the tapering or withdrawal of immunosuppressants is associated with a lifelong risk of recurrence affecting the native heart (2, 4, 5). To date, no optimal regimen and duration of immunosuppressive therapy have yet been established to prevent or treat recurrent giant cell myocarditis. We herein report a case of recurrent giant cell myocarditis that was successfully treated with triple combination therapy.\n\nCase Report\nA 58-year-old man with a history of ulcerative colitis was transferred to our hospital with cardiogenic shock for which he had been treated with catecholamines, intra-aortic balloon pumping, percutaneous cardiopulmonary support, and mechanical ventilation. He had a recent history of generalized myalgia, muscle weakness, and diplopia. A significant elevation in the muscular, as well as cardiac enzyme levels were observed. Based on these specific clinical features, electromyographic findings (myogenic changes), and magnetic resonance imaging findings (hyperintense signal in the extraocular muscle on T2-weighted images), he was diagnosed with polymyositis (including extraocular myositis as the cause of diplopia). An endomyocardial biopsy performed on the day of admission confirmed CD3+ T-lymphocyte (predominantly CD8+ vs. CD4+) and CD68+ multinucleated giant cell infiltration (Fig. 1). Although myocardial infiltration of the multinucleated giant cells is also a characteristic pathological finding in cardiac sarcoidosis, no clinical or laboratory findings suggesting cardiac, lung, skin, or ocular sarcoidosis were detected in this case. Accordingly, following the diagnosis of fulminant giant cell myocarditis associated with polymyositis, he was treated with 9-day rescue implantation of a left ventricular assist device, 3-day methylprednisolone pulse therapy, and intravenous immunoglobulin therapy, followed by maintenance immunosuppressive therapy with prednisolone (50 mg/day) and cyclosporine (150 mg/day). During this initial clinical course, his peak brain natriuretic peptide and troponin I levels increased to 809 pg/mL and 27.5 ng/mL, respectively. He recovered completely after 3 months of hospitalization without any neurological and/or physical deficit and was discharged with prednisolone 20 mg/day and cyclosporine 100 mg/day. The left ventricular ejection fraction improved rapidly from 6% to 51% on day 21 and to 68% on day 50 with a reduction in serum cardiac troponin I levels to <0.1 ng/mL (6).\n\nFigure 1. Histopathological findings of serial endomyocardial biopsies. A Hematoxylin and Eosin staining image (upper panel) using 400× magnification shows inflammation with myocardial shedding and interstitial fibrosis. Giant cells (black arrows) are confirmed only in the initial specimen obtained upon admission (left panel). Immunostaining performed using 200× magnification shows infiltration of CD68+histiocytes (mid-line panel) and CD8+T-lymphocytes (lower panel). It should be noted that the giant cells are CD68 positive. The right panel shows the findings of the endomyocardial biopsy repeated on day 52 of admission. Inflammation is observed to have subsided in this specimen compared with that observed in the biopsy obtained on day 3 of admission (middle panel). However, smoldering inflammation is observed in this specimen, which necessitated the addition of mycophenolate mofetil to the combined regimen of prednisolone and cyclosporine.\n\nA month after discharge, his oral prednisolone was reduced from 20 mg/day to 19 mg/day. However, 16 days after this 1 mg/day dose reduction, he was re-admitted with cardiogenic shock. During re-hospitalization, his left ventricular ejection fraction had worsened to 15%. Clinically, he showed no evidence of worsened polymyositis. The serum brain natriuretic peptide and troponin I levels showed a re-elevation to 3,781 pg/mL and 0.66 ng/mL, respectively. He was promptly administered catecholamine and received intra-aortic balloon pumping followed by 3-day methylprednisolone pulse therapy and intravenous immunoglobulin therapy. The prednisolone dose was again increased to 60 mg/day with a maintenance dose of continuous cyclosporine at 100 mg/day. An endomyocardial biopsy performed on day 3 showed active myocarditis with myocardial shedding, interstitial fibrosis, and CD3+ T-lymphocyte (predominantly CD8+ vs. CD4+) and CD68+ histiocyte infiltration. Although multinucleated giant cells could not be identified in the histopathological specimens, he was clinically diagnosed with recurrent giant cell myocarditis (Fig. 1). Fortunately, his hemodynamic status gradually improved without left ventricular assist device implantation. The left ventricular ejection fraction improved to 25% on day 5, and intra-aortic balloon pumping could be discontinued on day 8. Although his serum troponin I level decreased to 0.15 ng/mL on day 14, it again increased to 0.75 ng/mL on day 17 without any significantly worsened hemodynamics. Additional 3-day methylprednisolone pulse therapy was administered, which reduced his serum troponin I level to 0.1-0.2 ng/mL. The serum C-reactive protein level also decreased to <0.01 mg/dL over time. He was transferred to the general ward on day 32 without catecholamine support. Although the peak serum troponin I level was lower and hemodynamic impairment was milder during his second admission than that during his initial presentation, the left ventricular ejection fraction recovery was poorer as evidenced by a left ventricular ejection fraction of 24% on day 40 with persistently elevated serum troponin I levels of approximately 0.1-0.2 ng/mL. 18F-fluorodeoxyglucose positron emission tomography/computed tomography performed on day 45 showed no specific accumulation involving the heart as well as other organs. Based on these mixed findings, we did not reduce the dose of prednisolone below 60 mg/day. Finally, an endomyocardial biopsy repeated on day 52 confirmed an improved, but smoldering inflammation with myocardial shedding, interstitial fibrosis, and residual CD3+ T-lymphocyte (predominantly CD8+ vs. CD4+) and CD68+ histiocyte infiltration without giant cells (Fig. 1). Considering the glucocorticoid/cyclosporine-resistant smoldering inflammation, mycophenolate mofetil (1.5 g/day) was added to his regimen on day 53 with a gradual increase in dose to 3.0 g/day as replacement therapy for the gradual prednisolone taper from 60 mg/day to 40 mg/day over the subsequent 3 weeks. Fortunately, the serum troponin I levels showed a gradual reduction to <0.1 ng/mL along with a gradual improvement in left ventricular ejection fraction to 32% on day 106 (Fig. 2). Eventually, he was discharged 4 months after re-hospitalization with triple combination immunosuppressive therapy including prednisolone 25 mg/day, cyclosporine 100 mg/day, and mycophenolate mofetil 3.0 g/day in addition to the standard regimen prescribed for the management of heart failure with a reduced ejection fraction (perindopril 2 mg/day, bisoprolol 2.5 mg/day, and eplerenone 12.5 mg/day). His clinical course which had been monitored as an outpatient has been uneventful, and the patient is asymptomatic 25 months after his discharge following re-hospitalization. Ventricular arrhythmia had not been observed throughout the clinical course. The serum brain natriuretic peptide and troponin I levels have been maintained at approximately 100 pg/mL and 0.01-0.02 ng/mL, respectively, with the administration of prednisolone 11 mg/day, cyclosporine 100 mg/day, and mycophenolate mofetil 3.0 g/day. The left ventricular ejection fraction has further improved to 45%.\n\nFigure 2. The patient’s clinical course during his second admission. After the administration of mycophenolate mofetil, the serum troponin I levels decreased gradually along with a gradual improvement in the left ventricular ejection fraction. EMB: endomyocardial biopsy, IABP: intra-aortic balloon pumping, mPSL: methylprednisolone, PSL: prednisolone\n\nDiscussion\nGiant-cell myocarditis is a rapidly progressive myocardial disease of unknown pathogenesis, presumably mediated by T-lymphocytes and anti-myosin autoantibodies (2). Histopathological examinations reveal multifocal or diffuse infiltration of predominantly CD8+ T-lymphocytes, eosinophils, and multinucleated giant cells (7). Previous reports have shown that contemporary immunosuppression with the administration of cyclosporine and corticosteroids improved the prognosis, and approximately two-thirds of such patients achieved a partial clinical remission characterized by recovery from severe heart failure without the need for transplantation (4), compared with a mean 3-month survival period in patients who did not receive immunosuppressants (1). Recurrent giant cell myocarditis has been observed in 12% of cases, following a decrease in the dose or withdrawal of immunosuppressants even up to 8 years after the initial diagnosis (2, 5). The 5-year transplantation-, recurrence-, heart failure-, and ventricular arrhythmia-free survival rate was 35% (5).\n\nThus, as shown in the present case, giant cell myocarditis is a chronic condition with a high risk of recurrence in the native heart (8). To date, no optimal treatment regimen or duration of immunosuppressive therapy has been conclusively established even as primary treatment, even more so in patients with recurrence. Dual therapy with cyclosporine and corticosteroids or triple therapy with cyclosporine, azathioprine, and corticosteroids may prolong survival when promptly initiated at the time of diagnosis or in patients with a suspected diagnosis (7). Alternative immunosuppressive regimens, including the use of proliferation signal inhibitors, mycophenolate mofetil, tacrolimus, sirolimus, methotrexate, and anti-thymocyte globulin have been reported (7-9). Based on the possible pathogenesis, therapy targeting T-lymphocytes and anti-myosin autoantibodies appears to be effective in successfully treating giant cell myocarditis, particularly in combined regimens.\n\nAfter oral administration and absorption, mycophenolate mofetil is rapidly hydrolyzed to yield mycophenolic acid, an active immunosuppressive agent. Mycophenolic acid is a relatively selective antimetabolite, which exerts a potent and reversible inhibition of the inosine monophosphate dehydrogenase level (rate-limiting enzyme in the de novo pathway for purine synthesis and proliferation of lymphocytes) expressed in stimulated lymphocytes. In vitro, mycophenolate mofetil blocks the proliferation of both B- and T-lymphocytes, inhibits antibody formation and the generation of cytotoxic T-lymphocytes, and decreases the expression of adhesion molecules, thus impairing the ability of lymphocytes to bind to endothelial cells (10). Mycophenolate mofetil is widely used as a standard and first-line component of several different immunosuppressive regimens, particularly in the field of solid organ transplantation (11) and in patients with lupus nephritis (12). Azathioprine is a useful alternative; however, it was not considered in this particular case owing to liver dysfunction observed in the patient at the time.\n\nGiant cell myocarditis is diagnosed based on endomyocardial biopsy findings. The biopsy should be performed during the acute phase of the disease to enable the prompt initiation of immunosuppressive therapy. In this case, the sensitivity of the first endomyocardial biopsy performed at the time of diagnosis was relatively low at 68% and subsequently increased to 93% by the time the third biopsy was performed. Thus, an accurate diagnosis of giant cell myocarditis often requires repeat endomyocardial biopsies (4). A diagnosis based on endomyocardial biopsy may be inaccurate, particularly in patients with a recurrence of giant cell myocarditis in the native heart, as was observed in the present case (giant cells were not identified even in the repeat biopsy specimens). In patients receiving immunosuppressants, giant cells tend to disappear early during the disease process, and the inflammatory manifestation that disappears last is smoldering lymphocytic myocarditis, which is followed by replacement-type interstitial fibrosis (5). In cases of recurrence, therefore, the giant cell number did not affect immunosuppressive regimen (5). Thus, immunosuppressive therapy should be restarted or switched to more aggressive regimens in patients with a high index of suspicion for recurrent giant cell myocarditis. As was confirmed in the present case, the detection of CD68+ histiocytes may indicate that a similar pathogenetic mechanism is involved in those with recurrence (based on the presumption that histiocytes are possible precursors of CD68+ giant cells). The serum troponin I levels (which indicate latent and smoldering myocarditis) therefore need to be closely and regularly monitored.\n\nIn conclusion, our case highlights the efficacy of adding mycophenolate mofetil to a combined regimen of prednisolone and cyclosporine to treat patients with recurrent giant cell myocarditis. This regimen could control the smoldering myocardial inflammation, achieve a reduction in the prednisolone dose, and thus lead to the functional recovery of the left ventricle.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nCooper LT Jr, Berry GJ , Shabetai R \nIdiopathic giant-cell myocarditis-natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators . N Engl J Med \n336 : 1860 -1866 , 1997 .9197214 \n2. \nCooper LT Jr, ElAmm C \nGiant cell myocarditis. Diagnosis and treatment . Herz \n37 : 632 -636 , 2012 .22930389 \n3. \nCooper LT Jr, Hare JM , Tazelaar HD , et al \nGiant Cell Myocarditis Treatment Trial Investigators \nUsefulness of immunosuppression for giant cell myocarditis . Am J Cardiol \n102 : 1535 -1539 , 2008 .19026310 \n4. \nKandolin R , Lehtonen J , Salmenkivi K , Räisänen-Sokolowski A , Lommi J , Kupari M \nDiagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression . Circ Heart Fail \n6 : 15 -22 , 2013 .23149495 \n5. \nMaleszewski JJ , Orellana VM , Hodge DO , Kuhl U , Schultheiss HP , Cooper LT \nLong-term risk of recurrence, morbidity and mortality in giant cell myocarditis . Am J Cardiol \n115 : 1733 -1738 , 2015 .25882774 \n6. \nOoka J , Tanaka H , Hatani Y , et al \nTreatment of fulminant giant cell myocarditis associated with polymyositis using a left ventricular assist device and subsequent corticosteroid and immunosuppressive therapy leading to remission . Intern Med \n56 : 2155 -2158 , 2017 .28781324 \n7. \nShih JA , Shih JA \nSmall steps for idiopathic giant cell myocarditis . Curr Heart Fail Rep \n12 : 263 -268 , 2015 .25895034 \n8. \nYeen WC , Haas G , Mehmood SA , Crestanello JA \nRelapse of giant cell myocarditis supported with veno-arterial extracorporeal membrane oxygenation . Interact Cardiovasc Thorac Surg \n12 : 829 -831 , 2011 .21297147 \n9. \nFluschnik N , Escher F , Blankenberg S , Westermann D \nFatal recurrence of fulminant giant cell myocarditis and recovery after initialisation of an alternative immunosuppressive regime . BMJ Case Rep \n2014 : bcr2014206386 , 2014 .\n10. \nRemuzzi G , Cravedi P , Costantini M , et al \nMycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial . J Am Soc Nephrol \n18 : 1973 -1985 , 2007 .17460145 \n11. \nvan Gelder T , Hesselink DA \nMycophenolate revisited . Transpl Int \n28 : 508 -515 , 2015 .25758949 \n12. \nGinzler EM , Dooley MA , Aranow C , et al \nMycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis . N Engl J Med \n353 : 2219 -2228 , 2005 .16306519\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "cyclosporine; giant cell myocarditis; mycophenolate mofetil; prednisolone; recurrence",
"medline_ta": "Intern Med",
"mesh_terms": "D003131:Combined Modality Therapy; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D015726:Giant Cells; D006353:Heart-Assist Devices; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009205:Myocarditis; D011239:Prednisolone; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
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"pages": "2035-2039",
"pmc": null,
"pmid": "30918193",
"pubdate": "2019-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16306519;17460145;19026310;21297147;22930389;23149495;25246472;25758949;25882774;25895034;28781324;9197214",
"title": "Successful Triple Combination Immunosuppressive Therapy with Prednisolone, Cyclosporine, and Mycophenolate Mofetil to Treat Recurrent Giant Cell Myocarditis.",
"title_normalized": "successful triple combination immunosuppressive therapy with prednisolone cyclosporine and mycophenolate mofetil to treat recurrent giant cell myocarditis"
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"abstract": "Botulinum toxin (BoNT) injection is widely used to improve spasticity. However, after the treatment, the patient may experience pain, inflammation, swelling and redness at the injection site. In this case, we addressed deep vein thrombosis (DVT) after BoNT treatment of the upper limb. A male aged 37 years had spasticity and dystonia in his left upper extremity. BoNT-A 100 U was injected into the left biceps brachii and an equal amount into the brachialis to relieve spasticity. After three days, he developed redness and painful swelling in the left upper arm and the next day, through the upper extremity computed tomography venography, DVT was identified in the left cephalic vein. The thrombus resolved after the anticoagulation therapy with rivaroxaban (Xarelto). We hypothesized the role of mainly three mechanisms in the development of DVT in this case: repetitive strenuous activity, relative stasis due to reduced muscle tone, and possible direct mechanical damage to the vessel wall.",
"affiliations": "Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.;Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.",
"authors": "Lim|Nana|N|;Lee|Geun Su|GS|;Won|Ki Hong|KH|;Kang|Jin Sun|JS|;Lee|Sung Hoon|SH|;Kang|Eun Young|EY|;Lee|Hyun Kyung|HK|;Cho|Youn Kyung|YK|",
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"doi": "10.5535/arm.20118",
"fulltext": "\n==== Front\nAnn Rehabil Med\nAnn Rehabil Med\nARM\nAnnals of Rehabilitation Medicine\n2234-0645\n2234-0653\nKorean Academy of Rehabilitation Medicine\n\n33849088\n10.5535/arm.20118\narm-20118\nCase Report\nUpper Extremity Deep Vein Thrombosis After Botulinum Toxin Injection: A Case Report\nhttp://orcid.org/0000-0001-5743-9135\nLim Nana MD\nhttp://orcid.org/0000-0003-2131-3148\nLee Geun Su MD\nhttp://orcid.org/0000-0002-1456-7943\nWon Ki Hong MD\nhttp://orcid.org/0000-0003-0507-4044\nKang Jin Sun MD\nhttp://orcid.org/0000-0002-2071-7936\nLee Sung Hoon MD\nhttp://orcid.org/0000-0001-6805-5727\nKang Eun Young MD\nhttp://orcid.org/0000-0002-1464-2560\nLee Hyun Kyung MD PhD\nhttp://orcid.org/0000-0003-4906-6089\nCho Youn Kyung MD\nDepartment of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea\nCorresponding author: Youn Kyung Cho Department of Rehabilitation Medicine, Kwangju Christian Hospital, Yangrimro 37, Namgu, Gwangju 61661, Korea. Tel: +82-62-650-5167, Fax: +82-62-671-7447, E-mail: 10191@kchgw.org\n4 2021\n14 4 2021\n45 2 160164\n8 6 2020\n28 8 2020\n6 10 2020\nCopyright © 2021 by Korean Academy of Rehabilitation Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBotulinum toxin (BoNT) injection is widely used to improve spasticity. However, after the treatment, the patient may experience pain, inflammation, swelling and redness at the injection site. In this case, we addressed deep vein thrombosis (DVT) after BoNT treatment of the upper limb. A male aged 37 years had spasticity and dystonia in his left upper extremity. BoNT-A 100 U was injected into the left biceps brachii and an equal amount into the brachialis to relieve spasticity. After three days, he developed redness and painful swelling in the left upper arm and the next day, through the upper extremity computed tomography venography, DVT was identified in the left cephalic vein. The thrombus resolved after the anticoagulation therapy with rivaroxaban (Xarelto). We hypothesized the role of mainly three mechanisms in the development of DVT in this case: repetitive strenuous activity, relative stasis due to reduced muscle tone, and possible direct mechanical damage to the vessel wall.\n\nUpper extremity DVT\nBotulinum toxins\nMuscle spasticity\n==== Body\nINTRODUCTION\n\nSpasticity after central nervous system injury is a common complication, with a reported occurrence of 4% to 42.6% in stroke patients. It could lead to various impairments in the reduction of the daily life functions, pain, secondary skin disease, and so on. It increases the burden of patient care, such as the difficulty in changing the position of his or her body or handling the feces and urine. There are various methods for treating spasticity, such as passive stretching, pharmacologic management, chemodenervation, intrathecal therapies, and the surgical intervention. Among them, botulinum toxin injection may temporarily reduce spasticity, particularly in patients with focal spasticity. Furthermore, injection is not as invasive as surgical treatment. It has a better therapeutic effect with fewer side effects on the target area than oral medications, having systemic consequences. Therefore, it is a treatment of choice causing marked improvement in spasticity if proper technique is followed.\n\nBotulinum toxin is widely used in spasticity due to the pharmacological action of lowering muscle tone by interfering with the secretion of acetylcholine from the presynaptic terminal plate acting on the neuromuscular junction. Therefore, a number of researches have been conducted about its treatment methods and treatment variables. Typical side effects after botulinum toxin injection include dysphagia, muscle weakness, allergic reactions, flu-like symptoms, and injection site trauma [1]. Thromboembolic events are rarely described as reported adverse reactions [1-3]. Cote et al. [1] reviewed all (therapeutic and cosmetic use) serious adverse events to the US Food and Drug Administration (FDA) from December 1989 to May 2003, and only two cases of pulmonary embolism were reported. Recently, we experienced a case of deep vein thrombosis (DVT) of the upper extremity, diagnosed 4 days after botulinum toxin injection. We describe a case of upper extremity DVT after botulinum toxin injection with a discussion of etiology, diagnosis, and management. To our knowledge, this is the first report of the upper extremity DVT after botulinum toxin type A (BoNT-A) injection. This case report was approved by the Institutional Review of Board of Kwangju Christian Hospital (No. KCH-RE-2019-09-003), which waived the requirement for imformed consent owing to the retrospective nature of this study.\n\nCASE REPORT\n\nA male patient aged 37 years visited the local hospital and planned to undergo botulinum toxin injection to relieve spasticity and dystonia of his left upper limb 3 years after subarachnoid hemorrhage. His past medical history revealed the fact that he had been affected by dystonia and spasticity in his left upper limb, especially the hand, secondary to tuberculous meningitis at the age of 3. The patient reported that for decades his left upper limb muscle strength was normal, however, it decreased to fair grade after the subarachnoid hemorrhage with worsening of dystonic and spastic symptom.\n\nThe degree of spasticity before the treatment was Modified Ashworth Scale (MAS) 2 in upper arm flexor muscles. The patient received a total of 200 U of onabotulinum toxin A (Botox): 100 U each into the left biceps brachii muscle and the brachialis muscle to relieve spasticity. Guiding techniques such as the ultrasound or electromyography were not used, but no complications were noted during injection. Electrical stimulation therapy was applied to the treated muscle, and the patient stretched his arm repeatedly to improve the range of motion. He performed exercises of the arm and shoulders at least 3 hours daily at a higher intensity than usual. During the exercise, there was no discomfort, and later, he increased exercise intensity. However, 3 days later, progressive edema and pain occurred in the left upper limb and he was transferred to our hospital the next day. He had no history of trauma except the stretching exercise, with no history of previous cardiovascular or other hemorrhagic diseases. He did not take drugs that affecting blood coagulation tendency. There were no known drug allergies. The thrombophilia profile was negative except for the mildly elevated D-dimer concentration (2.2 μg/mL) (Table 1).\n\nThe strength of the left shoulder flexor and extensor muscle at the time of visiting our clinic was fair grade (manual muscle test, 3/5). The spasticity of the upper arm flexor muscle was identified as MAS 1+. Physical examination revealed edema, heat and tenderness of the left upper extremity (Fig. 1). No sign of a local infection or tenderness was observed in the area of BoNT-A injection conducted 4 days back. The circumferences measured bilaterally at 5 cm above medial epicondyle were 33.5 cm on right and 37.6 cm on left, respectively. Given the patient’s symptoms, DVT was suspected, and thus, Doppler ultrasonography was performed. The results revealed the presence of DVT at the lower region of the left brachial and axillary veins (Fig. 2). In addition, venous computed tomography (CT) angiography was conducted to identify the distribution of thrombosis. Thus, the thrombus was observed from the lower region of internal jugular vein including the brachiocephalic and the axillary veins (Fig. 3).\n\nThe patient was placed in a sling to immobilize the arm and anticoagulation therapy was initiated with rivaroxaban (Xarelto; 15 mg twice daily per oral). After 1 week, compressive therapy was combined using compression bandage with icepack to reduce febrile sensation and edema. The edema in the upper extremity improved with time and the pain with febrile sensation disappeared.\n\nAt the 2-week follow-up, the patient had no pain or swelling. CT performed one month later revealed the resolution of filling defect with only small residual thrombosis in the brachiocephalic vein (Fig. 4). To reduce the risk of recurrence of DVT, rivaroxaban (Xarelto) was continued at the dosage of 20 mg once daily for 6 months.\n\nDISCUSSION\n\nVirchow’s triad is a well-known theory which explaining venous thrombus formation and is primarily composed of three factors: blood flow congestion, blood coagulation, and vascular wall damage. The DVT of the upper limbs accounts for approximately 4% to 10% of the total DVTs. As DVT in the upper extremity is relatively rare, it is less studied than in the lower extremities. Recently, more attempts have been made to probe the pathogenesis and clinical meaning of the upper extremity DVT. Kucher [4] categorized upper extremity DVT into two subgroups on the basis of pathogenesis: a primary and a secondary form due to obvious underlying causes, mainly cancer and indwelling central venous catheters. He spilt the primary upper extremity into three subtypes of venous thoracic outlet syndrome, effort-related thrombosis, and idiopathic type which has no relation to the thoracic outlet syndrome or to exertion. The author suggested mechanisms of venous thoracic outlet syndrome as compression of the subclavian vein resulting from abnormality of structures. Effort-related thrombosis, accounting for approximately two-thirds of the primary upper extremity, is defined as the direct damage to the vein from muscular stretching, later termed as “Paget-Schroetter syndrome” [4,5].\n\nIn this case report, although the cause of DVT in the patient was unclear, the probable rationales were as follows.\n\nFirst, the patient did not have the mentioned anatomical abnormalities, mechanisms of venous thoracic outlet syndrome such as compression by the first rib, clavicle, subclavius muscle, costoclavicular ligament, or anterior scalene muscle. However, he underwent repetitive and highly intensive passive range of motion exercise from the day after the botulinum toxin injection. As the spasticity progressively improved, his exercise intensity and duration subsequently increased. During exercise, the vessels with a constant length for many years, stretched extensively, possibly resulting in intimal injury in blood vessels. Recurrent microtrauma in the subclavian vein, as in effortful DVT, might have affected the etiology and triggered fibrosis and extrinsic constriction of the vessel wall. Generally, the exercise-induced venous thrombosis is observed in athletes involved in a wide variety of sports such as ball games, combatant sport and heavy athletics, games with rackets or clubs, and aquatic sports [6].\n\nSecond, the tone reduction after the injection might have contributed to the relative venous stasis. Spasticity improves venous return, thereby minimizing the development of thrombophlebitis, similar to that observed in patients with spinal cord injury. In these patients, spasticity conveys some protection against DVT [7].\n\nLastly, there might be direct vascular injury during the injection procedure. Even though there were no complications soon after the procedure, there remains the possibility of needle-induced mechanical damage because guide technique such as ultrasound was not used during the procedure [2,3].\n\nRecently, there were two case reports of thrombosis after botulinum toxin injection. First, Mines et al. [2] reported a case of the lower extremity DVT after BoNT-A for spasticity. The patient’s characteristics were similar as she was spastic and dystonic secondary to cerebral palsy caused by neonatal anoxia. In this case, the author suggested a direct effect on vascular smooth muscles and relief of muscle hypertonia as possible explanations for DVT formation. However, the additional suggestion given by the author of decreased mobility playing a role is contrary to our case. The author accessed the interval between the BoNT-A injection and the onset of lower extremity DVT as “plausible” according to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment system [8]. In our case, the formation of DVT is not an objective and specific medical disorder or a recognized pharmacological phenomenon. Although the interval between the start of the drug and the onset of the event is “plausible,” this case report belongs to “probable” according to the WHO-UMC causality assessment system [8,9].\n\nSecond, Pisani et al. [3] described a case of the axillary vein thrombosis after BoNT-A for hyperhidrosis in a female patient aged 32 years. Similar to the previous case report, the author suggested causality as reduced tissue tone surrounding the axillary vein, post-multiple injection traumatic inflammation, and stasis. However, in that case report, the meaning of “stasis” was unclear. Moreover, the patient had no underlying disease, which was different from the previous one and ours.\n\nWith respect to the effects of botulinum toxin on the vessel wall itself, several laboratory studies of flap viability in animal models [10] reported botulinum toxin has vasodilatory effect and preventing vasospasm and thrombosis. The mechanism of the effect is that it influences the neurons of the autonomic nervous system, resulting in increase of vessel diameter and blood perfusion.\n\nHowever, in clinical setting, we assumed that the vasodilatory effect of botulinum toxin when injected into spastic muscles, not flaps, may impede the velocity of venous return. Because spasticity is known to improve venous return, reducing the incidence of thrombosis [7]. Therefore, establishing the clinical evidence whether BoNT increase or decrease the formation of DVT would be a challenge depending on the situation. Additional work is required to confirm and explain the effect of BoNT about formation of DVT.\n\nIn conclusion, there are a variety of treatments to control post-stroke spasticity, and among them, the dramatic changes in spasticity may occur after neural interventions such as the BoNT-A injection. To our knowledge, this is the first case report of the upper extremity DVT after BoNT-A injection. Although generally safe, clinicians should be careful during injection. An ultrasonography guide is recommended to avoid potential mechanical vessel wall injury and localize the target muscles. In particular, patients should be recommended progressive range of motion exercise due to possible excessive stretch on vessel intima layer.\n\nFig. 1. Erythematous swelling on the left hand, forearm, and shoulder region.\n\nFig. 2. Ultrasound showed deep vein thrombosis in the brachial vein (A), axillary vein (B), and superficial cephalic vein (C).\n\nFig. 3. Computed tomography venography showed deep vein thrombosis in the internal jugular vein (A), brachiocephalic vein (B), axillary vein (C), and brachial vein (D) in the left extremity of the patient.\n\nFig. 4. Computed tomography venography performed 1 month later revealed a resolution of filling defect with only small residual thrombosis in the brachiocephalic vein (A) and brachial vein (B).\n\nTable 1. Patient’s coagulation profile\n\nParameter\tValue\t\nProthrombin time (s)\t12.9 (9.8–12.7)\t\nProthrombin time (INR)\t1.12 (0.85–1.15)\t\nProthrombin time (%)\t71.2 (75–130)\t\nActivated partial thromboplastin time (s)\t30.1 (23.0–39.0)\t\nD-dimer (μg/mL)\t2.2 (0–1.0)\t\nFibrin degradation products (μg/mL)\t2.7 (0–5)\t\nAntithrombin III (%)\t114.6 (75–125)\t\nBleeding time (min)\t3 (1–5)\t\nValues are presented as median (range).\n\nINR, international normalized ratio.\n\nNo potential conflict of interest relevant to this article was reported.\n\nConceptualization: Cho YK, Lim NN. Methodology: Cho YK, Kang EY, Lee GS. Formal analysis: Lee HK, Won KH, Lee GS. Project administration: Cho YK, Lim NN, Kang JS. Visualization: Cho YK, Lim NN, Won KH. Writing - original draft: Cho YK, Lim NN, Kang JS, Lee GS. Writing - review and editing: Cho YK, Lim NN, Lee SH. Approval of the final manuscript: all authors.\n==== Refs\nREFERENCES\n\n1 Cote TR Mohan AK Polder JA Walton MK Braun MM Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases J Am Acad Dermatol 2005 53 407 15 16112345\n2 Mines ML Pacheco T Castel-Lacana E de Boissezon X Marque P Montastruc F Venous thrombosis after botulinum therapy in lower limb: a case report and literature review Ann Phys Rehabil Med 2019 62 457 8 31707008\n3 Pisani LR Bramanti P Calabro RS A case of thrombosis of subcutaneous anterior chest veins (Mondor’s disease) as an unusual complication of botulinum type A injection Blood Coagul Fibrinolysis 2015 26 685 6 26126167\n4 Kucher N Clinical practice: deep-vein thrombosis of the upper extremities N Engl J Med 2011 364 861 9 21366477\n5 Illig KA Doyle AJ A comprehensive review of PagetSchroetter syndrome J Vasc Surg 2010 51 1538 47 20304578\n6 Zell L Kindermann W Marschall F Scheffler P Gross J Buchter A Paget-Schroetter syndrome in sports activities: case study and literature review Angiology 2001 52 337 42 11386385\n7 Green D Hartwig D Chen D Soltysik RC Yarnold PR Spinal Cord Injury Risk Assessment for Thromboembolism (SPIRATE Study) Am J Phys Med Rehabil 2003 82 950 6 14627932\n8 Uppsala Monitoring Centre The use of the WHOUMC system for standardized case causality assessment [Internet] Geneva, Switzerland World Health Organization 2013 [cited 2021 Mar 1]. Available from: https://www.who.int/publications/m/item/WHO-causality-assessment\n9 Moore N Berdai D Blin P Droz C Pharmacovigilance: the next chapter Therapie 2019 74 557 67 31623850\n10 Fathi M Fathi H Mazloumi M Khalilzadeh O Amanpour S Meysamie A Preventive effect of botulinum toxin A in microanastomotic thrombosis: a rabbit model J Plast Reconstr Aesthet Surg 2010 63 e720 4 20673655\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2234-0645",
"issue": "45(2)",
"journal": "Annals of rehabilitation medicine",
"keywords": "Botulinum toxins; Muscle spasticity; Upper extremity DVT",
"medline_ta": "Ann Rehabil Med",
"mesh_terms": null,
"nlm_unique_id": "101573065",
"other_id": null,
"pages": "160-164",
"pmc": null,
"pmid": "33849088",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "14627932;20304578;21366477;31707008;11386385;31623850;20673655;26126167;16112345",
"title": "Upper Extremity Deep Vein Thrombosis After Botulinum Toxin Injection: A Case Report.",
"title_normalized": "upper extremity deep vein thrombosis after botulinum toxin injection a case report"
} | [
{
"companynumb": "KR-ALLERGAN-2116557US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONABOTULINUMTOXINA"
},
"drugadditional": null,
... |
{
"abstract": "Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterised by defective cytotoxic function and hypercytokinaemia leading to macrophage expansion and haemophagocytosis. Patients often present with unexplained fevers, hepatosplenomegaly and pancytopenia, with elevation in serum ferritin and triglyceride. Acquired forms are triggered by infection, malignancy or rheumatological disorders. HLH in the setting of chronic lymphocytic leukaemia is rarely reported, however, and is usually associated with infection or as a consequence of chemotherapy. We present a case of HLH in a 64-year-old Caucasian woman with the only identified trigger being her hitherto untreated CLL.",
"affiliations": "Department of Haematology, Imperial College Healthcare NHS Trust, London, UK.;Department of Haemato-Oncology, Royal Marsden Hospital, London, UK.;Department of Haematology, UCLH, London, UK.",
"authors": "Bailey|Chris|C|http://orcid.org/0000-0002-1602-8396;Dearden|Claire|C|;Ardeshna|Kirit|K|",
"chemical_list": "D005047:Etoposide; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-219057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Chemotherapy; Haematology (incl blood transfusion); Malignant disease and immunosuppression",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003907:Dexamethasone; D005047:Etoposide; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D051359:Lymphohistiocytosis, Hemophagocytic; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D012772:Shock, Septic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28446487",
"pubdate": "2017-04-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12022333;16937360;18045564;20008190;21709200;21724431;21881043;23129836;23533846;24319239;24581757;24628491;24782338;24796145;24966707;25758828",
"title": "Haemophagocytic lymphohistiocytosis as a consequence of untreated B-cell chronic lymphocytic leukaemia.",
"title_normalized": "haemophagocytic lymphohistiocytosis as a consequence of untreated b cell chronic lymphocytic leukaemia"
} | [
{
"companynumb": "GB-ACCORD-052643",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"... |
{
"abstract": "The administration of statins in patients with liver disease is not an absolute contraindication. Hepatotoxicity is a rare and often dose-related event and in the literature there are only a few described cases of fatal rhabdomyolysis in patients with chronic liver disease after statin administration. During treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, the factors responsible for myopathy may either be related to the patient, or due to interactions with other medications that are metabolic substrates of the same isozymes and therefore able to increase blood statin concentration. The most important side effects consist of increased transaminase levels, abdominal pain or muscle weakness, increased serum levels of creatine kinase and rhabdomyolysis. In this article we report a case of fatal rhabdomyolysis with acute renal failure after gastric endoscopy, where midazolam was used as a sedation agent in a patient with chronic liver disease treated with a high dose of atorvastatin. Therefore, we suggest paying particular attention to the potential risks of associating atorvastatin and midazolam in patients with chronic liver disease who need to undergo gastric endoscopy.",
"affiliations": "Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.;Antonietta Gigante, Gianluca Di Lazzaro Giraldi, Maria Ludovica Gasperini, Biagio Barbano, Marta Liberatori, Liborio Sardo, Francesca Di Mario, Antonella Giorgi, Filippo Rossi-Fanelli, Antonio Amoroso, Department of Clinical Medicine, \"Sapienza\" University of Rome, 00185 Rome, Italy.",
"authors": "Gigante|Antonietta|A|;Giraldi|Gianluca Di Lazzaro|GD|;Gasperini|Maria Ludovica|ML|;Barbano|Biagio|B|;Liberatori|Marta|M|;Sardo|Liborio|L|;Mario|Francesca Di|FD|;Giorgi|Antonella|A|;Rossi-Fanelli|Filippo|F|;Amoroso|Antonio|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4292/wjgpt.v5.i3.196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-5349",
"issue": "5(3)",
"journal": "World journal of gastrointestinal pharmacology and therapeutics",
"keywords": "Alcoholic liver cirrhosis; Chronic liver disease; Midazolam; Rhabdomyolysis; Statins",
"medline_ta": "World J Gastrointest Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101547456",
"other_id": null,
"pages": "196-9",
"pmc": null,
"pmid": "25133049",
"pubdate": "2014-08-06",
"publication_types": "D002363:Case Reports",
"references": "17628739;24176465;22148003;15558515;19528564;19627660;14740969",
"title": "Rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin.",
"title_normalized": "rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin"
} | [
{
"companynumb": "IT-PFIZER INC-2014235592",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "RAMIPRIL"
},
"drugadditional": null,
... |
{
"abstract": "Radium-223 (Xofigo) is the first therapy with bone tropism for metastatic castrate-resistant prostate cancer (mCRPC) that has been shown to improve overall survival (OS). Although radium-223 has a positive effect on OS in men with mCRPC, there has been a paucity of reports from community practitioners, especially with regard to concurrent abiraterone and enzalutamide therapy. Significant differences in patient characteristics encountered may exist.\n\n\n\nWe conducted a retrospective study of men with mCRPC who received at least 1 cycle of radium-223 (n = 35). Baseline pain and ECOG PS as well as concurrent usage of abiraterone or enzalutamide were recorded. Side effect profiles for each patient throughout treatment were noted.\n\n\n\nBaseline cohort characteristics include a median age of 75 years. 37% had an ECOG PS ≥ 2 and 23% reported severe pain at baseline. 31% received concomitant enzalutamide 31% concomitant abiraterone. Patients treated concurrently with either abiraterone or enzalutamide did not display additional toxicity. Median cohort OS was 10 months. Patients with no or mild pain had longer median OS than those with moderate or severe pain, 14 versus 7 months (P = 0.028). Patients with ECOG PS < 2 had longer median OS than those with ECOG PS ≥ 2, 13 versus 10 months (P = 0.0233).\n\n\n\nThis study highlights key differences in patient characteristics encountered by community practitioners. In this population, which presented with clinically advanced disease, there was an improved survival benefit for those treated earlier in their disease. Radium-223 was well tolerated and concurrent treatment with abiraterone or enzalutamide did not add additional toxicity. These 2 points seem to advocate for aggressive and early treatment of patients with radium-223 in the community.",
"affiliations": "Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA. Electronic address: jrathbun@salud.unm.edu.;Department of Radiation Oncology, New Mexico Cancer Center, Albuquerque, NM, USA.",
"authors": "Rathbun|John Tyler|JT|;Franklin|Gregg E|GE|",
"chemical_list": "D000736:Androstenes; D001549:Benzamides; D014408:Biomarkers, Tumor; D009570:Nitriles; D010669:Phenylthiohydantoin; C000615150:Radium-223; C540278:enzalutamide; C089740:abiraterone; D011883:Radium",
"country": "United States",
"delete": false,
"doi": "10.1016/j.currproblcancer.2018.05.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-0272",
"issue": "43(3)",
"journal": "Current problems in cancer",
"keywords": "Abiraterone; Biomarkers; Enzalutamide; PSA; Radium-223; Xofigo",
"medline_ta": "Curr Probl Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D014408:Biomarkers, Tumor; D059248:Chemoradiotherapy; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant; D011883:Radium; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "7702986",
"other_id": null,
"pages": "205-212",
"pmc": null,
"pmid": "29983206",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Radium-223 (Xofigo) with concurrent abiraterone or enzalutamide: predictive biomarkers of improved overall survival in a clinically advanced cohort.",
"title_normalized": "radium 223 xofigo with concurrent abiraterone or enzalutamide predictive biomarkers of improved overall survival in a clinically advanced cohort"
} | [
{
"companynumb": "US-JNJFOC-20190531022",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENZALUTAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Sodium valproate is one of the most common first-line antiepileptics prescribed for primary and secondary generalised seizures. However, serious complications associated with sodium valproate, such as acute pancreatitis, need to be considered when choosing this medication for treating epilepsy in certain populations such as children and persons with intellectual disability. We report a case of a 21-year-old man with intellectual disability who presented to the emergency department with an acute abdomen, vomiting and diarrhoea. He had to undergo an emergency exploratory laparotomy during which acute necrotising pancreatitis was diagnosed intra-operatively. We believe that the recent increase in sodium valproate dosage for his epilepsy was the cause of the pancreatitis. Carers of such persons should be adequately informed regarding possible life-threatening complications of medications prescribed to avoid delay in diagnosis and unwanted incidents.",
"affiliations": "Department of Family Medicine.;Department of Clinical sciences, Universiti Tungku Abd.",
"authors": "Ali|M F|MF|;Loh|K Y|KY|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1985-2274",
"issue": "8(3)",
"journal": "Malaysian family physician : the official journal of the Academy of Family Physicians of Malaysia",
"keywords": "anticonvulsants; complications; drug induced; intellectual disability/mental retardation; pancreatitis; valproic acid",
"medline_ta": "Malays Fam Physician",
"mesh_terms": null,
"nlm_unique_id": "101466855",
"other_id": null,
"pages": "28-30",
"pmc": null,
"pmid": "25893054",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "12169885;114966;17322992;23640149;12699868;24276803;10228193;20227028;20587742;15253060;20200771",
"title": "Sodium valproate induced necrotising pancreatitis: A case report.",
"title_normalized": "sodium valproate induced necrotising pancreatitis a case report"
} | [
{
"companynumb": "MY-BION-009543",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "1",
"drug... |
{
"abstract": "An unusual case of pleural empyema related to Nocardia farcinica and Ureaplasma urealyticum, occurring after autologous haematopoietic stem cell transplantation in a 30-year-old patient with lymphoma, is reported. This case illustrates the role of repeated and comprehensive microbiological investigations and the contribution of molecular techniques in reaching the aetiological diagnosis.",
"affiliations": "Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Fédération d'Infectiologie, Paris, France. Electronic address: etienne.canoui@aphp.fr.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Unité de Soins Intensifs Respiratoires, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Bactériologie, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Réanimation Médicale, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Fédération d'Infectiologie, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Unité de Soins Intensifs Respiratoires, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Service d'Hémato-oncologie, Paris, France.;CHU et Université de Bordeaux, Bactériologie, Bordeaux, France.;Research Group on Bacterial Opportunistic Pathogens and Environment, UMR 5557, Ecologie Microbienne, French Observatory of Nocardiosis, Université de Lyon 1, CNRS, VetAgro Sup, Northern Hospital Group, Hospices Civils de Lyon, Lyon, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Microbiologie, Unité Mobile de Microbiologie Clinique, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Fédération d'Infectiologie, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Chirurgie Thoracique, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Unité de Soins Intensifs Respiratoires, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Fédération d'Infectiologie, Paris, France; INSERM 1181 Biostatistics, Biomathematics, Pharmacoepidemiology, and Infectious Diseases (B2PHI), Paris, France.",
"authors": "Canouï|Etienne|E|;Blanc|Kim|K|;Loubinoux|Julien|J|;Valade|Sandrine|S|;Hamard|Cécile|C|;Lefebvre|Aurélie|A|;Amorim|Sandy|S|;Bébéar|Cécile|C|;Rodriguez-Nava|Veronica|V|;Lebeaux|David|D|;Launay|Odile|O|;Alifano|Marco|M|;Rabbat|Antoine|A|;Kernéis|Solen|S|",
"chemical_list": "D004269:DNA, Bacterial; D012336:RNA, Ribosomal, 16S",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2017.09.015",
"fulltext": null,
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"issn_linking": "1201-9712",
"issue": "64()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Immunocompromised patient; Molecular microbiological diagnosis; Nocardia farcinica; Pleuropneumonia; Ureaplasma urealyticum",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D004269:DNA, Bacterial; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D058889:Molecular Typing; D009615:Nocardia; D009617:Nocardia Infections; D011001:Pleuropneumonia; D016133:Polymerase Chain Reaction; D000072078:Positron Emission Tomography Computed Tomography; D012336:RNA, Ribosomal, 16S; D016869:Ureaplasma Infections; D016990:Ureaplasma urealyticum",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "93-95",
