article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "To rapidly start systemic anticoagulation there are few alternatives to heparin; those that may be used are often less effective and are impractical substitutes for various reasons. We report the cases of seven patients in whom anticoagulant therapy was begun with ancrod instead of heparin for one or more of the following reasons: (1) failure to achieve systemic anticoagulation in response to heparin (e.g., antithrombin III deficiency), (2) heparin-associated complications (e.g., thrombocytopenia, thrombosis, or both), and (3) combined anticoagulation and improved blood rheology considered to be potentially more beneficial than anticoagulation alone (e.g., massive thrombosis). In the cases reported, ancrod permitted systemic anticoagulation equal to that of heparin; this was achieved without bleeding complications. In contrast to streptokinase or urokinase, ancrod does not degrade preformed, fully cross-linked thrombin fibrin; consequently hemorrhagic complications are uncommon. Ancrod appears to be an appropriate alternative to heparin and may be preferable to it in certain circumstances.",
"affiliations": "Departments of Surgery, Ottawa Civic Hospital, Ontario, Canada.",
"authors": "Cole|C W|CW|;Bormanis|J|J|",
"chemical_list": "D006493:Heparin; D000721:Ancrod",
"country": "United States",
"delete": false,
"doi": "10.1067/mva.1988.avs0080059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-5214",
"issue": "8(1)",
"journal": "Journal of vascular surgery",
"keywords": null,
"medline_ta": "J Vasc Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000721:Ancrod; D001780:Blood Coagulation Tests; D005260:Female; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D012307:Risk Factors; D013924:Thrombophlebitis; D014682:Vena Cava, Inferior",
"nlm_unique_id": "8407742",
"other_id": null,
"pages": "59-63",
"pmc": null,
"pmid": "3385879",
"pubdate": "1988-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ancrod: a practical alternative to heparin.",
"title_normalized": "ancrod a practical alternative to heparin"
} | [
{
"companynumb": "CA-PFIZER INC-2020276820",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "The worldwide use of opiates is increasing yet there is little evidence that in long-term, non-cancer patients, they have an efficacious effect on functional outcomes and quality of life measures. Although it seems paradoxical, chronic opiate use may lead to a pro-nociceptive state. Mechanisms for the development of the hyperalgesic state include activation of the opiate bimodal regulatory systems, dynorphin and spinal cord glia. A potential consequence of chronic opiate usage is the development of narcotic bowel syndrome, which is characterized by chronic or intermittent colicky abdominal pain or discomfort that worsens after the narcotic effects of opiates wear off. It is likely that this is an under-recognized diagnosis. We describe here a case of 26-year old female who had visited our institution multiple times with intractable chronic abdominal pain in the context of normal findings on haematological, biochemical, metabolic, endoscopic and radiological investigations. She had been treated with a multitude of opioid agonists with escalating doses. A diagnosis of narcotic bowel syndrome was made. On elective admission her daily analgesic requirements were 150 µg/hr fentanyl, 100 mg oramorph and 400 mg tramadol (equating to 740 mg oral morphine/24 hr). A detoxification regimen was prescribed which included rapid opiate withdrawal couple with the commencement of methadone, lorazepam, clonidine and duloxetine. She was discharged opiate free, with no abdominal pain, 14 days after admission. Clinicians must be aware of narcotic bowel syndrome, which is often erroneously labelled as a functional gastrointestinal disorder, in patients who have been on long-term opiates.",
"affiliations": "Center for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. ; Department of Gastroenterology, Shrewsbury and Telford NHS Trust, Shropshire, UK.",
"authors": "Farmer|Adam D|AD|;Ferdinand|Ella|E|;Aziz|Qasim|Q|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5056/jnm.2013.19.1.94",
"fulltext": "\n==== Front\nJ Neurogastroenterol MotilJ Neurogastroenterol MotilJNMJournal of Neurogastroenterology and Motility2093-08792093-0887Korean Society of Neurogastroenterology and Motility 10.5056/jnm.2013.19.1.94Case ReportOpioids and the Gastrointestinal Tract - A Case of Narcotic Bowel Syndrome and Literature Review Farmer Adam D 12Ferdinand Ella 2Aziz Qasim 11 Center for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.2 Department of Gastroenterology, Shrewsbury and Telford NHS Trust, Shropshire, UK.\nCorrespondence: Adam D Farmer, MB, BS, BSc (Hons), PhD, MRCP (UK). Princess Royal Hospital, Apley Castle, Telford, Shropshire TF1 6TF, UK. Tel: +44-1952641222 (ext. 5644), Fax: +44-7880540584, a.farmer@qmul.ac.uk1 2013 08 1 2013 19 1 94 98 12 9 2012 16 9 2012 17 9 2012 © 2013 The Korean Society of Neurogastroenterology and Motility2013This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The worldwide use of opiates is increasing yet there is little evidence that in long-term, non-cancer patients, they have an efficacious effect on functional outcomes and quality of life measures. Although it seems paradoxical, chronic opiate use may lead to a pro-nociceptive state. Mechanisms for the development of the hyperalgesic state include activation of the opiate bimodal regulatory systems, dynorphin and spinal cord glia. A potential consequence of chronic opiate usage is the development of narcotic bowel syndrome, which is characterized by chronic or intermittent colicky abdominal pain or discomfort that worsens after the narcotic effects of opiates wear off. It is likely that this is an under-recognized diagnosis. We describe here a case of 26-year old female who had visited our institution multiple times with intractable chronic abdominal pain in the context of normal findings on haematological, biochemical, metabolic, endoscopic and radiological investigations. She had been treated with a multitude of opioid agonists with escalating doses. A diagnosis of narcotic bowel syndrome was made. On elective admission her daily analgesic requirements were 150 µg/hr fentanyl, 100 mg oramorph and 400 mg tramadol (equating to 740 mg oral morphine/24 hr). A detoxification regimen was prescribed which included rapid opiate withdrawal couple with the commencement of methadone, lorazepam, clonidine and duloxetine. She was discharged opiate free, with no abdominal pain, 14 days after admission. Clinicians must be aware of narcotic bowel syndrome, which is often erroneously labelled as a functional gastrointestinal disorder, in patients who have been on long-term opiates.\n\nAnalgesicsGastrointestinal tractNarcoticsOpioid\n==== Body\nIntroduction\nChronic pain represents a considerable worldwide public health concern, consuming considerable healthcare resources. Opioids are often prescribed for chronic pain but their utility is frequently limited by their gastrointestinal (GI) side effects. For instance, constipation is known to occur in 15-90% of patients receiving opiates and is known to have a negative impact on health related quality of life (QOL).1 Whilst the long-term use of opiates in patients with chronic non-cancer pain escalates, evidence suggests that opiates fail to fulfil any of the key outcomes in terms of adequate pain relief, improved QOL or improvements in functional capacity.2,3\n\nCase Report\nA 26-year old woman had presented our institution on multiple occasions with a 5-year history of intractable chronic abdominal pain. Three years prior to admission she had been diagnosed with slow transit constipation, on the basis of a colonic marker study, and had been tried on multiple laxatives. In the absence of any discernable therapeutic benefit she was referred for a tertiary opinion where she underwent anorectal physiology and biofeedback without any changes in her symptoms. Subsequently, she underwent a subtotal colectomy, which increased the frequency of her bowel movement but had no effect on her pain.\n\nShe described the pain as being omnipresent, burning in nature throughout her abdomen. There were no specific findings on the haematological, biochemical, metabolic, immunological, endoscopic and radiological investigations. Of specific note, her computed tomographical scan of abdomen and pelvis and ileocolonoscopy with histology revealed normal findings in the last 12 months. She was then started on a number of opioid agonists in increasing doses.\n\nThe first author decided to electively admit her for further management. At this point her daily analgesic requirements were 150 µg/hr fentanyl, 100 mg oramorph and 400 mg tramadol (equivalent to approximately 740 mg oral morphine/24 hr). A clinical diagnosis of narcotic bowel syndrome (NBS) was made. A detoxification regimen was prescribed which included rapid opiate withdrawal and commencement of methadone, lorazepam, clonidine and duloxetine. She was discharged opiate free, with no abdominal pain, 14 days post admission. At outpatient review for 3 months after discharge, her abdominal pain has not returned and she remains well with no further hospital admissions. She is under active follow-up. Informed written consent was obtained from the patient.\n\nDiscussion\nParadoxically hyperalgesia can be a consequence of long-term chronic opiate usage. Despite being recognized as a clinical entity over 25 years, it remains as under-recognized side effect amongst clinicians.4 NBS is characterized by chronic or intermittent colicky abdominal pain or discomfort that worsens after the narcotic effects of opiates wear off. Over time, the pain free periods become shorter in duration despite increasing doses of opiates. Escalating the opiate dosage only worsens the effect on pain sensitivity by further reducing GI secretion and motility (Fig. 1).\n\nEmerging evidence from a number of published studies has shown that pain is dynamically modulated by central and peripheral factors which can inhibit, as well as facilitate, pain perception.5 Chronic opiate use induces neuroplastic changes that paradoxically enhance hyperalgesia and give rise to tolerance. It has been proposed that there are at least 3 mechanisms induced by long-term opiates, thereby leading to this state: bimodal opioid dysregulation, abnormalities in counter-regulatory mechanisms and glial activation.5\n\nBimodal Opioid Regulatory System\nBimodal refers to both the excitatory and inhibitory modulation of the sensory neuron action by opiates, mediated by Gs receptor activation at the dorsal root ganglia. Preferential activation of these excitatory pathways may, over time, lead to opiate toleration and pain augmentation. These excitatory effects have been seldom recognized due to the inhibitory effects that opioids have when administered in analgesically active (high) concentrations. Through chronic opiate administration, the Gs receptor becomes super-sensitized resulting in tolerance and ultimately hyperalgesia.6 These observations provide rationale for concomitant administration of low dose opiate antagonists, such as methylnaltrexone and alvimopan, in preventing Gs receptor mediated super-sensitivity thereby enhancing exogenous opioid mediated analgesia at lower doses.7\n\nCounter Regulatory Mechanisms\nDynorphin, an endogenous opiate, when released at the level of the spinal cord increases the release of excitatory neurotransmitters from primary afferents thereby amplifying the afferent signal. Evidence for this pro-nociceptive role comes from observations that dynorphin is increased in chronic pain states and that pain behaviours in animals are attenuated following the administration of dynorphin antagonists.8,9 Chronic opiate up regulates dynorphin production at the dorsal horn, inducing further hyperalgesia. Studies blocking this effect have demonstrated that hyperalgesia is reduced, analgesia is restored and opiate tolerance is prevented.10\n\nGlial Activation and Opioid Facilitation\nActivation of spinal cord glia is a relatively recently described mechanism that is involved in pain amplification in chronic pain states. Spinal dorsal horn glia, which is considered to be part of the supporting tissue for neurons, can be activated in response to a number of factors including inflammation, infection, opiates, peripheral injury and in response to central signals allowing the possibility of central effects of stress facilitating the pain at a peripheral level.11 Exogenous opiates, binding directly to the mu receptor cause the activation of glia with the concomitant release of pro-inflammatory cytokines, to which glial cells express receptors, thereby accelerating the development of hyperalgesia. Glia, in response to the release of inflammatory mediators, may activate neurons through a novel chemokine, known as fractalkine, mediated mechanism.12\n\nManagement of Narcotic Bowel Syndrome\nTo date there is an absence of international consensus with respect to the management of NBS, but central to a successful outcome is the physician-patient relationship. In particular, validation of a patient's symptoms in a supportive environment is, in our opinion, an absolute cornerstone of treatment. For instance, many, if not most, of these patients may have been erroneously diagnosed with a functional GI disorder (FGID) or experienced negative attitudes towards their opiate needs from non-specialist healthcare professionals for many years prior to a definitive diagnosis being made. In this respect, patient education of the pathophysiology of NBS, and therefore the rationale for opiate withdrawal, is a prerequisite step before initiation of treatment. Whereas the preparatory phase for treatment may be undertaken as an outpatient, we advocate that the opiate withdrawal should be started as an in-patient a secondary or tertiary care hospital under the supervision of an experienced specialist.\n\nTreatment modalities\nThe specific goals of treatment involve the initiation of treatments that minimize the immediate withdrawal effects of opiates in addition to treating psychological co-morbidities whilst achieving pain control for the underlying pathology. The time frame that is needed for a successful opiate withdrawal is extremely variable but it is our experience that the typical period needed for full detoxification is 10-14 days. Grunkemeier et al,5 in their excellent article, advocated switching the established opiate for an equivalent dose of a medium to long acting opioid, such as methadone, and then decreasing the dose of this by 10-33% per day. A divided daily dose should be used to limit large variations in plasma concentrations thereby avoiding rebound pain during trough levels.5 However, clinician should be cautious as methadone may systemically accumulate from the fifth day after administration.13 When rapid withdrawal regimens are used, patients need to be closely monitored for orthostatic hypotension, syncope, urinary retention or cardiac dysrhythmias. Concomitant medications can be started during the opiate withdrawal phase, for variable periods, to treat coexisting anxiety, psychological co-morbidity and provide long-term central analgesia such as antidepressants, benzodiazepines and clonidine. Figure 2 summarizes a suggested pharmacological approach to opiate withdrawal.14 The suggested protocol was useful in our patient, however close liaison with other disciplines, such as the pain management team, could be useful in improving outcomes.\n\nPatients may develop constipation during opiate withdrawal and in the absence of GI obstruction may be treated with laxatives. Although there is no convincing evidence for recommending one particular type of cathartics over another, polyethylene glycol solutions have been shown to be efficacious in the treatment of chronic idiopathic constipation and in our experience are well tolerated.15 As discussed earlier, novel mu opioid receptor antagonists, such as methylnaltrexone and alvimopan, may have benefit in the management of opioid induced constipation. A recent reported study evaluated the efficacy of 12 weeks of treatment with sub-cutaneous methylnatrexone in 4 patients with NBS.16 It was shown that methylnatrexone had a positive impact on symptoms, although transient pain was problematic following its administration. Long-term psychological support after the initial detoxification is invariably needed. Educating patients in psychological strategies allowing them to manage their chronic pain may improve long-term symptom management and empowers patients to achieve a sense of control over their symptoms.\n\nIn conclusion, NBS is a recognised sequelae of chronic opiate administration. Accumulating experimental evidences are providing support to the hypothesis of opiate mediated hyperalgesia. Clinicians must remain mindful of the diagnosis of NBS in patients whom have been administered on long-term opiates. Such patients are often erroneously diagnosed - at best as having FGID and at worst as an opiate addict. Further research is now warranted to explore the molecular mechanisms that underlie this paradox, the identification of risk factors for development of this disorder and finally the most efficacious withdrawal regimens.\n\nFinancial support: None.\n\nConflicts of interest: None.\n\nAuthor contributions: ADF and EF provided clinical care and wrote the manuscript. QA revised the manuscript for important intellectual content.\n\nFigure 1 The development of narcotic bowel syndrome. The patient presents with chronic, often abdominal pain and is prescribed with escalating doses of opiates, resulting in no relief in pain. For a number of reasons this can lead to breakdown of the doctor patient relationship.\n\nFigure 2 Summary of the treatments for opiate withdrawal in narcotic bowel syndrome. The diagnosis of narcotic bowel syndrome needs to be made and a therapeutic doctor patient relationship should be established before starting the treatment. Reproduced from Hakim et al14 with permission.\n==== Refs\n1 Davis MP The opioid bowel syndrome: a review of pathophysiology and treatment J Opioid Manag 2005 1 153 161 17315419 \n2 Trescot AM Boswell MV Atluri SL Opioid guidelines in the management of chronic non-cancer pain Pain Physician 2006 9 1 39 16700278 \n3 Eriksen J Sjøgren P Bruera E Ekholm O Rasmussen NK Critical issues on opioids in chronic non-cancer pain: an epidemiological study Pain 2006 125 172 179 16842922 \n4 Sandgren JE McPhee MS Greenberger NJ Narcotic bowel syndrome treated with clonidine. Resolution of abdominal pain and intestinal pseudo-obstruction Ann Intern Med 1984 101 331 334 6147108 \n5 Grunkemeier DM Cassara JE Dalton CB Drossman DA The narcotic bowel syndrome: clinical features, pathophysiology, and management Clin Gastroenterol Hepatol 2007 5 1126 1139 17916540 \n6 Crain SM Shen KF Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability Pain 2000 84 121 131 10666516 \n7 Lobmaier P Kornor H Kunoe N Bjorndal A Sustained-release naltrexone for opioid dependence Cochrane Database Syst Rev 2008 2 CD006140 18425938 \n8 Vanderah TW Gardell LR Burgess SE Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance J Neurosci 2000 20 7074 7079 10995854 \n9 Bian D Ossipov MH Ibrahim M Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum Brain Res 1999 831 55 63 10411983 \n10 Nichols ML Lopez Y Ossipov MH Bian D Porreca F Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1-13) or MK-801 in a nerve-ligation model of peripheral neuropathy Pain 1997 69 317 322 9085307 \n11 Milligan ED Sloane EM Watkins LR Glia in pathological pain: a role for fractalkine J Neuroimmunol 2008 198 113 120 18547654 \n12 Watkins LR Hutchinson MR Johnston IN Maier SF Glia: novel counter-regulators of opioid analgesia Trends Neurosci 2005 28 661 669 16246435 \n13 Nicholson AB Methadone for cancer pain Cochrane Database Syst Rev 2007 4 CD003971 17943808 \n14 Hakim A Keer R Grahame R Hypermobility, fibromyalgia and chronic pain 2010 London Churchill Livingstone \n15 Di Palma JA Cleveland MV McGowan J Herrera JL An open-label study of chronic polyethylene glycol laxative use in chronic constipation Aliment Pharmacol Ther 2007 25 703 708 17311603 \n16 Gibson PR Morrison G Effects of methylnaltrexone in patients with narcotic bowel syndrome: a pilot observational study Intern Med J 2012 42 907 912 22289023\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2093-0879",
"issue": "19(1)",
"journal": "Journal of neurogastroenterology and motility",
"keywords": "Analgesics; Gastrointestinal tract; Narcotics; Opioid",
"medline_ta": "J Neurogastroenterol Motil",
"mesh_terms": null,
"nlm_unique_id": "101530189",
"other_id": null,
"pages": "94-8",
"pmc": null,
"pmid": "23350054",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": "22289023;16246435;9085307;18425938;18547654;17916540;16842922;17943808;17311603;6147108;10995854;10411983;17315419;10666516;16700278",
"title": "Opioids and the gastrointestinal tract - a case of narcotic bowel syndrome and literature review.",
"title_normalized": "opioids and the gastrointestinal tract a case of narcotic bowel syndrome and literature review"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2015-01680",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional"... |
{
"abstract": "Cutaneous non-tuberculous mycobacterial (NTM) infections have rapidly increased in incidence in recent years. Currently there is no standard treatment and the variable and nonspecific ways in which cutaneous NTM infection presents makes it a therapeutic and diagnostic challenge. We describe a 67-year-old immunocompetent woman with cutaneous NTM infection after she recently underwent a root canal procedure. Although the species was not identified and she was unable to tolerate multiple antibiotics, she ultimately responded well to three months of treatment with linezolid. Given that cutaneous NTM infection can present in immunocompetent patients and that the incidence is rising, it is important for clinicians to maintain a high index of clinical suspicion, especially in patients with a recent history of surgery, trauma, or cosmetic procedures. Linezolid has coverage against non-tuberculous mycobacteria and is an effective therapeutic option for cutaneous NTM cases in which identification to the species level is not possible or when adverse effects limit therapeutic options.",
"affiliations": "Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX. Misha.V.Koshelev@uth.tmc.edu.",
"authors": "McNally|Michelle A|MA|;Farooq|Sahira|S|;Tschen|Jaime|J|;Koshelev|Misha V|MV|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "26(9)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001706:Biopsy; D005260:Female; D006801:Humans; D000069349:Linezolid; D009165:Mycobacterium Infections, Nontuberculous; D012390:Root Canal Therapy; D017192:Skin Diseases, Bacterial",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33054940",
"pubdate": "2020-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid as a treatment option for cutaneous non-tuberculous mycobacterial infections.",
"title_normalized": "linezolid as a treatment option for cutaneous non tuberculous mycobacterial infections"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
"drugadministrationr... |
{
"abstract": "Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian STeroid-associated Osteoporosis in the Pediatric Population (\"STOPP\") Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.",
"affiliations": "The Ottawa Pediatric Bone Health Research Group, The Children's Hospital of Eastern Ontario Genetic and Metabolic Bone Disease Clinic, University of Ottawa, Ottawa, ON, Canada.",
"authors": "Ward|Leanne M|LM|",
"chemical_list": "D005938:Glucocorticoids",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2020.00576",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392 Frontiers Media S.A. \n\n10.3389/fendo.2020.00576\nEndocrinology\nReview\nGlucocorticoid-Induced Osteoporosis: Why Kids Are Different\nWard Leanne M. * The Ottawa Pediatric Bone Health Research Group, The Children's Hospital of Eastern Ontario Genetic and Metabolic Bone Disease Clinic, University of Ottawa, Ottawa, ON, Canada\nEdited by: Madhusmita Misra, Massachusetts General Hospital and Harvard Medical School, United States\n\nReviewed by: Alan David Rogol, University of Virginia, United States; Louis Chung Kai Low, The University of Hong Kong, Hong Kong\n\n*Correspondence: Leanne M. Ward lward@cheo.on.caThis article was submitted to Pediatric Endocrinology, a section of the journal Frontiers in Endocrinology\n\n\n16 12 2020 \n2020 \n11 57630 4 2020 14 7 2020 Copyright © 2020 Ward.2020WardThis 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.Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian STeroid-associated Osteoporosis in the Pediatric Population (“STOPP”) Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.\n\nglucocorticoidschildrenfracturesosteoporosisbone densityrisk factorspreventiontreatmentCanadian Institutes of Health Research10.13039/501100000024University of Ottawa10.13039/100008572\n==== Body\nIntroduction\nGlucocorticoids (GC) are one of the most potent osteotoxic drugs that are routinely prescribed to treat serious childhood illnesses. Despite major advances in the management of systemic childhood illnesses, GC remain the cornerstone of treatment for many conditions, including leukemia and other cancers, systemic inflammatory or autoimmune disorders, organ transplantation, and some of the neuromuscular disorders such as Duchenne muscular dystrophy (DMD). In the last decade, longitudinal observational cohort studies, including the Canadian STeroid-associated Osteoporosis in the Pediatric Population (“STOPP”) study, have unveiled key clinical-biological principles about GC-induced osteoporosis (GIO) that together inform effective monitoring, diagnosis and treatment strategies. This has been important, since most GC-induced osteoporosis (GIO) recommendations to date have been informed by adult studies and concepts (1), and have thereby fallen short of acknowledging the pediatric-specific principles that guide GIO management in the young.\n\nGiven the number and variety of GC-treated disorders in childhood, not to mention the variability in GC prescriptions across and even within diseases, it is important to consider the child's overall health and GC exposure trajectory individually when developing GIO management plans. Since it is beyond the scope of this review article to provide in-depth recommendations on every pediatric GC-treated disease, not to mention on the different clinical scenarios within a given disease, this article instead focuses on key clinical-biological principles that inform the overall approach to pediatric GIO management. In so doing, this article serves as a blueprint for early identification of osteoporosis in any child who is receiving GC therapy, in any clinical context, and provides guidance as to whether osteoporosis therapy is indicated, or not. This article also reviews the evidence for treatment responses to bisphosphonate therapy in those deemed at risk for lack of recovery from GIO, and describes the unmet needs that drive future directions.\n\nThe Effects of Glucocorticoids on the Pediatric Skeleton, and the Impact of the Underlying Disease\nThere is a long list of GC-treated diseases of childhood. Those that are most frequently associated with skeletal fragility include leukemia and other cancers, systemic inflammatory and autoimmune disorders (such as, but not limited to, inflammatory bowel disease, and rheumatic conditions including systemic lupus erythematosus, systemic-onset juvenile arthritis, juvenile dermatomyositis, systemic vasculitis, and overlap syndromes), renal diseases (e.g., nephrotic syndrome), neuromuscular conditions (e.g., DMD), and organ transplantation. Importantly, many of the underlying diseases themselves carry risk of skeletal fragility, particularly the neuromuscular disorders due to lack of weight-bearing, and the systemic inflammatory and hematological disorders because of the adverse effect of disease-related cytokines on skeletal metabolism (e.g., interleukin [IL] 6 and 1, tumor-necrosis factor-alpha [TNF-α]) (2).\n\nAmong the most compelling observations that highlight the cross-talk between cytokines and bone are that severe VF can be one of the presenting signs of childhood leukemia, rheumatic disorders, and inflammatory bowel disease (3–5). The effects of TNF-α on bone are highly similar to the bone formation-blunting effects of GC, with inhibition of osteoblast differentiation, reduction in collagen synthesis by osteoblasts, and promotion of osteoblast apoptosis. Furthermore, IL-1, IL-6, and TNF-α all increase receptor activator of NF-kB ligand (RANKL), which drives osteoclastogenesis. Among boys with DMD, VF are uncommon prior to GC therapy, but long bone fractures can occur before GC initiation because of the adverse effect of the myopathy on bone development. Beyond the loss of normal mechanical strain on bone in DMD from lack of walking, the myopathic process itself is implicated in the bone fragility. The aberrant muscle-bone interactions in DMD involve muscle-derived myokines, bone-derived osteokines, and shared cytokines that catalyze common signaling pathways to incite muscle fibrosis, inflammation, and bone loss (6). Due to the myriad adverse effects of the underlying diseases on bone, the term GIO is often replaced by GC-associated osteoporosis. For the purpose of this article, the conventional term GIO will be used, recognizing that GC are not the only factor leading to bone strength loss, as highlighted in the examples, above.\n\nGC have diverse direct, and indirect, effects on the growth plate and developing skeleton, as recently reviewed in detail (7, 8), and outlined in Figure 1A. The multiplicity of adverse GC effects on skeletal strength is perhaps best understood according to the mechanostat model of bone development, as shown in Figure 1B. According to mechanostat theory, bone development is driven by two mechanical challenges during the pediatric years: increases in muscle forces, and increases in bone length (9). These two “mechanical challenges” induce bone tissue strain, which is monitored by the master bone cells—the osteocyte system. When bone tissue strain exceeds a genetically-determined threshold, osteocytes initiate effector cascades that signal osteoclasts to resorb damaged bone at the site of bone tissue strain, and osteoblasts to repair this site by laying down new bone (10, 11). These adaptive responses ensure that skeletal strength is maintained in the face of increasing mechanical challenges brought about by growth and muscle development.\n\nFigure 1 (A) The direct, and indirect, adverse effects of glucocorticoids on growth plate and skeletal metabolism. Together, these effects result in loss of bone strength, resulting in fragility fractures. (B) The impact of glucocorticoids on the mechanostat model of bone strength development in childhood. Glucocorticoids interfere with the two key mechanical challenges that normally foster bone strength in childhood—increases in bone length, and increases in muscle mass. They also have a direct, adverse effect on growth plate chondrocytes, and on all three bone cell lines (osteocytes, responsible for sensing bone tissue strain, osteoclasts, responsible for resorbing damaged bone at the site of bone issue strain, and osteoblasts, responsible for bone repair at the site of bone tissue strain, by laying down new bone). Adapted with permission from Rauch and Schoenau (9).\n\nInterestingly, estrogen appears to lower the threshold at which mechanical strains are sensed by the osteocyte, such that less of an osteogenic stimulus is needed to trigger the osteoclast-osteoblast response (12). The higher bone mineral content to muscle mass ratio that is observed in girls around the time of puberty is hypothesized to serve as a reservoir that can be tapped into at the time of pregnancy and lactation (9). With delayed puberty, there is loss of the estrogen-lowering effect on the mechanostat set-point in girls. Delayed puberty also leads to a reduction in muscle mass development in both sexes, which further diminishes bone tissue strain, and its subsequent positive, adaptive responses.\n\nThe adverse effect of GC on bone strength in childhood is not surprising, since GC disrupt numerous facets of the mechanostat model (7). First, GC have a profound, adverse effect on the growth plate, most often by causing chondrocyte apoptosis, and less commonly, by interfering with hypothalamic-pituitary growth hormone secretion. Attenuated linear growth, in turn, brings about loss of a potent determinant of bone tissue strain, as described earlier. Premature death of the osteocyte also appears to be a major contributor to GC osteotoxicity, resulting in loss of mechanosensing, and therefore a reduction in important effector pathways that normally coordinate adaptive changes to promote bone strength. In addition, GC cause excessive bone resorption, through promotion of osteoblast/osteocyte apoptosis, and prolongation of osteoclast survival. The bone formation pathway is also negatively impacted, since GC blunt factors which normally stimulate bone formation, including the WNT signaling system (7, 13, 14). As a result, none of the bone cells are spared the osteotoxic effects of GC therapy. It is not surprising, then, that reduced trabecular bone formation, along with increased endocortical resorption, are consistently aberrant findings that contribute to bone strength loss. The combined effects of GC on bone are not only to reduce bone mineral density (BMD) (15), but to alter bone microarchitecture, with a predilection for the trabecular-rich spine (16, 17).\n\nTo unravel the complexity of GC effects on the developing skeleton from a practical perspective, natural history studies have taught us to categorize GC-treated children into one of three groups (Figure 2): those with aggressive but transient GC exposure (such as children with leukemia), those with variable GC exposure (such as children with GC-treated rheumatic disorders, and nephrotic syndrome), and those with aggressive and long-term GC exposure (such as boys with GC-treated DMD). This categorization can orient the clinician to one of the most important decisions in the management of pediatric GIO—whether the child has the capacity to recover from GC-induced osteotoxicity without osteoporosis therapy. The child's ability to recover from GIO is determined by the extent to which there is sufficient residual linear growth to support skeletal modeling following transient GC exposure, vs. insufficient residual growth resulting in persistent BMD reductions, and permanent vertebral deformity following spine fractures. This “potential for medication-unassisted recovery from GIO” is pivotal to the overall approach, and will therefore be a major focus in the ensuing discussions.\n\nFigure 2 The overall approach to the management of glucocorticoid-induced osteoporosis varies with the aggressivity and duration of risk factors. Children are categorized into those with aggressive, but transient, glucocorticoid exposure, those with variable glucocorticoid exposure, and those with aggressive plus long-term glucocorticoid exposure. These categories, in turn, influence the potential for recovery from osteoporosis without bisphosphonate therapy. DMD, Duchenne muscular dystrophy.\n\nMonitoring and Diagnosis\nClinical-Biological Principles That Inform the Early Identification of GIO, and the Decision to Treat vs. Observe\nOver the last two decades, a number of important clinical observations have informed the definition, diagnosis, and monitoring of osteoporosis in children with GC-treated diseases. Together, these observations can be distilled down to key “clinical-biological principles” representing concepts that can guide the clinician in navigating the management of any child with a GC-treated disorder. These principles are summarized in Figure 3 (monitoring and diagnosis) and Figure 4 (treatment).\n\nFigure 3 The approach to the monitoring and diagnosis of bone fragility in children with glucocorticoid-treated disorders. BMD, bone mineral density; BMI, body mass index.\n\nFigure 4 The treatment of bone fragility in children with glucocorticoid-treated illnesses. *Annual maximum initiation doses: pamidronate 4.5 to 9 mg/kg body mass/year, divided into three treatment cycles (i.e., one cycle is given every four months); zoledronic acid 0.05 to 0.1 mg/kg body mass/year, divided into two treatment cycles (i.e., one cycle is given every six months). **Annual maintenance doses: pamidronate 4.5 mg/kg/year, divided into three treatment cycles; zoledronic acid 0.025 to 0.05 mg/kg/year, divided into two treatment cycles NB: Intravenous bisphosphonate therapy for children less than 2 years of age, a rare event in pediatric GIO, is administered more frequently (i.e., pamidronate is given every two months, zoledronic acid is given every three months, same maximal annual initiation and maintenance doses as for older children).\n\nThe Diagnosis of Osteoporosis in Children Has Shifted Away From a “BMD-Centric,” to a “Fracture- and Clinical Context-Focused” Approach, With GC Exposure Representing One of the Most Important Clinical Contexts With a Higher Risk of Bone Fragility\nChildren with GC-treated illnesses can present with disabling complications of osteoporosis, including painful VF, permanent vertebral deformity, and premature loss of ambulation following long bone fractures in those with tenuous ambulation (such as DMD) (18–20). At the same time, fractures in the general pediatric population are frequent, with almost 50% of children experiencing at least one fracture (21, 22), and almost a quarter of children sustaining recurrent broken bones (23). In view of this, Pediatric Positions Task Forces working with the International Society for Clinical Densitometry (ISCD) over the years have sought to guide clinicians in the definition of osteoporosis in children, by developing definitions that attempt to identify children with “…an intrinsic skeletal issue resulting in bone fragility,” compared with those who break bones during play and sports (24, 25).\n\nThe most recent ISCD recommendations (24) noted that osteoporosis should not be diagnosed on the basis of solely bone density criteria; a clinically significant fracture history is also required. The ISCD definition of osteoporosis included non-traumatic VF, without the need for BMD criteria, which served to acknowledge that low-trauma VF represent an osteoporotic event in childhood. Without a VF, the ISCD definition of osteoporosis involves both a clinically significant fracture history (≥two long bone fractures by age 10 years, or ≥three long bone fractures by 19 years), and a gender- and age-matched BMD Z-score of ≤-2.0 (along with appropriate corrections for bone size). The ISCD definition also noted that a BMD Z-score >-2.0 in this context “does not preclude the possibility of skeletal fragility and increased fracture risk.”\n\nThis ISCD definition of osteoporosis in childhood (24) has been used worldwide to inform clinical practice guidelines, eligibility for pediatric osteoporosis trials, and hospital protocols. One of the successes of the definition is that it mitigates over-diagnosis of osteoporosis, and therefore unnecessary treatment of those without true skeletal fragility. This is important, because osteoporosis therapies [intravenous (IV) pamidronate, neridronate, and zoledronic acid] are not without side effects, and therefore require judicious prescription.\n\nOn the other hand, it is can be challenging to distinguish low-trauma fractures due to underlying bone fragility from fractures sustained during childhood play. When applied to the letter, the 2013 ISCD definition leads to the under-diagnosis, and thus under-treatment, of some children who would benefit from osteoporosis therapy. Why? Because waiting for a subsequent long bone fracture, or for a low BMD after a single pathological fracture, delays the start of treatment in fracture-prone children. This is a crucial point, because even a single fracture can cause permanent disability in high-risk children. Furthermore, timely initiation of osteoporosis intervention is paramount to restoring normal vertebral dimensions during the critical, rapidly-closing window of growth.\n\nYet another point of controversy is the inclusion of a BMD Z-score threshold in the definition of pediatric osteoporosis. It may be under-appreciated by DXA users, that age- and gender-matched BMD Z-scores produced by different DXA machines vary by as much as two standard deviations for a given child, depending on the normative data used to generate the Z-scores (26). This observation was published by three research groups using Lunar- and Hologic-derived pediatric normative data (26–28); the largest of these studies generated lumbar spine (LS) areal BMD Z-scores from all of the available pediatric reference data published in the English language, up to and including 2015 (26). Ultimately, the tremendous disparity in BMD Z-scores arising from different reference databases challenges the use of a Z-score cut-off as part of a global definition of pediatric osteoporosis. At the same time, it has been shown that the various reference databases are highly co-linear (26). As a result of the co-linearity among reference databases, the associations between LS BMD Z-scores and VF are highly similar, regardless of the normative data used to generate the BMD Z-scores (26). Therefore, the lower the BMD Z-score generated by any reference database, the more likely a child is to sustain a fragility fracture (29). A second issue that arises from the inclusion of a universal BMD Z-score threshold as part of a pediatric osteoporosis definition is that children with intrinsic skeletal fragility, including children with GC-treated disorders, can have fragility fractures at BMD Z-scores >-2.0 (18, 19, 26, 30), a fact recognized in the 2013 ISCD statement.\n\nWith these observations in mind, it has been suggested that BMD Z-scores should be viewed along a continuum that inversely correlates with bone strength, but without diagnostic cut-offs. This is because the position of the healthy BMD average, and the corresponding outer limits of normal, will vary on the continuum depending on the normative data used in a given patient to generate the BMD Z-scores (31).\n\nAn additional concern is the confounding effect of stature on DXA-based areal BMD Z-scores. The ISCD noted that appropriate adjustments should be made for short stature, and delayed puberty, when interpreting DXA-based areal BMD measurements (24). This is particularly relevant to GC-treated children, given the adverse effect of GC therapy on linear growth, and on pubertal development. The size-dependent nature of DXA-based areal BMD parameters is another reason that the fracture history figures so prominently in the diagnosis of osteoporosis among children, including those with GIO.\n\nAs a result of these issues, a more nuanced approach to the diagnosis of osteoporosis in children with GC-treated disorders factors in the child's clinical context, which includes the known risk of a fracture, the mechanism of injury (degree of trauma), and the fracture characteristics, without a specific BMD Z-score requirement (31). This approach is catalyzed not only by the limitations of BMD thresholds to define pediatric osteoporosis, but by advances in our knowledge about the natural history of osteoporotic fractures in children with GC-treated diseases, as outlined in the following sections.\n\nVertebral Fractures Are the Hallmark of GIO in the Young, but Are Frequently Asymptomatic, Necessitating Routine Spine Imaging With Validated Diagnostic Criteria\nAmong the most significant findings arising from the STOPP study were that VF are the clinical signature of GIO in children, underscoring the vulnerability of the trabecular-rich spine to the adverse effects of GC. By showing that VF associate with biologically-relevant factors such as LS BMD Z-scores, back pain, second metacarpal percent cortical area, and an increased risk of future fractures (3, 19, 20, 30), the STOPP Consortium validated that >20% loss of vertebral height ratio, based on the modified Genant semi-quantitative method (32, 33), defines a VF in children (Figure 5A). The most compelling observation that validated the use of the Genant semi-quantitative method in children arose from a report in pediatric leukemia, where Genant-defined VF at diagnosis were a strong predictor of new vertebral and long bone fractures over the next 5 years (20). In cases where physiological anterior rounding of the vertebral body can be difficult to distinguish from a fracture, the decision can be facilitated by qualitative signs including endplate interruption, loss of endplate parallelism, and more rarely, anterior cortical buckling (Figure 5A) (34). Examples of osteoporotic vertebral fractures in children are shown in Figure 5B.\n\nFigure 5 (A) Standardized quantification of vertebral fractures, the hallmark of glucocorticoid-induced osteoporosis in children. The depiction of the Genant semi-quantitative method is adapted with permission from Genant et al. (32). (B) Examples of vertebral fractures in children with glucocorticoid-treated leukemia. Top, left to right: Grade 1, 2, and 3 vertebral fractures. Bottom, left to right: Radiological signs of fractures, including loss of endplate parallelism (left), anterior cortical buckling (middle), and endplate interruption (right). Adapted with permission from Halton et al. (3).\n\nVF in children are rare in the absence of traumatic injury (21), and rates vary according to their method of detection. The highest frequencies of VF in secondary osteoporosis occur in boys with GC-treated DMD, where the VF prevalence is >50% (35), and the cumulative incidence is 28% over a median follow-up of 4 years from GC initiation (36). Children with leukemia, typically on intermittent GC therapy, have a VF prevalence of 16% at the time of diagnosis (3), and a cumulative incidence of 33% up to 6 years following diagnosis (20). In rheumatic disorders, studies have shown a 7% prevalence within 30 days of GC initiation (5), a prevalence of 29–45% later in the disease and treatment course, and up to a 33% incidence in the first few years of GC therapy, as reviewed by Hansen et al. (37).\n\nIn both children and adults, the most common VF shape is anterior wedge deformity, there is a bimodal distribution of all fracture morphologies, and the peak frequency of VF occurs in the mid-thoracic region. These are robust observations that have been demonstrated in different disease groups, at different points in the disease course (3, 18, 19, 30) (Figure 6A). The bimodal distribution of fractures in children is slightly more rostral and caudal compared with adults, as shown in Figure 6B, a finding that is attributed to the less marked thoracic kyphosis and lumbar lordosis of the immature spine (38).\n\nFigure 6 (A) The bi-modal distribution of vertebral fractures, and fracture morphology, in children with leukemia at diagnosis. Adapted with permission from Halton et al. (3). (B) The distribution of osteoporotic fractures in children compared with adults. Adapted with permission from Siminoski et al. (38).\n\nVF often go undiagnosed in children with GC-treated illnesses for two main reasons. First, VF are frequently asymptomatic (3, 5, 30, 39–41), even when moderate or severe (3, 42). For example, almost half of children with VF at leukemia diagnosis were asymptomatic (3), an observation recapitulated in other pediatric GC-treated contexts (19), and well-documented in adult osteoporosis studies (43). Yet, even mild, asymptomatic VF predict future VF in children (42), an observation which underscores the importance of detecting asymptomatic disease. Secondly, surveillance with periodic spine imaging has not previously been an important part of osteoporosis monitoring in pediatric GC-treated disorders. This philosophy is changing as we shift from a BMD-centric, to a fracture-focused, diagnostic approach (31).\n\nGiven the importance of VF screening in high risk populations, there is tremendous interest in the utility of a technique called “vertebral fracture assessment” (VFA) by dual-energy x-ray absorptiometry (DXA). VFA is attractive in children, because it is an extremely low-radiation approach, which is useful when periodic VF surveillance is recommended to identify asymptomatic vertebral collapse. In addition, the fan-beam technology acquires the whole spine on a single image, obviating discrepancies in reporting due to challenges in identifying vertebral levels on two cassettes. Finally, the fan-beam technology also avoids divergence of beam issues causing parallax, making it easier to identify vertebral collapse. Newer DXA machines have a “c-arm” which rotates around the patient, obviating the need to re-position from supine to lateral when performing VFA. Image quality can vary depending on the DXA machine, as recently reviewed in detail, with newer DXA machines showing higher quality spine images (44). Recent guidelines have now been published on the use of VFA as an initial screen in children requiring periodic spine imaging for VF detection (44). Since VF detection in children involves distinguishing normal variants from pathological fractures, and since non-fracture pathology can also be seen on a VFA image, pediatric radiologists should still be involved in the assessment of VF captured by DXA.\n\nVF have been diagnosed as early as 4 to 6 months following GC initiation in children with GC-treated rheumatic disorders and DMD (18, 30). With this in mind, bone health monitoring, including lateral thoracolumbar spine imaging, should start around the time of GC initiation in very high risk populations such as DMD (45), and as soon as possible in other diseases where children are anticipated to receive ≥3 months of daily oral, or intermittent IV, GC therapy. Lateral spine imaging should be repeated a maximum of 12 months after the initial assessment in patients who remain on GC therapy, because of the increased VF risk in the first year (30), and yearly thereafter if GC continue. Spine imaging for VF assessment is recommended sooner if there is back pain, or in the presence of ≥0.5 decline in BMD Z-score. The overall approach to monitoring is outlined in Figure 3.\n\nVertebral Fractures Can Occur Early in the GC Treatment Course, and Readily Measurable Clinical Features in the First 6 to 12 Months of GC Therapy Predict Incident VF\nNot only can VF occur in the first few months of GC exposure (18, 30), but the peak annual VF incidence has been shown to occur at 1 year after starting GC in both GC-treated leukemia (20), and rheumatic disorders (19) (Figure 7). This is not surprising, since the peak frequency of fractures directly mirrors the period of maximum GC exposure, along with corresponding declines in height and BMD Z-scores, increases in disease activity (for rheumatic conditions), and increases in body mass index, as shown in Figure 7 (19, 20, 30, 42).\n\nFigure 7 The frequency of vertebral and non-vertebral fractures from the time of glucocorticoid initiation in children with leukemia and rheumatic disorders, and the longitudinal changes in glucocorticoid exposure, body mass index, and lumbar spine bone mineral density Z-scores. Adapted with permission from LeBlanc et al. (19), Ward et al. (20), and Cummings et al. (42). (A) The prevalence of vertebral and non-vertebral fractures at leukemia diagnosis, and the annual incidence of fractures during the six years following diagnosis. (B) The changes in average GC daily dose (for boys and girls), BMI (both genders combined), and LSBMD Z-score (both genders combined) in children with leukemia during the four years following diagnosis. (C) The prevalence of vertebral fractures at the time of GC initiation in children with rheumatic disorders, and the annual incidence of vertebral fractures in the three years following diagnosis. (D) The changes in average GC daily dose, disease activity, BMI Z-score, and LSBMD Z-score in children with rheumatic disorders during the three years following diagnosis. GC, glucocorticoid; LSBMD, lumbar spine bone mineral density; BMI, body mass index.\n\nFrom studies assessing the baseline and longitudinal factors associated with VF in GC-treated children, a number of useful themes have emerged. First of all, GC exposure is a consistent, independent predictor of incident VF, and both cumulative and average daily GC dose predict incident VF in a number of different diseases, as previously reviewed (46). Intermittent (pulse) therapy in children with leukemia (quantified as GC “dose intensity,” the cumulative GC dose during the observation period, divided by the number of days in receipt of GC), also predict incident VF (42).\n\nStudies in children with GC-treated leukemia have shown that the strongest predictor of future fractures is prevalent VF around the time of GC initiation, a phenomenon known as “the VF cascade” (40, 42). Even mild, asymptomatic VF are independent predictors of future vertebral fractures, highlighting the importance of identifying early signs of vertebral collapse through periodic surveillance (40, 42). Figure 8 shows an example of the VF cascade in a boy with GC-treated DMD who has progressive VF in the absence of bone protection.\n\nFigure 8 Progressive signs of vertebral collapse in a boy with glucocorticoid-treated Duchenne muscular dystrophy, in the absence of bone protection: “the vertebral fracture cascade.” Adapted with permission from Ma et al. (18).\n\nThe fact that prevalent VF at the time of starting GC predict future VF underscores the importance of knowledge about the skeletal phenotype early in the child's disease course. The first year of GC therapy is also a critical time to scrutinize the child's clinical trajectory for other predictors of incident VF. In children with GC-treated rheumatic disorders, readily measurable clinical features in the first year independently predicted subsequent incident VF, including increases in body mass index in the first 6 months of GC therapy, increases in disease activity scores in the first 12 months of GC therapy, and decreases in LS BMD Z-scores in the first 6 months of GC therapy (19). In children with solid organ transplantation, older age also predicted an increased VF risk (47–50). As a general rule of thumb, any child with Cushingoid features should be considered at increased risk for VF and undergo routine spine monitoring accordingly (Figure 3). Although not tested in longitudinal studies, it is hypothesized that children with adrenal suppression due to exogenous GC therapy may also be at increased risk of VF, since adrenal hypoactivity is yet another sign of clinically significant GC exposure. While back pain was associated with VF at diagnosis in two studies, one of children with GC-treated leukemia, and the other of children with rheumatic disorders (3, 5), back pain did not predict future VF (19, 42). From these studies, we learned that the absence of back pain does not preclude incident VF in at-risk children, an observation that, in the author's experience, holds true in clinical practice.\n\nThere are no reports describing the critical GC dose or duration that is linked to an increased risk of incident VF in children, and formal prediction models to estimate absolute fracture risks in individuals do not exist. This is largely due to the small numbers of at-risk patients (relative to adults), and the fact that GC exposure is necessarily weight- or body surface area-based, with wide variability during the pediatric years. Van Staa showed a 30% increase in overall fracture risk among children with a history of four or more courses of oral GC (average duration only 5 days) (51). Studies focusing on fragility fractures specifically have reported that VF can occur around the time when GC therapy is first initiated (3, 39), that incident VF can occur as early as 4 months following GC initiation (30), and that peak annual incidences of VF mirror the period of maximum GC exposure (19, 42). These studies have informed the recommendation to screen for VF early in the child's GC treatment course, for those anticipated to remain on GC for ≥3 months (Figure 3). Since there is no evidence in children to suggest that physiological doses of GC cause overt bone fragility (i.e., ≤8 to 10 mg/body surface area in hydrocortisone equivalents), provided the underlying disease is well-controlled and itself is not a risk to skeletal health, the practical decision to initiate bone health monitoring in children is triggered by ≥3 months of daily oral, or intermittent IV, GC therapy at supraphysiological doses, as outlined in Figure 3.\n\nBone Mineral Density Remains Useful in Vertebral Fracture “Case-Finding” Paradigms, and in Tracking a Child's Bone Health Trajectory Over Time\nWhat is the role, then, of BMD in the bone health monitoring of GC-treated children? A low BMD raises the index of suspicion for an osteoporotic fracture, but it is not diagnostic, because BMD can be low due to size artifact (i.e., short stature), and Z-scores can decline due to poor linear growth velocity, weight loss, and delayed puberty. Furthermore, BMD Z-scores can be >2.0 in GC-treated children with fractures (3, 18, 30), as previously discussed. In practical terms, BMD is but one of numerous pieces of information that orients the pediatrician as to whether the child has sustained an osteoporotic fracture, if it is not already obvious from the clinical context (i.e., a low-trauma long bone or vertebral fracture, plus a Cushingoid appearance, height deceleration, increases in body mass index, or declines in BMD Z-scores that are beyond the limits of the measurement precision).