"pmc": null,
"pmid": "28951103",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The value of molecular techniques to diagnose Ureaplasma urealyticum and Nocardia farcinica pleuropneumonia in a patient with diffuse large B-cell lymphoma.",
"title_normalized": "the value of molecular techniques to diagnose ureaplasma urealyticum and nocardia farcinica pleuropneumonia in a patient with diffuse large b cell lymphoma"
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"abstract": "Hodgkin lymphoma (HL) is one of the most common types of cancer in the young and one of the most curable forms of cancer. Therefore, there has been an increasing interest in the study of long-term morbidities. The aims of the present study were to evaluate the prevalence and risk factors for impaired gonadal function in a retrospective cohort of 238 HL female survivors from Italy and Brazil and to analyse the role of oral contraceptives (OC) and GnRH-analogues. Besides data collection from HL databases, a specific questionnaire was administered to collect data on gonadal function. The median age at diagnosis was 25 years and the median follow-up was 7 years. Overall, 25% of the patients developed impaired gonadal function. Older age at diagnosis, front-line therapies containing alkylating agents and more than one treatment were independent risk factors, whereas the use of OC or GnRH-a reduced independently the risk of impaired gonadal function. The fertility rate among fertile survivors was low when compared with the general population. We confirmed that older age, type of front-line chemotherapy and a higher number of therapies are associated with gonadal function impairment in terms of infertility and premature menopause in female HL survivors. Also, the use of GnRH-a or OC was independently identified as a protective factor. Further prospective studies are needed to better understand the barriers to parenthood in HL survivors.",
"affiliations": "Dipartimento di Ematologia, Ospedale Civile Spirito Santo, Pescara, Italy.",
"authors": "Falorio|Simona|S|;Biasoli|Irene|I|;Luminari|Stefano|S|;Quintana|Giovanni|G|;Musso|Maurizio|M|;Dell'olio|Matteo|M|;Specchia|Maria Rosaria|MR|;di Renzo|Nicola|N|;Cesaretti|Marina|M|;Buda|Gabriele|G|;Vallisa|Daniele|D|;Mannina|Donato|D|;Andriani|Alessandro|A|;Chiattone|Carlos Sérgio|CS|;Delamain|Márcia Torresan|MT|;de Souza|Cármino A|CA|;Spector|Nelson|N|;Angrilli|Francesco|F|;Federico|Massimo|M|",
"chemical_list": "D003276:Contraceptives, Oral",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2029",
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"issn_linking": "0278-0232",
"issue": "31(2)",
"journal": "Hematological oncology",
"keywords": null,
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001938:Brazil; D003276:Contraceptives, Oral; D005260:Female; D059247:Fertility Preservation; D006689:Hodgkin Disease; D006801:Humans; D007246:Infertility; D007558:Italy; D010053:Ovary; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D055815:Young Adult",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "72-8",
"pmc": null,
"pmid": "23027689",
"pubdate": "2013-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk factors for impaired gonadal function in female Hodgkin lymphoma survivors: final analysis of a retrospective multicenter joint study from Italian and Brazilian Institutions.",
"title_normalized": "risk factors for impaired gonadal function in female hodgkin lymphoma survivors final analysis of a retrospective multicenter joint study from italian and brazilian institutions"
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"abstract": "BACKGROUND\nComplete removal of pain with regional anesthesia has been reported to cause fatal respiratory depression in opioid-dependent patients, which leads us to choose general anesthesia. We hereby report three cases of chronically opioid-treated cancer patients operated under spinal anesthesia without respiratory event.\n\n\nMETHODS\nCase 1: a 32-year-old female treated with high-dose morphine for her cancer pain was planned for cesarean section. Case 2: a 65-year-old female on moderate dose of oxycodone was planned for surgery of her femoral bone fracture. Case 3: a 65-year-old male on low-dose oxycodone was planned for intramedullary nailing for metastatic femoral bone tumor. In all three cases, spinal anesthesia was chosen. Continuous respiratory monitoring revealed no apnea or bradypnea.\n\n\nCONCLUSIONS\nSpinal anesthesia was safely performed without respiratory depression in chronic opioid users for cancer pain.",
"affiliations": "Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Chiba, 260-8670, Japan. nnoztag@faculty.chiba-u.jp.;Department of Anesthesiology, Chiba Cerebral and Cardiovascular Center, Chiba, Japan.;Department of Anesthesiology, Chiba Emergency Medical Center, Chiba, Japan.;Department of Anesthesiology, Chiba University Hospital, Chiba, Japan.;Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Chiba, 260-8670, Japan.",
"authors": "Nozaki-Taguchi|Natsuko|N|http://orcid.org/0000-0001-7855-6138;Ueda|Yuko|Y|;Inada|Azusa|A|;Son|Kyongsuk|K|;Isono|Shiroh|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-020-00355-2",
"fulltext": "\n==== Front\nJA Clin Rep\nJA Clin Rep\nJA Clinical Reports\n2363-9024 Springer Berlin Heidelberg Berlin/Heidelberg \n\n355\n10.1186/s40981-020-00355-2\nCase Report\nA report of three cancer patients on opioid analgesia receiving spinal anesthesia: abrupt pain elimination without respiratory depression\nhttp://orcid.org/0000-0001-7855-6138Nozaki-Taguchi Natsuko nnoztag@faculty.chiba-u.jp 1 Ueda Yuko 2 Inada Azusa 3 Son Kyongsuk 4 Isono Shiroh 1 1 grid.136304.30000 0004 0370 1101Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Chiba, 260-8670 Japan \n2 grid.418492.20000 0004 0377 1935Department of Anesthesiology, Chiba Cerebral and Cardiovascular Center, Chiba, Japan \n3 Department of Anesthesiology, Chiba Emergency Medical Center, Chiba, Japan \n4 grid.411321.40000 0004 0632 2959Department of Anesthesiology, Chiba University Hospital, Chiba, Japan \n1 7 2020 \n1 7 2020 \n12 2020 \n6 497 5 2020 24 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background\nComplete removal of pain with regional anesthesia has been reported to cause fatal respiratory depression in opioid-dependent patients, which leads us to choose general anesthesia. We hereby report three cases of chronically opioid-treated cancer patients operated under spinal anesthesia without respiratory event.\n\nCase presentation\nCase 1: a 32-year-old female treated with high-dose morphine for her cancer pain was planned for cesarean section. Case 2: a 65-year-old female on moderate dose of oxycodone was planned for surgery of her femoral bone fracture. Case 3: a 65-year-old male on low-dose oxycodone was planned for intramedullary nailing for metastatic femoral bone tumor. In all three cases, spinal anesthesia was chosen. Continuous respiratory monitoring revealed no apnea or bradypnea.\n\nConclusion\nSpinal anesthesia was safely performed without respiratory depression in chronic opioid users for cancer pain.\n\nKeywords\nChronic opioidRespiratory depressionToleranceissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nRecently, the number of patients coming to the operating room with opioid analgesics is increasing, as opioids are used more regularly in both cancer and non-cancer pain. It is often believed that sudden and complete removal of pain with neuraxial anesthesia causes respiratory depression in opioid-consuming patients, since pain itself is considered to antagonize the respiratory depressant effect of opioids [1]. Case reports show fatal respiratory distress [2, 3], which guides our decision to choose general anesthesia for intraoperative safety. Patient conditions may not allow general anesthesia, or in some cases, regional anesthesia is favored. We report here three cases of cancer pain patients with several dose range of opioid analgesia, successfully treated with regional anesthesia which eliminated both cancer and surgical pain without any respiratory event.\n\nWritten informed consent for case report was obtained from patient herself in case 1, and from family members of the deceased in cases 2 and 3. Institutional IRB approval for submission was gained in October 2019 (#3564).\n\nThis manuscript adheres to the applicable EQUATOR guideline.\n\nCase presentation\nCase 1: a 32-year-old pregnant woman (height 163 cm, body weight (BW) on admission 37 kg) was diagnosed with rectal cancer with liver and bone metastasis at 24 gestational weeks. Cancer pain due to bone metastasis of T12, L3 spine (Fig. 1a) was treated with morphine which dose increased gradually due to disease progression. She received chemotherapy until 32 gestational weeks when cesarean section was planned. At the time of surgery, after 8 weeks opioid use, she was suffering from severe low back pain and lancinating pain in her semi-paralyzed left leg. She was treated with oral paracetamol and intravenous morphine 60 mg/h with frequent rescue doses, which totaled to as much as 2 g/day. Since the baby was planned to enter NICU while the patient was completely bedridden, the operating room could be her only chance to meet the baby. Regional anesthesia was chosen after careful assessment of the feasibility, risk, and the mother’s will. Anesthesia was induced with 2.4 ml hyperbaric 0.5% bupivacaine which produced anesthesia up to T9 dermatome, which also treated her cancer pain completely for few hours. Intraoperative monitoring consisted of ECG, SpO2, and non-invasive blood pressure (BP) measurement. Respiratory rate (RR) and end-tidal CO2 were continuously monitored with capnography (WEC-7301: NIHON KOHDEN, Japan) attached to a nasal cannula supplying 2 L/min oxygen during the surgery. Capnography revealed no apnea nor bradypnea (Fig. 1b). Average RR during surgery was 18 ± 7/min, and lowest RR observed was 9/min. After the mother had met the baby, she was given general anesthesia while colostomy was performed (total surgery time: 1 h 16 min). After recovery from general anesthesia, still with anesthesia level to T10, continuous respiratory monitoring was applied for 6 h which revealed average RR of 20 ± 8/min with no apnea. In short, her cancer pain in addition to postoperative pain returned.\nFig. 1 a Magnetic resonance imaging of the spine taken 8 months before the surgery showing multiple bone metastasis of the rectal cancer. b Compressed figure of capnography monitored during the surgery. Left and right axes show end-tidal CO2 and respiratory rate, respectively\n\n\n\nCase 2: a 65-year-old female (153 cm, 39 kg) was diagnosed with recurrence of esophageal cancer and metastasis of lung and bone. She was receiving intravenous oxycodone which was gradually increased for 18 days to 4.5 mg/h for her pain due to metastasis of her right sacral bone. Femoral trochanteric fracture was diagnosed after tumbling on the floor and she was planned for intramedullary nailing. As her preoperative chest x-ray revealed narrowing of the trachea due to lung metastasis (Fig. 2a), regional anesthesia with spinal anesthesia was selected. Isobaric 0.5% bupivacaine 2 ml completely treated her pain due to both fracture and bone metastasis (no record of anesthesia level). Oxycodone was continued during the surgery (surgery time, 1 h 48 min) and continuous RR and end-tidal CO2 monitoring was applied in accordance with the standard monitoring of ECG, SpO2, and BP. No respiratory event was recorded throughout the surgery (Fig. 2b) with average RR of 18 ± 6/min.\nFig. 2 a Preoperative chest x-ray of the patient showing lung metastatic tumor compressing the trachea forming atelectasis of the left upper lobe. b Compressed figure of capnography monitored during the surgery. Left and right axes show end-tidal CO2 and respiratory rate, respectively\n\n\n\nCase 3: a 65-year-old male (182 cm, 67 kg) diagnosed with femoral metastasis of gastric cancer was planned for elective intramedullary nailing. He was receiving oral oxycodone 20 mg/day for more than 50 days. His bone cancer pain was under control. Regional anesthesia was chosen as the surgery was a simple procedure. He took the regular morning dose of oxycodone before surgery and lumbar anesthesia was performed with 2.6 ml hyperbaric 0.5% bupivacaine, and he was free from pain (no record of anesthesia level). Continuous RR and end-tidal CO2 monitoring with the standard monitoring during the surgery showed no apnea nor bradypnea during the surgery (surgery time, 1 h 33 min) (Fig. 3) with average RR of 18 ± 5/min while he was observed to be sleeping without any sedatives during the operation.\nFig. 3 Compressed figure of capnography monitored during the surgery. Left and right axes show end-tidal CO2 and respiratory rate, respectively\n\n\n\nDiscussion\nAnalgesic effect of opioid, the major drug in pain treatment, has always been balanced with its side effect, especially respiratory depression. Existence of pain is known to stimulate respiration, thus antagonizes the respiratory depressant effect of opioids [1]. Abrupt removal of the pain by local anesthetics changes this balance between pain and respiratory depression. Combes et al. [4] have shown that abolition of postoperative pain by regional anesthesia in opioid-treated patients increased the incidence of abnormal respiratory events associated with oxygen desaturation.\n\nIn the case of chronic opioid users, the problem becomes more complex. In patients with long-time opioids, they are likely to have developed tolerance to both the analgesic effect and also the respiratory depressant effects. However, the level of tolerance may vary. The level of tolerance depends, possibly on the total dose or duration of opioids, but we have no clinically measurable method.\n\nFew case reports show us the risk or respiratory arrest after complete and sudden abolition of pain by regional anesthesia [2, 3]. Our report is the first to show result from continuous monitoring on respiration under these conditions. Whether respiratory arrest can be predicted by slowing of respiratory rate or increase in irregular breathing is not well investigated. In our three cases, opioid dose ranged from small dose of 20 mg of po oxycodone to 2 g of iv morphine. Duration of opioid use ranged from 18 days to 2 months. Tolerance level to opioid is probably different amongst three patients and also amongst opioid effect, analgesia, and respiratory depression. We observed no bradypnea, no apnea, and not even decreased respiratory rate in all three patients after removal of pain. They seemed to be totally tolerant to the respiratory depressant effect of opioids at doses given preoperatively. The observation of increased respiratory events treated with opioids in opioid naïve patients [4], compared with our results suggest us that tolerance to respiratory depression may develop within weeks. However, this needs further investigation.\n\nOur clinical observation of no respiratory depressant events shows that, under continuous and intent monitoring, choice of regional anesthesia in chronic opioid-consuming patients with clear indication for neuraxial block can be safely managed. Especially in long-time opioid users, we experience the need for escalated dose of postoperative opioid [5] or even intraoperative opioid, which sometimes results in opioid-induced hyperalgesia postoperatively and uncontrolled pain after surgery [6]. Regional anesthesia may be a better choice in such patients. Though we do not have clear evidence, general anesthesia is considered to produce immunosuppression such may affect malignant tumor recurrence [7], another reason to prefer regional to general anesthesia. Importantly, unexpected fatal respiratory arrest being reported after regional anesthesia in long-term opioid consumers [2, 3], continuous monitoring of respiration is mandatory under these conditions. Bradypnea is often not accompanied with desaturation with supplemental oxygen. Accordingly, oximetry may be a late indicator for hypoventilation. Though capnometer may not be an accurate end-tidal CO2 monitor when used in spontaneously breathing patients, it is strongly recommended for early detection of apnea or bradypnea [8].\n\nConclusion\nIn conclusion, regional anesthesia which may completely abolish the cancer pain in patients under chronic opioid analgesia can be safely administered. As presence or level of tolerance to respiratory depressant effect of opioids cannot be detected preoperatively, continuous monitoring is mandatory.\n\nAbbreviations\nRRRespiratory rate\n\nBPBlood pressure\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nAuthors’ contributions\nYU helped to summarize data of the first two cases.\n\nAI was responsible for the first case anesthesia.\n\nKS was responsible for the second case anesthesia.\n\nSI helped for the discussion of three cases and manuscript preparation.\n\nAll authors read and approved the final manuscript.\n\nFunding\nNone for all authors\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nInstitutional IRB approval for submission was gained in October 2019 (#3564).\n\nConsent for publication\nWritten informed consent for case report was obtained from patient herself in case 1, and from families of the deceased for cases 2 and 3.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Borgbjerg FM Nielsen K Franks J Experimental pain stimulates respiration and attenuates morphine-induced respiratory depression: a controlled study in human volunteers Pain 1996 64 123 128 10.1016/0304-3959(95)00088-7 8867254 \n2. Hanks GW Twycross RG Lloyd JW Unexpected complication of successful nerve block. Morphine induced respiratory depression precipitated by removal of severe pain Anaesthesia 1981 36 37 39 10.1111/j.1365-2044.1981.tb08596.x 6894066 \n3. Piquet CY Mallaret MP Lemoigne AH Barjhoux CE Danel VC Vincent FH Respiratory depression following administration of intrathecal bupivacaine to an opioid-dependent patient Ann Pharmacother. 1998 32 6 653 655 10.1345/aph.17182 9640484 \n4. Combes X Cerf C Bouleau D Duvaldestin P Dhonneur G The effects of residual pain on oxygenation and breathing pattern during morphine analgesia Anesth Analg. 2000 90 1 156 160 10.1097/00000539-200001000-00033 10624997 \n5. Rapp SE Ready LB Nessly ML Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review Pain 1995 61 195 201 10.1016/0304-3959(94)00168-E 7659429 \n6. Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis Br J Anaesth 2014 112 6 991 1004 10.1093/bja/aeu137 24829420 \n7. Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Anaesthetic techniques for risk of malignant tumour recurrence. Cochrane Database Syst Rev. 2014 Nov 7;11.\n8. Lam T Nagappa M Wong J Singh M Wong D Chung F Continuous pulse oximetry and capnography monitoring for postoperative respiratory depression and adverse events: a systematic review and meta-analysis Anesth Analg. 2017 125 6 2019 2029 10.1213/ANE.0000000000002557 29064874\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "6(1)",
"journal": "JA clinical reports",
"keywords": "Chronic opioid; Respiratory depression; Tolerance",
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"pages": "49",
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"title": "A report of three cancer patients on opioid analgesia receiving spinal anesthesia: abrupt pain elimination without respiratory depression.",
"title_normalized": "a report of three cancer patients on opioid analgesia receiving spinal anesthesia abrupt pain elimination without respiratory depression"
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"abstract": "BACKGROUND\nMedulloepithelioma (ME) is a rare embryonal tumor predominantly located in the eye or in the central nervous system without an established treatment.\n\n\nMETHODS\nWe report of a case of a localized peripheral ME treated with conventional and high dose chemotherapy, surgery and local radiotherapy. At relapse, the tumor tissue revealed a different molecular signature compared to the initial tumor mass. This molecular signature revealed a high expression of platelet derived growth factor receptor (PDGFR). Sorafenib plus irinotecan and temozolomide was started with a 5 month progression free survival.\n\n\nCONCLUSIONS\nOur experience suggests a possible role of sorafenib or different PDGFR inhibitors in ME. Targeting treatment could represent an adjuvant and/or alternative therapy for ME and other rare tumors.",
"affiliations": "Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, Piazza Sant'Onofrio, 4 - 00165 Rome, Italy. mdebora.depasquale@opbg.net.",
"authors": "De Pasquale|Maria Debora|MD|;De Ioris|Maria Antonietta|MA|;Gallo|Angela|A|;Mastronuzzi|Angela|A|;Crocoli|Alessandro|A|;Cozza|Raffaele|R|;Boldrini|Renata|R|",
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"fulltext": "\n==== Front\nJ Transl MedJ Transl MedJournal of Translational Medicine1479-5876BioMed Central 1479-5876-12-492455924810.1186/1479-5876-12-49ResearchPeripheral medulloepithelioma: a rare tumor with a potential target therapy De Pasquale Maria Debora 1mdebora.depasquale@opbg.netDe Ioris Maria Antonietta 1mantonietta.deioris@opbg.netGallo Angela 1angela.gallo@opbg.netMastronuzzi Angela 1angela.mastronuzzi@opbg.netCrocoli Alessandro 2alessandro.crocoli@opbg.netCozza Raffaele 1raffaele.cozza@opbg.netBoldrini Renata 3renata.boldrini@opbg.net1 Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, Piazza Sant’Onofrio, 4 - 00165 Rome, Italy2 Surgery Department, Bambino Gesù Children’s Hospital, Rome, Italy3 Pathology Department, Bambino Gesù Children’s Hospital, Rome, Italy2014 21 2 2014 12 49 49 8 12 2013 16 2 2014 Copyright © 2014 De Pasquale et al.; licensee BioMed Central Ltd.2014De Pasquale 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.Background\nMedulloepithelioma (ME) is a rare embryonal tumor predominantly located in the eye or in the central nervous system without an established treatment.\n\nCase presentation\nWe report of a case of a localized peripheral ME treated with conventional and high dose chemotherapy, surgery and local radiotherapy. At relapse, the tumor tissue revealed a different molecular signature compared to the initial tumor mass. This molecular signature revealed a high expression of platelet derived growth factor receptor (PDGFR). Sorafenib plus irinotecan and temozolomide was started with a 5 month progression free survival.\n\nConclusion\nOur experience suggests a possible role of sorafenib or different PDGFR inhibitors in ME. Targeting treatment could represent an adjuvant and/or alternative therapy for ME and other rare tumors.\n\nPeripheral medulloepitheliomaTreatmentTarget therapyPDGF\n==== Body\nBackground\nMedulloepithelioma (ME) is a rare embryonal tumor with a distinctive pathology characterized by papillary and tubular patterns recalling the primitive epithelium of the medullary plate and the embryonal neural tube [1].\n\nME is usually located in the eye or in central nervous system (CNS); a peripheral location has been rarely reported. Intraocular ME is often a well-circumscribed and benign tumor, while CNS ME is an aggressive neoplasm associated with a good prognosis only if completely removed [2,3]. Considering the rarity of peripheral medulloephitelioma (PME), the optimal treatment has yet to be established.\n\nWe report a case of PME with an interesting target protein expression suggesting a possible alternative therapeutic strategy for this rare tumor.\n\nCase presentation\nA 3 year old female presented with a one-month history of abdominal pain and anorexia. The abdominal ultrasonography showed a retroperitoneal mass (7 × 6 × 6 cm) confirmed by CT scan with a right hydronephrosis without evidence of metastatic spread (Figure 1A). An open biopsy of the lesion was performed. The pathology revealed a malignant neoplasm composed of tubules, papillary structures, ribbons of primitive stratified columnar cells, vesicular nuclei, and high nuclear-cytoplasmic ratio. This histopathology is similar to the structure of the primitive epithelium of the medullary plate and neural tube. The absence of cilia and blepharoplasts ruled out the hypothesis of a papillary ependymoma. The neoplastic cells showed a diffuse positivity for CD56 and WT1 (cytoplasmic) and a variable positivity for NSE, Synaptophisin, S100 protein and Cytokeratin MNF116, while they were negative for CD99, alpha-fetoprotein, CD30, OCT3/4, β-HCG. The diagnosis was neuroectodermal embryonal tumor with patterns of ME (Table 1, Figure 2 and Figure 3).\n\nFigure 1 A: CT scans showing the tumor at diagnosis right hydronephrosis is also present; scans after 4 courses of CT, demonstrating partial response to therapy; C: recurrence of the tumor after six months from stop therapy. CT at diagnosis (A), after chemotherapy (B) and at relapse (C).\n\nTable 1 Tumor immunochemistry at diagnosis and at relapse\n\nImmunochemistry\tDiagnosis\tRelapse\t\nCD56\t++\t++\t\nWT1\t++ (cytoplasmatic)\t++\t\nNSE\t+-\t+-\t\nSynaptophisin\t+-\t+-\t\nS100 protein\t+-\t+-\t\nCytokeratin MNF116\t+-\t+-\t\nCD99\t-\t-\t\nAlpha-fetoprotein\t-\t-\t\nCD30\t-\t-\t\nOCT 3/$\t-\t-\t\nβ-HCG\t-\t-\t\nEGFR\t-\t-\t\nPDGFR\t+\t++\t\nADAR 1\t+\t+\t\nADAR 2\t-\t-\t\nLEGEND: EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; ADAR, adenosine deaminases that act on RNA.\n\nFigure 2 Pathology of the tumor at diagnosis. Papillary and tubular patterns represent the distinctive appearance of medulloepithelioma; HE 4 × (A). Positivity of the neoplastic cells for S100 protein 60× (B) and for PanCytokeratin 60× (C).\n\nFigure 3 Pathology of the tumor at diagnosis. Areas of tumor at higher magnification show stratified columnar cells bordered by internal and external limiting membrane HE 40× (A) and 60× (B). Positivity of the neoplastic cells for NSE 60× (C) and for CD56 60× (D).\n\nThe child started chemotherapy according to our local protocol for Ewing Sarcoma Family Tumor [4]. After 2 ICE courses (Ifosfamide 2 gr/m2 for 3 days, Carboplatin 400 mg/m2 for 2 days and Etoposide 150 mg/m2 for 3 days) and 2 CAV (Cyclophosphamide 1.5 mg/m2 for 2 days, Vincristine 0.5 mg/m2 for 3 days and Doxorubicin 25 mg/m2 for 3 days), she achieved partial response, the mass measuring 5 × 3.3 × 3.8 cm (Figure 1B). Grade 4 bone marrow toxicity that required red blood cells and platelets transfusion and hospitalization for neutopenic fever, was recorded after all courses.\n\nA complete resection of the lesion was performed. The pathology showed extensive involutive post-chemotherapy aspects. The residual viable tumor showed histologic aspects overlapping with these of the first biopsy, partly characterized by more solid areas, with the same immunophenotypic pattern (Figure 4).\n\nFigure 4 Pathology after chemotherapy. The post chemotherapy tumor shows extensive involution area, calcifications HE4 × (A) and a predominant solid pattern 4× (B).\n\nThe child, in complete remission, completed the treatment with two CE courses (Cyclophosphamide 1.5 gr/m2 for 2 days and Etoposide 150 mg/m2 for 2 days) and a last CAV course. As a consolidation treatment, she received a high-dose chemotherapy based on Busulfan and Melphalan with autologous peripheral blood stem cells rescue and, finally, radiotherapy to the primary tumor bed (19, 5 Gy). During the entire chemotherapy treatment, only grade IV bone marrow toxicity was recorded. During radiotherapy the patient presented only grade I diarrhea.\n\nSix months after treatment discontinuation, she presented with an abdominal relapse (Figure 1C). Surgery was performed, achieving a second complete remission. The pathology confirmed a ME with the same characteristics of the primary tumor. At relapse, expression of tumor target proteins was evaluated on tissue specimens obtained both at diagnosis and at recurrence. Immunohistochemistry showed the tumor cells always negative for epidermal growth factor receptor (EGFR). By contrast, there was some positive staining with platelet-derived growth factor receptor (PDGFR) in the primary specimen, with a few cellular clusters showing cytoplasmic positivity, while at recurrence a clear diffuse cytoplasmatic positivity for PDGFR reaching almost 100% of the cells was observed. ADAR2 (adenosine deaminases that act on RNA) was absent in both primary and recurrent tumors; ADAR1 was expressed in the nucleus and cytoplasm, both at diagnosis and at recurrence. Figure 5 shows the EGFR, PDGFR, ADAR 1 and ADAR2 expression in tumor specimen at diagnosis and at recurrence. (See also Table 1).\n\nFigure 5 EGFR, PDGFR, ADAR 1 and ADAR2 expression in tumor specimen at diagnosis and at recurrence.\n\nAccording to the target protein expression, the patient started sorafenib 200 mg once daily orally, plus temozolomide 100 mg/m2/day orally for five consecutive days and irinotecan 10 mg/m2/day orally for 14 consecutive days; the course was repeated every 28 days.\n\nTreatment was well tolerated, only generalized skin rash associated with grade I dry skin not requiring treatment discontinuation was recorded. A progression-free survival was achieved for five months when peritoneal carcinomatosis with an important neoplastic peritoneal effusion appeared. The patient died for progressive disease a few weeks later.\n\nDiscussion\nPME is a very rare neoplasm and only few reports describe this entity (see Table 2 for more details) [5-9]. Similar to classical ME, surgery in PME, with or without systemic chemotherapy and/or local radiotherapy, represents a therapeutic option. Complete surgery seems to be associated with better outcome [5-9]. All reported PME were located in the pelvic cavity (Table 2). Some authors hypothesized that these tumors originated from undifferentiated cells of the pre-sacral remnant [6]. Four patients with ovarian ME had a good prognosis after surgery either alone or associated with adjuvant chemotherapy and/or radiotherapy [5]. In a case of congenital pelvic ME, prolonged disease-free survival was achieved after partial surgical removal and chemotherapy [7]. In a similar case, pelvic ME was resistant to chemotherapy and the patient died of metastatic pulmonary progression [6].\n\nTable 2 Review of literature for peripheral ME\n\nReference\tSex\tAge\tSite\tStage\tMetastasis\tTherapy\tOutcome\t\nKleinman et al.\tF\t20 yr\tovary\tI\tNo\tComplete surgery, CT\tNED, 108 mo\t\nKleinman et al.\tF\t32 yr\tovary\tI\tNo\tComplete surgery, CT\tNED, 36 mo\t\nKleinman et al.\tF\t13 yr\tovary\tIII\tNo\tComplete surgery\tDOD, 20 mo\t\nKleinman et al.\tF\t23 yr\tovary\tIII\tNo\tComplete surgery, CT, RT\tDOD, 2 mo\t\nFigarella-Branger et al.\tF\t17 yr\tpelvis\tIV\tLung\tSurgery on primitive tumor, CT\tDOD, 8 mo\t\nBruggers et al.\tF\tNewborn\tpelvis\tIII\tNo\tPartial resection, CT\tNED, 50 mo\t\nDonner et al.\tF\t12 yr\tpelvis\tIII\tNo\tCT\tNED, 36 mo\t\nNakamura et al.\tM\t6 mo\tpelvis (sciatic nerve)\tIII\tNo\tComplete surgery\tNED, 84 mo\t\nLegend: F, female; M, male; yr, years; mo, months; CT, chemotherapy; RT, radiotherapy; NED, non evidence of disease; DOD, died of disease.\n\nAnalyzing the reported cases, it seems that some PME with favorable prognosis were sensitive to chemotherapy, while, for chemo-resistant tumors, the only curative treatment was represented by radical surgery [5-9]. In our case, we decided to treat the patient with an aggressive first-line therapy. The patient achieved complete remission but she relapsed only six months after the end of treatment. At relapse we evaluated the expression of tumor target proteins focusing on the protein expression profile often involved in brain cancers with possible therapeutic implications, such as PDGFR and EGFR. The PDGFR is a cell surface receptor linked to a tyrosine kinase (TK) involved in several processes, including autocrine cancer cells growth and angiogenesis. Few PDGFR antagonists have been developed and introduced in clinical practice, such as sorafenib or STI571/imatinib mesylate [10]. Similarly, EGFR is a cell-surface receptor involved in DNA synthesis and cell migration, adhesion and proliferation. Anticancer drugs directed against EGFR include gefitinib, erlotinib and cetuximab [11].\n\nWe also studied the ADARs (adenosine deaminases that act on RNA) expression on tumor specimens. The ADARs are enzymes responsible for Adenosine-to-Inosine conversion on coding and non-coding RNA (such as microRNA) that are emerging as important key proteins in cancers. Recent evidences have connected ADARs (ADAR1 and ADAR2) deregulation to several cancers [12].\n\nSurprisingly, at recurrence, we observed PDGFR expression, not present at diagnosis, in almost all tumor cells.\n\nSorafenib is a small molecular inhibitor of several TK protein, such as vascular endothelial growth factor receptor, PDGFR and Raf kinases (more avidly C-Raf than B-Raf). The drug has been approved by the U.S. Food and Drug Administration for use in the treatment of advanced renal cancer, unresectable hepatocellular carcinoma and locally recurrent or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment [13-15]. Some authors showed that sorafenib blocks STAT3 (a signal transducer and activator of transcription), as well as the expression of proteins regulating the cell cycle and the apoptosis process, both in cell lines and primary tumor cells of medulloblastoma. These findings provide a rationale for treatment of pediatric medulloblastoma with sorafenib [16]. ME is classified in the group of the embryonal tumors together with medulloblastoma according to WHO classification.\n\nAt recurrence, we proposed, as compassionate treatment, sorafenib plus temozolomide and irinotecan. After obtaining IRB approval the three drug combination was started. Treatment was well tolerated and only a mild skin rash was observed.\n\nSorafenib was chosen according to the PDGFR expression on tumor specimen, while temozolomide and irinotecan had demonstrated activity in medulloblastoma [17,18]. We anticipated an efficacy of this drug combination with a good tolerance and a good quality of life considering the oral assumption.\n\nThe finding of poor expression of PDGFR at diagnosis and its massive expression at relapse could suggest that a cell clone with high expression of PDGFR was responsible for the relapse. This leads us to hypothesize that sorafenib, if it had been administered at diagnosis, could have allowed to maintain a longer complete remission.\n\nConclusion\nOur experience is only a single report, with obvious anecdotal consideration. However this report may suggest that in cases of ME the target protein expression in tumor tissue should be evaluated aimed to identify possible therapeutic targets. Moreover, a possible therapeutic role of PDGFR inhibitors was never reported before.\n\nA TK-inhibitor could be considered and employed also during first line treatment. Indeed, only a multicentric trial could asses the clinical benefit of TK inhibitors combined with chemotherapy; clearly the tumour target protein profile should be evaluated in different phases of treatment as well as at diagnosis or after chemotherapy or at relapse.\n\nFurthermore, we would underline the importance of targets expression study in ME as in all rare pediatric tumors with a poor prognosis in order to identify alternative therapeutic strategies. We also propose regular molecular monitoring of the protein expression profile in tumor samples at reasonable time points during therapy administration. This may help taking decisions in drug selection including appropriate change or adjustment of chemotherapy.\n\nAbbreviations\nME: Medulloepithelioma; PME: Peripheral Medulloepithelioma; PDGFR: Platelet derived growth factor receptor; CNS: Central nervous system.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMDDP conceptualized the report and designed the target studies addressing the patient treatment, collected clinical data, drafted the initial manuscript and approved the final manuscript as submitted. MADI reviewed and revised the manuscript, and approved the final manuscript as submitted. AG performed targeting studies on tumor specimens, critically reviewed the manuscript, and approved the final manuscript as submitted. AM critically reviewed the manuscript and approved the final manuscript as submitted. AC collected clinical data and approved the final manuscript as submitted. RC collected clinical data and approved the final manuscript as submitted. RB designed the target studies, performed and discussed targeting studies on tumor specimens, critically reviewed the manuscript and approved the final manuscript as submitted.\n\nAcknowledgment\nThe authors would like to thank Professor Franco Locatelli for critically reviewing the paper\n\nFunding source\nNo funding was secured for this study.\n\nFinancial disclosure\nThe authors have no financial relationships relevant to this article to disclose.\n==== Refs\nBroughton WL Zimmerman LE A clinicopathological study of 56 cases of intraocular medulloepotheliomas Am J Opthalmol 1978 85 3 407 418 \nSaunders T Margo CE Intraocular medulloepithelioma Arch Pathol Lab Med 2012 136 2 212 216 10.5858/arpa.2010-0669-RS 22288972 \nMolloy PT Yachnis AT Rorke LB Dattilo JJ Needle MN Millar WS Goldwein JW Sutton LN Phillips PC Central nervous system medulloepithelioma: a series of eight cases including two arising in the pons J Neurosurg 1996 84 3 430 436 10.3171/jns.1996.84.3.0430 8609554 \nMilano GM Cozza R Ilari I High histologic and overall response to dose intensification of ifosfamide, carboplatin, and etoposide with cyclophosphamide, doxorubicin, and vincristine in patients with high-risk Ewing sarcoma family tumors: the Bambino Gesù Children's Hospital experience Cancer 2006 106 8 1838 1845 10.1002/cncr.21780 16532434 \nGm K Young R Re S Primary neuroectodermal tumors of the ovary: a report of 25 cases Am J Surg Pathol 1993 17 8 764 778 10.1097/00000478-199308000-00002 8393302 \nFigarella-Branger D Gambarelli D Perez-Castillo M Gentet JC Grisoli F Pellissier JF Ectopic intrapelvic medulloepithelioma: case report Neuropathol Appl Neurobiol 1992 18 4 408 414 10.1111/j.1365-2990.1992.tb00802.x 1528392 \nBruggers CS Welsh CT Boyer RS Byrne RS Pysher TJ Successful therapy in a child with a congenital peripheral medulloepithelioma and disruption of hindquarter development J Pediatr Hematol Oncol 1999 21 2 161 164 10.1097/00043426-199903000-00015 10206465 \nDonner LR Teshima I Peripheral medulloepithelioma: an immunohistochemical, ultrastructural, and cytogenetic study of a rare, chemotherapy-sensitive, pediatric tumor Am J Surg Pathol 2003 27 7 1008 1012 10.1097/00000478-200307000-00018 12826895 \nNakamura Y Becker LE Mancer K Gillespie R Peripheral medulloepithelioma. Acta Neuropathol 1982 57 2–3 137 142 7124342 \nOstman A PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma Cytokine Growth Factor Rev 2004 15 4 275 286 10.1016/j.cytogfr.2004.03.002 15207817 \nGan HK Burgess AW Clayton AH Scott AM Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy Cancer Res 2012 72 12 2924 2930 10.1158/0008-5472.CAN-11-3898 22659454 \nGaleano F Tomaselli S Locatelli F Gallo A A-to-I RNA editing: the \"ADAR\" side of human cancer Semin Cell Dev Biol 2012 23 3 244 250 10.1016/j.semcdb.2011.09.003 21930228 \nEscudier B Eisen T Stadler WM Szczylik C Oudard S Staehler M Negrier S Chevreau C Desai AA Rolland F Demkow T Hutson TE Gore M Anderson S Hofilena G Shan M Pena C Lathia C Bukowski RM Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial J Clin Oncol 2009 27 20 3312 3318 10.1200/JCO.2008.19.5511 19451442 \nWang ZG Zhang GF Wu JC Jia MK Adjuvant therapy for hepatocellular carcinoma: Current situation and prospect Drug Discov Ther 2013 7 4 137- 143 24071575 \nHaraldsdottir S Shah MH An update on clinical trials of targeted therapies in thyroid cancer Curr Opin Oncol 2014 26 36 44 10.1097/CCO.0000000000000029 24240178 \nYang F van Meter TE Buettner R Hedvat M Liang W Kowolik CM Mepani N Mirosevich J Nam S Chen MY Tye G Kirschbaum M Jove R Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas Mol Cancer Ther 2008 7 11 3519 3526 10.1158/1535-7163.MCT-08-0138 19001435 \nWang CH Hsu TR Wong TT Chang KP Efficacy of temozolomide for recurrent embryonal brain tumors in children Childs Nerv Syst 2009 25 5 535 541 10.1007/s00381-008-0781-7 19107490 \nBomgaars LR Bernstein M Krailo M Kadota R Das S Chen Z Adamson PC Blaney SM Phase II trial of irinotecan in children with refractory solid tumors: a Children's Oncology Group Study J Clin Oncol 2007 25 29 4622 4627 10.1200/JCO.2007.11.6103 17925558\n\n",
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"medline_ta": "J Transl Med",
"mesh_terms": "D001932:Brain Neoplasms; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D058990:Molecular Targeted Therapy; D018242:Neuroectodermal Tumors, Primitive; D014057:Tomography, X-Ray Computed",
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"title": "Peripheral medulloepithelioma: a rare tumor with a potential target therapy.",
"title_normalized": "peripheral medulloepithelioma a rare tumor with a potential target therapy"
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"abstract": "Central serous chorioretinopathy occurs primarily in young caucasian men. It is characterized by the development of a serous detachment of the sensory retina with the apparition of a relative central scotomata. An association with phosphodiesterase 5 inhibitors is reported in some articles. We described two cases of central serous chorioretinopathy following the use of tadalafil and sildenafil.",
"affiliations": "Service d'Ophtalmologie, CHR de la Citadelle, Liège, Belgique.;Service d'Ophtalmologie, CHR de la Citadelle, Liège, Belgique.;Service d'Ophtalmologie, CHR de la Citadelle, Liège, Belgique.",
"authors": "Smal|C|C|;Lepièce|G|G|;Bonnet|S|S|",
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"keywords": " Central serous chorioretinopathy ; Choroidal thickening; Serous detachment of the sensory retina ; Phosphodiesterase 5 inhibitors ",
"medline_ta": "Rev Med Liege",
"mesh_terms": "D056833:Central Serous Chorioretinopathy; D006801:Humans; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D000068581:Tadalafil; D041623:Tomography, Optical Coherence",
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"title": "Central serous chorioretinopathy following the use of phosphodiesterase 5 inhibitors.",
"title_normalized": "central serous chorioretinopathy following the use of phosphodiesterase 5 inhibitors"
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"abstract": "OBJECTIVE\nPostoperative pain can limit the recovery of children undergoing craniotomy for tumor resection, and pain management is highly variable between institutions and practitioners. Nonsteroidal antiinflammatory drugs (NSAIDs) are effective in treating postoperative pain following craniotomy, but their use has been limited by concerns about postoperative hemorrhage. The risk of postoperative hemorrhage is not insignificant in patients undergoing craniotomy for tumor resection. No study has specifically addressed the safety of NSAIDs in the immediate postoperative setting following craniotomy for tumor resection in pediatric patients.\n\n\nMETHODS\nThe authors performed a retrospective cohort study in patients younger than 18 years of age who underwent craniotomy for tumor resection at a single tertiary referral center between 2009 and 2019. The study outcomes were 1) postoperative hemorrhage requiring return to the operating room for decompression, evacuation, or CSF diversion for hemorrhage-associated hydrocephalus; and 2) more-than-minimal hemorrhage on routine postoperative imaging. Patients receiving any NSAID in the hospital formulary on the same day as surgery (postoperative day zero [POD0]) were designated as such.\n\n\nRESULTS\nTwo hundred seventy-six children underwent 308 craniotomies for tumor resection over the study period. One hundred fifty-four patients (50.0%) received at least one dose of an NSAID on POD0. Six patients (1.9%) required a return to the operating room for a hemorrhagic complication, including 3 who received an NSAID on POD0 (OR 1.00, 95% CI 0.20-5.03). Seventeen patients (6.3% of patients imaged) had more-than-minimal hemorrhage on routine postoperative imaging, 9 of whom received an NSAID on POD0 (OR 1.08, 95% CI 0.40-2.89).\n\n\nCONCLUSIONS\nUse of NSAIDs on POD0 was not associated with either an increased risk of hemorrhage requiring a return to the operating room or asymptomatic hemorrhage on routine postoperative imaging. The overall incidence of clinically significant postoperative intracranial hemorrhage is low. These data support the use of NSAIDs as a safe measure for pain control in the postoperative setting for children undergoing craniotomy for tumor resection.",
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"authors": "Nesvick|Cody L|CL|;Oushy|Soliman|S|;Daniels|David J|DJ|;Ahn|Edward S|ES|",
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"keywords": "COX = cyclooxygenase; EVD = external ventricular drain; IQR = interquartile range; IVH = intraventricular hemorrhage; JPA = juvenile pilocytic astrocytoma; NSAID; NSAID = nonsteroidal antiinflammatory drug; POD0 = postoperative day zero; RCT = randomized controlled trial; SAH = subarachnoid hemorrhage; VPS = ventriculoperitoneal shunt; craniotomy; nonsteroidal antiinflammatory drug; pain; tumor",
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"title": "Safety of immediate use of nonsteroidal antiinflammatory drugs after pediatric craniotomy for tumor.",
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"abstract": "We report a case of a child whose EEG demonstrated extreme spindles (ES) after acute lymphoblastic leukemia treatment. This finding has not been reported previously. In 1962, Gibbs and Gibbs described the ES EEG pattern due to its high amplitude (200 to 400 μV). ES are a rare spindle variant that is found in EEGs of 0.05% of normal children (average age, 3 years, with a range of 1 to 12 years), and are even rarer after 11 years. Moreover due to changes in the white matter of the frontal lobe, ES have been associated with such conditions as cerebral palsy and mental retardation, residual brain damage, undefined infections, infantile neuroaxonal dystrophy, Menkes' kinky-hair syndrome, congenital muscular dystrophy, hydrocephalus, porencephaly, epilepsy, progressive cerebellar degeneration, and mycoplasma encephalitis. Methotrexate has a notably toxic effect on the central nervous system, with leukoencephalopathy being the most common form. In our case, frontocentral ES were associated with hyperintense lesions in the white matter of the frontal lobe. Lesional deafferentation can be the substrate for an almost continuous ES, since both initiation and termination of spindle oscillations are thought to originate in thalamocortical neurons. Thus, we postulate that in some cases a partial functional cortical differentiation could generate ES.",
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"issue": "55(4)",
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"mesh_terms": "D002675:Child, Preschool; D003937:Diagnosis, Differential; D004569:Electroencephalography; D006801:Humans; D056784:Leukoencephalopathies; D008297:Male; D008727:Methotrexate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
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"title": "Extreme Spindles and Leukoencephalopathy after Acute Lymphoblastic Leukemia Treatment: An Undescribed Association.",
"title_normalized": "extreme spindles and leukoencephalopathy after acute lymphoblastic leukemia treatment an undescribed association"
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"abstract": "The combination of frequently abnormal hemostatic markers and catastrophic bleeding as seen with variceal hemorrhage has contributed to the longstanding misperception that chronic liver disease (CLD) constitutes a bleeding diathesis. Laboratory studies of hemostasis in liver disease consistently challenge this with global coagulation assays incorporating activation of the protein C pathway demonstrating rebalanced hemostasis. It is now recognized that bleeding in CLD is predominantly secondary to portal hypertension (rather than a coagulopathy) and additionally that these patients are at increased risk of venous thrombosis, particularly in the portal venous system. This narrative review describes the current understanding of hemostasis in liver disease, as well as the periprocedural management of hemostasis and anticoagulation for management of venous thromboembolism in patients with CLD.",
"affiliations": "King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom.",
"authors": "Roberts|Lara N|LN|",
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"doi": "10.1182/hematology.2021000283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1520-4383",
"issue": "2021(1)",
"journal": "Hematology. American Society of Hematology. Education Program",
"keywords": null,
"medline_ta": "Hematology Am Soc Hematol Educ Program",
"mesh_terms": null,
"nlm_unique_id": "100890099",
"other_id": null,
"pages": "485-491",
"pmc": null,
"pmid": "34889414",
"pubdate": "2021-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rebalanced hemostasis in liver disease: a misunderstood coagulopathy.",