\n\nThere are two main ways in which BMD can be used to inform the clinician about the child's skeletal status in the monitoring phase. The first scenario is based on an approach which seeks to minimize radiation exposure by using clinical features to improve prevalent VF detection on spine radiographs—called “case-finding approaches.” A recent report on a large cohort of children with GC-treated acute lymphoblastic leukemia, rheumatic conditions, and nephrotic syndrome explored the accuracy of VF detection in the presence of back pain alone, low LS BMD Z-score alone, back pain or a low LS BMD Z-score, or a combination of back pain and a low LS BMD Z-score (52). Such an approach is predicated upon the known VF prevalence in the population of children in question, and acknowledges that the BMD Z-score cut-off varies according to the normative database used to generate the Z-scores. As such, the details provided in the next paragraph are specifically relevant to the cohort that was studied.\n\nForty-four out of 400 children with GC-treated diseases (11%) had prevalent VF in this case-finding study (52). Logistic regression analysis between LS BMD and prevalent VF gave an odds ratio of 1.9 for each reduction in Z-score unit, an area under the receiver operating characteristic curve of 0.70, and an optimal BMD Z-score threshold of −1.6. Case identification using either low BMD alone (Z-score <-1.6), or back pain alone, produced similar data for sensitivity (55% and 52%, respectively), specificity (78% and 81%, respectively), positive predictive value (24% and 25%, respectively), and negative predictive value (93% and 93%, respectively). Low BMD plus back pain showed lower sensitivity (32%), higher specificity (96%), higher positive predictive value (47%), and similar negative predictive value (92%). The approach using low BMD, or back pain, had the highest sensitivity (75%), lowest specificity (64%), lowest positive predictive value (20%), and highest negative predictive value (95%). All approaches had increased sensitivities for higher fracture grades.\n\nWith this in mind, if the clinician's focus is to minimize x-rays, a useful screening approach is the presence of a low BMD and back pain. This strategy would require that only 8% of this cohort would need x-rays, the approach would detect a third of patients with a prevalent VF, and it would detect an even larger number with higher fracture grades. This also means that one fracture would be found for every two patients who underwent x-rays. For a clinician who wanted to improve on this detection rate, the strategy of back pain or low BMD could be taken. This identified ¾ of all patients with fractures in this cohort, and had 100% sensitivity for Grade 3 VF. This paradigm provides the best strategy for ruling out a fracture, since the likelihood of a prevalent VF was only 5% in the absence of low BMD or back pain. On the other hand, the trade-off for the higher detection rate is that for this particular cohort, 41% would undergo x-rays, and one child would be identified with a prevalent VF for every 5 children who underwent a spine radiograph. Either way, this provides a strategy for using BMD to judiciously inform the request for x-rays in a given child, in order to detect prevalent VF. The specific strategy chosen depends on the importance of VF detection to the child's care, and the physician's attitude to radiography.\n\nThe other main utility of BMD in the monitoring phase is to signal the child with true bone loss (loss in absolute bone mineral content with declining Z-scores), or failure to gain bone at a normal rate (declining Z-scores). Declines in BMD Z-scores ≥0.4 are typically considered clinically significant based on natural history observations. For example, for every 1 g increase in cumulative GC exposure/body surface area in the first 5 weeks of GC exposure, lumbar BMD Z-scores were lower by 0.37 in GC-treated children with nephrotic syndrome (39). In a second example, this time in children with rheumatic disorders, a greater decline in LS BMD Z-score was reported in the first 6 months of GC therapy, by a difference of 0.4, in those with incident VF at 12 months compared to those without (30). While LS BMD is the site most often measured in children, recent studies have shown that total body (less head) and hip BMD are clinically sensitive in GC-treated children (53, 54). Bone mineral accrual Z-score equations were recently published; these can be explored in research studies for their ability to predict future VF (55).\n\nA Single, Low-Trauma Long Bone Fracture May Represent a Major Osteoporotic Event in Those at Risk, Even Prior to GC Initiation\nThe overall risk of a fracture in healthy children, of which VF are exceedingly rare, ranges in boys from 42 to 64%, and in girls from 27 to 40% (22). The most frequently fractured bone is the radius/ulna, which results in nearly half of all fractures (22, 29). In addition, 65% of long bone fractures in childhood affect the upper extremities, while 7 to 28% occur in the lower extremities (22).\n\nSince long bone fractures are extremely common in childhood, the ISCD 2013 Position Statement declared that a significant fracture history was represented by ≥2 long bone fractures by age 10 years, or ≥3 long bone fractures by age 19 years (24). These frequencies are reasonable for a child without risk factors for an underlying bone fragility condition. However, for a child with a known risk of a fragility fracture, such as those with GC-treated disorders, these criteria have been recently proposed as overly stringent (31), recognizing that other features of the fracture, and its clinical context, should be considered.\n\nImportant in the assessment of GC-treated children with long bone fractures is the definition of low-trauma. Low-trauma has been characterized in numerous ways. The 2013 ISCD Pediatric Positions Task Force defined a low-trauma fracture as one that occurred outside car accidents, or when falling from <10 feet (three meters). In GC-treated children, falling from a standing height or less at no more than walking speed has been used to define low trauma (20). This definition is valid in the chronic illness setting, because VF predicted incident low-trauma long bone fractures that were defined in this way among children with GC-treated conditions (20).\n\nLower extremity fractures are frequent in boys with DMD even in the absence of GC therapy, occurring in up to 40% (56, 57), with doubling of the long bone fracture risk in the presence of GC therapy (56). The high rate of lower extremity fractures prior to GC initiation speaks to the adverse effect of the myopathy on bone strength. In children with leukemia, long bone fractures occurred in 23% over the 5 years following diagnosis (with no new fractures between 5 and 6 years) (20). Beyond BMD, gracile bones (reduced periosteal circumference) are also characteristic of the osteoporosis phenotype in GC-naïve DMD (Figure 9A).\n\nFigure 9 (A) A 10 year old boy with Duchenne muscular dystrophy who presented 2 years after glucocorticoid initiation with a low-trauma femur fracture, causing permanent, premature loss of ambulation. The low-trauma femur fracture was the patient's first osteoporotic event. Note the generalized osteopenia, gracile femoral shaft, and thin cortices. (B) A 13 year old boy with Duchenne muscular dystrophy who presented with multiple, painful vertebral fractures 7 years after a low-trauma tibia fracture. The patient's first osteoporotic event was at six years of age (at the time of the low-trauma tibia fracture). Adapted with permission from Ma et al. (18).\n\nEven a single, low-trauma long bone fracture may be a major osteoporotic event in those with GC-treated disorders. As an example, among boys with GC-treated DMD, VF were frequent in the years following a single, low-trauma long bone fracture (18) (Figure 9B); this observation provided proof of principle that the long bone fracture was the child's first osteoporotic event. Lower extremity fractures typically have the greatest impact on day-to-day life because of the adverse effect on mobility. The starkest example of this arises from boys with DMD who experience premature, permanent loss of ambulation following a long bone fracture (18). This can be devastating to families living with DMD who have anticipated a certain duration of ambulation. Low-trauma femur fractures are one of the signatures of pediatric osteoporosis, but even a single tibia or upper arm fracture can represent an osteoporotic event in those at risk. Comminuted fractures, and those with atypical displacement, are also significant, especially in the absence of trauma.\n\nAlthough forearm fractures are extremely common in childhood, the clinical context surrounding the fracture (low or high trauma, radiologic features), plus the GC-treated child's clinical profile (height, body mass index, puberty and BMD trajectories, GC dose and duration, presence or absence of VF, Cushingoid appearance, and disease activity) usually provides sufficient information to aid the physician in assessing the fracture's clinical significance.\n\nSome Children Can Recover From GIO Through Reshaping of Fractured Vertebral Bodies and Restitution of Bone Mass, Obviating the Need for Osteoporosis Treatment\nThe pediatric skeleton is a dynamic structure which holds the ability to not only reclaim BMD that has been lost during transient bone health threats, but also to reshape previously fractured vertebral bodies, through a process known as skeletal modeling. Both BMD reclamation and vertebral body reshaping are important measures of recovery in children, either spontaneously or following osteoporosis therapy (i.e., bisphosphonates). Restoration of normal vertebral dimensions is thought to be growth-mediated, since it has not been unequivocally reported in adults (58).\n\nGiven the tremendous drive to recover from osteoporosis among children with transient risk factors and sufficient residual growth potential, not all children with GIO require osteoporosis intervention. Determining which children have insufficient potential for complete vertebral body reshaping following VF is a pivotal step in the management of pediatric GIO.\n\nThe disease that was best-studied for signs of recovery from skeletal insult, in the absence of osteoporosis treatment, is childhood leukemia. This is unsurprising, since leukemia is a transient threat to bone health in the vast majority of children. The fact that reshaping can take place during leukemia therapy (which includes high-dose GC therapy) is hypothesized to result from the intermittent pattern of GC exposure that is the basis for current treatment protocols (Figure 10A, patient #1). Vertebral body reshaping has also been reported in children with rheumatic disorders following GC cessation (Figure 10B). Reshaping does not occur quickly, evolving over years in children with more severe collapse. Case in point, older children who lack sufficient residual growth potential can be left with permanent vertebral deformity following vertebral collapse (Figure 10A, patients #2 and 3) (20, 59). The long-term consequences of permanent deformity remain unknown; however, adult studies report reduced quality of life due to chronic back pain, and also significant functional limitations (60, 61). Whether this is true in adults who experience permanent vertebral deformity as children merits further study. In the aging, VF contribute to excess mortality (62), and among adult post-menopausal women without a history of pulmonary disease, those with VF had restrictive pulmonary dysfunction compared to those without VF (63). Together, these adult studies suggest that permanent reductions in vertebral height sustained in childhood may have important consequences later in life. The GC-treated disease where this dialogue is particularly relevant is DMD, given the shortened lifespan due to cardiorespiratory failure.\n\nFigure 10 (A) Pediatric patients with complete, partial, and absent vertebral body reshaping following acute lymphoblastic leukemia diagnosis, in the absence of bisphosphonate therapy. The first age shown for each patient is the age at diagnosis. Patient #1 is still growing at 11 years of age, and has undergone complete reshaping. Patient #2 has finished growing at 14 years of age, and has undergone partial reshaping. Patient #3 had already reached adult height at the time of leukemia diagnosis (absent reshaping). Adapted with permission from Ward et al. (20) and Dal Osto et al. (59). (B) Progressive vertebral body reshaping following discontinuation of glucocorticoid therapy in a young girl with systemic juvenile arthritis. This patient developed vertebral fractures at 18 months of age (12 months after starting glucocorticoid therapy). She went on to show near-complete reshaping at 10 years of age, following discontinuation of glucocorticoid therapy, and in the absence of bisphosphonate treatment (referred to as “spontaneous vertebral body reshaping”). Adapted from Ward et al. (46) with permission.\n\nTo explore the phenomenon of vertebral body reshaping further, the Canadian STOPP Consortium studied determinants of incomplete vs. complete reshaping in bisphosphonate-naïve pediatric patients with leukemia (20). Children who had at least one VF at any time point over 6 years following diagnosis including baseline, plus at least one spine radiograph available for VF evaluation after the first documented VF, were evaluated for vertebral body reshaping. To do this, a method known as the “spinal deformity index” (SDI) was used (64), which equals the sum of the Genant grades. For example, three Grade 1 VF is equivalent to an SDI of 3, and two Grade 3 VF equals an SDI of 6. Therefore, the SDI is a metric of overall spine fracture burden for a given child, one that can be tracked over time to quantify both incident VF, and vertebral body reshaping. In childhood leukemia, vertebral body reshaping was defined by the magnitude of the SDI decline from baseline to the last follow-up visit, as follows (20): (1) Absence of vertebral body reshaping: no change in the SDI (i.e., the last SDI was the same as the maximum SDI at previous time points); (2) Incomplete vertebral body reshaping: a decline in the SDI by <100% (i.e., 0 < last SDI < maximum SDI at previous time points); and (3) Complete vertebral body reshaping: a decline in the SDI by 100% (i.e., the last available radiograph showed the SDI was 0).\n\nForty-four children (23.7% of the cohort) were eligible for evaluating reshaping of vertebral bodies based on the required criteria. Using the SDI methodology, the vertebral body reshaping profile in children with leukemia was as follows (20): 77% had complete reshaping by their last follow-up visit, 18% had incomplete reshaping, and 5% had no change in the SDI. Children with incomplete or absent vertebral body reshaping were older (on average 8 years of age at diagnosis, compared with 4.8 years in those with complete reshaping), and more frequently had moderate and severe collapse at the time of the maximum SDI (90% of children with incomplete or absent vertebral body reshaping had moderate or severe vertebral collapse at the time of the maximum SDI, compared to 38.2% of children with complete reshaping). In practical terms, these data taught us that younger children, and those with less severe collapse, reshape vertebral bodies more frequently, provided risk factors for bone fragility have abated. These data further suggested that the peri-pubertal period (i.e., ≥8 years of age in girls, and ≥9 years of age in boys) was a critical point in determining whether a child had sufficient residual growth potential to effectuate vertebral body reshaping.\n\nBecause the drive to recovery among children with leukemia stands unique, the osteoporosis monitoring algorithm provided in Figure 3 does not strictly apply to this disease group. In children with leukemia, spine imaging should be conducted in any child with back pain, at any time during their leukemia treatment course, in order to identify VF. Spine imaging should also be carried out around 3 months following diagnosis, regardless of back pain, in children who are peri-pubertal or older (≥8 years in girls, ≥9 years in boys) at the time of diagnosis. The purpose of the latter recommendation is to identify older children with asymptomatic vertebral collapse outside of the induction phase, who have less residual growth potential to undergo complete vertebral body reshaping.\n\nThe next question, then, is whether children with VF, and with persistent bone health threats, can undergo spontaneous (i.e., medication-unassisted) vertebral body reshaping in the context of diseases other than leukemia. Figure 10B provides an example in a child with systemic-onset juvenile arthritis, one of the more frequently GC-treated rheumatic disorders. As evident from both Figure 10A (leukemia) and Figure 10B (an inflammatory condition), vertebral body reshaping does not occur quickly in the face of moderate to severe collapse, but rather evolves over many years. The average rate at which vertebral bodies reshape per year for a given age range has never been studied, and would be a challenging undertaking given the heterogeneity of the GC-treated diseases, and of linear growth patterns. In GC-treated DMD, where the VF frequency is particularly high, there are no published reports of vertebral body reshaping without bisphosphonate therapy. This is likely due to the long-term GC prescription, and the progressive underlying disease despite GC therapy, that is inherent to the DMD setting. As such, bisphosphonate treatment studies which demonstrate vertebral body reshaping in this context, even when uncontrolled, are showing important reversal of the progressive osteoporotic phenotype in DMD.\n\nBMD restitution is another important index of recovery. In childhood leukemia, studies have shown degrees of BMD restitution in the years after chemotherapy has finished (65, 66). Cranial and spinal radiation predict lack of BMD restitution, particularly at doses ≥ 24 Gy (66). However, it is noteworthy that the reduction in spine areal BMD among those with radiation exposure may be due in part to growth hormone deficiency-related short stature. In leukemia survivors, other reported risk factors for incomplete BMD restitution include vitamin D deficiency, hypogonadism, and reduced physical activity (67). In practical terms, pediatric bone health clinicians look for normalization of the BMD Z-score for height as a sign of BMD restitution, and a return to a normal rate of BMD accrual for age, gender and pubertal stage. In 2019, pediatric bone mineral accrual Z-score equations were published, which may be useful in clinical practice to gauge catch-up vs. deficits in a child's BMD recovery post-insult (55). Vertebral body reshaping, normalization of BMD for height, and normalization of BMD accrual rates for age/bone and gender, are all important parts of the pediatric GIO monitoring pathways, as outlined in Figures 3, 4.\n\nPrevention and Treatment\nPrevention of First-Ever Osteoporotic Fractures Walks the Tightrope Between Effective Treatment of the Underlying Disease, and GC-Induced Osteotoxicity\nAchieving disease remission is the cornerstone of optimizing bone strength in GC-treated disorders. The challenge, of course, is striking the balance between effective treatment of the underlying disease, and minimizing side effects including osteoporosis. This is not always possible, in which case treatment of the underlying diseases, which are often chronic, serious, and with significant adverse consequences if left poorly controlled, is the top priority. In this sense, the algorithm shown in Figure 3 seeks to safeguard against progressive, undetected osteoporosis in those where the underlying disease course necessitates ongoing GC therapy.\n\nConcerted endeavors to minimize skeletal morbidity, while prioritizing treatment of the underlying disease, have met with variable success. In childhood leukemia, transitioning from daily dexamethasone to alternate-week dexamethasone during the delayed intensification phase led to a significant reduction in the incidence of osteonecrosis (17% vs. 9%), especially in patients ≥16 years of age (38% vs. 11%) (68). The fact that intermittent GC therapy is now the standard for many leukemia protocols is hypothesized to contribute to the high frequency of vertebral body reshaping following VF in this context (20). On the other hand, attempts to reduce GC doses in DMD, without compromising muscle function, have not been as promising. Crabtree et al. (69) studied boys with DMD on intermittent (alternating day, or weekend only) vs. daily GC therapy in relationship to anthropometry, VF and ambulatory status over 2 years. Age, and GC dose were similar at baseline. Boys on intermittent vs. daily therapy were taller (average height Z-score −0.8 vs. −1.4), lighter (body mass index Z-score +0.8 vs. +1.5), and had fewer VF after 2 years (8% vs. 40%). However, boys on intermittent therapy more frequently lost ambulation (40% vs. 20%). These data highlight that any attempts to balance effective treatment of the underlying disease against GC-induced osteotoxity need to be carried out in a disease-specific manner, with a clear understanding of the impact of different approaches on the child's overall well-being.\n\nThe idea that some GC drugs are bone-sparing has arisen from studies of prednisone, methylprednisone, and deflazacort, specifically in children following renal transplant, and in children with chronic arthritis. However, comparisons among different GC preparations were made challenging in these studies by the fact that the calculated steroid dose equivalencies were heterogeneous. Disease outcomes were positive in the deflazacort-treated patients, including improvements in anthropometry, and in BMD parameters (70–72). On the other hand, a recent publication raises doubt about the bone-sparing nature of deflazacort, since bone fragility is frequent in deflazacort-treated boys with DMD (35). This observation is undoubtedly, at least in part, related to the high, long-term doses used in DMD.\n\nIn view of the side effects of traditional GC therapy in pediatric DMD, where GC are prescribed in the spirit of long-term and high-dose use, international efforts are currently underway to understand the relative benefits, and risks, of different GC regimens that are currently used in routine clinical care. A large multi-national, double-blind, randomized controlled study studying the three more commonly-prescribed GC regimens, called “Finding the Optimum Regimen for Duchenne Muscular Dystrophy” study (FOR-DMD, ClinicalTrials.gov Identifier NCT01603407) is currently underway to study prednisone 0.75 mg/kg/day, prednisone 0.75 mg/kg 10 days on, 10 days off (intermittent therapy), and deflazacort 0.9 mg/kg/day (73). The results of this ground-breaking study are highly anticipated.\n\nThe narrow therapeutic window of traditional GC therapy raises the need for an effective therapy that holds fewer systemic side effects than traditional GC such as prednisone and deflazacort. Vamorolone (VBP15) is a “dissociative steroid” that holds such promise (74)—dissociative because it retains the beneficial trans-repression (anti-inflammatory) activity of traditional GC but with a significant reduction in trans-activation (hormonal gene transcription) effects (75). Phase I studies have been carried out in healthy adults and confirm a lack of short-term adverse effects of vamorolone on bone turnover markers compared to prednisone (76). Phase IIa pharmacokinetic and dose-finding studies in pediatric DMD have also been successfully completed with favorable results, as recently published following 24 weeks of vamorolone therapy (77). Longer-term and placebo-controlled studies are presently underway.\n\nOther prevention measures include timely identification and treatment of endocrinopathies, encouraging mobility within the limits of the underlying disease, and treating nutritional deficiencies. Delayed puberty is a frequent consequence of GC therapy, as are delays that arise from poorly-controlled disease. In boys with GC-treated DMD, hypogonadotrophic hypogonadism is frequent, and recent care considerations have encouraged treatment with testosterone for those with delayed puberty (45, 78).\n\nPoor growth is also a feature of GC therapy, most often due to a direct adverse effect of GC on the growth plate, rather than abnormal GH secretory status. In patients with recombinant human growth hormone (rhGH)-treated inflammatory disorders, the effect of rhGH on height has been modest at best, with most trials nevertheless describing a favorable effect on muscle and bone (79, 80). However, some children also experienced adverse events, including glucose intolerance, reactivation of the underlying disease, and osteonecrosis (79, 80); whether these side effects were related to the rhGH, to concomitant GC administration, or to other factors, is unclear.\n\nShort stature is a significant problem for boys with GC-treated DMD (78), particularly during the ambulatory phase when height differences are most noticeable. The main effect of rhGH on bone strength is via improved muscle strength; however, muscle damage and fibrosis begin early in the life of a boy with DMD. Therefore, it is unlikely that rhGH would be a major modifier of bone strength in this context. Furthermore, whether rhGH might cause muscle damage in DMD over the longer term is unknown.\n\nThe effect of rhGH on height in pediatric DMD was tested in an uncontrolled pre-post study (average age 11.5 years, 39 boys), which showed an increase in height velocity, on average, from 1.2 cm in the year before rhGH therapy, to 5.3 cm in the year while on rhGH (81). The therapy appeared to prevent a decline in growth velocity, with height Z-scores stabilizing on average at −2.9 (81); however, the impact of rhGH on skeletal maturation was not measured, rendering the potential impact on adult height uncertain. rhGH did not impact the velocity of muscle or cardiopulmonary decline in this short-term study. Three patients experienced side effects (benign intra-cranial hypertension, worsening of scoliosis, and impaired fasting glucose). Given the cost of rhGH, the burden of sub-cutaneous injections that are given multiple times per week, the potential for important adverse events, and questions about long-term safety, the benefits of rhGH to prevent osteoporosis in DMD, outside of hormone replacement for those with a truly deficient secretory status, do not seem to justify the risks, costs, and inconvenience at the present time.\n\nNon-pharmacotherapeutic measures to optimize bone health, including weight-bearing physical activity, nutrition, and maintenance of a healthy weight are also important, with excessive weight gain being a major complication in GC-treated children undergoing therapy at supra-physiological doses (78, 82). Given the complexity of care involved in the management of a child with GIO, a multi-disciplinary team is typically implicated, including the physician most responsible for the treatment of the underlying disease, the bone health clinician (often an endocrinologist given the links to growth, puberty, calcium, and vitamin D metabolism), an orthopedic surgeon, a radiologist for vertebral fracture ascertainment, a bone densitometrist with experience in acquiring DXA scans in children, and allied health professionals for the purpose of physiotherapy/physical activity prescription, psychological support, and nutritional counseling.\n\nThe most well-described nutritional factors to foster bone strength are vitamin D and calcium; however, numerous other nutrients also influence skeletal strength, including vitamins A, C, and K, iron, copper, fluoride, zinc, protein, potassium, and magnesium.\n\nGC decrease synthesis, and increase catabolism, of vitamin D, putting GC-treated children at increased risk for vitamin D deficiency even beyond classic factors such as Northern latitudes, darker skin color, obesity, and low vitamin D dietary intake (83). The recommended intake of vitamin D is at least 600 IU/day (84), though higher doses may be needed to meet target levels, particularly in children with multiple risk factors for vitamin D deficiency. Vitamin D adequacy has been defined at a serum 25-hydroxyvitamin D (25-OHD) threshold ≥50 nmol/L (20 ng/mL) (84, 85) or ≥75 nmol/L (30 ng/mL) (86), largely based on adult studies. In children, the optimal serum 25-OHD threshold remains controversial. A meta-analysis did not show a significant effect of vitamin D supplementation, or 25-OHD levels ≥50 nmol/L, on BMD in healthy children (87). Similarly, calcium plus vitamin D supplementation had no effect on spine BMD in children with inflammatory bowel disease (88), nor in children with leukemia (89). From a practical perspective, a 25-OHD level ≥50 nmol/L (20 ng/mL) is recommended through diet and/or supplementation combined, with measurement of 25-OHD levels in GC-treated children annually, ideally at the end of winter to determine the 25-OHD trough.\n\nThe Institute of Medicine (84) has established age-specific dietary reference intakes for calcium across the lifespan. The recommended dietary allowance of calcium to fulfill the needs of 97.5% of the healthy pediatric population is 700 mg/day for children 1 to 3 years of age, 1,000 mg/day between 4 and 8 years, and 1,300 mg/day for those 9 to 18 years of age (84). Higher daily supplementation may be required in children on GC therapy. Optimizing calcium intake through diet is preferred, because of questions raised following reports of adverse cardiovascular outcomes in adults on supplementation (90), and due to concerns about exacerbation of hypercalciuria in children with GC-treated mobility disorders.\n\nCalcium, Vitamins D and K, Vitamin D Analogs, and Oral Bisphosphonate Therapy Are Relatively Weak Modulators of BMD in GC-Treated Children, and Do Not Appear Effective in Preventing Fragility Fractures\nThe role of calcium, vitamin D, vitamin K, and vitamin D analog therapy for the prevention of pediatric GC-treated diseases has recently been reviewed by Jayasena in a small number of studies with few patients (91). These studies showed at best modest LS BMD improvements, or prevention of decline, in treated patients compared with controls (92–94).\n\nSince BMD is often low at the time of GC initiation in children with serious underlying diseases (3, 5, 95), the ideal preventative therapy would not only mitigate declines in BMD, but reverse the BMD downward trajectory. The role of alfacalcidol in the optimization of BMD was studied in a recent large, randomized, controlled trial of GC-treated children (n = 217) with rheumatic disorders, and showed that LS BMD Z-scores declined similarly after 1 year in both the alfacalcidol and placebo groups (96). The same study further showed that the difference in LS BMD Z-score change over 1 year on risedronate compared with placebo was 0.274 (p < 0.001), and on risedronate compared with alfacalcidol was 0.326 (p < 0.001), both favoring the risedronate group. Although the trial was not powered to assess differences in fracture rates, it is nevertheless concerning that in this study (96), three children on risedronate had incident VF at 12 months, including one child who progressed from absence of fractures at baseline, to a severe (Genant Grade 3) VF at 12 months. Even more concerning was that bone resorption and formation markers increased on risedronate (96), when a decline in bone turnover markers is the biochemical signature of effective anti-resorptive therapy (97).\n\nIn a non-randomized trial of oral risedronate vs. no treatment in pediatric GC-treated DMD, 5/15 patients in the untreated group had incident VF, compared to 3/52 in the risedronate treated arm. While encouraging, the controls were also treated with GC on average 1.4 years longer than the risedronate-treated group, and the duration of GC therapy was a significant negative predictor of the change in LS volumetric BMD Z-score. Furthermore, there was no difference in the change in LS volumetric BMD Z-score, nor in the change in total body bone mineral content (less head) Z-score, over the 3.6 years of observation.\n\nTogether, these studies do not provide compelling evidence to prescribe nutritional supplements for the prevention of GC-related declines in BMD, beyond general bone health measures such as ensuring recommended intakes of calcium and vitamin D. Furthermore, oral risedronate given preventatively appears to increase BMD compared to no treatment, and compared to alfacalcidol, in pediatric GC-treated rheumatic disorders, but does not bring about the expected decline in serum bone resorption markers, and does not appear to prevent significant VF progression. These conclusions are similar to those arising from the osteogenesis imperfecta literature (98).\n\nThe Ideal Candidates for Osteoporosis Treatment Are Children With Early (Rather Than Late) Signs of Bone Fragility, Plus Lack of Potential for Spontaneous Recovery\nIf prevention fails, and a child sustains a low-trauma vertebral or long bone fracture, the next step is to gauge the child's capacity to undergo “medication-unassisted” recovery from osteoporosis. Children who are younger, with transient GC exposure and sufficient residual growth potential, are more likely to recover, and can be monitored optimistically provided they are not suffering from undue back pain. Indeed, significant back pain from VF is an absolute indication for bisphosphonate therapy, irrespective of the child's capacity for spontaneous recovery from GIO. On the other hand, older children (girls ≥ 8 years, and boys ≥ 9 years) with less residual growth potential, and those with ongoing bone health threats regardless of age, have less capacity for spontaneous reshaping of vertebral bodies, as described in an earlier section. Understanding the child's clinical trajectory and ongoing GC needs is an important part of the “potential for spontaneous recovery assessment,” one that often includes speaking to the child's attending physician in order to understand the projected plan around GC prescription.\n\nOverall, the goal of monitoring high-risk children is to identify early- rather than late-stage osteoporosis, in order to activate strategies that prevent progression (i.e., secondary prevention). The other aim of monitoring for early osteoporosis identification is to capitalize on the synergistic effects of anti-resorptive therapy during growth. Because VF are a key manifestation of pediatric GIO, one of the over-arching aims is to avoid leaving a child with permanent vertebral deformity at the time of epiphyseal fusion. These concepts provide the impetus for the approaches outlined in Figures 3, 4.\n\nIntravenous, Not Oral, Bisphosphonates Are the Recommended First-Line Therapy for Treatment of Pediatric GIO\nAlthough IV bisphosphonates are the most frequently prescribed agents for pediatric bone fragility, regardless of etiology (46, 99, 100), they remain off-label worldwide with the exception of neridronate in osteogenesis imperfecta (Italy). Most data on IV bisphosphonates have arisen from the pediatric osteogenesis imperfecta literature, where it has been shown that children receiving IV pamidronate, neridronate, and more recently zoledronic acid, demonstrate improvements in lumbar BMD Z-scores, vertebral height ratios, muscle strength, activities of daily living, cortical thickness on trans-iliac biopsies, and reductions in long bone fracture rates (101–103). The evidence to support the recommendation that oral bisphosphonates should not be used as first-line therapy in pediatric GIO is provided in the section entitled: Calcium, vitamins D and K, vitamin D analogs, and oral bisphosphonates are relatively weak modulators of BMD in GC-treated children, and do not appear effective in preventing fragility fractures.\n\nIn pediatric GIO, placebo-controlled trials are ideal, given observations of medication-unassisted recovery when GC exposure is transient, and the frequency of disease-related symptoms that can mimic the first-infusion side effects of IV bisphosphonate therapy. However, in contrast to the osteogenesis imperfecta literature, there have been relatively few studies on the response to IV bisphosphonate therapy in pediatric GIO, in part due to challenges studying a population with heterogeneous underlying diseases and treatments, a lower frequency of fractures compared to osteogenesis imperfecta, and unpredictable relapses and remissions. In pediatric GIO, the only randomized, controlled trial of IV pamidronate, compared with oral calcium and calcitriol, was prematurely abandoned over 15 years ago (104). With a target sample size of 30 in each group in order to achieve sufficient power on the change in lumbar BMD Z-score, this study enrolled a total of 12 patients over 4 years before halting the trial due to irreconcilable feasibility issues (104).\n\nOn this background, it is not surprising that there have been only two other controlled trials studying the efficacy and safety of IV bisphosphonates specifically in children with GIO; these studies were non-randomized, case-control trials conducted over a decade ago, each on small numbers of patients (105, 106). The first study examined IV pamidronate in 17 GC-treated children with fractures who had underlying renal and rheumatic disorders, compared to an equal number of treatment-naïve controls matched for age, gender, disease and GC exposure (106). The second report assessed IV alendronate in five GC-treated children with rheumatic disorders, compared to six untreated controls for whom the clinical characteristics were not described (105). Obviously, neither study was powered to assess differences in fracture rates over 1 or 2 years of observation; however, between-group increases from baseline were significant at the spine on monthly IV pamidronate compared to the control group (106), and a transient flu-like illness was reported in 18% of patients following the first dose. On the other hand, no side effects were observed in the smaller study of five children who received IV alendronate every 3 months. In this alendronate study, within-group changes from baseline were positive at the femoral neck compared with lack of change from baseline in the untreated controls (105).\n\nWhile IV pamidronate has historically been the most frequently used bisphosphonate (46, 99), in recent years, zoledronic acid has been of interest due to the numerous indications for its use in adults, a shorter infusion time, and a longer duration of action compared with pamidronate. IV zoledronic acid is the most potent bisphosphonate available, approved globally to treat osteoporosis in men, in post-menopausal women, in adult GIO, and in the prevention of future fractures in adults with a prior history of low-trauma hip fractures.\n\nTwo small, uncontrolled studies on the use of zoledronic acid in childhood osteoporosis, including GC-treated illnesses, showed improvement in BMD and absence of new VF (107, 108). Further, IV pamidronate or zoledronic acid given for 2 years in a retrospective observational study of boys with GC-treated DMD who had a total of 27 painful VF (67% percent of which were moderate or severe VF), showed improvements in back pain, stabilization or improvements in vertebral height ratios of previously fractured vertebral bodies, and an absence of incident VF (109). The stabilization or reshaping of VF on IV zoledronic acid or pamidronate, albeit on a small number of patients with high fracture burden, was nevertheless an important observation in GC-treated DMD, because medication-unassisted vertebral body reshaping following VF has never been described. This is not surprising, given the high doses of GC used to treat this condition, and the relentlessly progressive myopathy. Finally, a randomized trial of zoledronic acid (N = 7) versus IV placebo (N = 6) in children with Crohn's disease (two of whom had received GC therapy in each group) showed a greater increase in LS BMD Z-score at 6 months on zoledronic acid (+0.7) versus placebo (+0.1, p < 0.001). A 50% decline in urinary C-telopeptide of type I collagen was also observed, compared with no change on placebo (110).\n\nOne of the questions that is frequently asked is whether oral bisphosphonates can supplant IV therapy for the treatment of pediatric osteoporosis, including GIO. This is an attractive option, given their convenient route of administration and fewer side effects. However, the bioavailability of oral bisphosphonates is low (111). Furthermore, evidence from randomized, placebo-controlled trials of oral bisphosphonates in children with osteogenesis imperfecta does not support the use of oral instead of IV agents, as reviewed extensively elsewhere (46, 98). The recent randomized controlled trial of oral risedronate in pediatric GC-treated rheumatic disorders described earlier under prevention of GIO, also fails to provide sufficient evidence to support the use of oral bisphosphonates for the treatment of pediatric GIO (96).\n\nAnother question that frequently arises in the management of pediatric osteoporosis, is whether bisphosphonate therapy should be interrupted following a long bone fracture. To date, there has been no evidence in children with GIO, nor in children with primary bone fragility such as osteogenesis imperfecta, that healing is delayed following spontaneous fractures in children on intravenous bisphosphonate therapy. Therefore, based on present knowledge, it seems reasonable to continue bisphosphonate therapy after a long bone fracture in pediatric GIO.\n\nThe side effects of IV bisphosphonate therapy are not trivial, especially in children with underlying diseases (99, 112). The most frequent is “the acute phase reaction,” most marked following the first dose, consisting of fever, myalgias, arthralgias, bone pain, nausea, and vomiting. The acute phase reaction can precipitate signs and symptoms of adrenal insufficiency in those with adrenal suppression, necessitating “steroid stress dosing.” Hypocalcemia is also frequent in the first few days following IV bisphosphonate therapy. Although typically mild and asymptomatic, hospitalization for an IV calcium infusion has been rarely described (99, 112). The acute phase reaction is typically self-limited to a few days, aided by supportive care to minimize the intensity and duration including anti-pyretics, anti-inflammatories, and anti-nauseants. Pre- and post-treatment vitamin D and calcium supplementation are also recommended. Osteonecrosis of the jaw, a concern highlighted in the adult bisphosphonate literature, has not emerged as an issue in children despite almost 30 years of IV bisphosphonate prescription. In addition, there are no reports of atypical femur fractures in pediatric GC-treated conditions. Given the potency of IV bisphosphonate agents, combined with the potential for side effects that appear to be amplified in children with secondary osteoporosis, their prescription by a physician experienced in their use is recommended. Additional discussion on the side effects of IV bisphosphonate therapy and their management is provided elsewhere (46).\n\nTaken together, the current recommendations for the treatment of pediatric GIO are similar to other osteoporosis conditions of childhood, and involves the initiation of IV bisphosphonate therapy at early, rather than late, signs of bone fragility in children with limited potential for spontaneous recovery. These principles are reiterated in Figures 3, 4. Figure 11 provides an example of these recommendations, summarily compiled in internationally-endorsed clinical care considerations for patients with GC-treated DMD (45, 78). IV bisphosphonates should be prescribed to children by physicians who are experienced in their use, and signs and symptoms of adrenal insufficiency should be promptly identified and treated if they arise following the first infusion.\n\nFigure 11 The diagnosis and treatment of osteoporosis, and delayed puberty, in boys with Duchenne muscular dystrophy. This is an internationally-endorsed, osteoporosis identification and treatment paradigm in a patient population with long-term glucocorticoid prescription [as described in Birnkrant et al. (45)].\n\nIn patients with aggressive forms of GIO such as DMD, both published and unpublished experience teaches that IV bisphosphonate therapy may not rescue the phenotype in all cases. In the study of VF outcomes on IV bisphosphonate therapy over 2 years by Sbrocchi et al. (109), there were two boys who had loss of vertebral height in one vertebral body each. Neither vertebral height loss reached fracture grade (i.e., the degree of vertebral height loss was <20%); however, the reduction in vertebral height ratio, albeit minimal, was nevertheless clear with longitudinal observation. This finding is hypothesized to be influenced by the extent of vertebral collapse at the time of IV bisphosphonate initiation, with greater collapse conferring a lower threshold for triggering future VF, known as “the vertebral fracture cascade.” The magnitude of the ongoing risk factors is likely also a contributing factor to progressive vertebral height ratio loss. These observations provide rationale for initiating intravenous bisphosphonate therapy prior to the first-ever fracture. To date, there are no published studies of intravenous bisphosphonate treatment which have tackled prevention of first-ever fractures in a high risk population such as DMD.\n\nThe Synergistic of Effects of Anti-resorptive Therapy Combined With Linear Growth Provide the Rationale for Not Withholding Bisphosphonate Therapy From a Child With Low Bone Turnover Osteoporosis\nAnother question that is frequently asked in pediatric GIO, and in other osteoporotic conditions of childhood characterized by low bone turnover, is whether the prescription of an anti-resorptive agent is prudent. Indeed, low bone turnover is the hallmark of pediatric GIO, which has been verified on trabecular surfaces through trans-iliac bone biopsies (113). While the use of an anti-resorptive is notionally imperfect in low bone turnover states, it is important to recognize that withholding bisphosphonate therapy in low bone turnover prior to growth cessation will prevent positive, growth-mediated skeletal effects arising from the unique synergy between anti-resorptives and bone modeling, as outlined in the following paragraph.\n\nAt the level of the vertebral body growth plates, bisphosphonates do not interfere with endochondral bone formation (the bone modeling process which increases vertebral height), since bone turnover on trabecular surfaces, which is suppressed by bisphosphonate therapy, is unlinked to endochondral bone formation. As a result, fractured vertebral bodies can reshape by endochondral bone formation despite low trabecular bone turnover, provided a child has some degree of residual linear growth. Bisphosphonates thereby have a permissive effect on vertebral body reshaping by increasing BMD, thereby allowing growth-related bone modeling to take place in an unfettered fashion.\n\nThis principle has been nicely demonstrated in boys with GC-treated DMD. On trans-iliac bone biopsies, further declines in the already-low bone formation at trabecular surfaces pre- vs. post-IV pamidronate and zoledronic acid nevertheless were associated with increases in vertebral dimensions through endochondral bone formation (109). The caveat here is that the extent of vertebral body reshaping is directly related to linear growth potential, and whether the insult to bone (such as GC exposure) is ongoing, attenuated, or withdrawn. To this end, reshaping of previously fractured vertebral bodies is not a realistic goal for bisphosphonate-treated children with ongoing GC exposure and poor linear growth. In such cases, the goals of therapy at the level of the spine are limited to prevention of incident low-trauma VF, and minimization of back pain.\n\nAlong the same lines, periosteal apposition is the growth-dependent process by which long bones increase in width as they growth in length, in order to maintain bone strength close to a genetically-determined set-point. Bisphosphonates decrease resorption on endocortical surfaces; however, periosteal apposition continues on exocortical surfaces, giving rise to a net increase in cortical thickness during growth (114). This is because bone resorption (on endocortical surfaces), and growth-mediated bone formation (on exocortical surfaces), are uncoupled at the cortex (in contrast to the trabeculae where the two processes are linked). This causes a net increase in long bone cortical width during bisphosphonate treatment while patients are growing, a phenomenon first demonstrated by Rauch et al. in children with osteogenesis imperfecta (114). Just like vertebral body reshaping, poor linear growth will also attenuate the extent to which cortical thickness can increase with IV bisphosphonate therapy. It should be further noted that similar to osteogenesis imperfecta, prevention of long bone fractures is not guaranteed with IV bisphosphonate therapy in pediatric GIO, in part because cortical thickness will not increase when there is GC-induced linear growth retardation (109). The other reason that long bone fractures may persist despite IV bisphosphonate therapy, is that reductions in periosteal circumference, a feature of conditions with altered weight-bearing such as GC-naïve and GC-treated DMD, are not ameliorated with IV bisphosphonate therapy.\n\nTogether, the potential for vertebral body reshaping, and increases in cortical width (both growth-mediated), provide rationale for not withholding bisphosphonate therapy in children with GIO, despite the low bone turnover that is characteristic of the osteoporosis. For patients with attenuated linear growth, efforts should be made to restore normal growth using GC-sparing approaches if possible, and to recognize the limitations of anti-resorptive therapy when it is not possible to overcome the growth failure. In such cases, mitigation of incident VF and back pain are the main goals of IV bisphosphonate therapy.\n\nLongitudinal Growth Influences the Duration of Treatment\nOnce a decision has been made to provide bone protection in a GC-treated child, bisphosphonate therapy should be continued for as long as GC exposure persists at supra-physiological doses, and then for a period of time thereafter (1 year, provided the patient is showing signs of recovery from osteoporosis). A number of seminal observations unique to children have been responsible for this recommendation, as follows.\n\nFollowing bisphosphonate discontinuation in patients with open epiphysis, and therefore ongoing endochondral bone formation, the newly formed bone adjacent to the growth plate is “treatment naïve,” and therefore lower in BMD. This creates a stress riser between higher density (i.e., recently treated), and lower density (i.e., untreated), bone (115). As a result, long bone metaphyseal fractures have been reported post-bisphosphonate discontinuation, at the interface between the treated and treatment-naïve bone, in patients with open epiphyses and persistent osteoporosis risk factors (116). In fact, metaphyseal fractures have even occurred while receiving cyclical IV bisphosphonate therapy, at the interface between the dense metaphyseal lines created at the time of each cycle, and the adjacent, treatment-naïve bone (117). This begs the question as to whether IV bisphosphonates should be administered with as short an interval between infusions as possible, a consideration that is challenged by patient burden due to frequent infusions. In any case, observations of fractures at the interface between treated and newly formed, treatment-naïve bone have led to the recommendation that bisphosphonates should be continued until the end of linear growth, as long as the risk factors for low BMD persist during this time.\n\nFor children with resolution of osteoporosis risk factors during growth (i.e., controlled inflammation, discontinuation of GC therapy, normal mobility), cessation of bisphosphonate therapy can be considered once the child has been fracture-free for at least 12 months after GC therapy has been stopped. This is provided, however, that previously fractured vertebral bodies have undergone reshaping in patients with residual growth potential. Cessation of bisphosphonate therapy is also contingent upon attainment of BMD Z-scores appropriate for height, and normal rates of age- and gender-matched bone mineral accrual (Figure 4). Re-introduction of bisphosphonate therapy may be required during growth if the prior risk factors for osteoporosis recur, and if the patient goes on to develop new bone fragility.\n\nThe rationale for the continuation of bisphosphonate therapy for 1 year following resolution of risk factors and signs of osteoporosis recovery, is based on a number of important observations. In children with leukemia, we observed a decline in annual VF and non-VF incidences by 4 years following diagnosis, but a slight increase in fracture rates between 4 and 5 years following leukemia diagnosis (with most children recently off chemotherapy at that time) (20). This suggested a period of relative fragility following chemotherapy discontinuation. A report over a decade ago in children with leukemia made a similar observation of increased fracture rates in the year following therapy cessation (118).\n\nA study by Mostoufi-Moab et al. (119) went on to shed light on a possible explanation for the increased bone fragility in the year following GC cessation. Using peripheral quantitative computed tomography at the tibia in children who had recently completed leukemia therapy, it was shown that initial increases in cortical dimensions due to growth recovery were associated with declines in cortical BMD. A year later, cortical dimensions stabilized, which were followed by increases in cortical BMD (119). The authors speculated that the lag between growth-mediated increases in cortical dimensions, and subsequent increases in cortical BMD, may have resulted from the recovery time needed for newly-formed bone to undergo mineralization. This, in turn, might explain the period of relative bone fragility after completion of leukemia therapy that was observed in the two longitudinal studies from different countries (20, 118). Taken together, it appears that the year following resolution of risk factors, including cessation of GC therapy, may be a period of true bone fragility. Therefore, we recommend that bone protection continue for 1 year following GC cessation, to prevent fractures during this vulnerable phase of recovery.\n\nUnmet Needs That Drive Future Directions in the Management of Pediatric GIO\nThe Need for a Pediatric GIO Treatment With a Convenient Route of Administration and Minimal Side Effects\nThe first-infusion side effects of IV bisphosphonate therapy, along with the inconvenience of the IV route, have spurred interest in alternative forms of anti-resorptive therapy. RANKL is an essential mediator of osteoclast formation, function and survival (120). Denosumab is a fully human, monoclonal antibody that targets RANKL to prevent the activation of RANK, thus inhibiting cortical and trabecular bone resorption, and increasing bone strength, without directly interacting with bone surfaces (121). Large studies in adults have shown that denosumab 60 mg every 6 months reduces hip, vertebral, and non-vertebral fracture risk without an increased frequency of adverse events, compared with placebo (122). Other adult studies have also confirmed that adverse events with denosumab are similar to an active comparator (oral alendronate), including the frequency and magnitude of hypocalcemia (122, 123). Denosumab is approved for osteoporotic men, and post-menopausal women, with a high risk for fracture; it is also approved for adult GIO. In children, the compassionate use of denosumab has been reported in a few studies of osteogenesis imperfecta (including osteogenesis imperfecta type VI, a sub-type that is not as responsive to IV bisphosphonate treatments as other forms) (124), giant cell tumors (125), aneurysmal bone cysts (126), and fibrous dysplasia (127). Currently, denosumab is being studied in children with osteoporosis, including GC-treated DMD, compared to standard-of-care IV zoledronic acid (NCT 02632916).\n\nOne concern with the use of denosumab is the “rebound phenomenon,” which includes loss of BMD, and an increase in VF, following denosumab administration in adults (128), and frank hypercalcemia-hypercalciuria in children (129). This phenomenon arises from exuberant skeletal resorption following reactivation of osteoclasts, presumably as the effect of the antibody wanes. In pediatric GIO, where bone turnover is invariably low, and linear growth is often attenuated, it is unclear whether this phenomenon will be a concern. On the other hand, rebound may theoretically occur when bone turnover increases at the time of puberty, or following GC cessation. These safety considerations merit careful study in clinical trials. Since RANKL is also implicated in the inflammatory pathway that contributes to muscle destruction in DMD (6), studies assessing the impact of denosumab on muscle strength in DMD are also of interest.\n\nPrevention of First-Ever Fractures Using Drugs That Are Anabolic to Bone, and Sequential Therapy\nThe BMD of trabecular-rich bone such as the spine is more readily modifiable by anti-resorptive therapy than cortical bone, because porous (spongy) bone has greater capacity to accommodate a bone density-altering therapy, compared with compact bone (Figure 12). In addition, while anti-resorptive therapy increases cortical width of long bones in children who are growing, the reductions in long bone periosteal circumference that are germane to diseases like DMD (Figure 12) are not modifiable by any therapy that acts only on endocortical and trabecular surfaces (such as anti-resorptive drugs); therefore, medications are needed that also target periosteal apposition.\n\nFigure 12 Aspects of the skeletal phenotype that are more or less modifiable by anti-resorptive osteoporosis therapy in glucocorticoid-treated Duchenne muscular dystrophy. Prevention of first fractures in glucocorticoid-treated, and in glucocorticoid-naïve, Duchenne muscular dystrophy is one of the greatest unmet needs in the pediatric osteoporosis field, at the current time. Note the arrow (left), pointing to a distal femur fracture in a boy with Duchenne muscular dystrophy, along with thin cortices, and a reduction in femur width, relative to the healthy control. DMD, Duchenne muscular dystrophy.\n\nAs such, the door is decidedly open to novel therapies that are anabolic to bone, and which would be ideal in children with a need for prolonged GC therapy, with poor growth, and with reductions in periosteal circumference (the latter, whether due to myopathies as in DMD, or due to the periosteal apposition-limiting effects of prolonged GC). The overall goal of such an approach would be to prevent first-ever fractures in children with the greatest risk of bone fragility, and the least potential for recovery.\n\nTeriparatide, recombinant human PTH (1–34), is approved by the United States Food and Drug Administration (FDA) for initial treatment of post-menopausal osteoporosis with a high risk of fracture, for patients who have failed prior osteoporosis therapy, and for adults with GC-associated osteoporosis (130). Teriparatide reduces the risk of VF, and non-VF, in post-menopausal women; the effect on fractures of the hip was inconclusive due to a low incidence of hip fractures in a large, randomized controlled trial (131). Overall, teriparatide positively affects spine BMD, but not BMD at the hip or forearm (131). Where children are concerned, this anabolic drug has an FDA black box warning against its use due to the development of osteosarcoma in growing rats treated at doses that were three to 50 times higher than human, adult equivalents (132). Subsequent studies in the same strain of rats found no evidence of malignancy with doses that were three times higher than the human equivalent (133).\n\nBMD declines rapidly in the 12 months following teriparatide cessation, although fracture reductions persist for up to 2 years (134). Teriparatide, followed by alendronate, mitigates this loss (135). A recent case report of teriparatide in a 20 year old man with DMD described improvement in back pain due to VF after 6 months of teriparatide, plus increases in LS BMD, improvement in quality of life, and increases in suppressed bone biomarkers (136). These findings support further study of PTH in DMD post-epiphyseal fusion. On the other hand, the impact of PTH on bone is attenuated in adults when administered after bisphosphonate therapy (137). This may undermine its use in men with DMD who received bisphosphonates in childhood.\n\nSclerostin is a potent, negative regulator of bone formation, secreted by the osteocyte to inhibit the anabolic Wnt signaling pathway. Sclerostin antibody therapy releases the inhibition on sclerostin-mediated bone formation, and has been approved for women with post-menopausal osteoporosis (romosozumab). Mice treated with sclerostin antibody demonstrate not only increases in BMD and bone turnover markers, but show bone strength-enhancing changes in bone geometry (such as increases in periosteal circumference) that are not possible with anti-resorptive therapy (138). Sclerostin antibody-based drug trials for osteoporotic children with frequent fractures, low BMD, and reduced periosteal circumference are currently in the strategic development phase. In adults receiving anti-sclerostin antibody, bone formation returns to baseline by about 6 months after the first sub-cutaneous injection, and subsequent doses appear to have less of a beneficial effect on bone formation (139). As a result, it has been recommended to “seal in” the gains of sclerostin antibody treatment with a sequential therapy approach, using a long-acting anti-resorptive treatment (139, 140). These mechanisms of action will need to be considered in any future trial of sclerostin in pediatric GIO.\n\nThere Is a Need for High Quality Intervention Studies That Acknowledge the Barriers to “Gold Standard” Clinical Trial Designs in Pediatric GIO\nAt the time of this writing, there are four drug trials listed on ClinicalTrials.gov targeting osteoporosis in GC-treated children (last accessed 28 June 2020). The first is a 1 year, international, phase 3, double-blind, randomized, controlled trial of intravenous zoledronic acid vs. intravenous placebo (both twice yearly) in children with GIO (NCT00799266, completed). The second is an extension to the aforementioned study, involving a 1 year, international, open-label extension of zoledronic acid twice yearly in children with GIO (NCT01197300, completed). The third trial is a 3 year, international, phase 3, double-blind, randomized, placebo-controlled, parallel-group study of denosumab in children with GIO (NCT03164928, recruiting). The fourth study registered with ClinicalTrials.gov is a 2 year, single-center, randomized, controlled, pilot study of 6 monthly intravenous zoledronic acid vs. 6 monthly sub-cutaneous denosumab in children with osteoporosis (NCT02632916, completed). This pilot study is sponsored by the author (LMW), in collaboration with the Children's Hospital of Eastern Ontario Research Institute. The study enrolled 10 children with osteoporosis, of whom eight had GC-treated DMD, and two had juvenile osteoporosis. The manuscripts for the three completed trials, examining the effect of zoledronic acid or denosumab on osteoporosis in GC-treated children, are currently in preparation for submission to peer-reviewed journals. Together, these trials will provide much-needed data on the use of anti-resorptive therapy in pediatric GIO.\n\nWhile we eagerly await the results of these trials, it should be recognized that if medications to treat pediatric GIO are ever to achieve health authority-endorsed labeling on sufficient numbers of patients, pediatric trials may need to be adjudicated differently than adult osteoporosis studies. The pediatric approach must not compromise on safety data, but should acknowledge the debilitating consequences of pediatric GIO, and the need for guidance on the treatment of GIO in childhood, despite the formidable logistical challenges of studies in children with uncommon conditions. To this end, pragmatic study designs may be needed that provide reasonable proof of efficacy, including biomarkers to demonstrate the anticipated biology of the drug, surrogates of bone strength (e.g., BMD and bone geometry), patient-reported outcomes (e.g., pain, quality of life), functional studies (e.g., mobility), and careful fracture phenotyping (including vertebral fractures). Methodologically sound patient registries, and natural history comparator studies, may help overcome barriers in this context. Ultimately, innovative drug studies that maneuver the challenges of pediatric GIO trials are needed, in order to avoid uninformed off-label prescription in a well-intentioned effort to help a child with GIO.\n\nAuthor Contributions\nThe author confirms being the sole contributor of this work and has approved it for publication.\n\nConflict of Interest\nLW has participated in clinical trials with ReveraGen BioPharma, PTC Therapeutics, Catabasis Pharmaceuticals, Novartis, Ultragenyx, and Amgen. LW has also received unrestricted educational grants from Alexion and Ultragenyx, and consulting fees from Ipsen, Ultragenyx, PTC Therapeutics, Novartis, and Amgen, with funds to LW's institution.\n\nLW would like to thank the investigators, collaborators, research assistants, children, and families who participated in the Canadian STeroid-induced Osteoporosis in the Pediatric Population (STOPP) study, Dr. Marie-Eve Robinson, Dr. Karine Khatchadourian, and Marika Pagé for their care of patients with GIO at the Children's Hospital of Eastern Ontario, Dr. Frank Rauch (Shriners Hospital Canada, Montréal) for over two decades of collaboration, and the research staff and scientists affiliated with the Ottawa Pediatric Bone Health Research Group who have been dedicated to the study of children with GIO for many years (Maya Scharke, Elizabeth Sykes, Lynn MacLeay, Scott Walker, Colleen Hartigan, and Drs. Nazih Shenouda, Mary-Ann Matzinger, Jacob Jaremko, Khaldoun Koujok, Jinhui Ma, Stefan Jackowski, Nasrin Khan, Victor Konji, Brian Lentle, and Kerry Siminoski).\n\nFunding. LW has been supported by Tier 1 and Tier 2 Research Chairs from the University of Ottawa, by the Children's Hospital of Eastern Ontario Departments of Pediatrics and Surgery, and by the Children's Hospital of Eastern Ontario Research Institute. The STeroid-induced Osteoporosis in the Pediatric Population (STOPP) study was funded by the Canadian Institutes for Health Research (Funding Reference Number 64285).\n==== Refs\nReferences\n1. Buckley L Guyatt G Fink HA Cannon M Grossman J Hansen KE \n2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis\n. Arthritis Rheumatol (2017 ) 69 :1521 –37\n. 10.1002/acr.23279 \n2. Lorenzo J \nCytokines and bone: osteoimmunology\n. Handb Exp Pharmacol . (2020 ) 10.1007/164_2019_346 . [Epub ahead of print].\n3. Halton J Gaboury I Grant R Alos N Cummings EA Matzinger M . Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian steroid-associated osteoporosis in the pediatric population (STOPP) research program\n. J Bone Miner Res. (2009 ) 24 :1326 –34\n. 10.1359/jbmr.090202 19210218 \n4. Thearle M Horlick M Bilezikian JP Levy J Gertner JM Levine LS . Osteoporosis: an unusual presentation of childhood Crohn's disease\n. J Clin Endocrinol Metab. (2000 ) 85 :2122 –6\n. 10.1210/jc.85.6.2122 10852438 \n5. Huber AM Gaboury I Cabral DA Lang B Ni A Stephure D . Prevalent vertebral fractures among children initiating glucocorticoid therapy for the treatment of rheumatic disorders\n. Arthritis Care Res (Hoboken). (2010 ) 62 :516 –26\n. 10.1002/acr.20171 20391507 \n6. Boulanger Piette A Hamoudi D Marcadet L Morin F Argaw A Ward L . Targeting the muscle-bone unit: filling two needs with one deed in the treatment of Duchenne muscular dystrophy\n. Curr Osteoporos Rep. (2018 ) 16 :541 –53\n. 10.1007/s11914-018-0468-2 30225627 \n7. Hartmann K Koenen M Schauer S Wittig-Blaich S Ahmad M Baschant U . Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy\n. Physiol Rev. (2016 ) 96 :409 –47\n. 10.1152/physrev.00011.2015 26842265 \n8. Nephrotic syndrome in children: a randomized trial comparing two prednisone regimens in steroid-responsive patients who relapse early \nReport of the international study of kidney disease in children\n. J Pediatr . (1979 ) 95 :239 –43\n.109598 \n9. Rauch F Schoenau E \nThe developing bone: slave or master of its cells and molecules?\n\nPediatr Res. (2001 ) 50 :309 –14\n. 10.1203/00006450-200109000-00003 11518815 \n10. Frost HM . The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents\n. Bone Miner. (1987 ) 2 :73 –85\n. 3333019 \n11. Frost HM Schonau E . The “muscle-bone unit” in children and adolescents: a 2000 overview\n. J Pediatr Endocrinol Metab. (2000 ) 13 :571 –90\n. 10.1515/JPEM.2000.13.6.571 10905381 \n12. Rauch F Bailey DA Baxter-Jones A Mirwald R Faulkner R . The 'muscle-bone unit' during the pubertal growth spurt\n. Bone. (2004 ) 34 :771 –5\n. 10.1016/j.bone.2004.01.022 15121007 \n13. Weinstein RS Jilka RL Parfitt AM Manolagas SC . Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone\n. J Clin Invest. (1998 ) 102 :274 –82\n. 10.1172/JCI2799 9664068 \n14. Weinstein RS Chen JR Powers CC Stewart SA Landes RD Bellido T . Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids\n. J Clin Invest. (2002 ) 109 :1041 –8\n. 10.1172/JCI0214538 11956241 \n15. Santiago RA Silva CA Caparbo VF Sallum AM Pereira RM . Bone mineral apparent density in juvenile dermatomyositis: the role of lean body mass and glucocorticoid use\n. Scand J Rheumatol. (2008 ) 37 :40 –7\n. 10.1080/03009740701687226 18189194 \n16. Dalle Carbonare L Arlot ME Chavassieux PM Roux JP Portero NR Meunier PJ . Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis\n. J Bone Miner Res. (2001 ) 16 :97 –103\n. 10.1359/jbmr.2001.16.1.97 11149495 \n17. Canalis E Mazziotti G Giustina A Bilezikian JP . Glucocorticoid-induced osteoporosis: pathophysiology and therapy\n. Osteoporos Int. (2007 ) 18 :1319 –28\n. 10.1007/s00198-007-0394-0 17566815 \n18. Ma J McMillan HJ Karaguzel G Goodin C Wasson J Matzinger MA . The time to and determinants of first fractures in boys with Duchenne muscular dystrophy\n. Osteoporos Int. (2017 ) 28 :597 –608\n. 10.1007/s00198-016-3774-5 27774565 \n19. LeBlanc CM Ma J Taljaard M Roth J Scuccimarri R Miettunen P . Incident vertebral fractures and risk factors in the first three years following glucocorticoid initiation among pediatric patients with rheumatic disorders\n. J Bone Miner Res. (2015 ) 30 :1667 –75\n. 10.1002/jbmr.2511 25801315 \n20. Ward LM Ma J Lang B Ho J Alos N Matzinger MA . Bone morbidity and recovery in children with acute lymphoblastic leukemia: results of a six-year prospective cohort study\n. J Bone Miner Res. (2018 ) 33 :1435 –43\n. 10.1002/jbmr.3447 29786884 \n21. Cooper C Dennison EM Leufkens HG Bishop N van Staa TP . Epidemiology of childhood fractures in Britain: a study using the general practice research database\n. J Bone Miner Res. (2004 ) 19 :1976 –81\n. 10.1359/jbmr.040902 15537440 \n22. Clark EM . The epidemiology of fractures in otherwise healthy children\n. Curr Osteoporos Rep. (2014 ) 12 :272 –8\n. 10.1007/s11914-014-0227-y 24973964 \n23. Mayranpaa MK Makitie O Kallio PE . Decreasing incidence and changing pattern of childhood fractures: a population-based study\n. J Bone Miner Res. (2010 ) 25 :2752 –9\n. 10.1002/jbmr.155 20564246 \n24. Bishop N Arundel P Clark E Dimitri P Farr J Jones G . Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD (2013). Pediatric official positions\n. J Clin Densitom. (2014 ) 17 :275 –80\n. 10.1016/j.jocd.2014.01.004 24631254 \n25. Baim S Leonard MB Bianchi ML Hans DB Kalkwarf HJ Langman CB \nOfficial positions of the international society for clinical densitometry and executive summary of the (2007). ISCD pediatric position development conference\n. J Clin Densitom. (2008 ) 11 :6 –21\n. 10.1016/j.jocd.2007.12.002 18442749 \n26. Ma J Siminoski K Alos N Halton J Ho J Lentle B \nThe choice of normative pediatric reference database changes spine bone mineral density Z-scores but not the relationship between bone mineral density and prevalent vertebral fractures\n. J Clin Endocrinol Metab. (2015 ) 100 :1018 –27\n. 10.1210/jc.2014-3096 25494661 \n27. Leonard MB Propert KJ Zemel BS Stallings VA Feldman HI . Discrepancies in pediatric bone mineral density reference data: potential for misdiagnosis of osteopenia\n. J Pediatrics. (1999 ) 135 (Pt. 1):182 –8\n. 10.1016/S0022-3476(99)70020-X 10431112 \n28. Kocks J Ward K Mughal Z Moncayo R Adams J Hogler W . Z-score comparability of bone mineral density reference databases for children\n. J Clin Endocrinol Metab. (2010 ) 95 :4652 –9\n. 10.1210/jc.2010-0677 20668038 \n29. Fiscaletti M Coorey CP Biggin A Briody J Little DG Schindeler A . Diagnosis of recurrent fracture in a pediatric cohort\n. Calcif Tissue Int. (2018 ) 103 :529 –39\n. 10.1007/s00223-018-0449-6 29943187 \n30. Rodd C Lang B Ramsay T Alos N Huber AM Cabral DA . Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study\n. Arthritis Care Res. (2012 ) 64 :122 –31\n. 10.1002/acr.20589 22213727 \n31. Ward LM Weber DR Munns CF Hogler W Zemel BS . A contemporary view of the definition and diagnosis of osteoporosis in children and adolescents\n. J Clin Endocrinol Metab. (2020 ) 105 :e2088 –97\n. 10.1210/clinem/dgz294 31865390 \n32. Genant HK Wu CY van Kuijk C Nevitt MC \nVertebral fracture assessment using a semiquantitative technique\n. J Bone Miner Res. (1993 ) 8 :1137 –48\n. 10.1002/jbmr.5650080915 8237484 \n33. Genant HK Jergas M Palermo L Nevitt M Valentin RS Black D . Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis the study of Osteoporotic Fractures Research Group\n. J Bone Miner Res. (1996 ) 11 :984 –96\n. 10.1002/jbmr.5650110716 8797120 \n34. Jaremko JL Siminoski K Firth GB Matzinger MA Shenouda N Konji VN . Common normal variants of pediatric vertebral development that mimic fractures: a pictorial review from a national longitudinal bone health study\n. Pediatr Radiol. (2015 ) 45 :593 –605\n. 10.1007/s00247-014-3210-y 25828359 \n35. Singh A Schaeffer EK Reilly CW . Vertebral fractures in Duchenne muscular dystrophy patients managed with deflazacort\n. J Pediatr Orthop . (2016 ) 38 :320 –24\n. 10.1097/BPO.0000000000000817 27328118 \n36. Joseph S Wang C Bushby K Guglieri M Horrocks I Straub V . Fractures and linear growth in a nationwide cohort of boys with Duchenne muscular dystrophy with and without glucocorticoid treatment: results from the UK northstar database\n. JAMA Neurol. (2019 ) 76 :701 –9\n. 10.1001/jamaneurol.2019.0242 30855644 \n37. Hansen KE Kleker B Safdar N Bartels CM . A systematic review and meta-analysis of glucocorticoid-induced osteoporosis in children\n. Semin Arthritis Rheum. (2014 ) 44 :47 –54\n. 10.1016/j.semarthrit.2014.02.002 24680381 \n38. Siminoski K Lee KC Jen H Warshawski R Matzinger MA Shenouda N . Anatomical distribution of vertebral fractures: comparison of pediatric and adult spines\n. Osteoporos Int. (2012 ) 23 :1999 –2008\n. 10.1007/s00198-011-1837-1 22109742 \n39. Feber J Gaboury I Ni A Alos N Arora S Bell L . Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome\n. Osteoporos Int. (2012 ) 23 :751 –60\n. 10.1007/s00198-011-1621-2 21494860 \n40. Alos N Grant RM Ramsay T Halton J Cummings EA Miettunen PM . High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy\n. J Clin Oncol. (2012 ) 30 :2760 –7\n. 10.1200/JCO.2011.40.4830 22734031 \n41. Phan V Blydt-Hansen T Feber J Alos N Arora S Atkinson S . Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome\n. Osteoporos Int. (2014 ) 25 :627 –37\n. 10.1007/s00198-013-2466-7 23948876 \n42. Cummings EA Ma J Fernandez CV Halton J Alos N Miettunen PM . Incident vertebral fractures in children with leukemia during the four years following diagnosis\n. J Clin Endocrinol Metab. (2015 ) 100 :3408 –17\n. 10.1210/JC.2015-2176 26171800 \n43. Dennison E Cooper C . Epidemiology of osteoporotic fractures\n. Horm Res. (2000 ) 54 (Suppl. 1 ):58 –63\n. 10.1159/000063449 11146381 \n44. Weber DR Boyce A Gordon C Hogler W Kecskemethy HH Misra M . The utility of DXA assessment at the forearm, proximal femur, and lateral distal femur, and vertebral fracture assessment in the pediatric population: the 2019 official pediatric positions of the ISCD\n. J Clin Densitom . (2019 ) 22 :567 –89\n. 10.1016/j.jocd.2019.07.002 31421951 \n45. Birnkrant DJ Bushby K Bann CM Alman BA Apkon SD Blackwell A . Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management\n. Lancet Neurol. (2018 ) 17 :347 –61\n. 10.1016/S1474-4422(18)30025-5 29395990 \n46. Ward LM Konji VN Ma J . The management of osteoporosis in children\n. Osteoporos Int. (2016 ) 27 :2147 –79\n. 10.1007/s00198-016-3515-9 27125514 \n47. Helenius I Remes V Salminen S Valta H Makitie O Holmberg C . Incidence and predictors of fractures in children after solid organ transplantation: a 5-year prospective, population-based study\n. J Bone Miner Res. (2006 ) 21 :380 –7\n. 10.1359/JBMR.051107 16491285 \n48. Valta H Jalanko H Holmberg C Helenius I Makitie O . Impaired bone health in adolescents after liver transplantation\n. Am J Transplant. (2008 ) 8 :150 –7\n. 10.1111/j.1600-6143.2007.02015.x 17973968 \n49. Valta H Makitie O Ronnholm K Jalanko H . Bone health in children and adolescents after renal transplantation\n. J Bone Miner Res. (2009 ) 24 :1699 –708\n. 10.1359/jbmr.090407 19419296 \n50. Vautour LM Melton LJ IIIClarke BL Achenbach SJ Oberg AL McCarthy JT . Long-term fracture risk following renal transplantation: a population-based study\n. Osteoporos Int. (2004 ) 15 :160 –7\n. 10.1007/s00198-003-1532-y 14666400 \n51. van Staa TP Cooper C Leufkens HG Bishop N . Children and the risk of fractures caused by oral corticosteroids\n. J Bone Miner Res. (2003 ) 18 :913 –8\n. 10.1359/jbmr.2003.18.5.913 12733732 \n52. Ma J Siminoski K Wang P Alos N Cummings EA Feber J . The accuracy of prevalent vertebral fracture detection in children using targeted case-finding approaches\n. J Bone Miner Res. (2020 ) 35 :460 –8\n. 10.1002/jbmr.3922 31742768 \n53. Tian C Wong BL Hornung L Khoury JC Miller L Bange J . Bone health measures in glucocorticoid-treated ambulatory boys with Duchenne muscular dystrophy\n. Neuromuscul Disord. (2016 ) 26 :760 –7\n. 10.1016/j.nmd.2016.08.011 27614576 \n54. Mostoufi-Moab S Kelly A Mitchell JA Baker J Zemel BS Brodsky J . Changes in pediatric DXA measures of musculoskeletal outcomes and correlation with quantitative CT following treatment of acute lymphoblastic leukemia\n. Bone. (2018 ) 112 :128 –35\n. 10.1016/j.bone.2018.04.012 29679731 \n55. Kelly A Shults J Mostoufi-Moab S McCormack SE Stallings VA Schall JI . Pediatric bone mineral accrual z-score calculation equations and their application in childhood disease\n. J Bone Miner Res. (2019 ) 34 :195 –203\n. 10.1002/jbmr.3589 30372552 \n56. King WM Ruttencutter R Nagaraja HN Matkovic V Landoll J Hoyle C . Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy\n. Neurology . (2007 ) 68 :1607 –13\n. 10.1212/01.wnl.0000260974.41514.83 17485648 \n57. Larson CM Henderson RC . Bone mineral density and fractures in boys with Duchenne muscular dystrophy\n. J Pediatr Orthop. (2000 ) 20 :71 –4\n. 10.1097/01241398-200001000-00016 10641693 \n58. Nelson DA Kleerekoper M Peterson EL \nReversal of vertebral deformities in osteoporosis: measurement error or “rebound”?\n\nJ Bone Miner Res. (1994 ) 9 :977 –82\n. 10.1002/jbmr.5650090704 7942166 \n59. Dal Osto LC Konji VN Halton J Matzinger MA Bassal M Rauch F . The spectrum of recovery from fracture-induced vertebral deformity in pediatric leukemia\n. Pediatr Blood Cancer. (2016 ) 63 :1107 –10\n. 10.1002/pbc.25942 26878592 \n60. Burger H Van Daele PL Grashuis K Hofman A Grobbee DE Schutte HE . Vertebral deformities and functional impairment in men and women\n. J Bone Miner Res. (1997 ) 12 :152 –7\n. 10.1359/jbmr.1997.12.1.152 9240738 \n61. Nevitt MC Ettinger B Black DM Stone K Jamal SA Ensrud K . The association of radiographically detected vertebral fractures with back pain and function: a prospective study\n. Ann Intern Med. (1998 ) 128 :793 –800\n. 10.7326/0003-4819-128-10-199805150-00001 9599190 \n62. Center JR . Fracture burden: what two and a half decades of dubbo osteoporosis epidemiology study data reveal about clinical outcomes of osteoporosis\n. Curr Osteoporos Rep. (2017 ) 15 :88 –95\n. 10.1007/s11914-017-0352-5 28258372 \n63. Watanabe R Shiraki M Saito M Okazaki R Inoue D . Restrictive pulmonary dysfunction is associated with vertebral fractures and bone loss in elderly postmenopausal women\n. Osteoporos Int. (2018 ) 29 :625 –33\n. 10.1007/s00198-017-4337-0 29218382 \n64. Kerkeni S Kolta S Fechtenbaum J Roux C . Spinal deformity index (SDI) is a good predictor of incident vertebral fractures\n. Osteoporos Int. (2009 ) 20 :1547 –52\n. 10.1007/s00198-008-0832-7 19137350 \n65. Marinovic D Dorgeret S Lescoeur B Alberti C Noel M Czernichow P . Improvement in bone mineral density and body composition in survivors of childhood acute lymphoblastic leukemia: a 1-year prospective study\n. Pediatrics. (2005 ) 116 :e102 –8\n. 10.1542/peds.2004-1838 15995009 \n66. Gurney JG Kaste SC Liu W Srivastava DK Chemaitilly W Ness KK . Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude lifetime cohort study\n. Pediatr Blood Cancer. (2014 ) 61 :1270 –6\n. 10.1002/pbc.25010 24585546 \n67. Makitie O Heikkinen R Toiviainen-Salo S Henriksson M Puukko-Viertomies LR Jahnukainen K . Long-term skeletal consequences of childhood acute lymphoblastic leukemia in adult males: a cohort study\n. Eur J Endocrinol. (2013 ) 168 :281 –8\n. 10.1530/EJE-12-0702 23197573 \n68. Mattano LA JrDevidas M Nachman JB Sather HN Hunger SP Steinherz PG . Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial\n. Lancet Oncol. (2012 ) 13 :906 –15\n. 10.1016/S1470-2045(12)70274-7 22901620 \n69. Crabtree NJ Adams JE Padidela R Shaw NJ Hogler W Roper H . Growth, bone health & ambulatory status of boys with DMD treated with daily vs. intermittent oral glucocorticoid regimen\n. Bone. (2018 ) 116 :181 –6\n. 10.1016/j.bone.2018.07.019 30055340 \n70. Ferraris JR Pasqualini T Alonso G Legal S Sorroche P Galich AM \nEffects of deflazacort vs. methylprednisone: a randomized study in kidney transplant patients\n. Pediatr Nephrol. (2007 ) 22 :734 –41\n. 10.1007/s00467-006-0403-0 17294225 \n71. Ferraris JR Pasqualini T Legal S Sorroche P Galich AM Pennisi P . Effect of deflazacort versus methylprednisone on growth, body composition, lipid profile, and bone mass after renal transplantation. The Deflazacort Study Group\n. Pediatr Nephrol. (2000 ) 14 :682 –8\n. 10.1007/s004670000337 10912543 \n72. Loftus J Allen R Hesp R David J Reid DM Wright DJ . Randomized, double-blind trial of deflazacort versus prednisone in juvenile chronic (or rheumatoid) arthritis: a relatively bone-sparing effect of deflazacort\n. Pediatrics. (1991 ) 88 :428 –36\n. 1881719 \n73. Guglieri M Bushby K McDermott MP Hart KA Tawil R Martens WB . Developing standardized corticosteroid treatment for Duchenne muscular dystrophy\n. Contemp Clin Trials. (2017 ) 58 :34 –39\n. 10.1016/j.cct.2017.04.008 28450193 \n74. Heier CR Damsker JM Yu Q Dillingham BC Huynh T Van der Meulen JH . VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects\n. EMBO Mol Med. (2013 ) 5 :1569 –85\n. 10.1002/emmm.201302621 24014378 \n75. Reeves EKM Hoffman EP Nagaraju K Damsker JM McCall JM . VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid\n. Bioorg Med Chem. (2013 ) 21 :2241 –9\n. 10.1016/j.bmc.2013.02.009 23498916 \n76. Hoffman EP Riddle V Siegler M Dickerson D Backonja M Kramer W \nPhase 1 blinded clinical trial of vamorolone, a first-in-class dissociative steroidal drug, shows improvements in side effects via biomarkers bridged to clinical outcomes\n. Sterodis . (2017 ) 134 :43 –52\n. 10.1016/j.steroids.2018.02.010 \n77. Conklin LS Damsker JM Hoffman EP Jusko WJ Mavroudis PD Schwartz BD . Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug\n. Pharmacol Res. (2018 ) 136 :140 –50\n. 10.1016/j.phrs.2018.09.007 30219580 \n78. Weber DR Hadjiyannakis S McMillan HJ Noritz G Ward LM . Obesity and endocrine management of the patient with Duchenne muscular dystrophy\n. Pediatrics. (2018 ) 142 (Suppl. 2 ):S43 –52\n. 10.1542/peds.2018-0333F 30275248 \n79. Frittoli RB Longhi BS Silva AM Filho AAB Monteiro M Appenzeller S . Erratum to “Effects of the use of growth hormone in children, adolescents with juvenile idiopathic arthritis: a systematic review” (Rev Bras Reumatol. 2017;57(2):100-106)\n. Rev Bras Reumatol Engl Ed . (2017 ) 57 :500 . 10.1016/j.rbre.2017.09.003 29037325 \n80. Frittoli RB Longhi BS Silva AM Filho AAB Monteiro M Appenzeller S \nEffects of the use of growth hormone in children and adolescents with juvenile idiopathic arthritis: a systematic review\n. Rev Bras Reumatol Engl Ed. (2017 ) 57 :100 –106\n. 10.1016/j.rbr.2016.04.004 28343613 \n81. Rutter MM Collins J Rose SR Woo JG Sucharew H Sawnani H . Growth hormone treatment in boys with Duchenne muscular dystrophy and glucocorticoid-induced growth failure\n. Neuromuscul Disord. (2012 ) 22 :1046 –56\n. 10.1016/j.nmd.2012.07.009 22967789 \n82. Shiff NJ Brant R Guzman J Cabral DA Huber AM Miettunen P . Glucocorticoid-related changes in body mass index among children and adolescents with rheumatic diseases\n. Arthritis Care Res. (2013 ) 65 :113 –21\n. 10.1002/acr.21785 22826190 \n83. Bian Q McAdam L Grynpas M Mitchell J Harrington J . Increased rates of vitamin D insufficiency in boys with Duchenne muscular dystrophy despite higher vitamin D3 supplementation\n. Glob Pediatr Health. (2019 ) 6 :2333794X19835661 . 10.1177/2333794X19835661 30906820 \n84. Ross AC Manson JE Abrams SA Aloia JF Brannon PM Clinton SK . The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know\n. J Clin Endocrinol Metab. (2011 ) 96 :53 –8\n. 10.1210/jc.2010-2704 21118827 \n85. Misra M Pacaud D Petryk A Collett-Solberg PF Kappy M . Vitamin D deficiency in children and its management: review of current knowledge and recommendations\n. Pediatrics. (2008 ) 122 :398 –417\n. 10.1542/peds.2007-1894 18676559 \n86. Holick MF Binkley NC Bischoff-Ferrari HA Gordon CM Hanley DA Heaney RP . Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline\n. J Clin Endocrinol Metab. (2011 ) 96 :1911 –30\n. 10.1210/jc.2011-0385 21646368 \n87. Winzenberg T Powell S Shaw KA Jones G \nEffects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis\n. BMJ. (2011 ) 342 :c7254 \n10.1136/bmj.c7254 21266418 \n88. Benchimol EI Ward LM Gallagher JC Rauch F Barrowman N Warren J \nEffect of calcium and vitamin D supplementation on bone mineral density in children with inflammatory bowel disease\n. J Pediatr Gastroenterol Nutr. (2007 ) 45 :538 –45\n. 10.1097/MPG.0b013e3180dca0cc 18030230 \n89. Kaste SC Qi A Smith K Surprise H Lovorn E Boyett J . Calcium and cholecalciferol supplementation provides no added benefit to nutritional counseling to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL)\n. Pediatr Blood Cancer. (2014 ) 61 :885 –93\n. 10.1002/pbc.24882 24395288 \n90. Bolland MJ Avenell A Baron JA Grey A MacLennan GS Gamble GD . Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis\n. BMJ. (2010 ) 341 :c3691 . 10.1136/bmj.c3691 20671013 \n91. Jayasena A Atapattu N Lekamwasam S . Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review\n. Int J Rheum Dis. (2015 ) 18 :287 –93\n. 10.1111/1756-185X.12560 25923606 \n92. Rianthavorn P Pisutikul K Deekajorndech T Tepmongkol S Suphapeetiporn K \nPrevention of bone loss in children receiving long-term glucocorticoids with calcium and alfacalcidol or menatetrenone\n. J Pediatr Endocrinol Metab. (2012 ) 25 :307 –12\n. 10.1515/jpem-2011-0441 22768661 \n93. Bak M Serdaroglu E Guclu R . Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome\n. Pediatr Nephrol. (2006 ) 21 :350 –4\n. 10.1007/s00467-005-2118-z 16382319 \n94. Inoue T Sugiyama T Matsubara T Kawai S Furukawa S . Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol\n. Endocr J. (2001 ) 48 :11 –8\n. 10.1507/endocrj.48.11 11403096 \n95. Huber AM Ward LM . The impact of underlying disease on fracture risk and bone mineral density in children with rheumatic disorders: a review of current literature\n. Semin Arthritis Rheum . (2016 ) 46 :49 –63\n. 10.1016/j.semarthrit.2016.02.003 27020068 \n96. Rooney M Bishop N Davidson J Beresford MW Pilkington C Donagh JM . The prevention and treatment of glucocorticoid-induced osteopaenia in juvenile rheumatic disease: a randomised double-blind controlled trial\n. EClinMed. (2019 ) 12 :79 –87\n. 10.1016/j.eclinm.2019.06.004 31388666 \n97. Rauch F Plotkin H Travers R Zeitlin L Glorieux FH . Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism\n. J Clin Endocrinol Metab. (2003 ) 88 :986 –92\n. 10.1210/jc.2002-021371 12629073 \n98. Ward LM Rauch F . Oral bisphosphonates for paediatric osteogenesis imperfecta?\n\nLancet. (2013 ) 282 :1388 –9\n. 10.1016/S0140-6736(13)61531-7 23927912 \n99. Nasomyont N Hornung LN Gordon CM Wasserman H . Outcomes following intravenous bisphosphonate infusion in pediatric patients: a 7-year retrospective chart review\n. Bone. (2019 ) 121 :60 –67\n. 10.1016/j.bone.2019.01.003 30616029 \n100. Trejo P Rauch F . Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment\n. Osteoporos Int. (2016 ) 27 :3427 –37\n. 10.1007/s00198-016-3723-3 27492436 \n101. Palomo T Fassier F Ouellet J Sato A Montpetit K Glorieux FH . Intravenous bisphosphonate therapy of young children with osteogenesis imperfecta: skeletal findings during follow up throughout the growing years\n. J Bone Miner Res . (2015 ) 30 :2150 –7\n. 10.1002/jbmr.2567 26059976 \n102. Gatti D Antoniazzi F Prizzi R Braga V Rossini M Tato L . Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study\n. J Bone Miner Res. (2005 ) 20 :758 –63\n. 10.1359/JBMR.041232 15824848 \n103. Antoniazzi F Zamboni G Lauriola S Donadi L Adami S Tato L . Early bisphosphonate treatment in infants with severe osteogenesis imperfecta\n. J Pediatr. (2006 ) 149 :174 –9\n. 10.1016/j.jpeds.2006.03.013 16887429 \n104. Brown JJ Zacharin MR . Attempted randomized controlled trial of pamidronate versus calcium and calcitriol supplements for management of steroid-induced osteoporosis in children and adolescents\n. J Paediatr Child Health. (2005 ) 41 :580 –2\n. 10.1111/j.1440-1754.2005.00720.x 16398842 \n105. Inoue Y Shimojo N Suzuki S Arima T Tomiita M Minagawa M . Efficacy of intravenous alendronate for the treatment of glucocorticoid-induced osteoporosis in children with autoimmune diseases\n. Clin Rheumatol. (2008 ) 27 :909 –12\n. 10.1007/s10067-008-0864-6 18330609 \n106. Acott PD Wong JA Lang BA Crocker JF . Pamidronate treatment of pediatric fracture patients on chronic steroid therapy\n. Pediatr Nephrol. (2005 ) 20 :368 –73\n. 10.1007/s00467-004-1790-8 15690187 \n107. Simm PJ Johannesen J Briody J McQuade M Hsu B Bridge C . Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis\n. Bone. (2011 ) 49 :939 –43\n. 10.1016/j.bone.2011.07.031 21820091 \n108. Ooi HL Briody J Biggin A Cowell CT Munns CF . Intravenous zoledronic acid given every 6 months in childhood osteoporosis\n. Horm Res Paediatr. (2013 ) 80 :179 –84\n. 10.1159/000354303 24052046 \n109. Sbrocchi AM Rauch F Jacob P McCormick A McMillan HJ Matzinger MA . The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy\n. Osteoporos Int. (2012 ) 23 :2703 –11\n. 10.1007/s00198-012-1911-3 22297733 \n110. Sbrocchi AM Forget S Laforte D Azouz EM Rodd C . Zoledronic acid for the treatment of osteopenia in pediatric Crohn's disease\n. Pediatr. Int. (2010 ) 52 :754 –61\n. 10.1111/j.1442-200X.2010.03174.x 20524999 \n111. Ward LM Denker AE Porras A Shugarts S Kline W Travers R . Single-dose pharmacokinetics and tolerability of alendronate 35- and 70-milligram tablets in children and adolescents with osteogenesis imperfecta type I\n. J Clin Endocrinol Metab. (2005 ) 90 :4051 –6\n. 10.1210/jc.2004-2054 15827104 \n112. George S Weber DR Kaplan P Hummel K Monk HM Levine MA . Short-term safety of zoledronic acid in young patients with bone disorders: an extensive institutional experience\n. J Clin Endocrinol Metab. (2015 ) 100 :4163 –71\n. 10.1210/jc.2015-2680 26308295 \n113. Misof BM Roschger P McMillan HJ Ma J Klaushofer K Rauch F . Histomorphometry and bone matrix mineralization before and after bisphosphonate treatment in boys with Duchenne muscular dystrophy: a paired transiliac biopsy study\n. J Bone Miner Res. (2016 ) 31 :1060 –9\n. 10.1002/jbmr.2756 26615086 \n114. Rauch F Travers R Plotkin H Glorieux FH . The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta\n. J Clin Invest. (2002 ) 110 :1293 –9\n. 10.1172/JCI0215952 12417568 \n115. Rauch F Munns C Land C Glorieux FH . Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation\n. J Clin Endocrinol Metab. (2006 ) 91 :1268 –74\n. 10.1210/jc.2005-2413 16434452 \n116. Rauch F Cornibert S Cheung M Glorieux FH . Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta\n. Bone. (2007 ) 40 :821 –7\n. 10.1016/j.bone.2006.11.020 17223617 \n117. Biggin A Briody JN Ormshaw E Wong KK Bennetts BH Munns CF . Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen\n. Horm Res Paediatr. (2014 ) 81 :204 –10\n. 10.1159/000355111 24356182 \n118. van der Sluis IM van den Heuvel-Eibrink MM Hahlen K Krenning EP de Muinck Keizer-Schrama SM . Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia\n. J Pediatr. (2002 ) 141 :204 –10\n. 10.1067/mpd.2002.125728 12183715 \n119. Mostoufi-Moab S Brodsky J Isaacoff EJ Tsampalieros A Ginsberg JP Zemel B . Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation\n. J Clin Endocrinol Metab. (2012 ) 97 :3584 –92\n. 10.1210/jc.2012-2393 22865901 \n120. Eghbali-Fatourechi G Khosla S Sanyal A Boyle WJ Lacey DL Riggs BL . Role of RANK ligand in mediating increased bone resorption in early postmenopausal women\n. J Clin Invest. (2003 ) 111 :1221 –30\n. 10.1172/JCI200317215 12697741 \n121. Hofbauer LC Zeitz U Schoppet M Skalicky M Schuler C Stolina M . Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL\n. Arthritis Rheum. (2009 ) 60 :1427 –37\n. 10.1002/art.24445 19404943 \n122. Dempster DW Lambing CL Kostenuik PJ Grauer A . Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data\n. Clin Ther. (2012 ) 34 :521 –36\n. 10.1016/j.clinthera.2012.02.002 22440513 \n123. Cummings SR San Martin J McClung MR Siris ES Eastell R Reid IR . Denosumab for prevention of fractures in postmenopausal women with osteoporosis\n. N Engl J Med. (2009 ) 361 :756 –65\n. 10.1056/NEJMoa0809493 19671655 \n124. Semler O Netzer C Hoyer-Kuhn H Becker J Eysel P Schoenau E . First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI\n. J Musculoskelet Neuronal Interact. (2012 ) 12 :183 –8\n. 22947550 \n125. Karras NA Polgreen LE Ogilvie C Manivel JC Skubitz KM Lipsitz E . Denosumab treatment of metastatic giant-cell tumor of bone in a 10-year-old girl\n. J Clin Oncol. (2013 ) 31 :e200 –2\n. 10.1200/JCO.2012.46.4255 23509309 \n126. Lange T Stehling C Frohlich B Klingenhofer M Kunkel P Schneppenheim R \nDenosumab: a potential new and innovative treatment option for aneurysmal bone cysts\n. Eur Spine J. (2013 ) 22 :1417 –22\n. 10.1007/s00586-013-2715-7 23455951 \n127. Boyce AM Chong WH Yao J Gafni RI Kelly MH Chamberlain CE . Denosumab treatment for fibrous dysplasia\n. J Bone Miner Res. (2012 ) 27 :1462 –70\n. 10.1002/jbmr.1603 22431375 \n128. Lamy O Gonzalez-Rodriguez E Stoll D Hans D Aubry-Rozier B . Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report\n. J Clin Endocrinol Metab. (2017 ) 102 :354 –8\n. 10.1210/jc.2016-3170 27732330 \n129. Trejo P Rauch F Ward L . Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI\n. J Musculoskelet Neuronal Interact. (2018 ) 18 :76 –80\n. 29504582 \n130. Camacho PM Petak SM Binkley N Clarke BL Harris ST Hurley DL \nAmerican Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016\n. Endocr Pract. (2016 ) 22 (Suppl. 4 ):1 –42\n. 10.4158/EP161435.GL \n131. Neer RM Arnaud CD Zanchetta JR Prince R Gaich GA Reginster JY . Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis\n. N Engl J Med. (2001 ) 344 :1434 –41\n. 10.1056/NEJM200105103441904 11346808 \n132. Vahle JL Sato M Long GG Young JK Francis PC Engelhardt JA . Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety\n. Toxicol Pathol. (2002 ) 30 :312 –21\n. 10.1080/01926230252929882 12051548 \n133. Vahle JL Long GG Sandusky G Westmore M Ma YL Sato M . Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose\n. Toxicol Pathol. (2004 ) 32 :426 –38\n. 10.1080/01926230490462138 15204966 \n134. Lindsay R Scheele WH Neer R Pohl G Adami S Mautalen C . Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis\n. Arch Intern Med. (2004 ) 164 :2024 –30\n. 10.1001/archinte.164.18.2024 15477438 \n135. Black DM Bilezikian JP Ensrud KE Greenspan SL Palermo L Hue T . One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis\n. N Engl J Med. (2005 ) 353 :555 –65\n. 10.1056/NEJMoa050336 16093464 \n136. Catalano A Vita GL Russo M Vita G Lasco A Morabito N . Effects of teriparatide on bone mineral density and quality of life in Duchenne muscular dystrophy related osteoporosis: a case report\n. Osteoporos Int. (2016 ) 27 :3655 –9\n. 10.1007/s00198-016-3761-x 27589974 \n137. Obermayer-Pietsch BM Marin F McCloskey EV Hadji P Farrerons J Boonen S . Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment\n. J Bone Miner Res. (2008 ) 23 :1591 –600\n. 10.1359/jbmr.080506 18505369 \n138. Ominsky MS Vlasseros F Jolette J Smith SY Stouch B Doellgast G . Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength\n. J Bone Miner Res. (2010 ) 25 :948 –59\n. 10.1002/jbmr.14 20200929 \n139. Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S . Romosozumab treatment in postmenopausal women with osteoporosis\n. N Engl J Med. (2016 ) 375 :1532 –43\n. 10.1056/NEJMoa1607948 27641143 \n140. Perosky JE Khoury BM Jenks TN Ward FS Cortright K Meyer B . Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model\n. Bone . (2016 ) 93 :79 –85\n. 10.1016/j.bone.2016.09.013 27641475\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "11()",
"journal": "Frontiers in endocrinology",
"keywords": "bone density; children; fractures; glucocorticoids; osteoporosis; prevention; risk factors; treatment",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D015519:Bone Density; D002648:Child; D005938:Glucocorticoids; D006801:Humans; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D012307:Risk Factors",
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "576",
"pmc": null,
"pmid": "33391179",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "17566815;25923606;27641475;18189194;17223617;26878592;11346808;11518815;26842265;15827104;23197573;18442749;9240738;21118827;17294225;7942166;16434452;16398842;15121007;27641143;29943187;12697741;22865901;16382319;24631254;15537440;15690187;18676559;10431112;9599190;22768661;24356182;10905381;29524454;29786884;3333019;26171800;21646368;22109742;32006259;24973964;16887429;21494860;19210218;22213727;12417568;24014378;22440513;8237484;11146381;25494661;14666400;19137350;23927912;29679731;27589974;28258372;30055340;26059976;31865390;22947550;15477438;17485648;30855644;8797120;16093464;15824848;20391507;28450193;10641693;25801315;29395990;12051548;19671655;24585546;23498916;30219580;22297733;16491285;27662240;24052046;20668038;12629073;20564246;20524999;22901620;27732330;9664068;31742768;31388666;26615086;30372552;27020068;19404943;20671013;15995009;30906820;17973968;10852438;12183715;18330609;27492436;22967789;22734031;26308295;23455951;15204966;21266418;1881719;28585410;28343613;22431375;23948876;27614576;24680381;30616029;10912543;30225627;20200929;12733732;11956241;19419296;27125514;24395288;18505369;18030230;29218382;109598;22826190;11149495;29037325;27328118;25828359;23509309;11403096;31421951;21820091;27774565;30275248;29504582",
"title": "Glucocorticoid-Induced Osteoporosis: Why Kids Are Different.",
"title_normalized": "glucocorticoid induced osteoporosis why kids are different"
} | [
{
"companynumb": "GB-ALLERGAN-2106649US",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VITAMIN D NOS"
},
"drugadditional": null,
... |
{
"abstract": "Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients.\n\n\n\nWe performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab.\n\n\n\n41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%).\n\n\n\nThis is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.",
"affiliations": "Department of Dermatology, Campus Kiel, University Hospital Schleswig-Holstein (UKSH), Rosalind-Franklind-Str. 7, 24105, Kiel, Germany. kkaehler@dermatology.uni-kiel.de.;Department of Dermatology, Eberhard-Karls University of Tübingen, Tübingen, Germany.;Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.;Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.;Department of Dermatology, University Medical Center of Mainz, Mainz, Germany.;Department of Dermatology, University of Dresden, Dresden, Germany.;Department of Dermatology, Medical Center - Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Dermatology, Saarland University Medical School, Homburg/saar, Germany.;Department of Dermatology, Skin Cancer Center at Center of Integrated Oncology (CIO), University Hospital Cologne, Cologne-Bonn, Germany.;Department of Dermatology, Campus LübeckUniversity, Hospital (UKSH), Lübeck, Germany.;Department of Dermatology, University Medical Center Göttingen, Göttingen, Germany.;Department of Dermatology, University Hospital Leipzig, Leipzig, Germany.;Department of Dermatology, Essen, Germany and German Cancer Consortium (DKTK), University Duisburg-Essen, University Hospital Essen, Heidelberg, Germany.;Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hanover, Germany.",
"authors": "Kähler|Katharina C|KC|;Eigentler|Thomas K|TK|;Gesierich|Anja|A|;Heinzerling|Lucie|L|;Loquai|Carmen|C|;Meier|Friedegund|F|;Meiss|Frank|F|;Pföhler|Claudia|C|;Schlaak|Max|M|;Terheyden|Patrick|P|;Thoms|Kai M|KM|;Ziemer|Mirjana|M|;Zimmer|Lisa|L|;Gutzmer|Ralf|R|;|||",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-018-2134-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "67(5)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Autoimmunity; Immune-related adverse events; Ipilimumab; Melanoma",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001327:Autoimmune Diseases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "825-834",
"pmc": null,
"pmid": "29487980",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders.",
"title_normalized": "ipilimumab in metastatic melanoma patients with pre existing autoimmune disorders"
} | [
{
"companynumb": "DE-ALLERGAN-1852550US",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "3",
"... |
{
"abstract": "We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD).\n\n\n\nThis was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 ± 2.35 years; 105 boys and 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained before treatment and at week 16.\n\n\n\nIn 97 children with a mean of 22.9 ± 2.8 weeks of risperidone exposure, there was a 5.4 ± 3.4 kg weight gain over 24 weeks (p < .0001); waist circumference increased from 60.7 ± 10.4 cm to 66.8 ± 11.3 cm (p < .0001). At baseline, 59 of 97 children (60.8%) were classified as having normal weight; by week 24, only 25 of 85 (29.4%) remained in that group. Growth curve analysis showed a significant change in body mass index (BMI) z scores from pretreatment to week 24 (p < .0001). This effect was significantly greater for children with reported increased appetite in the first 8 weeks. From before treatment to week 16, there were significant increases in glucose (p = .02), hemoglobin A1c (p = .01), insulin (p <.0001), homeostatic model assessment-insulin resistance (HOMA-IR; p < .001), alanine aminotransferase (p = .01), and leptin (p < .0001). Adiponectin declined (p = .003). At baseline, 7 children met conventional criteria for metabolic syndrome; by week 16, 12 additional children were so classified.\n\n\n\nRapid weight gain with risperidone treatment may promote the cascade of biochemical indices associated with insulin resistance and metabolic syndrome. Appetite, weight, waist circumference, liver function tests, blood lipids, and glucose warrant monitoring. Clinical trial registration information-Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://clinicaltrials.gov/; NCT00080145.",
"affiliations": "Emory University School of Medicine and Marcus Autism Center, Atlanta. Electronic address: lawrence.scahill@emory.edu.;Yale University School of Nursing, West Haven, CT.;Yale University School of Nursing, West Haven, CT.;Harvard Medical School, Massachusetts General Hospital, and Lurie Center for Autism, Boston.;Nisonger Center, Ohio State University, Columbus.;Yale School of Medicine, New Haven, CT.;Division of Child Psychiatry, University of California, Los Angeles.;Yale School of Medicine, New Haven, CT.;Nisonger Center, Ohio State University, Columbus.;Washington University, St. Louis.;Yale University.;Emory University School of Medicine.;National Institute of Mental Health (NIMH), Bethesda, MD.",
"authors": "Scahill|Lawrence|L|;Jeon|Sangchoon|S|;Boorin|Susan J|SJ|;McDougle|Christopher J|CJ|;Aman|Michael G|MG|;Dziura|James|J|;McCracken|James T|JT|;Caprio|Sonia|S|;Arnold|L Eugene|LE|;Nicol|Ginger|G|;Deng|Yanhong|Y|;Challa|Saankari A|SA|;Vitiello|Benedetto|B|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "55(5)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": "autism spectrum disorder; insulin resistance; metabolic syndrome; risperidone; weight gain",
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D000067877:Autism Spectrum Disorder; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome; D000066553:Problem Behavior; D018967:Risperidone; D015430:Weight Gain",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "415-23",
"pmc": null,
"pmid": "27126856",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "18596007;18507788;21147643;23022179;22040842;21881456;25440308;24165702;15286277;18568083;25898050;19861668;16871574;17375138;22911903;15169706;15480363;19948625;12043359;16926246;16239862;23799528;20368487;24224089;7814313;20829185;24114081;24564519;3158201;15175438;17850473;19490496;24051674;15930063;22265360;17069546;12151468;19858761;22342106;26262903;23965896;11893791;15492353;23519708",
"title": "Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder.",
"title_normalized": "weight gain and metabolic consequences of risperidone in young children with autism spectrum disorder"
} | [
{
"companynumb": "US-JNJFOC-20160503452",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a patient having a first-time seizure after receiving venlafaxine and trimipramine for depression.\n\n\nMETHODS\nA 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/d and trimipramine 50 mg/d. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grand-mal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified.\n\n\nCONCLUSIONS\nBoth venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. We hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures.\n\n\nCONCLUSIONS\nClinicians should be aware of the proepileptogenic effect of venlafaxine and trimipramine at therapeutic doses and that this combination may eventually increase the risk of seizures.",
"affiliations": "Department of Internal Medicine, University Hospital Basel, Switzerland. juergen.drewe@unibas.ch",
"authors": "Schlienger|R G|RG|;Klink|M H|MH|;Eggenberger|C|C|;Drewe|J|J|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D014299:Trimipramine; D000069470:Venlafaxine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.10050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "34(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D012640:Seizures; D014299:Trimipramine; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1402-5",
"pmc": null,
"pmid": "11144696",
"pubdate": "2000-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures associated with therapeutic doses of venlafaxine and trimipramine.",
"title_normalized": "seizures associated with therapeutic doses of venlafaxine and trimipramine"
} | [
{
"companynumb": "CH-PFIZER INC-HQ6428626JAN2001",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRIMIPRAMINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nHistamine-mediated angioedema is a potentially life-threatening reaction following exposures that incite mast cell activation. In Florida, red tides are a frequent phenomenon caused by overgrowth of the harmful algae species Karenia brevis, which contain environmentally detrimental brevetoxins. Even in low concentrations, brevetoxins can cause disease in humans through inducing histamine release. We report the first documented case of angioedema associated with red tide exposure.\n\n\nMETHODS\nA 52-year-old-male presented with severe angioedema encompassing both lips within a few hours after exposure to red tide algae. Other symptoms included voice changes and difficulty swallowing. Laboratory findings revealed complement factors that were within reference range, which ruled out a bradykinin-mediated pathology and supported the diagnosis of histaminergic angioedema. Symptoms resolved after 24 hours in the intensive care unit under management with epinephrine, diphenhydramine, methylprednisolone, and famotidine.\n\n\nCONCLUSIONS\nIn coastal regions, red tide algae should be recognized as a rare cause of acute angioedema. Emergency management of histamine-mediated angioedema should focus on preventing respiratory compromise with frequent airway monitoring and treatment with steroids, antihistamines, and epinephrine.",
"affiliations": "Charles E. Schmidt College of Medicine, Department of Emergency Medicine, Boca Raton, Florida.;Charles E. Schmidt College of Medicine, Department of Emergency Medicine, Boca Raton, Florida.",
"authors": "Rabinowitz|Sarah|S|;Solano|Joshua J|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5811/cpcem.2021.3.51920",