"title_normalized": "rebalanced hemostasis in liver disease a misunderstood coagulopathy"
} | [
{
"companynumb": "GB-TEVA-2022-GB-2016478",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": "3",
... |
{
"abstract": "Compared with solvent-based taxanes, nanoparticle albumin-bound (nab®) paclitaxel has demonstrated improved efficacy and tolerability in several solid tumor malignancies. Studies evaluating nab paclitaxel in patients with lymphoma are lacking. In this planned phase-I/phase-II study, we sought to determine the safety and efficacy of nab-paclitaxel in patients with relapsed/refractory (R/R) lymphoma. Eligible patients (R/R to ≥2 prior systemic therapies) received weekly nab-paclitaxel on days 1, 8 and 15 every 28 days. Dosing was initiated at 100 mg/m2 with dose escalations in 25 mg/m2 increments up to 150 mg/m2 in a classic 3 + 3 design. Twenty heavily pretreated patients (median 5 prior regimens), including 65% with refractory disease, enrolled. The maximum dose tested was well tolerated and grade 3/4 hematologic adverse events (neutropenia 25%, thrombocytopenia 20% and anemia 15%) were modest. The overall response rate was 10% with two partial responses, leading to a decision to close the study prematurely.",
"affiliations": "a St. Louis University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.;b Siteman Comprehensive Cancer Center, Washington University , St. Louis , MO , USA.",
"authors": "Goyal|Sagun|S|;Oak|Eunhye|E|;Luo|Jingqin|J|;Cashen|Amanda F|AF|;Carson|Kenneth|K|;Fehniger|Todd|T|;DiPersio|John|J|;Bartlett|Nancy L|NL|;Wagner-Johnston|Nina D|ND|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2017.1330954",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "59(2)",
"journal": "Leukemia & lymphoma",
"keywords": "Nab paclitaxel; lymphoma and Hodgkin disease; phase-1 study; sparc",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D000072078:Positron Emission Tomography Computed Tomography; D012008:Recurrence; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "357-362",
"pmc": null,
"pmid": "28597723",
"pubdate": "2018-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Minimal activity of nanoparticle albumin-bound (nab) paclitaxel in relapsed or refractory lymphomas: results of a phase-I study.",
"title_normalized": "minimal activity of nanoparticle albumin bound nab paclitaxel in relapsed or refractory lymphomas results of a phase i study"
} | [
{
"companynumb": "US-CELGENEUS-USA-20170605922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Herein, the authors present the case of a 54-year-old male diagnosed with coronavirus disease 2019 (COVID-19) during a screening test. The patient was asked to self-isolate at home and report with any exacerbations of symptoms. He presented later with pneumonia complicated by encephalopathy at days 14 and 15 from initial diagnosis, respectively. MRI of the brain showed bithalamic and gangliocapsular FLAIR signal abnormality with mild right-sided thalamic and periventricular diffusion restriction. A CT venogram was obtained given the distribution of edema and demonstrated deep venous thrombosis involving the bilateral internal cerebral veins and the vein of Galen. CSF workup was negative for encephalitis, as the COVID-19 polymerase chain reaction (PCR) test and bacterial cultures were negative. A complete hypercoagulable workup was negative, and the venous thrombosis was attributed to a hypercoagulable state induced by COVID-19. The mental decline was attributed to bithalamic and gangliocapsular venous infarction secondary to deep venous thrombosis. Unfortunately, the patient's condition continued to decline, and care was withdrawn.",
"affiliations": null,
"authors": "Hoelscher|Christian|C|;Sweid|Ahmad|A|;Ghosh|Ritam|R|;Al Saiegh|Fadi|F|;Keppetipola|Kavantissa M|KM|;Farrell|Christopher J|CJ|;Jallo|Jack|J|;Jabbour|Pascal|P|;Tjoumakaris|Stavropoula|S|;Gooch|M Reid|MR|;Rosenwasser|Robert H|RH|;Shah|Syed O|SO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": null,
"journal": "Journal of neurosurgery",
"keywords": "COVID-19; COVID-19 = coronavirus disease 2019; CSF = cerebrospinal fluid; EVD = external ventricular drain; ICP = intracranial pressure; SARS-CoV-2; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; central nervous system; cerebrovascular disease; deep venous thrombosis; hypercoagulable state; infection; vascular disorders",
"medline_ta": "J Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "32886922",
"pubdate": "2020-09-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cerebral deep venous thrombosis and COVID-19: case report.",
"title_normalized": "cerebral deep venous thrombosis and covid 19 case report"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-22000",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditiona... |
{
"abstract": "The prognosis of patients with relapsed/refractory precursor B-acute lymphoblastic leukemia (ALL) is dismal. Antibody-based therapies, such as blinatumomab or inotuzumab ozogamycin (IO) have led to improved outcomes. The impact of prior immunotherapy on chimeric antigen receptor (CAR) T-Cell therapeutic efficacy and toxicity is unknown.\n\n\n\nWe describe a case series of ALL patients with prior exposure to blinatumomab or IO, who were treated with anti-CD19 CAR T cells with CD28 co-stimulatory domain (NCT02772198). We then review the literature on CAR-T post antibody-based therapy with either antibodies.\n\n\n\nFive adult patients with B-ALL were included. Three had active disease, and two were in morphological complete remission (CR) with minimal residual disease (MRD+). Therapy before CAR-T included blinatumomab (3/5 [60 %]) and IO (3/5 [60 %]), with one patient receiving both. One patient experienced severe cytokine release syndrome and central nervous system toxicity and subsequently died. At 28 days following treatment, two patients achieved CR with MRD negativity, and two had an MRD + CR. Two patients received allogeneic hematopoietic stem cell transplantation. At a median of 10 months (range, 5-26, three out of the four patients are still in CR, and one relapsed. The literature review identified a deficiency on data on the influence of blinatumumab and IO on outcomes post CAR-T therapy.\n\n\n\nCD19 CAR T-cell therapy after treatment with blinatumomab and/or IO in patients with relapsed/refractory B-ALL is feasible and results in promising response rates in this case series. Future trails should specifically address outcomes in this population.",
"affiliations": "Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Ella Lemelbaum Institute for Immuno Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: shouval@gmail.com.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Danylesko|Ivetta|I|;Chowers|Guy|G|;Shouval|Roni|R|;Besser|Michal J|MJ|;Jacoby|Elad|E|;Shimoni|Avichai|A|;Nagler|Arnon|A|;Avigdor|Abraham|A|",
"chemical_list": "D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000074322:Antineoplastic Agents, Immunological; C000604811:CD19 molecule, human; D047428:Protein Kinase Inhibitors; C510808:blinatumomab; D000080045:Inotuzumab Ozogamicin",
"country": "France",
"delete": false,
"doi": "10.1016/j.retram.2019.12.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2452-3186",
"issue": "68(1)",
"journal": "Current research in translational medicine",
"keywords": "Acute lymphoblastic leukemia; Blinatumomab; Chimeric antigen receptor T cells; Inotuzumab ozogamycin",
"medline_ta": "Curr Res Transl Med",
"mesh_terms": "D000328:Adult; D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D000080424:Cytokine Release Syndrome; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D000080045:Inotuzumab Ozogamicin; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D016879:Salvage Therapy",
"nlm_unique_id": "101681234",
"other_id": null,
"pages": "17-22",
"pmc": null,
"pmid": "31882377",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment with anti CD19 chimeric antigen receptor T cells after antibody-based immunotherapy in adults with acute lymphoblastic leukemia.",
"title_normalized": "treatment with anti cd19 chimeric antigen receptor t cells after antibody based immunotherapy in adults with acute lymphoblastic leukemia"
} | [
{
"companynumb": "IL-HEALTHCARE PHARMACEUTICALS LTD.-2081148",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nOptimal management of patients with large vessel occlusion (LVO) and low NIHSS score is unknown, which was the aim to investigate in this study.\n\n\nMETHODS\nThis is a retrospective analysis of a prospective single tertiary care centre 14-year cohort of patients with LVO in the anterior circulation and NIHSS score ≤ 5 on admission. Outcome was analysed according to primary intended therapy.\n\n\nRESULTS\nAmong 185 patients (median age 67.4 years), 52.4% received primary conservative therapy (including 26.8% secondary reperfusion in case of secondary neurological deterioration), 12.4% IV thrombolysis (IVT) only and 35.1% primary endovascular therapy (EVT). 95 (51.4%) patients experienced neurological deterioration until 3 months. Primary-IVT-only and primary-EVT compared to conservative-therapy patients had better 3 months' outcome (54.5% vs. 30.8%: adjustedOR 6.02; adjustedp = 0.004 for mRS 0-1 and 54.7% vs. 30.8%: adjustedOR 5.09; adjustedp = 0.002, respectively). Also mRS shift analysis favored primary-IVT-only and primary-EVT patients (adjustedOR 6.25; adjustedp = 0.001 and adjustedOR 3.14; adjustedp = 0.003). Outcome in primary-IVT-only vs. primary-EVT patients did not differ significantly. Patients who received secondary EVT because of neurological deterioration after primary-conservative-therapy had worse 3 months' outcome than primary-EVT patients (20.8% vs. 30.8%: adjustedOR 0.24; adjustedp = 0.047 for mRS 0-1 and adjustedOR 0.31; adjustedp = 0.019 in mRS shift analysis). Survival and symptomatic intracranial haemorrhage did not differ amongst groups.\n\n\nCONCLUSIONS\nOur data indicate that primary IVT and/or EVT may be better than primary conservative therapy in patients with LVO in the anterior circulation and low NIHSS score. Furthermore, primary EVT was better than secondary EVT in case of neurological deterioration. There is an unmet need for RCTs to find the optimal therapy for this patient group.",
"affiliations": "Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland. mirjam.heldner@insel.ch.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.;Department of Neurology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.",
"authors": "Heldner|Mirjam R|MR|http://orcid.org/0000-0002-3594-2159;Chaloulos-Iakovidis|Panagiotis|P|http://orcid.org/0000-0002-4620-9155;Panos|Leonidas|L|http://orcid.org/0000-0002-5372-1819;Volbers|Bastian|B|http://orcid.org/0000-0003-0453-1530;Kaesmacher|Johannes|J|http://orcid.org/0000-0002-9177-2289;Dobrocky|Tomas|T|http://orcid.org/0000-0002-6167-3343;Mordasini|Pasquale|P|http://orcid.org/0000-0003-1712-4168;El-Koussy|Marwan|M|http://orcid.org/0000-0003-1142-4944;Gralla|Jan|J|http://orcid.org/0000-0003-1953-9033;Arnold|Marcel|M|http://orcid.org/0000-0002-4274-4644;Fischer|Urs|U|http://orcid.org/0000-0003-0521-4051;Mattle|Heinrich P|HP|http://orcid.org/0000-0001-7968-1731;Jung|Simon|S|http://orcid.org/0000-0002-8288-6102",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-020-09744-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "267(6)",
"journal": "Journal of neurology",
"keywords": "Different therapy modalities; Large vessel occlusion; Low NIHSS score; NIHSS score subitems; Outcome",
"medline_ta": "J Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001157:Arterial Occlusive Diseases; D002539:Cerebral Arterial Diseases; D057510:Endovascular Procedures; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D012189:Retrospective Studies; D012720:Severity of Illness Index; D062606:Tertiary Care Centers",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "1651-1662",
"pmc": null,
"pmid": "32062782",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "26898852;27567239;19608992;23471266;27125526;17673713;23976971;25472576;27050916;28408627;29089458;27589861;28768820;29174232;30659890;30355086;31008335;29367334;29998337;31545353;31591276;19423857;7974549;3363593;29998321",
"title": "Outcome of patients with large vessel occlusion in the anterior circulation and low NIHSS score.",
"title_normalized": "outcome of patients with large vessel occlusion in the anterior circulation and low nihss score"
} | [
{
"companynumb": "CH-ROCHE-2637115",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "To describe a fatal case of invasive Aspergillus flavus sinusitis in a 43-year old female with sickle cell disease (SCD) complicated by intracerebral aspergilloma and invasive Salmonella infection. Cerebral aspergilloma carries a very high mortality rate. The patient developed post-craniotomy intracerebral hemorrhage at the site of biopsy, Salmonella species sepsis and ventriculitis. She presented with a 2-month history of headache, dizziness, personality and behavioral changes, and vomiting. Initial clinical evaluation raised the suspicion of brain tumor. Brain magnetic resonance imaging revealed a left frontal, thick-walled ring-enhancing lesion with extensive surrounding edema suggestive of a neoplastic lesion, or a contiguous inflammatory or infectious process from the skull base. Despite early diagnosis and appropriate antifungal and surgical management, she eventually died from severe infection and respiratory arrest. In conclusion, invasive aspergillosis should be included in the differential diagnosis of SCD patients with central nervous system (CNS) lesions.",
"affiliations": "Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail. ofawzia@ksu.edu.sa.",
"authors": "Al Otaibi|Fawzia E|FE|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.15537/smj.2018.9.22821",
"fulltext": "\n==== Front\nSaudi Med JSaudi Med JSaudi Medical Journal0379-5284Saudi Medical Journal Saudi Arabia 30251738SaudiMedJ-39-93510.15537/smj.2018.9.22821Case ReportFatal case of cerebral aspergilloma complicated by ventriculitis and bacteremia due to Salmonella species in a sickle cell disease patient Alotaibi Fawzia E. MD, MBBSFrom the Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Kingdom of Saudi ArabiaAddress correspondence and reprint request to: Dr. Fawzia E. Alotaibi, Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail: ofawzia@ksu.edu.sa ORCID ID: orcid.org/0000-0002-7173-52379 2018 39 9 935 939 06 5 2018 25 7 2018 Copyright: © Saudi Medical Journal2018This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.To describe a fatal case of invasive Aspergillus flavus sinusitis in a 43-year old female with sickle cell disease (SCD) complicated by intracerebral aspergilloma and invasive Salmonella infection. Cerebral aspergilloma carries a very high mortality rate. The patient developed post-craniotomy intracerebral hemorrhage at the site of biopsy, Salmonella species sepsis and ventriculitis. She presented with a 2-month history of headache, dizziness, personality and behavioral changes, and vomiting. Initial clinical evaluation raised the suspicion of brain tumor. Brain magnetic resonance imaging revealed a left frontal, thick-walled ring-enhancing lesion with extensive surrounding edema suggestive of a neoplastic lesion, or a contiguous inflammatory or infectious process from the skull base. Despite early diagnosis and appropriate antifungal and surgical management, she eventually died from severe infection and respiratory arrest. In conclusion, invasive aspergillosis should be included in the differential diagnosis of SCD patients with central nervous system (CNS) lesions.\n==== Body\nCerebral aspergillosis, including infection of the sinuses is a serious infection and difficult to diagnose because it is usually misdiagnosed as tumor and is associated with high mortality.1,2 Surgical exploration and intra-operative diagnosis is required for accurate diagnosis and is made by histopathological examination.2 Early surgical intervention and aggressive antifungal treatment are considered as cornerstone management strategies.2 Aspergillosis of the sinuses is a spectrum of diseases that range from local infection involving the sinuses to invasive aspergillosis with extension to the brain and orbit.3,4 Invasive aspergillosis affects primarily immunocompromised hosts and rarely immunocompetent individuals.1-7 Causes of Immunosuppression such as hematological malignancies, prolonged neutropenia and solid organ transplant are among the recognized risk factors for invasive aspergillosis.1-6 Hematogenous dissemination of the infection to the brain or directly via the paranasal sinuses is associated with poor prognosis.3-7 Cerebral abscess and ventriculitis caused by Salmonella species as a postoperative complication of craniotomy associated with fungal infection are extremely rare. This report presents the challenge of postoperative infectious complications in patients presenting with cerebral aspergillosis. It describes an unusual case of invasive aspergillosis of the paranasal sinuses involving the brain in a sickle cell disease (SCD) patient who eventually died because of post-craniotomy Salmonella ventriculitis, abscess collections and severe brain edema. The rapid clinical progression and complications of invasive sinusitis presented in this case highlight the importance of early diagnosis and initiation of antifungal treatment in such cases. This is a case report of invasive aspergillosis in a SCD patient from the Middle East region.\n\nCase Report\nPatient information\nA 43-year-old female, a known case of SCD, presented to the Emergency room with a 2-month history of headache, dizziness, personality and behavioral changes, and recurrent vomiting.\n\nClinical findings\nPhysical examination revealed an axillary temperature of 37.4°C; heart rate 156 bpm; respiratory rate 22 cpm; blood pressure 112/84 mmHg; and SpO2 99%. She was examined by the ear, nose, and throat (ENT) specialist, and endoscopic evaluation of the sinuses suggested that the sinuses was the source of infection.\n\nDiagnostic assessment\nFunctional endoscopic sinus surgery was performed and endoscopic examination of the left nostril showed slough and dead tissue; pus was seen in the frontal sinus and the mucosa was unhealthy. During examination, she underwent debridement of the slough and dead tissue of the sphenoidal sinus, periorbita and septum mucosa. Local intranasal ceftriaxone and caspofungin were used during debridement of the sinuses. A brain computed tomography (CT) scan revealed a left frontal intra-axial thick-walled ring-enhancing lesion with extensive surrounding edema, possibly a high-grade neoplastic lesion (glioma) involving the corpus callosum, or a contiguous inflammatory or infectious process originating from the skull base. There were also bony and dural changes along the anterior skull base with erosion of the sella turcica and lateral sphenoid bone toward the cavernous sinus (Figure 1). Initial clinical and radiological evaluation raised the suspicion of a brain tumor. Based on clinical examination, the decision was to perform a craniotomy and excisional biopsy of the frontal lobe lesion for diagnostic and therapeutic purposes. The risks associated with the surgery included infection, bleeding, recollection of abscesses, and recurrence. During surgery, a neuronavigation-guided frozen section of the brain lesion was performed which was sent to the histopathology laboratory. The intraoperative diagnosis was left granulomatous invasive fungal sinusitis with erosion of the sella turcica and lateral sphenoid bone toward the cavernous sinus. A granuloma was observed histologically and a few days later, cultures from the brain lesion and nasal tissue yielded many septate branching fungal hyphae identified as Aspergillus flavus (Figure 2). The fungus was resistant to amphotericin B (minimum inhibitory concentration (MIC=2µg/mL), and susceptible to voriconazole (MIC=0.12µg/mL), itraconazole (MIC=0.12µg/mL) and posaconazole (MIC=0.06µg/mL). Aspergillus antigen test (galactomannan and IgG) yielded negative results. The final diagnoses, based on culture findings were invasive sinus aspergillosis and intracerebral aspergilloma.\n\nFigure 1 Post contrast administration MRI-Brain; A) Axial T1WI, A large mass lesion is noted in left frontal lobe, measuring about 6 x 5 cm. B) Axial T2WI, There is dural thickening and enhancement along the left cribriform plate, tuberculum sella and floor of sella. Mucosal thickening and abnormal density is noted in the sphenoid sinus and the left sphenoid sinus with well demarcated osseous defect on left side. C) Sagittal T1WI, bony and dural changes along the anterior skull base and left frontal intra-axial mass thick-walled ring enhancing lesion with extensive surrounding edema possibly aggressive neoplastic lesion, or less likely contiguous inflammatory or infectious process from skull base.\n\nFigure 2 Photomicrograph of the brain lesion showing A) branched and septate fungal hyphae typical of aspergillosis in Grocott’s methenamine silver stain. B) aspergillus flavus conidiophore bearing vesicle (phialides arise circumferentially from the globose vesicle) in Lactophenol cotton blue (LPCB).\n\nTherapeutic intervention\nUnfortunately, diagnostic endonasal sinus debridement was incomplete due to extensive infection that might spread to involve the cavernous sinus on aggressive management. Therefore, she underwent surgery (craniotomy) and repeated debridements were also carried out. Post-operatively, she tolerated the operation well, she was intubated and transferred to the surgical intensive care unit for observation and started on antifungal medication voriconazole (600 mg/day) and caspofungin (70 mg/day IV) and (50 mg/day IV) thereafter.\n\nFollow up and outcomes\nShe was afebrile, she had no basal discharge, she could move all limbs and was taking orally. Her Glasgow coma scale (GCS) score was 15/15 with no focal neurological deficit. The wound was clean and dry. She received cefazolin, dexamethasone, haloperidol (2.5 mg, IM, q6hr), metoclopramide (10 mg, q8hr), and phenytoin (100 mg, IV, q8hr). In the context of her clinical condition, vasculitis screening for antineutrophil cytoplasmic antibodies, antinuclear antibody, HIV test and CD4 count was requested. The results revealed reduced levels of IgG and IgM. Consultation with an immunologist suggested that the low immunoglobulin level could explain her underlying fungal infection. Seven days after surgery she showed decreased level of consciousness due to intracerebral hemorrhage at the biopsy site and sepsis caused by Gram-negative bacilli. She became febrile, tachycardic, and had leukocytosis (white blood cell [WBC] count, 12.34×109/L). She was evaluated by the infectious diseases and ENT specialists. Her renal function tests showed high creatinine (150 µmol/L) and blood urea nitrogen levels. Because of her new symptoms, she underwent a second craniotomy which revealed subgaleal, left epidural and subdural and intraventricular abscesses that were evacuated and irrigated thoroughly. Pure pus drained after insertion of an external ventricular drain in the right frontal abscess. Specimens were collected during surgery and pus from abscesses and tissue samples were sent for culture and histopathology. Cerebrospinal fluid (CSF) analysis showed a red blood cell count of 50/mm3 and WBC 700×106/L (90% polymorphs and 10% mononuclear cells). All cultures of specimens including blood, stool, CSF, brain abscess, and scalp wound yielded ampicillin and ciprofloxacin-resistant (MIC=0.094 µg/mL, Nalidixic Acid=R) group B Salmonella species. Intravenous (IV) ceftriaxone (2 g) 12-hourly was started. A brain CT scan showed purulent fluid, edema with subsequent mass effect on the frontal horn of the lateral ventricles and a small suspicious communication with the left frontal horn and abscess collection in the left lateral ventricle with mild enhancement of the ventricular outlines suggestive of ventriculitis (Figure 3). The patient developed seizures triggered by sepsis and neuroleptics. Her clinical condition deteriorated over time due to Salmonella sepsis and ventriculitis, renal impairment, malnutrition, pancytopenia and high risk of aspiration pneumonia. She was intubated, drowsy (GCS: 11/15), moved all 4 limbs, grasped both hands on command, and had symmetric and reactive pupils. She exhibited convulsive movements of the left eyelids and right distal foot. Despite aggressive management, the patient died due to severe infection and respiratory arrest. A timeline table showing the progress of the patient since admission and throughout the hospitalization course is shown in (Table 1).\n\nFigure 3 Postoperative MRI-Brain. Complex signal abnormality noted at the surgical bed at bifrontal (A) and (B), region most likely representing subacute blood, some purulent fluid, pneumocephalus and edema with possible communication with the left lateral ventricle (C) and (D). No brain infarction or venous sinus thrombosis.\n\nTable 1 A timeline table showing the progress of the patient since admission and throughout the hospitalization course.\n\nDiscussion\nInvasive aspergillosis is a fatal infection that commonly affects immunocompromised hosts. Individuals at the highest risk of acquiring invasive aspergillosis include patients with leukemia during induction therapy; solid organ transplant, prolonged neutropenia, immunodeficiency, and corticosteroid use.1-3 Invasive aspergillosis is rare in immunocompetent individuals.5-7\n\nAlthough no clear association exists in the literature between SCD and invasive aspergillosis, SCD is suggested to have contributed to the pathogenesis of invasive aspergillosis in the present case. In addition, her underlying hematological disease combined with the incomplete sinus debridement, Intensive care unit admission, and surgical interventions triggered a complicated clinical course including intracerebral aspergilloma and Gram-negative Salmonella bacteremia. Additionally, multiple catheterization, abnormal renal function and mechanical ventilation might have adversely affected the immune function and led to the poor outcome.\n\nThe most frequent symptoms in patients with Central Nervous System (CNS) aspergillosis are headache, vomiting, convulsions, fever, and cranial nerve paralysis. Our patient presented mainly with prolonged headache and dizziness. This suggests that in SCD patients, such history should raise the clinical suspicion of possible fungal infection caused by Aspergillus species. In addition, environmental factors including airborne mold concentrations, geographic location, and constructional work may influence IA development.8\n\nAn interesting magnetic resonance imaging finding in this case is the observation of irregularity and mild narrowing of the arteries of the circle of Willis, including the terminal internal carotid, proximal middle cerebral, anterior cerebral and posterior cerebral arteries due to the patient’s SCD. We proposed that might be the reason for the rapid progression and invasiveness of the fungal infection in this case.\n\nVoriconazole, isavuconazole and amphotericin B are the antifungal agents used for the first-line treatment of IA.9,10 Caspofungin have been shown to exert in vitro and in vivo activity against Aspergillus spp and is approved for the treatment of IA in patients who are intolerant to first-line therapy.9 Our patient was treated with voriconazole and caspofungin. Combination therapy with voriconazole and caspofungin in treatment of CNS aspergillosis is promosing.10 However, we believe that, the severity of infection, coinfection with Salmonella ventriculitis and sepsis contribute to the poor outcome in this patient.\n\nIn conclusion, invasive aspergillosis should be included in the differential diagnosis of SCD patients with CNS lesions, particularly if presented with chronic symptoms suggestive of CNS involvement. Rapid diagnosis and aggressive medical and surgical management are of the utmost importance.\n\nAcknowledgment\nWe would like to thank Editage (http://www.editage.com/) for English language editing.\n\n\nDisclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.\n==== Refs\nReferences\n1 Taccone FS Van den Abeele AM Bulpa P Misset B Meersseman W Cardoso T Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes Crit Care 2015 19 7 25928694 \n2 Alsalman J Zaid T Makhlooq M Madan M Mohamed Z Alarayedh A A retrospective study of the epidemiology and clinical manifestation of invasive aspergillosis in a major tertiary care hospital in Bahrain J Infect Public Health 2017 10 49 58 27033677 \n3 Baeesa SS Bokhari RF Alghamdi KB Alem HB Al-Maghrabi JA Madani TA Invasive aspergillus sinusitis with orbitocranial extension Asian J Neurosurg 2017 12 172 179 28484525 \n4 Jariwal R Heidari A Sandhu A Patel J Shoaepour K Natarajan P Granulomatous Invasive Aspergillus flavus Infection Involving the Nasal Sinuses and Brain J Investig Med High Impact Case Rep 2018 6 2324709618770473 \n5 Ahmadzai H Raley DA Masters L Davies M An unusual case of a pituitary fossa aspergilloma in an immunocompetent patient mimicking infiltrative tumour J Surg Case Rep 2013 2013 rjt018 24964429 \n6 Ouyang T Zhang N Wang L Jiao J Zhao Y Li Z Primary Aspergillus sellar abscess simulating pituitary tumor in immunocompetent patient J Craniofac Surg 2015 26 e86 e88 25675014 \n7 Bangash M Aspergillus flavus Brain Abscess in Immunocompetent Teenagers: A Case Series with Review of Literature Journal of Case Reports 2017 7 8 12 \n8 Garcia-Vidal C Peghin M Cervera C Gudiol C Ruiz-Camps I Moreno A Causes of death in a contemporary cohort of patients with invasive aspergillosis PLoS One 2015 10 e0120370 25803853 \n9 Patterson TF Thompson GR 3rd Denning DW Fishman JA Hadley S Herbrecht R Practice Guidelines for the Diagnosis and Management of Aspergillosis:2016 Update by the Infectious Diseases Society of America Clin Infect Dis 2016 63 e1 e60 27365388 \n10 Bassetti M Peghin M Vena A Challenges and Solution of Invasive Aspergillosis in Non-neutropenic Patients: A Review Infect Dis Ther 2018 7 17 27 29273978\n\n",
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"issue": "39(9)",
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"mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D000935:Antifungal Agents; D001231:Aspergillus flavus; D016470:Bacteremia; D001927:Brain Diseases; D058565:Cerebral Ventriculitis; D003399:Craniotomy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D020953:Neuroaspergillosis; D010254:Paranasal Sinus Diseases; D011183:Postoperative Complications; D012480:Salmonella Infections",
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"title": "Fatal case of cerebral aspergilloma complicated by ventriculitis and bacteremia due to Salmonella species in a sickle cell disease patient.",
"title_normalized": "fatal case of cerebral aspergilloma complicated by ventriculitis and bacteremia due to salmonella species in a sickle cell disease patient"
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"abstract": "Immune checkpoint inhibitor (ICI)-associated adrenal insufficiency is rare but may become a serious adverse event in patients treated with ICIs. The present case report documents two cases of adrenal insufficiency developed during chemotherapy plus tislelizumab (, Baize'an; BeiGene Ltd.) therapy in patients with advanced gastric cancer. Adrenal insufficiency developed after 6 and 13 cycles of treatment and was well controlled with hydrocortisone. The patients also developed hypothyroidism, which was managed with levothyroxine. Two patients showed a partial response, and one patient out of two achieved a near-complete response, sustaining over 11 months. Increased awareness of ICI-related adrenal insufficiency is crucial for early detection and prompt management of patients treated with ICIs.",
"affiliations": "Department of Oncology/Hematology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.",
"authors": "Baek|Jin Ho|JH|",
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"doi": "10.12701/yujm.2021.00934",
"fulltext": "\n==== Front\nJ Yeungnam Med Sci\nJ Yeungnam Med Sci\nJYMS\nJournal of Yeungnam Medical Science\n2799-8010\nJournal of Yeungnam Medical Science\n\n33866751\n10.12701/yujm.2021.00934\nyujm-2021-00934\nCase Report\nAdrenal insufficiency development during chemotherapy plus anti-programmed death receptor-1 monoclonal antibody (tislelizumab) therapy in patients with advanced gastric cancer: two case reports\nAdrenal insufficiency developed during tislelizumab therapy in patients with AGC\nhttp://orcid.org/0000-0003-2523-9950\nBaek Jin Ho\nDepartment of Oncology/Hematology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea\nCorresponding author: Jin Ho Baek, MD, PhD Department of Oncology/Hematology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea Tel: +82-53-200-2674 Fax: +82-53-200-2029 E-mail: wwhite71@hanmail.net\n1 2022\n19 4 2021\n39 1 6266\n21 1 2021\n8 3 2021\n9 3 2021\nCopyright © 2022 Yeungnam University College of Medicine, Yeungnam University Institute of Medical Science\n2022\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nImmune checkpoint inhibitor (ICI)-associated adrenal insufficiency is rare but may become a serious adverse event in patients treated with ICIs. The present case report documents two cases of adrenal insufficiency developed during chemotherapy plus tislelizumab (百泽安, Baize’an; BeiGene Ltd.) therapy in patients with advanced gastric cancer. Adrenal insufficiency developed after 6 and 13 cycles of treatment and was well controlled with hydrocortisone. The patients also developed hypothyroidism, which was managed with levothyroxine. Two patients showed a partial response, and one patient out of two achieved a near-complete response, sustaining over 11 months. Increased awareness of ICI-related adrenal insufficiency is crucial for early detection and prompt management of patients treated with ICIs.\n\nAdverse events\nImmune checkpoint inhibitors\nStomach neoplasms\nTislelizumab\n==== Body\npmcIntroduction\n\nGastric cancer is the fifth most common malignancy and the third leading cause of cancer-related mortality worldwide, even though rapid advances in treatment options have improved its prognosis [1]. Remarkable progress in tumor biology has led to the development of new therapeutics that target critical aspects of oncogenic pathways or the immune system. However, the prognosis of patients treated with standard treatment for advanced gastric cancer remains poor [2]. Programmed cell death protein 1 (PD-1) is a cell surface receptor that plays a significant role in downregulating the immune system and promoting self-tolerance by suppressing T-cell activity. Antibodies that block the interaction between PD-1 and programmed death-ligand 1 (PD-L1) allow the immune system to attack cancer cells. Anti-PD-1 and anti-PD-L1 antibodies have revolutionized the treatment of melanoma and non-small cell lung cancer (NSCLC) and are being evaluated in a broad range of other cancers, including gastric cancer.\n\nTislelizumab (百泽安, Baize’an; BeiGene Ltd., Beijing, China) is a humanized monoclonal antibody (mAb) with high affinity and specificity for PD-1 that was engineered to minimize binding to Fc-γ receptor I (FcγRI) on macrophages to greatly reduce antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy [3].\n\nThe use of immune checkpoint inhibitors (ICIs) in cancer therapy is complicated by numerous mechanism-based toxicities, termed immune-related adverse events (irAEs), affecting dermatological, gastrointestinal, hepatic, endocrine, and other systems. Adrenal insufficiency is an irAE and may manifest as nonspecific symptoms. Delay in diagnosis and inadequate care can lead to serious complications. Although it is necessary to elucidate the detailed clinical features of this adverse event (AE) for early detection, the clinical features of anti-PD-1 therapy-induced adrenal insufficiency remain poorly described.\n\nTwo cases of adrenal insufficiency are described in this study that developed during chemotherapy plus anti-PD-1 mAb (tislelizumab) therapy in patients with advanced gastric cancer in the clinical trial setting.\n\nCases\n\nEthical statements: This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2019-05-021). Informed consent was obtained from the patients.\n\n1. Case 1\n\nA 58-year-old male was diagnosed with clinical T4N3M1, stage IV Her-2 negative gastric adenocarcinoma, with portal vein tumor thrombosis. He underwent palliative chemotherapy with capecitabine (1,000 mg/m2 twice daily, D1–D14), oxaliplatin (130 mg/m2, D1), and tislelizumab (200 mg/m2, D1) at 3-week intervals. He received palonosetron (0.25 mg) and dexamethasone (10 mg), intravenously, before the infusion of oxaliplatin for the prevention of emesis. The initial treatment was well tolerated, and follow-up scans showed a partial response. He developed severe fatigue, and his serum sodium level was 109 mmol/L (range, 135–145 mmol/L) after six cycles of treatment. Further investigations revealed the following: random urinary sodium, 64 mmol/L; free T3, 0.39 pg/mL (range, 2.00–4.40 pg/mL); free T4, 0.15 ng/dL (range, 0.89–1.8 ng/dL); and thyroid-stimulating hormone (TSH) 136.50 mIU/L (range, 0.3–4.0 mIU/L). The levels of antithyroglobulin antibody and antithyroid peroxidase were 70.60 U/mL (range, 0–60 U/mL) and 55.02 U/mL (range, 0–60 U/mL), respectively. Thyroid ultrasonography showed atrophic changes in both lobes of the thyroid gland. The random serum adrenocorticotropic hormone (ACTH) level was 20.23 pg/mL (range, 0–60 pg/mL), and a rapid ACTH test was conducted. Before the administration of 250 µg of synthetic ACTH (cosyntropin), serum cortisol was <0.5 µg/dL (range, 3.09–22.4 µg/dL). Postadministration values were 2.27 and 3.56 µg/dL, at 30 and 60 minutes, respectively. Magnetic resonance imaging (MRI) of the brain showed no abnormalities in the pituitary gland (Table 1). The patient was diagnosed with hypothyroidism and adrenal insufficiency. The patient received levothyroxine (0.15 mg) per day and 10 mg of hydrocortisone twice daily. His serum sodium level improved to 138 mmol/L after 1 week of treatment, and the patient reported improvement in fatigue. Follow-up investigations were conducted after 6 weeks of treatment and revealed the following: free T3, 3.03 pg/mL; free T4, 1.41 ng/dL; TSH, 13.10 mIU/L; and random serum cortisol, 14.77 µg/dL. Currently, the patient shows a near-complete response to treatment with capecitabine and tislelizumab. Hypothyroidism and adrenal insufficiency are well controlled with levothyroxine (0.15 mg) per day and hydrocortisone twice daily (10 mg on awakening and 5 mg in the early evening).\n\n2. Case 2\n\nA 59-year-old man was diagnosed with clinical T3N2M1, stage IV Her-2 negative gastric adenocarcinoma, with multiple metastases to the left paraaortic lymph node and liver. He underwent six cycles of palliative chemotherapy with capecitabine (1,000 mg/m2 twice daily, D1–D14), oxaliplatin (130 mg/m2, D1), and tislelizumab (200 mg/m2, D1) and seven cycles of capecitabine and tislelizumab from December 2019 to September 2020, resulting in a partial response. He received palonosetron (0.25 mg) and dexamethasone (10 mg), intravenously, before the infusion of oxaliplatin for the prevention of emesis.\n\nHe developed severe weakness and mild dizziness after 13 cycles of treatment. Further investigations revealed the following: serum sodium, 123 mmol/L; free T3, 4.44 pg/mL; free T4, 1.05 ng/dL; and TSH 8.28 mIU/L. Additional tests for antithyroid antibodies and thyroid ultrasonography were not performed. Random serum cortisol was found to be 0.79 µg/dL and serum ACTH was 51.90 pg/mL (Table 1). The patient was diagnosed with subclinical hypothyroidism and adrenal insufficiency. The patient was administered levothyroxine (0.05 mg per day) and hydrocortisone (10 mg) twice daily. His serum sodium level improved to 137 mmol/L after 1 week of treatment, and he reported improved condition and restarted treatment with capecitabine and tislelizumab. Follow-up investigations were conducted after 6 weeks of treatment and revealed the following: serum sodium, 135 mmol/L; free T3, 4.62 pg/mL; free T4, 1.46 ng/dL; TSH, 3.67 mIU/L; and random serum cortisol 9.15 µg/dL. His disease progressed after 16 cycles of treatment. Currently, the patient receives second-line treatment with ramucirumab and paclitaxel. Hypothyroidism and adrenal insufficiency are well controlled with levothyroxine (0.05 mg) per day and hydrocortisone twice daily (10 mg on awakening and in the early evening).\n\nDiscussion\n\nICIs are now considered the standard of care for melanoma, NSCLC, and renal cancer. An increasing number of agents are available, and the list of indications is growing, including gastric cancer. Tislelizumab is a humanized IgG4 anti-PD-1 mAb that has been developed for the treatment of hematological malignancies and advanced solid tumors [4]. The low affinity of tislelizumab for FcγRI may result in improved anticancer efficacy. ICIs have been shown to cause a unique set of toxicities, irAEs, which are different from those previously reported for cytotoxic agents. ICIs may affect peripheral tolerance to autoantigens, resulting in autoantibody formation, which could be associated with irAEs in various organs. Endocrine AEs are the most common irAEs. The majority of irAEs are mild to moderate and self-limiting, but a few of them, including adrenal insufficiency, can lead to potentially life-threatening events [5].\n\nICI-related adrenal insufficiency is a rare disease, and a systematic review reported that the incidence of adrenal insufficiency of any grade was 0.7%, and the incidence of grade 3 or higher was only 0.2% [6]. However, recognition is important because it may be severe or life-threatening. There is no clearly defined time frame for the development of adrenal insufficiency. It can develop in the first month of treatment, but some cases have been reported several years after treatment. In this study, adrenal insufficiency developed after six and 13 cycles of treatment in cases 1 and 2, respectively. The presentation of adrenal insufficiency may vary from asymptomatic laboratory abnormalities to serious medical conditions [7]. Symptoms are also vague and nonspecific; fatigue, dizziness, and anorexia are frequent symptoms, and refractory hypotension and altered state of consciousness may present in severe cases. Hyponatremia and hyperkalemia are frequently reported. Hyponatremia is mediated by increased release of antidiuretic hormone (ADH), which results in water retention and a dilutional decrease in serum sodium levels [8]. The increased secretion of ADH is caused by cortisol deficiency; hence, cortisol deficiency results in the increased hypothalamic secretion of corticotropin-releasing hormone, an ADH secretagogue [9]. Increased ADH secretion is also attributed in part to the reduction in systemic blood pressure and cardiac output. In addition, cortisol directly suppresses ADH secretion [10]. Differential diagnoses may include central (immune-mediated hypophysitis with secondary adrenal insufficiency, hypophyseal metastasis) and peripheral (adrenal metastasis, adrenal hemorrhage) potential causes, while infections, drugs, and infiltrative diseases should also be considered. Laboratory tests and imaging studies, including morning cortisol, ACTH, ACTH-stimulation test, adrenal gland computed tomography, and hypophysis MRI, may be helpful for differential diagnosis. Management should include holding ICIs until a patient is stabilized, hydrocortisone, and fluid resuscitation based on clinical severity. ICIs with appropriate hormone replacement can be continued.\n\nSome studies have suggested an association between irAEs and clinical benefits, but it has not yet been identified [11,12]. Hussaini et al. [13] reported a positive association between the development of irAEs and objective response rate (ORR), progression-free survival, and overall survival (OS). They also reported that grade 3 or 4 irAEs were associated with better ORR but worse OS. In our case studies, both patients showed a partial response. One patient achieved a near-complete response, and the response has been sustained for over 11 months. Further studies are required to investigate the association between irAEs and the efficacy of ICIs and to improve the control of irAEs and the clinical practice of ICIs.\n\nThis study presented two cases of adrenal insufficiency that developed during tislelizumab therapy in patients with advanced gastric cancer. The guidelines of the American Society of Clinical Oncology recommend testing for TSH and free T4 every 4 to 6 weeks as part of routine clinical monitoring or for case detection in symptomatic patients, but regular monitoring for adrenal insufficiency is not recommended [14]. Therefore, increased awareness of ICI-related adrenal insufficiency is crucial for early detection and prompt management in patients treated with ICIs.\n\nTable 1. Summary of patient characteristics and clinical symptom, laboratory result, and imaging\n\nCase\tAge (yr)/sex\tDiagnosis\tTime of symptom onset\tPresenting symptom\tLaboratory result\tImaging result\t\n1\t58/M\tAGC with portal vein tumor thrombosis\tCycle 6\tSevere fatigue\tPretreatment free T3: 3.29 pg/mL\tThyroid ultrasonography: atrophic changes in both lobes of the thyroid gland\t\nPretreatment free T4: 1.43 ng/dL\tBrain MRI: no abnormality in the pituitary gland\t\nPretreatment TSH: 0.67 mIU/L\t\t\nSerum sodium: 109 mmol/L\t\t\nRandom urinary sodium: 64 mmol/L\t\t\nFree T3: 0.39 pg/mL\t\t\nFree T4: 0.15 ng/dL\t\t\nTSH: 136.50 mIU/L\t\t\nAntithyroglobulin antibody: 70.60 U/mL\t\t\nAntithyroid peroxidase: 55.02 U/mL\t\t\nRapid ACTH testa) \t\t\n2\t59/M\tAGC with multiple metastases to left paraaortic lymph node and liver\tCycle 13\tSevere weakness and mild dizziness\tPretreatment free T3: 3.25 pg/mL\t\t\nPretreatment free T4: 1.12 ng/dL\t\nPretreatment TSH: 5.81 mIU/L\t\nSerum sodium: 123 mmol/L\t\nFree T3: 4.44 pg/mL\t\nFree T4: 1.05 ng/dL\t\nTSH: 8.28 mIU/L\t\nRandom serum cortisol: 0.79 µg/dL\t\nRandom serum ACTH: 51.90 pg/mL\t\nM, male; AGC, advanced gastric cancer; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging.\n\na) Serum cortisol is <0.5, 2.27, 3.56 µg/dL at 0, 30, 60 minutes, respectively; serum ACTH is 20.23 pg/mL at 0 minute.\n\nConflicts of interest\n\nNo potential conflict of interest relevant to this article was reported.\n==== Refs\nReferences\n\n1 Global Burden of Disease Cancer Collaboration Fitzmaurice C Allen C Barber RM Barregard L Bhutta ZA Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study JAMA Oncol 2017 3 524 48 27918777\n2 Jim MA Pinheiro PS Carreira H Espey DK Wiggins CL Weir HK Stomach cancer survival in the United States by race and stage (2001-2009): findings from the CONCORD-2 study Cancer 2017 123 Suppl 24 4994 5013 29205310\n3 Zhang T Song X Xu L Ma J Zhang Y Gong W The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions Cancer Immunol Immunother 2018 67 1079 90 29687231\n4 Lee A Keam SJ Tislelizumab: first approval Drugs 2020 80 617 24 32185681\n5 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 1627 39 26412456\n6 Barroso-Sousa R Barry WT Garrido-Castro AC Hodi FS Min L Krop IE Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis JAMA Oncol 2018 4 173 82 28973656\n7 Wang DY Salem JE Cohen JV Chandra S Menzer C Ye F Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis JAMA Oncol 2018 4 1721 8 30242316\n8 Oelkers W Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism N Engl J Med 1989 321 492 6 2548097\n9 Wolfson B Manning RW Davis LG Arentzen R Baldino F Jr Co-localization of corticotropin releasing factor and vasopressin mRNA in neurones after adrenalectomy Nature 1985 315 59 61 3873012\n10 Watts AG Tanimura S Sanchez-Watts G Corticotropin-releasing hormone and arginine vasopressin gene transcription in the hypothalamic paraventricular nucleus of unstressed rats: daily rhythms and their interactions with corticosterone Endocrinology 2004 145 529 40 14563696\n11 Judd J Zibelman M Handorf E O'Neill J Ramamurthy C Bentota S Immune-related adverse events as a biomarker in non-melanoma patients treated with programmed cell death 1 inhibitors Oncologist 2017 22 1232 7 28652280\n12 Horvat TZ Adel NG Dang TO Momtaz P Postow MA Callahan MK Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center J Clin Oncol 2015 33 3193 8 26282644\n13 Hussaini S Chehade R Boldt RG Raphael J Blanchette P Maleki Vareki S Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors: a systematic review and meta-analysis Cancer Treat Rev 2021 92 102134 33302134\n14 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline J Clin Oncol 2018 36 1714 68 29442540\n\n",
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"title": "Adrenal insufficiency development during chemotherapy plus anti-programmed death receptor-1 monoclonal antibody (tislelizumab) therapy in patients with advanced gastric cancer.",
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"drugadditional": "3",
"dru... |
{
"abstract": "Chimeric antigen receptor T cells (CAR-T) are an effective and potentially durable treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR-T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life-threatening. Providers have exercised caution in providing CAR-T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR-T cell infusion after bridging therapy with conventional chemotherapy.",