"fulltext": "\n==== Front\nClin Pract Cases Emerg Med\nClin Pract Cases Emerg Med\nClinical Practice and Cases in Emergency Medicine\n2474-252X\nUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine\n\n10.5811/cpcem.2021.3.51920\ncpcem-05-222\nCase Report\nWhen the Red Tide Rolls In: A Red Tide Associated Angioedema Case Report\nRabinowitz Sarah BS, BFA\nSolano Joshua J. MD\nCharles E. Schmidt College of Medicine, Department of Emergency Medicine, Boca Raton, Florida\nAddress for Correspondence: Joshua J. Solano, MD, Charles E. Schmidt College of Medicine, Department of Emergency Medicine, LL GME, 2815 S. Seacrest, Boynton Beach, FL 33435. Email: solanoj@health.fau.edu.\n5 2021\n23 4 2021\n5 2 222225\n26 1 2021\n04 3 2021\n12 3 2021\nCopyright: © 2021 Rabinowitz et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/\nIntroduction\n\nHistamine-mediated angioedema is a potentially life-threatening reaction following exposures that incite mast cell activation. In Florida, red tides are a frequent phenomenon caused by overgrowth of the harmful algae species Karenia brevis, which contain environmentally detrimental brevetoxins. Even in low concentrations, brevetoxins can cause disease in humans through inducing histamine release. We report the first documented case of angioedema associated with red tide exposure.\n\nCase Report\n\nA 52-year-old-male presented with severe angioedema encompassing both lips within a few hours after exposure to red tide algae. Other symptoms included voice changes and difficulty swallowing. Laboratory findings revealed complement factors that were within reference range, which ruled out a bradykinin-mediated pathology and supported the diagnosis of histaminergic angioedema. Symptoms resolved after 24 hours in the intensive care unit under management with epinephrine, diphenhydramine, methylprednisolone, and famotidine.\n\nConclusion\n\nIn coastal regions, red tide algae should be recognized as a rare cause of acute angioedema. Emergency management of histamine-mediated angioedema should focus on preventing respiratory compromise with frequent airway monitoring and treatment with steroids, antihistamines, and epinephrine.\n\nCase report\nangioedema\nred tide\nharmful algae\nbrevetoxin\n==== Body\nINTRODUCTION\n\nAngioedema is a localized, non-pitting edema of the deep dermis and submucosal tissues commonly affecting the eyelids, lips, tongue, and larynx as a result of vasodilation and increased vascular permeability mediated by histamine or bradykinin.1 It can be acquired, hereditary, or idiopathic and have both acute and chronic presentations.1,2 Emergency departments (ED) in the United States treat over 100,000 cases of angioedema annually.1,3 Of the different subtypes, acute histamine-mediated angioedema following allergic exposure is the most common, comprising 40–70% of all cases.1,2 There are also various environmental factors that can induce histamine release and cause angioedema.2\n\nIn Florida, blooms of the red tide algae Karenia brevis mainly occur along the Gulf of Mexico, affecting the southwest and northwest coasts of Florida.4 The algae blooms in response to increased macro-nutrients in coastal waters, and contributing factors include both natural ecological processes and artificial sources, such as sewage, industrial waste, and land runoffs.4,5 Red tides are considered “harmful algae blooms,” as exposure is highly toxic to marine life.4 Historically, significant blooms occurred infrequently; however, the Florida Fish and Wildlife Conservation (FWC) Research Institute has reported blooms with high concentrations of K. brevis annually since 2014 along the west coast of Florida.6 To date, there had been no known documented cases of angioedema induced by red tide exposure. We report one of the first cases of histamine-mediated angioedema occurring after exposure to red tide algae during a rare, east coast bloom.\n\nCASE REPORT\n\nA 52-year-old man with a past medical history of gastroesophageal reflux disease, chronic pancreatitis, chronic pain syndrome, hypertension, anxiety and depression presented to the ED for evaluation of worsening swelling in his upper and lower lips onset three hours prior to arrival. His symptoms began with spontaneous right lower lip swelling that quickly progressed to encompass both lips and caused mild voice changes. Review of systems was negative for difficulty breathing, difficulty swallowing, rashes, nausea, vomiting, diarrhea, and abdominal pain.\n\nThe patient denied personal and family history of angioedema reactions, prior red tide exposure, known food or drug allergies, seafood or nut intake, and new medication exposure. He reported no changes to his medication regimen and endorsed compliance with his bupropion, pantoprazole, and methadone. The patient had started taking vitamins B12 and D regularly two days prior and had taken these vitamins in the past without issue. He did not recall any insect bites or stings and had been desensitized to bee stings in childhood. The patient’s only notable exposure was to an outbreak of red tide algae at a Palm Beach County beach that morning just prior to symptom onset.\n\nVital signs showed that the patient was afebrile with a blood pressure of 163/119 millimeters mercury, heart rate of 68 beats per minute, respiratory rate of 15 breaths per minute, and pulse oximetry of 94% on room air. Physical exam was notable only for isolated, severe bilateral lip edema (Image) not involving the soft palate, tongue, and uvula.\n\nThe patient was placed on two liters per minute of oxygen via nasal cannula, which improved his oxygen saturation to 96%. Initial doses of diphenhydramine, methylprednisolone, and famotidine were administered with no improvement. While still in the ED, his edema progressed, and the patient began to experience difficulty swallowing. Intramuscular epinephrine was then administered with only mild improvement two hours later. He was diagnosed with angioedema of unclear etiology and admitted to the intensive care unit (ICU) for further management. Labs were significant for leukocytosis at a white blood cell count of 10.3 thousand cells per microliter (thousand/mcL) (reference range: 5.0–10.0 thousand/mcL) with increased neutrophils. Immunology/serology showed no abnormalities: C4 complement level of 37 milligrams per deciliter (mg/dL) (16–38 mg/dL), C1q Qn of 12.3 mg/dL (11.8–23.8 mg/dL), C1 esterase inhibitor 39 mg/dL (8–40 mg/dL) and C1 ester inhibitor function of 111 (reference range: greater than 67).\n\nCPC-EM Capsule\n\nWhat do we already know about this clinical entity?\n\nAngioedema is an inflammation of the deeper dermis and subcutaneous tissues. It can be hereditary or acquired by exposure to allergens, toxins, or physical insults\n\nWhat makes this presentation of disease reportable?\n\nWhile red tides are known to cause respiratory disease, this is the first reported case of histaminergic angioedema associated with red tide algae exposure.\n\nWhat is the major learning point?\n\nExposure to brevetoxins released from red tide algae may trigger angioedema reactions through mast cell activation and histamine release.\n\nHow might this improve emergency medicine practice?\n\nClinicians should be aware of local environmental triggers of histaminergic angioedema to rapidly identify and initiate appropriate treatment.\n\nIn the ICU, the angioedema improved after additional doses of diphenhydramine, methylprednisolone, and famotidine. He did not require higher oxygen supplementation or intubation. Repeat complete blood count in the morning showed resolution of the leukocytosis. With the angioedema subsided, the patient had no difficulty breathing with an oxygen saturation of 98% on room air. He felt well enough the next day for discharge and did not experience symptom recurrence over two years.\n\nDISCUSSION\n\nBrevetoxins are lipophilic neurotoxins found in the red tide algae K. brevis.5 Toxic exposure causing illness in humans mainly occurs through toxin inhalation and consumption of contaminated water and shellfish.4,5 Brevetoxins become aerosolized when the force of crashing waves lyses the cells of the K. brevis.4 The brevetoxin aerosols carried by the wind can travel up to a mile inland from their source.7 Their lipid solubility and small particle size enable them to penetrate skin, mucosa, and cell membranes and travel through the respiratory tract.8 In animal model studies, it has been demonstrated that once inside the body brevetoxins are able to disrupt voltage-gated sodium channels, causing an influx of sodium and subsequent depolarization with acetylcholine release.8,9 Consequently, this can trigger mast cell degranulation, cell apoptosis, and induce the release of inflammatory cytokines and histamine.8\n\nWhile there are no documented cases of angioedema induced by red tides, numerous reports exist of respiratory, gastrointestinal, and neurological illnesses caused by brevetoxins.4,5,8,9 Studies previously found that red tide blooms are positively correlated with an increased incidence of ED visits for asthma exacerbations and respiratory illnesses in coastal areas.5,8,10\n\nOur patient came in with severe lip angioedema of unclear etiology. His only significant novel exposure was to the outbreak of red tide algae at the beach on the same morning he developed symptoms. The October 2018 red tide bloom to which our patient had been exposed was the first red tide outbreak to affect the east coast of Florida in the last decade.6,11 According to data collected by the research institute of the Florida Fish and Wildlife Conservation Commission (Figure), the patient may have been exposed to medium to low concentrations of K. brevis.6,11 The presence of K. brevis in any concentration has the potential to cause symptoms in humans.5–71\n\nThe patient’s symptoms developed rapidly after a brief exposure and subsided within 24 hours, a clinical picture consistent with other reports of brevetoxin-induced illness, as well as non-urticarial histaminergic angioedema.1,2,8,9 The pathophysiology of angioedema and brevetoxin-induced illness described in the literature suggests a potential link, as both involve direct mast cell activation with histamine release and follow similar disease timeline.2,8,9\n\nAcute histaminergic angioedema is the most common form of angioedema.1 One subtype of histaminergic angioedema is allergic angioedema, which often occurs after exposure to allergens or environmental triggers.1,2 It follows a type 1 hypersensitivity reaction process with immunoglobulin E (IgE) as the mediator of histamine release from mast cells and basophils.2 Less commonly, a non-allergic, non-IgE mediated form of histaminergic angioedema results from the direct activation of mast cells following exposure to similar triggers, physical stimuli, drugs, infections, and idiopathic events.2 Aside from the mechanism of mast cell activation, non-allergic and allergic histaminergic angioedema involve the same inflammatory reactions and clinical manifestations.2,12\n\nClinically, histamine-mediated angioedema presents rapidly within 60 minutes of an inciting exposure and resolves 24–48 hours later.1,2 Similar to anaphylactic reactions, symptoms include hypotension, tachycardia, urticaria, flushing, pruritus, bronchospasm, wheezing, laryngeal edema, nausea, vomiting, and abdominal pain.1,2 Airway compromise from laryngeal edema can manifest as stridor, voice changes, and difficulty swallowing.1,2 It is important to note that both pathways of histaminergic angioedema can present with or without urticaria and, therefore, absence of urticaria does not exclude the diagnosis.12 The diagnosis is clinical.1,2 Patients are often hemodynamically stable, but the systemic vasodilation can induce hypovolemic shock and respiratory distress.2\n\nRoutine workup may show leukocytosis, as seen in our case.1 Acute histamine-mediated angioedema can have normal or elevated serum tryptase levels, but this is not routinely obtained.1 Otherwise, in the ED setting there are no specific laboratory findings that will indicate the diagnosis and guide management. Unlike in bradykinin-mediated angioedema, the levels and function of complement proteins (C4, C1q, C1 esterase inhibitor) are normal in histamine-mediated angioedema.1,2,12 Management involves airway preservation, epinephrine, steroids, and histamine H1/ H2 receptor blockers.1,2 In the ED setting, improvement of the angioedema in response to these treatments supports the diagnosis of histamine-mediated angioedema, even in cases without obvious urticaria or allergic manifestations.1,2\n\nThis is essential to recognize, as bradykinin-mediated angioedema subtypes follow along different pathways involving complement factor deficiencies; thus, they do not respond to treatment with steroids, epinephrine, and antihistamines, have higher rates of reoccurrence, and worse clinical outcomes.1,2 Therefore, early identification of a histaminergic process is crucial for emergency management, as treatment of bradykinin-mediated angioedema focuses on correcting the underlying completement deficiencies.1 Delays in initiating appropriate therapeutic intervention can become disastrous in the setting of worsening shock and respiratory compromise.1,2\n\nLastly, it is important to address the likelihood of the patient’s medications as underlying causes of his angioedema. There have been several case reports of urticarial angioedema occurring within the first four weeks after initiating bupropion therapy.13,14 Unlike the cases described in the literature, our patient had been taking a consistent dose of bupropion for longer than four weeks. Furthermore, his bupropion was continued throughout admission with resolution of his angioedema, which supports that his angioedema process was most likely unrelated to his bupropion exposure. Likewise, hypersensitivity reactions to opiates, proton pump inhibitors, and vitamin capsule ingredients have been occasionally cited as possible triggers causing urticaria and angioedema.2,15 However, complete resolution of symptoms would be dependent on discontinuing exposure to the substance.2,15 Our patient’s pantoprazole was also continued throughout admission, with methadone and vitamins resumed prior to discharge without issue. Re-exposure to these substances would have resulted in another episode of angioedema; therefore, it is unlikely that these medications were the cause.\n\nLIMITATIONS\n\nThe patient did not clarify the nature and duration of his red tide exposure. Therefore, it is unclear whether he had gone into the water and was still at the beach when his symptoms began.\n\nCONCLUSION\n\nAcute histamine-mediated angioedema is a common yet potentially fatal edematous reaction to triggers of mast cell degranulation and histamine release. Early recognition of a histamine-mediated etiology is essential for both acute treatment and long-term management, which depends on avoiding the inciting event. We present the first documented case of red tide-associated angioedema. In coastal areas where red tide blooms are common, it is important to consider K. brevis brevetoxins as a possible etiology in a patient presenting with acute onset of angioedema.\n\nFigure Map showing the statewide Karenia brevis concentrations October 1–31, 2018. Location of patient’s red tide exposure (white arrow). Reprinted with permission from the research institute of the Florida Fish and Wildlife Conservation Commission.11\n\nImage Impressive angioedema diffusely encompassing both lips (arrows).\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nPatient consent has been obtained and filed for the publication of this case report.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n\n1 Long BJ Koyfman A Gottlieb M Evaluation and management of angioedema in the emergency department West J Emerg Med 2019 20 4 587 600 31316698\n2 Busse PJ Smith T Histaminergic angioedema Immunol Allergy Clin North Am 2017 37 3 467 81 28687103\n3 Kelly M Donnelly JP McAnnally JR National estimates of emergency department visits for angioedema and allergic reactions in the United States Allergy Asthma Proc 2013 34 2 150 4 23484890\n4 Patel SS Lovko VJ Lockey RF Red tide: overview and clinical manifestations J Allergy Clin Immunol Pract 2020 8 4 1219 23 31761688\n5 Hoagland P Jin D Beet A The human health effects of Florida red tide (FRT) blooms: an expanded analysis Environ Int 2014 68 144 53 24727069\n6 Florida Fish and Wildlife Conservation Commission Red Tide Available at: https://myfwc.com/research/redtide/. Updated December 23, 2020 Accessed December 28, 2020\n7 Cheng YS Zhou Y Pierce RH Characterization of Florida red tide aerosol and the temporal profile of aerosol concentration Toxicon 2010 55 5 922 9 19879288\n8 Fleming LE Kirkpatrick B Backer LC Review of Florida red tide and human health effects Harmful Algae 2011 10 2 224 33 21218152\n9 Abraham WM Bourdelais AJ Sabater JR Airway responses to aerosolized brevetoxins in an animal model of asthma Am J Respir Crit Care Med 2005 171 1 26 34 15447946\n10 Kirkpatrick B Fleming LE Backer LC Environmental exposures to Florida red tides: effects on emergency room respiratory diagnoses admissions Harmful Algae 2006 5 5 526 33 20357898\n11 FWC Fish and Wildlife Research Institute Statewide Karenia brevis Concentrations 10 1–31 2018 Available at: https://www.flickr.com/photos/myfwc/31121209017/in/album-72157635398013168/ Accessed January 1, 2021\n12 Wu MA Perego F Zanichelli A Angioedema phenotypes: disease expression and classification Clin Rev Allergy Immunol 2016 51 2 162 9 27113957\n13 Tackett AE Smith KM Bupropion-induced angioedema Am J Health Syst Pharm 2008 65 17 1627 30 18714109\n14 Tuman TC Tuman BA Göksügür N Urticaria and angioedema associated with bupropion: three cases Prim Care Companion CNS Disord 2016 18 4\n15 Bowlby HA Dickens GR Angioedema and urticaria associated with omeprazole confirmed by drug rechallenge Pharmacotherapy 1994 14 1 119 22 8159596\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "5(2)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": null,
"medline_ta": "Clin Pract Cases Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101718968",
"other_id": null,
"pages": "222-225",
"pmc": null,
"pmid": "34437010",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": "18714109;23484890;31316698;28687103;27828705;20357898;8159596;21218152;15447946;27113957;19879288;31761688;24727069",
"title": "When the Red Tide Rolls In: A Red Tide Associated Angioedema Case Report.",
"title_normalized": "when the red tide rolls in a red tide associated angioedema case report"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2021GSK191170",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "A 38-year-old Japanese AIDS patient developed papular lesions which rapidly increased in number, eroded and crusted, and spread over not only skin but also the mucosal surface. High fever, sore throat, malaise and hepatosplenomegaly were also noted, and he died despite 2 months of intensive treatment. An autopsy revealed numerous histiocytes infected with Penicillium marneffei in the lymph nodes, liver, spleen, bone marrow, skin, and mucosal surface of the oral cavity to the pharynx. This case is thought to be the first Japanese case of penicilliosis marneffei.",
"affiliations": "Department of Dermatology, Yokohama City Hospital, 56 Okazawacho, Hodogaya-ku, Yokohama, Kanagawa 240-8555, Japan.",
"authors": "Mohri|S|S|;Yoshikawa|K|K|;Sagara|H|H|;Nakajima|H|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.3314/jjmm.41.23",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0916-4804",
"issue": "41(1)",
"journal": "Nihon Ishinkin Gakkai zasshi = Japanese journal of medical mycology",
"keywords": null,
"medline_ta": "Nihon Ishinkin Gakkai Zasshi",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D006801:Humans; D007564:Japan; D008297:Male; D009181:Mycoses; D010407:Penicillium",
"nlm_unique_id": "9425640",
"other_id": null,
"pages": "23-6",
"pmc": null,
"pmid": "10660639",
"pubdate": "2000",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of Penicillium marneffei infection in an AIDS patient: the first case in Japan.",
"title_normalized": "a case of penicillium marneffei infection in an aids patient the first case in japan"
} | [
{
"companynumb": "JP-PFIZER INC-2018428568",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "A 59-year-old man with an 18-year history of rheumatoid arthritis who had been treated with steroids, methotrexate, and infliximab presented with a high-grade fever, cervical lymphadenopathy, and hepatosplenomegaly. Epstein-Barr virus (EBV) hepatitis was diagnosed based on the liver histology and EBV antibody titer. The symptoms improved temporarily, but five months later, the fever, skin rash, jaundice, and thrombocytopenia relapsed. Bone marrow and liver biopsies demonstrated infiltration with Reed-Sternberg cells. Based on these findings, the patient was diagnosed with other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD), Hodgkin lymphoma type. This case followed a rare clinical course, in that acute hepatitis preceded the diagnosis of OIIA-LPD.",
"affiliations": "Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.;Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan.",
"authors": "Saburi|Masuho|M|;Ogata|Masao|M|;Yoshida|Natsumi|N|;Nashimoto|Yuko|Y|;Moroga|Yui|Y|;Takano|Kuniko|K|;Kohno|Kazuhiro|K|;Daa|Tsutomu|T|;Shirao|Kuniaki|K|",
"chemical_list": "D000069285:Infliximab; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9599-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2927949310.2169/internalmedicine.9599-17Case ReportOther Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder, Hodgkin Type, following Epstein-Barr Viral Hepatitis in a Patient with Rheumatoid Arthritis Saburi Masuho 12Ogata Masao 1Yoshida Natsumi 1Nashimoto Yuko 1Moroga Yui 1Takano Kuniko 1Kohno Kazuhiro 12Daa Tsutomu 3Shirao Kuniaki 1\n1 Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan\n2 Department of Hematology, Oita Kouseiren Tsurumi Hospital, Japan\n3 Department of Diagnostic Pathology, Faculty of Medicine, Oita University, JapanCorrespondence to Dr. Masuho Saburi, masuho-saburi@oita-u.ac.jp\n\n27 12 2017 15 4 2018 57 8 1145 1149 1 6 2017 19 8 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article 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 an 18-year history of rheumatoid arthritis who had been treated with steroids, methotrexate, and infliximab presented with a high-grade fever, cervical lymphadenopathy, and hepatosplenomegaly. Epstein-Barr virus (EBV) hepatitis was diagnosed based on the liver histology and EBV antibody titer. The symptoms improved temporarily, but five months later, the fever, skin rash, jaundice, and thrombocytopenia relapsed. Bone marrow and liver biopsies demonstrated infiltration with Reed-Sternberg cells. Based on these findings, the patient was diagnosed with other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD), Hodgkin lymphoma type. This case followed a rare clinical course, in that acute hepatitis preceded the diagnosis of OIIA-LPD. \n\nother iatrogenic immunodeficiency-associated lymphoproliferative disorderHodgkin lymphomaEpstein-Barr virus\n==== Body\nIntroduction\nOther iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) typically develops in patients with autoimmune diseases who are receiving methotrexate (MTX) and other biological drugs such as infliximab (IFX) (1). Epstein-Barr virus (EBV) may also have a causative role, especially in Hodgkin lymphoma-type OIIA-LPD (2,3). We herein describe a case of OIIA-LPD, Hodgkin lymphoma type, following EBV hepatitis. This case followed a rare clinical course in that acute hepatitis preceded a diagnosis of OIIA-LPD.\n\nCase Report\nA 59-year-old man developed rheumatoid arthritis (RA) in 1996 and had been treated with prednisolone (PSL) and MTX. IFX was started from 2006 in combination with PSL and MTX. In 2014, he presented with high-grade fever. Ten days later, he was examined in a clinic and was found to have slight anemia and increased hepatobiliary enzyme levels; viral capsid IgM antibody (VCA-IgM) [enzyme immunoassay (EIA)] was detected (2.4). He was referred to our hospital because of prolonged symptoms, which had persisted for 3 weeks after the onset of symptoms. Computed tomography (CT) showed mild para-aortic lymphadenopathy and hepatosplenomegaly. MTX and IFX were discontinued. A histological examination of a liver specimen revealed inflammatory cell infiltration. The laboratory findings showed no evidence of hepatitis A, B, or C, cytomegalovirus, drug-induced liver injury, or autoimmune hepatitis. The patient's EBV antibody titers [fluorescence antibody method (FA)] were as follows: viral-capsid antigen (VCA-IgM) <1:10; viral capsid IgG antibody (VCA-IgG) 1:320; and Epstein-Barr nuclear antibody (EBNA) <1:10. EBV hepatitis was diagnosed based on the liver histopathology and VCA-IgM (EIA) positivity, in addition to the other EBV antibody titers (FA). The symptoms temporarily improved without any treatment within 1 month after the onset, and his RA remained stable with PSL alone. At five months after the diagnosis of EBV hepatitis, the patient developed high-grade fever, skin rash, and jaundice. The laboratory findings included increased biliary enzymes, anemia, and thrombocytopenia. CT showed the worsening of the para-aortic lymphadenopathy and hepatosplenomegaly. The soluble interleukin-2 receptor level was 20,665 U/mL, and the EBV antibody titer demonstrated a previous infection pattern (VCA-IgM <1:10, VCA-IgG 1:640, EBNA 1:10). The EBV-DNA level was <20 copies/106 cells in the peripheral blood. A pathological examination of a liver specimen revealed epithelioid granuloma composed mainly of CD68a-positive histiocytes and CD3-positive T cells (CD4> CD8) within the expanded portal region of the liver parenchyma, and a few large, atypical nucleated cells were detected in the nodules (Fig. 1). The large cells were similar in appearance to Reed-Sternberg (RS) cells and were positive for CD30 and latent membrane protein 1 (LMP-1), and negative for CD79a, CD20, CD15, epithelial membrane antigen (EMA), and EBV nuclear antigen 2 on immunostaining. In situ hybridization for EBV-encoded RNA (EBER) detected RS cells. The pathological examination of a bone marrow clot showed the infiltration of lymphocytes around large cells with abnormal large multilobular nuclei (Fig. 2). The immunostaining and EBER profiles of these large cells were similar to the RS-like cells of the liver. Immunostaining of the lymphocytes around these cells revealed that they were positive for CD3, CD4 and CD8 (CD4> CD8), and negative for CD20 and CD79a. A pathological examination of a skin specimen showed no abnormal cellular infiltration. Due to the history of MTX and IFX use, OIIA-LPD (classical Hodgkin lymphoma-type, Stage IVB) was diagnosed in conformity with the fourth edition of the WHO classification. He had been treated with methylprednisolone (mPSL; 250 mg) for 3 days before the diagnosis of OIIA-LPD (Fig. 3). His fever waned, and the skin rash disappeared immediately after the administration of mPSL. Thrombocytopenia and the increased biliary enzyme levels improved but persisted. After the diagnosis of OIIA-LPD, he was treated with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), and the mPSL dose was tapered. After 1 course of ABVD, his platelet count and hepatobiliary enzymes normalized. After 2 courses of ABVD, he reached complete remission (CR); a total of 6 courses were administered. At two years after chemotherapy, he remains in CR. The patient is currently treated with low-dose prednisone and tacrolimus; there have been no exacerbations of RA with this regimen.\n\nFigure 1. Liver specimens were subjected to Hematoxylin and Eosin staining (original magnification ×20, ×40), immunohistochemical studies, and in situ hybridization for EBV-encoded RNA (EBER-ISH). Large, atypical nucleated cells were seen in the nodules. The large cells were similar in appearance to Reed-Sternberg (RS) cells and were positive for CD30 and latent membrane protein 1 (LMP-1) and negative for CD20, CD15, and EBV nuclear antigen 2 (EBNA2) on immunostaining. EBER-ISH detected RS cells.\n\nFigure 2. Bone marrow clot specimens were subjected to Hematoxylin and Eosin staining (original magnification ×20, ×40), immunohistochemical studies, and in situ hybridization for EBV-encoded RNA (EBER-ISH). The infiltration of lymphocytes was observed around large cells with abnormal, large, multilobular nuclei, which were similar in appearance to Reed-Sternberg (RS) cells. These cells were positive for CD30 and latent membrane protein 1 (LMP-1), and were negative for CD20, CD15, and EBV nuclear antigen 2 (EBNA2) on immunostaining. EBER-ISH detected RS cells.\n\nFigure 3. The clinical course from EBV hepatitis to the diagnosis of malignant lymphoma. PLT: platelet count, T-bil: total bilirubin, VCA-IgM: viral capsid IgM antibody, VCA-IgG: viral capsid IgG antibody, EBNA: Epstein-Barr nuclear antibody, EIA: enzyme immunoassay, FA: fluorescence antibody method, MTX: methotrexate, IFX: infliximab, PSL: prednisolone, mPSL: methylprednisolone\n\nDiscussion\nThe present patient developed EBV hepatitis while being treated for RA with MTX and IFX. Although his symptoms improved temporarily, OIIA-LPD developed in the form of Hodgkin lymphoma with increased biliary enzymes and thrombocytopenia at 5 months after the diagnosis of EBV hepatitis. OIIA-LPD is a heterogeneous group of diseases classified by a history of using immunosuppressive medication such as MTX in the setting of autoimmune disease. Diffuse large B-cell lymphoma and Hodgkin lymphoma are two major histological subtypes of OIIA-LPD. Fifty-four cases of OIIA-LPD have been reported in patients with the form of classical Hodgkin lymphoma (2). The administration of MTX for the treatment of RA was the most frequent patient characteristic. Lymphadenopathy was the common disease site, but two cases of bone marrow and two cases of liver involvement have also been reported (2). The frequency of EBV infection (EBER-positive and/or LMP-1-positive) was 80%, which is higher than that in patients with sporadic classical Hodgkin lymphoma (approximately 40%). Many cases require cytotoxic chemotherapy for treatment, as well as the discontinuation of immunomodulatory drugs (2,3). The clinical features of the present case were consistent with those of previous reports, but the clinical course was rare, in that acute hepatitis preceded the diagnosis of OIIA-LPD. As for the patient's acute hepatitis, two possibilities were considered based on the clinical course and laboratory findings.\n\nThe first possibility is that the liver involvement of OIIA-LPD went undiagnosed in the histological examination of the first liver biopsy specimen. The liver biopsy was performed by needle biopsy; thus, the specimen might not have contained abnormal lesions. In addition to the possible sampling error, the clinical course of the temporary improvement after the discontinuation of MTX and IFX fits the response to therapy for OIIA-LPD Hodgkin lymphoma. Two cases of Hodgkin lymphoma have been reported in RA patients with antecedent symptoms of suspected MTX-LPD (4). In this report, the antecedent symptoms improved temporarily with the discontinuation of MTX or steroid pulse therapy but were exacerbated after 1.5 years with aggressive manifestations. In one of the cases, the patient was not diagnosed by a liver biopsy and was only diagnosed at autopsy. It is unclear whether the antecedent symptoms were due to OIIA-LPD because no malignant cells were detected in the histological examination. However, similarly to our case, the antecedent symptoms were not diagnosed at the time of the first biopsy. We hypothesize that OIIA-LPD might sometimes become exacerbated with aggressive manifestations after temporary improvement following the discontinuation of immunosuppressive drugs.\n\nThe second possibility is that EBV hepatitis was the primary EBV infection. More than 90% of the world's adult population is infected with EBV (5). Thus, primary EBV infection would be rare in this 59-year-old patient. VCA-IgM sometimes increases with reactivation and is associated with false-positive results. In addition, there were no stored serum samples from before the manifestation of hepatitis; thus, it was not possible to prove the EBV seronegative status. However, EBV primary infection was considered because of seroconversion of EBNA and the results of the histological examination of the first liver specimen. The occasional viral lytic cycle is also thought to play a pivotal role in the development and maintenance of tumors because of its association with the secretion of cytokines and growth factors (6,7). Especially in renal transplantation, it has been reported that EBV-related posttransplantation lymphoproliferative disorder (PTLD) developed within a short period of time after primary EBV infection. EBV-seronegative patients who received a renal allograft from EBV-seropositive donors were at risk of developing EBV-related PTLD (8-10). Since primary EBV infection is a risk factor for LPD in a compromised host, it may be necessary to confirm a serological analysis to determine a patient's EBV status before the administration of immunosuppressive drugs such as MTX.\n\nIn conclusion, OIIA-LPD, Hodgkin lymphoma-type, developed after EBV hepatitis in a patient with RA. If the symptoms of suspected MTX-LPD are seen with no histological evidence of malignancy in RA patients who are on immunosuppressive treatment, the patient should be carefully followed to identify the potential exacerbation of undiagnosed LPD and to check their EBV status, while considering the possibility of primary infection with EBV.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nTokuhira M , Watanabe R , Nemoto T , et al \nClinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis . Leuk Lymphoma \n53 : 616 -623 , 2012 .21933041 \n2. \nLoo EY , Medeiros LJ , Aladily TN , et al \nClassical Hodgkin lymphoma arising in the setting of iatrogenic immunodeficiency: a clinicopathologic study of 10 cases . Am J Surg Pathol \n37 : 1290 -1297 , 2013 .23774171 \n3. \nCarbone A , Spina M , Gloghini A , Tirelli U \nClassical Hodgkin's lymphoma arising in different host's conditions: pathobiology parameters, therapeutic options, and outcome . Am J Hematol \n86 : 170 -179 , 2011 .21264899 \n4. \nTokuhira M , Tabayashi T , Tanaka Y , et al \nThe aggressive clinical courses of Hodgkin lymphoma primarily diagnosed as methotrexate-induced non-specific lymphoproliferative disorder in patients with rheumatoid arthritis . J Clin Exp Hematop \n56 : 165 -169 , 2017 .28331131 \n5. \nAndersson J \nEpstein-Barr virus and Hodgkin's lymphoma . Herpes \n13 : 12 -16 , 2006 .16732997 \n6. \nMurata T , Sato Y , Kimura H \nModes of infection and oncogenesis by the Epstein-Barr virus . Rev Med Virol \n24 : 242 -253 , 2014 .24578255 \n7. \nMurata T , Tsurumi T \nSwitching of EBV cycles between latent and lytic states . Rev Med Virol \n24 : 142 -153 , 2014 .24339346 \n8. \nHosseini-Moghaddam SM , Alhomayeed B , Soliman N , Weir MA , House AA \nPrimary Epstein-Barr virus infection, seroconversion, and post-transplant lymphoproliferative disorder in seronegative renal allograft recipients: a prospective cohort study . Transpl Infect Dis \n18 : 423 -430 , 2016 .27016725 \n9. \nLeaver S , Amlot P , Thuraisingham R , Norton A , Aitken C , Cavenagh JD \nSubacute immune response to primary EBV infection leading to post-transplant lymphoproliferative disease in a renal transplant patient . Clin Lab Haematol \n26 : 351 -353 , 2004 .15485466 \n10. \nSchachtner T , Reinke P \nPretransplant prophylactic rituximab to prevent Epstein-Barr virus (EBV) viremia in EBV-seronegative kidney transplant recipients from EBV-seropositive donors: results of a pilot study . Transpl Infect Dis \n18 : 881 -888 , 2016 .27632022\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Epstein-Barr virus; Hodgkin lymphoma; other iatrogenic immunodeficiency-associated lymphoproliferative disorder",
"medline_ta": "Intern Med",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D001706:Biopsy; D020031:Epstein-Barr Virus Infections; D006525:Hepatitis, Viral, Human; D006689:Hodgkin Disease; D006801:Humans; D007049:Iatrogenic Disease; D000069285:Infliximab; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1145-1149",
"pmc": null,
"pmid": "29279493",
"pubdate": "2018-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27016725;23774171;15485466;16732997;27632022;21933041;28331131;24339346;24578255;21264899",
"title": "Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder, Hodgkin Type, following Epstein-Barr Viral Hepatitis in a Patient with Rheumatoid Arthritis.",
"title_normalized": "other iatrogenic immunodeficiency associated lymphoproliferative disorder hodgkin type following epstein barr viral hepatitis in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1034103",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAbbreviated chemotherapy followed by radiotherapy or full cycles of chemotherapy is recommended as a standard treatment for limited-stage (LS) diffuse large B-cell lymphoma (DLBCL). After complete resection of tumors, however, Burkitt and childhood B-cell Non-Hodgkin lymphoma show favorable outcomes, even after abbreviated chemotherapy of only 2 or 3 cycles. We investigated the effectiveness of abbreviated chemotherapy in patients with LS DLBCL after complete tumor resection.\n\n\nMETHODS\nWe retrospectively reviewed 18 patients with LS DLBCL who underwent complete tumor resection followed by either 3 or 4 cycles of chemotherapy between March 2002 and May 2010.\n\n\nRESULTS\nWith a median follow-up period of 57.9 months (range, 31.8-130.2 months), no patients experienced disease relapse or progression; however, 1 patient experienced secondary acute myeloid leukemia during follow-up. The 5-year progression-free survival rate and overall survival rate were 93.3% and 94.1%, respectively.\n\n\nCONCLUSIONS\nThese results warrant further investigation into abbreviated chemotherapy as an alternative treatment for patients who have undergone complete resection of LS DLBCL.",
"affiliations": "Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Jo|Jungmin|J|;Yoon|Dok Hyun|DH|;Lee|Sang Wook|SW|;Park|Chan-Sik|CS|;Huh|Jooryung|J|;Lee|Kyoungmin|K|;Kang|Eun Hee|EH|;Kim|Shin|S|;Suh|Cheolwon|C|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5045/br.2014.49.2.115",
"fulltext": "\n==== Front\nBlood ResBlood ResBRBlood research2287-979X2288-0011Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 10.5045/br.2014.49.2.115Original ArticleAbbreviated chemotherapy for limited-stage diffuse large B-cell lymphoma after complete resection Jo Jungmin 1#Yoon Dok Hyun 1#Lee Sang Wook 2Park Chan-Sik 3Huh Jooryung 3Lee Kyoungmin 1Kang Eun Hee 1Kim Shin 1Suh Cheolwon 11 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.2 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.\nCorrespondence to Cheolwon Suh, M.D., Ph.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3209, Fax: +82-2-3010-6961, csuh@amc.seoul.kr#J.J and DH.Y contributed equally to this work.\n\n6 2014 25 6 2014 49 2 115 119 05 1 2014 21 2 2014 15 5 2014 © 2014 Korean Society of Hematology2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nAbbreviated chemotherapy followed by radiotherapy or full cycles of chemotherapy is recommended as a standard treatment for limited-stage (LS) diffuse large B-cell lymphoma (DLBCL). After complete resection of tumors, however, Burkitt and childhood B-cell Non-Hodgkin lymphoma show favorable outcomes, even after abbreviated chemotherapy of only 2 or 3 cycles. We investigated the effectiveness of abbreviated chemotherapy in patients with LS DLBCL after complete tumor resection.\n\nMethods\nWe retrospectively reviewed 18 patients with LS DLBCL who underwent complete tumor resection followed by either 3 or 4 cycles of chemotherapy between March 2002 and May 2010.\n\nResults\nWith a median follow-up period of 57.9 months (range, 31.8-130.2 months), no patients experienced disease relapse or progression; however, 1 patient experienced secondary acute myeloid leukemia during follow-up. The 5-year progression-free survival rate and overall survival rate were 93.3% and 94.1%, respectively.\n\nConclusion\nThese results warrant further investigation into abbreviated chemotherapy as an alternative treatment for patients who have undergone complete resection of LS DLBCL.\n\nDiffuse large B-cell lymphomaLimited StageResectionAbbreviated chemotherapy\n==== Body\nINTRODUCTION\nDiffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in adults [1]. Standard treatments for limited-stage (LS) DLBCL include both abbreviated systemic chemotherapy followed by involved-field radiotherapy (IFRT) and full-course chemotherapy [2].\n\nIn many cases, lesions are completely excised during the diagnostic process, especially in patients with stage I disease, as the diagnosis is best made based on histologic examination of tissues from an excisional biopsy. In addition, in the treatment of small bowel and ileocecal lymphomas with LS disease, initial surgical resection of the involved area is often performed due to the risk of obstruction or perforation of the bowel [3, 4, 5]. Although surgical resection is the most effective local therapy for the treatment of most cancers, full cycles of chemotherapy or combined treatment of chemotherapy and radiotherapy are still recommended for patients with completely resected DLBCL, similar to patients with gross tumors.\n\nDespite being a very aggressive variant of B-cell NHL, stage I Burkitt lymphoma is treated with only 3 cycles of chemotherapy after complete surgical resection [6, 7]. In the NHL-BFM 90 study, 2 courses of chemotherapy were sufficient to treat patients with childhood B-cell neoplasms after complete resection [8].\n\nFor patients with completely resected DLBCL, the number of cycles of chemotherapy has not been questioned so far. Thus, we aimed to investigate the effectiveness of an abbreviated course of chemotherapy after complete resection in patients with LS DLBCL.\n\nMATERIALS AND METHODS\nPatients\nBetween March 2002 and May 2010, 632 patients were diagnosed as having DLBCL in our center. Among them, 18 patients who had Ann Arbor stage I or II disease and who had initially undergone complete surgical resection of their tumors before chemotherapy and/or radiotherapy were included in this study. Diagnosis was made according to the World Health Organization criteria [9]. Patients with primary CNS lymphoma or mediastinal large B-cell lymphoma, involvement of the breast or testis, positive serology for HIV, previous organ transplantation, and concomitant or previous cancers were excluded. The institutional review board of the Asan Medical Center approved this study.\n\nTreatment\nA cycle of R-CHOP consisted of 375 mg/m2 rituximab, 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin and 1.4 mg/m2 vincristine (maximal dose of 2 mg), all on day 1. Patients also received 100 mg/day prednisolone orally on days 1.5. This cycle was repeated every 21 days. Patients diagnosed before 2003 were treated without rituximab. Primary prophylactic use of granulocyte colony stimulating factor (G-CSF) was not employed. Eighteen patients with completely resected DLBCL underwent 3 or 4 cycles of R-CHOP or CHOP chemotherapy at the discretion of the attending physician as well as according to the patients' preference. No patients underwent radiotherapy.\n\nResponses were evaluated according to the revised international workshop criteria [10]. Follow-up physical examinations, laboratory screenings, and neck, chest and abdominopelvic computed tomography (CT) scans were performed every 3 months for the first 2 years, then every 6 months for 3 years, and annually thereafter. Since there was no evaluable lesion after surgery, patients underwent CT scans to confirm whether they had relapsed or not. If a recurrence was suspected, we conducted an additional positron emission tomography (PET) scan.\n\nStatistical analyses\nProgression-free survival (PFS) was defined as the time from diagnosis to relapse or death from any cause. Overall survival (OS) was defined as the time from diagnosis to death from any cause. Survival was calculated using the Kaplan-Meier method. SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.\n\nRESULTS\nPatient characteristics\nPatient characteristics are shown in Table 1. The median age was 55.5 years (range, 25-64 years) at diagnosis and all patients were classified into the low-risk group according to the international prognostic index (IPI). The most commonly involved site was the ileocecum (Table 2). Out of the 18 patients, 6 (33.3%) had stage II disease. The colon or ileum was the primary disease site in 5 patients and the stomach was the primary site in the remaining patient; in this case, the patient was initially diagnosed with gastric adenocarcinoma and underwent gastrectomy. However, the diagnosis was revised to DLBCL after gastrectomy. One patient had a bulky disease in the small bowel and 2 patients had an approximately 10-cm mass at the same site. Out of 18 patients, 2 patients underwent 4 cycles of chemotherapy, and all the others had 3 cycles at the discretion of the physicians.\n\nThree patients had tonsil lymphoma and 2 patients had lymphoma in the submandibular and cervical lymph node, respectively. The patient with lymphoma in the submandibular lymph node underwent an excisional biopsy at an outside hospital and no lesion was observed on CT or PET-CT scans after the biopsy. Another patient had a large 8-cm cervical lymphadenopathy and underwent left radical neck dissection, which was confirmed to be an R0 resection. One patient had axillary lymph node involvement and underwent axillary lymph node dissection. A 5-cm mass was found, and no residual lesion was observed in a post-operative staging workup.\n\nTreatment outcomes\nThe median follow-up duration was 57.9 months (range, 31.8-130.2 months). None of the patients experienced relapse or progression of lymphoma. However, 1 patient developed AML after 28 months from completion of the treatment and died of AML progression. The 5-year PFS and OS were 93.3% and 94.1%, respectively, in the cohort (Fig. 1). The median PFS and OS had not yet been reached at the time of this analysis.\n\nTreatment-related toxicities\nNine patients (50.0%) suffered from grade 3 or 4 neutropenia. Of them, 1 patient experienced febrile neutropenia after the first cycle of R-CHOP. During follow-up, none of the patients experienced heart failure or grade 3/4 infections. Adverse events are summarized in Table 3.\n\nDISCUSSION\nThis study sought to determine if patients without any residual tumor require the same treatment as those with gross tumors. According to the current practice guidelines, every patient with LS DLBCL should be given full cycles of chemotherapy or a few cycles of chemotherapy followed by radiotherapy, even after complete resection of their tumor.\n\nSome aggressive lymphomas, such as Burkitt and childhood B-cell NHL, show very favorable outcomes with only 2 or 3 cycles of chemotherapy after tumor resection [6, 8]. Thus, we treated some of our patients with abbreviated cycles of chemotherapy after full discussion with the patients.\n\nNone of the patients experienced relapse or progressive disease and only 1 died of secondary AML resulting in the 5-year PFS of 93.3% and the 5-year OS of 94.1%. These outcomes are also similar to those from the prospective trials involving low-risk LS patients [11, 12]. The MabThera International Trial (MInT) included 597 young patients with stage II or bulky stage I disease [12, 13]. Patients with an age-adjusted IPI of 0 and no bulky disease treated with 6 cycles of CHOP-like chemotherapy plus rituximab had a 3-year event-free survival (EFS) and OS of 89% and 98%, respectively and those with an IPI of 1 or a bulky mass, or both, had an EFS and OS of 76% and 91%, respectively. In the Southwest Oncology Group (SWOG) 0014 study, 60 patients with LS disease were treated with 4 infusions of rituximab and 3 cycles of CHOP followed by IFRT. At a median follow-up of 5.3 years, the 4-year PFS and OS were 88% and 92%, respectively [11]. In another study that analyzed the prognostic value of the original IPI in 1,063 patients with aggressive B-cell lymphoma in the rituximab era, the 3-year EFS, PFS and OS in patients with an original IPI of 0 or 1 were 81%, 87%, and 91%, respectively [14]. Our results showed similar outcomes compared with these trials including the same IPI score or stages.\n\nThere were several trials for abbreviated chemotherapy without radiotherapy in patients with LS DLBCL. In a study by Sehn et al., older patients (median age 67 years; range 31-88 years) with LS DLBCL were just treated with a total of 4 cycles of R-CHOP chemotherapy if a complete metabolic response was achieved, as determined by PET analysis after 3 cycles of chemotherapy. The 2-year PFS and OS for PET-negative patients (N=49) were 93% and 97%, respectively. The GELA study for LS aggressive lymphoma in elderly patients (>60 years) compared 4 cycles of CHOP alone with 4 cycles of CHOP followed by radiotherapy [15]. In this trial, EFS and OS did not differ between the groups, and the 5-year EFS and OS of chemotherapy-alone group were 61% and 72%, respectively.\n\nAlthough R-CHOP is a relatively tolerable regimen, in a phase III trial of CHOP vs. R-CHOP as treatment for DLBCL in the elderly, the median nadir of the neutrophil count after the first cycle fell to 400/mm3. In this trial, 37% of patients required treatment with G-CSF for neutropenia, and 12% of patients experienced grade 3/4 infections during treatment [16]. In the MInT trial, 37% of patients experienced grade 3/4 toxicities, including leucocytopenia (7%), even though G-CSF could be given at the treating physician's discretion for the alleviation or prophylaxis of neutropenia [12]. However, other trials that compared a brief course of R-CHOP/CHOP followed by IFRT to R-CHOP/CHOP alone showed more frequent episodes of grade 3/4 neutropenia in the prolonged chemotherapy arms [1, 2]. We infer from these results that abbreviated chemotherapy might reduce the frequency of severe toxicities.\n\nPatients with NHL are at a higher risk for secondary malignant neoplasms (SMNs) than the general population and a combined modality of treatment was significantly associated with the risk for overall SMNs in a meta-analysis [17]. In our study, 1 patient developed AML during follow-up after treatment, even though he was given only abbreviated chemotherapy. In addition, cardiotoxicity is associated with increasing dose of doxorubicin [18, 19]. In a study of 3,941 patients treated with doxorubicin, 88 developed symptomatic heart failure during follow-up, and the incidence ranged from 0.14% in those who received <400 mg/m2, to 7% of those who received 550 mg/m2, and 18% of those beyond 700 mg/m2 [20, 21]. There is a variable sensitivity to doxorubicin among patients, with some experiencing cardiotoxicity at doses lower than 300 mg/m2 [22]. The factors that determine inter-individual variability with respect to the sensitivity to the cardiotoxic effects of anthracyclines are not well understood [23]. In the SEER study, the risk of heart failure was 47% higher among elderly patients treated with doxorubicin 6 or more times than among those not treated with chemotherapy [24]. The cumulative dose of doxorubicin would be reduced to 150-200 mg/m2 compared with 300-400 mg/m2, which might potentially reduce the risk of cardiac failure rates. In addition, abbreviated R-CHOP would be advantageous in terms of convenience as well as the cost of treatment.\n\nThis study has several limitations, stemming from its small sample size, relatively short follow-up period, and retrospective design. We are currently undertaking a prospective phase II trial to validate these data. In conclusion, the current results suggest that patients with LS DLBCL given only 3-4 cycles of chemotherapy after complete resection may have comparable efficacy outcomes to those given conventional treatment, which warrants a validation in prospective trials. These results indicate that more may not be always better.\n\nNo potential conflicts of interest relevant to this article were reported.\n\nFig. 1 Kaplan-Meier curves of (A) progression-free survival and (B) overall survival.\n\nTable 1 Patient characteristics.\n\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; WNL, within normal limits; IPI, International prognostic index; R-CHOP, ritixumab, cyclophosphamide, doxorubicin, vincristine, prednisolone.\n\nTable 2 Involvement sites.\n\nTable 3 Profile of adverse events during treatment.\n\nAbbreviations: AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase.\n==== Refs\n1 Miller TP Dahlberg S Cassady JR Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma N Engl J Med 1998 339 21 26 9647875 \n2 Hong J Kim AJ Park JS Additional rituximab-CHOP (R-CHOP) versus involved-field radiotherapy after a brief course of R-CHOP in limited, non-bulky diffuse large B-cell lymphoma: a retrospective analysis Korean J Hematol 2010 45 253 259 21253427 \n3 Kim SJ Kang HJ Kim JS Comparison of treatment strategies for patients with intestinal diffuse large B-cell lymphoma: surgical resection followed by chemotherapy versus chemotherapy alone Blood 2011 117 1958 1965 21148334 \n4 Koch P del Valle F Berdel WE Primary gastrointestinal non-Hodgkins lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92 J Clin Oncol 2001 19 3861 3873 11559724 \n5 Rawls RA Vega KJ Trotman BW Small Bowel Lymphoma Curr Treat Options Gastroenterol 2003 6 27 34 12521569 \n6 Diviné M Casassus P Koscielny S Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol Ann Oncol 2005 16 1928 1935 16284057 \n7 Mead GM Sydes MR Walewski J An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study Ann Oncol 2002 13 1264 1274 12181251 \n8 Reiter A Schrappe M Tiemann M Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90 Blood 1999 94 3294 3306 10552938 \n9 Vardiman JW Thiele J Arber DA The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009 114 937 951 19357394 \n10 Cheson BD Pfistner B Juweid ME Revised response criteria for malignant lymphoma J Clin Oncol 2007 25 579 586 17242396 \n11 Persky DO Unger JM Spier CM Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014 J Clin Oncol 2008 26 2258 2263 18413640 \n12 Pfreundschuh M Trumper L Osterborg A CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group Lancet Oncol 2006 7 379 391 16648042 \n13 Pfreundschuh M Kuhnt E Trumper L CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group Lancet Oncol 2011 12 1013 1022 21940214 \n14 Ziepert M Hasenclever D Kuhnt E Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era J Clin Oncol 2010 28 2373 2380 20385988 \n15 Bonnet C Fillet G Mounier N CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte J Clin Oncol 2007 25 787 792 17228021 \n16 Coiffier B Lepage E Briere J CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 2002 346 235 242 11807147 \n17 Pirani M Marcheselli R Marcheselli L Bari A Federico M Sacchi S Risk for second malignancies in non-Hodgkin's lymphoma survivors: a meta-analysis Ann Oncol 2011 22 1845 1858 21310758 \n18 Praga C Beretta G Vigo PL Adriamycin cardiotoxicity: a survey of 1273 patients Cancer Treat Rep 1979 63 827 834 455324 \n19 Von Hoff DD Layard MW Basa P Risk factors for doxorubicin-induced congestive heart failure Ann Intern Med 1979 91 710 717 496103 \n20 Bristow MR Mason JW Billingham ME Daniels JR Dose-effect and structure-function relationships in doxorubicin cardiomyopathy Am Heart J 1981 102 709 718 7282516 \n21 Swain SM Whaley FS Ewer MS Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials Cancer 2003 97 2869 2879 12767102 \n22 Shan K Lincoff AM Young JB Anthracycline-induced cardiotoxicity Ann Intern Med 1996 125 47 58 8644988 \n23 Blanco JG Sun CL Landier W Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes-a report from the Children's Oncology Group J Clin Oncol 2012 30 1415 1421 22124095 \n24 Hershman DL McBride RB Eisenberger A Tsai WY Grann VR Jacobson JS Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma J Clin Oncol 2008 26 3159 3165 18591554\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-979X",
"issue": "49(2)",
"journal": "Blood research",
"keywords": "Abbreviated chemotherapy; Diffuse large B-cell lymphoma; Limited Stage; Resection",
"medline_ta": "Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101605247",
"other_id": null,
"pages": "115-9",
"pmc": null,
"pmid": "25025013",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "7282516;8644988;11559724;9647875;12181251;18591554;18413640;17242396;16648042;21940214;12767102;19357394;20385988;17228021;22124095;21253427;455324;11807147;21148334;21310758;12521569;10552938;16284057;496103",
"title": "Abbreviated chemotherapy for limited-stage diffuse large B-cell lymphoma after complete resection.",
"title_normalized": "abbreviated chemotherapy for limited stage diffuse large b cell lymphoma after complete resection"
} | [
{
"companynumb": "KR-MYLAN-2014M1003218",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nWe evaluated the efficacy and safety of itraconazole after first-line chemotherapy in patients with metastatic biliary tract cancer (BTC).\n\n\nMETHODS\nWe retrospectively reviewed data from patients with histologically-diagnosed BTC with distant metastases who had received one or more lines of chemotherapy and subsequent itraconazole chemotherapy.\n\n\nRESULTS\nAmong 28 enrolled patients, 26 (93%) received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (AUC4) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. Two patients received docetaxel plus itraconazole with irinotecan. Two complete responses and 14 partial responses were observed, with a response rate of 57%. The median overall survival was 12.0 months. During 160 cycles, 21 (75%) and 17 (61%) patients had grade 3/4 neutropenia and thrombocytopenia, respectively. Two patients (7%) experienced febrile neutropenia.\n\n\nCONCLUSIONS\nCombination chemotherapy with itraconazole after first-line chemotherapy is promising for patients with metastatic BTC.",
"affiliations": "Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Hyogo, Japan Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan tsuba@hyo-med.ac.jp.;Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Hyogo, Japan.;Department of Surgery, Meiwa Hospital, Nishinomiya, Hyogo, Japan.;Department of Medical Oncology, Kohnan Hospital, Higashinada-ku, Kobe, Japan.;Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Hyogo, Japan Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.;Department of Surgery, Meiwa Hospital, Nishinomiya, Hyogo, Japan.",
"authors": "Tsubamoto|Hiroshi|H|;Sonoda|Takashi|T|;Ikuta|Shinichi|S|;Tani|Satoshi|S|;Inoue|Kayo|K|;Yamanaka|Naoki|N|",
"chemical_list": "D000970:Antineoplastic Agents; D017964:Itraconazole",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(9)",
"journal": "Anticancer research",
"keywords": "biliary tract cancer; itraconazole; second-line chemotherapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms; D005260:Female; D006801:Humans; D017964:Itraconazole; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4923-7",
"pmc": null,
"pmid": "26254389",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of Itraconazole After First-line Chemotherapy on Survival of Patients with Metastatic Biliary Tract Cancer.",
"title_normalized": "impact of itraconazole after first line chemotherapy on survival of patients with metastatic biliary tract cancer"
} | [
{
"companynumb": "JP-JNJFOC-20150809230",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nUveitis associated with psoriasis vulgaris is usually seen as an anterior segment inflammation, and it is very rare that the inflammation extends to the posterior segment. We herein report a case of severe panuveitis associated with psoriasis vulgaris presenting as retinal neovascularization, leading to vitreous hemorrhages that were successfully treated with infliximab (IFX).\n\n\nMETHODS\nA 27-year-old male with psoriasis vulgaris was referred to our hospital due to prolonged severe uveitis OU. He showed a severe anterior chamber inflammation with fibrin formation and total posterior iris synechia OU. With topical corticosteroid treatment, these conditions were relieved for a short time; however, the intraocular inflammation was exacerbated with vitreous hemorrhages caused by retinal neovascularization OS. After the administration of IFX therapy, the intraocular inflammation and retinal neovascularization was resolved, and so far, no severe recurrences have been seen for 3 years with the therapy.\n\n\nCONCLUSIONS\nWhen we see patients with severe panuveitis associated with psoriasis extending to the posterior segment, IFX treatment may be a good therapeutic option.",
"affiliations": "Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.",
"authors": "Sakurai|Yuri|Y|;Namba|Kenichi|K|;Mizuuchi|Kazuomi|K|;Nomura|Toshihumi|T|;Ishida|Susumu|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000445285",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000445285cop-0007-0191Published online: April, 2016A Case of Severe Panuveitis Associated with Psoriasis Vulgaris Successfully Treated with Infliximab Sakurai Yuri aNamba Kenichi a*Mizuuchi Kazuomi aNomura Toshihumi bIshida Susumu aaDepartment of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, JapanbDepartment of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan*Kenichi Namba, MD, PhD, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, N15-W7, Kita-ku, Sapporo 060-8638 (Japan), E-Mail knamba@med.hokudai.ac.jpJan-Apr 2016 2 4 2016 2 4 2016 7 1 191 194 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Purpose\nUveitis associated with psoriasis vulgaris is usually seen as an anterior segment inflammation, and it is very rare that the inflammation extends to the posterior segment. We herein report a case of severe panuveitis associated with psoriasis vulgaris presenting as retinal neovascularization, leading to vitreous hemorrhages that were successfully treated with infliximab (IFX).\n\nCase Report\nA 27-year-old male with psoriasis vulgaris was referred to our hospital due to prolonged severe uveitis OU. He showed a severe anterior chamber inflammation with fibrin formation and total posterior iris synechia OU. With topical corticosteroid treatment, these conditions were relieved for a short time; however, the intraocular inflammation was exacerbated with vitreous hemorrhages caused by retinal neovascularization OS. After the administration of IFX therapy, the intraocular inflammation and retinal neovascularization was resolved, and so far, no severe recurrences have been seen for 3 years with the therapy.\n\nConclusion\nWhen we see patients with severe panuveitis associated with psoriasis extending to the posterior segment, IFX treatment may be a good therapeutic option.\n\nKey Words\nUveitisPsoriasisNeovascularizationInfliximab\n==== Body\nIntroduction\nUveitis associated with psoriasis vulgaris is usually seen as an anterior segment inflammation, and it is very rare that the inflammation extends to the posterior segment [1, 2]. Our patient experienced panuveitis that was associated with psoriasis vulgaris and was accompanied by retinal vasculitis with retinal neovascularization leading to repeated vitreous hemorrhages. Infliximab (IFX) treatment was effective in resolving these issues.\n\nCase Presentation\nA 27-year-old male visited an ophthalmology clinic with a complaint of blurred vision OU. He showed bilateral uveitis that had been controlled with eye drops; however, it later exacerbated, and he was referred to our hospital.\n\nHe had suffered from psoriasis vulgaris since he was 14 years old and had been treated with topical corticosteroids and phototherapy by dermatologists; however, he had ceased all treatments on his own accord 2 years earlier. Since then, his skin condition had become worse due to the lack of medication.\n\nAt the first visit, the best-corrected visual acuity (BCVA) was 0.5 OD and counting fingers OS. Intraocular pressure was 13 mm Hg OD and 5 mm Hg OS. A slit-lamp examination showed ciliary injections and 3+ flare and 3+ cells, fibrin formation in the anterior chamber with total posterior iris synechia OU, and fundi were invisible OU (fig. 1).\n\nBesides psoriasis, other extraocular lesions such as oral aphthous ulcers or genital ulcers, or symptoms for Behçet's disease were not found. The patient's psoriasis was very severe; the skin over the whole body including the face and eyelids formed erythroderma and thick desquamation. Screening blood and urine tests did not show any positive results indicating sarcoidosis or other uveitis.\n\nHe underwent dexamethasone conjunctival injections, and topical treatments with 0.1% betamethasone eye drops and mydriatic eye drops were applied every hour. For psoriasis, corticosteroid ointment and ultraviolet irradiation were promptly started. With these medications, the anterior segment intraocular inflammation was reduced, and BCVA improved to 1.2 OD and 0.8 OS 3 months later; however, the posterior synechia was not removed and fundi were still invisible OU. Ten months later, the patient underwent cataract surgery, and the posterior synechia was removed OS. After surgery, the vitreous opacity was mild, and the BCVA improved to 0.9 OS. However, the anterior chamber inflammation suddenly exacerbated with a vitreous hemorrhage OS 1 month postoperatively. The fundus was too blurred to be seen in detail; however, fluorescein angiography revealed marked leakage suggestive of retinal neovascularization (fig. 2). Since the patient developed further vitreous hemorrhages with a recurrence of anterior uveitis with his psoriasis not controlled well, IFX was administered 19 months following the first visit.\n\nIFX (5 mg/kg) was infused 2 and 6 weeks following the first infusion and every 8 weeks thereafter. After the IFX administration, a new vitreous hemorrhage occurred only once; however, it quickly disappeared and has not recurred. During the 3 years of IFX therapy, no severe recurrences were seen, and cataract surgery could be performed safely without postoperative inflammations OD. The final BCVA was 1.2 OD and 0.8 OS. The patient's psoriasis was also gradually improved.\n\nDiscussion\nUveitis associated with psoriasis vulgaris is mostly seen as acute anterior uveitis [1, 2]. Although a case of panretinal vasculitis with cystoid macular edema has already been reported [3], to the best of our knowledge, this is the first report of retinal vasculitis with retinal neovascularization leading to vitreous hemorrhages associated with psoriasis. We considered other causes of uveitis including sarcoidosis or Behçet's disease; however, all of them were excluded because of negative results of systemic examinations and no signs of extraocular symptoms related to these diseases. Because the patient's uveitis exacerbated along with the exacerbation of psoriasis, we diagnosed this case as psoriasis-associated uveitis. It is speculated that the systemic inflammatory disease in this patients was so severe as to induce inflammation in the posterior segment in addition to anterior segment.\n\nThis case was so severe that vitreous hemorrhages recurred frequently, even with topical corticosteroid treatment. However, after the IFX therapy, the ocular inflammation was relieved and has never recurred. Moreover, cataract surgery could be performed under the IFX treatment without severe postoperative inflammation.\n\nIFX is a chimeric monoclonal antibody to tumor necrosis factor-α and has shown excellent efficacies in its worldwide use in the treatment of various immunological diseases [4, 5] including rheumatoid arthritis [4, 6] and Crohn's disease [5]. In psoriasis vulgaris, IFX is now available for severe cases that are refractory to existing treatments [7, 8].\n\nSome uveitis cases with psoriasis that have undergone IFX treatment have been reported. Asukata et al. [9] reported a case of intractable anterior uveitis; Huynh et al. [10] reported 2 panuveitis cases, 1 anterior uveitis case and 1 scleritis case, and Goto et al. [3] reported a case showing retinal vasculitis with macular edema. In all cases, there was a remission of ocular inflammation, and skin lesions were well controlled with IFX administration. Our case presented a more severe panuveitis with inflammatory retinal neovascularization; however, IFX was effective in controlling the severe uveitis. Uveitis with psoriasis seems to be a good indication for the administration of IFX.\n\nStatement of Ethics\nThis case report has been approved by the Ethics Committee of Hokkaido University Hospital, Sapporo, Japan.\n\nDisclosure Statement\nThe authors have no financial interest to disclose in this work.\n\nFig. 1 Clinical findings during the initial visit. Ciliary injections and severe anterior chamber inflammations, such as 3+ flare and 3+ cells, and fibrin formation combined with total posterior synechia, were seen in OD (a) and OS (b). Erythroderma and thick desquamation were seen in the lower limbs (c).\n\nFig. 2 Before the IFX treatment, the ocular fundus was too blurred to be seen in detail due to a vitreous hemorrhage (a), and fluorescein angiography showed a marked leakage suggestive of retinal neovascularization (b).\n==== Refs\nReferences\n1 Lambert JR Wright V Eye inflammation in psoriatic arthritis Ann Rheum Dis 1976 35 354 356 970993 \n2 Knox DL Psoriasis and intraocular inflammation Trans Am Ophthalmol Soc 1979 127 270 \n3 Goto M Ujihara H Matsubara M A case of psoriatic panuveitis treated by systemic infliximab Jpn J Clin Ophtalmol 2010 64 1165 1168 \n4 Maini R St Clair EW Breedveld F Furst D Kalden J Weisman M Smolen J Emery P Harriman G Feldmann M Lipsky P Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group Lancet 1999 354 1932 1939 10622295 \n5 Hanauer S Feagan BG Lichtenstein GR Mayer LF Schreiber S Colombel JF Rachmilewitz D Wolf DC Olson A Bao W Rutgeerts P Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Lancet 2002 359 1541 1549 12047962 \n6 Elliott MJ Maini RN Feldmann M Long-Fox A Charles P Bijl H Woody JN Repeated therapy with monoclonal antibody to tumor necrosis factor alpha (cA2) in patients rheumatoid arthritis Lancet 1994 344 1125 1127 7934495 \n7 Christian A Bernhard M Infliximab for psoriasis and psoriatic arthritis Clin Exp Rheumatol 2002 20 122 125 \n8 Chaudhari U Romano P Mulcahy LD Dooley LT Baker DG Gottlieb AB Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial Lancet 2001 351 1842 1847 11410193 \n9 Asukata Y Kawagoe T Ishihara M Nishida T Nakamura S Hayashi K Mizuki N Systemic infliximab was effective in a case of uveitis with psoriatic arthritis (in Japanese) Jpn J Clin Ophtalmol 2011 65 1117 1121 \n10 Huynh N Cervantes-Castaneda RA Bhat P Gallagher MJ Foster CS Biological response modifier therapy for psoriatic ocular imflammatory disease Ocul Immunol Inflamm 2008 16 89 93 18569794\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Infliximab; Neovascularization; Psoriasis; Uveitis",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "191-4",
"pmc": null,
"pmid": "27239187",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "11410193;10622295;12047962;12463461;18569794;970993;7934495;575684",
"title": "A Case of Severe Panuveitis Associated with Psoriasis Vulgaris Successfully Treated with Infliximab.",
"title_normalized": "a case of severe panuveitis associated with psoriasis vulgaris successfully treated with infliximab"
} | [
{
"companynumb": "JP-JNJFOC-20160606119",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).\n\n\nMETHODS\nThirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.\n\n\nRESULTS\nAdequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).\n\n\nCONCLUSIONS\nThe LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.",
"affiliations": "U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O. Diagnostica per Immagini-Figlie di San Camillo-Via F Filzi 56, Cremona, Italy.;U.O. di Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O. di Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;CRUK Tumor Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DS, UK.;CRUK Tumor Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DS, UK.;Dipartimento di Medicina Sperimentale, Via Volturno, 39, 43100 Parma, Italy.;Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.;Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.;U.O. Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O. Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.;Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.;U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.",
"authors": "Bazzola|L|L|;Foroni|C|C|;Andreis|D|D|;Zanoni|V|V|;R Cappelletti|M|M|;Allevi|G|G|;Aguggini|S|S|;Strina|C|C|;Milani|M|M|;Venturini|S|S|;Ferrozzi|F|F|;Giardini|R|R|;Bertoni|R|R|;Turley|H|H|;Gatter|K|K|;Petronini|P G|PG|;Fox|S B|SB|;Harris|A L|AL|;Martinotti|M|M|;Berruti|A|A|;Bottini|A|A|;Reynolds|A R|AR|;Generali|D|D|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009570:Nitriles; D010671:Phenylurea Compounds; D014230:Triazoles; D009536:Niacinamide; D000077289:Letrozole; D003520:Cyclophosphamide; D000077157:Sorafenib",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2014.563",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201456310.1038/bjc.2014.56325461806Clinical StudyCombination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer Combination of LCS and primary breast cancerBazzola L 1Foroni C 1Andreis D 1Zanoni V 1R Cappelletti M 1Allevi G 1Aguggini S 1Strina C 1Milani M 1Venturini S 1Ferrozzi F 2Giardini R 3Bertoni R 3Turley H 4Gatter K 4Petronini P G 5Fox S B 6Harris A L 7Martinotti M 8Berruti A 8Bottini A 1Reynolds A R 10Generali D 1*1 U.O.di Patologia Mammaria—Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy2 U.O. Diagnostica per Immagini-Figlie di San Camillo-Via F Filzi 56, Cremona, Italy3 U.O. di Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy4 CRUK Tumor Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DS, UK5 Dipartimento di Medicina Sperimentale, Via Volturno, 39, 43100 Parma, Italy6 Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia7 Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK8 U.O. Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy9 Department of Medical Oncology, Azienda Spedali Civili, 21121 Brescia, Italy10 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK* E-mail: d.generali@ospedale.cremona.it06 01 2015 02 12 2014 112 1 52 60 20 07 2014 24 09 2014 04 10 2014 Copyright © 2015 Cancer Research UK2015Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Purpose:\nTo assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).\n\nMethods:\nThirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.\n\nResults:\nAdequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by 18FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).\n\nConclusions:\nThe LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.\n\nbreast cancersorafenibendocrine resistanceneoadjuvantprimary hormone therapyletrozole\n==== Body\nTreatment with aromatase inhibitors (AIs), such as letrozole, has demonstrated increased response rate compared with tamoxifen in patients with breast cancer (BC) (Smith and Dowsett, 2003). However, the development of resistance to endocrine therapy is a significant problem involving the activation of other signalling pathways such as EGFR, HER2, IGFR, MAPK, PI3K-AKT or PKC (Nicholson et al, 2004, 2005; Osborne et al, 2005; Generali et al, 2009). This provides a strong rationale for combining endocrine therapies with signal-transduction inhibitors to bypass endocrine therapy resistance and achieve a more potent anti-tumour effect (Gligorov et al, 2007; Johnston et al, 2007).\n\nSorafenib (Nexavar, BAY43-9006) is an oral multi-targeted kinase inhibitor, which is capable of inhibiting several kinases involved in tumour progression and angiogenesis (Iyer et al, 2010). It was also recently shown that sorafenib can inhibit both mTOR and (Kumar et al, 2007; Huynh et al, 2009) and MAPK signalling (Keswani et al, 2008). Moreover, our preclinical data demonstrate that the combination of letrozole with sorafenib in aromatase-expressing BC cells shows a synergistic inhibition of cell proliferation in vitro (Bonelli et al, 2010). We showed that sorafenib inhibited BC-cell proliferation in a concentration-dependent manner through a mechanism involving downregulation of mTORC and its downstream targets p70S6K and 4E-binding protein 1 (4E-BP1) (Bonelli et al, 2010). In BC cells treated with letrozole and sorafenib, suppression of cell proliferation was associated with enhanced accumulation of cells in the G0/G1 phase of the cell cycle due to a downregulation of c-myc, cyclin D1 and phospho-Rb expression (Bonelli et al, 2010). Moreover, experiments involving long-term exposure to sorafenib showed that it prevented the acquisition of resistance towards letrozole in BC cells in vitro (Bonelli et al, 2010). These preclinical data provide a strong rational for testing letrozole combined with sorafenib in patients with BC.\n\nMetronomic chemotherapy is the frequent administration of cytotoxic drugs at a low dose that is designed to avoid dose-limiting adverse effects that would require rest periods. In addition, metronomic chemotherapy is proposed to target tumour growth indirectly by inhibiting angiogenesis, rather than directly targeting tumour cells (Pasquier et al, 2010). Our group has previously shown that the combination of letrozole with a metronomic regimen of cyclophosphamide is active in elderly patients with primary BC (Bottini et al, 2006). These data do contrast with studies that combined endocrine therapy with conventional high-dose chemotherapy regimens, where the combination was shown to be antagonistic (Osborne et al, 1989; Albain et al, 2009). However, the favourable results we reported with metronomic cyclophosphamide probably stem from the lower-toxicity profile observed with this regimen and the fact that this therapy targets the vascular compartment instead of targeting tumour cells directly.\n\nOn the basis of these findings, we have planned a randomised phase II trial to explore the activity of the letrozole, metronomic chemotherapy and sorafenib combination. This is a neoadjuvant trial in postmenopausal breast cancer patients with ER positive, HER2 negative primary breast cancer and is currently ongoing (Eudract Number 2007-006208-39). In this paper, we present pharmacokinetic, toxicity, response and biomarker data for this regimen in the first thirteen consecutive patients enrolled in the study before randomisation.\n\nMaterials and methods\nPatients and treatment\nThis study involved 13 postmenopausal women with ER positive, HER2 negative, T2-4, N0-1 BC enrolled in a single institution. Inflammatory breast cancer was excluded from the study. Eligibility criteria for inclusion were the same as those described for our previous study, which examined the combination of letrozole with metronomic cyclophosphamide in BC (Bottini et al, 2006). Patients received one tablet (2.5 mg) of letrozole per day (Femara; Novartis), one tablet (50 mg) of cyclophosphamide per day (Endoxan; Baxter) and every 5th day they received two tablets (400 mg bid) of sorafenib (Nexavar, Bayer). These drugs were given continuously for 6 months. At the end of treatment the patients underwent definitive surgery. All adverse events (AE) were graded by the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0.\n\nWith regard to the pharmacokinetic profile, during the first 5 days the patients received only letrozole and cyclophosphamide. The administration of sorafenib started from day 6 onwards. The pharmacokinetic profile of sorafenib was assessed on day 29. The pharmacokinetic profile of cyclophosphamide and 4-hydroxy-cyclophosphamide was assessed on days 5 and 29. This approach permitted us to test the safety and tolerability of this regimen and the pharmacokinetic interaction between sorafenib and cyclophosphamide. The decision to continue the study or not depended on evaluations of tolerability, safety and pharmacokinetic profile of cyclophosphamide after 6 weeks. A dose escalation was not planned. If <33% of these patients experienced no significant toxicity on the treatment, the study continued until the conclusion of the pre-planned enrolment. If 33% or more of the patients experienced a significant toxicity during the treatment, the study would have been closed due to unacceptable toxicity. The dose-limiting unacceptable toxicity was defined by the following adverse events during the first cycle that could be correlated to the drug combination:\nHaematological toxicity:\nNeutropenia <0.5 × 109 l−1 not associated with fever lasting longer than 10 days\n\nNeutropenia <0.5 × 109 l−1 associated to fever >38.5 °C\n\nPiastrinopenia <25 × 109 l−1 or grade 3 piastrinopenia associated with bleeding\n\n\n\nNon-haematological toxicity:\ngrade 3–4 non-haematological toxicity with the exclusion of:\nallergic reactions controlled by an adequate therapy\n\ngrade 4 hypertension crises related to sorafenib\n\ngrade 3 hypertension\n\n\n\n\n\n\n\nAny toxicity correlated to the study drug was unacceptable according to the opinion of the investigators.\n\nPharmacokinetic analysis\nThe pharmacokinetic analysis was performed in the Laboratory of Dr Frank-Thorsten Hafner (Bayer HealthCare AG, Preclinical Pharmacokinetics—Bioanalytics, Pharma Research Center, Building 468 D-42096 Wuppertal, Germany). For measurement of sorafenib, plasma samples were collected on day 1 of Cycle 2 (Day 29) following multiple dosing of both 400 mg bid sorafenib and 50 mg of cyclophosphamide in combination with 2.5 mg of letrozole (see Figure 1A). Plasma samples from 13 patients were collected before dosing and at 0.5, 1, 2, 4, 8, 10 and 12 h after dosing. For measurement of cyclophosphamide and its metabolite 4-hydroxy-cyclophosphamide, plasma samples were collected on Day 5 of Cycle 1 (before sorafenib treatment) and on Day 1 of Cycle 2 (Day 29) (after concomitant treatment with multiple oral doses of both drugs) (see Figure 1A). This allowed us to evaluate the effect of multiple oral doses of sorafenib on the pharmacokinetics of cyclophosphamide. Plasma samples from 13 patients were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after dosing. The concentration of the drugs was assessed by using a one-way analysis of variance model for dose-normalised and log-transformed maximum observed serum concentration considering the concentration-time curve (AUC). Statistical significance of the factor of dose was set at P=0.05.\n\nResponse assessment\nThe size of the primary tumour and the axillary lymph nodes was measured monthly with callipers by the same clinician. Tumour size measurements obtained by breast MRI, using protocols described elsewhere (Bonelli et al, 2010), were made at baseline and at the 14th day of treatment and were independently reviewed by two experienced radiologists. Any discrepant readings were resolved by consensus. Response evaluated by either clinical palpation or breast MRI was assessed by the measurement of the changes in the product of the two largest diameters recorded at baseline, at the 14th day and at the end of therapy before surgery, according to the RECIST Criteria.\n\nThe 18FDG-PET/CT scans (CT 8 slice) were carried out using a Discovery ST PET/CT scanner (GE Healthcare, Milwaukee, WI, USA) and performed at baseline, after 30 days of treatment and before definitive surgery. The 18FDG-PET/CT images were read independently by two experienced radiologists. Standardised uptake values (SUVs) were calculated. Lesions were scored for response by Modified CT Criteria using 18FDG-PET/CT scans obtained at baseline, after 30 days of treatment and just before definitive surgery. Lesions were scored as follows: CR (disappearance of lesion), PR (decrease in tumour size of ⩾10% or decrease in tumour density of ⩾15%), SD (does not meet the criteria for CR, PR or PD) and PD (an increase in tumour size of ⩾10% and does not meet criteria of PR by tumour density on CT) (Choi et al, 2007).\n\nThe observers were blinded for any clinical data including the site of the primary tumour. Discrepancies were resolved by consensus. During the study, clinicians and pathologists were blinded to the 18FDG-PET/CT related data.\n\nCollection and processing of tissue samples\nTissue was obtained from patients at three time points: tissue from incision biopsy performed at presentation, tissue from tru-cut biopsy performed after 14 days of treatment and tissue obtained at definitive surgery. Surgery (quadrantectomy or mastectomy) was planned after full clinical reassessment. All patients subjected to quadrantectomy underwent irradiation of the residual breast (60 Gys delivered in 6 weeks). Immunohistochemistry was performed on paraffin-embedded tumour samples obtained at all three time points. HER-2, ER, PgR, Ki67, CD31 and VEGF-A staining was performed using standard protocols as described elsewhere (Koukourakis et al, 2005; Bottini et al, 2006).\n\nStatistical analysis\nKi67, CD31, VEGF-A, MRI and SUVmax were analysed as continuous variables. Non-parametric statistical methods (Mann–Whitney test for unpaired data, Wilcoxon's matched-pairs signed-rank test for paired data, Spearman Rho for simple correlation analysis) were used in the primary analyses of the data. The PK analysis was carried out using ANOVA test. All tests were two-sided; P<0.05 was considered as statistically significant. Statistical analysis was performed on an IBM-compatible personal computer using Statistica software (Statsoft, Tulsa, OK, USA) for Windows (Microsoft, Redmond, WA, USA) software.\n\nEthical approval\nThe Local Ethical Committee of A.O. Istituti Ospitalieri di Cremona approved this prospective study and signed informed consent was obtained from each patient.\n\nResults\nDetails of the study population\nThirteen postmenopausal women (median 67 years old, range 53–79) with T2-4, N0-1 (11 patients with T2, and 2 with T4, 6 with node negative and 7 with node positive, 5 with grade 2 and 8 with grade 3) and ER+ve (13/13) and HER2-ve (0/13) BC were prospectively enrolled between April 2009 and May 2010 into the trial. See Table 1A and 1B for details of patient characteristics.\n\nPharmacokinetic analysis of sorafenib\nWe examined whether the pharmacokinetics of sorafenib were affected when sorafenib was dosed in combination with letrozole and metronomic cyclophosphamide. Plasma samples were collected on day 1 of Cycle 2 (Day 29) at which time point patients had already received multiple doses of sorafenib, cyclophosphamide and letrozole (Figure 1A). Plasma samples from 13 patients were collected before dosing and at 0.5, 1, 2, 4, 8, 10 and 12 h after dosing. A time course of circulating sorafenib concentrations is shown in Figure 2A. The results for AUC (0–12) and Cmax of sorafenib for Day 1 of Cycle 2 are given as individual and geometric mean values (see Table 1A). The geometric means for AUC (0–12) and Cmax calculated were within the range of values observed after multiple dosing with 400 mg per b.i.d. sorafenib in previous studies (Strumberg et al, 2005, 2007). These findings show that circulating concentrations of sorafenib were not significantly affected by dosing in combination with cyclophosphamide and letrozole.\n\nPharmacokinetic analysis of cyclophosphamide\nWe then examined whether dosing of sorafenib affects the pharmacokinetics of cyclophosphamide. Plasma samples were collected on Day 5 of Cycle 1 (before sorafenib treatment) and on Day 1 of Cycle 2 (Day 29) (after concomitant treatment with multiple oral doses of both sorafenib and cyclophosphamide) (see Figure 1A). This allowed us to evaluate the effect of multiple oral doses of sorafenib on the pharmacokinetics of cyclophosphamide. Although cyclophosphamide was measurable in all samples up to 12 h, only a few isolated plasma samples obtained at 24 h contained concentrations above the lower limit of quantification (LLOQ), so we limited our pharmacokinetic analysis to the time points up to 12 h. Geometric mean plasma concentration time courses of cyclophosphamide obtained in patients before and after exposure to sorafenib are shown in Figure 2A. The results for AUC (0–24), Cmax and t1/2 of cyclophosphamide for Day 5 of Cycle 1 and for Day 1 of Cycle 2 are given as individual and geometric mean values in Table 1B. Mean plasma concentrations of cyclophosphamide were consistently lower following concomitant administrations of sorafenib and letrozole compared with concomitant administration of letrozole alone (Figure 2B). This trend was confirmed by the comparison of corresponding AUC (0–24) and Cmax values from Day 5, Cycle 1 and Day 1 of Cycle 2. AUC (0–24) of cyclophosphamide was consistently lower in all subjects when both drugs were co-administered, on average by 29% (Table 1B). Cmax was also reduced in most subjects on Day 1 of Cycle 2 but to a lesser degree, on average by 12%. The decrease in AUC (0–24) was accompanied by a corresponding decrease in t1/2, on average by 27%. These data indicate that concomitant administration of sorafenib moderately decreases the exposure to cyclophosphamide.\n\nToxicity assessment\nWe did not observe particular haematological toxicity; only neutropenia grade 1–2 (38.5% of the cases) and grade 3 (7.7% of the cases). The non-haematological toxicity of letrozole and cyclophospamide in combination with sorafenib was mainly grade 1 or 2 as reported in Table 2. The most common drug-related grade 3–4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%), diarrhoea (46.1%). Examples of skin rash and hand-foot skin reaction are depicted in Figure 3A and B, respectively. Dosing interruptions or reductions due to an AE did not occur.\n\nResponse assessment by palpation, mammography and pathology\nComplete response by clinical palpation, evaluated at the end of treatment before definitive surgery, was observed in 6 out of 13 patients (46%), whereas partial response was observed in the remaining 7 patients (54%). Complete response by mammography was observed in 5 out of 13 patients (38.4%), whereas partial response was observed in the remaining 8 patients (61.6%) before definitive surgery. At the definitive surgery, we observed two patients with pT1b tumour, three patients with pT1c tumour, five patients with pT2 tumour, two patients with pT4b tumour, with 11 out of 13 patients having lymph node involvement. No change of tumour grading between the baseline sample and post-treatment samples was noted. None of the enrolled patients showed a post-treatment pathologic complete response.\n\nImaging assessment by MRI, FDG-PET and Modified CT criteria\nTumour response was assessed by an MRI scan at baseline and at 14 days of treatment (Figure 1B). Median tumour size evaluated by an MRI was 31 mm (range 17–90 mm) at baseline, 27 mm (range 11–90 mm) at day 14 with a small but statistically significant reduction in tumour size being observed in all 13 patients at day 14 (P=0.005).\n\nThe metabolic activity of the tumours was evaluated by a 18FDG -PET/CT scan at baseline (PET1), after 1 month of treatment (PET2) and at the end of the treatment before definitive surgery (PET3) for all 13 patients (Figures 1B, 4A and 4B). At PET1 the mean average SUVmax was 5.01 with a median of 4.5 (range 1.8–12). At PET 2 the mean average SUVmax was 2.39 with a median of 1.9 (range 0–4.5). At PET3 the mean average SUVmax was 0.71 with a median of 0 (range 0–3.9). In this series of patients we identified a significant reduction between PET1 and PET2 (P=0.015), between PET2 and PET3 (P=0.006) and between PET1 and PET3 (P=0.0002) (Figure 4B).\n\nWe also monitored the SUVmax in the lymph nodes. At baseline, 10 out of 13 patients presented a positive uptake suggesting tumour involvement of lymph nodes. After 1 month of treatment, seven patients showed a reduction in SUVmax values in the lymph nodes. By the end of treatment, all of the patients had a complete metabolic response in the lymph nodes and in the remaining patients the lymph nodes still showed lower metabolic activity compared with baseline. The average of the SUVmax at PET1 was 2.89 (median=2.50, range 1.1–7.1); at PET2 it was 1.52 (median=1.30, range 0–3.3) and at PET3 it was 0.17 (median=0, range 0–1.7). A significant reduction of SUVmax in the lymph nodes was therefore observed between PET1 and PET2 (P=0.045), PET2 and PET3 (P=0.0008), and PET1 and PET3 (P=0.0002). Using the Modified CT Criteria (Choi et al, 2007), to evaluate response at 30 days and response just before surgery, our study showed response (CR or PR) in 8 patients and 2 patients with stable disease (n=10 evaluable patients) at 30 days and a response in 11 patients (n=11 evaluable patients) at definitive surgery (Table 3).\n\nAssessment of biological markers\nBiological markers were assessed in samples obtained at baseline, at 14 days and at definitive surgery (Figure 1B). Ki67 labelling index was assessable in 11 of the 13 patients, but there was insufficient tissue available for the remaining two patients. At baseline the mean average Ki67 index was 20.69% with median of 20% (range 8–36), at day 14 the mean was 10.64% with median of 10% (range 1–20) and at definitive surgery the mean was 11.38% with median of 7% (range 0–34) (Figure 5A). We observed a marked suppression of the Ki67 proliferation index after 14 days in the 11 patients that could be evaluated (P<0.00001), and there was a significant reduction in Ki67 index at definitive surgery compared with baseline (P=0.03). However, 4 patients out of the 11 evaluated showed an increase in Ki67 index at definitive surgery. At the end of treatment, these four patients showed a clinical partial response, which corresponded to a pT2 and pT4 at the pathology report. It is possible that these four patients experienced early-onset resistance to the therapeutic regimen.\n\nChange in expression of the angiogenesis-related markers CD31 and VEGF-A was also evaluated (Figure 5B). CD31 expression could be evaluated in 10 of the 13 patients at baseline (median expression=3, range 1–5), in 8 out of 13 at day 14 (median expression=1, range 1–3) and in 8 out of 13 at definitive surgery (median expression=1, range 1–3). The CD31 expression showed a significant reduction at day 14 (P=0.006) and at definitive surgery (P=0.01) compared with baseline. VEGF-A expression could be evaluated in 9 of the 13 patients at baseline (median expression=2, range 1–2), in 8 out of 13 at day 14 (median expression=1, range 1–3) and in 9 out of 13 at definitive surgery (median expression=1, range 1–3). No significant difference in VEGF-A expression was found between baseline and day 14, but a significant reduction at the definitive surgery compared with baseline was observed (P=0.007) (Figure 5B). A correlation was observed between the decrease in CD31 and the decrease in VEGF-A expression, both at day 14 (P<0.0001) and at the definitive surgery (P<0.0001).\n\nDiscussion\nEndocrine resistance presents a major challenge in the management of ER+ve breast cancer and is an area under intense investigation. Non-genomic cross-talk between ER and growth factor receptors can activate intracellular signalling cascades involved in oestrogen-independent growth, such as the Ras-Raf-mitogen-activated protein kinase (MAPK) (Massarweh et al, 2008) and the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathways (Johnston et al, 2005). Moreover, both MAPK and AKT can directly enhance the classic genomic transcriptional activity of ER in the absence of oestrogens (Le Goff et al, 1994) further contributing to endocrine resistance. It has been shown that letrozole-based treatment is able to significantly reduce PI3K and phospho-mTOR expression (Generali et al, 2008) and that HIF-1alpha and p44/42 MAPK expression is independent factor for endocrine resistance in neoadjuvant setting (Generali et al, 2009). These data suggest that targeting these pathways could potentiate the aromatase inhibitor effect, preventing or postponing the onset of endocrine resistance. Therefore, combined inhibition of the oestroge pathway and growth factor signalling represents an attractive target for pharmacological intervention. Sorafenib is an oral multikinase inhibitor, capable of inhibiting mTOR signalling and HIF-1alpha expression (Kumar et al, 2007; Huynh et al, 2009) or MAPK expression and related proliferation proteins (Keswani et al, 2008). Our previous in vitro experiments with the combination of letrozole and sorafenib demonstrated a potential role for this combination in the treatment of hormone-dependent BC cells (Bonelli et al, 2010). However, to date, the combination of sorafenib with letrozole and metronomic administration of cyclophosphamide has never been tested in a clinical setting. We have therefore investigated the pharmacology, toxicity and efficacy of this regimen in primary breast cancer patients.\n\nPharmacokinetic analysis showed there was no impact of the combination regimen on the circulating levels of sorafenib in patients. Moreover, the analysis of the pharmacokinetic data showed that there was no relevant impact of sorafenib (400 mg BID) on the pharmacokinetics of cyclophosphamide when these compounds were co-administered. However, the data do indicate that concomitant sorafenib moderately decreased the exposure (Cmax and AUC0–24) to cyclophosphamide, without being influenced by the sorafenib total dose. Indeed it is recognised that cyclophosphamide is a potent inducer of microsomal enzymes and is able to increase levels of CYP2C8, 2C9 and 3A4 inducing its own metabolism (Chang et al, 1997). As previously shown, a similar induction by cyclophosphamide of human CYP2B6 and 3A4 enzyme expression occurs (Gervot et al, 1999; Lindley et al, 2002). This auto-induction in cyclophosphamide metabolism is detectable within 24 h after the start of the treatment and might explain the reduction of cyclophosphamide plasma concentrations. However, further investigation in a larger population of cancer patients and a more accurate evaluation of all cyclophosphamide-derived metabolites is warranted.\n\nThe metronomic administration of chemotherapy compounds is a good treatment option for breast cancer patients, has a low-toxicity profile and high efficacy in most patients (Montagna et al, 2014). We previously demonstrated that co-administration of endocrine therapy with the metronomic administration of cyclophosphamide is well tolerated without any particular adverse events (Bottini et al, 2006).\n\nIn the current study, we show that sorafenib administered with cyclophosphamide and letrozole had a safety profile consistent with that of the individual agents in patients with breast cancer. The most common toxicities were skin rash, hand-foot skin reaction and diarrhea Although all are reported to be associated with sorafenib (Gomez & Lacouture, 2011), it is difficult to determine whether sorafenib was the sole agent responsible for the relative high incidence of these events among the enrolled patients. Across three phase 2 randomised studies where advanced breast cancer patients were treated with sorafenib in combination with chemotherapy (Baselga et al, 2012; Gradishar et al, 2013; Schwartzberg et al, 2013), the incidence of hand-foot syndrome, rash and diarrhea was 31–44, 2–4 and 3–6%, respectively. By comparison, the incidence of hand-foot syndrome (69.3%), rash (69.3%) and diarrhea (46.1%) was elevated in our study. On the contrary, the incidence of other grade 3/4 toxicities reported in our study, such as fatigue and neutropenia, was similar to those reported in these previous studies that combined chemotherapy with sorafenib. However, despite this incidence of toxicity, in our experience the timely detection of adverse events in patients helps to mitigate their clinical consequences.\n\nIt is also of interest to compare the toxicity profile of LCS with a previous study that combined endocrine therapy with sorafenib in breast cancer. Isaacs et al (2011) reported a phase I/II study that employed a combination of sorafenib and anastrazole in patients with metastatic breast cancer. In that study, 77% of patients required dose reductions of sorafenib and 31% came off study due to toxicity. The most common grade 3/4 toxicities were hand-foot syndrome (34%), fatigue (17%), rash (11%), emesis (11%) and hypertension (11%). Among the 35 women enrolled into that phase I/II trial, 46% had an ECOG ⩾1, 23% had visceral metastasis, 43% had bone metastasis and all had received one or two lines of previous therapy. In contrast, the women enrolled in our study were naive of any treatment and without any visceral/bone involvement. These differences in the patient populations may explain the different toxicity profile reported by our group in comparison with the study by Isaacs et al (2011).\n\nClinical anti-cancer activity (complete and partial responses) was observed in all patients. This was objectively confirmed by the 18FDG-PET/CT scan, with decreased SUVmax values observed in all 13 patients after treatment. However, FDG PET/CT failed to detect 11 instances of isolated tumour cells, micro-embolic or plural-embolic in axillary nodes, which were reported in the definitive pathological report. In some studies the role of FDG PET/CT in the axillary staging of breast cancer has been questioned with FDG PET/CT proving to have poor sensitivity compared with immunohistochemistry on lymph nodes biopsy in which multistep sectioning is commonly used to identify axillary micrometastases (that is, clusters of malignant cells >0.2 mm to ⩽2.0 mm in diameter) (Guller et al, 2002; Kelemen et al, 2002; van der Hoeven et al, 2002). Thus, the limited spatial resolution of the current FDG PET/CT scanners in comparison with the more accurate pathological examination techniques is a reason for these modest results of PET in the detection of micro-metastases.\n\nThe Ki67 labelling index after 2 weeks of therapy and at definitive surgery was significantly lower than the labelling index at the baseline for eight patients. In particular, we noticed that the reduction of Ki67 expression was greater between the beginning and the end of the treatment than after 15 days of treatment. Taken together, these data suggest that the tried and tested letrozole-cyclophosphamide combination (Bottini et al, 2006) with sorafenib is promising in terms of metabolic activity and suppression proliferation index. Of note, however, are four patients that did not show a reduction in tumour proliferation activity at the end of the treatment. As previously described by Dowsett et al (2005), this might be an indicator of endocrine resistance. However, Ki67 may not be the most reliable indicator of tumour cell proliferation. As Dowsett et al (2005) have proposed, to better investigate the anti-proliferative effect of therapy, it might be more appropriate to analyse other indices of cell proliferation, such as S phase markers or MCM2.\n\nPrevious reports showed the metronomic schedule is able to modulate several factors, such as VEGF-A, circulating endothelial cells and fibroblast growth factor 2, which are all involved in remodelling of cancer vessels (Mancuso et al, 2006; Calleri et al, 2009; Isaacs et al, 2011). Our group has shown that the combination of letrozole and metronomic cyclophosphamide has an anti-angiogenic effect with a significant reduction of VEGF-A after 6 months of neoadjuvant treatment (Bottini et al, 2006). Here we investigated the expression of two robust markers, CD31 and VEGF-A, supported also by published data on their modulation and their correlation with treatment response to bevacizumab (Yang et al, 2008). The expression of CD31 and VEGF-A was significantly decreased after treatment, supporting the contention that the administered regimen has an anti-angiogenic effect in primary BC.\n\nIn this study, we also used the breast MRI technique as a more accurate method than breast ultrasound and mammography or clinical palpation (Bodini et al, 2004) in evaluating the disease response to therapy and because of its ability to delineate anatomic detail of breast cancers. In our study, there was only a modest evidence of significant changes in tumour dimensions after 14 days of treatment, maybe due to the short interval between the two evaluations. In the future, it would be preferable to perform the breast MRI at time points further into treatment to monitor properly any differences in clinical response induced by the treatment (Bodini et al, 2004). Moreover, improvements in an MRI technology for the monitoring of blood-flow as a marker of tumour angiogenesis (Mehta et al, 2011) are warranted in future trials containing anti-angiogenic drugs such as sorafenib and or metronomic cyclophosphamide.\n\nIn conclusion, the addition of sorafenib to the already tested letrozole-cyclophosphamide combination was associated with a clinical response, a significant decrease in tumour metabolic activity, in proliferation index and in angiogenesis in patients with hormone receptor positive primary breast cancer. Conceivably, this benefit may be due to the ability of sorafenib to overcome resistance to endocrine therapy and/or the increased anti-angiogenic activity when sorafenib is combined with the metronomic administration of cyclophosphamide.\n\nThis study was partly funded by the FIRM (Fondazione Internazionale per la Ricerca In Medicina), Cremona, Italy. Dr Reynolds acknowledges support from Breakthrough Breast Cancer.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nThe authors have declared no conflict of interest.\n\nFigure 1 (A) Schematics illustrating the design of the study. (B) Pharmacodynamic profile of the study.\n\nFigure 2 Pharmaockinetics of sorafenib and cyclophosphamide. (A) Plasma concentrations of sorafenib following multiple doses of 400 mg per b.i.d. sorafenib in combination with 50 mg of cyclophosphamide and 2.5 mg of letrozole on Day 1 of Cycle 2 (geometric means, geometric s.d.; n=13). (B) Plasma concentrations of cyclophosphamide (*) following multiple doses of 50 mg of cyclophosphamide in combination with 2.5 mg of letrozole without (Day 5, Cycle 1) and after concomitant treatment (Day 1, Cycle 2) with multiple oral doses of 400 mg per b.i.d. sorafenib (G.M.=geometric means, G.s.d.= geometric standard deviation; n=13) *More than one-third of individual plasma concentrations were below LLOQ at 24 h after dosing on both profile days. No corresponding geometric mean concentrations was calculated.\n\nFigure 3 Common drug-related adverse events. (A) Grade 2 skin rash. (B) Grade 2 hand-foot syndrome. Both of these reactions are adverse events related to the treatment with sorafenib.\n\nFigure 4 Measurment of responses with 18FDG PET/CT imaging. (A) Example images of 18FDG PET/CT scan obtained from the same patient before (PET1) and after treatment (PET3). A change in the metabolic activity of the tumour between baseline and end of the treatment is clearly observed. (B) Tumour SUVmax values by the 18FDG PET/CT scan. The trend of the tumour metabolic activity during treatment for each patient. A significant reduction in SUVmax has been quantified in all thirteen patients from baseline to the definitive surgery (P-value: between PET1 and PET2 (P=0.015), between PET2 and PET3, (P=0.006) and between PET1 and PET3 (P=0.0002)).\n\nFigure 5 Analysis of molecular markers. (A) Ki67 labelling index at baseline, day 14 and at the definitive surgery. Proliferation trend is reported for each patient. A significant reduction in mean average proliferation index is observed between baseline and day 14 (P=0.00001) and between baseline and end of treatment (P=0.031). (B) Immunohistochemistry demonstrating the expression of angiogenesis-related markers (CD31 and VEGF-A) in pre-treatment and post-treatment samples.\n\nTable 1A Preliminary pharmacokinetic parameters of sorafenib following multiple doses of 400 mg per b.i.d. sorafenib in combination with 50 mg of cyclophosphamide and 2.5 mg of letrozole on Day 1 of Cycle 2\nPatient\nNo.\tAUC(0–12) (mg h l−1)\tCmax\n(mg l−1)\t\n1\t80.2\t8.40\t\n2\t101\t10.7\t\n3\t263\t23.2\t\n5\t45.7\t4.98\t\n6\t56.0\t5.73\t\n7\t86.8\t11.4\t\n8\t103\t11.6\t\n9\t46.3\t6.10\t\n10\t79.0\t9.00\t\n11\t113\t16.4\t\n12\t41.7\t4.22\t\n13\t94.5\t17.6\t\nGeometric mean\t82.7\t9.77\t\nGeometric s.d.\t1.64\t1.68\t\nTable 1B Preliminary pharmacokinetic parameters of cyclophosphamide following multiple doses of 50 mg od cyclophosphamide in combination of 2.5 mg of letrozole without (Day 5, Cycle 1) and after concomitant treatment (Day 1, Cycle 2) with multiple oral doses of 400 mg bid sorafenib\n \tAUC(0–24) (mg h l−1)\tCmax\n(mg l−1)\tt1/2\n(h)\t\nPatient\nNo.\tCycle 1\tCycle 2\tRatio cycles 2/1\tCycle 1\tCycle 2\tRatio cycles 2/1\tCycle 1\tCycle 2\t\n1\t22.4\t21.4\t0.96\t1.86\t1.89\t1.02\t13.7\t9.86\t\n2\t20.1\t12.1\t0.60\t2.28\t1.61\t0.71\t7.56\t4.74\t\n3\t19.7\t10.7\t0.54\t1.91\t1.13\t0.59\t8.13\t7.41\t\n5\t6.58\t5.51\t0.84\t1.57\t1.43\t0.91\t3.25\t3.10\t\n6\t19.8\t14.4\t0.73\t2.60\t2.29\t0.88\t8.46\t6.83\t\n7\t12.0\t7.99\t0.67\t1.56\t1.44\t0.92\t6.16\t4.52\t\n8\t16.6\t12.9\t0.78\t2.19\t2.67\t1.22\t7.25\t5.04\t\n9\t21.1\t17.8\t0.84\t2.20\t2.12\t0.96\t8.76\t7.15\t\n10\t19.3\t17.1\t0.89\t1.98\t1.80\t0.91\t9.27\t7.29\t\n11\t35.2\t21.2\t0.60\t2.74\t1.99\t0.73\t13.8\t8.88\t\n12\t14.9\t10.2\t0.68\t1.72\t1.48\t0.86\t5.81\t3.69\t\n13\t11.7\t8.17\t0.70\t2.07\t1.90\t0.92\t5.84\t3.92\t\nMeana\t16.7\t11.9\t0.71\t2.01\t1.77\t0.88\t7.39\t5.43\t\nS.d.b\t1.50\t1.52\t1.20\t1.19\t1.26\t1.20\t1.48\t1.47\t\na Geometric means.\n\nb Geometric s.d.\n\nTable 2 Adverse Events\nAdverse Events\tGrade 1 or 2\tGrade 3 or 4\t\nHand-foot syndrome\t4 (30.7%)\t9 (69,3%)\t\nFatigue\t4 (30.7%)\t1 (7.7%)\t\nRash\t4 (30.7%)\t9 (69.3%)\t\nEmesis\t0\t0\t\nHypertension\t2 (15.4%)\t0\t\nNausea\t0\t0\t\nArthralgias\t3 (23%)\t0\t\nDiarrhea\t2 (15.4%)\t6 (46.1%)\t\nDehydration\t4 (30.7%)\t2 (23%)\t\nInfection\t0\t0\t\nAnorexia\t4 (30.7%)\t0\t\nHeadache\t1 (7.7%)\t0\t\nMucositis\t2 (15.4%)\t0\t\nElevated liver function tests\t0\t0\t\nRigors/chills\t1 (7.7%)\t0\t\nJoint function\t3 (23%)\t1 (7.7%)\t\nNeutropenia\t5 (38.5%)\t1 (7.7%)\t\nDyspnea\t0\t0\t\nAcne\t3 (23%)\t1 (7.7%)\t\nHypotension\t0\t0\t\nHypophosphatemia\t0\t0\t\nAlopecia\t10 (76.9%)\t0\t\nSensory neuropathy\t5 (38.5%)\t0\t\nWeight loss\t5 (38.5%)\t0\t\nTable 3 Response scored using Modified CT Criteria\n \tNumber of patients (%)\t\n \tCR\tPR\tSD\tPD\t\n30 days time pointa\t1\t7\t2\t0\t\nDefinitive surgery time pointb\t7\t4\t0\t0\t\nAbbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.\n\na (n=13 patients; in 3 out of 13 patients data were not available).\n\nb (n=13 patients; in 2 out of 13 patients data were not available).\n==== Refs\nAlbain KS Barlow WE Ravdin PM Farrar WB Burton GV Ketchel SJ Cobau CD Levine EG Ingle JN Pritchard KI Lichter AS Schneider DJ Abeloff MD Henderson IC Muss HB Green SJ Lew D Livingston RB Martino S Osborne CK Breast Cancer Intergroup of North A 2009 Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial Lancet 374 (97072055 2063 20004966 \nBaselga J Segalla JG Roche H Del Giglio A Pinczowski H Ciruelos EM Filho SC Gomez P Van Eyll B Bermejo B Llombart A Garicochea B Duran MA Hoff PM Espie M de Moraes AA Ribeiro RA Mathias C Gil Gil M Ojeda B Morales J Kwon Ro S Li S Costa F 2012 Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer J Clin Oncol 30 (131484 1491 22412143 \nBodini M Berruti A Bottini A Allevi G Fiorentino C Brizzi MP Bersiga A Generali D Volpi D Marini U Aguggini S Tampellini M Alquati P Olivetti L Dogliotti L 2004 Magnetic resonance imaging in comparison to clinical palpation in assessing the response of breast cancer to epirubicin primary chemotherapy Breast Cancer Res Treatment 85 (3211 218 \nBonelli MA Fumarola C Alfieri RR La Monica S Cavazzoni A Galetti M Gatti R Belletti S Harris AL Fox SB Evans DB Dowsett M Martin LA Bottini A Generali D Petronini PG 2010 Synergistic activity of letrozole and sorafenib on breast cancer cells Breast Cancer Res Treatment 124 (179 88 \nBottini A Generali D Brizzi MP Fox SB Bersiga A Bonardi S Allevi G Aguggini S Bodini G Milani M Dionisio R Bernardi C Montruccoli A Bruzzi P Harris AL Dogliotti L Berruti A 2006 Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients J Clin Oncol 24 (223623 3628 16877730 \nCalleri A Bono A Bagnardi V Quarna J Mancuso P Rabascio C Dellapasqua S Campagnoli E Shaked Y Goldhirsch A Colleoni M Bertolini F 2009 Predictive potential of angiogenic growth factors and circulating endothelial cells in breast cancer patients receiving metronomic chemotherapy plus bevacizumab Clin Cancer Res 15 (247652 7657 19996223 \nChang TK Yu L Maurel P Waxman DJ 1997 Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines Cancer Res 57 (101946 1954 9157990 \nChoi H Charnsangavej C Faria SC Macapinlac HA Burgess MA Patel SR Chen LL Podoloff DA Benjamin RS 2007 Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria J Clin Oncol 25 (131753 1759 17470865 \nDowsett M Smith IE Ebbs SR Dixon JM Skene A Griffith C Boeddinghaus I Salter J Detre S Hills M Ashley S Francis S Walsh G Trialists I 2005 Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival Clin Cancer Res 11 (2 Pt 2951s 958ss 15701892 \nGenerali D Buffa FM Berruti A Brizzi MP Campo L Bonardi S Bersiga A Allevi G Milani M Aguggini S Papotti M Dogliotti L Bottini A Harris AL Fox SB 2009 Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer J Clin Oncol 27 (2227 234 19064988 \nGenerali D Fox SB Brizzi MP Allevi G Bonardi S Aguggini S Milani M Bersiga A Campo L Dionisio R Vergoni F Giardini R Dogliotti L Bottini A Harris AL Berruti A 2008 Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer Clin Cancer Res 14 (92673 2680 18451231 \nGervot L Rochat B Gautier JC Bohnenstengel F Kroemer H de Berardinis V Martin H Beaune P de Waziers I 1999 Human CYP2B6: expression, inducibility and catalytic activities Pharmacogenetics 9 (3295 306 10471061 \nGligorov J Azria D Namer M Khayat D Spano JP 2007 Novel therapeutic strategies combining antihormonal and biological targeted therapies in breast cancer: focus on clinical trials and perspectives Crit Rev Oncol Hematol 64 (2115 128 17702596 \nGomez P Lacouture ME 2011 Clinical presentation and management of hand-foot skin reaction associated with sorafenib in combination with cytotoxic chemotherapy: experience in breast cancer Oncologist 16 (111508 1519 22016478 \nGradishar WJ Kaklamani V Sahoo TP Lokanatha D Raina V Bondarde S Jain M Ro SK Lokker NA Schwartzberg L 2013 A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer Eur J Cancer 49 (2312 322 22954665 \nGuller U Nitzsche EU Schirp U Viehl CT Torhorst J Moch H Langer I Marti WR Oertli D Harder F Zuber M 2002 Selective axillary surgery in breast cancer patients based on positron emission tomography with 18F-fluoro-2-deoxy-D-glucose: not yet! Breast Cancer Res Treatment 71 (2171 173 \nHuynh H Ngo VC Koong HN Poon D Choo SP Thng CH Chow P Ong HS Chung A Soo KC 2009 Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma J Cell Mol Med 13 (8B2673 2683 19220580 \nIsaacs C Herbolsheimer P Liu MC Wilkinson M Ottaviano Y Chung GG Warren R Eng-Wong J Cohen P Smith KL Creswell K Novielli A Slack R 2011 Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aromatase inhibitor resistant metastatic breast cancer Breast Cancer Res Treatment 125 (1137 143 \nIyer R Fetterly G Lugade A Thanavala Y 2010 Sorafenib: a clinical and pharmacologic review Expert Opin Pharmacother 11 (111943 1955 20586710 \nJohnston SR Martin LA Head J Smith I Dowsett M 2005 Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance J Steroid Biochem Mol Biol 95 (1-5173 181 15996863 \nJohnston SR Martin LA Leary A Head J Dowsett M 2007 Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer J Steroid Biochem Mol Biol 106 (1-5180 186 17624764 \nKelemen PR Lowe V Phillips N 2002 Positron emission tomography and sentinel lymph node dissection in breast cancer Clin Breast Cancer 3 (173 77 12020398 \nKeswani RN Chumsangsri A Mustafi R Delgado J Cohen EE Bissonnette M 2008 Sorafenib inhibits MAPK-mediated proliferation in a Barrett's esophageal adenocarcinoma cell line Dis Esophagus 21 (6514 521 18840136 \nKoukourakis MI Giatromanolaki A Sivridis E Gatter KC Harris AL Tumour, Angiogenesis Research G 2005 Inclusion of vasculature-related variables in the Dukes staging system of colon cancer Clin Cancer Res 11 (24 Pt 18653 8660 16361550 \nKumar SM Yu H Edwards R Chen L Kazianis S Brafford P Acs G Herlyn M Xu X 2007 Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma Cancer Res 67 (73177 3184 17409425 \nLe Goff P Montano MM Schodin DJ Katzenellenbogen BS 1994 Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity J Biol Chem 269 (64458 4466 8308015 \nLindley C Hamilton G McCune JS Faucette S Shord SS Hawke RL Wang H Gilbert D Jolley S Yan B LeCluyse EL 2002 The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes Drug Metab Dispos 30 (7814 822 12065440 \nMancuso P Colleoni M Calleri A Orlando L Maisonneuve P Pruneri G Agliano A Goldhirsch A Shaked Y Kerbel RS Bertolini F 2006 Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy Blood 108 (2452 459 16543470 \nMassarweh S Osborne CK Creighton CJ Qin L Tsimelzon A Huang S Weiss H Rimawi M Schiff R 2008 Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function Cancer Res 68 (3826 833 18245484 \nMehta S Hughes NP Buffa FM Li SP Adams RF Adwani A Taylor NJ Levitt NC Padhani AR Makris A Harris AL 2011 Assessing early therapeutic response to bevacizumab in primary breast cancer using magnetic resonance imaging and gene expression profiles J Natl Cancer Inst Monogr 2011 (4371 74 22043045 \nMontagna E Cancello G Dellapasqua S Munzone E Colleoni M 2014 Metronomic therapy and breast cancer: A systematic review Cancer Treatment Rev 40 (8942 950 \nNicholson RI Hutcheson IR Hiscox SE Knowlden JM Giles M Barrow D Gee JM 2005 Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer Endocr Relat Cancer 12 (Suppl 1S29 S36 16113097 \nNicholson RI Hutcheson IR Knowlden JM Jones HE Harper ME Jordan N Hiscox SE Barrow D Gee JM 2004 Nonendocrine pathways and endocrine resistance: observations with antiestrogens and signal transduction inhibitors in combination Clin Cancer Res 10 (1 Pt 2346S 354SS 14734490 \nOsborne CK Kitten L Arteaga CL 1989 Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens J Clin Oncol 7 (6710 717 2715802 \nOsborne CK Shou J Massarweh S Schiff R 2005 Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer Clin Cancer Res 11 (2 Pt 2865s 870ss 15701879 \nPasquier E Kavallaris M Andre N 2010 Metronomic chemotherapy: new rationale for new directions Nat Rev Clin Oncol 7 (8455 465 20531380 \nSchwartzberg LS Tauer KW Hermann RC Makari-Judson G Isaacs C Beck JT Kaklamani V Stepanski EJ Rugo HS Wang W Bell-McGuinn K Kirshner JJ Eisenberg P Emanuelson R Keaton M Levine E Medgyesy DC Qamar R Starr A Ro SK Lokker NA Hudis CA 2013 Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab Clin Cancer Res 19 (102745 2754 23444220 \nSmith IE Dowsett M 2003 Aromatase inhibitors in breast cancer N Engl J Med 348 (242431 2442 12802030 \nStrumberg D Clark JW Awada A Moore MJ Richly H Hendlisz A Hirte HW Eder JP Lenz HJ Schwartz B 2007 Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors Oncologist 12 (4426 437 17470685 \nStrumberg D Richly H Hilger RA Schleucher N Korfee S Tewes M Faghih M Brendel E Voliotis D Haase CG Schwartz B Awada A Voigtmann R Scheulen ME Seeber S 2005 Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors J Clin Oncol 23 (5965 972 15613696 \nvan der Hoeven JJ Hoekstra OS Comans EF Pijpers R Boom RP van Geldere D Meijer S Lammertsma AA Teule GJ 2002 Determinants of diagnostic performance of [F-18]fluorodeoxyglucose positron emission tomography for axillary staging in breast cancer Ann Surg 236 (5619 624 12409668 \nYang SX Steinberg SM Nguyen D Wu TD Modrusan Z Swain SM 2008 Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer Clin Cancer Res 14 (185893 5899 18794102\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "112(1)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D059250:Administration, Metronomic; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009536:Niacinamide; D009570:Nitriles; D010671:Phenylurea Compounds; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D014230:Triazoles",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "52-60",