"affiliations": "Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky.;Pediatric Cancer and Blood Disorders, University of Louisville School of Medicine, Louisville, Kentucky.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.",
"authors": "Rubinstein|Jeremy D|JD|0000-0002-1934-2954;Nelson|Adam S|AS|;Krupski|Christa|C|;O'Brien|William|W|;Taylor|J Michael|JM|;Badgett|Tom C|TC|;Huang|Michael|M|;Davies|Stella M|SM|;Phillips|Christine L|CL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28199",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(4)",
"journal": "Pediatric blood & cancer",
"keywords": "CAR-T; cellular therapy; neurotoxicity; pre-B ALL",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D009422:Nervous System Diseases; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28199",
"pmc": null,
"pmid": "32020723",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chimeric antigen receptor T-cell therapy in patients with neurologic comorbidities.",
"title_normalized": "chimeric antigen receptor t cell therapy in patients with neurologic comorbidities"
} | [
{
"companynumb": "US-PFIZER INC-2020133248",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "1",... |
{
"abstract": "•Drug induced parkinsonism caused by valbenazine and deutetrabenazine.•Possible side effects of VMAT-2 inhibitors.•Valbenazine and deutetrabenazine can unmask underlying Parkinson's Disease.",
"affiliations": "University of Kentucky Medical Center, United States.;University of Kentucky Medical Center, United States.;University of Kentucky Medical Center, United States.",
"authors": "Vasireddy|Rani Priyanka|RP|;Sokola|Brent|B|;Guduru|Zain|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.prdoa.2020.100078",
"fulltext": "\n==== Front\nClin Park Relat Disord\nClin Park Relat Disord\nClinical Parkinsonism & Related Disorders\n2590-1125\nElsevier\n\nS2590-1125(20)30046-3\n10.1016/j.prdoa.2020.100078\n100078\nCor\nNew generation VMAT2 inhibitors induced parkinsonism\nVasireddy Rani Priyanka rani.vasireddy@uky.edu\na⁎\nSokola Brent Brent.Sokola@uky.edu\na\nGuduru Zain Zain.Guduru@uky.edu\na\na University of Kentucky Medical Center, United States\n⁎ Corresponding author. rani.vasireddy@uky.edu\n07 11 2020\n2020\n07 11 2020\n3 10007831 3 2020\n18 10 2020\n24 10 2020\n© 2020 The Author(s)\n2020\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nHighlights\n\n• Drug induced parkinsonism caused by valbenazine and deutetrabenazine.\n\n• Possible side effects of VMAT-2 inhibitors.\n\n• Valbenazine and deutetrabenazine can unmask underlying Parkinson’s Disease.\n==== Body\n1 Introduction\n\nTardive syndrome (TS), is one of the most common drug-induced movement disorders. TS is primarily caused by the prolonged use of dopamine-blocking agents such as antipsychotics. Tetrabenazine is vesicular monoamine transporter type 2 (VMAT-2) inhibitor which is FDA approved for chorea in Huntington’s disease and also used off-label for TS. VMAT-2 inhibitors deplete monoamines such as dopamine, norepinephrine, serotonin, and histamine and are expected to reduce dyskinetic movements by reducing dopamine neurotransmission. However, tetrabenazine use is currently discouraged due to its side effect profile that includes depression and parkinsonism [1]. In 2017, valbenazine and deutetrabenazine were FDA approved for the treatment of tardive syndrome. Valbenazine and deutetrabenazine are VMAT-2 inhibitors and derivatives of tetrabenazine designed to increase the half-life and decrease fluctuations in plasma levels. These pharmacokinetic changes were targeted in hopes to reduce the frequency of adverse effects while providing consistent movement control.\n\nIn phase 3 randomized, double-blind, placebo-controlled trials for both valbenazine and deutetrabenazine, the side effect profile was limited primarily to somnolence, akathisia, and dry mouth, with no reports of drug induced parkinsonism (DIP) from valbenazine in the KINECT 3 trial, one patient identified with DIP in the KINECT 3 extension (Factor et al. (2017). J Clin Psychiatry), and only one case of DIP from deutetrabenazine the AIM-TS trial [2], [3]. In this paper, we report two cases of VMAT2 inhibitor induced DIP: one associated with valbenazine and one with deutetrabenazine.\n\n2 Case 1\n\nA 59-year-old man treated for depression with valproic acid for about 10 years was being switched to aripiprazole (15 mg/day) in 2015. On examination in 2017, he had only stereotypical movements involving tongue, mouth, face and head regions, cervical dystonia and blepharospasm (AIMS-TD score 12). Aripiprazole was stopped within a month of onset of TS symptoms. In May of 2018, deutetrabenazine was started for TS and titrated to 21 mg twice a day. Within a few weeks, the TS symptoms had improved, but the patient complained of somnolence and dizziness. These effects persisted even after reduction of the dose to 12 mg twice a day. Tapering further to 6 mg qAM and 12 mg qPM resolved the somnolence and dizziness, but TS reappeared. Deutetrabenazine was changed to valbenazine 80 mg daily. With this dose, he had somnolence and therefore, the dose was decreased to 40 mg daily. In the next 2 months of initiation of this medication, TS symptoms significantly improved but the patient presented with right hand resting tremor and slow walking, and on examination he had asymmetrical parkinsonism (MDS-UPDRS III score: 18). Patient preferred to continue valbenazine at 40 mg/day despite the Parkinsonian symptoms for his TS. With slow progression of parkinsonism, carbidopa/levodopa 25/100 mg 1 tab by mouth three times a day was added, and the patient initially reported significant improvement in his parkinsonism and continued to have improvement in TS. On follow-up, his tremor had returned and his DAT scan showed decreased uptake in his right putamen. Please see the attached DAT scan image below.\n\n3 Case 2\n\nAn 86-year-old woman with gastroparesis who was on metoclopramide for twenty years presented with involuntary tongue movements for 6 months. Metoclopramide was immediately stopped, and the involuntary movements worsened to involve the trunk too. On examination in August of 2019, she had oro-bucco-lingual movements and truncal dyskinetic movements s/o TS (AIMS-TD score 14). She was started on deutetrabenazine and the dose was titrated to 18 mg twice a day. In the next 6 weeks, TS was significantly improved but she complained of slowness of spontaneous movements, along with a masked face and low-pitched voice. On examination in October 2019, she was noted to have symmetrical parkinsonism (bradykinesia-rigidity predominant) and the dose of deutetrabenazine was decreased to 12 mg twice a day. Within a few weeks, parkinsonism has resolved and continued to have significant improvement of TS. Patient refused a DAT scan.\n\n4 Discussion\n\nWe report two cases of VMAT-2 inhibitors induced Parkinsonism of which one of them is a man in whom we propose that the underlying Parkinson’s disease (based on decreased uptake in right putamen and clinical presentation) was unmasked secondary to newly introduced dopamine-depleting medication. In case 1, we added carbidopa/levodopa to manage DIP symptoms as the patient was experiencing a significant benefit from valbenazine. In Case 2, we still consider one of the two possibilities of either unmasking the underlying Parkinson’s disease (more likely) or a Drug induced Parkinsonism secondary to deutetrabenazine as we couldn’t get a DAT scan for more definitive answer. To access the video of both the patients exhibiting signs and symptoms of Parkinsonism, click on the image below (online version only).\n\nBased on the review of literature to-date there has been only one article that addressed valbenazine-induced parkinsonism, our cases demonstrate a similar side effect profile [4]. There are no comparator trials between these medications and this adverse effect is relatively rare so it is not advised to compare the results of these clinical trials for prevalence or severity. Per the prescribing information, the frequency of Parkinsonism for valbenazine is 3% and less than 1% in those who received placebo. One of 221 patients treated with deutetrabenazine in the AIM-TS trial was reported to develop Parkinsonism. With tetrabenazine, 10% prevalence of Parkinsonism was reported in 48 week open label study. Valbenazine and deutetrabenazine are considered as first line choices of pharmacotherapy for TS [5] but are not devoid of unmasking of underlying PD or DIP. The clinicians should be cautious and maintain a high index of clinical suspicion for DIP, in individuals treated with newer generation VMAT2 inhibitors, irrespective of the dose.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAppendix A Supplementary data\n\nThe following are the Supplementary data to this article:Supplementary video 3\n\nSupplementary data 1\n\nSupplementary data 2\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.prdoa.2020.100078.\n==== Refs\nReferences\n\n1 Mehta S.H. Morgan J.C. Sethi K.D. Drug-induced movement disorders Neurol. Clin. 33 1 2015 153 174 25432728\n2 Anderson K.E. Stamler D. Davis M.D. Factor S.A. Hauser R.A. Isojarvi J. Jarskog L.F. Jimenez-Shahed J. Kumar R. McEvoy J.P. Ochudlo S. Ondo W.G. Fernandez H.H. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial Lancet Psychiatry 4 8 2017 595 604 28668671\n3 Hauser R.A. Factor S.A. Marder S.R. Knesevich M.A. Ramirez P.M. Jimenez R. Burke J. Liang G.S. O'Brien C.F. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia Am. J. Psychiatry 174 5 2017 476 484 28320223\n4 Akbar U. Kim D.S. Friedman J.H. Valbenazine-induced parkinsonism Parkinsonism Relat. Disord. 70 2019 13 14 31785443\n5 Ward K.M. Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs tardive dyskinesia-key differences in pathophysiology and clinical management Neurol. Ther. 7 2 2018 233 248 30027457\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2590-1125",
"issue": "3()",
"journal": "Clinical parkinsonism & related disorders",
"keywords": null,
"medline_ta": "Clin Park Relat Disord",
"mesh_terms": null,
"nlm_unique_id": "101761473",
"other_id": null,
"pages": "100078",
"pmc": null,
"pmid": "34316656",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28320223;30027457;28668671;25432728;31785443",
"title": "New generation VMAT2 inhibitors induced parkinsonism.",
"title_normalized": "new generation vmat2 inhibitors induced parkinsonism"
} | [
{
"companynumb": "US-APOTEX-2021AP007467",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "It remains unclear whether type of antiplatelet (AP) therapy, AP combination therapy, and AP continuing or switching strategy affect the risk of post-polypectomy bleeding (PPB). In this study, we sought to elucidate this risk.\n\n\n\nWe analyzed 1050 patients who underwent colonoscopic polypectomy: 525 AP users and 525 controls matched for age, sex, comorbidities, concomitant non-steroidal anti-inflammatory drugs use, and polyp characteristics who did not receive antithrombotics. PPB risk was evaluated by AP number, type, and continuing or switching strategies during the peri-endoscopic period.\n\n\n\nIn multivariate analysis, bleeding risk increased significantly as the number of AP agents used increased (monotherapy, adjusted odds ratio [aOR], 3.7; dual antiplatelet therapy (DAPT), 4.6; triple antiplatelet therapy (TAPT), 11.1) compared with controls. With monotherapy, significantly increased PPB risk was found for aspirin (aOR 4.3), thienopyridine (aOR 6.3), and cilostazol (aOR 5.9), but not for eicosapentaenoic acid or other APs (beraprost, limaprost, sarpogrelate, dilazep, or dipyridamole). With DAPT, significantly increased PPB risk was found for combination aspirin plus cilostazol, but not aspirin plus other APs. Bleeding rates for continuing monotherapy were 4.3% for aspirin and 0% for thienopyridine, cilostazol, and other APs, respectively.\n\n\n\nAnalysis of this large polypectomy dataset showed that the use of low-dose aspirin, thienopyridine, or cilostazol and a combination of these is associated with increased PPB risk. Although PPB risk was high with DAPT or TAPT, PPB rate in any antiplatelet monotherapy even with a continuing strategy was low at < 5%.",
"affiliations": "Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. nnagata_ncgm@yahoo.co.jp.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Ohta Nishinouchi Hospital, Fukushima, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.;Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of Gastroenterology and Hepatology, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan.",
"authors": "Watanabe|Kazuhiro|K|;Nagata|Naoyoshi|N|;Yanagisawa|Naohiro|N|;Shimbo|Takuro|T|;Okubo|Hidetaka|H|;Imbe|Koh|K|;Yokoi|Chizu|C|;Yanase|Mikio|M|;Kimura|Akio|A|;Akiyama|Junichi|J|;Uemura|Naomi|N|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-020-07402-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "35(1)",
"journal": "Surgical endoscopy",
"keywords": "ASGE guidelines; Delayed bleeding; Dual antiplatelet therapy (DAPT); ESGE guidelines; JGES guidelines; acetylsalicylic acid",
"medline_ta": "Surg Endosc",
"mesh_terms": "D000368:Aged; D003111:Colonic Polyps; D004724:Endoscopy; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "317-325",
"pmc": null,
"pmid": "32030553",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25271734;26890676",
"title": "Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding: validation of endoscopy guidelines.",
"title_normalized": "effect of antiplatelet agent number types and pre endoscopic management on post polypectomy bleeding validation of endoscopy guidelines"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1879366",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CILOSTAZOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAnaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country.\n\n\nMETHODS\nWe collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features.\n\n\nRESULTS\nThe cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.",
"affiliations": "Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service d'anatomopathologie, hôpital Cochin, AP-HP, université Paris Descartes, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service d'anatomopathologie, hôpital Cochin, AP-HP, université Paris Descartes, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service d'anatomopathologie, hôpital Cochin, AP-HP, université Paris Descartes, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service de virologie, hôpital de la Pitié Salpêtrière, université Pierre-et-Marie-Curie, AP-HP, 47-83, boulevard de l'Hôpital, 75013 Paris, France.;Service d'anatomopathologie, hôpital Cochin, AP-HP, université Paris Descartes, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.;Service d'anatomopathologie, hôpital Cochin, AP-HP, université Paris Descartes, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France.;Service de dermatologie, hôpital Cochin, pavillon Tarnier, université Paris Descartes, AP-HP, 89, rue d'Assas, 75006 Paris, France. Electronic address: nicolas.dupin@aphp.fr.",
"authors": "Chapalain|M|M|;Goldman-Lévy|G|G|;Kramkimel|N|N|;Carlotti|A|A|;Franck|N|N|;Lheure|C|C|;Audard|V|V|;Avril|M-F|MF|;Marcelin|A-G|AG|;Damotte|D|D|;Terris|B|B|;Aractingi|S|S|;Dupin|N|N|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2017.09.593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "145(1)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "Anaplasique; Anaplastic; Chemotherapy; Chimiothérapie; HHV-8; KSHV; Kaposi's sarcoma; Maladie de Kaposi; Radiotherapy; Radiothérapie",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000671:Amputation; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D015658:HIV Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D007866:Leg; D008209:Lymphedema; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D018714:Radiotherapy, Adjuvant; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D019562:Viral Load",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "21-28",
"pmc": null,
"pmid": "29290414",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.",
"title_normalized": "anaplastic kaposi s sarcoma 5 cases of a rare and aggressive type of kaposi s sarcoma"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1031276",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Most concern over the untoward effects of monoamine oxidase inhibitors (MAOIs) has concentrated on the hypertensive crises and recently on orthostatic hypotension, hypomania, and sexual dysfunction. However, little has been written about withdrawal effects when MAOIs are discontinued. This article reports an acute organic psychosis marked by visual, auditory, and tactile hallucinations after abrupt discontinuation of phenelzine in two young women without previous history of psychotic symptoms.",
"affiliations": null,
"authors": "Liskin|B|B|;Roose|S P|SP|;Walsh|B T|BT|;Jackson|W K|WK|",
"chemical_list": "D010624:Phenelzine; D003975:Diazepam",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "5(1)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D003975:Diazepam; D005260:Female; D006212:Hallucinations; D006801:Humans; D006963:Hyperphagia; D010624:Phenelzine; D011618:Psychotic Disorders; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "46-7",
"pmc": null,
"pmid": "3973072",
"pubdate": "1985-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute psychosis following phenelzine discontinuation.",
"title_normalized": "acute psychosis following phenelzine discontinuation"
} | [
{
"companynumb": "US-PFIZER INC-2020244607",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENELZINE SULFATE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nPalivizumab is a monoclonal antibody which can prevent infection with respiratory syncytial virus (RSV). Due to its high cost, it is recommended for high-risk infants only. We aimed to determine the proportion of infants eligible for palivizumab treatment in England who receive at least one dose.\n\n\nMETHODS\nWe used the Hospital Treatment Insights database, which contains hospital admission records linked to hospital pharmacy dispensing data for 43 out of 153 hospitals in England. Infants born between 2010 and 2016 were considered eligible for palivizumab if their medical records indicated chronic lung disease (CLD), congenital heart disease (CHD) or severe immunodeficiency (SCID), and they met additional criteria based on gestational age at birth and age at start of the RSV season (beginning of October). We calculated the proportion of infants who received at least one dose of palivizumab in their first RSV season, and modelled the odds of treatment according to multiple child characteristics using logistic regression models.\n\n\nRESULTS\nWe identified 3712 eligible children, of whom 2479 (67%) had complete information on all risk factors. Palivizumab was prescribed to 832 of eligible children (34%). Being born at <30 weeks' gestation, aged <6 months at the start of RSV season, and having two or more of CLD, CHD or SCID were associated with higher odds of treatment.\n\n\nCONCLUSIONS\nIn England, palivizumab is not prescribed to the majority of children who are eligible to receive it. Doctors managing these infants may be unfamiliar with the eligibility criteria or constrained by other considerations, such as cost.",
"affiliations": "Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Great Ormond Street Hospital, London, UK.;Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.;Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.",
"authors": "Zylbersztejn|Ania|A|https://orcid.org/0000-0003-1035-1448;Almossawi|Ofran|O|;Gudka|Nikesh|N|;Tompsett|Daniel|D|;De Stavola|Bianca|B|;Standing|Joseph F|JF|https://orcid.org/0000-0002-4561-7173;Smyth|Rosalind|R|;Hardelid|Pia|P|",
"chemical_list": null,
"country": "England",
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"doi": "10.1111/bcp.15069",
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"journal": "British journal of clinical pharmacology",
"keywords": "neonatology; paediatrics; prescribing; respiratory medicine",
"medline_ta": "Br J Clin Pharmacol",
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"pmid": "34478568",
"pubdate": "2021-09-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Access to palivizumab among children at high risk of respiratory syncytial virus complications in English hospitals.",
"title_normalized": "access to palivizumab among children at high risk of respiratory syncytial virus complications in english hospitals"
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"abstract": "The combination of cetuximab (CTX) and chemotherapy, such as FOLFOX or FOLFIRI, is currently the standard treatment for metastatic colorectal cancer (mCRC). Zoledronic acid (ZOL) is used in patients with bone metastasis. We herein report our experience with the case of a 58-year-old male patient with metastatic rectal cancer who was treated with ZOL + CTX as third-line therapy, and in whom this combination appeared to be effective. Although the patient developed bone metastasis and cardiac tamponade due to the recurrence of rectal cancer, he survived for approximately 10 months after the initiation of ZOL and CTX treatment.",
"affiliations": "Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.;Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, Japan.",
"authors": "Tokumaru|Yoshihisa|Y|;Matsuhashi|Nobuhisa|N|;Takahashi|Takao|T|;Tanahashi|Toshiyuki|T|;Matsui|Satoshi|S|;Imai|Hisashi|H|;Tanaka|Yoshihiro|Y|;Yamaguchi|Kazuya|K|;Yoshida|Kazuhiro|K|",
"chemical_list": null,
"country": "England",
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"doi": "10.3892/mco.2019.1836",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2019.1836MCO-0-0-1836ArticlesEfficacy of combination therapy with zoledronic acid and cetuximab for unresectable rectal cancer with bone metastases: A case report Tokumaru Yoshihisa Matsuhashi Nobuhisa Takahashi Takao Tanahashi Toshiyuki Matsui Satoshi Imai Hisashi Tanaka Yoshihiro Yamaguchi Kazuya Yoshida Kazuhiro Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Gifu 501-1194, JapanCorrespondence to: Dr Nobuhisa Matsuhashi, Department of Surgical Oncology, Gifu University School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan, E-mail: nobuhisa517@hotmail.com6 2019 03 4 2019 03 4 2019 10 6 571 574 07 5 2018 14 3 2019 Copyright: © Tokumaru et al.2019This is an open access article distributed 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.The combination of cetuximab (CTX) and chemotherapy, such as FOLFOX or FOLFIRI, is currently the standard treatment for metastatic colorectal cancer (mCRC). Zoledronic acid (ZOL) is used in patients with bone metastasis. We herein report our experience with the case of a 58-year-old male patient with metastatic rectal cancer who was treated with ZOL + CTX as third-line therapy, and in whom this combination appeared to be effective. Although the patient developed bone metastasis and cardiac tamponade due to the recurrence of rectal cancer, he survived for approximately 10 months after the initiation of ZOL and CTX treatment.\n\nzoledronic acidcetuximabunresectable rectal cancerbone metastases\n==== Body\nIntroduction\nColorectal cancer (CRC) was estimated to account for 881,000 deaths worldwide in 2018 and it remains one of the major causes of death globally (1). The incidence of distant metastasis is as high as 25% at initial diagnosis, and approximately half of the patients with CRC will develop metastatic disease (2).\n\nCetuximab (CTX; Erbitux, Merck KGaA, Darmstadt, Germany) is a monoclonal antibody that inhibits ligand binding and ligand-dependent downstream signaling by specifically targeting the epidermal growth factor receptor (EGFR) (3,4). Accumulation of data from several clinical studies revealed the efficacy of CTX combined with the standard therapy arm (FOLFOX/FOLFIRI) in treating patients with metastatic CRC (mCRC) with wild-type KRAS (5,6). Therefore, in the clinical setting, the use of CTX is currently restricted to patients with wild-type mCRC.\n\nZoledronic acid (ZOL) is a member of the bisphosphonate molecular class and is used in the clinical setting to reduce skeletal-related events in patients with bone metastasis. Previous studies reported on the antitumor activity of ZOL against several human cancers, such as breast, prostate and colorectal cancers, in vitro or in vivo (7,8).\n\nWe herein report the clinical course and computed tomography (CT) imaging findings in a patient with mCRC treated with ZOL and CTX.\n\nCase report\nA 58-year-old male patient presented to Gifu University Hospital (Gifu, Japan) with abdominal pain, symptoms of colonic penetration due to stenosis caused by rectal cancer in January 2014, and initially underwent an ileostomy. Peritoneal dissemination was detected during the ileostomy procedure, and CTX + mFOLFOX was started to treat the unresectable wild-type KRAS CRC. Analysis of RAS and EGFR status performed by SRL, Inc. (Tokyo, Japan) revealed wild-type RAS and high expression of EGFR in this patient. The patient underwent 6 courses of CTX + mFOLFOX before undergoing low anterior resection and D3 lymphadenectomy as the second surgery. Since R0 resection could be performed, 6 courses of mFOLFOX were administered as postoperative chemotherapy, after which time the patient was observed. A follow-up CT scan 6 months after the second surgery revealed a metastasis to the thoracic spine that was treated with X-ray radiation therapy 20 Gy/5 fr.\n\nApproximately 9 months after the second surgery, the patient complained of gradual onset of fatigue and shortness of breath; a chest CT scan revealed pericardial effusion and cardiac tamponade, which were managed by pericardial drainage (Fig. 1).\n\nAt 1 year after the second surgery, the patient began to have difficulty walking, which was caused by the thoracic spine metastasis and compression of the spinal cord. At that time, combination therapy with CTX and ZOL (CTX: 400 mg weekly, ZOL: 4 mg/body tri-weekly) was initiated. There were several reasons for selecting CTX and ZOL in this patient: First, the idea of using irinotecan (CPT-11) was abandoned, as the patient had cardiac and pleural effusion. Second, we hypothesized that the tumor was refractory to oxaliplatin, as recurrence occurred within 3 months after chemotherapy. An alternative treatment for this patient would be the administration of regorafenib or TAS-102; however, these drugs are associated with increased risks in patients with renal dysfunction, such as in the present case.\n\nFollowing treatment with CTX and ZOL, the size of the thoracic and lung metastasis was found to be decreased on CT imaging ~5 months following the initiation of the combination therapy. In parallel with these findings, the levels of the tumor markers carcinoembryonic antigen (normal <5.0 ng/ml) and carbohydrate antigen 19-9 (normal <37.0 U/ml) also decreased from 15.1 to 8.6 and 266.8 to 38.2 respectively (Figs. 2 and 3). However, the disease gradually progressed 3 months after the initiation of the ZOL + CTX combination therapy. In total, the patient was administered 28 courses of CTX and 8 courses of ZOL, but eventually succumbed to the disease 2 years and 3 months after the first surgery.\n\nDiscussion\nFollowing its approval in 2004, bevacizumab, a humanized recombinant monoclonal antibody against vascular endothelial growth factor-A, became the first biological therapy for the initial treatment of mCRC. Bevacizumab achieved improvements in progression-free and overall when combined with chemotherapy, such as FOLFIRI and FOLFOX, in several studies (9,10). In the same year, a randomized trial of CTX alone or in combination with CPT-11 exhibited clinical effectiveness in CPT-11-refractory CRC, confirming the results of phase 2 studies of third-line therapy. CPT-11 and combination therapy achieved markedly higher response rates compared with CTX monotherapy alone. However, CTX monotherapy was effective compared with placebo and was associated with only mild toxicity, including skin toxicity; thus, it may be a viable option for patients who are not considered candidates for further treatment or who choose not to receive such combination therapy (11). In addition, in 2006, CTX, which is a monoclonal antibody against EGFR, was introduced as treatment for CRC and these drugs are currently considered to largely contribute to the better prognosis of patients with CRC.\n\nMolecules of the EGFR family constitute a signaling pathway that plays an important role in intracellular reactions. Three major pathways are involved in EGFR-mediated signaling. The first pathway is that of the mitogen-activated protein kinase (MAPK) cascades. EGFR tyrosine autophosphorylation activates Ras, which leads to a multistep phosphorylation event and subsequently activates MAPKs and extracellular signal-regulated protein kinase (ERK)1 and ERK2. These kinases regulate a large number of molecules that are involved in cell transformation, proliferation and survival (12). Another important pathway secondary to the EGFR activation is phosphatidylinositol-3-kinase and the downstream protein serine/threonine kinase Akt. Akt transduces intracellular signals linked to cell survival, proliferation and motility (13). The third pathway is represented by Jak2/STAT3. EGF, the mitogenic hormone that activates EGFR, plays an important role in regulating the proliferation and differentiation of normal and neoplastic cells in vitro and in vivo.\n\nAs the newest nitrogen-containing bisphosphonate, the suppression of bone resorption of ZOL increases by 2,000 times in comparison with that of flexor chloride sodium phosphate, and it is 200 times that of pamidronate, which is widely used to prevent and treat bone metastases from solid tumors, and to delay the development of cancer-related bone damage. Clinical experience has proven that ZOL does not only prevent bone diseases, but also affects cancer activity by inhibiting the proliferation and reducing the activity of cancer cell0s (14). The efficacy of combination therapy with ZOL and CTX on CRC cells was previously reported in a preclinical study (8). The administration of ZOL carries the risk of osteonecrosis of jaw. However, this side effect did not occur for this patient.\n\nThere are two mechanisms underlying the antitumor effect of the ZOL and CTX combination therapy in our patient: One mechanism includes the inhibition of RAS signaling by both agents. In KRAS wild-type tumors, CTX inhibits the intracellular signaling cascades, such as the RAS signaling pathways that promote cell growth, by competing with the ligand for binding to the EGFR receptor (3,15). In a preclinical study, ZOL exerted an antitumor effect on CRC by inhibiting prenylation of RAS (8). The other mechanism is the antitumor activity occurring via targeting pathways unrelated to EGFR, such as antibody-dependent cytotoxicity (ADCC) (16). A previous report suggested that ZOL enhances ADCC by increasing the number of δγT cells (17). This evidence suggests that combination therapy with ZOL and CTX may synergistically enhance ADCC activity and exert an antitumor effect.\n\nIn our patient, radiotherapy alone was selected after the recurrence to the thoracic spine, as there are currently no reports confirming the effectiveness of an anti-EGFR agent against the bone metastases of CRC in the English literature; furthermore, the recurrence was limited to the thoracic spine (18).\n\nOur patient had difficulty walking due to the thoracic spine metastasis and compression of the spinal cord. Combination therapy with ZOL and CTX for unresectable rectal cancer with bone metastases was very effective in improving the patient's ability to walk. The compression of the spinal cord diminished after treatment and the patient did not complain of any more difficulty walking while he was alive.\n\nIt is not possible to determine whether CTX and ZOL, alone or in combination, had antitumor effects. Their effectiveness against the lung metastasis may be due to the re-administration of CTX. However, as mentioned above, the effectiveness of anti-EGFR therapy for bone metastases is uncertain and the administration of ZOL may have contributed to the reduction in tumor size. These findings suggest that ZOL may play an important role as an effector for cancer therapy. To the best of our knowledge, this is the first report of the clinical course of a patient while under treatment with the combination of ZOL and CTX.\n\nIn conclusion, our results demonstrated that combination therapy with ZOL and CTX inhibited the growth of metastatic rectal cancer. Therefore, the efficacy of this combination therapy should be proven in future clinical trials.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nPatient consent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\nAuthors' contributions\nThe supervision of the current study was by KY; YT, NM, TaT, ToT, SM, HI, YT, KY interpreted the clinical data and YT and NM wrote, reviewed and/or revised the manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAbbreviations\nADCCantibody-dependent cytotoxicity\n\nCRCcolorectal cancer\n\nCTcomputed tomography\n\nCTXcetuximab\n\nEGFRepidermal growth factor receptor\n\nERKextracellular signal-regulated protein kinase\n\nMAPKmitogen-activated protein kinase\n\nmCRCmetastatic CRC\n\nZOLzoledronic acid\n\nFigure 1. Computed tomography scan showing the pericardial effusion.\n\nFigure 2. Comparison of computed tomography (CT) scan before and after the administration of ZOL + CTX. The CT images show a reduction in the size of the metastatic lesions (arrows). Top row, bone metastasis; bottom row, lung metastasis. ZOL, zoledronic acid; CTX, cetuximab.\n\nFigure 3. Tumor marker levels over the course of treatment. CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; ZOL, zoledronic acid; CTX, cetuximab; LAR, lower anterior resection.\n==== Refs\nReferences\n1 Bray F Ferlay J Soerjomataram J Siegel RL Torre LA Jemal A Global cancer statistics, 2018 GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cance J Clin 68 394 424 2018 10.3322/caac.21492 \n2 Van Cutsem E Oliveira J ESMO Guidelines Working Group Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up Ann Oncol 4 Suppl S61 S63 2009 \n3 Goldstein NI Prewett M Zuklys K Rockwell P Mendelsohn J Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model Clin Cancer Res 1 1311 1318 1995 9815926 \n4 Li S Schmitz KR Jeffrey PD Wiltzius JJ Kussie P Ferguson KM Structural basis for inhibition of the epidermal growth factor receptor by cetuximab Cancer Cell 7 301 311 2005 10.1016/j.ccr.2005.03.003 15837620 \n5 Bokemeyer C Bondarenko I Hartmann JT de Braud F Schuch G Zubel A Celik I Schlichting M Koralewski P Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study Ann Oncol 22 1535 1546 2011 10.1093/annonc/mdq632 21228335 \n6 Van Cutsem E Kohne CH Hitre E Zaluski J Chang Chien CR Makhson A D'Haens G Pintér T Lim R Bodoky G Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer N Engl J Med 360 1408 1417 2009 10.1056/NEJMoa0805019 19339720 \n7 Corey E Brown LG Quinn JE Poot M Roudier MP Higano CS Vessella RL Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer Clin Cancer Res 9 295 306 2003 12538482 \n8 Kato J Futamura M Kanematsu M Gaowa S Mori R Tanahashi T Matsuhashi N Yoshida K Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status Int J Cancer 138 1516 1527 2016 10.1002/ijc.29881 26437179 \n9 Hurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Berlin J Baron A Griffing S Holmgren E Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 350 2335 2342 2004 10.1056/NEJMoa032691 15175435 \n10 Tournigand C Andre T Achille E Lledo G Flesh M Mery-Mignard D Quinaux E Couteau C Buyse M Ganem G FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study J Clin Oncol 22 229 237 2004 10.1200/JCO.2004.05.113 14657227 \n11 Cunningham D Humblet Y Siena S Khayat D Bleiberg H Santoro A Bets D Mueser M Harstrick A Verslype C Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer N Engl J Med 351 337 345 2004 10.1056/NEJMoa033025 15269313 \n12 Lewis TS Shapiro PS Ahn NG Signal transduction through MAP kinase cascades Adv Cancer Res 74 49 139 1998 10.1016/S0065-230X(08)60765-4 9561267 \n13 Vivanco I Sawyers CL The phosphatidylinositol 3-Kinase AKT pathway in human cancer Nat Rev Cancer 2 489 501 2002 10.1038/nrc839 12094235 \n14 Han FS Lin MB Zhu HY Chen YQ Shui W Xu JM Anti-proliferation effect of zoledronic acid on human colon cancer line SW480 Asian Pac J Trop Med 9 168 171 2016 10.1016/j.apjtm.2016.01.005 26919949 \n15 Schubbert S Shannon K Bollag G Hyperactive Ras in developmental disorders and cancer Nat Rev Cancer 7 295 308 2007 10.1038/nrc2175 17384584 \n16 Correale P Marra M Remondo C Migali C Misso G Arcuri FP Del Vecchio MT Carducci A Loiacono L Tassone P Cytotoxic drugs up-regulate epidermal growth factor receptor (EGFR) expression in colon cancer cells and enhance their susceptibility to EGFR-targeted antibody-dependent cell-mediated-cytotoxicity (ADCC) Eur J Cancer 46 1703 1711 2010 10.1016/j.ejca.2010.03.005 20399639 \n17 Maniar A Zhang X Lin W Gastman BR Pauza CD Strome SE Chapoval AI Human gammadelta T lymphocytes induce robust NK cell-mediated antitumor cytotoxicity through CD137 engagement Blood 116 1726 1733 2010 10.1182/blood-2009-07-234211 20519625 \n18 Nakamura S Fukui T Suzuki S Takeda H Watanabe K Yoshioka T Long-term survival after a favorable response to anti-EGFR antibody plus chemotherapy to treat bone marrow metastasis: A case report of KRAS-wildtype rectal cancer Onco Targets Ther 10 1143 1147 2017 10.2147/OTT.S129275 28260928\n\n",
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"issue": "10(6)",
"journal": "Molecular and clinical oncology",
"keywords": "bone metastases; cetuximab; unresectable rectal cancer; zoledronic acid",
"medline_ta": "Mol Clin Oncol",
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"nlm_unique_id": "101613422",
"other_id": null,
"pages": "571-574",
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"pubdate": "2019-06",
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"title": "Efficacy of combination therapy with zoledronic acid and cetuximab for unresectable rectal cancer with bone metastases: A case report.",
"title_normalized": "efficacy of combination therapy with zoledronic acid and cetuximab for unresectable rectal cancer with bone metastases a case report"
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"abstract": "Atypical femoral fractures (AFFs) occur in both osteoporosis patients and cancer patients who receive long-term bisphosphonate treatment. Denosumab offers an alternative approach for the treatment of bone metastases. We describe a 59-year-old woman with a history of breast carcinoma and bone metastasis who was prescribed denosumab for 4 years. The patient had no history of any prior bisphosphonate use. Bone scintigraphy showed an abnormal uptake in the right femur, which was confirmed as an impending AFF or atypical femoral stress reaction. In oncological patients receiving long-term denosumab, AFF should be included as a differential diagnosis for focal femoral findings.",
"affiliations": null,
"authors": "Sugihara|Tsutomu|T|;Koizumi|Mitsuru|M|;Hayakawa|Keiko|K|;Ito|Yoshinori|Y|;Sata|Naohiro|N|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000069448:Denosumab",
"country": "United States",
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"issue": "43(5)",
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"mesh_terms": "D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D002277:Carcinoma; D000069448:Denosumab; D003937:Diagnosis, Differential; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D008875:Middle Aged; D058866:Osteoporotic Fractures",
"nlm_unique_id": "7611109",
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"pubdate": "2018-05",
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"references": null,
"title": "Impending Atypical Femoral Fracture in a Patient of Breast Cancer With Bone Metastases Receiving Long-term Denosumab.",
"title_normalized": "impending atypical femoral fracture in a patient of breast cancer with bone metastases receiving long term denosumab"
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"abstract": "OBJECTIVE\nCell-free DNA (cfDNA) and circulating tumor cell (CTC) based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, due to complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (e.g. CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in >80% of metastatic patients and its association with disease resistance presents an opportunity to improve upon current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity.\n\n\nMETHODS\nWe developed a targeted sequencing and analysis method as part of a new assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlate these events with therapy resistance, progression-free survival (PFS) and overall survival (OS).\n\n\nRESULTS\nEnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS: 30% vs. 71%, P=0.0002; 6-month OS: 59% vs. 100%, P=0.0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay which was also run on a subset of patients.\n\n\nCONCLUSIONS\ncfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.",
"affiliations": "Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Dang|Ha X|HX|;Chauhan|Pradeep S|PS|;Ellis|Haley|H|;Feng|Wenjia|W|;Harris|Peter K|PK|;Smith|Grace|G|;Qiao|Mark|M|;Dienstbach|Katherine|K|;Beck|Rachel|R|;Atkocius|Andrew|A|;Qaium|Faridi|F|;Luo|Jingqin|J|;Michalski|Jeff M|JM|;Picus|Joel|J|;Pachynski|Russell K|RK|;Maher|Christopher A|CA|;Chaudhuri|Aadel A|AA|",
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"pages": "680-713",
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"pmid": "32903952",
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"references": "23228172;29899824;31040929;26903579;29367197;29206995;30941670;24705333;30380390;30086276;27018799;30371878;30033370;28899864;30865549;28368512;27262168;21612468;25184630;28472366;28233803;29955787;22894553;30638634;29909987;26329698;29909985",
"title": "Cell-free DNA alterations in the AR enhancer and locus predict resistance to AR-directed therapy in patients with metastatic prostate cancer.",
"title_normalized": "cell free dna alterations in the ar enhancer and locus predict resistance to ar directed therapy in patients with metastatic prostate cancer"
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"abstract": "Central nervous system involvement in melioidosis is rare. We describe a 48 year old woman who developed septicaemia and a brain abscess due to Pseudomonas pseudomallei. Since there is a continuing practical problem in bacteriological confirmation of the aetiological agent, diagnosis of melioidosis has to be made on clinical suspicion.",
"affiliations": "Department of Microbiology, Faculty of Medicine, National University of Malaysia, Kuala Lumpur.",
"authors": "Pit|S|S|;Chea|F K|FK|;Jamal|F|F|",
"chemical_list": null,
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"delete": false,
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"mesh_terms": "D000208:Acute Disease; D001921:Brain; D001922:Brain Abscess; D005260:Female; D006801:Humans; D008554:Melioidosis; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
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"pubdate": "1988-02",
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"references": "4869109;5001752;1163890;2934486;7245336;7035636;381328",
"title": "Melioidosis with brain abscess.",
"title_normalized": "melioidosis with brain abscess"
} | [
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"abstract": "To evaluate the long-term effects of intravitreal dexamethasone implants (IDIs) in eyes with macular edema (ME) due to retinal vein occlusion (RVO).\n\n\n\nWe reviewed the records of 10 patients followed for 5 years after they received their first IDI. The main outcome measures included changes in best corrected visual acuity (BCVA), central macular thickness (CMT), and central macular volume (CMV), and the incidence of side effects.\n\n\n\nTen patients were included in the study with a mean follow-up of 65.51 months. Forty IDI injections were performed. An improvement in BCVA was observed after 92.5% of the IDI injections (P < 0.05), while the CMT and the CMV decreased significantly (P < 0.05) after 97.5% of the injections. After 27.5% of the injections, the intraocular pressure rose more than 10 mmHg and 3 of the 7 phakic patients required phacoemulsification surgery.\n\n\n\nIDI is an effective therapy for the treatment of ME secondary to RVO with a favorable long-term safety profile.",
"affiliations": "Department of Ophthalmology, Araba University Hospital , Vitoria-Gasteiz, Spain .;Department of Ophthalmology, Araba University Hospital , Vitoria-Gasteiz, Spain .",
"authors": "Garay-Aramburu|Gonzaga|G|;Gómez-Moreno|Ángela|Á|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D009883:Ophthalmic Solutions; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1089/jop.2017.0148",
"fulltext": null,
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"issn_linking": "1080-7683",
"issue": "34(6)",
"journal": "Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics",
"keywords": "adverse events; intravitreal dexamethasone implant; macular edema; ocular hypertension; retinal vascular occlusion; steroids",
"medline_ta": "J Ocul Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D012170:Retinal Vein Occlusion; D012189:Retrospective Studies",
"nlm_unique_id": "9511091",
"other_id": null,
"pages": "436-441",
"pmc": null,
"pmid": "29708803",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A 5-Year Follow-Up Study of the Treatment of Macular Edema Due to Retinal Vein Occlusion Using Dexamethasone Intravitreal Implants.",
"title_normalized": "a 5 year follow up study of the treatment of macular edema due to retinal vein occlusion using dexamethasone intravitreal implants"
} | [
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"activesubstancename": "DEXAMETHASONE"
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... |
{
"abstract": "Lactic acidosis is a rare but serious adverse event linked to treatment with linezolid, an oxazolidinone antibiotic. Presented is a case of a 67-year-old man treated for 26 days with linezolid for staphylococcal osteomyelitis of the right foot with subsequent sepsis. During the course of treatment, severe lactic acidosis developed, requiring hospitalization in an intensive care unit. The likely mechanism of this potentially life-threatening complication is discussed.",
"affiliations": "Infectious Department, Masaryk´s Hospital, Usti nad Labem, Czech Republic, e-mail: jana.pazderkova@kzcr.eu.",
"authors": "Pazderkovák|Jana|J|;Kotora|Vladislav|V|;Dlouhý|Pavel|P|;Bartoš|Hynek|H|",
"chemical_list": "D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "Czech Republic",
"delete": false,
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"issue": "25(3)",
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"keywords": null,
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"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D000900:Anti-Bacterial Agents; D006801:Humans; D000069349:Linezolid; D008297:Male; D010019:Osteomyelitis; D023303:Oxazolidinones; D018805:Sepsis; D013203:Staphylococcal Infections; D016896:Treatment Outcome",
"nlm_unique_id": "101189112",
"other_id": null,
"pages": "92-96",
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"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Linezolid-induced lactic acidosis - a brief overview with a case report.",
"title_normalized": "linezolid induced lactic acidosis a brief overview with a case report"
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"abstract": "Self-reported side effects of pain medication are important determinants of treatment course that can affect patient adherence, medication discontinuation and physician decisions. Yet, few studies have investigated patient-level predictors of self-reported pain medication side effects. The present study sought to fill this gap by exploring the impact of physical or sexual abuse history on self-reported pain medication side effects and considered a mediation model in which those effects are transmitted through a centralized pain phenotype and pain catastrophizing.\n\n\n\nWe conducted a cross-sectional analysis of 3118 patients presenting to a tertiary-care, outpatient pain clinic.\n\n\n\nApproximately 15% of the sample (n=479) reported a lifetime history of abuse. Patients with a lifetime history of abuse, particularly abuse that occurred in both childhood and adulthood, reported more pain medication side effects compared with patients reporting no abuse history. Furthermore, path analysis showed that a centralized pain phenotype and pain catastrophizing mediated the association between lifetime abuse history and the sum of pain medication side effects.\n\n\n\nThis suggests that individuals who experience abuse may develop a heightened physiological sensitivity to stimuli, as well as a tendency to interpret stimuli negatively, exaggerate the impact of aversive stimuli and undermine their ability to cope with the stressor. This study highlights the need for physicians to understand patient-level predictors of medication tolerance and to consider a history of abuse and trauma in decisions regarding treatment and medication management.",
"affiliations": "Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA jmboik@med.umich.edu.;Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.;Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.;Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.;Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.;Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.",