"pmc": null,
"pmid": "25461806",
"pubdate": "2015-01-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16543470;17470685;19996223;22412143;15111758;20531380;17409425;15701879;18794102;18451231;24998489;17624764;10471061;14734490;12409668;12020398;11881913;15613696;20004966;18245484;16361550;19064988;22016478;22043045;16113097;15701892;18840136;15996863;20586710;20976541;9157990;17702596;8308015;12065440;16877730;17470865;2715802;22954665;12802030;20054642;23444220;19220580",
"title": "Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer.",
"title_normalized": "combination of letrozole metronomic cyclophosphamide and sorafenib is well tolerated and shows activity in patients with primary breast cancer"
} | [
{
"companynumb": "IT-BAYER-2014-184880",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"... |
{
"abstract": "We report the case of a young adult who became unresponsive after insufflating what he believed to be \"crushed Xanax.\" Naloxone was administered, reversing his altered mental status and respiratory depression. Clinicians suspected opioid toxicity; however, the patient adamantly denied opioid use. Because of unclear etiology of his symptoms, blood and urine specimens were obtained. A urine specimen was split and then submitted for a clinical comprehensive drug screen using gas chromatography-mass spectrometry. The blood specimen and the remaining urine specimen were sent to a reference laboratory for analysis using liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry. The standard, clinical gas chromatography-mass spectrometry urine drug testing procedure only detected caffeine; however, analysis by liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry confirmed the presence of U-47700 (a high-potency clandestine opioid) and its metabolites in the urine and blood. These findings implicate U-47700 as the agent responsible for the patient's signs of opioid toxicity. In this case, a young adult intending to use alprazolam encountered U-47700 with life-threatening effect. Clinicians must remain vigilant for symptoms consistent with opioid overdose, especially with increasing prevalence of counterfeit drugs containing clandestine opioids. Clinicians must also consider obtaining specimens for appropriate analytical testing to improve surveillance and facilitate public health interventions.",
"affiliations": "From the Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA.;From the Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA.;Center for Forensic Science Research and Education at the Fredric Rieders Family Foundation, Willow Grove, PA.;Center for Forensic Science Research and Education at the Fredric Rieders Family Foundation, Willow Grove, PA.;Department of Emergency Medicine, Hartford Hospital, Hartford, CT.;Center for Forensic Science Research and Education at the Fredric Rieders Family Foundation, Willow Grove, PA.;From the Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA.",
"authors": "Chapman|Brittany P|BP|;Lai|Jeffrey T|JT|;Krotulski|Alex J|AJ|;Fogarty|Melissa F|MF|;Griswold|Matthew K|MK|;Logan|Barry K|BK|;Babu|Kavita M|KM|",
"chemical_list": "D000701:Analgesics, Opioid; D001549:Benzamides; C000614521:U-47700; D000525:Alprazolam",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001775",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "37(9)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000525:Alprazolam; D000701:Analgesics, Opioid; D001549:Benzamides; D062787:Drug Overdose; D006801:Humans; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e579-e580",
"pmc": null,
"pmid": "30789871",
"pubdate": "2021-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Unintentional Opioid (U-47700) Overdose in a Young Adult After Counterfeit Xanax Use.",
"title_normalized": "a case of unintentional opioid u 47700 overdose in a young adult after counterfeit xanax use"
} | [
{
"companynumb": "US-PFIZER INC-2019087128",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "Composite lymphoma is defined as the co-occurrence of two types of lymphoma, comprising 1-4% of lymphomas, and the association of B-cell-type chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma and peripheral T-cell lymphoma (PTCL) is rare. Here, we report a case (77-year-old woman) of advanced B-CLL complicated by newly appearing PTCL. Two years after the onset of B-CLL, CLL cells acquired CD38 antigen expression and the disease entity became CLL/prolymphocytic leukemia. Trisomy 12 and t(14;18) karyotypes were observed. Five years after the onset of B-CLL, large abnormal cells with convoluted nuclei appeared in the peripheral blood and rapidly increased in number. These cells were positive for CD3, CD4, CD5, CD30 (partially), CD56, and αβ-type T-cell receptor (TCR), in which PCR demonstrated monoclonal TCR-γ gene rearrangement. An additional diagnosis of PTCL, not otherwise specified was made. We treated her with an R-CHOP regimen, resulting in the marked reduction of B-CLL cells but progressive PTCL. Brentuximab vedotin had a transient effect, but the patient died of sepsis due to residual PTCL and pancytopenia. This case is highly informative for tumor biology of B-CLL in terms of emergence of both chromosomal abnormalities and PTCL with progression of this leukemia.",
"affiliations": "Departments of Hematology and.;Departments of Hematology and.;Cell Therapy, Shinko Hospital, and.;Departments of Hematology and.;Departments of Hematology and.;Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.;Departments of Hematology and.",
"authors": "Aoyama|Yumi|Y|;Kodaka|Taiichi|T|;Zushi|Yuriko|Y|;Goto|Yuta|Y|;Tsunemine|Hiroko|H|;Itoh|Tomoo|T|;Takahashi|Takayuki|T|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D009363:Neoplasm Proteins; C571759:R-CHOP protocol; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.17033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4280",
"issue": "58(1)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "18) (q32; B-cell-type chronic lymphocytic leukemia, composite lymphoma, t(14; q21), trisomy 12, peripheral T-cell lymphoma",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D000971:Antineoplastic Combined Chemotherapy Protocols; D002881:Chromosomes, Human, Pair 12; D003520:Cyclophosphamide; D004317:Doxorubicin; D017809:Fatal Outcome; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male; D009363:Neoplasm Proteins; D016609:Neoplasms, Second Primary; D011241:Prednisone; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069283:Rituximab; D014314:Trisomy; D014750:Vincristine",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "27-31",
"pmc": null,
"pmid": "29415977",
"pubdate": "2018-03-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10975943;12456221;15223953;1643016;19963136;23318849;24288111;24418862;24616310;25186047;25288894;27123263;28105149;3463362;9798660",
"title": "Composite Lymphoma as Co-occurrence of Advanced Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Carrying Trisomy 12 and t(14;18) and Peripheral T-cell Lymphoma.",
"title_normalized": "composite lymphoma as co occurrence of advanced chronic lymphocytic leukemia small lymphocytic lymphoma carrying trisomy 12 and t 14 18 and peripheral t cell lymphoma"
} | [
{
"companynumb": "JP-SEATTLE GENETICS-2018SGN00266",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BRENTUXIMAB VEDOTIN"
},
"drugadditiona... |
{
"abstract": "Conventional treatment strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT) include avoidance of strenuous exercise and competitive sports, drugs such as ß-blockers and flecainide and, cervical sympathectomy. An implantable cardioverter-defibrillator (ICD) has been utilized if the response to these strategies is inadequate; however, ICD use in CPVT patients, in addition to usual complications, is associated with an increased risk of life-threatening electrical storm. Ivabradine is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 generated funny current (If ), which has been shown to be efficacious in suppression of inappropriate sinus tachycardia, junctional tachycardia, atrial tachycardia, and ventricular ectopy in humans. We report an 18-year-old male with a severe CPVT phenotype refractory to flecainide, nadolol, and sympathectomy who exhibited suppression of ventricular arrhythmias after initiation of ivabradine. These findings are of importance as ivabradine could be an important add-on therapy in CPVT patients who are drug refractory or are unable to continue conventional therapies at the recommended doses.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatrics, Comer Children's Hospital and the Pritzker School of Medicine of the University of Chicago, Chicago, Illinois.;Center for Arrhythmia Care, Heart and Vascular Center, Pritzker School of Medicine of the University of Chicago, Chicago, Illinois.;Center for Arrhythmia Care, Heart and Vascular Center, Pritzker School of Medicine of the University of Chicago, Chicago, Illinois.;Center for Arrhythmia Care, Heart and Vascular Center, Pritzker School of Medicine of the University of Chicago, Chicago, Illinois.",
"authors": "Kohli|Utkarsh|U|0000-0003-3410-840X;Aziz|Zaid|Z|;Beaser|Andrew D|AD|;Nayak|Hemal M|HM|",
"chemical_list": "D002317:Cardiovascular Agents; D000077550:Ivabradine; D009248:Nadolol; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1111/pace.13913",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-8389",
"issue": "43(5)",
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": "RYR2 exon 3 deletion; catecholaminergic polymorphic ventricular tachycardia; drug and sympathectomy refractory; ivabradine; malignant syncope",
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": "D000293:Adolescent; D002317:Cardiovascular Agents; D004562:Electrocardiography; D005080:Exercise Test; D005424:Flecainide; D006801:Humans; D000077550:Ivabradine; D008297:Male; D009248:Nadolol; D010641:Phenotype; D013562:Sympathectomy; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "7803944",
"other_id": null,
"pages": "527-533",
"pmc": null,
"pmid": "32259298",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy.",
"title_normalized": "ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol flecainide and sympathectomy"
} | [
{
"companynumb": "US-VGYAAN PHARMACEUTICALS LLC-2086593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NADOLOL"
},
"drugadditional": nul... |
{
"abstract": "The aims of this study were to assess the safety and tolerability of nanoparticle albumin bound paclitaxel (nab-paclitaxel), doxorubicin, and cyclophosphamide as combination therapy for breast cancer patients in the neoadjuvant setting and to assess the overall clinical response and pathologic complete response (pCR).\n\n\n\nTwenty-six women with newly diagnosed stage II to III histologically or cytologically proven adenocarcinoma of the breast with negative HER2 status were enrolled. Patients were treated with nab-paclitaxel 100 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 on day 1 and nab-paclitaxel 100 mg/m2 on day 8 in a 21-day cycle for 6 cycles total.\n\n\n\nMost adverse events attributed to treatment were decreased white blood cell count, neutropenia, anemia, thrombocytopenia, and lymphopenia with a median duration of 8 days. Fifteen of 23 (65.2%; 95% confidence interval [CI], 45.7%-84.6%) had a complete clinical response and 8 of 23 (34.7%; 95% CI, 15.2%-54.1%) had a partial clinical response for an overall clinical response rate of 100%. Thirteen of 23 patients (56.5%; 95% CI, 36.2%-76.7%) had a pCR. All 10 triple-negative breast cancer (TNBC) patients (100%) achieved a pCR.\n\n\n\nThe regimen of nab-paclitaxel, doxorubicin, and cyclophosphamide chemotherapy was well tolerated and resulted in high clinical as well as pathologic responses, particularly in TNBC.",
"affiliations": "Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;Department of Surgery, University of Utah, Salt Lake City, UT.;Department of Medicine, University of Utah, Salt Lake City, UT.;Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT.;Department of Surgery, University of South Alabama, Mitchell Cancer Institute, Mobile, AL.;Department of Surgery, University of South Alabama, Mitchell Cancer Institute, Mobile, AL.;Banner M.D. Anderson Cancer Center, Gilbert, AZ.;Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Department of Surgery, University of Arizona, Tucson, AZ.;Oncology Division, Department of Medicine, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Department of Surgery, University of South Alabama, Mitchell Cancer Institute, Mobile, AL; Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL. Electronic address: hung.khong@moffitt.org.",
"authors": "Werner|Theresa L|TL|;Ray|Abhijit|A|;Lamb|John G|JG|;VanBrocklin|Matthew|M|;Hueftle|Kristin|K|;Cohen|Adam L|AL|;Beck|Anna C|AC|;Buys|Saundra S|SS|;Dyess|Donna L|DL|;Butler|Thomas W|TW|;Dumlao|Theresa L|TL|;Neumayer|Leigh|L|;Khong|Hung T|HT|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2017.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "17(7)",
"journal": "Clinical breast cancer",
"keywords": "Estrogen receptor; Pathologic complete response (pCR); SPARC; Triple-negative breast cancer",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D011379:Prognosis",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "503-509",
"pmc": null,
"pmid": "28579139",
"pubdate": "2017-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Phase I Study of Neoadjuvant Chemotherapy With Nab-Paclitaxel, Doxorubicin, and Cyclophosphamide in Patients With Stage II to III Breast Cancer.",
"title_normalized": "a phase i study of neoadjuvant chemotherapy with nab paclitaxel doxorubicin and cyclophosphamide in patients with stage ii to iii breast cancer"
} | [
{
"companynumb": "US-JNJFOC-20171118807",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nHepatitis C virus (HCV) chronic infection affects 10% to 15% of patients with bipolar disorder. Patients with HCV infection and comorbid psychiatric illness pose a tremendous clinical and therapeutic challenge. The cases presented in this report illustrate several critical issues facing clinicians who manage patients with comorbid HCV infection and bipolar disorder.\n\n\nMETHODS\nFive cases are described in which patients with DSM-IV bipolar disorder were treated with interferon-alpha-based therapies and ribavirin to induce viral clearance of HCV. In all cases, the patients were treated using an integrated model of care, and the treatment decision was a consensus between the treating hepatologists and psychiatrists.\n\n\nRESULTS\nIn the first case, the patient had no significant neuropsychiatric adverse effects and had viral clearance. In 2 other cases, viral clearance of HCV was achieved through the delicate management of affective symptoms induced by interferon-alpha and ribavirin. Interferon-alpha and ribavirin treatment was halted due to mania and suicidal ideation in the 2 remaining cases.\n\n\nCONCLUSIONS\nThese cases suggest that patients with hepatitis C and bipolar disorder should be evaluated for HCV antiviral treatments, as these patients can receive and tolerate these treatments if assessed meticulously, observed carefully, and followed extensively during interferon-alpha and ribavirin treatment. This case series will hopefully spark a dialogue about when HCV antiviral treatment should be withheld or delayed in these difficult cases.",
"affiliations": "Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Md, USA. AlyRifai@mail.nih.gov",
"authors": "Rifai|Muhamad Aly|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4088/pcc.v08n0607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1523-5998",
"issue": "8(6)",
"journal": "Primary care companion to the Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "Prim Care Companion J Clin Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "100887410",
"other_id": null,
"pages": "361-6",
"pmc": null,
"pmid": "17245458",
"pubdate": "2006",
"publication_types": "D016428:Journal Article",
"references": "12399946;9435767;12407598;12485309;12505819;12505820;12540795;12618532;12763304;12773598;12823087;14521647;14597693;14623619;14697814;14728113;10962774;11484704;11739908;11758095;11852590;12030950;12078026;12085716;12145801;12297615;14992966;15057920;15107183;15317637;15466851;15488246;15554428;15569919;16086622;16603757;12407572",
"title": "Hepatitis C treatment of patients with bipolar disorder: a case series.",
"title_normalized": "hepatitis c treatment of patients with bipolar disorder a case series"
} | [
{
"companynumb": "US-ROCHE-1450437",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe report a 9-year follow-up of a child with refractory juvenile idiopathic arthritis (JIA) with associated uveitis in which tocilizumab proved to be effective in achieving disease control.\n\n\nMETHODS\nA 16-month child was diagnosed with JIA and at the age of 3 developed bilateral non-granulomatous anterior uveitis. Throughout the follow-up, the patient presented frequent joint and ocular flares. Refractory anterior uveitis and topical corticosteroid therapy resulted in the development of bilateral cataract and high intraocular pressure (IOP). The patient underwent multiple ocular surgeries along with corticosteroids, immunosuppressive therapy with Methotrexate and Adalimumab failing to reach disease control. Only after the introduction of Tocilizumab a lower disease activity was achieved.\n\n\nCONCLUSIONS\nManagement of JIA-associated uveitis is challenging and requires a close collaboration between paediatric rheumatologists and ophthalmologists. Clinical remission can be difficult to achieve. However, one should always pursuit JIA inactivity with IOP and inflammation control. This report supports Tocilizumab as a useful therapeutic option for JIA-associated uveitis.",
"affiliations": "Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.;Centro Hospitalar Vila Nova de Gaia/Espinho.",
"authors": "Sousa-Neves|Filipe|F|;Braga|Joana|J|;Teixeira|Sara|S|;Barge|Sidnei|S|;Fonseca|Sofia|S|;Meira|Dália|D|;Rodrigues|Lúcia|L|;Varandas|Rosário|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "44(2)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000843:Ankle Joint; D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile; D002386:Cataract; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007719:Knee Joint; D009798:Ocular Hypertension; D013997:Time Factors; D014606:Uveitis, Anterior",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "151-154",
"pmc": null,
"pmid": "31455751",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tocilizumab in refractory juvenile idiopathic arthritis with associated uveitis: a case report.",
"title_normalized": "tocilizumab in refractory juvenile idiopathic arthritis with associated uveitis a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1124907",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BU and CY is a common conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). I.v. BU is increasingly used in place of the oral formulation for conditioning. We compared the outcomes of 135 consecutively treated AML and myelodysplastic syndrome patients who underwent allogeneic HPCT at our institution with BUCY2 using oral (n=93) or i.v. (n=42) BU, without dose adjustment. The i.v. BU patients had a lower incidence of any severity of oral mucositis (3 versus 55%, P=0.002) and severe mucositis (3 versus 24%, P=0.005). Other post transplant outcomes were comparable between the groups. In all 26 i.v. BU and 33 oral BU patients are alive; however, the median follow-up was significantly longer for the oral BU group. One- and two-year non-relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 23% and 29%, respectively. One- and two-year relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 24% and 29%, respectively. Substituting i.v. for oral BU reduces variability in drug exposure and potentially improves toxicity as suggested by our finding of significantly less oral mucositis and decreased severity with i.v. BU.",
"affiliations": "Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic,9500 Euclid Avenue, Cleveland, OH 44195, USA. sobeckr@ccf.org",
"authors": "Sobecks|R M|RM|;Rybicki|L|L|;Yurch|M|M|;Kalaycio|M|M|;Dean|R|R|;Andresen|S|S|;Pohlman|B|B|;Duong|H|H|;Bolwell|B|B|;Copelan|E|E|",
"chemical_list": "D002066:Busulfan",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2011.167",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "47(5)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012008:Recurrence; D012189:Retrospective Studies; D013280:Stomatitis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "633-8",
"pmc": null,
"pmid": "21874055",
"pubdate": "2012-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS.",
"title_normalized": "intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for aml and mds"
} | [
{
"companynumb": "US-OTSUKA-US-2015-11441",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
... |
{
"abstract": "Soma (Carisoprodol) is N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; a commonly prescribed, centrally acting skeletal muscle relaxant. Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of antipsychotic agents. Although diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur and more flexible diagnostic criteria than currently mandated, may be warranted. We wish to report a postoperative case of bilateral knee replacement who presented with carisoprodol (Soma) withdrawal resembling NMS that was a diagnostic dilemma. Subsequently, it was successfully treated with oral baclofen in absence of sodium dantrolene.",
"affiliations": "Department of Critical Care Medicine, Dayanand Medical College, Ludhiana, Punjab, India.;Department of Critical Care Medicine, Dayanand Medical College, Ludhiana, Punjab, India.;Department of Orthopedics, Dayanand Medical College, Ludhiana, Punjab, India.",
"authors": "Paul|Gunchan|G|;Parshotam|Gautam L|GL|;Garg|Rajneesh|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0970-9185.173346",
"fulltext": "\n==== Front\nJ Anaesthesiol Clin PharmacolJ Anaesthesiol Clin PharmacolJOACPJournal of Anaesthesiology, Clinical Pharmacology0970-91852231-2730Medknow Publications & Media Pvt Ltd India JOACP-32-38710.4103/0970-9185.173346Case ReportCarisoprodol withdrawal syndrome resembling neuroleptic malignant syndrome: Diagnostic dilemma Paul Gunchan Parshotam Gautam L Garg Rajneesh 1Department of Critical Care Medicine, Dayanand Medical College, Ludhiana, Punjab, India1 Department of Orthopedics, Dayanand Medical College, Ludhiana, Punjab, IndiaAddress for correspondence: Dr. Gunchan Paul, Assitant Professor, Department of Critical Care Medicine, Dayanand Medical College, Ludhiana, Punjab, India. E-mail: gunchan@gmail.comJul-Sep 2016 32 3 387 388 Copyright: © Journal of Anaesthesiology Clinical Pharmacology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Soma (Carisoprodol) is N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; a commonly prescribed, centrally acting skeletal muscle relaxant. Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of antipsychotic agents. Although diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur and more flexible diagnostic criteria than currently mandated, may be warranted. We wish to report a postoperative case of bilateral knee replacement who presented with carisoprodol (Soma) withdrawal resembling NMS that was a diagnostic dilemma. Subsequently, it was successfully treated with oral baclofen in absence of sodium dantrolene.\n\nKey words\nCarisoprodolcarisoprodol abusecarisoprodol withdrawalneuroleptic malignant syndromesoma\n==== Body\nIntroduction\nSoma (Carisoprodol) is a commonly prescribed, centrally acting skeletal muscle relaxant that inhibits interneuronal transmission in the descending reticular formation and spinal cord.[1] A few case reports have now been reported in the literature suggesting the addiction potential of carisoprodol.\n\nCase Report\nA 57-year-old chronic alcoholic, diabetic, hypertensive, hypothyroid male was admitted to a tertiary hospital for bilateral knee replacement. His daily medications included losartan (50 mg), metformin (1 g) and eltroxin (0.75 mg) for the last 2 years. Surgery was performed under combined spinal epidural anesthesia. On 2nd postoperative day, he developed altered sensorium with irrelevant speech. Gradually, he also developed visual hallucinations, restlessness, insomnia, and profuse sweating. With the possibility of metabolic disturbance, routine biochemistry was sent. In view of worsening delirium intravenous haloperidol was given in escalating doses (15 mg/day). In spite of treatment with haloperidol and zolpidem his condition worsened and was shifted to the critical care unit for assessment of need of mechanical ventilation. In the Intensive Care Unit (ICU), his pulse rate was 112/min, blood pressure of 128/74 mmHg, respiratory rate of 30/min, temperature 101°F and SpO294% on oxygen supplementation. He had generalized rigidity with distal upper limb myoclonus. His general condition kept on deteriorating with increasing tachypnoea up to 40/min, tachycardia (130/min), and worsening delirium (detected using the confusion assessment method - CAM score). Laboratory investigations showed an elevated white blood cell count (19,000/mm3), creatinine phosphokinase -11560 units/dL, (MB isoenzyme 45 units/dL), serum glutamic oxaloacetic transaminase -238 units/dL, serum glutamic pyruvic transaminase -154 units/dL and lactate dehydrogenase-124 units/dL, blood urea-45 mg/dL. Serum creatinine was 0.7 mg/dL and arterial blood gas showed metabolic acidosis. Urine analysis, serum electrolytes, chest roentgenogram, electrocardiography, computed tomography head, drug screen, blood cultures, lumbar puncture, and thyroid profile were all unremarkable. The other differential diagnoses considered in the ICU were an infectious pathology, pulmonary embolism, alcohol withdrawal or NMS. The whole case was re-evaluated, and it was revealed that the patient was consuming Soma to alleviate his knee pain. Over time, he became dependent and consumed double the indicated dose (6-7 tablets) daily since last 10 years. Due to the presence of a generalized rigidity, high-grade fever, fluctuations in sensorium, autonomic dysfunction, distal myoclonus, and marked elevated creatine phosphokinase (CPK) possibility of possible NMS was considered and he was started on baclofen (30 mg/day) and lorazepam (6 mg/day). Over the next 48 h, he was calm and oriented though sedated. In the next two days, myoclonus and rigidity disappeared, CPK levels dramatically declined (189 mg/dl), and his condition completely stabilized. He was discharged from hospital 10 days thereafter in a satisfactory condition.\n\nDiscussion\nSoma (Carisoprodol) is N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; and is routinely used in primary care settings for the treatment of musculo-skeletal disorders associated with muscle spasms and back pain.[2] It exerts its effect through central sedation and has an indirect agonist effect on the gamma-aminobutyric acid-A receptors.[3]\n\nCarisoprodol undergoes hepatic transformation to metabolites which are excreted by the kidneys. It is accepted that therapeutic effects of carisoprodol and its abuse potential are due to its conversion to meprobamate.[4] Half-life of carisoprodol and pharmacologically active metabolite, meprobamate is 2-3 h and 11 h, respectively, but may increase to 48 h with chronic use.[5]\n\nTo the best of our knowledge, there are only five case reports reported till date.[6] Withdrawal symptoms have occurred when intake of 700-2100 mg/day of carisoprodol was suddenly stopped after 9 months.[7] Propose that carisoprodol withdrawal may have precipitated NMS when daily intake of large doses was abruptly stopped in this case. This diagnosis was supported by clinical features and laboratory parameters with complete resolution of the syndrome after institution of treatment and normalization of laboratory parameters. Long-term consumption of heavy doses induces neural adaptation to their presence and rebound resurgence of neural electrical activity occurs after its sudden withdrawal.[8] The rebound leads to symptoms ranging from anxiety, jitteriness to delirium, depending on the severity of withdrawal and degree of neuronal hyperactivity. The typical meprobamate withdrawal syndrome may involve various degrees of insomnia, vomiting, tremors, muscle twitching, overt anxiety, anorexia, ataxia, and bizarre behavior. Our patient was consuming 2100 mg daily for the last 10 years. He had insomnia, delirium, hallucinations, and cold sweating after 48 h of drug cessation with associated features like fever, rigidity, myoclonus, and high CPK levels.\n\nIn our patient, the initial features resembled postoperative delirium. As he developed respiratory distress, pulmonary embolism in the setting of postoperative period was a differential. When he developed fever, muscular rigidity, leukocytosis, altered consciousness, and elevated CK levels diagnosis of NMS was considered.\n\nOur patient had possible NMS as there were clinical features to suggest the syndrome and normalization of the laboratory parameters after start of specific treatment. However, in our patient, it was the cessation of Soma abuse which led to NMS as the symptoms appeared prior to administration of haloperidol. As dantrolene was not readily available baclofen was used for controlling muscular rigidity. It resolved the rigidity in few hours with improvement in sensorium, general condition, and CK levels.\n\nConclusion\nOur patient was addicted to Soma, and sudden withdrawal may have precipitated NMS in the postoperative period which was successfully managed with supportive therapy and specific treatment with baclofen and benzodiazepine. Thus, clinicians should exercise high degree of suspicion in managing postoperative psychosis and NMS.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Reeves RR Beddingfield JJ Mack JE Carisoprodol withdrawal syndrome Pharmacotherapy 2004 24 1804 6 15585447 \n2 Reeves RR Parker JD Somatic dysfunction during carisoprodol cessation: Evidence for a carisoprodol withdrawal syndrome J Am Osteopath Assoc 2003 103 75 80 12622352 \n3 Littrell RA Hayes LR Stillner V Carisoprodol (Soma): A new and cautious perspective on an old agent South Med J 1993 86 753 6 8322081 \n4 Olsen H Koppang E Alvan G Mørland J Carisoprodol elimination in humans Ther Drug Monit 1994 16 337 40 7974621 \n5 Littrell RA Sage T Miller W Meprobamate dependence secondary to carisoprodol (Soma) use Am J Drug Alcohol Abuse 1993 19 133 4 8438828 \n6 Bailey DN Briggs JR Carisoprodol: An unrecognized drug of abuse Am J Clin Pathol 2002 117 396 400 11888078 \n7 Wyller TB Korsmo G Gadeholt G Dependence on carisoprodol (Somadril).A prospective withdrawal study among prisoners? Tidsskr Nor Laegeforen 1991 111 193 5 1998178 \n8 Haizlip TM Ewing JA Meprobamate habituation: A controlled clinical study N Engl J Med 1958 258 1181 6 13552940\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-9185",
"issue": "32(3)",
"journal": "Journal of anaesthesiology, clinical pharmacology",
"keywords": "Carisoprodol; carisoprodol abuse; carisoprodol withdrawal; neuroleptic malignant syndrome; soma",
"medline_ta": "J Anaesthesiol Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "9516972",
"other_id": null,
"pages": "387-8",
"pmc": null,
"pmid": "27625493",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "8438828;11888078;12622352;13552940;8322081;15585447;1998178;7974621",
"title": "Carisoprodol withdrawal syndrome resembling neuroleptic malignant syndrome: Diagnostic dilemma.",
"title_normalized": "carisoprodol withdrawal syndrome resembling neuroleptic malignant syndrome diagnostic dilemma"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2017-IPXL-01469",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARISOPRODOL"
},
"drugadditi... |
{
"abstract": "Valacyclovir is an oral antiviral agent being used more frequently than acyclovir because of the ease of administration and efficacy. Serious neuropsychiatric side effects have been demonstrated with the use of valacyclovir in renal failure patients. We report a case of valacyclovir neurotoxicity to emphasis the importance of dose adjustment in patients with chronic kidney disease and on dialysis.",
"affiliations": "Department of Internal Medicine, East Tennessee State University, Quillen College of Medicine, Johnson City, TN.",
"authors": "Chaudhari|Dhara|D|;Ginn|David|D|",
"chemical_list": "D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e318289bae9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(6)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020258:Neurotoxicity Syndromes; D010530:Peritoneal Dialysis; D051436:Renal Insufficiency, Chronic; D000077483:Valacyclovir; D014633:Valine",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e215-7",
"pmc": null,
"pmid": "23528373",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Valacyclovir-associated neurotoxicity in peritoneal dialysis patients.",
"title_normalized": "valacyclovir associated neurotoxicity in peritoneal dialysis patients"
} | [
{
"companynumb": "US-ACTAVIS-2015-16000",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report our experience with intraoperative complications involving the internal carotid artery (ICA) during trans-sphenoidal surgery and their outcome with reconstructive endovascular management.\n\n\nMETHODS\nA retrospective review was conducted of patients with an ICA injury related to trans-sphenoidal surgery from 2000 to 2012. Demographic data, clinical charts, indications for treatment, radiographic images, lesion characteristics, operative notes, endovascular procedure notes and post-procedure hospital course were reviewed.\n\n\nRESULTS\nThree men and one woman of mean age of 52 years (range 33-74) were identified. The lesions included two macroadenomas, one meningioma and one chondrosarcoma. Risk factors for ICA rupture included two patients with carotid dehiscence, one with sphenoid septal attachment to the ICA, two with revision surgery, one with prior radiation to the tumor, one with bromocriptine treatment and two with acromegaly. In three patients, covered stent placement achieved hemostasis at the site of injury within the ICA. One patient developed delayed bleeding 6 h after covered stent placement and underwent successful endovascular occlusion of the ICA but died 6 days after the injury. The fourth patient had an intraoperative ICA stroke requiring suction thrombectomy, thrombolysis, stent placement and evacuation of an epidural hematoma. At 1-year follow-up, two patients had a modified Rankin score (mRS) and National Institute of Health Stroke Scale (NIHSS) score of 0; in the patient who had a stroke the mRS score was 1 and the NIHSS score 2.\n\n\nCONCLUSIONS\nEndovascular management with arterial reconstruction is helpful in the treatment of ICA injuries during trans-sphenoidal surgery.",
"affiliations": "Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.;Division of NeuroInterventional Radiology, Department of Radiology, University of Michigan Health System, Ann Arbor, Michigan, USA Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan, USA Cranial Base Surgery Program, Department of Otolaryngology, University of Michigan Health System, Ann Arbor, Michigan, USA.;Division of NeuroInterventional Radiology, Department of Radiology, University of Michigan Health System, Ann Arbor, Michigan, USA Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan, USA.;Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan, USA Cranial Base Surgery Program, Department of Otolaryngology, University of Michigan Health System, Ann Arbor, Michigan, USA.;Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan, USA Cranial Base Surgery Program, Department of Otolaryngology, University of Michigan Health System, Ann Arbor, Michigan, USA.;Division of NeuroInterventional Radiology, Department of Radiology, University of Michigan Health System, Ann Arbor, Michigan, USA Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan, USA.",
"authors": "Griauzde|Julius|J|;Gemmete|Joseph J|JJ|;Pandey|Aditya S|AS|;McKean|Erin L|EL|;Sullivan|Stephen E|SE|;Chaudhary|Neeraj|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/neurintsurg-2013-010878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-8478",
"issue": "7(1)",
"journal": "Journal of neurointerventional surgery",
"keywords": "Stent; Thrombectomy; Thrombolysis; Trauma; Tumor",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D001932:Brain Neoplasms; D020212:Carotid Artery Injuries; D002343:Carotid Artery, Internal; D057510:Endovascular Procedures; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D019651:Reconstructive Surgical Procedures; D013101:Sphenoid Sinus; D016896:Treatment Outcome",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "67-71",
"pmc": null,
"pmid": "24408926",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Emergency reconstructive endovascular management of intraoperative complications involving the internal carotid artery from trans-sphenoidal surgery.",
"title_normalized": "emergency reconstructive endovascular management of intraoperative complications involving the internal carotid artery from trans sphenoidal surgery"
} | [
{
"companynumb": "US-SA-2016SA082395",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BK polyoma viral infection occurs as an asymptomatic infection in a high proportion of normal hosts without obvious sequelae. In the kidney transplant population, the virus is reactivated because of reduced immunity and, if not appropriately managed, can lead to BK viral nephropathy, which has emerged as a common cause of acute kidney injury and progressive chronic kidney disease in renal transplant recipients. BK viremia almost always occurs during the first 2 years after transplantation, when immunosuppressive therapy is high, or at other periods when immunosuppression is intensified. BK viremia is now detected by routine screening of transplant patients for the first few years, and BK viral nephropathy is considered to be high in the differential diagnosis of acute kidney injury in recently transplanted patients. We report a case of BK viral nephropathy developing 10 years after transplantation and present the challenges of managing advanced disease.",
"affiliations": "Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa.;Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa; Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa; Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa; Department of Obstetrics, University of Iowa College of Medicine, Iowa City, Iowa; Veterans Affairs Medical Center, Iowa City, Iowa. Electronic address: christie-thomas@uiowa.edu.",
"authors": "Mathew|J C|JC|;Holanda|D G|DG|;Figanbaum|T L|TL|;Fraer|M|M|;Thomas|C P|CP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D001739:BK Virus; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D027601:Polyomavirus Infections; D066027:Transplant Recipients; D014412:Tumor Virus Infections",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2386-90",
"pmc": null,
"pmid": "25242792",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-onset BK viral nephropathy in a kidney transplant recipient.",
"title_normalized": "late onset bk viral nephropathy in a kidney transplant recipient"
} | [
{
"companynumb": "PHHY2014US151792",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "The risk of developing nephrogenic systemic fibrosis in patients with end stage renal disease may increase with exposure to gadolinium-based contrast dyes during magnetic resonance imaging.",
"affiliations": "is a Chief Resident in the University of California Department of Medicine in Los Angeles. is a Hospitalist, and is a Pulmonologist at West Los Angeles VAMC Medical Center in California.;is a Chief Resident in the University of California Department of Medicine in Los Angeles. is a Hospitalist, and is a Pulmonologist at West Los Angeles VAMC Medical Center in California.;is a Chief Resident in the University of California Department of Medicine in Los Angeles. is a Hospitalist, and is a Pulmonologist at West Los Angeles VAMC Medical Center in California.",
"authors": "Chuang|Kelley|K|;Kaneshiro|Casey|C|;Betancourt|Jaime|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-4497",
"issue": "35(6)",
"journal": "Federal practitioner : for the health care professionals of the VA, DoD, and PHS",
"keywords": null,
"medline_ta": "Fed Pract",
"mesh_terms": null,
"nlm_unique_id": "9500574",
"other_id": null,
"pages": "40-43",
"pmc": null,
"pmid": "30766365",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "11041404;16461069;17699423;17907148;19404939;21079195;21531325;24582176;25257840;26076348;27147669;28657062",
"title": "Nephrogenic Systemic Fibrosis in a Patient With Multiple Inflammatory Disorders.",
"title_normalized": "nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders"
} | [
{
"companynumb": "US-GUERBET-US-20190025",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GADOVERSETAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Pentazocine has activities both of kappa-opioid receptor agonist and weak micro-opioid receptor antagonist. Recent study has suggested that kappa-opioid receptor agonists have antipruritic effects. We experienced a case of pentazocine inhibiting itch evoked by intrathecal fentanyl in a patient with idiopathic pulmonary fibrosis (IPF). A 50-year-old woman with IPF was diagnosed with fallopian tube abscess and which necessitated emergency surgery. We mainly performed regional anesthetic management to prevent acute exacerbation of IPF by tracheal intubation under general anesthesia. About 30 minutes after intrathecal administration of a combination of bupivacaine and fentanyl, she began to complain of itch. Although propofol was given intravenously, pruritus still recurred. Following that, when pentazocine was administered intravenously, pruritus disappeared immediately and then never recurred. Therefore, it is suggested that pentazocine can be useful in reducing pruritus on intrathecal opioid-induced itch. Future studies are necessary to evaluate the efficacy of pentazocine for the treatment and prevention of opioid-induced itch.",
"affiliations": null,
"authors": "Hirabayashi|Masato|M|;Imamachi|Noritaka|N|;Sakakihara|Manabu|M|;Saito|Yoji|Y|",
"chemical_list": "D000701:Analgesics, Opioid; D000982:Antipruritics; D017473:Receptors, Opioid, kappa; D010423:Pentazocine; D005283:Fentanyl",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "63(6)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000038:Abscess; D000701:Analgesics, Opioid; D000768:Anesthesia, General; D000982:Antipruritics; D004632:Emergency Medical Services; D005184:Fallopian Tube Diseases; D005260:Female; D005283:Fentanyl; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D007262:Infusions, Intravenous; D007278:Injections, Spinal; D008875:Middle Aged; D010423:Pentazocine; D011537:Pruritus; D017473:Receptors, Opioid, kappa; D016896:Treatment Outcome",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "696-9",
"pmc": null,
"pmid": "24979869",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Treatment of intrathecal fentanyl-induced itch with pentazocine: a case report.",
"title_normalized": "treatment of intrathecal fentanyl induced itch with pentazocine a case report"
} | [
{
"companynumb": "JP-WATSON-2014-20287",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
"dr... |
{
"abstract": "Peritoneal dialysis is one of the three available options for renal replacement therapy. This method of treatment of end-stage renal disease gives patients relatively high sense of independence and control over their disease, especially in comparison with hemodialysis, and therefore is often preferable method for young individuals wishing to lead an active lifestyle. We present a case of 22 year old female patient with stage 5 of chronic kidney disease, which is a consequence of multi-agent chemotherapy for endo-dermal sinus tumor of the right ovary (diagnosed at the age of 13). Particularly important in the context of treating our patient with peritoneal dialysis is the fact of confirmed metastases into the peritoneum, which was the reason for the use of chemotherapy reserved for high-risk patients (ifosfamide + etoposide + cisplatin). The selected program of chemotherapy provided effective eradication of cancer, but a side effect of treatment was renal tubular damage. In the period from 03.2006 to 05.2007 our patient required hemodialysis (with gradually reduce dose of dialysis), at a later time to 12.2011 patient did not require renal replacement therapy (stable renal function were observed at the stage 4 of chronic kidney disease), but in 12.2011 resumption of dialysis was necessary and the patient, in accordance with her selection, is receiving peritoneal dialysis. Qualification of our patient for treatment with peritoneal dialysis was associated with reasonable concern about the ability to provide acceptable adequacy of dialysis. Apprehensions proved to be unfounded, the clinical observation of the patient presents proper ratios of dialysis adequacy. Our patient was also qualified for renal transplantation.",
"affiliations": null,
"authors": "Jaśkowski|Piotr|P|;Krzanowska|Katarzyna|K|;Miarka|Przemysław|P|;Krzanowski|Marcin|M|;Sułowicz|Wiadysław|W|",
"chemical_list": "D005047:Etoposide; D002945:Cisplatin; D007069:Ifosfamide",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2240",
"issue": "71(8)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D007684:Kidney Tubules; D010051:Ovarian Neoplasms; D010530:Peritoneal Dialysis; D010534:Peritoneal Neoplasms; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "456-9",
"pmc": null,
"pmid": "25546920",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Patient receiving peritoneal dialysis after treatment of ovarian cancer.",
"title_normalized": "patient receiving peritoneal dialysis after treatment of ovarian cancer"
} | [
{
"companynumb": "PL-ACCORD-028085",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Dexmedetomidine is a selective α2-agonist, frequently used in perioperative medicine as anesthesia adjunct. The medication carries a Food and Drug Administration pregnancy category C designation and is therefore rarely used for parturients undergoing nonobstetric surgery. We are reporting the use of dexmedetomidine in the anesthetic management of a parturient undergoing minimally invasive unilateral adrenalectomy for pheochromocytoma during the second trimester of pregnancy. Additionally, because of the multiple endocrine neoplasia type 2A constellation with diagnosis of medullary thyroid cancer, the patient underwent a total thyroidectomy 1 week after the adrenalectomy.",
"affiliations": "From the Departments of Anesthesiology.;From the Departments of Anesthesiology.;From the Departments of Anesthesiology.;Surgery, University of Kentucky, Lexington, Kentucky.;From the Departments of Anesthesiology.",
"authors": "Faulkner|Amanda L|AL|;Swanson|Eric|E|;McLarney|Thomas L|TL|;Lee|Cortney Y|CY|;Rebel|Annette|A|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "12(5)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000315:Adrenalectomy; D000328:Adult; D018712:Analgesics, Non-Narcotic; D018278:Carcinoma, Neuroendocrine; D020927:Dexmedetomidine; D005260:Female; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a; D010673:Pheochromocytoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D013964:Thyroid Neoplasms; D013965:Thyroidectomy",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "136-140",
"pmc": null,
"pmid": "30095445",
"pubdate": "2019-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.",
"title_normalized": "use of dexmedetomidine in a parturient with multiple endocrine neoplasia type 2a undergoing adrenalectomy and thyroidectomy a case report"
} | [
{
"companynumb": "US-TEVA-2019-US-1061388",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "We present a case of tenosynovitis caused by a novel, slowly growing, nonchromogenic, nontuberculous mycobacterium (NTM). Originally misidentified as Mycobacterium tuberculosis complex, the NTM cross-reacts with the M. tuberculosis complex nucleic acid hybridization probe, a M. tuberculosis gamma interferon release assay, and is closely related to M. tuberculosis by 16S rRNA gene sequencing.",
"affiliations": "Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.;Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Mycobacteria/Nocardia Laboratory, Department of Microbiology, University of Texas Health Science Center, Tyler, Texas, USA.;Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Mycobacteria/Nocardia Laboratory, Department of Microbiology, University of Texas Health Science Center, Tyler, Texas, USA.;Mycobacteria/Nocardia Laboratory, Department of Microbiology, University of Texas Health Science Center, Tyler, Texas, USA.;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.;Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA wengenack.nancy@mayo.edu.",
"authors": "Simner|Patricia J|PJ|;Hyle|Emily P|EP|;Buckwalter|Seanne P|SP|;Branda|John A|JA|;Brown-Elliott|Barbara A|BA|;Franklin|Jameelah|J|;Toney|Nadege C|NC|;de Man|Tom J B|TJ|;Wallace|Richard J|RJ|;Vasireddy|Ravikiran|R|;Gandhi|Rajesh T|RT|;Wengenack|Nancy L|NL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D012336:RNA, Ribosomal, 16S",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.00967-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "52(12)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016000:Cluster Analysis; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D003951:Diagnostic Errors; D003955:Diagnostic Tests, Routine; D005260:Female; D006801:Humans; D059425:Interferon-gamma Release Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D009693:Nucleic Acid Hybridization; D010802:Phylogeny; D012336:RNA, Ribosomal, 16S; D017422:Sequence Analysis, DNA; D013717:Tenosynovitis",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "4414-8",
"pmc": null,
"pmid": "25253791",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19810590;7588854;19906898;12682128;9157152;14662964;22090409;15653890;8381805;10878076;15034147;14715809;17135430;15750059",
"title": "Tenosynovitis caused by a novel nontuberculous Mycobacterium species initially misidentified as a member of the Mycobacterium tuberculosis complex.",
"title_normalized": "tenosynovitis caused by a novel nontuberculous mycobacterium species initially misidentified as a member of the mycobacterium tuberculosis complex"
} | [
{
"companynumb": "US-BAYER-2014-183064",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo analyze the type of prior tumor and treatment in therapy-related acute promyelocytic leukemia (tAPL) that occurs after chemotherapy and/or radiotherapy (RT), and the hematologic characteristics and outcome of tAPL.\n\n\nMETHODS\nSixteen patients with tAPL who were gathered during a 10-year period (1982 to 1991) in seven hematologic centers were analyzed retrospectively.\n\n\nRESULTS\nThere were 13 women and three men. The median age was 46 years (range, 12 to 82). Prior tumor was breast carcinoma in 10 cases, another solid tumor in three cases, and lymphoma in three cases. Two patients had received RT alone, and 14 had received chemotherapy (with RT in 11 cases). Prior chemotherapeutic agents generally included a combination of cyclophosphamide (used for limited periods), fluorouracil (5-FU), vinca alkaloids, and doxorubicin, mitoxantrone, or etoposide (VP16). By contrast, alkylating agents other than cyclophosphamide had been used in only two patients. Median interval between onset of treatment for the prior tumor and diagnosis of APL was 25 months. No patient had a known preleukemic phase. Hematologic and cytogenetic characteristics of the cases of tAPL were identical to those of the usual de novo APL, which included the presence of t(15; 17) in nine of the 10 patients tested. Two patients had early death. Seven patients were treated with intensive chemotherapy, and six achieved complete remission (CR). Three of them subsequently relapsed. Seven patients were treated with all-trans-retinoic acid (ATRA), and four achieved CR through the differentiation of blasts into mature granulocytes. None has relapsed so far.\n\n\nCONCLUSIONS\nOur findings suggest that tAPL is not exceptional, and usually has several features in common with other types of therapy-related AML with specific karyotype (ie, t(8;21),t(9;11), inv(16)): solid tumor rather than hematologic malignancy as primary tumor, short interval of development, absence of known preleukemic phase, prior chemotherapy with a combination of several drugs that often included an agent that targets topoisomerase II (doxorubicin or mitoxantrone, but less often VP16). Hematologic characteristics and response to therapy (intensive chemotherapy or ATRA) in tAPL do not seem to differ from those of de novo APL.",
"affiliations": "Department of Hematology, Centre Hospital University, (CHU), Lille, France.",
"authors": "Detourmignies|L|L|;Castaigne|S|S|;Stoppa|A M|AM|;Harousseau|J L|JL|;Sadoun|A|A|;Janvier|M|M|;Demory|J L|JL|;Sanz|M|M|;Berger|R|R|;Bauters|F|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.1992.10.9.1430",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "10(9)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D007621:Karyotyping; D015473:Leukemia, Promyelocytic, Acute; D007953:Leukemia, Radiation-Induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011878:Radiotherapy; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1430-5",
"pmc": null,
"pmid": "1517786",
"pubdate": "1992-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapy-related acute promyelocytic leukemia: a report on 16 cases.",
"title_normalized": "therapy related acute promyelocytic leukemia a report on 16 cases"
} | [
{
"companynumb": "FR-BAUSCH-BL-2018-022630",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "We report a 12-week-old boy presenting with incomplete refractory Kawasaki disease (KD) complicated with macrophage activation syndrome (MAS). The infant presented with cerebral irritability, pain, tachypnoea and vomiting for 10 days. He did not fulfil any of the classic diagnostic criteria for KD. Pericardial effusion on echocardiography in addition to severe dilatation of the coronary arteries in combination with leucocytosis and raised acute phase reactants led to the diagnosis of incomplete KD. Treatment with intravenous immunoglobulin and aspirin was initiated but without any response. The condition was subsequently refractory to additional treatment with infliximab and high-dose methylprednisolone. His condition worsened, fulfilling the criteria for MAS. High-dose anakinra was initiated, and remission of the inflammation was achieved.",
"affiliations": "Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.;Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.;Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.",
"authors": "Lind-Holst|Marie|M|http://orcid.org/0000-0003-2585-8102;Hartling|Ulla Birgitte|UB|;Christensen|Anne Estmann|AE|",
"chemical_list": "D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "paediatrics (drugs and medicines); vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D018501:Antirheumatic Agents; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein; D055501:Macrophage Activation Syndrome; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31383678",
"pubdate": "2019-08-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21132551;20693540;27639924;28400731;25045337;20008190;15930186;27792871;28390409;25077692;25386930;16937360;21543760;28356445;22689319;22361326;26865703;29885546;26461152;27482265;28408126;25200945",
"title": "High-dose anakinra as treatment for macrophage activation syndrome caused by refractory Kawasaki disease in an infant.",
"title_normalized": "high dose anakinra as treatment for macrophage activation syndrome caused by refractory kawasaki disease in an infant"
} | [
{
"companynumb": "DK-FRESENIUS KABI-FK201910172",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nThe Pipeline Embolization Device (PED; Medtronic) has been used off-label for the treatment of challenging posterior circulation aneurysms. Data on this modality are primarily limited to small retrospective single-center series.\n\n\nOBJECTIVE\nTo assess safety and efficacy of this treatment by establishing an international, multicenter collaboration.\n\n\nMETHODS\nConsecutive posterior circulation aneurysms treated with the PED from 2012 to 2019 across 11 neurovascular centers were retrospectively reviewed. Baseline demographics, aneurysm and treatment characteristics, complications, occlusion status, and functional outcome were assessed.\n\n\nRESULTS\nThere were 149 posterior circulation aneurysms treated with PED in 146 patients. A total of 24 (16.4%) patients presented with subarachnoid hemorrhage. Most aneurysms were dissecting/blister (36.2%) in morphology, followed by saccular (35.6%) and fusiform (28.2%). The most common locations were the vertebral (51.7%) and basilar arteries (22.8%). Complete or near-complete occlusion (>90%) was achieved in 90.9% of aneurysms at a median follow-up of 12 mo. Dissecting/blister aneurysms were most likely to occlude (P = .06). Symptomatic neurologic complications occurred in 9.4% of aneurysms, associated with larger size, ruptured presentation, presentations with brain stem compression, cranial nerve palsy, or stroke. Favorable functional outcome (modified Rankin Score 0-2) was achieved in 86.2% of patients. There were 6 fatalities of which 4 occurred in aneurysmal subarachnoid hemorrhage patients.\n\n\nCONCLUSIONS\nThis multicenter study shows that PED for the treatment of posterior circulation is preferentially used for the treatment of fusiform and dissecting/blister aneurysm morphologies. Despite the challenges presented by these less-common morphologies, flow diversion may be performed with a neurologic complication rate of about 10% and favorable long-term aneurysm occlusion rates.",
"affiliations": "Department of Neurosurgery, Geisinger, Danville, Pennsylvania.;Boston Medical Center, Boston University, Boston, Massachusetts.;Department of Neurosurgery, University of Utah, Salt Lake City, Utah.;Department of Neurosurgery, University of Utah, Salt Lake City, Utah.;Department of Neurosurgery, University of Utah, Salt Lake City, Utah.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.;Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota.;Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota.;Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota.;Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.;Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.;Departments of Medical Imaging & Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.;Departments of Medical Imaging & Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.;Departments of Radiology & Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts.;Departments of Radiology & Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts.;Division of Vascular and Endovascular Neurosurgery, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Neurosurgery, Geisinger, Danville, Pennsylvania.;Department of Neurosurgery, Geisinger, Danville, Pennsylvania.;Department of Radiology, Geisinger, Danville, Pennsylvania.;Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria.;Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria.;Massachussetts General Hospital, Harvard University, Boston, Massachusetts.;Massachussetts General Hospital, Harvard University, Boston, Massachusetts.;Massachussetts General Hospital, Harvard University, Boston, Massachusetts.;Neuroscience and Rehabilitation Institute, Orlando Health, Orlando, Florida.;Neuroscience and Rehabilitation Institute, Orlando Health, Orlando, Florida.;Neuroscience and Rehabilitation Institute, Orlando Health, Orlando, Florida.;Division of Interventional Neuroradiology, Toronto Western Hospital, Toronto, Ontario, Canada.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.;Departments of Medical Imaging & Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Griessenauer|Christoph J|CJ|;Enriquez-Marulanda|Alejandro|A|;Taussky|Philipp|P|;Biswas|Arundhati|A|;Grandhi|Ramesh|R|;Xiang|Sissi|S|;Hong|Tao|T|;Rinaldo|Lorenzo|L|0000-0002-7800-7726;Lanzino|Giuseppe|G|;Brinjikji|Waleed|W|;Burkhardt|Jan-Karl|JK|;Kan|Peter|P|;Ghuman|Mandeep|M|;Yang|Victor X D|VXD|;Chen|Karen|K|;Aziz-Sultan|Mohammad A|MA|;Ghorbani|Mohammad|M|;Schirmer|Clemens M|CM|;Goren|Oded|O|;Dalal|Shamsher S|SS|;Killer-Oberpfalzer|Monika|M|;Müller-Thies-Broussalis|Erasmia|E|;Koch|Matthew J|MJ|;Stapleton|Christopher J|CJ|;Patel|Aman B|AB|;Foreman|Paul M|PM|;Cress|Marshall C|MC|;Hirschl|Robert A|RA|;Krings|Timo|T|;Zhang|Hongqi|H|;Dmytriw|Adam A|AA|0000-0003-0131-5699",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyaa277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "87(6)",
"journal": "Neurosurgery",
"keywords": "Aneurysm; Endovascular; Flow diversion; Pipeline; Pipeline Embolization Device; Posterior circulation; Vertebrobasilar disease",
"medline_ta": "Neurosurgery",
"mesh_terms": null,
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "1252-1261",
"pmc": null,
"pmid": "32629474",
"pubdate": "2020-11-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Experience With the Pipeline Embolization Device for Posterior Circulations Aneurysms: A Multicenter Cohort Study.",
"title_normalized": "experience with the pipeline embolization device for posterior circulations aneurysms a multicenter cohort study"
} | [
{
"companynumb": "US-BAYER-2021-137636",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "To our knowledge, this case report describes the first known case of sternocleidomastoid tendinopathy, occurring in a pediatric athlete who had gone undiagnosed for a period of 2 yrs. She presented to our pain clinic with bilateral otalgia, occipital headaches, and occasional bouts of tinnitus and dizziness. An extensive workup by otolaryngology (ENT) including computed tomography imaging of the head, ear pressure equalization, and an attempt at therapeutic tonsillectomy left her with no diagnosis and no symptom relief. A clinical diagnosis of sternocleidomastoid tendinopathy was made at the initial visit based on history and physical examination findings, after excluding other diagnoses. Conservative treatment with physical therapy, acupuncture, and a short course of meloxicam and gabapentin resulted in total symptom resolution. This case is a unique reminder to clinicians that head, neck, and ear pain may precipitate from musculoskeletal origins. It emphasizes the importance of understanding local anatomy, obtaining a thorough history, and performing a detailed physical examination in arriving at an accurate diagnosis.",
"affiliations": "From the Department of Physical Medicine & Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey (BC, TS, PF); University Hospital, Newark, New Jersey (BC, TS, PF); Touro University, Vallejo, California (SY); and Rutgers New Jersey Medical School, Newark, New Jersey (MD).",
"authors": "Chen|Boqing|B|;Yae|Sophia|S|;Delbert|Matthew|M|;Stitik|Todd|T|;Foye|Patrick|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PHM.0000000000001328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0894-9115",
"issue": "99(9)",
"journal": "American journal of physical medicine & rehabilitation",
"keywords": null,
"medline_ta": "Am J Phys Med Rehabil",
"mesh_terms": "D056352:Athletes; D001265:Athletic Injuries; D002648:Child; D057210:Delayed Diagnosis; D004244:Dizziness; D004433:Earache; D005260:Female; D006261:Headache; D006801:Humans; D008416:Mastoid; D009334:Neck Muscles; D013249:Sternum; D052256:Tendinopathy; D014012:Tinnitus",
"nlm_unique_id": "8803677",
"other_id": null,
"pages": "e111-e114",
"pmc": null,
"pmid": "31738282",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sternocleidomastoid Tendinopathy in a Pediatric Athlete.",
"title_normalized": "sternocleidomastoid tendinopathy in a pediatric athlete"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP006178",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELOXICAM"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nNivolumab, a programmed death-1(PD-1) inhibitor antibody, have demonstrated anti-tumor activity for multiple malignancies. Such immune checkpoint inhibitors induce novel and distinctive adverse effects, which are collectively named immune-related adverse events. Immune-related adverse events can theoretically occur at any part of the body, including the haemopoietic system. Most immune-related adverse events developed within 10 weeks of receiving immunotherapy. Thus far, there is no report of immune thrombocytopenia as an immune-related adverse event developed after discontinuation of immunotherapy.\n\n\nMETHODS\nWe describe a 62-year-old male with metastatic non-small cell lung cancer developed immune thrombocytopenia nearly two months after discontinuation of nivolumab. When thrombocytopenia was detected, the patient was undergoing radiotherapy of supraclavicular lymph nodes. After complex diagnosis-by-exclusion process, nivolumab-induced immune thrombocytopenia was diagnosed.\nIntravenous immunoglobulins 20 g daily for 5 days, intravenous methylprednisolone 40 mg daily for 14 days followed by oral prednisone, intermittent platelet transfusion and oral thrombopoietin receptor (eltrombopag 25 mg daily) were administered. After 30 days, his platelet count had achieved a level of adequate hemostasis and continued to improvement during the tapering period.\n\n\nCONCLUSIONS\nMost immune-related developed 6 months of immunotherapy. Clinicians need to be aware of a clinical diagnostic complex, developing months to years after discontinuation of immunotherapy, which recently is termed delayed immune-related events. This case is the first report of immune checkpoint inhibitors-induced thrombocytopenia that developed nearly 2 months after discontinuation of treatment with nivolumab for metastatic NSCLC. In future clinical practice, patients who have received immune checkpoint inhibitors develop new or unexplained symptom, irrespective of interval post-immunotherapy, immune-related adverse events should be considered.",
"affiliations": "Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.;Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.;Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.",
"authors": "Fu|Shengya|S|https://orcid.org/0000-0002-3203-0699;Wang|Ting|T|;Xu|Feng|F|",
"chemical_list": "D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220981155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Immune checkpoint inhibitors; delayed immune-related events; immune thrombocytopenia; immune-related adverse events; nivolumab",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D016553:Purpura, Thrombocytopenic, Idiopathic; D013921:Thrombocytopenia",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1548-1552",
"pmc": null,
"pmid": "33435825",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Delayed immune thrombocytopenia after discontinuation of nivolumab therapy: A case report and literature review.",
"title_normalized": "delayed immune thrombocytopenia after discontinuation of nivolumab therapy a case report and literature review"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-22228",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "Background: Coronary vasospasm leading to variant angina is uncommon, and the condition is rare in pregnant patients. Many physiologic changes occur during pregnancy, but how these changes affect the spasticity of coronary arteries in patients predisposed to vasospasm is unknown. Vasospasm causing unstable arrhythmia from multiple foci can be difficult to treat. Case Report: A 22-year-old gravida 1 para 0 female at 17 weeks' gestation with twins presented with chest pain refractory to sublingual nitroglycerin, ST segment elevation on electrocardiogram, and subsequent ventricular tachycardia requiring a shock by her implantable cardioverter defibrillator (ICD). The patient had a history of coronary vasospasm with ventricular arrhythmia that required placement of the ICD 5 years prior. Because of refractory symptoms, she required prolonged admission in the intensive care unit with high-dose intravenous nitroglycerin, calcium channel blockers, benzodiazepines, beta blockers, chemical sympathectomy, and intubation and sedation. Despite these measures, the patient continued to have vasospasm and ventricular tachycardia, so cesarean delivery and tubal ligation were performed. After delivery, she was rapidly weaned from all invasive treatment modalities and was discharged on oral nitrates and calcium channel blockers. Conclusion: To our knowledge, this case is the first report of severe drug-refractory vasospastic angina triggered by pregnancy. The hormonal and nervous system changes that occur during pregnancy appear to be a trigger for vasospasm, further highlighted by the quick resolution of the patient's symptoms postdelivery. A multidisciplinary approach for treatment of both mother and baby was necessary. Our case provides a cautionary tale that patients with refractory vasospastic angina may want to pursue definitive contraception.",
"affiliations": "Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA.;Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA.",
"authors": "Ergle|Kevin|K|;Bernard|Michael|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.18.0046",
"fulltext": "\n==== Front\nOchsner JOchsner JTOJochjnlThe Ochsner Journal1524-5012Academic Division of Ochsner Clinic Foundation 10.31486/toj.18.0046toj.18.0046Case Reports and Clinical ObservationsRefractory Ventricular Tachycardia From Coronary Vasospasm During Pregnancy Ergle, KRefractory Ventricular Tachycardia During PregnancyErgle Kevin MDBernard Michael MD, PhDDepartment of Cardiology, Ochsner Clinic Foundation, New Orleans, LAAddress correspondence to Michael Bernard, MD, PhD, Department of Cardiology, Ochsner Clinic Foundation, 1514 Jefferson Hwy., New Orleans, LA 70121. Tel: (504) 842-4721. Email: mbernard@ochsner.orgWinter 2019 Winter 2019 19 4 401 404 ©2019 by the author(s); Creative Commons Attribution License (CC BY)2019©2019 by the author(s); licensee Ochsner Journal, Ochsner Clinic Foundation, New Orleans, LA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (creativecommons.org/licenses/by/4.0/legalcode) that permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.Background: Coronary vasospasm leading to variant angina is uncommon, and the condition is rare in pregnant patients. Many physiologic changes occur during pregnancy, but how these changes affect the spasticity of coronary arteries in patients predisposed to vasospasm is unknown. Vasospasm causing unstable arrhythmia from multiple foci can be difficult to treat.\n\nCase Report: A 22-year-old gravida 1 para 0 female at 17 weeks’ gestation with twins presented with chest pain refractory to sublingual nitroglycerin, ST segment elevation on electrocardiogram, and subsequent ventricular tachycardia requiring a shock by her implantable cardioverter defibrillator (ICD). The patient had a history of coronary vasospasm with ventricular arrhythmia that required placement of the ICD 5 years prior. Because of refractory symptoms, she required prolonged admission in the intensive care unit with high-dose intravenous nitroglycerin, calcium channel blockers, benzodiazepines, beta blockers, chemical sympathectomy, and intubation and sedation. Despite these measures, the patient continued to have vasospasm and ventricular tachycardia, so cesarean delivery and tubal ligation were performed. After delivery, she was rapidly weaned from all invasive treatment modalities and was discharged on oral nitrates and calcium channel blockers.\n\nConclusion: To our knowledge, this case is the first report of severe drug-refractory vasospastic angina triggered by pregnancy. The hormonal and nervous system changes that occur during pregnancy appear to be a trigger for vasospasm, further highlighted by the quick resolution of the patient's symptoms postdelivery. A multidisciplinary approach for treatment of both mother and baby was necessary. Our case provides a cautionary tale that patients with refractory vasospastic angina may want to pursue definitive contraception.\n\nKeywords:\nCoronary vasospasmpregnancy complications–cardiovasculartachycardia–ventricular\n==== Body\nINTRODUCTION\nIn 1959, Prinzmetal and colleagues described a “variant type of angina” that occurred frequently at rest or during normal activity and was not worsened by effort as classic Heberden angina pectoris is.1 This variant form of angina—a type of vasospastic angina in which spasm of an epicardial coronary artery leads to myocardial ischemia with representative ST segment changes—is relatively uncommon, with a higher prevalence in eastern countries. Among patients with vasospastic angina, the majority will have single-vessel vasospasm, although data from a multicenter registry of the Japanese Coronary Spasm Association suggest that up to 32% of patients can have multivessel territories.2 Only approximately 2.4% of patients with coronary vasospasm will have out-of-hospital cardiac arrest.3\n\nSmoking is a major preventable risk factor, with male sex, magnesium deficiency, alcohol use, physical and mental stress, and autonomic nervous system agents all having an association with vasospastic angina.4 Treatment modalities include nitrates, calcium channel blockers, nicorandil (not available in the United States), and concomitant percutaneous coronary intervention for organic stenoses.5 Implantation of an automated implantable cardioverter defibrillator (ICD) is reasonable for patients with prior ventricular arrhythmia or cardiac arrest.5\n\nThe incidence of ischemic heart disease during pregnancy is low, occurring in only 1 in 10,000 patients.6 A review of 103 patients with acute myocardial infarction in pregnancy found only 2 cases attributed to coronary spasm.7 The effects that pregnancy may have on someone with a history of vasospastic angina, particularly patients with intractable vasospastic angina contributing to unstable cardiac arrhythmia, are unknown.\n\nCASE REPORT\nA 22-year-old primigravid female at 17 weeks’ gestation presented with chest pain refractory to sublingual nitroglycerin and an appropriate shock by her ICD. She had a history of anxiety, depression, and angiography-documented coronary vasospasm in multiple coronary territories. Prior cardiac arrest because of ventricular tachycardia that degenerated to ventricular fibrillation led to implantation of the ICD 5 years prior. Family history was negative for sudden cardiac death.\n\nThe patient was chronically maintained on verapamil 120 mg 3 times daily, isosorbide mononitrate 60 mg daily, and magnesium supplementation. She had a history of 7 ICD shocks, the last almost 4 years prior to this presentation. Starting at 9 weeks’ gestation of her pregnancy, she had had several admissions to outside facilities for angina requiring intravenous (IV) nitroglycerin administration, but those events were self-limited and no arrhythmia was noted.\n\nElectrocardiogram (ECG) on admission showed antero-septal ST segment elevation (Figure 1). Fetal ultrasound showed twin pregnancy with only one surviving fetus on admission. Echocardiogram showed mildly depressed left ventricular function with septal hypokinesis. The patient was admitted to the intensive care unit, and IV nitroglycerin was started. ECG changes and the patient's chest pain resolved. The night after admission, however, she felt crushing chest pain and had 6 appropriate shocks by her ICD for ventricular fibrillation. She was intubated, sedated on propofol and fentanyl continuous IV infusions, and continued on IV nitroglycerin to 500 mcg/min and verapamil 120 mg 3 times daily.\n\nFigure 1. Admission electrocardiogram shows anteroseptal and lateral ST segment elevation.\n\nMultidisciplinary discussion involving electrophysiology, maternal-fetal medicine, cardiology, and interventional cardiology determined that given the patient's history, vasospastic angina was likely the cause of the arrhythmia, and alternative diagnoses such as spontaneous coronary artery dissection were less likely. Subsequent ECGs during her hospitalization showed ST segment elevation in different territories, further solidifying the diagnosis (Figures 2 and 3).\n\nFigure 2. Inpatient electrocardiogram shows inferior ST segment elevation.\n\nFigure 3. Inpatient electrocardiogram shows lateral ST segment elevation.\n\nDespite these initial measures, the patient continued to have angina with refractory ventricular tachycardia and ventricular fibrillation. In addition to high-dose intravenous nitroglycerin 500 mcg/min, dihydropyridine and nondihydropyridine calcium channel blockers (nifedipine 90 mg daily and verapamil 240 mg 3 times daily), and strict electrolyte control, the patient was treated with benzodiazepines (scheduled diazepam 7 mg 3 times daily with lorazepam as needed), a beta blocker (metoprolol tartrate 25 mg 3 times daily), and sedation with intubation to attempt to control her coronary vasospasm. Psychiatry was consulted to help with control of her anxiety. Despite these treatments, she continued to have refractory tachyarrhythmias, leading to multiple appropriate shocks by her ICD. After discussion with thoracic surgery and anesthesiology, chemical sympathectomy was performed with ropivacaine 4 mg/hr via a stellate ganglion catheter. This treatment initially improved the patient's angina; however, at 24-weeks’ gestation she again developed refractory ventricular tachycardia. In total, she had more than 20 shocks by her ICD by this point in her pregnancy.\n\nDiscussion with the patient, her family, maternal-fetal medicine, obstetrics, critical care, and cardiology concluded that the best option for the patient and the baby was to proceed with cesarean section and delivery of the baby, which occurred at 24 weeks, 6 days. With consent of the patient and family, permanent sterilization via bilateral tubal ligation was performed.\n\nAfter delivery, the patient was able to be rapidly weaned from all IV medications and the chemical sympathectomy catheter. She was discharged home on postoperative day 4 asymptomatic and on the following oral medications: alpraz-olam 1 mg every 6 hours as needed for anxiety, metoprolol tartrate 12.5 mg twice daily, isosorbide mononitrate 30 mg daily, magnesium oxide 400 mg daily, nitroglycerin 0.4 mg sublingual as needed for chest pain, oxycodone-acetaminophen 10/325 every 6 hours as needed for severe pain, sertraline 50 mg daily, and verapamil 80 mg 3 times daily. Her baby did not survive. The infant died in the neonatal intensive care unit more than a month later.\n\nDISCUSSION\nOur case demonstrates the difficulty in treating arrhythmia-inducing refractory vasospastic angina. This case was unique, with vasospasm documented in multiple coronary arteries and leading to unstable ventricular arrhythmia. The progression of symptoms throughout pregnancy required a prolonged stay in the intensive care unit and was dangerous for both the mother and fetus.\n\nPregnancy appears to be a trigger for coronary vasospasm, perhaps mediated by hormonal and nervous system changes throughout gestation. Pregnancy involves complex physiologic changes; primary systemic vasodilation leads to increases in sympathetic hormones and to the release of vasopressin and stimulation of the renal-angiotensin-aldosterone system,8 which may play a role in coronary vasospasm.\n\nIn our patient, high-dose IV medications and sedation did not control her vasospasm and subsequent ventricular arrhythmia. Chemical sympathectomy, which has been successful in refractory ventricular tachyarrhythmia,9 was temporizing but ultimately unable to completely suppress her symptoms. After having 7 shocks in the 5 years leading up to pregnancy, our patient had more than 20 shocks in a 6-week period during pregnancy despite intensive therapy. After considering the risks and benefits, the patient decided to proceed with tubal ligation to prevent future pregnancy.\n\nCONCLUSION\nTo our knowledge, this case is the first report of recurrent, drug-refractory vasospastic angina triggered by pregnancy. The physiologic changes of pregnancy appeared to be the trigger, making adequate treatment extremely challenging. The case highlights the aggressive therapy required to treat coronary vasospasm in pregnancy. A multidisciplinary approach was necessary with input from cardiology, maternal-fetal medicine, obstetrics, thoracic surgery, anesthesiology, and psychiatry. However, our patient had previously documented unstable tachyarrhythmia from coronary vasospasm. It is unknown if patients with controlled coronary vasospasm without arrhythmia could progress during pregnancy or if they could safely carry a pregnancy to term with conservative therapy.\n\nACKNOWLEDGMENTS\nThe authors have no financial or proprietary interest in the subject matter of this article. This case was presented at the American College of Cardiology Conference, March 10, 2018 in Orlando, FL.\n\n\nThis article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.\n==== Refs\nREFERENCES\n1. Prinzmetal M , Kennamer R , Merliss R , Wada T , Bor N \nAngina pectoris I. A variant form of angina pectoris: preliminary report . Am J Med . 1959 \n9 ;27 (3 ):375 -388 . doi: 10.1016/0002-9343(59)90003-8 .14434946 \n2. Takagi Y , Yasuda S , Takahashi J , et al; Japanese Coronary Spasm Association. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association . Eur Heart J . 2013 \n1 ;34 (4 ):258 -267 . doi: 10.1093/eurheartj/ehs199 .22782943 \n3. Takagi Y , Yasuda S , Tsunoda R , et al; Japanese Coronary Spasm Association. Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association . Circ Arrhythm Electrophysiol . 2011 \n6 ;4 (3 ):295 -302 . doi: 10.1161/CIRCEP.110.959809 .21406685 \n4. Hung MJ , Hu P , Hung MY \nCoronary artery spasm: review and update . Int J Med Sci . 2014 \nAug 28 ;11 (11 ):1161 -1171 . doi: 10.7150/ijms.9623 .25249785 \n5. JCS Joint Working Group . Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013) . Circ J . 2014 ;78 (11 ):2779 -2801 .25273915 \n6. Kealey A \nCoronary artery disease and myocardial infarction in pregnancy: a review of epidemiology, diagnosis, and medical and surgical management . Can J Cardiol . 2010 \nJun-Jul ;26 (6 ):185 -189 . doi: 10.1016/S0828-282X(10)70397-4 .\n7. Roth A , Elkayam U \nAcute myocardial infarction associated with pregnancy . J Am Coll Cardiol . 2008 \nJul 15 ;52 (3 ):171 -180 . doi: 10.1016/J.JACC.2008.03.049 .18617065 \n8. Tkachenko O , Shchekochikhin D , Schrier RW \nHormones and hemodynamics in pregnancy . Int J Endocrinol Metab . 2014 \nApr 1 ;12 (2 ):e14098 . doi: 10.5812/ijem.14098 .24803942 \n9. Meng L , Tseng CH , Shivkumar K , Ajijola O \nEfficacy of stellate ganglion blockade in managing electrical storm: a systemic review . JACC Clin Electrophysiol . 2017 \n9 ;3 (9 ):942 -949 . doi: 10.1016/j.jacep.2017.06.006 .29270467\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1524-5012",
"issue": "19(4)",
"journal": "The Ochsner journal",
"keywords": "Coronary vasospasm; pregnancy complications–cardiovascular; tachycardia–ventricular",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "401-404",
"pmc": null,
"pmid": "31903064",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "14434946;25249785;22782943;20548979;24803942;18617065;25273915;21406685;29270467",
"title": "Refractory Ventricular Tachycardia From Coronary Vasospasm During Pregnancy.",
"title_normalized": "refractory ventricular tachycardia from coronary vasospasm during pregnancy"
} | [
{
"companynumb": "US-USP-000078",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drugadmin... |
{
"abstract": "We report our experience with a case of colorectal cancer treated with chemotherapy for a liver metastasis patient on hemodialysis. The patient was a 67-year-old man with a history of chronic renal failure, who was on hemodialysis since 2005. High anterior resection was performed for sigmoid colon and rectal cancer in January, 2010. After starting chemotherapy while planning to use FOLFOX6+bevacizumab(BV)as a postoperative standard chemotherapy, in combination with hemodialysis three times a week while performing dose escalation, administration postponement was continued for myelosuppression that was considered to be the effect of oxaliplatin. Oxaliplatin was administered for only 2 courses, and was then changed to BV+sLV5FU2 therapy. We continued treating the metastases approximately on schedule. Imaging revealed, the liver metastases were CR because they had disappeared. The BV use case of the dialysis case had few reports, but was thought to be able to use it by careful administration safely.",
"affiliations": "Dept. of Surgery, Fukui Prefectural Hospital, Japan.",
"authors": "Sato|Yoshiki|Y|;Doden|Kenji|K|;Nishida|Yoji|Y|;Shimizu|Satsuki|S|;Tanaka|Nobuhiro|N|;Yagi|Daisuke|D|;Asaumi|Yoshihide|Y|;Hirano|Yasumitsu|Y|;Maeda|Kazuya|K|;Miyanaga|Tamon|T|;Hattori|Masakazu|M|;Hashizume|Yasuo|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "40(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D003131:Combined Modality Therapy; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D006435:Renal Dialysis; D012811:Sigmoid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "647-50",
"pmc": null,
"pmid": "23863592",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Bevacizumab therapy for a colorectal cancer patient or hemodialysis with hepatic metastasis.",
"title_normalized": "bevacizumab therapy for a colorectal cancer patient or hemodialysis with hepatic metastasis"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1032944",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 μmol/L and a peak of 252 μmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 μmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.",
"affiliations": "Division of Clinical Pharmacology and Toxicology and Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, Ohio ; Northeast Ohio Medical University, Rootstown, Ohio.",
"authors": "Blackford|Martha G|MG|;Do|Stephanie T|ST|;Enlow|Thomas C|TC|;Reed|Michael D|MD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-18.2.128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "18(2)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "hyperammonemia; levocarnitine; serum carnitine; topiramate; valproic acid",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "128-36",
"pmc": null,
"pmid": "23798907",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports",
"references": "8937454;11952778;3093213;22180549;15794187;15079854;2007943;21700501;19280426;20163200;16010067;7249508;16774619;19952878;20814502;10636156;9674826;9565442;6813444;3145882",
"title": "Valproic Acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine.",
"title_normalized": "valproic acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine"
} | [
{
"companynumb": "DE-MYLANLABS-00P-062-0095885-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo evaluate the failure rate of the 150-treatment line for paracetamol overdose in Hong Kong, and the impact if the treatment threshold was lowered.\n\n\nMETHODS\nPublic hospitals, Hong Kong.\n\n\nMETHODS\nAll patients with acute paracetamol overdose reported to the Hong Kong Poison Information Centre from 1 January 2011 to 31 December 2013 were studied and analysed for the timed serum paracetamol concentration and their relationship to different treatment lines. Presence of significant liver injury following paracetamol overdose was documented. The potential financial burden of different treatment lines implemented locally was estimated.\n\n\nRESULTS\nOf 893 patients, 187 (20.9%) had serum paracetamol concentration above the 150-treatment line, 112 (12.5%) had serum paracetamol concentration between the 100- and 150-treatment lines, and 594 (66.5%) had serum paracetamol level below the 100-treatment line. Of the 25 (2.8%) patients who developed significant liver injury, two were between the 100- and 150-treatment lines, and the other two were below the 100-treatment line. The failure rate of the 150-treatment line was 0.45%. Lowering the treatment threshold to the 100-treatment line might lower the failure rate of the treatment nomogram to 0.22% but approximately 37 more patients per year would need to be treated. It would incur an additional annual cost of HK$189 131 (US$24 248), and an additional 1.83 anaphylactoid reactions per year. The number needed-to-treat to potentially reduce one significant liver injury is 112.\n\n\nCONCLUSIONS\nLowering the treatment threshold of paracetamol overdose may reduce the treatment-line failure rate. Nonetheless such a decision must be balanced against the excess in treatment complications and health care resources.",
"affiliations": "Department of Accident and Emergency, United Christian Hospital, Kwun Tong, Hong Kong.;Hong Kong Poison Information Centre, United Christian Hospital, Kwun Tong, Hong Kong.;Hong Kong Poison Information Centre, United Christian Hospital, Kwun Tong, Hong Kong.",
"authors": "Chan|Simon T B|ST|;Chan|C K|CK|;Tse|M L|ML|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "China",
"delete": false,
"doi": "10.12809/hkmj144481",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-2708",
"issue": "21(5)",
"journal": "Hong Kong medical journal = Xianggang yi xue za zhi",
"keywords": "Acetaminophen; Drug overdose/drug therapy; Liver diseases",
"medline_ta": "Hong Kong Med J",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D005260:Female; D006723:Hong Kong; D006801:Humans; D008297:Male; D049451:Nomograms; D061366:Numbers Needed To Treat; D012189:Retrospective Studies; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "9512509",
"other_id": null,
"pages": "389-93",
"pmc": null,
"pmid": "26234689",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Paracetamol overdose in Hong Kong: is the 150-treatment line good enough to cover patients with paracetamol-induced liver injury?",
"title_normalized": "paracetamol overdose in hong kong is the 150 treatment line good enough to cover patients with paracetamol induced liver injury"
} | [
{
"companynumb": "PHHY2015HK148540",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"d... |
{
"abstract": "A 28-year-old man with type 1 diabetes mellitus was admitted for shock and coma due to diabetic ketoacidosis. Despite aggressive treatment and management of the patient's underlying clinical issues, the patient remained in a comatose state. Further investigations revealed an excess consumption of psychotropic agents; however, there was no evidence of an insulin overdose. Physicians should be aware that, in patients who are highly dependent upon insulin, an overdose of psychotropic agents can lead to hypoxic-ischemic brain injury.",
"affiliations": "Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.;Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, Japan.",
"authors": "Kawashita|Takeshi|T|;Nakajima|Mikio|M|;H Kaszynski|Richard|R|;Shirokawa|Masamitsu|M|;Nakano|Tomotsugu|T|;Ochiai|Koji|K|;Inoue|Yoshitaka|Y|;Goto|Hideaki|H|",
"chemical_list": "D001381:Azepines; D007004:Hypoglycemic Agents; D007328:Insulin; D011619:Psychotropic Drugs; D004155:Diphenhydramine; C084599:clotiazepam",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1041-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3021011010.2169/internalmedicine.1041-18Case ReportPersistent Vegetative State after Diabetic Ketoacidosis Triggered by an Overdose of Psychotropic Agents Kawashita Takeshi 1Nakajima Mikio 1H. Kaszynski Richard 1Shirokawa Masamitsu 1Nakano Tomotsugu 1Ochiai Koji 1Inoue Yoshitaka 1Goto Hideaki 1\n1 Emergency and Critical Care Center, Tokyo Metropolitan Hiroo Hospital, JapanCorrespondence to Dr. Takeshi Kawashita, m09034tk@jichi.ac.jp\n\n12 9 2018 15 1 2019 58 2 247 250 17 2 2018 2 7 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The 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 28-year-old man with type 1 diabetes mellitus was admitted for shock and coma due to diabetic ketoacidosis. Despite aggressive treatment and management of the patient's underlying clinical issues, the patient remained in a comatose state. Further investigations revealed an excess consumption of psychotropic agents; however, there was no evidence of an insulin overdose. Physicians should be aware that, in patients who are highly dependent upon insulin, an overdose of psychotropic agents can lead to hypoxic-ischemic brain injury. \n\ndiabetic ketoacidosishypoglycemiahypoxic-ischemic brain injurydrug overdosepersistent vegetative state\n==== Body\nIntroduction\nDiabetic ketoacidosis (DKA) is a serious life-threatening acute complication associated with diabetes mellitus (DM) and is caused by the absolute or relative depletion of insulin, which leads to severe hyperglycemia and ketoacidosis. Changes in the mental status usually occur in the acute phase of DKA; however, it can become a persistent clinical feature in an isolated fraction of cases. Some have reported that cerebral edema with poor neurological outcomes can be a complication of DKA in pediatric patients (1).\n\nWe herein report a case of DKA triggered by an overdose of psychotropic agents in an adult patient who proceeded into a persistent vegetative state (2), most likely as a result of underlying hypoxic-ischemic brain injury. The present case report serves as a reminder that, under certain conditions, DKA patients are at a higher risk of developing a persistent vegetative state.\n\nCase Report\nA 28-year-old man diagnosed with type 1 DM at 3 years of age was discovered in his house lying unconscious on his back. He was in a comatose state and was admitted to our emergency department. Three days prior to admission, the patient had been confirmed to be in a healthy state by his family; however, his family recalled the patient contemplating notions of suicide. He had never been diagnosed or treated for any psychological disorders and did not have a family history of DM. He had been treated with 24 units of insulin degludec and 7-8 units of insulin aspart in the morning, 6-8 units of insulin aspart at midday, and 13-15 units of insulin aspart in the evening.\n\nOn arrival, the patient was in deep comatose state, with a Glasgow Coma Scale (GCS) of E1V1M1. His body temperature was 36.0℃, blood pressure unmeasurable, heart rate 154 beats/min, and oxygen saturation (SpO2) 79% at 10 L/min supplemental oxygen. On a physical examination, the patient presented with a Kussmaul breathing pattern, and his pupils measured 2.5 mm bilaterally and were non-reactive to light. The remains of what appeared to be an admixture of gastric fluid/contents were found in varying amounts along the neck and face, suggesting frequent preceding episodes of nausea and vomiting. In his comatose state, the patient clamped his tongue with his jaws, resulting in discoloration and swelling that ultimately obstructed the patient's airway. He had a sacral decubitus ulcer measuring approximately 7 cm×7 cm.\n\nLaboratory tests showed metabolic acidosis, hemoconcentration, leukocytosis, elevated C-reactive protein levels, hyperglycemia (350 mg/dL), hypernatremia, hyperkalemia, renal dysfunction, and rhabdomyolysis (Table). Urine glucose and ketone levels were high as measured via Tes-TapeⓇ. Chest X-ray and computed tomography (CT) showed a consolidation in the lower-left lobe, which was likely due to chemical aspiration from vomiting. TriageⓇ Drugs of Abuse Panel (Sysmex, Kobe, Japan) and head CT showed no significant findings (Fig. 1).\n\nTable. Laboratory Data on Admission.\n\nComplete blood cell count\t\tArterial blood gas analysis (O2 at 10 L/min)\t\nWhite blood cells\t13,800\t/µL\t\tpH\t7.155\t\t\nHemoglobin\t19.0\tg/dL\t\tPaO2\t79.3\tmmHg\t\nHematocrit\t56.0\t%\t\tPaCO2\t24.4\tmmHg\t\nPlatelets\t30.7\t×104/µL\t\tHCO3-\t8.4\tmmol/L\t\n\t\t\t\tBase excess\t-18.2\tmmol/L\t\nBiochemical examination\t\tLactate‡\t5.25\tmmol/L\t\nSodium\t145\tmmol/L\t\t\t\t\t\nPotassium\t5.8\tmmol/L\t\tUrinalysis\t\t\t\nChloride\t108\tmmol/L\t\tProtein\t(3+)\t\t\nCalcium\t10.2\tmg/dL\t\tGlucose\t(3+)\t\t\nUrea nitrogen\t54.4\tmg/dL\t\tKetone bodies\t(3+)\t\t\nCreatinine\t1.15\tmg/dL\t\t\t\t\t\nTotal bilirubin\t1.7\tmg/dL\t\t\t\t\t\nCreatinine kinase\t2,298\tU/L\t\t\t\t\t\nLDH\t357\tU/L\t\t\t\t\t\nAST\t19\tU/L\t\t\t\t\t\nALT\t14\tU/L\t\t\t\t\t\nALP\t223\tU/L\t\t\t\t\t\nTotal protein\t8.6\tg/dL\t\t\t\t\t\nAlbumin\t4.5\tg/dL\t\t\t\t\t\nCRP\t17.39\tmg/dL\t\t\t\t\t\nGlucose\t465\tmg/dL\t\t\t\t\t\nHbA1c (NGSP) †\t7.6\t%\t\t\t\t\t\n†Reference value of HbA1C, 4.9–6.0%. ‡Reference value of blood lactate level, 0.50–2.00 mmol/L. LDH: lactate dehydrogenase, AST aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, CRP: C-reactive protein, HbA1c: glycated hemoglobin\n\nFigure 1. Head computed tomography findings on admission. There were no significant findings.\n\nWith a diagnosis of DKA, fluid resuscitation and continuous intravenous insulin infusion were initiated. After infusion of the initial 1,000 mL of extracellular fluid, the patient's blood pressure improved to 100/60 mmHg. Tracheal intubation and mechanical ventilation were warranted due to the patient's compromised mental status and respiratory failure. Shortly after intubation, the patient's SpO2 levels improved significantly. Glucose management was initiated with a target serum glucose level of 200 mg/dL. Despite the clinical correction of hypoxia, hypovolemia, hyperglycemia, renal dysfunction, infection, and electrolyte disorder, his altered mental status persisted.\n\nAn electroencephalogram on day 5 revealed generalized slow waves. Magnetic resonance imaging (MRI) of the brain with diffusion-weighted imaging and fluid-attenuated inversion recovery on the same day revealed hyperintensities in the bilateral basal ganglia but none in the thalamus, brainstem, or cerebellum. Other hyperintense regions were partially observed in the cortical layers (Fig. 2).\n\nFigure 2. Head magnetic resonance imaging on day 5. Hyperintensity in the bilateral basal ganglia was seen on (A) diffusion-weighted imaging and (B) fluid-attenuated inversion recovery. A hyperintense area was partially seen on the cortical layers on (C) diffusion-weighted imaging and (D) fluid-attenuated inversion recovery.\n\nSubsequent cursory observations of the patient's home by family members suggested that the patient had ingested 8 tablets of 25 mg diphenhydramine and 12 tablets of 5 mg clotiazepam, in what was most likely an attempted suicide. His insulin injectors were nearly full, and there was no evidence to suggest an insulin overdose. At its peak throughout the clinical course, the patient's mental status improved to a GCS of E3V1M4. The patient was subsequently transferred to a convalescent hospital on the 143rd hospital day.\n\nDiscussion\nAlthough rarely a persistent issue, disturbances in mental status are a frequent clinical feature of patients with DKA. We experienced a unique case in which the patient developed a persistent vegetative state (2) subsequent to DKA. Based upon the patient's clinical findings, the primary etiology of his status was attributed to hypoxic-ischemic brain injury due to airway obstruction caused by vomiting and suppression of breathing. His SpO2 on arrival was low despite being placed on highly concentrated oxygen supplementation. The presence of a sacral decubitus ulcer and rhabdomyolysis suggested that the patient had been unconscious in the supine position for an undetermined yet extended period of time. In addition, the ensuing hypovolemic shock from DKA likely aggravated the impaired oxygen delivery. High-intensity changes noted in the bilateral basal ganglia on T1-weighted imaging, as in this case, are associated with a poor neurological prognosis (3).\n\nHe ingested 3.08 kg/mg of diphenhydramine and 0.92 mg/kg of clotiazepam. This equates to a dosage equivalent to 41.9% of the lowest published human lethal dose of diphenhydramine (7.35 mg/kg) (4), 0.79% and 0.06% of the oral median lethal dose of diphenhydramine (390 mg/kg) (5) and clotiazepam (1,461 mg/kg) (6) in rats, respectively. No reports were available regarding the lowest published oral lethal dosage of clotiazepam in humans. We determined that neither of the drugs were within the lethal range; however, an overdose of diphenhydramine frequently causes nausea and vomiting, and clotiazepam holds the potential to suppress breathing. In addition, diphenhydramine exerts synergetic effects with central nervous system depressants. Therefore, these drugs may have contributed to the acceleration and exacerbation of the airway obstruction and respiratory suppression. In patients with ketoacidosis, hyperventilation usually occurs to compensate for the underlying metabolic acidosis. Patients with an overdose of psychotropic agents demonstrate a lack of respiratory compensation as a result of the drugs' natural tendencies to suppress ventilation, making these patients susceptible to pulmonary acidosis.\n\nGiven the consistency of the brain MRI findings, hypoglycemic encephalopathy is another differential diagnosis to consider with regard to the cause of the persistent vegetative state described in this case (7-9). Although there was no trace of insulin overdose, the patient could have developed hypoglycemia if he had ingested the psychotropic agent subsequent to delivering a normal dosage of insulin. While prognostic studies on hypoglycemic encephalopathy are limited, one study reported that irreversible central nervous system damage occurred more frequently when the hypoglycemic status was maintained for a period exceeding 60 min (10).\n\nIn this patient, disturbance of consciousness from an overdose of psychotropic agents may have led to an inability to self-medicate using insulin and subsequent DKA. The dehydration caused by the DKA likely delayed the excretion and clearance of the psychotropic agents and prolonged their sedative effects. Even when the effects of the psychotropic agents have dissipated, the simultaneous development of DKA resulted in the persistent disturbance of consciousness. Furthermore, vomiting, which is a hallmark of DKA (11, 12), most likely led to aspiration pneumonia, airway obstruction, and hypoxia in this patient.\n\nWe encountered a case of a persistent vegetative state in a patient with DKA compounded by a suicide attempt using psychotropic agents. Failure to administer insulin in type 1 DM patients causes DKA. Physicians should be aware that, in type 1 or type 2 DM patients who are highly dependent on insulin, an overdose of psychotropic agents can increase the risk of developing hypoxic-ischemic brain injury.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nWolfsdorf J , Glaser N , Sperling MA \nDiabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association . Diabetes Care \n29 : 1150 -1159 , 2006 .16644656 \n2. \nMulti-Society Task Force on PVS .\n \nMedical aspects of the persistent vegetative state (2) . N Engl J Med \n330 : 1572 -1579 , 1994 .8177248 \n3. \nNogami K , Fujii M , Kato S , et al \nAnalysis of magnetic resonance imaging (MRI) morphometry and cerebral blood flow in patients with hypoxic-ischemic encephalopathy . J Clin Neurosci \n11 : 376 -380 , 2004 .15080951 \n4. \nArena JM : Poisoning; Toxicology, Symptoms, Treatments. 2nd ed . Thomas , Springfield , 1970 : 73 .\n5. \nRuss Pharmacol Toxicol.\nEuromed Publications, London,\n40:\n42,\n1977\n.\n6. Drugs in Japan . 6th ed \nJiho , Tokyo , 1982 : 233 (in Japanese).\n7. \nKang EG , Jeon SJ , Choi SS , et al \nDiffusion MR imaging of hypoglycemic encephalopathy . AJNR Am J Neuroradiol \n31 : 559 -564 , 2010 .19875472 \n8. \nKuriyama A , Sato K \nHypoglycemic encephalopathy . CMAJ \n187 : E437 , 2015 .26170269 \n9. \nMa JH , Kim YJ , Yoo WJ , et al \nMR imaging of hypoglycemic encephalopathy: lesion distribution and prognosis prediction by diffusion-weighted imaging . Neuroradiology \n51 : 641 -649 , 2009 .19533113 \n10. \nSakel M \nThe methodical use of hypoglycemia in the treatment of psychoses. 1937 . Am J Psychiatry \n151 : 240 -247 , 1994 .8192206 \n11. \nMatz R \nHypothermia in diabetic acidosis . Hormones \n3 : 36 -41 , 1972 .4631908 \n12. \nImagawa A , Hanafusa T , Uchigata Y , et al \nFulminant type 1 diabetes: a nationwide survey in Japan . Diabetes Care \n26 : 2345 -2352 , 2003 .12882860\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(2)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "diabetic ketoacidosis; drug overdose; hypoglycemia; hypoxic-ischemic brain injury; persistent vegetative state",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D001381:Azepines; D003922:Diabetes Mellitus, Type 1; D003926:Diabetic Coma; D016883:Diabetic Ketoacidosis; D004155:Diphenhydramine; D062787:Drug Overdose; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D018458:Persistent Vegetative State; D011619:Psychotropic Drugs; D012769:Shock; D013406:Suicide, Attempted",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "247-250",
"pmc": null,
"pmid": "30210110",
"pubdate": "2019-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12882860;15080951;16644656;19533113;19875472;26170269;4631908;8177248;8192206",
"title": "Persistent Vegetative State after Diabetic Ketoacidosis Triggered by an Overdose of Psychotropic Agents.",
"title_normalized": "persistent vegetative state after diabetic ketoacidosis triggered by an overdose of psychotropic agents"
} | [
{
"companynumb": "JP-SA-2019SA035975",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Sudden unexpected death in epilepsy (SUDEP) has been defined as a sudden/unexpected, witnessed/unwitnessed, nontraumatic, and nondrowning death in epileptic patients with/without seizure evidence and documented status epilepticus. Identified as the leading cause of epilepsy-related deaths, SUDEP cases are highly unrecognized and underreported due to diagnostic difficulty. We report a case of a successfully revived hemodialysis patient who developed cardiopulmonary arrest after a witnessed convulsive seizure. Electroencephalogram revealed epileptic abnormalities. Therefore, this case could be seizure-induced cardiopulmonary arrest and near-SUDEP. Hence, the possibility of SUDEP should be considered even in hemodialysis patients having conventional coronary risk factors for sudden cardiac death.",
"affiliations": "Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan. g-kanzaki@jikei.ac.jp.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan.",
"authors": "Hatano|Satoki|S|;Kanzaki|Go|G|0000-0002-7795-369X;Marumoto|Hirokazu|H|;Niikura|Takahito|T|;Honda|Kosuke|K|;Nakada|Yasuyuki|Y|;Morita|Masayo|M|;Hasegawa|Takashi|T|;Yokoo|Takashi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-021-00611-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(4)",
"journal": "CEN case reports",
"keywords": "Cardiopulmonary arrest (CPA); Hemodialysis (HD); Seizure; Sudden unexpected death in epilepsy (SUDEP)",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "582-587",
"pmc": null,
"pmid": "34037940",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "31903040",
"title": "Near-sudden unexpected death in a patient with epilepsy undergoing hemodialysis: a case report.",
"title_normalized": "near sudden unexpected death in a patient with epilepsy undergoing hemodialysis a case report"
} | [
{
"companynumb": "JP-ROCHE-2953351",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "BACKGROUND\nTo prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC).\n\n\nMETHODS\n504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed.\n\n\nRESULTS\nA statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7-9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001).\n\n\nCONCLUSIONS\nThe presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients' prognosis.",
"affiliations": "Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece ; Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece.;Laboratory of Pathology, University General Hospital, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece ; Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece.;Laboratory of Pathology, University General Hospital, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece ; Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece ; Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece.",
"authors": "Saridaki|Zacharenia|Z|;Tzardi|Maria|M|;Sfakianaki|Maria|M|;Papadaki|Chara|C|;Voutsina|Alexandra|A|;Kalykaki|Aristea|A|;Messaritakis|Ippokratis|I|;Mpananis|Kyriakos|K|;Mavroudis|Dimitris|D|;Stathopoulos|Efstathios|E|;Georgoulias|Vassilis|V|;Souglakos|John|J|",