"authors": "Pierce|Jennifer|J|;Hassett|Afton L|AL|;Schneiderhan|Jill R|JR|;Divers|Jude|J|;Brummett|Chad M|CM|;Goesling|Jenna|J|",
"chemical_list": "D000700:Analgesics",
"country": "England",
"delete": false,
"doi": "10.1136/rapm-2019-101130",
"fulltext": null,
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"issue": "45(4)",
"journal": "Regional anesthesia and pain medicine",
"keywords": "chronic pain; pain medicine; psychological aspects of pain",
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics; D058443:Catastrophization; D003430:Cross-Sectional Studies; D005260:Female; D005356:Fibromyalgia; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain; D058748:Pain Perception; D000066550:Physical Abuse; D012742:Sex Offenses; D011795:Surveys and Questionnaires; D055815:Young Adult",
"nlm_unique_id": "9804508",
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"pages": "293-300",
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"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Centralized pain and pain catastrophizing mediate the association between lifetime abuse history and self-reported pain medication side effects.",
"title_normalized": "centralized pain and pain catastrophizing mediate the association between lifetime abuse history and self reported pain medication side effects"
} | [
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"abstract": "We report a rare case of meningitis due to a combination of Streptococcus mitis and Neisseria subflava. An 80-year-old female had a 4-year history of type II diabetes mellitus (DM) and an 11-year history of rheumatoid arthritis, which was treated with prednisolone, tacrolimus, and methotrexate. One month after the removal of a dental implant, she complained of a disturbance of consciousness and suffered a convulsion. A cerebrospinal fluid culture was found to be positive for both S. mitis and N. subflava. After 14 days of antibiotic treatment with 4 g/day ceftriaxone, her stiff neck, somnolence, and laboratory data greatly improved, and she was successfully discharged at 27 days after admission. Although both S. mitis and N. subflava are generally considered to be benign bacteria, they can cause meningitis in patients with the following risk factors: older age, on immunosuppressive treatment, DM, or dental treatment.",
"affiliations": "Department of Neurology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Infectious Diseases, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Infectious Diseases, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.",
"authors": "Fukumoto|Kana|K|;Manabe|Yasuhiro|Y|;Fujiwara|Shunya|S|;Omote|Yoshio|Y|;Narai|Hisashi|H|;Yamada|Haruto|H|;Saito|Takashi|T|;Abe|Koji|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000490695",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000490695crn-0010-0177Case ReportMeningitis due to a Combination of Streptococcus mitis and Neisseria subflava: A Case Report Fukumoto Kana aManabe Yasuhiro a*Fujiwara Shunya aOmote Yoshio aNarai Hisashi aYamada Haruto bSaito Takashi bAbe Koji caDepartment of Neurology, National Hospital Organization Okayama Medical Center, Okayama, JapanbDepartment of Infectious Diseases, National Hospital Organization Okayama Medical Center, Okayama, JapancDepartment of Neurology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan*Yasuhiro Manabe, MD, PhD, Department of Neurology, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Kita-ku, Okayama 701-1192 (Japan), E-Mail ymanabe@okayamamc.jpMay-Aug 2018 18 7 2018 18 7 2018 10 2 177 180 5 6 2018 5 6 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We report a rare case of meningitis due to a combination of Streptococcus mitis and Neisseria subflava. An 80-year-old female had a 4-year history of type II diabetes mellitus (DM) and an 11-year history of rheumatoid arthritis, which was treated with prednisolone, tacrolimus, and methotrexate. One month after the removal of a dental implant, she complained of a disturbance of consciousness and suffered a convulsion. A cerebrospinal fluid culture was found to be positive for both S. mitis and N. subflava. After 14 days of antibiotic treatment with 4 g/day ceftriaxone, her stiff neck, somnolence, and laboratory data greatly improved, and she was successfully discharged at 27 days after admission. Although both S. mitis and N. subflava are generally considered to be benign bacteria, they can cause meningitis in patients with the following risk factors: older age, on immunosuppressive treatment, DM, or dental treatment.\n\nKeywords\nStreptococcus mitisNeisseria subflavaBacterial meningitisCompromised host\n==== Body\nIntroduction\nStreptococcus mitis is a component of the normal flora of the oropharynx, skin, gastrointestinal system, and genital tract [1, 2]. Neisseria subflava is a natural inhabitant of the mucous membranes of the upper respiratory tract [3, 4, 5]. Both species are generally considered to be benign bacteria, and infections of the central nervous system involving these bacteria are very rare. In fact, there have only been a few reports about such cases, and they all involved pediatric patients [1, 2, 3, 4, 5, 6]. In addition, there have not been any reports about cases of meningitis involving a combination of S. mitis and N. subflava. Here, we report a case of meningitis caused by a combination of S. mitis and N. subflava.\n\nCase Report\nAn 80-year-old female complained of a disturbance of consciousness, which had started 2 days prior to her admission. It had subsequently worsened, resulting in a convulsion on the day of her admission. She had a history of rheumatoid arthritis since she had been 69 years of age, which had been controlled with prednisolone (5 mg) and tacrolimus (2 mg) every day, and methotrexate (6 mg) every week. She also suffered from type II diabetes mellitus (DM) since she had been 77 years of age, which was controlled with oral medications. Her glycated hemoglobin level on admission was 7.8%. She had had a dental implant removed 1 month prior to admission and had developed fever 27 days prior to admission. She had been treated with antibiotics (amoxicillin/clavulanic acid), and tacrolimus and methotrexate had been stopped 1 week prior to admission.\n\nPhysical examination revealed a temperature of 36.6°C. The patient appeared somnolent, and she had a Glasgow Coma Scale score of 12 (E3V4M5). On neurological examination, her cranial nerves revealed left conjugate deviation. Her motor function was intact. Her deep tendon reflexes were hyperactive in all four limbs, and no pathological reflexes, ataxia, or sensory disorders were noted. She had a stiff neck, but Kernig's sign was absent. Laboratory tests showed a white blood cell count of 13,400/μL and a C-reactive protein level of 5.6 mg/dL. During a lumbar puncture, her initial cerebrospinal fluid (CSF) pressure was 130 mm H2O, and her CSF cell count was 40/μL (96.6% mononuclear cells). Her CSF protein concentration was elevated (115 mg/dL), and her CSF glucose level was decreased (70 mg/dL; blood glucose level: 214 mg/dL). Brain magnetic resonance imaging did not show any parenchymal abnormalities. As empirical therapy for viral or fungal meningitis, she was initially treated with 800 mg/day acyclovir and 100 mg/day amphotericin B. However, her CSF cultures became positive for Streptococcus and Neisseria species 3 days after admission. We replaced the acyclovir and amphotericin B with 4 g/day ceftriaxone. Although her blood culture was negative at 6 days after admission, her CSF culture revealed S. mitis and N. subflava. She was diagnosed with bacterial meningitis due to a combination of S. mitis and N. subflava.\n\nThe patient's stiff neck, somnolence, and laboratory data had greatly improved by 14 days after admission. We replaced ceftriaxone with 4 g/day cefotaxime because thrombocytopenia occurred at 19 days after admission. Her C-reactive protein level normalized, and the total number of cells in her CSF decreased to 2/μL (100% mononuclear cells) at 22 days after admission. She was able to walk after rehabilitation and was discharged from the hospital at 27 days after admission (Fig. 1).\n\nDiscussion\nWe present a case in which an elderly immunocompromised patient developed meningitis due to a combination of S. mitis and N. subflava, both of which are natural inhabitants of the mucous membranes of the upper respiratory tract and are generally considered to be benign bacteria [1, 2, 3, 4, 5]. Meningitis has been reported to be caused by S. mitis or N. subflava alone in cases involving spinal anesthesia, neurosurgical procedures, malignancy, neurological complications of endocarditis, or in newborns [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. Older age, the use of immunosuppressants, DM, and dental treatment played important roles in the present case, in which the patient was treated with ceftriaxone because it diffuses more readily into the CSF than other drugs. To the best of our knowledge, this is the first reported case of meningitis caused by a combination of S. mitis and N. subflava.\n\nS. mitis and N. subflava might be more significant causes of meningitis than is generally understood. Balkundi et al. [1] reported a fatal case of penicillin-resistant S. mitis-induced meningitis in a 6-year-old child with acute lymphoblastic leukemia. In addition, Chong et al. [4] reported a fatal case of N. subflava-induced endocarditis, meningitis, and septicemia in a healthy 36-year-old male. We have to recognize that S. mitis and N. subflava can be pathogenic and can cause meningitis in patients with risk factors such as older age, on immunosuppressive treatment, DM, and dental treatment.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors state that they have no conflicts of interest.\n\nFunding Sources\nThe authors have nothing to disclose.\n\nFig. 1 The patient's clinical course. ACV, acyclovir; CRP, C-reactive protein; CSF, cerebrospinal fluid; CTRX, ceftriaxone; CTX, cefotaxime; L-AMB, amphotericin B; N. subflava, Neisseria subflava; S. mitis, Streptococcus mitis; WBC, white blood cell.\n==== Refs\nReferences\n1 Balkundi DR Murray DL Patterson MJ Gera R Scott-Emuakpor A Kulkarni R Penicillin-resistant Streptococcus mitis as a cause of septicemia with meningitis in febrile neutropenic children J Pediatr Hematol Oncol 1997 Jan-Feb 19 (1) 82 5 9065725 \n2 Jaing TH Chiu CH Hung IJ Successful treatment of meningitis caused by highly-penicillin-resistant Streptococcus mitis in a leukemic child Chang Gung Med J 2002 3 25 (3) 190 3 12022740 \n3 Lewin RA Hughes WT Neisseria subflava as a cause of meningitis and septicemia in children. Report of five cases JAMA 1966 3 195 (10) 821 3 12608164 \n4 Chong Y Song KS Lee SY Neisseria subflava infections—bacteriological aspects of two cases Yonsei Med J 1975 16 (1) 44 9 1224640 \n5 Baraldès MA Domingo P Barrio JL Pericas R Gurguí M Vazquez G Meningitis due to Neisseria subflava: case report and review Clin Infect Dis 2000 3 30 (3) 615 7 10722463 \n6 Kutlu SS Sacar S Cevahir N Turgut H Community-acquired Streptococcus mitis meningitis: a case report Int J Infect Dis 2008 11 12 (6) e107 9 18378176 \n7 Villevieille T Vincenti-Rouquette I Petitjeans F Koulmann P Legulluche Y Rousseau JM Streptococcus mitis-induced meningitis after spinal anesthesia Anesth Analg 2000 2 90 (2) 500 1 \n8 Domingo P Coll P Maroto P Verger G Prats G Neisseria subflava bacteremia in a neutropenic patient Arch Intern Med 1996 8 156 (15) 1762 5 8694678 \n9 Villion A Aischner M Chowers M Reisfeld S Spontaneous Streptococcus mitis meningitis in a patient with liver cirrhosis: a case report and literature review Case Report in Clinical Medicine 2014 3 (07) 398 401 \n10 Entesari-Tatafi D Bagherirad M Quan D Athan E Iatrogenic meningitis caused by Neisseria sicca/subflava after intrathecal contrast injection, Australia Emerg Infect Dis 2014 6 20 (6) 1023 5 24856004\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "10(2)",
"journal": "Case reports in neurology",
"keywords": "Bacterial meningitis; Compromised host; Neisseria subflava; Streptococcus mitis",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "177-180",
"pmc": null,
"pmid": "30140217",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "8694678;9065725;12022740;18378176;24856004;10648351;1224640;10722463;12608164",
"title": "Meningitis due to a Combination of Streptococcus mitis and Neisseria subflava: A Case Report.",
"title_normalized": "meningitis due to a combination of streptococcus mitis and neisseria subflava a case report"
} | [
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"activesubstancename": "TACROLIMUS"
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"abstract": "Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin (IL)-12 and IL-23 and is US Food and Drug Administration (FDA)-approved for plaque psoriasis, moderately to severely active Crohn's disease, and ulcerative colitis. We describe a case of an immediate hypersensitivity reaction to ustekinumab infusion with no reaction to subsequent ustekinumab subcutaneous maintenance therapy. We identify ethylenediaminetetraacetic acid as a unique excipient found in the intravenous formulation compared with the prefilled syringe used for subcutaneous injections, which is likely to account for this observation. No similar cases have been reported in the literature.",
"affiliations": "Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois, IL.;Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois, IL.;Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois, IL.",
"authors": "Krugliak Cleveland|Noa|N|;Masching|Alexandra|A|;Rubin|David T|DT|",
"chemical_list": null,
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"delete": false,
"doi": "10.14309/crj.0000000000000449",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253 Wolters Kluwer Maryland, MD \n\nACGCR-20-0200\n10.14309/crj.0000000000000449\n00018\nCase Report\nInflammatory Bowel Disease\nHypersensitivity to IV Ustekinumab but Tolerance to Subcutaneous Ustekinumab in a Patient With Crohn's Disease\nKrugliak Cleveland Noa MD1 Masching Alexandra APN1 Rubin David T. MD1 1 Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois, IL\nCorrespondence: David T. Rubin, MD (drubin@uchicago.edu).\n8 2020 \n25 8 2020 \n7 8 e0044905 3 2020 08 6 2020 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2020This 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.ABSTRACT\nUstekinumab is a monoclonal antibody against the p40 subunit of interleukin (IL)-12 and IL-23 and is US Food and Drug Administration (FDA)-approved for plaque psoriasis, moderately to severely active Crohn's disease, and ulcerative colitis. We describe a case of an immediate hypersensitivity reaction to ustekinumab infusion with no reaction to subsequent ustekinumab subcutaneous maintenance therapy. We identify ethylenediaminetetraacetic acid as a unique excipient found in the intravenous formulation compared with the prefilled syringe used for subcutaneous injections, which is likely to account for this observation. No similar cases have been reported in the literature.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nCrohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Patients with moderately to severely active disease are treated with glucocorticoids, immunosuppressants, and biological therapies. However, many of these therapies are associated with increased risk of infections, malignancies, and other adverse events.1–5 Ustekinumab, a monoclonal antibody that inhibits the activation of interleukin (IL)-12 and IL-23 by blockade of the p40 subunit, is US Food and Drug Administration (FDA)-approved for plaque psoriasis, moderately to severely active CD, and most recently, ulcerative colitis. Studies in both psoriasis and CD have demonstrated ustekinumab's favorable safety profile, which is not associated with an increased risk of infections or malignancies and low prevalence of immunogenicity.6–8 The induction dose for CD is an initial weight-based intravenous (IV) loading dose, followed by subcutaneous (SC) injections for maintenance. We describe a case of an immediate hypersensitivity reaction to ustekinumab infusion with clinical efficacy and no reaction to subsequent ustekinumab SC maintenance therapy.\n\nCASE REPORT\nA 26-year-old woman with a history of ileocolonic and perianal CD who previously underwent proctocolectomy with end ileostomy presented with oral ulcers and dysphagia. She was found to have active oral and esophageal CD. Her medical history included intolerance or inadequate response to infliximab (anaphylaxis), adalimumab with methotrexate (leukopenia), vedolizumab, certolizumab pegol, and off-label tofacitinib. She was prescribed ustekinumab at Crohn's dosing (260 mg IV followed by 90 mg SC q8w). At the time of IV loading infusion, she developed tachycardia, flushing, throat tightness, and difficulty breathing. Diphenhydramine 50 mg IV and methylprednisolone sodium succinate 100 mg IV were administered with rapid resolution of symptoms. A ustekinumab serum level obtained at day 50 postinfusion was 0.1 μg/mL without the presence of antidrug antibodies. We compared the list of excipients found in the IV formulation compared with the prefilled syringe used for SC injections and noted specifically that ethylenediaminetetraacetic acid (EDTA) was found to be in the infusion but not in the SC therapy (Table 1). The patient subsequently self-administered her first SC dose of ustekinumab and had no hypersensitivity reaction. EDTA was subsequently listed in her medical chart as an allergen. Her Crohn's-related oral and esophageal symptoms dramatically improved and has maintained deep remission at the 3-year follow-up.\n\nTable 1. Comparison of excipients found in the ustekinumab infusion and the prefilled syringe used for SC injection\n\nEDTA, ethylenediaminetetraacetic acid; PFS, prefilled syringe; SC, subcutaneous.\n\nDISCUSSION\nThe approval of ustekinumab for the treatment of moderately to severely active CD added a safe and efficacious treatment option for both anti-TNF-naïve patients and patients who have failed anti-TNF therapy. The pivotal trials leading to the FDA approval of ustekinumab, UNITI-1, and UNITI-2 were studies of induction therapy of patients who failed anti-TNF therapy and those who were anti-TNF naïve, respectively, and demonstrated the clinical efficacy of weight-based induction dosing in contradistinction to the previous studies that led to regulatory approval for plaque psoriasis, in which no such loading phase was developed. Patients who completed the induction trials were continued in IM-UNITI to assess the maintenance of remission. The rates of infusion reactions occurring within 1 hour after an ustekinumab infusion were similar across the treatment and control groups in both UNITI-1 and UNITI-2. The rates of injection-site reactions in IM-UNITI, however, were higher in the treatment groups compared with the placebo arm (2.3% for 90 mg every 12 weeks group and 6.9% in 90 mg every 8 weeks group vs 0.8% in the placebo).8,9 Ustekinumab is a biological therapy associated with very low immunogenicity; the induction trials reported ∼0.09% (2 patients only) and 2.3% in the maintenance of antidrug antibody development.\n\nWe report a single patient with a type-I immediate hypersensitivity reaction to the IV infusion of ustekinumab, but not to the SC formulation. There were no antidrug antibodies. We hypothesized that our patient's infusion reaction to the IV formulation was because of EDTA, an excipient found in the induction infusion formulation and not the maintenance injection formula. EDTA has had numerous pharmacologic uses, one of which is being a chelating agents for the treatment of heavy metal poisoning but also preventing oxidation and antibacterial role by its ability to improve the stability of drug preparations by chelating divalent metal ions, which are essential for bacterial growth.10,11\n\nWe believe that this reaction may have occurred from the EDTA, a chelating agent previously described to induce immediate hypersensitivity reactions.12 We suspect sensitization of EDTA developed from other therapy exposures (eg, propofol infusion). Her tolerance and clinical response to the SC formulation of ustekinumab supports this possibility, but careful consideration of other possible causes of hypersensitivity reactions and skin testing would confirm this allergy. We believe clinicians should be aware of this uncommon but serious reaction because it may not preclude further use of ustekinumab.\n\nDISCLOSURES\nAuthor contributions: NK Cleveland wrote and approved the final manuscript. A. Masching and DT Rubin approved the final manuscript and are the guarantors.\n\nFinancial disclosure: NK Clevland is a consultant for Takeda. DT Rubin is a consultant and receives grant support from AbbVie, Janssen, Pfizer, Takeda, and Prometheus Laboratories.\n\nPrevious presentation: This case was presented at the American College of Gastroenterology Annual Scientific Meeting, October 5-10, 2018; Philadelphia, Pennsylvania.Informed consent was obtained for this case report\n==== Refs\nREFERENCES\n1. Toruner M Loftus EV Harmsen WS \nRisk factors for opportunistic infections in patients with inflammatory bowel disease\n. Gastroenterology . 2008 ;134 (4 ):929 –36\n..18294633 \n2. Rutgeerts PJ \nReview article: The limitations of corticosteroid therapy in Crohn's disease\n. Aliment Pharmacol Ther . 2001 ;15 (10 ):1515 –25\n.11563990 \n3. Konidari A Matary WE \nUse of thiopurines in inflammatory bowel disease: Safety issues\n. World J Gastrointest Pharmacol Ther . 2014 ;5 (2 ):63 –76\n..24868487 \n4. Sandborn WJ Loftus EV \nBalancing the risks and benefits of infliximab in the treatment of inflammatory bowel disease\n. Gut . 2004 ;53 (6 ):780 –2\n..15138201 \n5. Lichtenstein GR Rutgeerts P Sandborn WJ \nA pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease\n. Am J Gastroenterol . 2012 ;107 (7 ):1051 –63\n.22613901 \n6. Papp KA Griffiths CEM Gordon K \nLong-term safety of ustekinumab in patients with moderate-to-severe psoriasis: Final results from 5 years of follow-up\n. Br J Dermatol . 2013 ;168 (4 ):844 –54\n.23301632 \n7. Papp K Gottlieb AB Naldi L \nSafety surveillance for ustekinumab and other psoriasis treatments from the Psoriasis Longitudinal Assessment and Registry (PSOLAR)\n. J Drugs Dermatol. \n2015 ;14 (7 ):706 –14\n.26151787 \n8. Feagan BG Sandborn WJ Gasink C \nUstekinumab as induction and maintenance therapy for Crohn's disease\n. N Engl J Med . 2016 ;375 (20 ):1946 –60\n.27959607 \n9. Sandborn WJ Rutgeerts P Gasink C \nLong-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy\n. Aliment Pharmacol Ther . 2018 ;48 (1 ):65 –77\n.29797519 \n10. Born T Kontoghiorghe CN Spyrou A Kolnagou A Kontoghiorghes GJ \nEDTA chelation reappraisal following new clinical trials and regular use in millions of patients: Review of preliminary findings and risk/benefit assessment\n. Toxicol Mech Methods . 2013 ;23 (1 ):11 –7\n.22991933 \n11. Thompson KA Goodale DB \nThe recent development of propofol (DIPRIVAN)\n. Intensive Care Med . 2000 ;26 (Suppl 4 ):S400 –404\n.11310902 \n12. Russo PAJ Banovic T Wiese MD Whyte AF Smith WB \nSystemic allergy to EDTA in local anesthetic and radiocontrast media\n. J Allergy Clin Immunol Pract. \n2014 ;2 (2 ):225 –9\n..24607055\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "7(8)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00449",
"pmc": null,
"pmid": "32904020",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": "11310902;27959607;11563990;22991933;24868487;18294633;15138201;24607055;26151787;22613901;23301632;29797519",
"title": "Hypersensitivity to IV Ustekinumab but Tolerance to Subcutaneous Ustekinumab in a Patient With Crohn's Disease.",
"title_normalized": "hypersensitivity to iv ustekinumab but tolerance to subcutaneous ustekinumab in a patient with crohn s disease"
} | [
{
"companynumb": "US-JNJFOC-20190529810",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
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... |
{
"abstract": "Levetiracetam (LEV) is a pyrrolidine derivative antiepileptic medication used for the treatment of seizures in pediatric and adult patients. We report a case of probable LEV-induced aseptic meningitis in a 13-year-old girl. The patient received LEV for a generalized seizure disorder and presented with symptoms 5 days after medication initiation. Ten days after LEV initiation, the patient presented to the hospital for further management. During her hospital course, infectious etiologies were ruled out with clinical and diagnostic testing. Upon discontinuation of LEV, the patient's symptoms resolved. Although select antiepileptic medications have been associated with drug-induced aseptic meningitis (DIAM), to date, no reports have been published about DIAM following the administration of LEV. We describe and categorize the probability of DIAM in association with LEV, as observed in a patient case.",
"affiliations": "Cooper University Hospital, Camden, New Jersey.;Hovnanian Children's Hospital at Hackensack Meridian Health, Hackensack, New Jersey.;Hovnanian Children's Hospital at Hackensack Meridian Health, Hackensack, New Jersey.;Hovnanian Children's Hospital at Hackensack Meridian Health, Hackensack, New Jersey.",
"authors": "McDonald|Danielle|D|0000-0001-8068-5668;Sultan|Richard|R|;Viswanathan|Anusha|A|;Siu|Anita|A|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "39(1)",
"journal": "Pharmacotherapy",
"keywords": "adverse reactions; anticonvulsants; aseptic; drug-related side effects; meningitis",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008582:Meningitis, Aseptic",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "109-113",
"pmc": null,
"pmid": "30488976",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Rare Case of Levetiracetam and Drug-Induced Idiopathic Aseptic Meningitis in a Pediatric Patient.",
"title_normalized": "a rare case of levetiracetam and drug induced idiopathic aseptic meningitis in a pediatric patient"
} | [
{
"companynumb": "PHHY2019US041396",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment.",
"affiliations": "Apotheke, Klinikum der Universitx00E4;t Mx00FC;nchen, Mx00FC;nchen, Germany.",
"authors": "Blassmann|Ute|U|;Roehr|Anka C|AC|;Frey|Otto R|OR|;Koeberer|Andreas|A|;Briegel|Josef|J|;Huge|Volker|V|;Vetter-Kerkhoff|Cornelia|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid; D012293:Rifampin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000445194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-7012",
"issue": "98(1-2)",
"journal": "Pharmacology",
"keywords": null,
"medline_ta": "Pharmacology",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016638:Critical Illness; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus; D012293:Rifampin; D013203:Staphylococcal Infections",
"nlm_unique_id": "0152016",
"other_id": null,
"pages": "51-5",
"pmc": null,
"pmid": "27046487",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin.",
"title_normalized": "decreased linezolid serum concentrations in three critically ill patients clinical case studies of a potential drug interaction between linezolid and rifampicin"
} | [
{
"companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2016-03118",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional"... |
{
"abstract": "To identify the prevalence of bradycardia associated with use of prednisolone in patients with Kawasaki disease and analyze the association between bradycardia and responsiveness to intravenous immunoglobulin (IVIG).\n\n\n\nWe performed a retrospective cohort study of 176 patients with severe Kawasaki disease admitted to the Tokyo Metropolitan Children's Medical Center between March 2010 and December 2015. The group treated with IVIG plus prednisolone therapy from February 2012 was compared with the control group who received IVIG monotherapy before this date. The primary outcome was the prevalence of bradycardia, defined as heart rate less than the first percentile for normal children. Next, we determined whether bradycardia was associated with the clinical course in the patient subgroup treated with IVIG plus prednisolone therapy.\n\n\n\nThe prevalence of bradycardia was significantly higher in the IVIG plus prednisolone subgroup than in the IVIG group (79.1% vs 7.1%; P?<?.001). The median time to bradycardia onset was 63.0 hours (2.6 days). Prednisolone decreased the heart rate by 15.1 beats/minute (95% CI 10.2-20.0; P?<?.001) on average from day 2 to 7 after the initial therapy. Logistic regression analysis revealed that bradycardia was associated with responsiveness to initial IVIG plus prednisolone therapy (OR 7.2; 95% CI 2.3-23.0; P?<?.001).\n\n\n\nBradycardia frequently occurred during IVIG plus prednisolone therapy in patients with Kawasaki disease, and was associated with responsiveness to IVIG.",
"affiliations": "Department of General Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Clinical Research Support Center, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Department of General Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Department of Cardiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan. Electronic address: masaru_miura@tmhp.jp.",
"authors": "Nagakura|Akito|A|;Morikawa|Yoshihiko|Y|;Sakakibara|Hiroshi|H|;Miura|Masaru|M|",
"chemical_list": "D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2017.02.074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "185()",
"journal": "The Journal of pediatrics",
"keywords": "Kawasaki disease; children; corticosteroids; heart rate; side effect",
"medline_ta": "J Pediatr",
"mesh_terms": "D001919:Bradycardia; D002675:Child, Preschool; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007223:Infant; D016015:Logistic Models; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D011239:Prednisolone; D012189:Retrospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "106-111.e1",
"pmc": null,
"pmid": "28343657",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bradycardia Associated with Prednisolone in Children with Severe Kawasaki Disease.",
"title_normalized": "bradycardia associated with prednisolone in children with severe kawasaki disease"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2019EDE000014",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugad... |
{
"abstract": "Chemotherapy-associated liver injury (CALI) increases the risk of liver resection and may prejudice further surgery and chemotherapy. The reversibility of CALI is therefore important; however, no data concerning this are available. This study aimed to retrospectively analyze the reversibility of CALI in patients undergoing liver resection for colorectal metastases.\n\n\n\nAll resections of colorectal liver metastases after oxaliplatin and/or irinotecan-based chemotherapy were included. First, liver resections were stratified by time between end of chemotherapy and hepatectomy and several possible cut-off values tested. CALI prevalence in various groups was compared. Second, CALI in the two specimens from each patient who had undergone repeat liver resections without interval chemotherapy were compared.\n\n\n\nOverall, 524 liver resections in 429 patients were analyzed. The median interval chemotherapy-surgery was 56days (15-1264). CALI prevalence did not differ significantly between groups with a chemotherapy-surgery interval <270days. Grade 2-3 sinusoidal dilatation (SOS, 19.4% vs. 40.0%, p=0.022) and nodular regenerative hyperplasia (NRH, 6.5% vs. 20.1%, p=0.063) occurred less frequently in patients with an interval >270days (n=31); prevalence of steatosis and steatohepatitis was similar in all groups. A chemotherapy-surgery interval >270days was an independent protector against Grade 2-3 SOS (p=0.009). Forty-seven patients had repeat liver resection without interval chemotherapy. CALI differed between surgeries only for a chemotherapy-surgery interval >270days (n=15), Grade 2-3 SOS having regressed in 4/5 patients and NRH in 7/8; whereas steatosis and steatohepatitis had persisted.\n\n\n\nCALI persists for a long time after chemotherapy. SOS and NRH regress only after nine months without chemotherapy, whereas steatosis and steatohepatitis persist.\n\n\n\nThe patients affected by colorectal liver metastases often receive chemotherapy before liver resection, but chemotherapy causes liver injuries that may increase operative risks and reduce tolerance to further chemotherapy. The authors analyzed the reversibility of the liver injuries after the chemotherapy interruption. Liver injuries persist for a long time after chemotherapy. Sinusoidal dilatation and nodular regenerative hyperplasia regress only nine months after the end of chemotherapy, whereas steatosis and steatohepatitis persist even after this long interval.",
"affiliations": "Dept. of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano (MI), Italy. Electronic address: luca.vigano@humanitas.it.;Dept. of Pathology, Ospedale Mauriziano Umberto I, Torino, Italy.;Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland.;Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland.;Dept. of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Torino, Italy.;Dept. of Oncology, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland.;Dept. of Oncology, Ospedale Mauriziano Umberto I, Torino, Italy.;Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland.;Dept. of Clinical Pathology, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland.",
"authors": "Vigano|Luca|L|;De Rosa|Giovanni|G|;Toso|Christian|C|;Andres|Axel|A|;Ferrero|Alessandro|A|;Roth|Arnaud|A|;Sperti|Elisa|E|;Majno|Pietro|P|;Rubbia-Brandt|Laura|L|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2017.02.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "67(1)",
"journal": "Journal of hepatology",
"keywords": "Chemotherapy-associated liver injury; Liver failure; Liver surgery for colorectal metastases; Nodular regenerative hyperplasia; Reversibility of liver injury; Sinusoidal dilatation; Steatohepatitis; Steatosis",
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D056486:Chemical and Drug Induced Liver Injury; D015179:Colorectal Neoplasms; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "84-91",
"pmc": null,
"pmid": "28284915",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reversibility of chemotherapy-related liver injury.",
"title_normalized": "reversibility of chemotherapy related liver injury"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1052308",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
... |
{
"abstract": "METHODS\nWe report on the case of a 47-year old woman with granulocyte colony-stimulating factor (G-CSF)-producing relapsed oropharyngeal squamous cell cancer. Palliative immunotherapy with nivolumab was started. Absolute neutrophilic count increased during the course of immunotherapy and correlated with tumour progression. Under chemotherapy with weekly paclitaxel, dramatic tumour regression and decreasing absolute neutrophilic count were noted. G-CSF concentration in serum increased from 4.77 to 9.61 pg/ml during the final phase of tumour progression. Immunohistochemical staining of the initial biopsies showed that some of the tumour cells as well as infiltrating cells stained positively for G-CSF, and some of the tumour cells even stained positively for the G-CSF receptor.\n\n\nCONCLUSIONS\nLeukaemoid reaction in malignant disease with increased neutrophilic granulocytes has been shown to correlate with dismal prognosis in other tumours. The role of G-CSF in progression and prognosis of head and neck squamous cell carcinomas is still unclear but in patients with these tumours there seems also to be a correlation between elevated G-CSF and poor prognosis. Further systematic evaluation of G-CSF secretion in this tumour entity should clarify the role and potential treatment possibilities for these tumours.",
"affiliations": "Department of Medical Oncology, Biel-Bienne, Switzerland.;Department of Medical Oncology, Biel-Bienne, Switzerland; martin.zweifel@szbchb.ch.;Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Onkologie, Spital Thun, Thun, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Department of Medical Oncology, Biel-Bienne, Switzerland.",
"authors": "Schurmann|Gregory|G|;Zweifel|Martin|M|;Giger|Roland|R|;Rau|Tilman T|TT|;Vinzens|Sarah|S|;Dettmer|Matthias S|MS|;Kurian|Yojena|Y|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.12438",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "35(3)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Oropharyngeal carcinoma; granulocyte colony-stimulating factor; immunotherapy; leukocytosis; neutrophilic granulocyte; paraneoplastic syndrome",
"medline_ta": "In Vivo",
"mesh_terms": "D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006258:Head and Neck Neoplasms; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "1785-1790",
"pmc": null,
"pmid": "33910863",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7689076;2642718;22110722;28011495;29399178;25624500;7531680;3082974;20179985;2447983;3257150;2462944;19551882;9036872;32432145;24875653;19097774;17097253;22638568;22713692;2439155;16962944;2453227;27316348;9213115;1689190;18801086;2467700",
"title": "Granulocyte Colony-stimulating Factor Producing Oropharyngeal Squamous Cell Carcinoma.",
"title_normalized": "granulocyte colony stimulating factor producing oropharyngeal squamous cell carcinoma"
} | [
{
"companynumb": "CH-ACCORD-225142",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "It is well known that aripiprazole co-treatment effectively reduces antipsychotic-induced hyperprolactinemia. However, the effectiveness of aripiprazole to treat high prolactin levels induced by antidepressant drugs with serotoninergic activity, such as duloxetine, remains unknown.\n\n\n\nAn 18-year-old female diagnosed with major depressive disorder (MDD) was treated with 100 mg sertraline once daily. After two weeks, galactorrhoea was observed. Blood biochemical tests revealed an elevated serum prolactin level of 241 ng/mL. Physiological causes and additional potential pathological causes were ruled out. Therefore, sertraline was cross tapered with mirtazapine. Galactorrhoea ceased, but the side-effect of sedation prompted a switch to 40 mg duloxetine twice daily. After two weeks, the patient developed menstrual irregularities and milky discharge concomitant with a serum prolactin level of 205 ng/mL. As a result, duloxetine was decreased to 60 mg once daily, and aripiprazole was initiated at 2.5 mg daily and titrated to 5 mg daily. Two weeks after the initiation of dual therapy, galactorrhoea stopped, and prolactin levels decreased to 118 ng/mL. After eight weeks, prolactin levels decreased to 39 ng/mL, and menstruation returned to normal. After antidepressant therapy finished, prolactin levels normalized to 19 ng/mL.\n\n\n\nThe case suggests that adjunctive aripiprazole may be useful as a treatment option for duloxetine-induced hyperprolactinemia in MDD.",
"affiliations": "Jiangxi Mental Hospital of Nangchang University, 43 Shangfang Road, Nanchang, Jiangxi 330029, PR China.;Jiangxi Mental Hospital of Nangchang University, 43 Shangfang Road, Nanchang, Jiangxi 330029, PR China.;Jiangxi Mental Hospital of Nangchang University, 43 Shangfang Road, Nanchang, Jiangxi 330029, PR China. Electronic address: yuanjimyang@yeah.net.;Jiangxi Mental Hospital of Nangchang University, 43 Shangfang Road, Nanchang, Jiangxi 330029, PR China. Electronic address: jxmh_wb@163.com.",
"authors": "Luo|Tao|T|;Liu|Qiao-Sheng|QS|;Yang|Yuan-Jian|YJ|;Wei|Bo|B|",
"chemical_list": "D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D011388:Prolactin; D000068736:Duloxetine Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jad.2019.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-0327",
"issue": "250()",
"journal": "Journal of affective disorders",
"keywords": "Antidepressants drugs induced hyperprolactinemia; Aripiprazole; Duloxetine; Galactorrhea; Major depressive disorder",
"medline_ta": "J Affect Disord",
"mesh_terms": "D000293:Adolescent; D000568:Amenorrhea; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003865:Depressive Disorder, Major; D004359:Drug Therapy, Combination; D000068736:Duloxetine Hydrochloride; D005260:Female; D005687:Galactorrhea; D006801:Humans; D006966:Hyperprolactinemia; D008599:Menstruation Disturbances; D011388:Prolactin; D017448:Receptors, Dopamine D2",
"nlm_unique_id": "7906073",
"other_id": null,
"pages": "330-332",
"pmc": null,
"pmid": "30875676",
"pubdate": "2019-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aripiprazole for the treatment of duloxetine-induced hyperprolactinemia: A case report.",
"title_normalized": "aripiprazole for the treatment of duloxetine induced hyperprolactinemia a case report"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2019-04303",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DULOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "Nefopam is a non-opiate analgesic commonly used for the treatment of moderate to severe pain. A case of a 37-year-old male who was found dead in the morning is presented. An autopsy was performed and femoral venous blood, heart blood, urine, and vitreous humor were submitted for toxicological analysis. A general drug screen detected the presence of nefopam, caffeine, nicotine, citalopram, gabapentin, amitriptyline, diazepam and paracetamol in cardiac blood. Nefopam was quantitated by high-performance liquid chromatography with diode-array detection. Nefopam was found at the following concentrations: 13.6 mg/L in unpreserved femoral blood; 14.7 mg/L in preserved (fluoride-oxalate) femoral blood; 21.2 mg/L in unpreserved cardiac blood and 4.5 mg/L in preserved vitreous. Citalopram was present at a concentration of 0.7 mg/L (femoral blood) and 0.9 mg/L (cardiac blood). Ethanol analyzed by headspace gas chromatography (GC-FID) was detected in preserved (fluoride-oxalate) vitreous (14 mg/100 mL) and preserved (fluoride-oxalate) urine 50 mg/100 mL. Death was attributed to atherosclerotic coronary artery disease and therapeutic drug toxicity.",
"affiliations": "Centre for Forensic and Legal Medicine, University of Dundee, Dundee DD1 4HN, UK Present address: School of Science and Technology, Nottingham Trent University, Nottingham, UK nitin.seetohul@ntu.ac.uk.;Centre for Forensic and Legal Medicine, University of Dundee, Dundee DD1 4HN, UK.;Centre for Forensic and Legal Medicine, University of Dundee, Dundee DD1 4HN, UK.;Centre for Forensic and Legal Medicine, University of Dundee, Dundee DD1 4HN, UK Present address: Department of Chemical and Forensic Sciences, University of Huddersfield, Huddersfield, UK.",
"authors": "Seetohul|L Nitin|LN|;De Paoli|Giorgia|G|;Drummond|Gail|G|;Maskell|Peter D|PD|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D009340:Nefopam",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkv036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "39(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D018712:Analgesics, Non-Narcotic; D001344:Autopsy; D002340:Carotid Artery Diseases; D002423:Cause of Death; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D062787:Drug Overdose; D006801:Humans; D008297:Male; D009340:Nefopam; D013405:Suicide",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "486-9",
"pmc": null,
"pmid": "25855761",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nefopam Hydrochloride: A Fatal Overdose.",
"title_normalized": "nefopam hydrochloride a fatal overdose"
} | [
{
"companynumb": "GB-ALKEM-000963",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NAPROXEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed.\n\n\n\nTwo therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups.\n\n\n\nThe rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).\n\n\n\nPreoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.\n\n\n\n1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.",
"affiliations": "Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Gustave Roussy Cancer Center, Department of Biostatistics, Paris-Saclay University, Villejuif, France.;Hospital Center of Luxembourg, Department of Oncology and Hematology, Luxembourg City, Luxembourg.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Necker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France.;Sainte Anne Hospital, Department of Neuropathology, Rene Descartes University, Paris, France.;Necker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France.;Necker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France.;Gustave Roussy Cancer Center, Department of Radiation Oncology, Paris-Saclay University, Villejuif, France.;Gustave Roussy Cancer Center, Department of Radiation Oncology, Paris-Saclay University, Villejuif, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Gui-de-Chauliac Hospital, Department of Neurosurgery, Montpellier University Hospital, Montpellier, France.;Necker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France.;Sainte Anne Hospital, Department of Neuropathology, Rene Descartes University, Paris, France.;Sainte Anne Hospital, Department of Neuropathology, Rene Descartes University, Paris, France.;Necker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.",
"authors": "Guerrini-Rousseau|Léa|L|;Abbas|Rachid|R|;Huybrechts|Sophie|S|;Kieffer-Renaux|Virginie|V|;Puget|Stéphanie|S|;Andreiuolo|Felipe|F|;Beccaria|Kévin|K|;Blauwblomme|Thomas|T|;Bolle|Stéphanie|S|;Dhermain|Frédéric|F|;Longaud Valès|Audrey|A|;Roujeau|Thomas|T|;Sainte-Rose|Christian|C|;Tauziede-Espariat|Arnault|A|;Varlet|Pascale|P|;Zerah|Michel|M|;Valteau-Couanet|Dominique|D|;Dufour|Christelle|C|;Grill|Jacques|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/noaa083",
"fulltext": "\n==== Front\nNeuro Oncol\nNeuro Oncol\nneuonc\nNeuro-Oncology\n1522-8517 1523-5866 Oxford University Press US \n\n32267940\n10.1093/neuonc/noaa083\nnoaa083\nPediatric Neuro-Oncology\nAcademicSubjects/MED00300\nAcademicSubjects/MED00310\nRole of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children\nGuerrini-Rousseau Léa 12 Abbas Rachid 3 Huybrechts Sophie 4 Kieffer-Renaux Virginie 15 Puget Stéphanie 6 Andreiuolo Felipe 7 Beccaria Kévin 6 Blauwblomme Thomas 6 Bolle Stéphanie 8 Dhermain Frédéric 8 Longaud Valès Audrey 1 Roujeau Thomas 9 Sainte-Rose Christian 6 Tauziede-Espariat Arnault 7 Varlet Pascale 7 Zerah Michel 6 Valteau-Couanet Dominique 1 Dufour Christelle 12 Grill Jacques 12 1 \nGustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France\n2 \nGustave Roussy Cancer Center, Combined Research Unit 8203, National Center of Scientific Research, Paris-Saclay University, Villejuif, France \n3 \nGustave Roussy Cancer Center, Department of Biostatistics, Paris-Saclay University, Villejuif, France\n4 \nHospital Center of Luxembourg, Department of Oncology and Hematology, Luxembourg City, Luxembourg\n5 \nSaint Maurice Hospital, Monitoring and Integration Center for Children and Adolescents with Acquired Brain Injury, Saint Maurice, France\n6 \nNecker Hospital, Department of Pediatric Neurosurgery, Paris Descartes University, Paris, France\n7 \nSainte Anne Hospital, Department of Neuropathology, Rene Descartes University, Paris, France \n8 \nGustave Roussy Cancer Center, Department of Radiation Oncology, Paris-Saclay University, Villejuif, France\n9 \nGui-de-Chauliac Hospital, Department of Neurosurgery, Montpellier University Hospital, Montpellier, France \nCorresponding Authors: Drs Léa Guerrini-Rousseau, Christelle Dufour and Jacques Grill, Department of Pediatric and Adolescent Oncology,Gustave Roussy, 114 rue Edouard Vaillant 94805 Villejuif Cedex, France, (lea.guerrini-rousseau@gustaveroussy.fr).Co-last authors.\n\n\n11 2020 \n08 4 2020 \n08 4 2020 \n22 11 1686 1695\n29 5 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.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\nPrevious pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed.\n\nMethods\nTwo therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups.\n\nResults\nThe rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).\n\nConclusion\n Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.\n\nKey Points\n1. Preoperative chemotherapy increases the rate of complete tumor removal.\n\n2. No additional risk (toxic or disease progression) is linked to the delayed surgery.\n\n3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.\n\nchildhood brain tumormedulloblastomaneuropsychological outcome preoperative chemotherapysurgery\n==== Body\nImportance of the Study\nIn various cancers, neoadjuvant chemotherapy is often used to treat metastatic disease and facilitate surgery of the primary tumor, but it is rarely proposed for brain tumors. Preoperative chemotherapy is feasible in metastatic medulloblastomas but its benefits and risks have not been assessed. This study compared retrospectively the 2 therapeutic strategies (surgery at diagnosis and surgery after neoadjuvant chemotherapy) in 92 patients with metastatic medulloblastoma. The results confirmed the efficacy of neoadjuvant chemotherapy radiologically and histologically, and showed that it increases the complete tumor excision rate with no additional risk for patients. Histological diagnosis of medulloblastoma was still feasible after neoadjuvant chemotherapy. Our study also suggests that this strategy could have a positive impact on patients’ neuropsychological outcome. Moreover, the response rate to neoadjuvant chemotherapy may help to better tailor post-surgery therapy in patients with very high risk and not chemosensitive medulloblastoma.\n\nMedulloblastoma is one of the most common malignant brain tumors in childhood. Young age at diagnosis, metastatic disease, incomplete surgical excision (residual disease >1.5 cm2),1,2 large-cell anaplastic histology,3,4 and several biological markers (especially MYC amplification)5,6 have been associated with poor outcome. Advances in molecular profiling have allowed classifying medulloblastoma into 4 subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4.7–9 The 2016 update of the World Health Organization (WHO) classification subsequently defined 5 entities: medulloblastoma WNT activated, medulloblastoma SHH activated with or without TP53 mutation, and Group 3 and 4 medulloblastomas.10 The role of residual tumor (>1.5 cm2), confirmed as a high risk factor in the recently published HIT-SIOP-PNET4 phase III trial,11 justifies the development of therapeutic strategies that could improve complete excision rate at minimal cost in terms of neuropsychological outcome.\n\nModern management strategies with multimodal and more intensive treatments, including high-dose chemotherapy (HDC), have improved the 5-year overall survival (OS) to about 70–80% even for high-risk patients.9,12,13 As more children with medulloblastoma are now being cured, the quality of survival becomes a major concern. The cerebellum has a critical role in motor skills and coordination, as well as in cognitive and executive functions.14,15 Children treated for a malignant tumor in the posterior fossa within and/or adjacent to the cerebellum are therefore at risk of intellectual impairment due to the tumor and its treatment, especially medulloblastoma survivors.16–21 Age at radiotherapy, radiation doses, and boost volume have a tremendous effect on cognition that worsens with time.22–27 Moreover, tumor location and brainstem infiltration, hydrocephalus, splitting of the vermis, damage of the dentate nuclei during surgery, and posterior fossa syndrome are associated with poorer neurocognitive outcome.28–32 We hypothesized that preoperative chemotherapy could decrease the surgical morbidity and improve its efficacy. We have shown the feasibility of this approach previously,33 and its role has been suggested by others in infants.34,35 Here, we compared tumor control and morbidity after preoperative chemotherapy or standard upfront surgery in a population-based single center study.\n\nPatients and Methods\nPatients\nThis study retrospectively analyzed data from 92 children with metastatic medulloblastoma followed at our center between 2002 and 2015. Most patients (n = 65) were operated at the Neurosurgical Department of the Necker Sick Children’s Hospital, Paris, France. Inclusion criteria were:\n\n• Newly diagnosed metastatic medulloblastoma treated by chemotherapy and/or radiotherapy between 2002 and 2015\n\n• Patients younger than 18 years at diagnosis\n\n• Histologically proven diagnosis of medulloblastoma after surgical excision or biopsy (if clinical condition allowed surgery)\n\n• Metastatic stage evaluated by the positivity of MRI and/or lumbar cerebrospinal fluid (CSF) sampling at diagnosis and subsequent evaluations\n\n• No contraindication to chemotherapy\n\n• Treatment of hydrocephalus when present\n\nData were retrospectively extracted from the medical files.\n\nMedulloblastoma Management\nThis study compared 2 strategies according to the intention-to-treat principle: (i) standard upfront surgery at diagnosis (group A) and (ii) delayed surgery after an initial biopsy (for histology-proven confirmation of medulloblastoma) and neoadjuvant chemotherapy (group B). Patients were not randomized but were assigned pragmatically to one of the 2 groups on the basis of the neurosurgeon’s choice. Both groups were treated during the same period of time with similar treatment regimens, according to the ongoing protocols at the time of diagnosis. Inclusions in both cohorts were distributed similarly during the recruiting period. In group B, all children received neoadjuvant chemotherapy before surgery: a combination of carboplatin (160 mg/m2/d, days 1–5) and etoposide (100 mg/m2/d, days 1–5) at conventional doses without hyperhydration.36 Post-surgery treatments were chosen according to the patients’ age and risk factors. The irradiation modalities changed slightly over time for both groups (technical improvement, dose modification according to the age and type of associated chemotherapy, reduction of the boost volume). Children older than 5 years received conventional-dose chemotherapy followed by radiotherapy (protocol SFOPTC9437) or tandem HDC (2 courses of thiotepa13 or 2 courses of melphalan38) with autologous stem cell transplantation (ASCT), followed by standard-dose (36 Gy) craniospinal irradiation (CSI). In children younger than 5 years, post-surgery management was adjusted to avoid radiotherapy or to decrease the irradiation dose. They received sequential HDC with ASCT followed by local radiation therapy to the posterior fossa (50–55 Gy) or reduced-dose CSI (18 or 24 Gy) according to the PNET HR protocol for children younger than 5 years (NCT00180791), or one course of tandem HDC with busulfan and thiotepa,39,40 or sequential HDC without radiotherapy (HRMB-5 protocol, NCT02025881). Informed consent of the parents or guardians was obtained for each patient, according to the institutional review board guidelines and the specific guidelines of each trial.\n\nRadiological Investigations\nAll children underwent neuraxis MRI at diagnosis for evaluation of tumor size and staging. The tumor size was defined as the sum of the products of the largest perpendicular diameters evaluated on brain MRIs. The responses to neoadjuvant chemotherapy were assessed by MRI at the end of treatment. Criteria used for response evaluation were those recommended by the Response Assessment in Pediatric Neuro-Oncology committee41: complete response (CR) was defined as the disappearance of the whole lesion; partial response (PR) as a decrease of at least 50% of the sum of the products of the largest perpendicular diameters; and progressive disease (PD) as a ≥25% increase in tumor size. Stable disease was defined as MRI features that do not meet the criteria for PR or PD. Early postoperative cerebral MRI, within 72 hours after surgery, was performed to assess the tumor resection extent.\n\nSurgical Procedure and Complications\nHistological confirmation of medulloblastoma before chemotherapy was requested if possible. It was obtained through either a biopsy of the primary tumor or a metastasis, or tumor excision. Surgery was considered complete (R0), when there was no evidence of residual tumor during the surgery and on the postoperative MRI. The excision was considered partial (R1) in the presence of a macroscopic residue and/or residual tumor >1.5 cm2 on postoperative MRI. The neurological immediate postoperative complications (cerebellar syndrome kinetic and/or static, cerebellar mutism, nystagmus, dysmetria, tremor and/or ataxia, cranial nerve palsies) were evaluated in each child. The severity of neurological postoperative complications was rated from 0 = absent to 3 = severe (grade ≥3 on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) scale). The postoperative course was considered complicated if prolonged postoperative obtundation or life-threatening complications led to new surgery or prolonged stay in the neurosurgical intensive care unit. Severe postoperative complications were recorded—such as neurological postoperative status grade ≥3 of the NCI-CTC, infection (meningitis or ventriculitis), hydrocephalus, air embolism, or hemorrhage after tumor resection.\n\nHistological Tumor Analysis\nFormalin-fixed paraffin-embedded specimens from all patients with available tumor tissue samples at diagnosis and/or after neoadjuvant chemotherapy were reviewed by 3 experienced neuropathologists. Standard histological analysis, including immunostaining with anti–beta-catenin, -YAP1, -GAB1, -Ki67, and -p53 antibodies, was used to identify the medulloblastoma type, according to the criteria defined by the 2007 and 2016 WHO classifications.10,42 N-myc and Myc amplification were analyzed by fluorescent in situ hybridization. Subgrouping with methylation profiling or NanoString was not available for most patients who underwent surgery before 2010. Matched tumor pairs (at diagnosis before chemotherapy and after surgery) were analyzed when available in group B.\n\nNeuropsychological Evaluation\nNeuropsychological evaluations were done according to a French national protocol and described previously.24 Specifically, aged-adapted Wechsler scales were used to assess the intellectual quotient (IQ), except in children younger than 3 years who were evaluated with the Brunet-Lezine scale. The scores of the subtests of the used scales were used to determine the Full-Scale Intellectual Quotient (FSIQ) and the Perceptual Reasoning/Organization Index (PRI), which evaluates the ability to interpret and organize visually presented nonverbal information. Complete neuropsychological testing was scheduled at diagnosis and usually 1, 3, 5 years or more after.\n\nStatistical Analysis\nContinuous variables were expressed as medians and interquartile ranges, and categorical variables as numbers and percentages. Baseline was defined as the date of diagnosis. Patients’ characteristics were compared between groups using the chi-square or Fisher’s exact test (as appropriate) for categorical variables, and the Mann–Whitney U-tests for continuous variables. Progression-free survival (PFS), event-free survival (EFS), and OS were calculated using the Kaplan–Meier method. PFS and EFS were defined as the time from the diagnosis date until the date of disease progression or first relapse/event, or last contact (death due to treatment-related toxicity was excluded). OS was defined as the time from the diagnosis date until death from any cause, or last contact. Survival rates are provided with the 95% confidence interval (CI) estimated using the Rothman method.\n\nLongitudinal neuropsychological measures were analyzed using linear mixed models with random intercepts and slopes. Separate models were built for each neuropsychological outcome. Each explicative covariate was introduced in the model with an interaction term with time as continuous measure (using the diagnosis date as origin). A first-order autoregressive covariance matrix was used because it showed the lowest Akaike information criteria in linear mixed models including the treatment group. This choice was confirmed in the final models. The neuropsychological score changes in groups A and B were adjusted to age (older or younger than 5 y), radiotherapy total dose to the brain (0, 18, 24, or 36 Gy), hydrocephalus (yes or no), and medulloblastoma histological subtype (nodular/desmoplastic compared with the other subtypes). Interactions between explanatory variables were explored. Explanatory variables for fixed effects were selected in a stepwise procedure to retain the best model. Each model fit was checked using Cholesky’s scaled residuals plots. All tests were two-sided and P < 0.05 was considered statistically significant. Statistical analyses were done using SAS version 9.4.\n\nResults\nPatient Characteristics\nThe 92 patients (32 girls and 60 boys) who met the inclusion criteria were distributed into group A (n = 54; 59%) and group B (n = 38; 41%). The median age at diagnosis was 5.0 years (range, 0.1–18.0). Sex, age at diagnosis, and medulloblastoma histological subtypes and initial tumor size at the primary site were comparable between groups A and B (Table 1). Global treatment strategies and the patients’ outcome also were similar between groups (Table 1). Conversely, hydrocephalus and place of surgery (Necker Sick Children’s Hospital in Paris vs other centers) were significantly more frequent in group B (P = 0.0025 and P = 0.0005, respectively).\n\nTable 1. Patients’ clinical characteristics, treatments, and outcome\n\n\tGroup A\tGroup B\t\nP-value\t\n\t\nn = 54 (%)\t\nn = 38 (%)\t\t\n\nBoys/girls\n\t36 /18 (66.7 / 33.3)\t24/14 (63.2 / 36.8)\t0.7279\t\n\nMedian age, y (range)\t4.7 (0.8–18.0)\t5.4 (0.1–13.9)\t\t\n\nAge class at diagnosis\n\t\t\t0.3970\t\n ≤5 y\t29 (53.7)\t17 (44.7)\t\t\n >5 y\t25 (46.3)\t21 (55.3)\t\t\n\nHistological diagnosis of medulloblastoma\n\t\t\t0.0542\t\n Classic\t35 (64.8)\t33 (86.8)\t\t\n Nodular/desmoplastic\t10 (18.5)\t2 (5.3)\t\t\n Anaplastic/large cell \t7 (13.0)\t1 (2.6)\t\t\n Other or NOS\t2 (3.7)\t2 (5.3) \t\t\n\nHydrocephalus (yes/no)\t31/23 (57.4 / 42.6)\t33/5 (86.8 / 13.2)\t0.0025\t\n\nPlace of the surgery (Necker/ other centers)\n\t30/24 (56 / 44)\t34 / 4 (89 / 11)\t0.0005\t\n\nMedian initial tumor size at the primary site, cm2 (range)\t12.66 (3.20–22.14)\t12.56 (2.42–31.30)\t0.8726\t\n\nTreatment regimen combined with surgery*\t\t\t0.2990\t\n CC + RT \t2 (3.7)\t1 (2.6)\t\t\n CC + HDC + standard RT \t22 (40.7)\t23 (60.5)\t\t\n CC + HDC + decreased RT CC + HDC without RT\t28 (51.9) 2 (3.7)\t13 (34.2) 1 (2.6)\t\t\n\nOutcome (dead/alive)\t25/29 (46.3 / 53.7)\t16/22 (42.1 / 57.9)\t0.6905\t\nAbbreviations: NOS not otherwise specified, CC conventional chemotherapy, RT radiotherapy, HDC high-dose chemotherapy.\n\n* Intent to treat.\n\nSurgical Management at Diagnosis\nAt diagnosis, 64 children (69.6%) had clinical signs of hydrocephalus. CSF shunting was performed, when needed, during the first surgery or afterward. Endoscopic third ventriculostomy was the preferred modality for obstructive hydrocephalus treatment. Among the 64 patients with clinical signs of hydrocephalus, no difference in terms of persistent CSF drainage with a ventriculoperitoneal shunt (VPS) was observed between the 2 groups: 18 patients had a VPS (n = 10 in group A and n = 8 in group B). In group A, tumor was removed 2.5 days (range, 0–14) after diagnostic MRI. In group B, a minimal tumor biopsy was carried out at diagnosis for the histological proof of medulloblastoma, except in 3 children because of their initial clinical instability. In these 3 patients, the histological diagnosis of medulloblastoma was obtained after tumor removal following neoadjuvant chemotherapy.\n\nNeoadjuvant Chemotherapy and Radiological Evaluation\nThe median time between tumor biopsy at diagnosis and neoadjuvant chemotherapy start was 8 days in group B, compared with 15 days between tumor excision and beginning of chemotherapy in group A, P < 0.0001. In group B, all children (n = 38) received etoposide and carboplatin before tumor removal: 1 course (n = 1), 2 courses (n = 31), 3 courses (n = 4), 4 courses (n = 1), or 8 courses (n = 1), according to the physician’s choice. This led to a decrease in the primary tumor size in all patients (see Fig. 1A for an example), 4/38 patients experiencing meanwhile a distant progression. No isolated local failure or progression of the primary tumor was observed. In 28/38 children in group B, tumor size on the brain MRI at diagnosis and at the end of neoadjuvant chemotherapy was remeasured centrally. Response was evaluated after 2 courses (n = 23 patients), 3 courses (n = 3 patients), 4 courses (n = 1 patient), or 8 courses (n = 1 patient). This radiological review showed that CR was observed in 2/28 patients (7%), PR in 12/28 patients (43%), and minor response or stable disease in 14/28 patients (50%) (Fig. 1D). One patient, with a PR after 2 courses of chemotherapy, subsequently presented a metastatic progression during HDC and quickly died from it. In group A, a disease progression was observed in 6 children during conventional chemotherapy. Progression on conventional chemotherapy was therefore similar in both groups (6/54 patients, ie, 11% vs 4/38 patients, ie, 10%). As CSF sampling was not systematically performed in patients with overt metastases on MRI, CSF response could not be assessed accurately in all patients with M stage above 1. Only 2 patients in group B had a positive CSF without metastases to the brain or spine at diagnosis (M1 disease). CSF sampling was repeated in these 2 patients to assess the response of metastatic disease. CSF was negative at the end of neoadjuvant chemotherapy.\n\nFig. 1 Response to neoadjuvant chemotherapy. (A) Radiological response to chemotherapy on brain MRI (sagittal sections T1 gadolinium) performed before and after neoadjuvant chemotherapy (scale bar 5 cm). Changes in the size of the primary tumor after neoadjuvant chemotherapy measured radiologically in 28 patients in group B with MRI at diagnosis and at the end of neoadjuvant chemotherapy available for comparison. Response was evaluated after 2 courses (23 patients), * 3 courses (3 patients), ** 4 courses (1 patient) or *** 8 courses (1 patient). (B) Medulloblastoma histopathological analysis before and after neoadjuvant chemotherapy. Sections showing: (B1 and B2) small blue round cell tumors consisting of densely packed undifferentiated embryonal cells (HPS), still existing after the adjuvant treatment (HPS) and (B3 and B4) significant decrease of the proliferation index (evaluated by MIB1 labeling index) between first surgery and the surgery after treatment (magnification 400x, scale bar 50µm). (C) Proliferation index changes after neoadjuvant chemotherapy in 17 patients from group B with available matched tumor pairs. (D) Progression-free survival in group A (surgery at diagnosis) and group B (surgery after neoadjuvant therapy) in function of time (years).\n\nResults of Primary Tumor Surgery and Histological Features\nAll patients in group A underwent surgery with the aim of maximal primary tumor removal (n = 54). In group B, the posterior fossa tumor excision was performed after conventional neoadjuvant chemotherapy ± subsequent HDC in 30/38 patients (79%). The median time between biopsy and tumor removal was 64 days (range, 34–210). Surgery could not be performed in 8 patients: 5 children with progressive disease during conventional neoadjuvant chemotherapy (n = 4) or HDC (n = 1); 1 child died before surgery because of hemorrhage from a metastasis while the local disease was controlled; and 2 children had mostly metastatic disease with a very small primary tumor that completely disappeared after adjuvant chemotherapy. The rate of complete excision of the primary tumor was significantly higher in group B than in group A: 28/30 patients (93.3%) versus 31/54 (57.4%), respectively (P = 0.0013) (Table 2). Four patients in each group developed transient postoperative akinetic mutism after tumor removal. Postoperative neurological status and incidence of postoperative complications were similar in both groups (non-neurological postoperative complications: 14/54 = 25.9% vs 8/30 = 26.7%, P = n.s.; severe postoperative complications: 19/54 = 35.2% vs 7/30 = 23.3%, P = n.s.) (Table 2). In group A, severe postoperative complications were observed in 19 patients: severe neurological complications (grade ≥3 of the NCI-CTC scale) including akinetic mutism (n = 14), sometimes associated with hydrocephalus that required transient external shunt or VPS (n = 4), hemorrhage or subdural air collection that sometimes required a shunt (n = 4), and meningitis (n = 1). In group B, severe postoperative complications were observed in 7 patients: akinetic mutism (n = 4), hydrocephalus that required transient external shunt or VPS (n = 2), and cerebellar ischemic stroke (n = 1).\n\nTable 2. Extension of resection of the primary medulloblastoma at diagnosis (group A) or after neoadjuvant chemotherapy (group B) and postoperative complications\n\n\tGroup A N = 54 (%)\tGroup B N = 30 (%)\t\nP-value\t\n\nTumor resection\n\t\t\t0.0013\t\nComplete tumor resection (R0) Partial tumor resection (R1) \t31 (57.4) 23 (42.6)\t28 (93.3) 2 (6.7)\t\t\n\nNonneurological postoperative complications (hydrocephalus, infection, hemorrhage or subdural air collection) No Yes \t40 (74.1) 14 (25.9)\t22 (73.3) 8 (26.7)\t0.9410\t\n\nNeurological postoperative status None = 0 Mild (NCI-CTC grade 1) = 1 Moderate (NCI-CTC grade 2) = 2 Severe (NCI-CTC grade 3, 4, or 5), including akinetic mutism = 3\t15 (27.8) 17 (31.5) 8 (14.8) 14 (25.9)\t10 (33.3) 10 (33.3) 6 (20) 4 (13.3)\t0.5810\t\n\nSevere postoperative complications: severe neurological status (3), or other severe postoperative complications Not severe Severe \t35 (64.8) 19 (35.2)\t23 (76.7) 7 (23.3)\t0.2602\t\nIn group B, of the 30 patients who had secondary surgery, 3 did not have an initial biopsy at the time of diagnosis. Of the 27 remaining patients who underwent 2 surgeries (biopsy at diagnosis and surgery after chemotherapy), only 19 matched tumor pair samples were available for comparison. Histological examination showed that live medulloblastoma cells could still be found after the second surgery despite the preoperative chemotherapy. In 16 of these patients, the medulloblastoma histological and immunophenotypic profiles (classic, non-WNT, and non-SHH in all samples) did not change (Fig. 1B1 and 1 B2). In the other 3 patients, tumors were considered as not otherwise specified at the time of the biopsy, and were characterized as classic, non-WNT/non-SHH medulloblastoma after tumor removal. Comparison of the proliferation index between paired samples was possible in 17 cases and it was significantly decreased by more than 50% in 8/17 patients after neoadjuvant treatment (Fig. 1B3 and 1 B4 and Fig. 1C).\n\nOutcome\nThe median follow-up was 10 years in group A and 8 years in group B. The 5-year OS rates were 60% (95% CI: 47–72) in group A and 68% (95% CI: 52–81) in group B (log rank P = n.s., available in Supplementary Material). In all patients but 2, death was due to progressive disease or relapse. Only one child in each group died from treatment-related toxicity without progressive disease (veno-occlusive disease in one patient and metastatic hemorrhage in the other). The 5-year PFS rates were 57% (95% CI: 43–69) in group A and 53% (95% CI: 37–68) in group B (log rank P = n.s.) (Fig. 1E), and the EFS rate was 51% in both groups (log rank P = n.s., available in Supplementary Material). Disease progression or recurrence is summarized in Table 3. Local control (Table 3) was similar in both groups (22% in group A and 13% in group B, P = n.s.). Seven second malignancies occurred: high-grade glioma in 4 patients (4.9, 5.9, 6.5, and 8 y after the medulloblastoma diagnosis) and thyroid carcinoma in 3 patients (6.1, 9.3, and 12.9 y after the first diagnosis).\n\nTable 3. Disease progression or recurrence in groups A and B\n\nDisease Progression and Recurrence\tGroup A n = 54\tGroup B n = 38\t\n Local and metastatic disease progression\t4\t2\t\n Metastatic disease progression\t6\t3\t\n Local recurrence\t6\t1\t\n Local and metastatic recurrence\t2\t2\t\n Metastatic recurrence\t6\t10\t\n Median time to disease progression or recurrence, y (range)\t0.56 (0.2–7.3)\t1.1 (0.15–6.1)\t\n Median follow-up, 50% (95% CI), y\t10 (8–13)\t8 (5.5–11)\t\nNeurocognitive Behavior\nNeuropsychological evaluations were available for 69 patients (75% of the whole cohort; n = 39 in group A and n = 30 in group B) (median number of evaluations per patient = 2; range, 1–6): 183 FSIQ and 166 PRI scores. In linear mixed models with continuous time measurement, the FSIQ and PRI scores significantly decreased with time (P < 0.0001 and 0.0044) and were significantly correlated with the age class at diagnosis (P = 0.0182 and 0.0392) and the radiotherapy total doses delivered to the brain (P = 0.0417 and <.0001) in both groups. Hydrocephalus and medulloblastoma histological subtype (nodular/desmoplastic compared with the other subtypes) were not associated with the FSIQ and PRI scores. The predicted mean FSIQ and PRI estimates from the mixed model at 1, 3, 5, and 7 years after diagnosis (Table 4) highlighted that they tended to be higher in group B than in group A, although not significantly (P = 0.1764 and 0.1789, respectively). In linear mixed models, the FSIQ score progressively worsened over time, with no significant difference between groups (Fig. 2).\n\nTable 4. Predicted mean FSIQ and PRI estimates (mixed model) for groups A and B at 1, 3, 5, and 7 years after diagnosis\n\nTime, y\t\tT0\tT1\tT3\tT5\tT7\t\nPredicted mean FSIQ\tGroup A\t85.5 (79–92)\t83 (77–90)\t79 (73–86)\t75 (68–82)\t71 (63–79)\t\n\tGroup B\t91 (84–99)\t89 (82–96)\t85 (78–92)\t81 (73–88)\t77 (68–85)\t\nPredicted mean PRI\tGroup A\t84 (77–91)\t82 (76–89)\t79 (73–85)\t76 (69–83)\t73 (64–81)\t\n\tGroup B\t90 (82–98)\t88.5 (81–96)\t85 (79–92)\t82 (75–89)\t79 (70–87)\t\nFig. 2 Changes of the predicted FSIQ in patients in function of the age class at diagnosis (≤5 and >5 y).\n\nDiscussion\nThis study showed a significantly higher complete tumor excision rate in patients operated after preoperative chemotherapy in group B versus in group A (57.4%, similar rate to what is usually reported40,43). Carboplatin-etoposide regimen was very effective in the neoadjuvant setting, as shown in recurrent medulloblastoma,33,36 and led to a decrease of the primitive tumor size and an earlier efficient treatment of metastases before tumor removal. In group B, the complete tumor resection rate (93.3%) was similar to that described in our previous pilot study33 and for various brain tumors in infants and young children (85% and 89%, respectively), thanks to the effectiveness of preoperative chemotherapy on the size of the primary tumor, especially in embryonal tumors.34,35 Neoadjuvant chemotherapy enabled the surgery to be performed in the absence of raised intracranial pressure, on a smaller tumor and in a patient in better clinical condition. The higher rate of complete tumor excision may represent a prognostic advantage, as past studies have shown that residual tumor had an adverse prognostic impact.11 Maximum safe surgical resection should remain the standard of care in medulloblastoma. These goals were achieved with the strategy of tumor excision performed after neoadjuvant chemotherapy. Despite the significantly higher complete excision rate for patients in group B, we did not observe a higher rate of acute postoperative complications, especially neurological impairment. Late severe neurological complications were rare. Their low number of cases would not allow expectation of a statistically significant difference between both groups. Neuropsychological evaluation is more subtle. Analysis of the extensive longitudinal neuropsychological data showed that in both groups, IQ decline was correlated with young age at diagnosis, radiation doses to the brain, and time, as previously reported.25,44 Hydrocephalus did not have any effect, although its frequency was not balanced between groups. As hydrocephalus was more frequent in group B, this may have limited the neuropsychological benefit of delayed surgical therapy in this group because hydrocephalus is known to worsen the neuropsychological outcome.29 Although no significant difference was found between groups, children in group B tended to have a better neuropsychological outcome, based on the FSIQ and PRI scores after surgery and after treatment completion. This trend might be explained by the reduced surgery impact on normal brain due to the smaller tumor size and, possibly, hydrocephalus treatment before primary tumor surgery. A recent study showed that the medulloblastoma molecular subgroups influence the intellectual outcome, especially the SHH subgroup.9,45 Unfortunately, appropriate subgrouping was not available for part of our patients. Nevertheless, as desmoplastic/nodular medulloblastomas are almost exclusively SHH-activated tumors, analysis of this variable showed no significant correlation between the desmoplastic/nodular histological profile and neuropsychological impairment.\n\nNo negative impact of neoadjuvant chemotherapy was reported: no toxic complication due to chemotherapy or additional disease progression, especially local progression, linked to the delayed surgery of the primary tumor. Disease progression rate during etoposide-carboplatin courses was similar and no isolated local failure was observed in group B before surgery. No detrimental effect of delayed surgery after neoadjuvant chemotherapy was observed on survival, as indicated by the similar 5-year PFS and OS rates in the 2 groups. These results are comparable with those already published for patients with high-risk medulloblastoma,9,12,13 but better than reported in our pilot study.33 The safety of this approach in terms of tumor control suggests that a very aggressive surgery approach at diagnosis might not be needed and that second look surgery could be scheduled after chemotherapy.\n\nThe histological study of 19 matched tumor pairs led to the conclusion that diagnosis is still possible on residual medulloblastoma tumors despite the preoperative chemotherapy with no change in the histological subtype. This finding is of paramount importance because it allowed the safe and consistent histological proof to be obtained in every patient. Molecular grouping should be conserved, although not shown in this study, since it is conserved at relapse as demonstrated previously.46 This should not question the need for a biopsy at diagnosis, since alternative diagnoses may need different treatment approaches. Neoadjuvant chemotherapy significantly decreased the proliferation index in almost half of them. The sample size was too small to measure the influence of the histological response on survival.\n\nOne of the interesting perspectives raised by our study showing the safety of preoperative chemotherapy is the possibility to use this therapeutic window to test new drugs upfront. Response rate here with the standard combination of etoposide and carboplatin36 is high and setup a landmark. Previous studies have also shown that the response to preoperative chemotherapy could predict outcome in metastatic medulloblastomas47 and could therefore help to identify high-risk patients who do not respond to conventional chemotherapy.\n\nOur study has some limitations. Patients were not randomized between surgery upfront and neoadjuvant chemotherapy before surgery, and the choice was mostly based on the interpretation of tumor operability by the neurosurgeon. Therefore, higher-risk patients (presence of hydrocephalus, worse clinical or neurological status) were mostly in group B. Nevertheless, our results show that the complete tumor excision rate was higher and neuropsychological behavior tended to be better in this group. This suggests that this strategy, initially proposed to patients with metastatic disease to improve disease control and start chemotherapy earlier, could be discussed also for patients with localized medulloblastoma where surgical difficulties are anticipated due to the higher rate of complete tumor resection.\n\nConclusion\nPreoperative chemotherapy in patients with metastatic medulloblastoma is advantageous. It allows an early efficient treatment of the whole disease, increases the rate of complete tumor removal, and could have a positive impact on the neuropsychological outcome of patients. Our study did not show any additional risk concerning postoperative complications, disease control, and patient outcome in the group with chemotherapy before the surgery. Histological diagnosis was still feasible and reliable after preoperative chemotherapy. These findings are important because this strategy may be integrated and tested in future protocols for the treatment of children with metastatic medulloblastoma.\n\nSupplementary Material\nnoaa083_suppl_Supplementary_Figure Click here for additional data file.\n\n Funding\nNone.\n\n \nConflict of interest statement. No conflicts.\n\n \nAuthorship statement. Léa Guerrini-Rousseau, Sophie Huybrechts, Virginie Kieffer-Renaux, Stéphanie Bolle, Frédéric Dhermain, Audrey Longaud, Dominique Valteau-Couanet, Christelle Dufour, and Jacques Grill provided clinical data. Christian Sainte-Rose, Stéphanie Puget, Michel Zerah, Thomas Roujeau, Thomas Blauwblomme, and Kévin Beccaria performed surgery and provided surgical data. Pascale Varlet, Felipe Andreiuolo, and Arnault Tauziede-Espariat provided histological data and performed the histological review. Rachid Abbas provided the statistical analysis. Chantal Kalifa, Christelle Dufour, Jacques Grill, and Léa Guerrini-Rousseau contributed to the study design. All authors contributed to writing, reviewing and editing.\n==== Refs\nReferences\n1. \nAlbright AL , Wisoff JH , Zeltzer PM , Boyett JM , Rorke LB , Stanley P \nEffects of medulloblastoma resections on outcome in children: a report from the Children’s Cancer Group\n. Neurosurgery. 1996 ;38 (2 ):265 –271\n.8869053 \n2. \nZeltzer PM , Boyett JM , Finlay JL , et al. \n 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. 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"issue": "22(11)",
"journal": "Neuro-oncology",
"keywords": "childhood brain tumor; medulloblastoma; neuropsychological outcome ; preoperative chemotherapy; surgery",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Role of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children.",
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"abstract": "BACKGROUND\nPostpartum ovarian thrombosis is an uncommon condition. It appears with the nonspecific, predominantly right-sided abdominal symptoms and must be differentiated from other acute visceral conditions. If left untreated, postpartum ovarian thrombosis can have severe consequences, including sepsis, pulmonary embolism, and even death. Momentarily, there are no specific guidelines for postpartum ovarian thrombosis management. We present a case of postpartum ovarian thrombosis admitted to our hospital with symptoms of acute appendicitis. CASE PRESENTATION : A 39-year-old Omani obese multiparous woman of Afro-Arab origin was admitted with acute symptoms, mainly abdominal pain, fever, and vomiting 1 week postpartum. Clinical picture and biochemical profile did not exhibit a recognizable pattern. Ultrasonography excluded retained products of conception. Computerized scan for abdomen and pelvis with oral and intravenous contrast reported a dilated tubular structure in the right adnexa extending up to the right renal hilum level with surrounding inflammation. Those findings were consistent with the thrombophlebitis of the right ovarian vein. Blood cultures and sensitivity showed group A β-hemolytic streptococci sensitive to penicillin G and clindamycin. The patient was treated successfully with antibiotics and therapeutic anticoagulants and discharged home 3 days later; follow-up was arranged.\n\n\nCONCLUSIONS\nThis pathology is an exceptional entity in Oman. Therefore, awareness of this unique condition is required so that clinicians will be vigilant, exploring similar cases with imaging and avoiding unnecessary surgical interventions.",
"affiliations": "York Teaching Hospital, NHS Foundation Trust, Scarborough, UK. ctsitlakidis@yahoo.co.uk.;Surgical Department, Sultan Qaboos University Hospital, Muscat, Oman.;Royal Hospital, Muscat, Oman.;York Teaching Hospital, NHS Foundation Trust, Scarborough, UK.",
"authors": "Tsitlakidis|Christos|C|http://orcid.org/0000-0001-5922-2239;Al Ajmi|Khalil Ibrahim Salim|KIS|;Al Madhani|Alya Yousuf|AY|;Ahmidat|Adel Hassan|AH|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3102\n10.1186/s13256-021-03102-y\nCase Report\nPostpartum ovarian vein thrombosis manifesting as acute appendicitis: a case report\nhttp://orcid.org/0000-0001-5922-2239\nTsitlakidis Christos ctsitlakidis@yahoo.co.uk\n\n1\nAl Ajmi Khalil Ibrahim Salim 2\nAl Madhani Alya Yousuf 3\nAhmidat Adel Hassan 1\n1 grid.439905.2 0000 0000 9626 5193 York Teaching Hospital, NHS Foundation Trust, Scarborough, UK\n2 grid.412855.f 0000 0004 0442 8821 Surgical Department, Sultan Qaboos University Hospital, Muscat, Oman\n3 grid.416132.3 0000 0004 1772 5665 Royal Hospital, Muscat, Oman\n25 10 2021\n25 10 2021\n2021\n15 52123 12 2020\n6 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nPostpartum ovarian thrombosis is an uncommon condition. It appears with the nonspecific, predominantly right-sided abdominal symptoms and must be differentiated from other acute visceral conditions. If left untreated, postpartum ovarian thrombosis can have severe consequences, including sepsis, pulmonary embolism, and even death. Momentarily, there are no specific guidelines for postpartum ovarian thrombosis management. We present a case of postpartum ovarian thrombosis admitted to our hospital with symptoms of acute appendicitis.\n\nCase presentation \n\nA 39-year-old Omani obese multiparous woman of Afro-Arab origin was admitted with acute symptoms, mainly abdominal pain, fever, and vomiting 1 week postpartum. Clinical picture and biochemical profile did not exhibit a recognizable pattern. Ultrasonography excluded retained products of conception. Computerized scan for abdomen and pelvis with oral and intravenous contrast reported a dilated tubular structure in the right adnexa extending up to the right renal hilum level with surrounding inflammation. Those findings were consistent with the thrombophlebitis of the right ovarian vein. Blood cultures and sensitivity showed group A β-hemolytic streptococci sensitive to penicillin G and clindamycin. The patient was treated successfully with antibiotics and therapeutic anticoagulants and discharged home 3 days later; follow-up was arranged.\n\nConclusion\n\nThis pathology is an exceptional entity in Oman. Therefore, awareness of this unique condition is required so that clinicians will be vigilant, exploring similar cases with imaging and avoiding unnecessary surgical interventions.\n\nKeywords\n\nOvarian vein\nThrombosis\nPostpartum\nAcute appendicitis\nAppendicectomy\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nOvarian vein thrombosis is a complication during pregnancy and the postpartum period. Postpartum (puerperal) ovarian vein thrombosis (POVT) appears in 0.05–0.18% after vaginal delivery [1] and 1–2% after caesarean section [2–4]. The underlying physiology driving the thrombus formation can be seen within Virchow’s triad: venous stasis, vessel wall damage, and the presence of a hypercoagulable state [5]. Apart from pregnancy and the puerperium, where a hypercoagulability state exists due to the surge of estrogens [4], Virchow’s conditions also arise from major pelvic surgery, inflammatory disease, coagulopathy, and malignancy, thus addressing the disease over a broad age population [6]. Furthermore, nine idiopathic OVT cases have been acknowledged [7]. Anatomically, there is a notable predilection for the right ovarian vein to be thrombosed. Valve incompetence and absence of retrograde flow both promote thrombus extension in the right ovarian vein. During puerperium, diminished fibrinolytic activity and elevation of coagulation factors aid in hemostasis and prevent blood loss [8]; besides, the uterus undergoes physiological dextrorotation and predisposes the right vein to thrombosis due to the acute angle formed where it enters the inferior vena cava [9, 10]. As a result, in 80–90% of postpartum cases, there is a unilateral right-sided involvement, in contrast with other etiologies where OVT entanglement was observed on either side or bilaterally [11]. Clinically, OVT asymptomatic appearance in most cases with malignancy is in contrast with the typical presentation during the postpartum period: fever with chills, diffuse pelvic and right iliac fossa pain, and a tender, rope-like mass palpable in the lower abdomen [6], and leukocytosis 2–15 days postpartum. Fatal cases have been reported [6] from sepsis, thrombosis of the inferior vena cava, renal veins, and pulmonary embolism.\n\nCase report\n\nA 39-year-old woman, Omani of Afro-Arab origin, para 5, obese, was admitted 7 days after spontaneous vaginal delivery with right-sided lower abdominal pain, nausea and vomiting (food content, no blood), and fever (38 °C) with chills. The onset of the symptoms was 2 days of feeling unwell and having generalized abdominal pain. She lost her appetite and was unable to eat. Other symptoms included four episodes of loose motions with watery stools on admission, lethargy, and difficulty standing. In addition, she reported a mild dry cough for 4 days and a sore throat. She had an uneventful vaginal delivery of a live term male; her pregnancy had been complicated by chronic hypertension, well controlled on labetalol and gestational diabetes managed with metformin. She had no history of thrombophilia. Vitals on admission showed a respiratory rate of 20 breaths/minute, SaO2 99% on room air, temperature 37.1 °C, pulse rate of 130 beats/minute, and 129/69 mmHg blood pressure.\n\nBlood studies on admission showed white blood cells (WBC) and neutrophil count normal, lactate 2.5 mmol, prolonged activated partial thromboplastin time (APTT) of 40.5 (normal value 26.4–38.9) seconds, derived fibrinogen 5.18 (normal value 1.6–4) g/l, and thrombin time of 17.5 (normal value 14.3–17.8) seconds. International normalized ratio (INR) was 1.25 (normal value 0.82–1.05). The liver function profile was normal. The renal function panel revealed a picture of acute kidney injury. D-dimer was not done.\n\nOn abdominopelvic examination, there was abdominal tenderness over the right iliac fossa, with rebound tenderness. Rovsing’s sign was positive. In addition, there was a uterine subinvolution (20 weeks size). No calf tenderness or swelling was noted on leg examination to suggest deep venous thrombosis. Similarly, speculum examination was unremarkable; lochia was present in small amounts, without foul odor. Surgical consultation ruled out the possibility of acute appendicitis.\n\nAbdominopelvic ultrasound reported an intramural fibroid and congested veins surrounding the uterus in keeping with postpartum status. The appendix and the ovaries have not been visualized, and there were no retained products of conception. In addition, the patient experienced severe probe tenderness during the transvaginal scan (TVS).\n\nAn abdominal CT scan with oral and intravenous contrast revealed a tubular-like structure (Figs 1, 2, 3, 4) extending from the pelvis to the abdomen up to the right renal hilum level, not separable from the right adnexa, measuring 11 × 3 cm in size. This mass had heterogeneous density with surrounding significant fat stranding, extending from the retroperitoneal area to the renal level. This dilated tubular structure with the surrounding inflammation was typical for thrombophlebitis of the right ovarian vein. The appendix was seen in the right iliac fossa with a normal appearance; it measured 7 mm in cross-section image, and there was intraluminal gas seen with contrast within the lumen. Surgical clips were visible at the site of previous laparoscopic cholecystectomy. Echocardiography ruled out infective endocarditis and showed normal cardiac function.Fig. 1 Arrow: thrombosed right ovarian vein. Arrowhead: inferior vena cava. Figs. 1, 2, 3, 4: Halima Al-Amri (2020). Radiologic images of the patient, Sultan Qaboos University Hospital, Muscat, Oman\n\nFig. 2. Arrow: inferior vena cava. Dashed arrow: thrombosed right ovarian vein. Arrowhead: right kidney. Figs. 1, 2, 3, 4: Halima Al-Amri (2020). Radiologic images of the patient, Sultan Qaboos University Hospital, Muscat, Oman\n\nFig. 3 Arrow points to right ovarian vein. Figs. 1, 2, 3, 4: Halima Al-Amri (2020). Radiologic images of the patient, Sultan Qaboos University Hospital, Muscat, Oman\n\nFig. 4 Arrow points to the right kidney. Arrowhead: thrombosed right ovarian vein. Dashed arrow: inferior vena cava. Figs. 1, 2, 3, 4: Halima Al-Amri (2020). Radiologic images of the patient, Sultan Qaboos University Hospital, Muscat, Oman\n\nTherapeutically, this patient was administered vancomycin and tazocin, which then changed to penicillin G and clindamycin following blood culture and sensitivity results unveiling the growth of group A β-hemolytic streptococci.\n\nHematology team opinion was obtained, and the patient started therapeutic anticoagulation with enoxaparin sodium and warfarin overlap (target INR 2–3). She was planned to continue for a minimum of 3 months, and the investigation of other causes for thrombosis was deferred as it was likely provoked by postpartum.\n\nThe patient clinically improved and was eventually discharged home 3 days later in good condition. Her discharge medication was warfarin 3.5 mg once daily for a total of 3 months and a full course of antibiotics for 1 week; follow-up was arranged, 6 weeks following discharge from the hospital with a view of repeat imaging if deemed necessary. The patient continued to follow up in a secondary care hospital rather than this tertiary center.\n\nDiscussion\n\nOvarian vein thrombosis is rare; compared with deep vein thrombosis occurrence of 1 in 1000 adults (DVT), incidence rates are 60-fold lower [12]. Symptomatic POVT appears in 0.01–0.03% after vaginal delivery [13]. Only two POVT cases have been documented in Oman; these were treated initially as a dilated ureter [14]. Initial presentation with pulmonary embolism was in 6% of patients with OVT compared with 16% of those with DVT [12]. Predisposing factors include cancer, hormonal stimulation, and hospitalization; preceding surgery and personal history of thromboembolism are independent factors for recurrence but with no difference in the overall survival for those treated with anticoagulants [12]. In cases with malignancy, the OVT association has detrimental effects on survival rates from the disease [12]. Aggravating symptoms in OVT can occur from delay in diagnosis; extension of the thrombus into the inferior vena cava (25–30%) or left renal vein [13]; sepsis and pulmonary embolism appear in one out of four cases, raising the mortality rate to 4% [4]. Differential diagnoses, apart from endometritis, a commonly mistaken diagnosis [15], include a hydroureter or appendix, and this is attributed to the gas-filled bowel located in the same region [14, 16]; ovarian torsion and ovarian cyst are also considered [4]. OVT poses a diagnostic puzzle that does not fit into a recognizable pattern and requires radiological imaging [6]. D-dimer (DD) has poor diagnostic value during pregnancy and postpartum; however, a cut-off at 500 ng ml (−1) DD measurement has been reported to be useful 4 weeks after delivery [17]. The choice of initial imaging technique largely depends on test availability and the clinical picture [13]. Ultrasound may be used as first-line imaging, and if not obscured by bowel gas, it will show the thrombosed vein, enlarged with an intraluminal echogenic mass [2]. The supplementary use of Doppler with ultrasound yields a higher sensitivity in detecting the condition [13]. On color Doppler, there will be reduced or no flow within the lumen of the vein and probably increased flow in the perivascular region due to inflammation [2]. Additional imaging is required to investigate for ovarian vein thrombosis as ultrasound does not exclude it [18]. Intravenous contrast-enhanced CT allows accurate delineation of OVT [19]. Complications of POVT include sepsis, ureteral compression, pulmonary embolism, and propagation of the thrombus to the inferior vena cava and renal veins [1]. MRI is a tool of choice and has the highest sensitivity and specificity [13]; it provides the benefit of avoiding radiation and assessing the superior extent of the thrombus into the inferior vena cava or the renal veins [2].\n\nMedical treatment includes the use of anticoagulation alone, which presented similar results with combined therapy [20], in contrast with previous beliefs where the addition of heparin to antimicrobial therapy did not result in better outcomes [21]. The most favorable treatment of choice is a combination of anticoagulation and antibiotics [18]. Antibiotics choices are like those used in septic pelvic thrombophlebitis and consist of intravenous agents like imipenem and cilastatin, ampicillin and sulbactam, clindamycin, and gentamicin single-drug therapy with a second- or third-generation cephalosporin [22]. Non-evidence-based drug prescription should be avoided; such practice has led to antibiotic resistance, a worldwide peril especially for immunosuppressed patients [23]. The use of anticoagulation with heparin precludes the passages and propagation of septic emboli and quickens fever’s abatement [22]. The duration of antibiotic treatment is 48–72 hours. Anticoagulation is recommended for 7–10 days or at least 7–10 days after fever resolution.\n\nLow-molecular-weight heparin (LMWH) and unfractionated heparin are comparable in efficacy. LMWH is preferable over unfractionated heparin as it has a favorable adverse event profile compared with unfractionated heparin [18]. Specific therapeutic interventions are indicated in patients with recurrent pulmonary embolism, poor compliance, and contraindicated anticoagulation. Interventional procedures include thrombectomy and filter placement in the inferior vena cava. Surgical treatment includes vein ligation, oophorectomy, and hysterectomy [13, 15, 18, 24]. Commencement of treatment with unfractionated heparin followed by warfarin or LMWH has been traditionally used as an anticoagulation regimen treatment that ranges between 3 and 6 months [26]. Three months of anticoagulation therapy were seen with no thrombosis recurrence over a median follow-up of 40 months [20]. Although there is no agreed consensus for the length of anticoagulation therapy and POVT has a high rate of resolution after short treatment [20], 3-month treatment with anticoagulants is suggested in cases of symptomatic postpartum OVT, with the addition of antibiotics [13]. A small thrombotic pelvic vein can be treated with a short therapy lasting 2–3 weeks [25]. Besides, asymptomatic POVT can be managed without anticoagulants unless there is evidence from imaging of thrombus extension or pulmonary embolism occurrence [13]. Warfarin is the better alternative as it is more convenient with no injections and safe breastfeeding [16]. It was reported that the recurrence risk of postpartum ovarian vein thrombosis in future pregnancies is low; however, there is a paucity of data in this regard [18]; nonetheless, patients with a history of thrombotic events necessitate anticoagulant cover in future pregnancies, and thrombophilia screening should be evaluated in non-pregnancy related cases.\n\nConclusion\n\nThe condition presents a differential diagnosis in cases of inexplicable postpartum abdominal pain with a worsening clinical condition. Singular treatment with antibiotics could lead to severe morbidity from septic embolism of renal veins and occasional death from a pulmonary embolus. A multidisciplinary approach to suspected ovarian vein thrombosis is paramount for optimal postnatal outcomes and involves obstetricians, hematologists, microbiologists, and radiology specialists. Awareness and clinical knowledge are crucial in treating accordingly and avoiding unnecessary surgical interventions.\n\nAbbreviations\n\nAPTT Activated partial thromboplastin time\n\nCT Computerized tomography scan\n\nINR International normalized ratio\n\nLMWH Low-molecular-weight heparin\n\nMDCT Multiple detector computerized tomography scan\n\nMRI Magnetic resonance scan\n\nOVT Ovarian vein thrombosis\n\nPOVT Postpartum (puerperal) ovarian vein thrombosis\n\nTVS Transvaginal scan\n\nWBC White blood cells\n\nAcknowledgements\n\nDr Halima Al-Amri reported and interpreted the radiologic images of the patient.\n\nAuthors’ contributions\n\nKISAA is the junior doctor who was presented with this case in Oman. He played a major role as part of the team that treated this patient successfully. He collected all data and had a contribution to the manuscript. CT is a consultant in the UK and was a major contributor in writing the manuscript. AYAM managed the patient’s care and contributed to authorizing this case report. AHA reviewed this case report. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding source was involved.\n\nAvailability of data and materials\n\nSupporting data are available on request\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval not applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Aidara CM, Diop AD, Ahmed K, Diouf AA, Diallo M, Diop AN, Diop SB, Niang EH. 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Ovarian vein thrombosis | Radiology Reference Article | Radiopaedia.org. [online] Radiopaedia.org. 2012. https://radiopaedia.org/articles/ovarian-vein-thrombosis?lang=gb [Accessed 5 Jul. 2021].\n12. Lenz CJ Wysokinski WE Henkin S Cohoon KP Casanegra A Simmons BS Saadiq RA Daniels PR Wysokinska EM Bjarnason H McBane RD Ovarian vein thrombosis Obstet Gynecol 2017 130 5 1127 1135 10.1097/AOG.0000000000002319 29016487\n13. Bannow BTS Skeith L Diagnosis and management of postpartum ovarian vein thrombosis Hematology 2017 2017 1 168 171 10.1182/asheducation-2017.1.168 29222252\n14. Dhinakar M. Puerperal ovarian vein thrombosis presenting as rt loin pain and hydronephrosis: report of 2 cases. Oman Med J. 2010. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191649/ [Accessed 5 Jul. 2021].\n15. Giraud J-R Poulain P Renaud-Giono A Darnault J-P Proudhon J-F Grall J-Y Mocquet P-Y Diagnosis of post-partum ovarian vein thrombophlebitis by color Doppler ultrasonography: about 10 cases Acta Obstet Gynecol Scand 1997 76 8 773 778 10.3109/00016349709024346 9348257\n16. Dougan C Phillips R Harley I Benson G Anbazhagan A Postpartum ovarian vein thrombosis Obstet Gynaecol 2016 18 4 291 299\n17. Epiney M Boehlen F Boulvain M Reber G Antonelli E Morales M Irion O de Moerloose P D-dimer levels during delivery and the postpartum J Thromb Haemost 2005 3 2 268 271 10.1111/j.1538-7836.2004.01108.x 15670031\n18. Klima DA Snyder TE Postpartum ovarian vein thrombosis Obstet Gynecol 2008 111 2 431 435 10.1097/AOG.0b013e318162f6c0 18238984\n19. Bhosale PR Javitt MC Atri M Harris RD Kang SK Meyer BJ Pandharipande PV Reinhold C Salazar GM Shipp TD Simpson L Sussman BL Uyeda J Wall DJ Zelop CM Glanc P ACR appropriateness Criteria® acute pelvic pain in the reproductive age group Ultrasound Q 2016 32 2 108 115 10.1097/RUQ.0000000000000200 26588104\n20. Rottenstreich A Da’as N Kleinstern G Spectre G Amsalem H Kalish Y Pregnancy and non-pregnancy related ovarian vein thrombosis: clinical course and outcome Thrombosis Res 2016 146 84 88 10.1016/j.thromres.2016.09.001\n21. Brown CE Stettler RW Twickler D Cunningham FG Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy Am J Obstet Gynecol 1999 181 1 143 148 10.1016/S0002-9378(99)70450-3 10411810\n22. Kominiarek MA Hibbard JU Postpartum ovarian vein thrombosis: an update Obstet Gynecol Survey 2006 61 5 337 342 10.1097/01.ogx.0000216564.53044.f1\n23. Devaraj NK Antibiotic resistance: a real menace Oman Med J 2017 32 6 531 531 10.5001/omj.2017.102 29218134\n24. Lotze EC Kaufman RH Kaplan AL Postpartum ovarian vein thrombophlebitis Obstet Gynecol Survey 1966 21 6 853 870 10.1097/00006254-196612000-00001\n25. Garcia J, Aboujaoude R, Apuzzio J, Alvarez JR. Septic pelvic thrombophlebitis: diagnosis and management. Infect Dis Obstetrics Gynecol, 2006. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1581461/ [Accessed 26 Nov. 2020].\n26. Naoum J Mohsen A Daher J Eid T Novel management of ovarian vein thrombosis: a case report Saudi Pharm J 2018 26 5 608 610 10.1016/j.jsps.2018.03.003 29988955\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute appendicitis; Appendicectomy; Ovarian vein; Postpartum; Thrombosis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D001064:Appendicitis; D005260:Female; D006801:Humans; D049590:Postpartum Period; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "521",
"pmc": null,
"pmid": "34689824",
"pubdate": "2021-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Postpartum ovarian vein thrombosis manifesting as acute appendicitis: a case report.",
"title_normalized": "postpartum ovarian vein thrombosis manifesting as acute appendicitis a case report"
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"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2021-10925",
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"abstract": "Reports are increasing regarding atypical femoral fractures (AFFs) caused by minor trauma in patients using bisphosphonates (BPs) for long periods. Patients with malignant skeletal metastases potentially are at greater risk for these AFFs, especially considering the high dose and the duration of treatment with BPs. We evaluated a case of atypical femoral shaft fracture treated with an intramedullary nail in a patient treated for five years with zoledronate who had breast cancer with metastases to bone. Although bone union was achieved without cessation of zoledronate therapy by applying low-intensity pulsed ultrasounds (LIPUS), the remodeling phase of the fracture healing process was delayed. For BPs-associated AFFs, LIPUS is an alternative to parathyroid hormone (PTH) analogs such as teriparatide that are contraindicated in patients with malignant skeletal metastases. LIPUS is an effective treatment for fracture healing and may avoid the necessity to discontinue BP therapy.",
"affiliations": "Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.;Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Arakawa|Shoutaro|S|;Saito|Mitsuru|M|;Kubota|Makoto|M|;Suzuki|Hidehiko|H|;Tsuchida|Shigeki|S|;Hashimoto|Kurando|K|;Marumo|Keishi|K|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.11138/ccmbm/2015.12.3.269",
"fulltext": null,
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"issn_linking": "1724-8914",
"issue": "12(3)",
"journal": "Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases",
"keywords": "LIPUS; atypical femoral fracture; bisphosphonate; breast cancer; malignant skeletal metastasis; zoledronate",
"medline_ta": "Clin Cases Miner Bone Metab",
"mesh_terms": null,
"nlm_unique_id": "101250935",
"other_id": null,
"pages": "269-72",
"pmc": null,
"pmid": "26811711",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "21430030;11028459;18373056;19669853;18815855;10780852;23712442;24596367;20020334;8288661;11277259;24460109;18843515;10352106;22634175;24490096;15336600;15063521;24996528;21610533;15592795",
"title": "Applying low-intensity pulsed ultrasounds (LIPUS) to a zoledronate-associated atypical femoral shaft fracture without cessation of zoledronate therapy for 3 years follow up: a case report.",
"title_normalized": "applying low intensity pulsed ultrasounds lipus to a zoledronate associated atypical femoral shaft fracture without cessation of zoledronate therapy for 3 years follow up a case report"
} | [
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"companynumb": "JP-ACTAVIS-2016-00978",
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"activesubstancename": "ZOLEDRONIC ACID"
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"abstract": "In patients with advanced gastric cancer refractory to chemotherapy, the treatment options are limited. Via this phase II study, we aimed to assess the efficacy and safety of oxaliplatin in combination with 5-fluorouracil and l-leucovorin (modified FOLFOX6).\n\n\n\nPatients who had histologically confirmed metastatic gastric cancer refractory to ≥ two previous chemotherapy regimens were included. The primary endpoint was the overall response rate (ORR) by an independent central review. According to an assumption of a threshold ORR of 10% and expected ORR of 25%, with α = 0.05 and β = 0.20, at least 33 patients were required. The secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life measured by EQ-5D, and safety.\n\n\n\nAmong the 35 enrolled patients, 33 were included in the primary analysis. All patients previously received fluoropyrimidines, cisplatin, and taxanes, and 24 (73%) were pretreated with irinotecan. The confirmed ORR was 27% [95% confidence interval (CI) 13-46]. The median PFS and OS were 2.2 (95% CI 1.2-3.2) and 5.6 (95% CI 4.1-7.0) months, respectively. In the multivariate analyses, immunotherapy within 90 days and a Glasgow Prognostic Score of 0 were associated with better treatment outcomes. The most common grade ≥ 3 adverse event was neutropenia (36%), and no febrile neutropenia was observed. The median EQ-5D scores did not change from baseline at 2, 4, and 8 weeks (p value = 0.38, 0.79, and 0.98, respectively).\n\n\n\nModified FOLFOX6 (mFOLFOX6) showed substantial activity and acceptable toxicity for chemotherapy-refractory advanced gastric cancer.\n\n\n\nUMIN Clinical Trial Registry (UMIN000016416).",
"affiliations": "Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. skadowaki@aichi-cc.jp.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.",
"authors": "Mitani|Seiichiro|S|;Kadowaki|Shigenori|S|http://orcid.org/0000-0001-9923-5309;Komori|Azusa|A|;Kondoh|Chihiro|C|;Oze|Isao|I|;Kato|Kyoko|K|;Masuishi|Toshiki|T|;Honda|Kazunori|K|;Narita|Yukiya|Y|;Taniguchi|Hiroya|H|;Ando|Masashi|M|;Tanaka|Tsutomu|T|;Tajika|Masahiro|M|;Muro|Kei|K|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-020-01358-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "37(6)",
"journal": "Advances in therapy",
"keywords": "Chemotherapy; FOLFOX regimen; Gastric cancer; Phase II clinical trial",
"medline_ta": "Adv Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077982:Progression-Free Survival; D013274:Stomach Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "2853-2864",
"pmc": null,
"pmid": "32378071",
"pubdate": "2020-06",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "25220842;30475956;28993052;29543932;30034550;30355453;26589793;29658055;19097774;17245566;20516446;30568033;12007165;12598342;20369048;22693245;29187492;22740925;27027618;29191606;31864957;29101058;28412137",
"title": "A Phase II Study of Modified FOLFOX6 for Advanced Gastric Cancer Refractory to Standard Therapies.",
"title_normalized": "a phase ii study of modified folfox6 for advanced gastric cancer refractory to standard therapies"
} | [
{
"companynumb": "JP-PFIZER INC-2020197158",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents.\n\n\nMETHODS\nWe retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment.\n\n\nRESULTS\nTwenty-four patients received TKIs. The median duration of treatment was four (range: 1-19) cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment.\n\n\nCONCLUSIONS\nPatient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary.",
"affiliations": "Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.;Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece.",
"authors": "Chrisoulidou|Alexandra|A|;Mandanas|Stylianos|S|;Margaritidou|Efterpi|E|;Mathiopoulou|Lemonia|L|;Boudina|Maria|M|;Georgopoulos|Konstantinos|K|;Pazaitou-Panayiotou|Kalliopi|K|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S86322",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S86322ott-8-2435Original ResearchTreatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer Chrisoulidou Alexandra Mandanas Stylianos Margaritidou Efterpi Mathiopoulou Lemonia Boudina Maria Georgopoulos Konstantinos Pazaitou-Panayiotou Kalliopi Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, GreeceCorrespondence: Kalliopi Pazaitou-Panayiotou, Department of Endocrinology, Theagenio Cancer Hospital, 2 Al Simeonidi Street, Thessaloniki 54007, Greece, Tel +30 23 1089 8618, Fax +30 23 1089 8809, Email kpazaitoupanayiotou@gmail.com2015 03 9 2015 8 2435 2442 © 2015 Chrisoulidou et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nThe aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents.\n\nMethods\nWe retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment.\n\nResults\nTwenty-four patients received TKIs. The median duration of treatment was four (range: 1–19) cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment.\n\nConclusion\nPatient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary.\n\nKeywords\nmedullary thyroid carcinomadifferentiated thyroid cancerTKIssorafenibsunitinibvandetanib\n==== Body\nIntroduction\nDifferentiated thyroid cancer (DTC) is the most frequent type of thyroid cancer,1 comprising more than 90% of all cases. Thyroidectomy and radioactive iodine (RAI) ablation remain the cornerstones of treatment. Although the disease course is indolent in the majority of patients, aggressive cases with metastases (refractory to conventional treatment) exist, and remain challenging for clinicians. Over recent decades, the trend of an increasing incidence of thyroid cancer has inevitably given rise to a number of patients who present with aggressive disease and eventually succumb to it.2 The survival rate in patients with RAI-refractory metastatic DTC has been estimated to be 10% at 10 years.3 Until recently, the therapeutic options available for patients with progressive, metastatic, RAI-refractory DTC have been limited.\n\nC-cell-derived medullary thyroid carcinoma (MTC), although uncommon, has a much worse prognosis than iodine-positive DTC, which is approximately the same with RAI-refractory DTC.4 In most cases, MTC is already metastatic at initial presentation, with no available effective therapeutic options other than surgery, when possible.\n\nNovel tyrosine kinase inhibitors (TKIs), such as sorafenib, sunitinib, cabozantinib, and vandetanib, have been used recently for the treatment of refractory cases of thyroid cancer5–7 where all conventional treatment options (surgery, RAI, chemotherapy) have been proven ineffective. These molecules inhibit cellular signaling by targeting multiple tyrosine kinase receptors as well as platelet-derived growth factor receptors and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and proliferation of tumor cells. Simultaneous inhibition of these targets leads to reduced tumor vascularization, apoptosis of cancer cells, and ultimately tumor shrinkage. Some Phase II and III trials8,9 have reported promising results regarding favorable response rates in metastatic thyroid cancer that has been non-responsive to conventional treatment. Recently, vandetanib and cabozantinib were approved for patients with MTC and sorafenib was approved for those with DTC.9,10 However, because both agents target many different receptors, they have numerous side effects, including hematological, skin, and cardiac toxicities that may have a negative impact on patients’ quality of life.\n\nThe aim of the present study was to assess the effects of TKI inhibitors in a cohort of patients with refractory and progressive thyroid cancer (DTC or MTC), in particular severe adverse events during TKI therapy, ability and willingness of patients to remain on long-term treatment, and response rates.\n\nMaterials and methods\nData from patients with metastatic refractory thyroid cancer who received TKIs from April 2009 to December 2014 were retrospectively analyzed. Approval for the drug administration to every patient was obtained from the insitutional scientific committee and the National Drug Organization. Each patient was informed in detail about the efficacy and possible adverse events (minor or major) associated with the treatment. The same doctor (SM) educated all patients and confirmed their understanding of the possible complications of therapy and its expected efficacy. All patients agreed to start TKI therapy after they had been fully informed and given their written consent.\n\nAll patients were of Caucasian origin, of similar socioeconomic status, and lived in Northern Greece (population approximately 3 million inhabitants). Initially, candidates for sunitinib were those who had metastatic DTC to the lungs or bones refractory to iodine treatment and progressive disease within 12 months before baseline, documented by computed tomography (CT) or magnetic resonance imaging (MRI) and thyroglobulin; and for sorafenib were those who had metastatic MTC to the liver (with unresectable metastatic lesions) or bones and progressive disease within 12 months before baseline, documented by CT or MRI and by an increase in serum calcitonin levels. After approval by the European Medicines Agency (EMA) for sorafenib and vandetanib to be used in the treatment of DTC and MTC, respectively, patients with refractory thyroid cancer who were candidates for TKIs received these drugs. All patients were in general good health, defined as an Eastern Cooperative Oncology Group performance status of 0 or 1.11 A clinical evaluation was performed, and normal blood pressure, with appropriate treatment where necessary, was achieved before initiation of TKI treatment. All patients had normal liver, renal, and bone marrow function. No abnormalities were identified on baseline electrocardiography or echocardiography. Baseline QT intervals were in the normal range.\n\nSorafenib 400 mg was given orally twice daily continuously, sunitinib was given as 50 mg once daily on a 4–2 schedule (4 weeks of treatment followed by 2-week intervals without therapy), and vandetanib was given as 300 mg once daily. A 4-week treatment with each agent defined a cycle. Patients were evaluated weekly for the first cycle and monthly thereafter, in order to determine well-being and Eastern Cooperative Oncology Group performance status. At each visit, clinical examination, blood pressure, weight, and a complete blood count, urinalysis, and serum biochemical measurements were performed. Cardiac evaluation with an electrocardiogram and/or echocardiogram was periodically performed and when indicated according to patient symptoms. Extensive discussion, evaluation of predisposing factors (such as diabetes), and written information was provided regarding the side effects of the medication. Patients were advised to prevent stomatitis with systematic oral care hygiene using a soft toothbrush and bland rinses, and to use local anesthetics as/if needed.12 The patients were also asked to limit exposure of the hands and feet to hot water, chemicals, or sources of heat (eg, sitting in the sun), to take cool showers, wear well-ventilated shoes, and apply skin care creams to keep the hands moist in order to prevent and manage hand-foot syndrome.13 Patients were instructed to report any new symptom or sign to their physicians at every visit.\n\nAnswers to questions regarding changes in daily habits were recorded. Any adverse events were documented and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.14 The presence of adverse events that would need dose reduction or discontinuation of therapy was also documented at every visit.\n\nResponse to therapy was estimated by CT or MRI after three and six cycles and every four cycles thereafter. Disease progression was assessed according to the Response Evaluation Criteria in Solid Tumors (version 1.0).15 Thyroid-stimulating hormone (TSH) for all patients, thyroglobulin for DTC patients, and calcitonin for MTC patients were also evaluated concomitantly. The study was approved by the institutional review board. The presented data are expressed where appropriate as the median and range.\n\nResults\nTwenty-four patients (14 males, ten females) were identified from our clinical database to have received TKIs since April 2009. Fourteen patients had DTC and ten had MTC. Their median age was 58.29 (range: 42–74) years. The histological characteristics of the tumors are presented in Table 1. All patients had distant metastases located at one or more sites (liver 37.5%, lung 58%, bone 29.1%, and lower mediastinum 20.8%). The time between diagnosis of thyroid carcinoma and treatment with a TKI varied from a minimum of 6 months to a maximum of 9 years. Previous treatments included thyroidectomy (in all patients) with/without lymph node dissection and administration of RAI (in all DTC patients), external beam radiation, and local therapies for liver metastases (radiofrequency ablation and/or chemoembolization; for details, Table 1). All applied treatment was terminated at least 6 months prior to initiation of TKI therapy.\n\nAdverse events\nThe duration of TKI treatment ranged from one to 19 cycles. Younger patients tolerated longer treatment (Table 2). The first adverse events appeared after approximately 2 weeks of therapy, and were fatigue, mild diarrhea, and stomatitis. During treatment, the most commonly reported adverse events were diarrhea (81.25%), stomatitis (75%), fatigue (62.5%), and skin adverse effects (81.25%, comprising hand-foot syndrome, skin discoloration, and rash, Tables 2 and 3). A minority of patients developed anemia, neutropenia, and elevated triglyceride levels (Table 2). Although many adverse events were grade 1 and 2, 15 patients (62.5%) reported grade 3 and 4 toxicities (Tables 2 and 3). In particular, one female patient developed painful vulvar ulcers and refused to continue treatment with sunitinib even in lower dose, one man developed many ulcers across the surface of the scrotum while taking sorafenib, and there were one case with renal failure and one case with QT prolongation where both were on vandetanib. Two cases in particular warrant mention. The first was a 73-year-old female patient who developed congestive heart failure (ejection fraction 35%) while on sunitinib. This severe adverse event led to immediate drug withdrawal, with subsequent improvement of cardiac function. The second case was a man with RAI-refractory thyroid cancer in whom intense muscle pain and muscle weakness suddenly appeared 1 month after initiation of sorafenib, along with a nine-fold increase in creatine phosphokinase.\n\nReduction of the sunitinib dose from 50 to 37.5 mg once daily was required in five patients receiving sunitinib due to neutropenia (two patients), hypertension (two patients), and intense fatigue (one patient); from 400 to 200 mg twice daily for sorafenib in one patient due to scrotal ulcers; and from 300 to 200 mg for vandetanib in two patients (one due to renal failure and one due to QT prolongation). Sequential therapy was attempted with sunitinib followed by sorafenib in two patients due to severe neutropenia caused by sunitinib. Five patients (20.8%) opted to stop treatment after 1–4 cycles, regardless of the severity of the adverse event, because of inability to work long hours, decreased appetite, and restriction of outdoor activities. All adverse events encountered are shown in Table 3.\n\nOverall response\nOverall response, including stable disease and partial response, was estimated for the 17 of the 24 patients who continued treatment for more than three cycles (Table 2). Two patients with DTC showed improvement of lung metastases after 6 months of TKI administration as documented by CT, which improved further as treatment was continued. Metastatic sites favoring response were the lungs. At the time of collecting the data, all patients with DTC were alive; however, six of the ten MTC patients had died. There were no deaths related to TKI therapy.\n\nTumor markers\nMedian TSH was 0.26 (range: 0.01–1.44) μIU/mL at baseline and 0.48 (0.09–3.6) μIU/mL at 3 months. In three patients, an increase in thyroxine dose was decided. Thyroglobulin levels at baseline on thyroxine were 148 (1.3–7,572) ng/mL and at 3 months were 108 (1.3–1,629) ng/mL, while the calcitonin levels were 8,107 (874–8,920) pg/mL at baseline and 4,901 (441–5,068) pg/mL at 3 months.\n\nDiscussion\nA high treatment dropout rate was observed in this study, mainly due to drug toxicity along with reluctance of patients to continue treatment. Younger patients tolerated longer treatment, indicating that these patients were perhaps more motivated and willing to receive and continue therapy. The patients presented a high frequency of minor and major adverse events while on treatment. A preferential effect of TKI therapy on metastatic disease to the lung was observed.16 Finally, a non-significant trend for reduction of both thyroglobulin and calcitonin serum levels after the use of TKIs was also observed. Because a considerable number of patients (13 of 24) discontinued therapy due to side effects and not disease progression, calculation of progression-free survival or even overall survival would not provide an insight into the efficacy of TKI treatment in this cohort.\n\nWith the exception of anaplastic thyroid cancer, patients with MTC and DTC have in most cases a good prognosis, with a 5-year survival exceeding 60% for MTC17 and 90% for DTC.18 In this study, the survival of MTC cases was shorter than for DTC patients. Furthermore, while the disease is progressing, patients usually maintain a good quality of life. As a result, they have the expectation that applied therapies would not interfere with their normal everyday life and activities.\n\nIn the present study, we used sorafenib for the treatment of MTC patients (when vandetanib was not approved for the treatment of MTC) based on data concerning its activity at the RET and vascular endothelial growth factor receptors19 and from two studies published at that time showing a response in 40% of patients20 and stable disease in 50% of MTC patients.8 After approval of vandetanib, patients with MTC received this drug. On the other hand, sunitinib, known as a multitargeted inhibitor at that time,21 was administered to RAI-refractory DTC patients in an open-label Phase II study and showed a 13% partial response rate and a 68% disease stabilization rate.22 Very recently, data have been presented from DECISION, a randomized, double-blind Phase III trial examining the efficacy and safety of sorafenib versus placebo in RAI-refractory DTC patients.23 Four hundred and seventeen patients from 77 centers in the USA and Europe were randomized to receive either sorafenib or placebo. The study indicated that sorafenib improved progression-free survival by 5 months over placebo. In another randomized, double-blind Phase III study that included 331 patients with MTC, 231 patients received vandetanib and 100 received placebo. In that study, prolongation of progression-free survival was observed in patients who received vandetanib when compared with those who received placebo.10 A direct comparison with the earlier findings cannot be made because the design of our study did not include a placebo group or calculation of progression-free survival.\n\nLooking at the efficacy and adverse events between DTC and MTC patients, we can conclude that: sunitinib or sorafenib therapy in DTC patients was more efficacious than sorafenib or vandetanib in MTC patients, given that partial response and stable disease was seen only in DTC patients and adverse events were similar between DTC and MTC patients (Table 2).\n\nCardiac and hematological side effects were the most clinically important adverse events presented during therapy, and were the most significant medical reasons for withdrawing treatment. In general, cardiac toxicities, from changes on the electrocardiogram and left ventricular ejection fraction abnormalities to severe congestive heart failure and acute coronary syndromes, should be suspected and monitored for during TKI therapy.24,25 In our cohort, hematological toxicity of all grades was seen in five of our 24 patients and grade 3–4 events occurred in two patients. Epistaxis, seen in three patients, was an additional reason to withdraw treatment. These results are comparable with the published data for all-grade hematological toxicity of 60%–70% and grade 3–4 toxicity of 6%–8%.26 In addition, we observed hand-foot syndrome in 58.33% of patients, which is similar to published data reporting rates of 60%–91%.27 These skin reactions tend to appear early on in treatment and improve after the first six cycles,28 and were also seen in the present study. Finally, fatigue, which probably represents a multifactorial toxicity during use of TKIs,29 is debilitating and at times difficult to overcome, as suggested by our findings.\n\nGrade 3 and/or 4 toxicities are an indication for treatment discontinuation; however, lower-grade side effects may also lead to treatment withdrawal, especially when they appear in clusters and persist for a long time. Apart from implementation of supportive measures,30 as cited in our methodology, we applied drug discontinuation and dose reduction to alleviate symptoms in patients with toxicities.23 Recently, a schedule change from 4 weeks on/2 weeks off during treatment with sunitinib to 2 weeks on/1 week off has resulted in significantly fewer events of hand-foot syndrome and fatigue.31 This alternative dosing led to fewer grade 3/4 adverse events without compromising drug efficacy, and so far appears superior to dose reduction.32 Adverse events with one TKI agent do not preclude the use of another drug in this category;33 improvement of hematological toxicity was observed in two patients when treatment was switched from sunitinib to sorafenib.\n\nPrevious reports advocate the use of tumor markers (thyroglobulin and calcitonin) as surrogate markers34 for follow-up in treated patients, along with CT and MRI. Although our patient population was small, we also observed a non-significant trend for reduction of tumor markers with treatment. An elevation in TSH was observed, and thyroxine was increased in three patients. In athyreotic patients, increases in TSH with TKI treatment have been previously documented in 17%–33% of patients, depending on the drug used.30 TKIs induce hypothyroidism, probably associated with poor absorption of thyroxine along the gastrointestinal tract as a consequence of diarrhea, thyroid hormone metabolism, or reduction of TSH clearance.35\n\nThis was a retrospective study and included a relatively small number of patients. However, the fact that these data reflect the experience of a single center using standard therapeutic criteria and treating patients from a specific region could counterbalance some of the limitations. Further, since data related to specific populations are not widely available, the present series adds valuable information related to treatment with TKIs. Small groups of patients are common in this research area, as seen in other recently published studies that refer to similar numbers of patients36–38 and contain mixed DTC and MTC populations.16,39,40\n\nConclusion\nTKIs represent a valuable therapeutic option in patients with thyroid cancer. However, these agents should be used with caution and under expert supervision because of their adverse events. Younger patients tolerate treatment better. In patients who continue therapy, adverse events may improve over time and become more tolerable. Apart from thorough education of selected patients, topical therapies, dose reduction of the administered TKI, temporary treatment interruption, and/or permanent discontinuation in severe cases may be considered in those not able to continue long-term treatment. As toxicities impact negatively on patients’ quality of life and often restrict their everyday activities, candidate patients must be meticulous selected and close follow-up should be applied.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work. The authors alone are responsible for the content and writing of the paper.\n\nTable 1 Characteristics of patients who received tyrosine kinase inhibitors\n\nCharacteristics\tPatients (n=24)\t\nMedian age (years)\t58.29\t\n (range)\t(42–74)\t\nSex, n (%)\t\t\n Male\t14 (58)\t\n Female\t10 (42)\t\nHistology of TC (n)\t\t\nPapillary TC\t6\t\nFollicular TC\t3\t\nHurthle cell\t4\t\nPoorly differentiated\t1\t\nMTC\t10\t\nMetastatic disease (n)\t\t\nMediastinal mass\t5\t\nLungs\t14\t\nLiver\t9\t\nBone\t7\t\nECOG performance status, n (%)\t\t\n 0\t22 (91)\t\n 1\t2 (9)\t\nTime since diagnosis of TC (months)\t\t\n DTC\t29 (15–108)\t\n MTC\t64.3 (6–108)\t\nPrevious treatment, n\t\t\n DTC\t\t\n Surgery\t14\t\n Systemic chemotherapy\t3\t\n Radioiodine (median dose, range)\t14 (319, 150–900 mCi)\t\n External beam irradiation\t6\t\n MTC\t\t\n Surgery\t10\t\n Systemic chemotherapy\t2\t\n Radiofrequency ablation\t2\t\n Chemoembolization\t4\t\n External beam irradiation\t4\t\nNote: Values expressed as the median (range).\n\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; TC, thyroid cancer; DTC, differentiated thyroid cancer; MTC, medullary thyroid carcinoma.\n\nTable 2 Duration of treatment, medication used and response to therapy\n\nCases\tSex\tAge (years)\tDiagnosis\tDuration of treatment (months)\tMedication\tResponse to treatment\tTreatment discontinuation\tNumber of AEs in each patient\t\n1\tF\t49\tDTC\t18\tSUN\tPR\tNo\tFatigue, hypertension, diarrhea, stomatitis, HFS, rash, hypertriglyceridemia\t\n2\tF\t49\tDTC\t19\tSUN\tPR\tNo\tFatigue, hypertension, neutropenia, stomatitis, HFS, hypertension,\t\n3\tM\t55\tDTC\t14\tSUNa\tPD\tYes (PD)\tneutropenia, thrombocytopenia, diarrhea, stomatitis, bleeding, HFS\t\n4\tM\t66\tDTC\t4\tSUN\tSD\tYes (patient decision)\tFatigue, hypertension, stomatitis, LVSD, hypertriglyceridemia\t\n5\tF\t58\tDTC\t4\tSUN\tSD\tYes (patient decision)\tFatigue, hypertension, diarrhea, stomatitis, loss of weight, HFS, rash, vulval ulcers\t\n6\tF\t73\tDTC\t3\tSUN\tSD\tYes (severe adverse events)\tFatigue, anemia, neutropenia, thrombocytopenia, diarrhea, stomatitis, LVSD, HFS, eyelid edema\t\n7\tF\t63\tDTC\t2\tSUN\tETE\tYes (severe adverse events)\tAnemia, neutropenia, thrombocytopenia, stomatitis\t\n8\tM\t66\tMTC\t1\tSOR\tETE\tYes (patient decision)\tFatigue, diarrhea, stomatitis, loss of weight, itch\t\n9\tM\t53\tDTC\t11\tSUNa\tPD\tYes (severe adverse events)\tFatigue, hypertension, anemia, neutropenia, thrombocytopenia, diarrhea, stomatitis, loss of weight, HFS, albuminuria\t\n10\tF\t71\tDTC\t14\tSUN\tPD\tYes (PD)\tDiarrhea\t\n11\tF\t52\tDTC\t7\tSUN\tPD\tYes (PD)\tHypertension, diarrhea, stomatitis, HFS, rash\t\n12\tM\t59\tMTC\t2\tSOR\tETE\tYes (patient decision)\tDiarrhea, nasal bleeding, HFS\t\n13\tM\t51\tMTC\t6\tSOR\tPD\tYes (PD)\tFatigue, diarrhea\t\n14\tM\t50\tMTC\t12\tSOR\tPD\tYes (PD)\tDiarrhea, HFS\t\n15\tM\t74\tMTC\t3\tSOR\tPD\tYes (patient decision)\tFatigue, diarrhea, stomatitis, loss of weight, nasal bleeding\t\n16\tM\t46\tMTC\t16\tSOR\tPD\tYes (PD)\tFatigue, diarrhea, stomatitis, HFS, itch\t\n17\tF\t71\tMTC\t1\tVAN\tETE\tYes (severe adverse events)\tDiarrhea, acute renal failure\t\n18\tM\t50\tMTC\t5\tVAN\tSD\tYes (severe adverse events)\tFatigue, exfoliative dermatitis due to sun exposure\t\n19\tM\t68\tMTC\t1\tVAN\tETE\tYes (severe adverse events)\tSevere recurrent nasal bleeding\t\n20\tM\t64\tDTC\t2\tSOR\tETE\tYes (severe adverse events)\tHypertension, diarrhea, stomatitis, HFS, rash fatigue, diarrhea, mastalgia and breast edema, rhabdomyolysis\t\n21\tF\t51\tDTC\t6\tSOR\tSD\tNo\tHFS, dry skin, hair loss\t\n22\tF\t64\tDTC\t6\tSOR\tSD\tNo\tStomatitis, diarrhea, hypertension, HFS, hair loss, vulval ulcers, weight loss\t\n23\tM\t42\tMTC\t6\tVAN\tPD\tYes (PD)\tFatigue, acne, hypertriglyceridemia, hemorrhoid bleeding, QTc prolongation\t\n24\tM\t54\tDTC\t1\tSOR\tETE\tYes (severe adverse events)\tHFS, hypertension, scrotal ulcers, generalized edema\t\nNotes:\n\na Patients 3 and 9 were switched from sunitinib to sorafenib therapy. Grade 3–4 toxicities are shown in bold.\n\nAbbreviations: PR, partial response; SD, stable disease; ETE, early to estimate; PD, progressive disease; AE, adverse events; DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; SUN, sunitinib; SOR, sorafenib; HFS, hand-foot syndrome; LVSD, left ventricular systolic dysfunction; VAN, vandetanib.\n\nTable 3 Adverse events in patients during treatment with tyrosine kinase inhibitors\n\nAdverse event\tGrade 1–2 CTC\n\tGrade 3 CTC\n\tGrade 4 CTC\n\t\nn\tn\tn\t\nFatigue\t9\t3\t1\t\nStomatitis\t12\t1\t0\t\nLoss of weight\t5\t0\t0\t\nDiarrhea\t14\t2\t0\t\nHFS, skin discoloration\t13\t0\t0\t\nSkin reactions (rash, acne)\t5\t0\t0\t\nExfoliative dermatitis due to sun exposure\t0\t1\t0\t\nScrotal/vulval ulcers\t1\t1\t0\t\nNeutropenia\t3\t1\t1\t\nThrombocytopenia\t4\t0\t0\t\nAnemia\t3\t0\t0\t\nDecreased ejection fraction\t1\t1\t0\t\nHypertension\t6\t3\t0\t\nBleeding\t2\t2\t1\t\nHypertriglyceridemia\t3\t0\t0\t\nRenal disease\t0\t1\t0\t\nRhabdomyolysis\t0\t1\t0\t\nBlurred vision\t1\t0\t0\t\nQTc prolongation\t0\t1\t0\t\nNotes: Column 2 shows the number of patients who developed grade 1 and 2 toxicities; columns 3 and 4 shows the number of patients with grade 3 and grade 4 toxicities, respectively.\n\nAbbreviations: CTC, common toxicity criteria; HFS, hand-foot syndrome.\n==== Refs\nReferences\n1 Ito Y Nikiforov YE Schlumberger M Vigneri R Increasing incidence of thyroid cancer: controversies explored Nat Rev Endocrinol 2013 9 178 184 23358352 \n2 Kilfoy BA Zheng T Holford TR International patterns and trends in thyroid cancer incidence, 1973–2002 Cancer Causes Control 2009 20 525 531 19016336 \n3 Durante C Haddy N Baudin E Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy J Clin Endocrinol Metab 2006 91 2892 2899 16684830 \n4 American Thyroid Association Guidelines Task Force Kloos RT Eng C Evans DB Medullary thyroid cancer: management guidelines of the American Thyroid Association Thyroid 2009 19 565 612 19469690 \n5 Kloos RT Ringel MD Knopp MV Phase II trial of sorafenib in metastatic thyroid cancer J Clin Oncol 2009 27 1675 1684 19255327 \n6 Klein Hesselink EN Steenvoorden D Kapiteijn E Therapy of endocrine disease. Response and toxicity of small molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic analysis Eur J Endocrinol 2015 172 R215 R225 25572389 \n7 Cabanillas ME Brose MS Holland J Ferguson KC Sherman SI A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer Thyroid 2014 24 1508 1514 25102375 \n8 Lam ET Ringel MD Kloos RT Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer J Clin Oncol 2010 28 2323 2330 20368568 \n9 Elisei R Schlumberger MJ Müller SP Cabozantinib in progressive medullary thyroid cancer J Clin Oncol 2013 31 3639 3646 24002501 \n10 Wells SA Jr Robinson BG Gagel RF Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial J Clin Oncol 2012 30 134 141 22025146 \n11 Oken MM Creech RH Tormey DC Toxicity and response criteria of the Eastern Cooperative Oncology Group Am J Clin Oncol 1982 5 649 655 7165009 \n12 Keefe DM Schubert MM Elting LS Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology Updated clinical practice guidelines for the prevention and treatment of mucositis Cancer 2007 109 820 831 17236223 \n13 Manchen E Robert C Porta C Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse J Support Oncol 2011 9 13 23 21465734 \n14 US Department of Health and Human Services Common terminology criteria for adverse events (CTCAE) Protocol development US National Institutes of Health 2010 Available from: http://ctep.cancer.gov/protocolDevelopment Accessed July 24, 2015 \n15 Therasse P Arbuck SG Eisenhauer EA New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 205 216 10655437 \n16 Capdevila J Iglesias L Halperin I Sorafenib in metastatic thyroid cancer Endocr Relat Cancer 2012 19 209 216 22285864 \n17 Abraham DT Low TH Messina M Medullary thyroid carcinoma: long-term outcomes of surgical treatment Ann Surg Oncol 2011 18 219 225 20878247 \n18 Davies L Welch HG Increasing incidence of thyroid cancer in the United States, 1973–2002 JAMA 2006 295 2164 2167 16684987 \n19 Ball DW Medullary thyroid cancer: therapeutic targets and molecular markers Curr Opin Oncol 2007 19 18 23 17133107 \n20 Kober F Hermann M Handler A Krotla G Effect of sorafenib in symptomatic metastatic medullary thyroid cancer J Clin Oncol 2007 25 Suppl 18 S14065 \n21 Faivre S Delbaldo C Vera K Safety, pharmacokinetics, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer J Clin Oncol 2006 24 25 35 16314617 \n22 Ravaud A de la Fouchardiere C Courbon F Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial J Clin Oncol 2008 26 Suppl 15 S6058 \n23 Brose MS Nutting CM Jarzab B DECISION investigators Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double blind, phase 3 trial Lancet 2014 384 319 328 24768112 \n24 Khakoo AY Kassiotis CM Tannir N Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor Cancer 2008 112 2500 2508 18386829 \n25 Chu TF Rupnick MA Kerkela R Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib Lancet 2007 370 2011 2019 18083403 \n26 Schwandt A Wood LS Rini B Dreicer R Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma Onco Targets Ther 2009 2 51 61 20616894 \n27 Autier J Escudier B Wechsler J Spatz A Robert C Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor Arch Dermatol 2008 144 886 892 18645140 \n28 Flaherty KT Brose MS Sorafenib-related hand-foot skin reaction improves, not worsens, with continued treatment Clin Cancer Res 2009 15 7749 20008857 \n29 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Cancer related fatigue Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed July 24, 2015 \n30 Carhill AA Cabanillas ME Jimenez C The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring J Clin Endocrinol Metab 2013 98 31 42 23185034 \n31 Najjar YG Mittal K Elson P A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma Eur J Cancer 2014 50 1084 1089 24559686 \n32 Atkinson BJ Kalra S Wang X Outcomes associated with sunitinib alternative schedule compared to traditional schedule: a single-center experience J Clin Oncol 2013 31 Suppl 15 e15611 \n33 Zimmermann K Schmittel A Steiner U Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib Oncology 2009 76 350 354 19321976 \n34 Cabanillas ME Waguespack SG Bronstein Y Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience J Clin Endocrinol Metab 2010 95 2588 2595 20392874 \n35 Illouz F Braun D Briet C Schweizer U Rodien P Endocrine side-effects of anti-cancer drugs: thyroid effects of tyrosine kinase inhibitors Eur J Endocrinol 2014 171 R91 R99 24833135 \n36 Chen L Shen Y Luo Q Yu Y Lu H Zhu R Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma Thyroid 2011 21 119 124 21186953 \n37 Frank-Raue K Ganten M Kreissl MC Raue F Rapid response to sorafenib in metastatic medullary thyroid carcinoma Exp Clin Endocrinol Diabetes 2011 119 151 155 20827665 \n38 Marotta V Ramundo V Camera L Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET Clin Endocrinol (Oxf) 2013 78 760 767 23009688 \n39 Carr LL Mankoff DA Goulart BH Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation Clin Cancer Res 2010 16 5260 5268 20847059 \n40 Ahmed M Barbachano Y Riddell A Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population Eur J Endocrinol 2011 165 315 322 21566072\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
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"journal": "OncoTargets and therapy",
"keywords": "TKIs; differentiated thyroid cancer; medullary thyroid carcinoma; sorafenib; sunitinib; vandetanib",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
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"pages": "2435-42",
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"title": "Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer.",
"title_normalized": "treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer"
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"abstract": "We describe a case of a 46-year-old man with schizophrenia treated with clozapine who presented as an emergency with abdominal pain on the background of a 1 month history of constipation. The initial presenting symptoms were vague and a diagnosis was difficult to establish. Initial CT of the abdomen and pelvis demonstrated only minor abnormalities. He continued to deteriorate until a further CT scan revealed worsening stercoral colitis. He subsequently underwent an emergency total colectomy and ileostomy formation and had a complicated prolonged postoperative recovery. This case highlights the risks that clozapine can have on slowing bowel transit and the dangerous consequences that can occur if not identified early.",
"affiliations": "Hepatobiliary Surgery, Northern General Hospital, Sheffield, UK.;General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.",
"authors": "George|Jayan|J|http://orcid.org/0000-0001-8899-6620;Hotham|Richard|R|;Melton|William|W|;Chapple|Keith|K|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
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"doi": "10.1136/bcr-2018-227718",
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"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; gastrointestinal surgery; schizophrenia",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D014150:Antipsychotic Agents; D003024:Clozapine; D003092:Colitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "31471354",
"pubdate": "2019-08-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17052340;18480098;27902153;23331762;24887575;2276009;30591547;15000267;27077119;28220347;22563265;7840373;26032569;12028277;28623627;11927763;30718235;26392790;9088503",
"title": "Clozapine-induced stercoral colitis: a surgical perspective.",
"title_normalized": "clozapine induced stercoral colitis a surgical perspective"
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"abstract": "Poisoning is a nationwide hazard. This was a cross-sectional observational study carried out from 2016 to 2017 focused on indoor patients of poisoning at the District Headquarters Hospital, Rawalpindi. We studied the gender-based differences in patients of poisoning to decipher information related to poisoning in which we noted eight variables. For the study 180 patients were included of which 54.4% were males and the rest females. Married patients outnumbered unmarried patients - 70.7% females and 50.2% males. The mean age was 30±12.9 and 27±12.6 respectively. Patients were predominantly of urban residence (56.1% & 52.4% respectively). Deliberate self-poisoning (DSP) was the most common intent among both genders, 81.7% in females and 72.4% among the males in contrast to accidental poisoning which was 23.5% in males and 18. 3 % in females. Aluminum-phosphide, organophosphates, snakebite and corrosive intake were the most common form of poisonings. Unknown causes of poisoning were found significantly more in males (P=0.001), while corrosive intake was more common among the females (P=0.002). Mean duration of hospitalisation for all was 4.22±3.5 days. Out of the 180 patients of poisoning, 18% expired as a result. Conclusively, among married women poisoning is more significant, homicidal poisoning is exclusive to males and corrosive poisoning is predominant in females.",
"affiliations": "Department of Neurosurgery, District Head Quarters Hospital, Rawalpindi.;Head of Department, Medicine, Benazir Bhutto Hospital, Rawalpindi.;General Surgery Holy Family Hospital, Rawalpindi.",
"authors": "Khan|Munema|M|;Khurram|Muhammad|M|;Raza|Salman|S|",
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"country": "Pakistan",
"delete": false,
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"issn_linking": "0030-9982",
"issue": "69(7)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": "Poisoning, Pakistan, Gender, Deliberate Self Harm, Aluminum-Phosphide, Corrosives",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D010154:Pakistan; D011041:Poisoning; D016728:Self-Injurious Behavior; D012737:Sex Factors; D055815:Young Adult",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "1025-1028",
"pmc": null,
"pmid": "31983739",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Gender based differences in patients of poisoning managed at a Medical Unit.",
"title_normalized": "gender based differences in patients of poisoning managed at a medical unit"
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"activesubstancename": "DIGOXIN"
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"abstract": "Gemcitabine-induced radiation recall (GIRR) is a phenomenon wherein the administration of gemcitabine induces an inflammatory reaction within an area of prior radiation. We present the case of a 39-year-old female patient with metastatic breast cancer who experienced GIRR myositis 3 months following postoperative radiotherapy, with additional potential paraspinal myositis following ablative radiotherapy to the thoracic spine. A review of previously published cases of GIRR myositis was performed. The case and literature review describe the clinical course and presentation of GIRR, and highlight the importance of including radiation recall as part of a differential diagnosis when a patient undergoing chemotherapy experiences an inflammatory reaction at a prior site of radiation.",
"affiliations": "University of Minnesota Medical School, Minneapolis, Minnesota, USA.;Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Ravishankar|Adarsh|A|;Park|Sean S|SS|;Olivier|Kenneth R|KR|;Corbin|Kimberly S|KS|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487478",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000487478cro-0011-0168Case ReportGemcitabine-Induced Radiation Recall Myositis: Case Report and Review of the Literature Ravishankar Adarsh aPark Sean S. bOlivier Kenneth R. bCorbin Kimberly S. b*aUniversity of Minnesota Medical School, Minneapolis, Minnesota, USAbDivision of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA*Kimberly S. Corbin, MD, Department of Radiation Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905 (USA), E-Mail Corbin.Kimberly@mayo.eduJan-Apr 2018 27 3 2018 27 3 2018 11 1 168 178 7 2 2018 7 2 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Gemcitabine-induced radiation recall (GIRR) is a phenomenon wherein the administration of gemcitabine induces an inflammatory reaction within an area of prior radiation. We present the case of a 39-year-old female patient with metastatic breast cancer who experienced GIRR myositis 3 months following postoperative radiotherapy, with additional potential paraspinal myositis following ablative radiotherapy to the thoracic spine. A review of previously published cases of GIRR myositis was performed. The case and literature review describe the clinical course and presentation of GIRR, and highlight the importance of including radiation recall as part of a differential diagnosis when a patient undergoing chemotherapy experiences an inflammatory reaction at a prior site of radiation.\n\nKeywords\nBreast cancerGemcitabineRadiationBone metastasis\n==== Body\nIntroduction\nRadiation recall describes a well-known, but poorly understood phenomenon by which administration of chemotherapy or another systemic agent induces an inflammatory reaction within a previously irradiated field [1]. Radiation recall was first described in 1959, when it was found that latent effects of radiation, such as dermatitis, could be induced by actinomycin D [2]. Though clinically rare, since that time radiation recall has been observed for various other systemic agents and inciting factors [3]. While the recall phenomenon is most commonly reported as dermatitis, it has also been observed in other organs including the lung, intestine, and muscles [1, 4, 5, 6]. Gemcitabine has previously been implicated in radiation recall. When reported, it is noted to preferentially affect internal tissue and organs [7]. Herein we report a case of a 39-year-old woman with myositis that is clinically consistent with gemcitabine-induced radiation recall (GIRR) myositis. We also review reported cases of GIRR myositis and discuss the findings and implications.\n\nCase Description\nEvents are outlined in the timeline (Fig. 1) and summarized below. In 2008, the 39-year-old patient was diagnosed with metastatic ER-negative, PR-negative, HER2-positive cancer. At initial presentation, PET scan demonstrated both regional lymph node involvement and osseous metastases. She was started on systemic therapy with Adriamycin and Cytoxan, followed by Taxol and Herceptin. Subsequent therapies included maintenance single-agent Herceptin, followed by Herceptin and lapatinib. By late 2011, her osseous disease showed complete radiologic response on PET scan, and she was offered local therapy to the primary tumor. In January 2012, she underwent a right mastectomy, with ypT2N1a disease, followed by postmastectomy radiation up to 50 Gy with a 10-Gy chest wall boost.\n\nIn late August 2012, she presented with a painful osseous lesion at the T12 vertebra and an impending pathologic fracture of the left distal femur. She underwent surgical stabilization of the femur with rod placement, followed by postoperative radiotherapy, 30 Gy in 10 fractions (Fig. 2a). T12 was treated with single-fraction stereotactic body radiotherapy (SBRT) up to 24 Gy.\n\nIn December 2012, gemcitabine (1,000 mg/m2, days 1 and 8) and Herceptin were given in a 21-day cycle. In January 2013, she presented to the Emergency Department with leg swelling, shortness of breath, and pleuritic chest pain to the lower thorax. Physical examination noted left leg swelling and some mild effusion of the left knee. The ultrasound was negative for deep vein thrombosis (DVT), and the chest CT was negative for pulmonary embolism. Symptoms were attributed to a viral syndrome with associated pleurisy.\n\nThe patient's symptoms had worsened at the time of her reexamination by oncology on March 2013. PET scan showed increased FDG activity and edema in the left thigh that was thought to be consistent with postradiation inflammatory changes (Fig. 2b). MRI of the thoracic spine demonstrated paraspinal muscle fluid collections and a new T12 fracture, and chemotherapy was held. CT-guided biopsy of the paraspinal fluid collection was negative for abscess or malignancy. Although a T12 vertebroplasty improved the chest/back pain and her swelling, her leg pain persisted.\n\nOn March 19, 2013, gemcitabine and Herceptin were resumed with a 20% gemcitabine dose reduction. Within 2 days, she developed worsening leg pain and swelling, and required the use of a cane for ambulation. Repeat extremity ultrasound showed no evidence of DVT, but revealed marked, diffuse enlargement of the vastus medialis or rectus femoris muscles of the left thigh, suggestive of myositis. At that time, her providers noted that her symptoms appeared and worsened following each gemcitabine administration, but improved off chemotherapy. Given the temporal relationship and other negative evaluation, the patient's symptoms were attributed to GIRR from the prior palliative radiotherapy to the left femur. Gemcitabine was stopped, and she was started on dexamethasone and physical therapy. The patient required dexamethasone for relief of her symptoms until August 2013. After a slow taper, she regained leg function and was not rechallenged with gemcitabine.\n\nOver the subsequent 3 years, she had received treatment with Herceptin, ado-trastuzumab, and eribulin/Herceptin without recurrence of the symptoms. Gait was described as normal at the most recent follow-up, and she was described as physically active, engaging in regular exercise. In retrospect, it is also possible that the exacerbation of pain and fluid collection within the paraspinal muscles of T12 seen in March of 2013 may have been related to recall myositis in that region.\n\nLiterature Review\nA literature search was performed using the search terms “gemcitabine,” “radiation,” “recall,” and “myositis” to compile known reports of GIRR myositis (Table 1, Table 2, Table 3). Twenty-one cases were identified as having myositis in a radiation port following gemcitabine treatment. Fractionated radiation doses ranged from 28 to 70.2 Gy.\n\nThe time interval between radiation and chemotherapy initiation ranged from 0 days to 4 months. The majority had chemotherapy more than 1 month after radiotherapy. The time between radiation and onset of recall symptoms varied from 4 weeks to 5.5 months. Only 1 patient had symptoms less than 1 month after radiation, 20 were ≥3 months, 10 were ≥4 months, and 7 were ≥5 months. All patients achieved at least partial improvement of their symptoms with discontinuation of gemcitabine, regardless of whether their treatment consisted of steroids (9 patients), NSAIDs (5 patients), analgesics (4 patients), or no treatment at all (2 patients). Out of the 9 confirmed patients who resumed chemotherapy following myositis, 5 patients underwent gemcitabine rechallenge, with only 1 patient requiring concomitant steroids for symptom control.\n\nThe patient described in the present report is consistent with other reported cases. The time intervals between chemotherapy, radiotherapy, and the onset of symptoms are within the range of the other cases. The current case of possible myositis at T12 was the only case associated with a single fraction of ablative radiotherapy. Interestingly, our patient had prior chest wall radiotherapy, but did not develop evidence of recall in that location. In review of the literature, this is consistent with other cases in which recall myositis did not appear in all prior sites of radiotherapy. Remote courses were less often affected by recall myositis. These findings are also consistent with prior reviews of radiation recall that suggest a possible relationship between the time interval from radiation to chemotherapy and the severity of recall symptoms [1, 3, 8]. However, such a correlation likely depends on the relationship between several factors, such as drug type, dosage, radiation location, radiation dosage, and timing of each treatment [3].\n\nDiscussion\nRadiation recall is a delayed inflammatory response at a site of prior radiation [9, 10]. GIRR has been noted to have a predilection for soft tissue and internal organs, resulting in a less typical appearance of radiation recall. For example, GIRR has been documented to cause pseudocellulitis, acute ascending colitis, abdominal wall and subcutaneous fat stranding, optic neuritis, lymphangitis, rectal hemorrhage, brainstem radionecrosis, and myositis [5, 9, 11, 12, 13]. These atypical presentations highlight the importance of clinical awareness of GIRR.\n\nThe diagnosis of GIRR myositis is challenging, as it may appear similar to infection, thrombosis, or other sources of inflammation [14]. A few key signs may help distinguish this condition. Primarily, the inflammation is confined to a prior radiation portal. Furthermore, there is a temporal relationship between the timing of gemcitabine administration and appearance of symptoms [9]. Radiologic studies may be used to support the diagnosis of myositis with appearance of swelling and edema of the underlying musculature. They may also assist in ruling out other potential etiologies [15]. Because reported cases of myositis have been associated with elevated creatinine kinase and even compartment syndrome, appropriate recognition and treatment is essential to facilitate recovery and minimize morbidity [10, 16, 17]. Review of cases suggests that the most important factor for resolution is the discontinuation of gemcitabine, with the potential use of anti-inflammatory medications.\n\nThe mechanisms of action of radiation recall remain poorly understood. However, the varied presentations of GIRR, even within an individual's prior sites of radiotherapy, suggest that multiple factors influence both the appearance and severity of recall. Jeter et al. [11] proposed that the doses of gemcitabine of 600 mg/m2 or higher may pose a higher recall risk. Others suggest that higher radiation treatment doses or shorter intervals between radiotherapy and chemotherapy may influence recall development [9]. However, these are not well-defined risk factors. With an increased use of gemcitabine across many tumor types, along with routine use of definitive and palliative radiotherapy, clinicians should be alerted to this possible complication.\n\nWe suspect that the exacerbation of pain at the site of T12 SBRT along with the MRI and biopsy findings are consistent with a focal recall myositis at that location. Our patient did not have further exacerbation of pain at that site with the dose-reduced gemcitabine. This suggests that the intervention with vertebroplasty may have affected the local environment. The underlying recall mechanism may also have differed from that in the leg. Radiation recall at an SBRT-treated site had been reported in the past, although the recall effect was induced by sorafenib and manifested itself in the form of dermatitis [18].\n\nDue to its rare and unpredictable onset, radiation recall continues to be a poorly understood phenomenon. This is further complicated by the possibility that there are multiple mechanisms for different medications (gemcitabine, carboplatin, etc.) and/or types of recall (dermatitis, myositis, etc.). Current hypotheses for explaining radiation recall include sensitivity of descendants of cells that survive radiation, changes in local vasculature, and drug-induced hypersensitivity reactions [1]. There is not enough evidence to support any definite mechanism [1, 9]. However, the drug-induced hypersensitivity hypothesis appears to best explain the characteristics of radiation recall. This hypothesis describes radiation recall as a nonimmune inflammatory reaction triggered by certain drugs at a site where the inflammatory threshold has been lowered by radiation. Prior radiation to a specific site may induce constant low-level expression of several inflammatory cytokines, including IL-1, IL-6, PGDF-β, TNF-α, and TGF- β [18]. Introduction of drugs such as gemcitabine may then lead to upregulation of such inflammatory cytokines inducing the recall reaction [1]. This theory is further supported by the various clinical presentations of radiation recall, including the timing of onset, the lack of worsening reactions following rechallenge in some cases, and the induction of recall from noncytotoxic agents (such as simvastatin) [1, 8].\n\nConclusion\nIn conclusion, GIRR myositis is a rare, but significant reaction that may present like other conditions such as DVT or infection. As such, it should be part of the differential diagnosis when a patient on gemcitabine reports pain and swelling to a previously irradiated area, although other causes should be thoroughly investigated. In particular, GIRR myositis should be considered when there is a shorter time interval between the completion of radiation and the initiation of chemotherapy. Discontinuation of chemotherapy and possibly the use of anti-inflammatory medications are important steps to reduce symptoms and improve the patient's quality of life. In some cases, patients have been successfully rechallenged with gemcitabine, although that may not always be possible.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose. IRB approval was obtained.\n\nDisclosure Statement\nThe authors declare that there is no conflict of interest.\n\nFig. 1 Timeline of the case.\n\nFig. 2 Top left: radiation fields of the left femur, with sagittal (top left), coronal (top right), and axial (bottom) views. The isodose levels shown are 16.7, 50, 95, and 100%. Top right: PET/CT showing edema and increased FDG uptake of the left thigh, consistent with myositis, with front-facing 3D (top) and axial (bottom) views. Bottom: MRI showing edema of the left thigh, consistent with myositis, with T1-weighted coronal images (top left), T2-weighted coronal images (top right), and T1-weighted axial images (bottom).\n\nTable 1 Collection of previous case reports of gemcitabine-induced radiation recall myositis\n\nAuthor\tCancer type\tRadiation location\tDose\tCTx regimen\tTime between RT and gemcitabine start\tTime between RT completion and recall symptoms\tClinical symptoms/signs\tUnder-going chemo at time of symptom onset?\tImaging findings (and modality)\tTreatment\tOutcome\tPost-treatment CTx?\t\nAlco et al. [19]\tPancreatic adeno carcinoma\tPancreas and regional lymph nodes\t1.8 Gy × 25 (45 Gy)\tGemcitabine 1,250 mg/m2/week, 3 weeks in 4 week cycle\t0 (concurrent)\t20 weeks\tTender mass, pain, and swelling of abdominal muscles\tNo (last dose 1 month before onset)\tEdema and inflammation of the anterior and right abdominal wall muscles (MRI)\tCorticosteroids, NSAIDs, and gabapentin\tSymptom reduction in 1 week; clinical and radiologic findings resolved in 1 month\tN/A\t\n\t\nAlco et al. [19]\tNSCLC\tLeft upper lobe and ipsilateral L2 lymph nodes\t62 Gy total (fractions N/A)\tGemcitabine (1,200 m/m2 for 1–8 days), and carboplatin (AUC 5.5 for days 1 and 30), for 3 cycles; gemcitabine reduced to 800 mg/m2 after first cycle because of intolerance\tN/A (CTx started after RT)\tN/A (∼104 days after starting CTx)\tPain and swelling of left breast and chest wall, with reduced ROM of arm and shoulder\tNo (last dose 2 weeks before onset)\tEdema and soft tissue reaction at the left breast musculature and subcutaneous soft tissue (MRI)\tCorticosteroids, NSAIDs, opioids, antihistamines, SOD, pentoxifylline, vitamin E, gabapentin, topical lidocaine and selenium\tMeds did not affect myositis; pain reduced after 4 months, resolved after 9 months, with lasting reduced ROM\tN/A\t\n\t\nDelavan et al. [15]\tBreast cancer\tLeft thigh\t8 Gy × 1 (8 Gy)\n(4 years prior)\n3 Gy × 13 (39 Gy)\n(4 months prior)\tGemcitabine (unknown dosage)\t17 days\t107 days\tIncreasing pain and swelling to the posterior left thigh, warm to palpation\tNo (last dose ∼3.5 weeks before onset)\tIncreased signal intensity in the posterior thigh musculature (MRI)\tDexamethasone\tSymptoms improved over 3 days, symptom free 1 week later\tNot reported\t\n\t\nEckardt et al. [17]\tSynovial sarcoma\tRight forearm\t3.5 Gy × 8 (28 Gy) preop, followed by 2 Gy × 10 (20 Gy) boost\tGemcitabine (900 mg/m2 on days 1 and 8) and docetaxel (100 mg/m2 on day 8) for 2 cycles at 21 and 28 days, respectively\t5 days\t40 days\tSwelling of the right forearm with progressively worsening range of motion, compartment syndrome\tNo (last dose 7 days before onset)\tEdema of the flexor compartment muscles, with layering fluid along the superficial fascia and between the muscles (MRI)\tDexamethasone\tPatient required slow taper corticosteroids for multiple months; patient continues to have muscle edema and myositis on 1-year follow-up MRI.\tNo\t\n\t\nFakih [20]\tPancreatic adenocarcinoma\tPancreas\t1.8 Gy × 28 (50.4 Gy)\tConcurrent fluorouracil (2,000 mg/m2/day for 5 days a week) and gemcitabine (200 mg/m2 weekly) followed by adjuvant gemcitabine (1,000 mg/m2/week for 3 weeks every 4-week cycle)\t0 days (concurrent)\n∼21 days to initiation of adjuvant dose gemcitabine\t∼18 weeks\tErythematosus rash overlying a tender mass in the epigastrium\tYes\tEnlarged left and right rectus abdominus with areas of heterogeneity (CT)\tNone, other than withholding gemcitabine\tComplete resolution\tYes (capecitabine, docetaxel, and cisplatin)\t\n\t\nFogarty et al. [21]\tNSCLC\tLung\t3 Gy × 12 (36 Gy)\tGemcitabine (1,000 mg/m2 on days 1 and 8) and carboplatin (AUC 5, day 1)\t∼3 months\t∼4.5 months\tPosterior chest wall pain with localized tenderness, skin rash, elevated CK, ESR\tYes\tEnhancement of the chest wall musculature consistent with nonspecific inflammatory change (MRI)\tNSAIDS, oral steroids\tSymptoms improved but persistent minor skin changes and subcutaneous fibrosis\tNot reported\t\nTable 2 Collection of previous case reports of gemcitabine-induced radiation recall myositis (continued)\n\nAuthor\tCancer type\tRadiation location\tDose\tCTx regimen\tTime between RT and gemcitabine start\tTime between RT completion and recall symptoms\tClinical symptoms/signs\tUndergoing chemo at time of symptom onset?\tImaging findings (and modality)\tTreatment\tOutcome\tPost-treatment CTx?\t\nFriedlander et al. [7]\tPancreatic adenocarcinoma\tPancreas and regional lymph nodes\t1.8 Gy × 28 (50.4 Gy)\tGemcitabine (40 mg/m2 biweekly and concurrently with radiation, followed by 1,000 mg/m2 weekly for 3 weeks per month)\t39 days\t3 months\tTenderness of rectus muscles, mild rash, elevated CK\tYes\tIncreased signal in the subcutaneous tissue of the anterior abdominal wall (MRI)\tCorticosteroids\tComplete resolution, no recurrence after steroid tapering\tNot reported\t\n\t\nGanem et al. [22]\tSquamous cell carcinoma of the lung\tPelvis\t3 Gy × 11 (33 Gy)\tGemcitabine (1,000 mg/m2 on days 1, 8, 15) and cisplatin (100 mg/m2 on day 15)\t1.5 months\t5 months\tRight buttock pain\tYes\tHypersignal and edema on gluteal soft tissue (MRI)\tOral opiates, antibiotics, steroids\tAlleviation over the course of 3 months\tNot reported\t\n\t\nGraf et al. [16]\tNSCLC and anal cancer, history of dermatomyositis\tPelvis\tNot reported\t5-FU and MMC given with pelvic RT for anal cancer, carboplatin and gemcitabine (dosage not given)\t2 months\t4 months\tErythema, swelling, warmth, and tenderness of the buttocks and groin area\tYes\tHigh signal in the bilateral gluteal maximus, quadratus femoris, adductor magnus, obturator externus and right iliopsoas muscles (MRI), elevated CK\tPrednisone and opiate analgesia\tGradual improvement with steroids\tNot reported\t\n\t\nGrover et al. [5]\tAdenocarcinoma and neuroendocrine neoplasm, unknown primary\tLeft hip and left acromion\t3 Gy × 10 (30 Gy)\tGemcitabine (1,250 mg/m2) and carboplatin (AUC 5)\t2 weeks\t4 weeks\tWorsening pain in left shoulder and hip\tYes\tSoft tissue edema of the muscles adjacent to the left acromion and the left hip (MRI)\tNarcotics\tPain resolved 5 months after radiotherapy\tGemcitabine therapy continued\t\n\t\nHoran et al. [23]\tNSCLC\tLung\t3 Gy × 8 (24 Gy)\tGemcitabine (1,000 mg/m2, weekly)\t2 months\t∼13 weeks\tPain and swelling of the right pectoralis major, biopsy proven muscle necrosis\tYes\tThickening of right pectoralis major muscle (CT)\tAnalgesics\tSymptoms gradually declined when gemcitabine was stopped\tGemcitabine re-challenge, no further symptoms\t\n\t\nJeter et al. [11]\tPancreatic adenocarcinoma\tPancreas\t1.8 Gy × 28 (50.4 Gy)\tGemcitabine (1,000 mg/m2 one dose; followed by 750 mg/m2 weekly for 9 months)\t3 weeks\t3 months\tAbdominal wall tenderness and erythema\tYes\tSubcutaneous fat stranding and decreased density of rectus muscles in radiation portal (CT)\tIbuprofen\tSymptoms responsive to ibuprofen\tGemcitabine re-challenge, no further symptoms\t\n\t\nLock et al. [24]\tHepatic adenocarcinoma\tLiver\t2.94 Gy × 15 (44.1 Gy)\tGemcitabine (1,000 mg/m2 for days 1 and 8 for a 3-week cycle)\t8 weeks\t18 weeks\tAbdominal discomfort with induration; overlying skin erythema\tYes\tEnhancement of abdominal muscles with thickening (MRI)\tIbuprofen, vitamin E, and vitamin C\tGradual resolution over the course of 6 weeks\tGemcitabine was continued, reduction of symptoms\t\n\t\nMiura et al. [25]a\tNSCLC\tRight hip\t2 Gy × 25 (50 Gy)\tConcurrent cisplatin (80 mg/m2 day 1) and vinorelbine (20 mg/m2, days 1, 8, and 15) followed by gemcitabine (800 mg/m2 biweekly)\t1 month\t3 months\tRight thigh pain\tN/A\tEdema within right thigh muscles (MRI)\tAnalgesics\tGradual resolution of symptoms\tYes (unknown regimen)\t\nTable 3 Collection of previous case reports of gemcitabine-induced radiation recall myositis (continued)\n\nAuthor\tCancer type\tRadiation location\tDose\tCTx regimen\tTime between RT and gemcitabine start\tTime between RT completion and recall symptoms\tClinical symptoms/signs\tUndergoing chemo at time of symptom onset?\tImaging findings (and modality)\tTreatment\tOutcome\tPost-treatment CTx?\t\nMiura et al. [25]a\tNSCLC\tLung\t2 Gy × 30 (60 Gy)\tConcurrent cisplatin and (80 mg/m2 day 1) and vinorelbine (20 mg/m2, days 1 and 8) followed by vinorelbine (13 mg/m2 biweekly) and gemcitabine (800 mg/m2 biweekly)\t3 months\t5.5 months\tUpper chest muscle pain\tN/A\tEnhancement of pectoralis muscles (MRI)\tNSAIDs\tImprovement of symptoms\tYes (gefitinib)\t\n\t\nO'Regan et al. [10]\tHodgkin lymphoma\tChest\t1.8 Gy × 22 (39.6 Gy)\t4 cycles of gemcitabine, vinorelbine, and liposomal doxorubicin (unknown dosage)\t2 months\t5 months\tWorsening bilateral anterior chest pain, pectoralis muscle necrosis by biopsy\tNo (last dose 2.5 weeks before presentation)\tDiffuse bilateral swelling of the pectoral muscles with mild stranding of the adjacent subcutaneous fat (CT)\tAnalgesics\tComplete resolution\tNot reported\t\n\t\nPatel et al. [26]\tNasopharyngeal carcinoma\tHead and neck\t70.2 Gy total (fractions N/A)\tGemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks\tN/A (CTx started after RT)\t6 months\tBilateral neck pain and swelling with restriction of neck movement\tYes\tDiffuse bilateral soft-tissue edema of the muscles in the cervical neck (MRI)\tDexamethasone\tSymptoms worsened with tapering of dexamethasone/low-dose prednisone started without recurrence.\tNot reported\t\n\t\nPinson et al. [27]b\tNSCLC\tLung\t3 Gy × 10 (30 Gy)\tCarboplatin (AUC 5 on day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8), 3-week cycle\t4 weeks\t14 weeks\tSkin erythema, upper chest muscle pain\tYes\tSwelling of the pectoralis major and pectoralis minor (CT)\tIbuprofen\tComplete resolution in 3 weeks\tNot reported\t\n\t\nSquire et al. [14]\tNSCLC\tPelvis (left sacroiliac and left acetabulum)\t3 Gy × 10 (30 Gy)\tGemcitabine (1,000 mg/m2)\t1 month\t3 months\tTenderness and discomfort to left hip and buttock, elevated CK\tYes\tEdema in gluteal muscles (MRI)\tOral prednisone\tSymptoms worsened with tapering of prednisone and improved with increasing doses\tGemcitabine continued for 5 more months, symptoms controlled with prednisone\t\n\t\nWelsh et al. [28]\tBladder cancer\tPara-sacral region\t2.5 Gy × 18 (45 Gy)\tGemcitabine and cisplatin (unknown dosage)\t4 weeks\t5 months\tPain in bilateral superolateral gluteal regions\tYes\tBand-like pattern of edema on gluteal region (MRI)\tNSAIDs, prednisone\tComplete resolution after 6 weeks, but with visible residual scar and muscular atrophy\tCTx continued\t\n\t\nCurrent\tBreast cancer\tLeft thigh (femur)/T12 vertebra\t3 Gy × 10 (30 Gy)/24 Gy × 1 (24 Gy)\tGemcitabine (1,000 mg/m2 for days 1 and 8) and herceptin (342 mg every 3 weeks)\t54 days/79 days\t3 months/5.7 months\tWorsening leg pain and swelling/Chest and back pain\tYes\tEnlargement of muscles of the left thigh (US)/ T12 fracture and paraspinal fluid collections (MRI)\tDexamethasone/T12 vertebroplasty\tProgressive resolution of symptoms after 4-month course of dexamethasone/Reduction of chest and back pain following vertebroplasty\tYes (herceptin)\t\na Paper is written in Japanese.\n\nb Paper is written in Dutch.\n==== 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preferentially involves internal tissue and organs Cancer 2004 May 100 (9) 1793 9 15112258 \n8 Camidge R Price A Characterizing the phenomenon of radiation recall dermatitis Radiother Oncol 2001 Jun 59 (3) 237 45 11369064 \n9 Burris HA 3rd Hurtig J Radiation recall with anticancer agents Oncologist 2010 15 (11) 1227 37 21045191 \n10 O'Regan KN Nishino M Armand P Kelly PJ Hwang DG Di Salvo D Sonographic features of pectoralis muscle necrosis secondary to gemcitabine-induced radiation recall case report and review of current literature J Ultrasound Med 2010 Oct 29 (10) 1499 502 20876906 \n11 Jeter MD Jänne PA Brooks S Burstein HJ Wen P Fuchs CS Gemcitabine-induced radiation recall Int J Radiat Oncol Biol Phys 2002 Jun 53 (2) 394 400 12023144 \n12 Nishimoto K Akise Y Miyazawa M Kutsuki S Hashimoto S Uchida A A Case of Severe Rectal Hemorrhage Possibly Caused by Radiation Recall after Administration of Gemcitabine Keio J Med 2016 65 (1) 16 20 27040885 \n13 Tan DH Bunce PE Liles WC Gold WL Gemcitabine-related “pseudocellulitis” report of 2 cases and review of the literature Clin Infect Dis 2007 Sep 45 (5) e72 6 17682983 \n14 Squire S Chan M Feller E Mega A Gold R An unusual case of gemcitabine-induced radiation recall Am J Clin Oncol 2006 Dec 29 (6) 636 17149004 \n15 Delavan JA Chino JP Vinson EN Gemcitabine-induced radiation recall myositis Skeletal Radiol 2015 Mar 44 (3) 451 5 25193536 \n16 Graf SW Limaye VS Cleland LG Gemcitabine-induced radiation recall myositis in a patient with dermatomyositis Int J Rheum Dis 2014 Jul 17 (6) 696 7 24283707 \n17 Eckardt MA Bean A Selch MT Federman N A child with gemcitabine-induced severe radiation recall myositis resulting in a compartment syndrome J Pediatr Hematol Oncol 2013 Mar 35 (2) 156 61 23274380 \n18 Hsieh CH Lin SC Shueng PW Kuo DY Recall radiation dermatitis by sorafenib following stereotactic body radiation therapy Onco Targets Ther 2014 Jun 7 1111 4 24971021 \n19 Alco G Gemcitabine induced radiation recall myositis report of two cases Int J Hematol Oncol 2009 19 (4) 249 53 \n20 Fakih MG Gemcitabine-induced rectus abdominus radiation recall JOP 2006 May 7 (3) 306 10 16685112 \n21 Fogarty G Ball D Rischin D Radiation recall reaction following gemcitabine Lung Cancer 2001 Aug–Sep 33 (2–3) 299 302 11551425 \n22 Ganem G Solal-Celigny P Joffroy A Tassy D Delpon A Dupuis O Radiation myositis the possible role of gemcitabine Ann Oncol 2000 Dec 11 (12) 1615 6 11205473 \n23 Horan G Smith SL Podd TJ Gemcitabine-induced radiation necrosis of the pectoralis major muscle Clin Oncol (R Coll Radiol) 2006 Feb 18 (1) 85 \n24 Lock M Sinclair K Welch S Younus J Salim M Radiation recall dermatitis due to gemcitabine does not suggest the need to discontinue chemotherapy Oncol Lett 2011 Jan 2 (1) 85 90 22870134 \n25 Miura G Matsumoto T Tanaka N Emoto T Kawamura T Matsunaga N Two cases of radiation myositis probably induced by recall phenomenon Nihon Igaku Hoshasen Gakkai Zasshi 2003 Sep 63 (8) 420 2 14587415 \n26 Patel SC Gemcitabine-induced radiation recall myositis in a patient with relapsed nasopharyngeal carcinoma Pract Radiat Oncol 2017 Jan–Feb 7 (1) e19 e22 27637134 \n27 Pinson PJ Griep C Sanders WH Lelie B Myositis as a “radiation-recall phenomenon” following palliative chemotherapy with carboplatin-gemcitabin for non-small-cell pulmonary carcinoma Ned Tijdschr Geneeskd 2006 Aug 150 (34) 1891 4 16970014 \n28 Welsh JS Torre TG DeWeese TL O'Reilly S Radiation myositis Ann Oncol 1999 Sep 10 (9) 1105 8 10572610\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Bone metastasis; Breast cancer; Gemcitabine; Radiation",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "168-178",
"pmc": null,
"pmid": "29681817",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "16168567;25413426;23274380;11551425;11205473;16685112;27637134;14587415;17682983;25193536;17149004;20876906;13813586;16477926;16970014;11369064;27040885;24971021;10572610;21045191;12023144;24283707;15112258;22870134;15237594;8625210",
"title": "Gemcitabine-Induced Radiation Recall Myositis: Case Report and Review of the Literature.",
"title_normalized": "gemcitabine induced radiation recall myositis case report and review of the literature"
} | [
{
"companynumb": "US-ACCORD-066146",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nTo illustrate the negative effect of calcium channel blocker (CCB) drugs on the gingival tissues and the reversibility of these lesions.\n\n\nMETHODS\nThe authors examined a forty-eight year-old male patient with drug-induced gingival enlargement associated with diltiazem, a CCB drug. Prior to initiating the proposed periodontal treatment, the patient was advised to consult his physician, for a possible switch to a different anti-hypertensive drug. The patient returned to the clinic three months later with a significant regression of the gingival overgrowth, which was induced by the patient ceasing the prescribed regimen without medical consultation or periodontal intervention.\n\n\nCONCLUSIONS\nAlthough CCBs are effective cardiovascular drugs, they can negatively impact the oral health by promoting gingival overgrowth in some patients. Substitution of these drugs is strongly recommended prior to any periodontal intervention in order to improve prognosis and prevent recurrence, and should be done only by the medical providers.",
"affiliations": null,
"authors": "Livada|Rania|R|;Shelton|Wes|W|;Bland|Paul S|PS|;Shiloal|Jacob|J|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D006852:Hydrochlorothiazide; D004110:Diltiazem",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3385",
"issue": "95(2)",
"journal": "The Journal of the Tennessee Dental Association",
"keywords": null,
"medline_ta": "J Tenn Dent Assoc",
"mesh_terms": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D055113:Chronic Periodontitis; D012534:Dental Scaling; D004110:Diltiazem; D057915:Drug Substitution; D005500:Follow-Up Studies; D019214:Gingival Overgrowth; D006801:Humans; D006852:Hydrochlorothiazide; D008297:Male; D008875:Middle Aged; D009910:Oral Hygiene; D016745:Root Planing",
"nlm_unique_id": "7503125",
"other_id": null,
"pages": "11-4; quiz 15-6",
"pmc": null,
"pmid": "27008764",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Regression of Calcium Channel Blocker--Induced Gingival Enlargement in the Absence of Periodontal Therapy.",
"title_normalized": "regression of calcium channel blocker induced gingival enlargement in the absence of periodontal therapy"
} | [
{
"companynumb": "US-BAUSCH-BL-2016-020853",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DILTIAZEM HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "We present the case of a 70-year-old patient affected by metastatic castration-resistant prostate cancer. He underwent radical prostatectomy in 2007 and subsequent adjuvant radiotherapy and hormonal therapy for 2 years. In 2011, he developed bilateral lung metastases, and therefore he received chemotherapy (eight cycles of docetaxel 75 mg/sqm every 3 weeks) with partial remission; rechallenge with the same drug was performed 7 months later due to recurrence of lung metastases. In August 2013, abiraterone acetate was started for progression of lung metastases. The patient received abiraterone for almost 5 years with stability of disease. During the 60th cycle of abiraterone, a diagnosis of acute myeloid leukemia was made.",
"affiliations": "Departments of Oncology.;Pathology, ASST-Lariana, Ospedale Sant'Anna, Como, Italy.;Departments of Oncology.",
"authors": "Bolzacchini|Elena|E|;Patriarca|Carlo|C|;Giordano|Monica|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000069501:Abiraterone Acetate",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000988",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "32(1)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000970:Antineoplastic Agents; D018450:Disease Progression; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008175:Lung Neoplasms; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D016896:Treatment Outcome",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "102-104",
"pmc": null,
"pmid": "32932280",
"pubdate": "2021-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abiraterone acetate and acute leukemia: a casual association?",
"title_normalized": "abiraterone acetate and acute leukemia a casual association"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-337315",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABIRATERONE"
},
"dru... |
{
"abstract": "Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.",
"affiliations": "Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.;Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.",
"authors": "Bhatnagar|Bhavana|B|;Zhao|Qiuhong|Q|;Mims|Alice S|AS|;Vasu|Sumithira|S|;Behbehani|Gregory K|GK|;Larkin|Karilyn|K|;Blachly|James S|JS|;Blum|William|W|;Klisovic|Rebecca B|RB|;Ruppert|Amy S|AS|;Orwick|Shelley|S|;Oakes|Christopher|C|;Ranganathan|Parvathi|P|;Byrd|John C|JC|;Walker|Alison R|AR|;Garzon|Ramiro|R|",
"chemical_list": "D006834:Hydrazines; D014230:Triazoles; C585161:selinexor; D000077209:Decitabine; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2019.1665664",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "61(2)",
"journal": "Leukemia & lymphoma",
"keywords": "Acute myeloid leukemia; clinical trials; decitabine; selinexor",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D001374:Azacitidine; D000077209:Decitabine; D006801:Humans; D006834:Hydrazines; D015470:Leukemia, Myeloid, Acute; D014230:Triazoles",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "387-396",
"pmc": null,
"pmid": "31545113",
"pubdate": "2020-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10502596;23373539;26202935;26803155;27211268;28468797;27323910;14673054;27557643;27458288;25716206;23817294;24144313;22677130;27358488;20368434;26926685;23270581;11585760;24631835;32645169",
"title": "Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study.",
"title_normalized": "selinexor in combination with decitabine in patients with acute myeloid leukemia results from a phase 1 study"
} | [
{
"companynumb": "US-OTSUKA-2019_033975",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SELINEXOR"
},
"drugadditional": null,
"... |
{
"abstract": "Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.",
"affiliations": "Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY.;Hospital 12 de Octubre, H12O-CNIO, Haematological Malignancies Clinical Research Unit, Universidad Complutense, Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.;University Hospital of Salamanca/Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.;Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.;Hôpital Bretonneau, Centre Hospitalier Régional Universitaire, Tours, France.;Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.;Hôpital Saint Louis, Paris, France.;Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Navarra, Spain.;Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX.;University of Chicago Medical Center, Chicago, IL.;Janssen Research & Development, LLC, Leiden, The Netherlands.;Janssen Research & Development, LLC, Raritan, NJ.;Janssen Research & Development, LLC, Spring House, PA.;Janssen Research & Development, LLC, Spring House, PA.;Janssen Research & Development, LLC, Raritan, NJ.;Winship Cancer Institute, Emory University, Atlanta, GA; and.;University Hospital Hôtel-Dieu, Nantes, France.",
"authors": "Chari|Ajai|A|;Martinez-Lopez|Joaquín|J|0000-0001-7908-0063;Mateos|María-Victoria|MV|;Bladé|Joan|J|;Benboubker|Lotfi|L|0000-0003-0167-8836;Oriol|Albert|A|0000-0001-6804-2221;Arnulf|Bertrand|B|;Rodriguez-Otero|Paula|P|;Pineiro|Luis|L|;Jakubowiak|Andrzej|A|;de Boer|Carla|C|;Wang|Jianping|J|;Clemens|Pamela L|PL|;Ukropec|Jon|J|;Schecter|Jordan|J|;Lonial|Sagar|S|;Moreau|Philippe|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; D009842:Oligopeptides; C556306:daratumumab; C524865:carfilzomib; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019000722",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "134(5)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D011379:Prognosis; D012008:Recurrence; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "421-431",
"pmc": null,
"pmid": "31113777",
"pubdate": "2019-08-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21799510;29866475;21187443;28151712;29231133;27028734;25184863;25760767;25439696;30828799;27557302;29285538;26671818;30237264;30536810;29991494;16855634;21292775;27896689;28679737;27491641;24007748;30098165;30403938;27316683;30237262;27705267;27222480;31097405",
"title": "Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.",
"title_normalized": "daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "US-AMGEN-USASP2019086172",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. The treatment of UC is challenging, especially when it is associated with primary sclerosing cholangitis (PSC), a chronic inflammatory disease of the bile ducts that affects around 5% of patients with UC, and leads to an increased risk of cholangiocarcinoma and colorectal cancer. Microbiota is considered to play an important role in the pathogenesis of UC, although the efficacy of antibiotics in this context is only limited and transient. Several studies have investigated the use of antibiotics for the treatment of PSC in adult and pediatric populations, with conflicting results. In this brief report, we describe the effect of oral vancomycin treatment in three patients with UC and PSC refractory to conventional and biologic therapies. All three patients achieved clinical remission and mucosal healing with vancomycin 500 mg twice a day administered orally. Maintenance treatment with oral vancomycin was well tolerated and led to sustained clinical and endoscopic remission in all three patients. Oral vancomycin also improved liver function tests in two patients who did not have pre-existing cirrhosis.",
"affiliations": "Gastroenterology and Hepatology Department.;Gastroenterology and Hepatology Department, Claude Huriez Hospital, University of Lille 2, Lille, France.;Department of Gastroenterology, Mersey Community Hospital, Tasmanian Health Service North West Region, Latrobe, Tasmania, Australia.;Gastroenterology and Hepatology Department, Claude Huriez Hospital, University of Lille 2, Lille, France.;Gastroenterology and Hepatology Department.;Gastroenterology and Hepatology Department.;Digestive Surgery and Transplantation Department, Montpellier University Hospital, Montpellier.;Digestive Surgery and Transplantation Department, Montpellier University Hospital, Montpellier.;Gastroenterology and Hepatology Department, Claude Huriez Hospital, University of Lille 2, Lille, France.;Gastroenterology and Hepatology Department, Claude Huriez Hospital, University of Lille 2, Lille, France.;Gastroenterology and Hepatology Department.",
"authors": "de Chambrun|Guillaume Pineton|GP|;Nachury|Maria|M|;Funakoshi|Natalie|N|;Gerard|Romain|R|;Bismuth|Michael|M|;Valats|Jean-Christophe|JC|;Panaro|Fabrizio|F|;Navarro|Francis|F|;Desreumaux|Pierre|P|;Pariente|Benjamin|B|;Blanc|Pierre|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000001223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "30(10)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000900:Anti-Bacterial Agents; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D008297:Male; D012074:Remission Induction; D019233:Retreatment; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1247-1252",
"pmc": null,
"pmid": "30052539",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral vancomycin induces sustained deep remission in adult patients with ulcerative colitis and primary sclerosing cholangitis.",
"title_normalized": "oral vancomycin induces sustained deep remission in adult patients with ulcerative colitis and primary sclerosing cholangitis"
} | [
{
"companynumb": "FR-BAUSCH-BL-2018-031155",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "Although uncommon, torsades de pointes (TdP) associated with astemizole and/or erythromycin use have been reported previously. We describe a 30-year-old woman who had congenital prolongation of QT interval and TdP occurred after taking astemizole and erythromycin. Temporary cardiac pacing was successful in suppressing TdP. Prolongation of QT interval had good response to oral propranolol.",
"affiliations": "Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan, ROC.",
"authors": "Hsieh|M H|MH|;Chen|S A|SA|;Chiang|C E|CE|;Tai|C T|CT|;Lee|S H|SH|;Wen|Z C|ZC|;Chang|M S|MS|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D006634:Histamine H1 Antagonists; D004917:Erythromycin; D016589:Astemizole; D011433:Propranolol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/0167-5273(96)02582-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "54(1)",
"journal": "International journal of cardiology",
"keywords": null,
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D016589:Astemizole; D002304:Cardiac Pacing, Artificial; D004562:Electrocardiography; D004917:Erythromycin; D005260:Female; D006634:Histamine H1 Antagonists; D006801:Humans; D008133:Long QT Syndrome; D011433:Propranolol; D012220:Rhinitis; D016171:Torsades de Pointes",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "85-8",
"pmc": null,
"pmid": "8792191",
"pubdate": "1996-04-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-induced torsades de pointes in one patient with congenital long QT syndrome.",
"title_normalized": "drug induced torsades de pointes in one patient with congenital long qt syndrome"
} | [
{
"companynumb": "TW-BAUSCH-BL-2015-013840",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASTEMIZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Adenovirus-induced fulminant hepatitis is rare. It has been reported in children with primary immunodeficiency, following transplantation or while receiving chemotherapy for hematological malignancy. We present the case of an infant recovering from chemotherapy for atypical teratoid rhabdoid tumor (ATRT) in whom a diagnosis of hepatic necrosis due to adenovirus was made.",
"affiliations": "Divisions of Immunology, Hematology, Oncology, Palliative Care and Environmental Health, University of Alberta, Edmonton, Alberta, Canada.;Divisions of Immunology, Hematology, Oncology, Palliative Care and Environmental Health, University of Alberta, Edmonton, Alberta, Canada.;Infectious Disease, University of Alberta, Edmonton, Alberta, Canada.;Gastroenterology and Nutrition, University of Alberta, Edmonton, Alberta, Canada.;Departments of Radiology, University of Alberta, Edmonton, Alberta, Canada.;Divisions of Immunology, Hematology, Oncology, Palliative Care and Environmental Health, University of Alberta, Edmonton, Alberta, Canada.;Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.",
"authors": "McKillop|Sarah J|SJ|;Belletrutti|Mark J|MJ|;Lee|Bonita E|BE|;Yap|Jason Y|JY|;Noga|Michelle L|ML|;Desai|Sunil J|SJ|;Sergi|Consolato|C|",
"chemical_list": "D004279:DNA, Viral",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "57(5)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "adenovirus; atypical teratoid/rhabdoid tumor; cidofovir; hepatic necrosis",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000256:Adenoviridae; D001706:Biopsy; D001932:Brain Neoplasms; D004279:DNA, Viral; D017809:Fatal Outcome; D006525:Hepatitis, Viral, Human; D006801:Humans; D007223:Infant; D008099:Liver; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D009336:Necrosis; D016133:Polymerase Chain Reaction; D018335:Rhabdoid Tumor; D013724:Teratoma",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "974-7",
"pmc": null,
"pmid": "26508178",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adenovirus necrotizing hepatitis complicating atypical teratoid rhabdoid tumor.",
"title_normalized": "adenovirus necrotizing hepatitis complicating atypical teratoid rhabdoid tumor"
} | [
{
"companynumb": "CA-CORDEN PHARMA LATINA S.P.A.-CA-2016COR000077",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"... |
{
"abstract": "Correct diagnosis of seizure type and epilepsy syndrome is the foundation for appropriate antiepileptic drug selection. Inappropriate medication choices occur in the treatment of generalized epilepsy and may aggravate some seizure types, including absence seizures, potentially leading to pseudo-drug resistance. Fortunately, a correct diagnosis of absence seizures is usually not difficult, though rarely demonstrates electroclinical overlap with focal seizures. EEG can be especially misleading when secondary bilateral synchronous discharges occur in patients with focal seizures. However, the semiology of focal seizures associated with mesial temporal lobe epilepsy has a characteristic and consistent semiology that is the mark of this common epilepsy syndrome in adulthood. We recently encountered a 53-year-old female with refractory seizures and a semiology strongly suggesting mesial temporal lobe epilepsy. Instead of focal seizures, prolonged absence seizures were validated by video-EEG monitoring and she became seizure-free after a change to broad-spectrum antiepileptic drugs. This case further expands our understanding of the complexity of semiology in electroclinical classification and the spectrum that may occur in adult absence seizures. It serves to underscore the need for ictal EEG recordings and the importance of concordance with the clinical course during the pre-surgical evaluation of patients with lesions and drug-resistant epilepsy. [Published with video sequences].",
"affiliations": "Department of Neurology, Mayo Clinic, Jacksonville, FL, Department of Neurology, Duke University, Durham, NC.;Department of Neurology, Mayo Clinic, Jacksonville, FL, Department of Neurology, Keesler Air Force Base, Biloxi, MS, USA.;Department of Neurology, Mayo Clinic, Jacksonville, FL.",
"authors": "Hurst|Rebecca|R|;Chiota-McCollum|Nicole|N|;Tatum|William|W|",
"chemical_list": "D000927:Anticonvulsants",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2014.0705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "16(4)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "absence seizures; antiepileptic drugs; focal seizures; temporal lobe epilepsy; video-EEG monitoring",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000927:Anticonvulsants; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D004569:Electroencephalography; D004832:Epilepsy, Absence; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006801:Humans; D008875:Middle Aged; D014743:Videotape Recording",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "471-6",
"pmc": null,
"pmid": "25465725",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adult absence semiology misinterpreted as mesial temporal lobe epilepsy.",
"title_normalized": "adult absence semiology misinterpreted as mesial temporal lobe epilepsy"
} | [
{
"companynumb": "US-APOTEX-2015AP006484",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": null,
... |
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