"chemical_list": "C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0084604",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 24367680PONE-D-13-2501610.1371/journal.pone.0084604Research Article\nBRAFV600E Mutation Analysis in Patients with Metastatic Colorectal Cancer (mCRC) in Daily Clinical Practice: Correlations with Clinical Characteristics, and Its Impact on Patients’ Outcome BRAF Mutations, Prediction, Metastatic CRCSaridaki Zacharenia \n1\n\n2\nTzardi Maria \n3\nSfakianaki Maria \n1\nPapadaki Chara \n1\nVoutsina Alexandra \n1\nKalykaki Aristea \n1\nMessaritakis Ippokratis \n1\nMpananis Kyriakos \n1\nMavroudis Dimitris \n1\n\n2\nStathopoulos Efstathios \n3\nGeorgoulias Vassilis \n1\n\n2\nSouglakos John \n1\n\n2\n\n*\n\n1 \nLaboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece\n\n2 \nDepartment of Medical Oncology, University General Hospital, Heraklion, Crete, Greece\n\n3 \nLaboratory of Pathology, University General Hospital, Heraklion, Crete, Greece\nReis Rui Manuel Editor\nUniversity de Minho, Portugal\n* E-mail: georgsec@med.uoc.grCompeting Interests: The authors have declared that no competing interests exist. Asst. Professor John Souglakos serves the PlOS ONE Journal as an academic editor. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: ZS DM ES VG JS. Performed the experiments: ZS MT MS CP AV AK IM KM JS. Analyzed the data: ZS JS. Contributed reagents/materials/analysis tools: ZS MT MS CP AV AK IM KM JS. Wrote the manuscript: ZS VG JS. \n\n2013 18 12 2013 8 12 e8460416 6 2013 15 11 2013 © 2013 Saridaki et al2013Saridaki et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nTo prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC). \n\nPatients and Methods\n504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed. \n\nResults\nA statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7–6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7–9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001). \n\nConclusions\nThe presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients’ prognosis.\n\nThis work was partly supported by a grant from the Cretan Association for Biomedical Research (CABR) and the Hellenic Society for Medical Oncology (HeSMO). Z.S., I.M. and A.V. are recipients of a CABR post-doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\n Mutations in the BRAF oncogene have been found in approximately 8% of human cancers, including 50-60% of melanomas, 30-70% of thyroid cancers, 30% of serous low-grade ovarian cancers and 10% of CRCs[1]. The most common oncogenic mutation accounting for more than 95% of the mutations in BRAF found in CRCs is the single substitution missense mutation V600E, which is located within the kinase domain of the gene[2]. This amino acid change results in constitutive activation of the BRAF kinase and promotes cell transformation[1,3].. Mutations in other codons of the BRAF gene in colon cancer are extremely rare, counting for <5% of all mutations in the gene [2].\n\nSeveral studies have reported that the existence of a BRAF mut ation in a primary CRC tumor marks patients who carry an especially poor prognosis, regardless o ftreatment type administration. Its presence has been associated with decreased survival in early-operable stages treated with adjuvant chemotherapy[4]. similarly, in the metastatic disease setting patients do not seem to respond to any of the existing chemotherapy regimens and their outcome resembles that of untreated patients[5-8]. In CRC, BRAF mutations are reported to occur more frequently in cases characterized by the presence of a defective DNA mismatch repair (dMMR) system resulting in microsatellite instability (MSI)[9-11]; this seems to be due to hMLH1 promoter hypermethylation (sporadic CRC) and not to germ-line alterations (hereditary CRC)[12,13]. As it has been previously reported, the BRAF mutation retains its prognostic value both in MSI-high and in microsatellite stable (MSS) tumors[4-6,14]; the latter being also confirmed by the recently published BRAF signature[15].\n\nBesides its prognostic implications, several retrospective studies have attributed a predictive role to the BRAFV600E mutation due to the observed lack of benefit related to treatment with anti-EGFR moAbs. This was, initially, first documented by Di Nicolantonio et al[3], and Souglakos et al[8], but over the years, this was further confirmed by subsequent studies[7,16,17]. Furthermore, this mutation’s adverse prognostic significance was confirmed in the post-hoc subgroup analysis in two first line phase III randomized trials [CAIRO2 and CRYSTAL][18,19]. Despite the fact that, the above mentioned data require further validation in prospective randomized trials, they support the notion that the natural history and response to treatment to various chemotherapeutic regimens of BRAF-mutant CRC tumors differ markedly from the BRAF wild type tumors. Apparently, a mutant BRAF does not simply substitute for KRAS activation in a linear signaling pathway; most likely it confers distinct characteristics with ominous consequences, something which justifies its utilization in patient selection and stratification in future clinical trials[8].\n\nIn order to evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice, to investigate its correlation with the various clinico-pathological characteristics, as well as, its prognostic and predictive impact, we sought to conduct this study in a prospective database of CRC patients treated for metastatic disease. \n\nPatients and Methods\nPatient population\nThe study was approved by the Ethics Committee/ Institutional review board of the University Hospital of Heraklion and all patients gave their written informed consent for the use of the tissue material for translational research. Since 1/1/2007 until 31/12/2012, we prospectively analyzed for BRAF V600E all patients with newly diagnosed mCRC at the Department of Medical Oncology, University Hospital of Heraklion (Crete, Greece). Five hundred and four consecutive patients, with histologically confirmed mCRC and available tumor material for molecular analysis, who were treated with at least one cycle of systemic chemotherapy with or without the addition of bevacizumab, cetuximab or panitumumab were enrolled. Patients’ evaluation was performed at baseline and every four cycles of chemotherapy. Disease status was coded, without the knowledge of the laboratory analysis. \n\nTissue selection and DNA extraction\nFormalin-fixed, paraffin-embedded (FFPE) tumor sections were reviewed by a pathologist (MT) to confirm the diagnosis and define tumor-enriched areas for dissection. Ten serial sections of 5μm thickness were stained with nuclear fast red (Sigma-Aldrich, St Louis, MO, USA) and scrape dissection under a binocular microscope was performed for samples with ≥ 80% tumor cells; for samples with < 80% malignant cells, microdissection with the piezoelectric Eppendorf microdissector (Eppendorf, Hamburg, Germany) was performed. DNA extraction was performed using the MasterPure™ Complete DNA and RNA Purification Kit according to the manufacturer’s instructions (Epicentre Biotechnologies, Madison, WI, USA) and the isolated cancer cells were lysed in buffer containing Proteinase K at 60 °C for 72 h.[11] \n\nKRAS mutational analysis\nKRAS mutational analysis was performed by Sanger sequencing after PCR amplification of KRAS exon 2. PCR conditions and primers sets used have been previously reported[8]. \n\nBRAF mutational analysis\nThe V600E BRAF mutation was detected by real-time PCR using the allelic discrimination method as previously described[11,20]. In brief, tumor cells’ DNA was amplified with the use of a set of primers and two hydrolysis probes in the ABI PRISM 7900T Sequence Detection System (AB; Applied Biosystems, Forest City; CA; USA). The two hydrolysis probes were labeled at 5’ with VIC and FAM fluorophores reporters for the wt and the mutant allele, respectively. The SDS 2.3 software was used for the analysis of the results.\n\nStudy Design\nThe aim of this study was to evaluate the usefulness of the BRAFV600E detection in the daily clinical practice and to correlate its existence with clinical and pathological characteristics, as well as treatment outcome in order to define possible prognostic and/or predictive implementations in a prospective database of patients with mCRC. All available biopsies of the primary tumor with more than 100 cells per section were included in the analysis. Associations between BRAF and baseline characteristics were assessed using the Fisher's exact test for categorical variables or logistic regression for continuous variables. Progression Free Survival (PFS) and overall survival (OS) were measured from the date of diagnosis of metastatic disease to the first radiographic documentation of disease progression or death, respectively. Kaplan–Meier curves were used to describe the proportion of patients who remained free of events over the follow-up period. Associations between prognostic factors and PFS or OS were examined using Cox proportional hazards regression models. All reported p-values are two-sided and not adjusted for multiple testing.\n\nResults\nPatients’ characteristics and disease features\nThe characteristics of the enrolled patients were typical for metastatic CRC and are summarized in Table 1. In brief, the median patients’ age was 64 year (range: 21-89), 59% were men and their PS (ECOG) was 0-1 (90%); the primary tumor was located in the rectum in 28% of the patients and in 40% of the cases was undifferentiated (high grade) (Table 1). Twenty-seven per cent of the patients had one metastatic site and 64 (13%) underwent a metastasectomy with curative intent after the administration of systemic treatment. The BRAFV600E mutation was detected in 41 (8.2%) patients and in all cases was mutually exclusive with KRAS mutations which were detected in 217 (43%) of the total study population. \n\n10.1371/journal.pone.0084604.t001Table 1 Patients’ and Tumors’ Characteristics and Univariate analysis of Survival.\n\nFeature\n\t\nΝ\n\t\n%\n\t\nProgression Free Survival\n\n\t\nOverall Surivival\n\n\t\n\t504\t100\tMedian (months)\tHR*\t95% CI@\n\t\np value\tMedian (months)\tHR*\t95% CI@\n\t\np value\t\nMedian Age (Range)\t64(21-89)\t\n\nAge\n\t\n≤ 65 years\t271\t54\t11.5\t1.17\t0.91-1.51\t0.225\t32.3\t0.82\t0.61-1.04\t0.07\t\n> 65 years \t231\t46\t10.0\t\t\t\t27.8\t\t\t\t\n\nGender\n\t\nMale \t297\t59\t9.9\t1.11\t0.86-1.43\t0.42\t33.2\t0.98\t0.76-1.25\t0.85\t\nFemale \t207\t41\t11.2\t\t\t\t34.6\t\t\t\t\n\nTumor Location\n\t\nColon\t362\t72\t10.7\t1.05\t0.72-1.52\t0.802\t33.8\t0.96\t0.71-1.71\t0.65\t\nRectum\t142\t28\t11.1\t\t\t\t33.7\t\t\t\t\n\nTumor Differentiation\n\t\nHigh Grade (Undifferentiated)\t200\t40\t7.9\t1.81\t1.40-2.34\t0.001\t23.8\t2.29\t1.74-3.02\t0.001\t\nLow Grade (Well-Moderate Differentiated) \t304\t60\t11.6\t\t\t\t34.9\t\t\t\t\n\nMucinousFeatures\n\t\nYes\t99\t20\t9.8\t1.27\t0.68-2.38\t0.089\t29.8\t1.42\t1.18-2.01\t0.124\t\nNo\t405\t80\t11.2\t\t\t\t33.5\t\t\t\t\n\nECOG PS#\n\t\n0-1\t454\t90\t11.9\t1.96\t1.54-2.83\t0.001\t35.7\t2.31\t1.18-4.06\t0.027\t\n2\t50\t10\t7.8\t\t\t\t17.5\t\t\t\t\n\nNumber of metastatic sites\n\t\n\n1\n\t139\t27\t11.4\t1.24\t0.84-1.82\t0.95\t33.8\t1.58\t0.91-2.13\t0.097\t\n\n>1\n\t365\t73\t9.8\t\t\t\t28.9\t\t\t\t\n\nMetastasectomy\n\t\nYes\t65\t13\t22.3\t0.29\t0.09-0.42\t<0.001\t52.7\t0.31\t0.19-0.50\t0.001\t\nNo\t439\t87\t9.8\t\t\t\t29.9\t\t\t\t\n\nKRAS mutations\n\t\nWild Type\t286\t57\t10.3\t1.06\t0.81-1.37\t0.69\t34.4\t1.23\t0.90-1.67\t0.189\t\nMutant\t218\t43\t10.9\t\t\t\t27.6\t\t\t\t\n\nBRAFV600E mutations\n\t\nWild Type\t462\t91.8\t11.6\t4.07\t2.66-6.20\t<0.001\t34.6\t5.43\t3.60-8.18\t<0.001\t\nMutant\t42\t8.2\t4.1\t\t\t\t14.0\t\t\t\t\n\nKRAS/BRAF\nV600E mutations\t\nDouble Wild Type\t244\t48\t13.3\t1.89\t1.65-2.18\t0.034\t36.2\t2.28\t1.79-3.01\t0.016\t\n\nKRAS or BRAF\nV600E mutant\t260\t52\t9.6\t\t\t\t21.6\t\t\t\t\n*HR: Hazard Ratio, @CI: Confidence Interval, #PS: Performance Status\n\nSystemic treatment and patients’ outcome\nThe median time from initial diagnosis to diagnosis of metastatic disease was 21.6 months (95% CI 17.6–24.2) for patients with early-stage disease (stage I-III) and the median interval from the diagnosis of metastatic disease to treatment initiation 0.6 months (95% CI 0.4–1.0). The median follow up time was 30.4 months (range, 2.6-72.9 months) and at the time of analysis 329 (65%) patients were deceased, mainly from disease progression (n=322; 98%); five (1%) deaths were treatment-related and two (0.4%) were due to reasons unrelated to disease or treatment. The median PFS was 10.5 months (95% CI: 8.9-12.4) and the median OS 29.9 months (95% CI: 26.8-34.5). All patients were treated with 5-FU-based first-line chemotherapy and in 96% of the cases the patients received an oxaliplatin or irinotecan combination (Table 2). Two hundred and thirty nine (48%) patients received also bevacizumab in combination with chemotherapy in the first line setting, while an anti-EGFR monoclonal antibody was administered in 74 (14.7%) of the patients in the first line setting and in 273 (54%) in the 2nd or subsequent treatment lines (Table 2). The vast majority of the patients has been treated with 2nd line systemic treatment. No difference was observed in the percentage of patients treated with 2nd line treatment between BRAF WT and mutant patients; groups (p=0.314) (Table 3). \n\n10.1371/journal.pone.0084604.t002Table 2 Systemic treatment.\n\nREGIMENS\n\t\nN\n\t\n%\n\t\nOxaliplatin-based1st line \t174\t34\t\nIrinotecan-based 1st line \t195\t39\t\nFOLFOXIRI \t115\t23\t\nFluoropyrimidins monotherapy \t18\t4\t\nBevacizumab + chemotherapy 1st line\t239\t48\t\nCetuximab or Panitumumab 1st line \t74\t15\t\nCetuximab or Panitumumab Salvage treatment \t273\t54\t\n10.1371/journal.pone.0084604.t003Table 3 Correlation of BRAFV600E mutation with clinical and pathological characteristics.\n\nFeature No (%)\n\n\t\nBRAFV600E\n\n\t\np value\n\t\n\t\tTotal\tWild Type\tMutant\t\t\n\nAge\n\t≤ 65 years\t270 (54)\t254 (94.1)\t16 (5.9)\t0.004\t\n\t> 65 years\t232 (46)\t207 (89.2)\t25 (10.8)\t\t\n\nTumor Differentiation\n\tLow grade\t303 (60)\t290 (95.7)\t13 (4.3)\t0.001\t\n\tHigh grade\t199 (40)\t171 (86.9)\t28 (14.1)\t\t\n\nTumor Location\n\tColon\t361 (72)\t324 (89.8)\t37 (10.2)\t<0.001\t\n\tRectum\t141 (28)\t137 (97.2)\t4 (2.8)\t\t\n\nMucinous\n\tYes\t98 (20)\t84 (86)\t14 (14)\t0.0037\t\n\tNo\t404 (80)\t377 (94.6)\t27 (5.4)\t\t\n\nECO PS#\n\t0-1\t453 (90)\t432 (95.2)\t21 (4.6)\t<0.001\t\n\t2\t49 (10)\t29 (39)\t20 (41)\t\t\n\nNumber of metastatic sites\n\t1\t138 (27)\t133 (96.4)\t5 (3.6)\t0.002\t\n\t>1\t364 (73)\t328 (90.1)\t36 (9.9)\t\t\n\n2nd line treatments\n\tYes\t489\t449 (90.1)\t40 (9.1)\t0.314\t\n\tNo\t25\t23 (86.7)\t2 (13.3)\t\t\n\nMetastasectomy\n\tYes\t65 (13)\t64 (98.5)\t1 (1.5)\t<0.001\t\n\tNo\t439 (87)\t398 (91)\t41 (9)\t\t\nCorrelations of BRAF mutation with clinico-pathological features and patients’ Progression Free and Overall Survival\nThe detection of the BRAFV600E mutation has been correlated with specific clinical characteristics and pathological features (Table 3). More precisely, the BRAFV600E mutation was detected in 10.8% and 5.9% (p=0.004) of the patients older and younger than 65 years old, respectively. Also, high grade tumors presented a higher frequency of the BRAFV600E mutation (14.1%) in comparison with low grade tumors (4.3%; p=0.001). In addition, a higher incidence of the BRAFV600E mutation was found in tumors located in the colon (10.2%) than in the rectum (2.8%; p<0.001), as well as in tumors with mucinous histology (14%) compared to those with non mucinous features (5.4%; p=0.037). Finally, the BRAFV600E mutation was more frequently detected in patients with ECOG PS 2 (41%) compared to those with PS 0-1 (4.6%; p<0.001) and in patients with multiple metastasis (9.9%) compared to those with one metastatic site (3.6%; p=0.002) (Table 3). There was no significant correlation between the BRAFV600E mutation status and the gender (p=0.412). Only one patient (1.5) with BRAF\nV600E mutation underwent a metastasectomy in comparison with 63 (13%) patients with WT BRAF tumors (p<0.001).\n\nUnivariate analysis revealed significant association of several clinical and pathological features with PFS and/or mOS. Indeed, patients with BRAFV600E mutated primary tumors presented significantly lower PFS (4.1 vs. 11.6 months; HR: 4.07, 95% CI: 2.66-6.20; p<0.001) in comparison with those with BRAF wild type primary tumors (Table 1 and Figure 1A); this finding was independent of the type of the administered first line treatment (all p values > 0.05). Similarly, the PFS was significantly lower in patients with high grade tumors (7.9 vs. 11.6 months; HR: 1.81, 95% CI: 1.40-2.34; p=0.001) and ECOG PS 2 (7.8 vs. 11.9 months; HR: 1.81, 95% CI: 1.54-2.83; p=0.001) in comparison to those with low grade tumors and ECOG PS 0-1, respectively (Table 1). In addition, patients with both KRAS/BRAFV600E WT tumors present significantly higher PFS (13.3 vs. 9.6 months; HR: 1.89, 95% CI: 1.65-2.16; p=0.034) in comparison with those with any mutation in KRAS or BRAF\nV600E (Table 1) In contrast, patients who underwent a metastasectomy of a metastasis with curative intent presented significantly higher PFS (22.3 vs. 9.8 months; HR: 0.29, 95% CI: 0.09-0.42; p<0.001) (Table 1). There was no significant association between PFS and age, gender, tumor location, mucinous histology, number of metastatic sites and KRAS mutations (Table 1).\n\n10.1371/journal.pone.0084604.g001Figure 1 Progression Free Survival in 1st systemic treatment according to BRAFV600Emutation in 504 patients with metastatic Colorectal Cancer (A) and Median Overall Survival according to BRAFV600Emutation in 504 patients with metastatic Colorectal Cancer (B).\nUnivariate analysis also showed that patients with BRAFV600E mutated primary tumors had significantly lower median OS (14.0 vs. 34.6 months; HR: 5.43, 95% CI: 3.60-8.18; p<0.001) in comparison with those with wt primary tumors (Table 1, Figure 1B), independently from the type of the administered first line treatment. In addition, the median overall survival was significantly higher in patients with low grade tumors (34.9 vs. 23.8 months; HR: 2.29, 95% CI: 1.74-3.02; p=0.001), PS 0-1 (35.7 vs 17.8 months; HR: 2.31, 95% CI: 1.18-4.06; p=0.001) and those who underwent metastasectomy (52.7 vs. 29.9 months; HR: 0.31, 95% CI: 0.19-0.50; p=0.001) (Table 1). Also, patients with both KRAS/BRAFV600E WT tumors present significantly prolonged median OS (36.2 vs. 21.6 months; HR: 2.28, 95% CI: 1.79-3.01; p=0.034) in comparison with those with any mutation in KRAS or BRAF\nV600E (Table 1). There was no significant association between mOS and gender, tumor location, mucinous histology, number of metastatic sites or KRAS mutations status, while a non significant trend has been observed for improved survival in patients younger than 65 years of age (32.3 vs. 27.8 months; HR: 0.82, 95% CI: 0.61-1.04; p=0.07) compared to those over 65 years of age (Table 1).\n\nThe multivariate analysis confirmed that the detection of the BRAFV600E mutation was strongly correlated with both decreased PFS (HR: 4.1, 95% CI: 2.7-6.2; p<0.001) and OS (HR: 5.9, 95% CI: 3.7-9.5; p<0.001) (Table 4). Likewise, high grade tumor and poor PS (ECOG 2) emerged as independent prognostic factors for shorter PFS (HR: 2.3, 95% CI: 1.4-3.1; p=0.008 and HR: 1.6, 95% CI: 1.2-2.1, respectively; p=0.034) and shorter mOS (HR: 2.8, 95% CI: 1.8-4.1; p=0.003 and HR: 1.7, 95% CI: 1.4-2.3, respectively; p=0.021) (Table 4). Similarly, metastasectomy with curative intent emerged as an independent prognostic factor for improved PFS (HR: 0.4, 95% CI: 0.26-0.8; p=0.003) and mOS (HR: 0.6, 95% CI: 0.4-0.9; p=0.028) (Table 4).\n\n10.1371/journal.pone.0084604.t004Table 4 Multivariate analysis.\n\t\nHazard Ratio\n\t\n95% CI*\n\t\np value\n\t\n\nProgression-Free Survival\n\t\n\nBRAF (mutant vs. WT*)\n\t4.1\t(2.7 -6.2)\t<0.001\t\n\nTumor Grade (High vs. Low) \t2.3\t(1.4 - 3.1)\t0.008\t\n\nMetastatectomy (yes vs. no) \t0.4\t(0.26- 0.8)\t0.003\t\n\nECOG PS (2 vs. 0-1)\n\t1.6\t(1.2-2.1)\t0.034\t\n\nOverall Survival\n\t\n\nBRAF (mutant vs. WT*)\n\t5.9\t(3.7 -9.5)\t<0.001\t\n\nTumor Grade (High vs. Low) \t2.8\t(1.8- 4.1)\t0.003\t\n\nMetastatectomy (yes vs. no) \t0.6\t(0.4 - 0.9)\t0.028\t\n\nECOG PS (2 vs. 0-1)\n\t1.7\t(1.4-2.3)\t0.021\t\nPredictive significance of BRAFV600E mutation in treatment with anti-EGFR monoclonal antibodies\nSeventy-four (25%) patients, with KRAS wt primary tumοrs, received an anti-EGFR monoclonal antibody in combination with chemotherapy as first line treatment. BRAF mutations were detected in 6 (8.1%) patients. Although the median PFS and OS were arithmeticaly lower in patients with BRAFV600E mutations compared to patients with wild type BRAFV600E status (4.2 vs. 11.1 months and 14.3 vs. 35.0 months, respectively) these differences were not statistically different probably because of the small sample size.. On the other hand, 273 patients with KRAS wt primary tumors were treated with an anti-EGFR mAb as second (84 patients, 31%) or subsequent line of treatment (189 patients, 69%). Patients with BRAFV600E mutant tumors (22 patients, 8%), presented significantly shortened PFS (2.2 vs. 6.0 months, p<0.0001) and mOS (4.3 vs. 17.4 months, p<0.0001) compared with those with BRAFV600E wt tumors (Figure 2A and B), stratified for the line of treatment. Another 13 patients with BRAF\nV600E mutation were not treated with anti-EGFR mAbs, in the 2nd or higher treatment lines. Eleven of them received 2nd line combination chemotherapy and the median PFS was 2.4 months while the median OS was 4.8, comparable with those observed in patients with BRAF\nV600E mutations treated with anti-EGFR mAbs.\n\n10.1371/journal.pone.0084604.g002Figure 2 Progression Free Survival to salvage treatment with an anti-EGFR monoclonal (stratified for the treatment line) antibody according to BRAF\nV600Emutation in 273 patients with metastatic Colorectal Cancer (A) and Median Overall Survival to salvage treatmentwith an anti-EGFR monoclonal antibody (stratified for the treatment line) according to BRAF\nV600Emutation in 273 patients with metastatic Colorectal Cancer (B).\nDiscussion\nIn this present study we evaluated the impact of BRAFV600E testing for mCRC patients in daily clinical practice. To the best of our knowledge this is the largest prospective series of patients ever reported in the literature providing valuable data regarding epidemiological patterns, as well as, the impact of the BRAFV600E mutation status on patients’ outcome. Indeed the incidence of the mutation is significantly higher in patients with ECOG PS 2 (41%) compared to those with ECOG PS 0-1 (4.6%; p<0.001), but also in patients with undifferentiated tumors (14.1%), multi-metastatic disease (9.9%) and advanced age (10.8%) in comparison to those with differentiated tumors (4.3%; p=0.001), disease confounded in one metastatic site (3.6%; p=0.002) and aged ≤ 65 years (5.9%; p=0.004). On the other hand, the incidence of the BRAFV600E mutation was very low in patients with metastatic rectal cancer (2.8%). These data indicate that the BRAFV600E mutation is correlated with other know detrimental clinical prognostic factors whose may influence the patients’ outcome. On the other hand, one may argue that the aggressive biological behavior of tumors harboring a BRAFV600E is responsible for the presence of these clinical factors such as rapidly progressive multimetastatic disease and poor performance status or low probability of a secondary metastasectomy. Our study proposes that the assessment of BRAFV600E mutation is a step forward into “personalized treatment” since may modify the treatment intent (palliative or curative) and by that may influence the treatment strategy. \n\nAlso, the current study, confirms in a prospectively analyzed patients’ cohort the adverse prognostic significance of the BRAFV600E mutation which has been previously reported in retrospective studies[3,6,8,11,14]. In fact, patients with BRAFV600E mutation in their primary tumor had significantly lower median PFS (4.1 vs. 11.6 months; HR: 4.07, 95% CI: 2.66-6.20; p<0.001) and OS (14.0 vs. 34.6 months; HR: 5.43, 95% CI: 3.60-8.18; p<0.001; Figure 1A-B), while the BRAFV600E mutation was revealed as the strongest independent factor for decreased PFS (HR: 4.1, 95% CI: 2.7-6.2; p<0.001) and OS (HR: 5.9, 95% CI: 3.7-9.5; p<0.001; Table 4). These findings are in agreement with previous retrospective studies from our group[8,11] and others[3,6,14,18] regarding the adverse prognostic significance of the BRAFV600E mutation in CRC. \n\nWe also observed, in accordance with previous reports[3,7,8,16,18], that patients with BRAFV600E gain a limited if any benefit from the treatment anti-EGFR mAbs. In fact, patients with BRAFV600E mutant tumors treated with an anti-EGFR mAB in the second or subsequent line, presented significantly decreased median PFS (2.2 vs. 6.0 months, p<0.0001) and mOS (4.3 vs. 17.4 months, p<0.0001) compared to those with BRAFV600E wt tumors (Figure 2A and B). The same finding has been observed both in retrospective studies in series of patients[3,7,8,16,21], as well as, in randomized clinical trials[18]. On the other hand, the investigators in the CRYSTAL study reported a minor benefit from the addition of cetuximab to chemotherapy (FOLFIRI) in patients with BRAFV600E mCRC, but this finding remains questionable since an interaction test is not provided[19]. However, the adverse prognostic significance of the BRAFV600E mutation is clearly demonstrated even in this retrospective analysis of the CRYSTAL trial[19].. Our data as well as those from the studies previously mentioned suggest that the anti-EGFR moAbs are not capable to reverse the adverse prognosis of the BRAFV600E mutation. The current study is not capable to answer the questions where the BRAFV600E mutation has a predictive value for the treatment with anti-EGFR moAbs or if the patients with BRAFV600E mutation should be treated or not with anti-EGFR mAbs. This question should be probable addressed in a prospective manner either with a combination of BRAF and anti-EGFR inhibitor using an adaptive model or in a randomize trial using the BRAFV600E mutation as stratification factor.\n\nNevertheless, the analysis of mutations in RAS/RAF pathway has been proven significantly important for the management of patients with mCRC. In the present study patients with double WT type tumors present significantly higher PFS (HR: 1.89; p=0.034) and median OS (HR: 2.28; p=0.016) in comparison with those with a mutation in either of KRAS or BRAF genes. In addition, recently reported studies emphasize the importance of KRAS mutations outside hotspots in codon 12 and 13, as well as, of the NRAS mutations, especially in patients treated with Panitumumab [22], All the data emphasize the importance of the testing for RAS/RAF family in mCRC in order to design the optimal treatment strategy in the daily clinical practice. \n\nFrom the biological point of view our results support the concept that CRC with BRAFV600E is a distinct subset of the disease with specific biological characteristics. Indeed, the BRAFV600E mutation in CRC is correlated with MSI-H status and cyclin D1 overexpression, and characterizes a subgroup of patients with poor prognosis[9-11]. In addition, the distinct natural history and unresponsiveness of BRAF-mutant tumors to the commonly used chemotherapeutic regimens implies that BRAFV600E mutation does not simply substitute for KRAS activation in a linear signaling pathway but likely confers additional or distinct properties. For example, in cell cultures, the V600E mutation increases BRAF activity independent of KRAS and shows lower transforming activity[1], while inhibition of MEK with small molecules prevents tumor growth in BRAF-mutant tumor xenografts but not in KRAS-mutant counterparts[23]. These dissimilarities may in part explain the differences regarding the prognostic value of activating KRAS and BRAF mutations.\n\nFinally, the analysis of the BRAFV600E in the daily clinical practice is feasible since it may be performed from the same DNA used for the analysis of the KRAS mutations which is mandatory for all patients with mCRC[24]. The analysis of the BRAFV600E using the allelic discrimination method is sensitive (sensitivity > 95%)[11,20], inexpesinsive [20] and provides the results within two hours. \n\nIn summary, the BRAFV600E mutation identifies a subgroup of mCRC patients with distinct biological behavior, clinical characteristics and pathological features. These patients often present metastatic disease in multiple sites, have poor PS and a poor prognosis, being resistant to all currently available treatment options. The analysis of the BRAFV600E mutation in the daily clinical practice may be a step forward in the concept of “personalized” management of patients with mCRC, since new agents targeting this specific mutation are urgently warranted.\n==== Refs\nReferences\n1 \nDavies H , Bignell GR , Cox C , Stephens P , Edkins S \net al. (2002 ) Mutations of the BRAF gene in human cancer . Nature \n417 : 949 -954 . doi:10.1038/nature00766 . PubMed: 12068308.12068308 \n2 http: and www.sanger.ac.uk/genetics/CGP/cosmic/ . COSMIC database. 13 A.D. Ref type: internet communication \n3 \nDi Nicolantonio F , Martini M , Molinari F , Sartore-Bianchi A , Arena S \net al. (2008 ) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer . J Clin Oncol \n26 : 5705 -5712 . doi:10.1200/JCO.2008.18.0786 . PubMed: 19001320.19001320 \n4 \nFrench AJ , Sargent DJ , Burgart LJ , Foster NR , Kabat BF \net al. (2008 ) Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer . Clin Cancer Res \n14 : 3408 -3415 . doi:10.1158/1078-0432.CCR-07-1489 . PubMed: 18519771.18519771 \n5 \nOgino S , Nosho K , Kirkner GJ , Kawasaki T , Meyerhardt JA \net al. (2009 ) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer . Gut \n58 : 90 -96 . doi:10.1136/gut.2008.155473 . PubMed: 18832519.18832519 \n6 \nSamowitz WS , Sweeney C , Herrick J , Albertsen H , Levin TR \net al. (2005 ) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers . Cancer Res \n65 : 6063 -6069 . doi:10.1158/0008-5472.CAN-05-0404 . PubMed: 16024606.16024606 \n7 \nSaridaki Z , Tzardi M , Papadaki C , Sfakianaki M , Pega F , et al. (2011 ) Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in >/= 2 line cetuximab-based therapy of colorectal cancer patients . PLOS ONE \n6 : e15980 .21283802 \n8 \nSouglakos J , Philips J , Wang R , Marwah S , Silver M \net al. (2009 ) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer . Br J Cancer \n101 : 465 -472 . doi:10.1038/sj.bjc.6605164 . PubMed: 19603024.19603024 \n9 \nOliveira C , Pinto M , Duval A , Brennetot C , Domingo E \net al. (2003 ) BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency . Oncogene \n22 : 9192 -9196 . doi:10.1038/sj.onc.1207061 . PubMed: 14668801.14668801 \n10 \nRajagopalan H , Bardelli A , Lengauer C , Kinzler KW , Vogelstein B \net al. (2002 ) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status . Nature \n418 : 934 . doi:10.1038/418934a . PubMed: 12198537.12198537 \n11 \nSaridaki Z , Papadatos-Pastos D , Tzardi M , Mavroudis D , Bairaktari E \net al. (2010 ) BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome . Br J Cancer \n102 : 1762 -1768 . doi:10.1038/sj.bjc.6605694 . PubMed: 20485284.20485284 \n12 \nDomingo E , Laiho P , Ollikainen M , Pinto M , Wang L \net al. (2004 ) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing . J Med Genet \n41 : 664 -668 . doi:10.1136/jmg.2004.020651 . PubMed: 15342696.15342696 \n13 \nWang L , Cunningham JM , Winters JL , Guenther JC , French AJ \net al. (2003 ) BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair . Cancer Res \n63 : 5209 -5212 . PubMed: 14500346.14500346 \n14 \nRoth AD , Tejpar S , Delorenzi M , Yan P , Fiocca R \net al. (2010 ) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial . J Clin Oncol \n28 : 466 -474 . doi:10.1200/JCO.2009.23.3452 . PubMed: 20008640.20008640 \n15 \nPopovici V , Budinska E , Tejpar S , Weinrich S , Estrella H \net al. (2012 ) Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer . J Clin Oncol \n30 : 1288 -1295 . doi:10.1200/JCO.2011.39.5814 . PubMed: 22393095.22393095 \n16 \nDe Roock W , Claes B , Bernasconi D , De Schutter J , Biesmans B \net al. (2010 ) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis . Lancet Oncol \n11 : 753 -762 . doi:10.1016/S1470-2045(10)70130-3 . PubMed: 20619739.20619739 \n17 \nLoupakis F , Ruzzo A , Cremolini C , Vincenzi B , Salvatore L \net al. (2009 ) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer . Br J Cancer \n101 : 715 -721 . doi:10.1038/sj.bjc.6605177 . PubMed: 19603018.19603018 \n18 \nTol J , Nagtegaal ID , Punt CJ (2009 ) BRAF mutation in metastatic colorectal cancer . N Engl J Med \n361 : 98 -99 . doi:10.1056/NEJMc0904160 . PubMed: 19571295.\n19 \nVan Cutsem E , Köhne CH , Láng I , Folprecht G , Nowacki MP \net al. (2011 ) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status . J Clin Oncol \n29 : 2011 -2019 . doi:10.1200/JCO.2010.33.5091 . PubMed: 21502544.21502544 \n20 \nBenlloch S , Payá A , Alenda C , Bessa X , Andreu M \net al. (2006 ) Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology . J Mol Diagn \n8 : 540 -543 . doi:10.2353/jmoldx.2006.060070 . PubMed: 17065421.17065421 \n21 \nPentheroudakis G , Kotoula V , De Roock W , Kouvatseas G , Papakostas P \net al. (2013 ) Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes . BMC Cancer \n13 : 49 . doi:10.1186/1471-2407-13-49 . PubMed: 23374602.23374602 \n22 \nOliner KS , Douillard J-Y , Siena S , Tabernero J , Burkes R \net al. (2013 ) Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC) . J Clin Oncol \n31 \nsuppl , Abstr: 3511 .\n23 \nSolit DB , Garraway LA , Pratilas CA , Sawai A , Getz G \net al. (2006 ) BRAF mutation predicts sensitivity to MEK inhibition . Nature \n439 : 358 -362 . doi:10.1038/nature04304 . PubMed: 16273091.16273091 \n24 \nSchmoll HJ , Van Cutsem E , Stein A , Valentini V , Glimelius B \net al. (2012 ) ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making . Ann Oncol \n23 : 2479 -2516 . doi:10.1093/annonc/mds236 . PubMed: 23012255.23012255\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "8(12)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e84604",
"pmc": null,
"pmid": "24367680",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19603024;19001320;20619739;20485284;22393095;15342696;12068308;21502544;12198537;19603018;16273091;18519771;19571295;16024606;18832519;23012255;14500346;14668801;17065421;20008640;23374602;21283802",
"title": "BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC) in daily clinical practice: correlations with clinical characteristics, and its impact on patients' outcome.",
"title_normalized": "brafv600e mutation analysis in patients with metastatic colorectal cancer mcrc in daily clinical practice correlations with clinical characteristics and its impact on patients outcome"
} | [
{
"companynumb": "GR-AMGEN-GRCSP2020011026",
"fulfillexpeditecriteria": "2",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Myopathy is possibly the most clinically relevant statin-induced side effect.\n\n\n\nWe report a case of a 63-year-old healthy male with mixed dyslipidemia. He developed bilateral myalgia of the forearms with fluvastatin 40 mg/day, pravastatin 20 mg/day, and combination of atorvastatin 10 mg and ezetimibe 10 mg/day. The only hypolipidemic treatment that was tolerable was the combination of pitavastatin 1 mg and ezetimibe 10 mg/day.\n\n\n\nPitavastatin demonstrated less potential for the development of myalgia compared to the so far considered most tolerable statins (i.e., fluvastatin and pravastatin). All the tested statins were used at the lowest approved dose for clinical use.\n\n\n\nThe combination of pitavastatin 1 mg and ezetimibe appears to be a promising treatment choice for individuals who are intolerant to statin therapy due to muscle complaints.",
"affiliations": "Laboratory of Sports Medicine, Sports Medicine Division, Aristotle University of Thessaloniki, Thessaloniki, Greece, georgios.christou@yahoo.gr.;Medical School, University of Ioannina, Ioannina, Greece.;Medical School, University of Ioannina, Ioannina, Greece.;Medical School, University of Ioannina, Ioannina, Greece.;Medical School, University of Ioannina, Ioannina, Greece.;First Cardiology Department, University Hospital of Ioannina, Ioannina, Greece.;Medical School, University of Ioannina, Ioannina, Greece.",
"authors": "Christou|Georgios A|GA|;Mprikos|Spyridon G|SG|;Christou|Konstantinos A|KA|;Christou|Maria A|MA|;Christou|Evangelos A|EA|;Nikas|Dimitrios N|DN|;Kiortsis|Dimitrios N|DN|",
"chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D014280:Triglycerides; D000069438:Ezetimibe; C108475:pitavastatin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-6312",
"issue": "145(7)",
"journal": "Cardiology",
"keywords": "Dyslipidemia; Myopathy; Pitavastatin; Tolerability",
"medline_ta": "Cardiology",
"mesh_terms": "D008078:Cholesterol, LDL; D004359:Drug Therapy, Combination; D050171:Dyslipidemias; D000069438:Ezetimibe; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D011804:Quinolines; D014280:Triglycerides",
"nlm_unique_id": "1266406",
"other_id": null,
"pages": "421-424",
"pmc": null,
"pmid": "32160627",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "High Tolerability of Pitavastatin Therapy: A Case Report of Comparison with other Statins.",
"title_normalized": "high tolerability of pitavastatin therapy a case report of comparison with other statins"
} | [
{
"companynumb": "GR-ALKEM LABORATORIES LIMITED-GR-ALKEM-2020-00998",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugad... |
{
"abstract": "In bucillamine-treated patients, persistent proteinuria caused by membranous nephropathy (MN) is a major adverse effect affecting the kidneys. We experienced a case of acute interstitial nephritis (AIN) with MN caused by bucillamine. An 81-year-old Japanese woman with a past medical history of rheumatoid arthritis and hypertension presented with a fever, epigastric pain, and nausea of 1 week's duration. She had commenced bucillamine 4 months earlier. At the time of admission, her baseline creatinine (0.8 mg/dl) had risen to 6.8 mg/dl. A renal biopsy revealed AIN with concomitant MN. Renal function gradually improved after bucillamine administration was stopped. In addition to MN, bucillamine can cause AIN, which requires a renal biopsy for definitive diagnosis. Given the host of pathological findings that tend to develop in patients using bucillamine, patients receiving the drug who present with symptoms of acute kidney injury should undergo a renal biopsy to determine the presence of AIN.",
"affiliations": "Department of General Internal Medicine, Teine Keijinkai Hospital, 1-12, Maeda, Teine-ku, Sapporo, Hokkaido, 006-8555, Japan. naokitakamatsu@hotmail.com.;Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan.;Hokkaido Renal Pathology Center, Sapporo IT Front Building, Sapporo, Japan.",
"authors": "Takamatsu|Naoki|N|;Takizawa|Hideki|H|;Sugawara|Hirohito|H|;Ogawa|Yayoi|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-015-0204-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "5(1)",
"journal": "CEN case reports",
"keywords": "Acute interstitial nephritis; Acute kidney injury; Bucillamine; Membranous nephropathy",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "103-107",
"pmc": null,
"pmid": "28509179",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "22759386;23961667;20336051;11473672;17164832;11920335;20813859;1294777;24927897;9776418;25185078;17014549;1472834;16633927;25849672;11072960",
"title": "Acute interstitial nephritis with membranous nephropathy in bucillamine-treated rheumatoid arthritis.",
"title_normalized": "acute interstitial nephritis with membranous nephropathy in bucillamine treated rheumatoid arthritis"
} | [
{
"companynumb": "JP-MEDA-2016070005",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TORSEMIDE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "BACKGROUND\nA method for qualitative detection of 57 drugs and metabolites in umbilical cord tissue using liquid chromatography time-of-flight (TOF) mass spectrometry is described.\n\n\nMETHODS\nResults from 32 deidentified positive specimens analyzed by an outside laboratory using \"screen with reflex to confirmation\" testing were compared with TOF results. In addition, 57 umbilical cord tissue specimens paired with corresponding chart review data and 37 with meconium test results were analyzed by TOF. Urine drug test results from mother (n = 18) and neonate (n = 30) were included if available. Cutoff concentrations, recovery, and matrix effects were determined by analyzing fortified drug-free cord tissue and negative specimens. Cutoffs (in nanograms per gram) ranged from 1 to 10 for opioids and opioid antagonists, 5-10 for benzodiazepines and nonbenzodiazepine hypnotics, 20-40 for barbiturates, 8 for stimulants, and 4 for phencyclidine. Adequate sensitivity for the detection of cannabis exposure could not be realized with this method.\n\n\nCONCLUSIONS\nLiquid chromatography time-of-flight mass spectrometry can provide accurate and sensitive detection of in utero drug exposure using umbilical cord tissue.",
"affiliations": "*ARUP Institute for Clinical and Experimental Pathology, and †ARUP Laboratories, Inc, Salt Lake City, Utah; ‡Department of Pathology, University of Iowa Hospitals and Clinics, Iowa, Iowa; and §Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah.",
"authors": "Marin|Stephanie J|SJ|;Metcalf|Anna|A|;Krasowski|Matthew D|MD|;Linert|Brian S|BS|;Clark|Chantry J|CJ|;Strathmann|Frederick G|FG|;McMillin|Gwendolyn A|GA|",
"chemical_list": "D013287:Illicit Drugs",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0b013e3182a0d18c",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "36(1)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D007231:Infant, Newborn; D013058:Mass Spectrometry; D008470:Meconium; D011247:Pregnancy; D012680:Sensitivity and Specificity; D015813:Substance Abuse Detection; D014470:Umbilical Cord",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "119-24",
"pmc": null,
"pmid": "24061447",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Detection of neonatal drug exposure using umbilical cord tissue and liquid chromatography time-of-flight mass spectrometry.",
"title_normalized": "detection of neonatal drug exposure using umbilical cord tissue and liquid chromatography time of flight mass spectrometry"
} | [
{
"companynumb": "US-JNJFOC-20140208294",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"d... |
{
"abstract": "We report a unique clinical case about an 18-year-old woman, immediately post-partum after an urgent C-section, who survived severe sepsis, acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) and was successfully treated with 11 different antibiotics, massive blood transfusions and repetitive surgeries and was on extracorporeal membrane oxygenation (ECMO) support for 22 days. Although, ECMO is a time-limited procedure and most manufacturers do not advise more than 14 days of use, the situation for this patient was life-threatening and ECMO, despite the dangerous risks listed above, was the only way to win time for the lungs to recover and for treatment of the underlying disease, while maintaining adequate oxygenation and circulation. Fortunately, the condition of this woman was stabilized and she achieved complete physical recovery, despite minor neurological deficit in the fingers of her right hand.",
"affiliations": "Department of Cardiac, Thoracic and Vascular Surgery, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.;Department of Cardiac, Thoracic and Vascular Surgery, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania.;Department of Cardiac, Thoracic and Vascular Surgery, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania Department of Anaesthesiology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.;Department of Cardiac, Thoracic and Vascular Surgery, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.;Department of Anaesthesiology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania vkadusauskaite@gmail.com.;Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.;Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.;Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania.",
"authors": "Benetis|Rimantas|R|;Nadisauskiene|Ruta|R|;Sirvinskas|Edmundas|E|;Lenkutis|Tadas|T|;Siudikas|Adakrius|A|;Kadusauskaitė|Vytaute|V|;Railaitė|Dalia|D|;Sukovas|Arturas|A|;Abraitis|Vytautas|V|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0267659115605885",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0267-6591",
"issue": "31(4)",
"journal": "Perfusion",
"keywords": "ARDS; extracorporeal membrane oxygenation; obstetric; respiratory failure; sepsis",
"medline_ta": "Perfusion",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D001803:Blood Transfusion; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008297:Male; D007744:Obstetric Labor Complications; D011247:Pregnancy; D012128:Respiratory Distress Syndrome; D018805:Sepsis",
"nlm_unique_id": "8700166",
"other_id": null,
"pages": "343-6",
"pmc": null,
"pmid": "26373682",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successfully treated severe obstetric sepsis and acute respiratory distress syndrome with extracorporeal membrane oxygenation.",
"title_normalized": "successfully treated severe obstetric sepsis and acute respiratory distress syndrome with extracorporeal membrane oxygenation"
} | [
{
"companynumb": "LT-PFIZER INC-202101048421",
"fulfillexpeditecriteria": "1",
"occurcountry": "LT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSacrococcygeal teratoma (SCT) is a rare tumor in the general population, arising from multipotent stem cells. Whereas most of the cases diagnosed postnatally have good prognosis, the rate of mortality and morbidities associated with prenatally diagnosed SCT remain high, with a reported mortality rate of 30% to 50%. The outcome of fetal SCT can be unpredictable, with some cases with slow growth during fetal life, whereas others grow rapidly, causing multiple complications; also, some of these tumor will develop triggering fetal (preterm delivery, high-output cardiac failure, hydrops fetalis, intrauterine death) or maternal complications (distocia, placentomegaly, maternal mirror syndrome-preeclampsia). Even if prenatal criteria seem to define tumors at risk, it can not totally predict postnatal outcome as treatment-related complications can occur.We present a case of giant prenatally detected SCT. The case was diagnosed at 24th week of gestation, and was closely monitored by serial ultrasound. The morphology of the lesion was defined by fetal MRI performed at 25th week of gestation. A baby girl with a huge sacrococcygeal tumor was born and surgery was performed 48 hours later. Pathological examination revealed a grade 3 immature teratoma. Because of the tumor size and pathological aspect, adjuvant chemotherapy was considered. The outcome was complicated by wound infection, sepsis, and subsequent hydrocephalus, induced by chemotherapy-induced immunosuppression.\n\n\nCONCLUSIONS\nOur case emphasizes not only the importance of prenatal monitoring of these cases but also the importance of individualized postnatal management, as unusual and unpredictable complications can occur and affect outcome.",
"affiliations": "Department of Pediatric and Orthopaedic Surgery, \"Sf. Maria\" Emergency Children Hospital Department of Obstetrics and Gynecology Department of Pediatrics, \"Sf. Maria\" Emergency Children Hospital Department of Morphofunctional Sciences, Discipline of Histology, \"Grigore T. Popa\" University of Medicine and Pharmacy, Iasi, Romania.",
"authors": "Sarbu|Ioan|I|;Socolov|Demetra|D|;Socolov|Razvan|R|;Miron|Ingrith|I|;Trandafirescu|Mioara|M|;Diaconescu|Smaranda|S|;Ciongradi|Carmen Iulia|CI|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000005244",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2778738810.1097/MD.0000000000005244052446200Research ArticleClinical Case ReportHydrocephalus secondary to chemotherapy in a case of prenatally diagnosed giant immature grade 3 sacrococcygeal teratoma A case report and literature reviewSarbu Ioan MD, MSc\naSocolov Demetra MD, PhD\nbSocolov Razvan MD, PhD\nbMiron Ingrith MD, PhD\ncTrandafirescu Mioara MD, PhD\ndDiaconescu Smaranda MD, PhD\ncCiongradi Carmen Iulia MD, PhD\na\n∗Hagander. Lars a Department of Pediatric and Orthopaedic Surgery, “Sf. Maria” Emergency Children Hospitalb Department of Obstetrics and Gynecologyc Department of Pediatrics, “Sf. Maria” Emergency Children Hospitald Department of Morphofunctional Sciences, Discipline of Histology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania.∗ Correspondence: Carmen Iulia Ciongradi, Assistant Professor, University of Medicine and Pharmacy, Department of Pediatric Surgery, “Sf. Maria” Emergency Children's Hospital, 62 Vasile Lupu Street, Iasi, Romania (e-mail: iuliaciongradi@yahoo.com).10 2016 28 10 2016 95 43 e524430 5 2016 9 10 2016 10 10 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0\nAbstract\nIntroduction:\nSacrococcygeal teratoma (SCT) is a rare tumor in the general population, arising from multipotent stem cells. Whereas most of the cases diagnosed postnatally have good prognosis, the rate of mortality and morbidities associated with prenatally diagnosed SCT remain high, with a reported mortality rate of 30% to 50%. The outcome of fetal SCT can be unpredictable, with some cases with slow growth during fetal life, whereas others grow rapidly, causing multiple complications; also, some of these tumor will develop triggering fetal (preterm delivery, high-output cardiac failure, hydrops fetalis, intrauterine death) or maternal complications (distocia, placentomegaly, maternal mirror syndrome—preeclampsia). Even if prenatal criteria seem to define tumors at risk, it can not totally predict postnatal outcome as treatment-related complications can occur.\n\nWe present a case of giant prenatally detected SCT. The case was diagnosed at 24th week of gestation, and was closely monitored by serial ultrasound. The morphology of the lesion was defined by fetal MRI performed at 25th week of gestation. A baby girl with a huge sacrococcygeal tumor was born and surgery was performed 48 hours later. Pathological examination revealed a grade 3 immature teratoma. Because of the tumor size and pathological aspect, adjuvant chemotherapy was considered. The outcome was complicated by wound infection, sepsis, and subsequent hydrocephalus, induced by chemotherapy-induced immunosuppression.\n\nConclusion:\nOur case emphasizes not only the importance of prenatal monitoring of these cases but also the importance of individualized postnatal management, as unusual and unpredictable complications can occur and affect outcome.\n\nKeywords\nchemotherapyfetal MRIhydrocephalusimmature teratomaprenatal diagnosissacrococcygeal teratomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSacrococcygeal teratoma (SCT) represents the most common tumor of the neonatal period, and accounts for 35% to 60% of all teratomas,[1] but they are rare lesions, with an incidence of 1 to 35,000 to 40,000 births.[2] In recent decades, an increasing number of SCT have been detected by prenatal ultrasound examination of the fetus. Antenatal diagnosis of these tumors helps to establish the extension of the tumor, its effect on fetal development (fetal hydrops, polihydramnios), the presence or absence of tumor hemorrhage, and the rate of fetal growth. Fetal magnetic resonance imaging (MRI) is an adjuvant tool used for better definition of this condition. Correct prenatal evaluation of fetuses with SCT is important for establishing prenatal (fetal therapy in selected cases) and postnatal management of these cases.\n\n2 Case report\nWe present a case of a female fetus, diagnosed by prenatal ultrasound with a sacrococcygeal tumor at 24th week of gestation. The pregnancy had been followed up regularly until the moment of the morphology scan, when the tumor was for the first time identified. At that moment, the lesion measured 36 × 26 mm, with a nonhomogenous appearance on the ultrasound sections, with no signs of fetal hydrops or placentomegaly. One week later, the fetal MRI investigation revealed a sacrococcygeal lesion with a mixed structure, with solid and cystic elements, measuring 38 × 35 × 30 mm (Fig. 1). The scan had also revealed some degree of placentomegaly, and no other morphological abnormalities. This appearance was suggestive at the moment of an Altman type I SCT.\n\nFigure 1 Fetal MRI. Note the sacrococcygeal lesion. MRI = magnetic resonance imaging.\n\nConsidering the supposed diagnosis, the fetal age, and the dimension of the lesion, a close outpatient ultrasound and external fetal and mother monitoring was decided to be appropriate in this case. Seriate ultrasounds were done to appreciate the fetal and tumor growth (Table 1), signs of fetal hydrops, or placentomegaly.\n\nTable 1 Tumor growth according to age of pregnancy.\n\nThere was no aggravation of the fetal or mother status, so a female infant was born at 39 weeks of gestation by a scheduled caesarean section. The child weighted 3850 g and had an Apgar score of 9 at 5 minutes. A large sacrococcygeal lesion was confirmed at postpartum examination, with a diameter of 22 cm (Fig. 2). Thirteen hours later, with good vital parameters, she was transferred to the Neonatal Intensive Care Unit of the Pediatric Surgery Department for proper management and cure. Biological and imagistic (abdominal, transfontanelar, and cardiac ultrasounds) examinations were done in the first 48 hours of life, which revealed no significant associated abnormalities. A type I Altman tumor was confirmed. The serum markers showed an elevated level of α-fetoprotein (AFP) (>4425.29 UI).\n\nFigure 2 Sacroccocygeal tumor, postnatal appearance.\n\nOn the second day of life, the child underwent surgical excision of the sacrococcygeal tumor, with early ligation of the medium sacral artery, coccyx excision, and no associated complication (Fig. 3). The excised lesion weighed 800 g. The pathological examination revealed an immature teratoma, with a large quantity of nervous mature and immature tissue with calcifications (Fig. 4).\n\nFigure 3 Intraoperative appearance.\n\nFigure 4 Optical microscopy, hematoxylin and eosin; (magnification 100×) showing calcifications in the mature nervous tissue (A) and associated immature and mature nervous structures (B).\n\nBecause of the histological appearance, the child underwent a bleomicyn, etoposide, and cisplatin (BEP) protocol of chemotherapy. The postoperative course was complicated by surgical wound dehiscence, infection, and sepsis, with blood culture positive for Klebsiella pneumoniae and Pseudomonas aeruginosa, treated by local wound care and prolonged intravenous (IV) antibiotics. Subsequently, the child developed subarachnoid hemorrhage and secondary progressive active hydrocephaly [diagnosed by ultrasound and computed tomography (CT) scan at the age of 6 weeks] (Fig. 5), that required a ventriculoperitoneal shunt at the age of 3 months.\n\nFigure 5 Computed tomography scan showing hydrocephalus (age 3 months).\n\nThe child's outcome was positive after 8 cycles of chemotherapy, with good clinical development, no impairment in micturition or defecation, functional ventriculoperitoneal shunt, normal neurological function, normal values of AFP (4.71 UI/mL), clear pelvic CT scan, with no signs of local recurrence at the age of 18 months.\n\n3 Discussion\nOverall survival rate of prenatally diagnosed SCT ranges between 47% and 83%, but is nearly 0% for those who will develop fetal hydrops.[3] There is no general consent regarding the prognostic factors for the postnatal outcome of prenatal diagnoses of SCT. The Altman classification of the tumor into 4 types, according to the prevalence of its extrapelvic or intrapelvic component, showed no correlation with the outcome. The relation type between the solid and cystic component of the tumor seems to be, in contrast, predictive for the outcome, as the solid part of the lesion is usually very vascularized, with high growth potential, and increased risk for cardiac failure and hemorrhage.[4\n5] Westerburg et al[6] suggested that the tumor's maximum diameter seemed not to be an independent factor for poor outcome, although no fetuses with tumors less than 10 cm in diameter died. In a study published on 28 cases, Coleman et al[7] reported that faster SCT growth during fetal life is associated with higher mortality, whereas patients with pour outcome and adverse events had an average growth rate 3 to 4 times higher than the ones with positive outcome. The study used the tumoral volume as growth parameter, but could not define a cut-off value for good or bad outcome.[7]\n\n\nA recent study tried to make a classification of these lesions according to their dimensions and their growing rate. There were 3 groups defined, as follows:Group A—with tumor diameter less than 10 cm, absent or mild vascularization, slow growth; this group seemed to be associated with no mortality. The mother morbidities lead to caesarean section if the tumor dimensions exceeded 7 cm.\n\nGroup B—with tumor diameter more than 10 cm, high vascularization or cardiac failure, and rapid growth; this group is associated with high fetal mortality and high rates of mother and child morbidities.\n\nGroup C—with tumor diameter more than 10 cm, but mild vascularization, predominant cystic structure, and slow growth.[8]\n\n\n\n\n\nIn the same study, a growth rate higher than 8 mm/wk was considered as a “fast growth rate” with poor prognosis. A tumor diameter greater than 4 cm at 20 weeks of gestation was also proven to be a sign for a complicated outcome.[9]\n\n\nIn our case, the prenatal diagnosis allowed for a close monitoring of tumor development. The fetal MRI was useful in identifying the tumor structure and vascularization. The closed ultrasound follow-up assessed the tumor rate growth and the absence of any complications as placentomegaly, hydrops fetalis, or cardiac failure. The tumor growth rate, of a medium of 8 mm/wk, was associated with a good fetal outcome, which allowed a scheduled c-section at 39th week of gestation.\n\nThe pathological appearance of the lesion was also defined as a predictor factor for the postnatal patients’ need for adjuvant chemotherapy, long-time outcome, and recurrence risk. According to Dehner,[10] teratoma can be classified as mature, immature (characterized by the presence of immature nervous tissue), and malignant (teratoma plus one or more malignant elements). The immature teratoma was also classified by O’Connor and Norris[11] into 3 grades: immature tissue less than 1 low power field/examined slide; immature tissue on 1 to 3 low power fields/examined slides; and immature tissue on more than 3 low power fields on examined slides. Malignancy in the neonatal period is rare (up to 22%)[12]; Altman et al reported an incidence of malignancy of only 5% when the tumor is treated in the first month of life. Most of the neonatal SCTs are benign, mature, or immature, and surgery (with wide and complete resection of the tumor, without rupture or splitting, and coccygectomy) is the main therapy. Associated chemotherapy is the choice for malignant lesions, and also for some immature tumors. The recurrence rate of SCT varies from 2% to 23%.[13\n14] The high-grade immature teratoma are known to have a high risk of recurrence comparing with matures’ one or low-grade immature. The recurrence rate was previously reported as being low for mature teratoma (0%–26% of the cases) and malignant ones (0%–36%), whereas 12% to 55% of immature teratomas will reoccur after correct surgical resection.[15] Most of the recurrences will appear in the first 3 years after the primary surgery, so serum markers (AFP) and rectal digital examination every 3 months are mandatory. In our case, the pathological examination revealed a type 3 immature teratoma, so adjuvant chemotherapy was considered, with no clinical, imagistic, or biological signs of reoccurence at the age of 3.\n\nAlthough, according to the UK Children's Cancer Study Group (GC3), and also the American National Cancer Institute, immature teratomas are treated only with surgical resection, we decide to associate the chemotherapy cycles, considering the case at high risk because of dimensions and pathologic aspect. There are several reports in the literature that sustain the idea that large tumors, over 10 cm diameter, may possibly have imperceptible tiny foci of malignant tissue that can mistakenly be reported on pathological examination as mature or immature. Those malignant foci of tissue can lead to tumor malignant recurrence,[16] so chemotherapy can play a role in lowering the rate of malignant recurrence.\n\nThe role of postoperative chemotherapy in the management of neonatal immature SCT is still controversial. There are some authors reporting a decrease in the malignant relapses in those cases,[17] whereas others recommended adjuvant therapy alone for incomplete resection.[18\n19]\n\n\nIn a study published by the UK Children's Cancer Study Group on extracranial teratomas in children, despite given protocols, from 98 cases of SCT, the chemotherapy was used in 6 cases of immature tumor, but no proven benefit was found, whether given preoperatively, as adjuvant therapy or for benign relapse, so the efficacy of chemotherapy in those benign tumors was difficult to asses.[20] There are many authors who raise concerns regarding the chemotherapy-related adverse effects that weighed against its doubtful efficiency in case of neonatal immature SCT, so they do not recommend it.\n\nThe most frequently reported postsurgical complications of SCT are bleeding, wound dehiscence, neuropathic bladder, bowel incontinence, and constipation. Large wound dehiscence associated with wound infection, sepsis, and subsequent subarachnoid hemorrhage is a rare complication of the tumor treatment.\n\nThe child in the presented case was treated with 8 cycles of BEP, as the authors considered it a high-risk tumor (huge grade 3 immature teratoma). As a consequence of the immunosuppression associated with chemotherapy cycles, the child developed sepsis and secondary hydrocephalus. We consider the hydrocephalus as an acquired lesion, a side effect associated with chemotherapy cycles, as the aspect of fetal cerebral ventricles was normal during prenatal scans, the immediate postnatal appearance of the transfontanelar ultrasound was normal, and clinical and imagistic signs of subarachnoid hemorrhage and hydrocephalus developed after wound infection associated with generalized sepsis. Thus, this case report may underscore the need for hesitancy concerning chemotherapy in immature teratoma and show a case of possible severe consequences.\n\n4 Conclusions\nSacrococcygeal teratomas are unusual tumors arising from the coccyx. Our case highlights the importance of prenatal diagnosis of giant SCT, associated with close ultrasound monitoring of its growth rate and of its fetal or maternal hemodynamic consequences, as prognostic factors for intra and postnatal outcome. Also, prenatal diagnosis will allow a clear definition of tumor structure and anatomy, provided by fetal MRI. Our case also emphasizes the importance of complete tumor resection and good pathological examination to minimize the reoccurrence risk, but, on the other hand, prenatal diagnosis cannot completely predict the postnatal outcome, because an individualized therapeutic approach must be considered in each case of SCT, as possible unusual complications can be associated with their outcome. We consider that this case report also stresses out the importance of clear treatment guidelines to avoid possible complications of aggressive treatment regimes. We consider in this particular case that the hydrocephalus was a rare and unpredictable complication associated with large surgical wound dehiscence, infection, sepsis, and immunosuppression induced by chemotherapy in a immature grade 3 teratoma.\n\nAbbreviations: AFP = α-fetoprotein, BEP = protocol of chemotherapy (bleomicyn, etoposide, and cisplatin), CT = computed tomography, MRI = magnetic resonance imaging, SCT = sacrococcygeal teratoma.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n1 \nShue E Bolouri M Jelin EB \nTumor metrics and morphology predict poor prognosis in prenatally diagnosed sacrococcygeal teratoma: a 25-year experience at a single institution . J Pediatr Surg \n2013 ; 48 :1225 –1231 .23845611 \n2 \nAly KAE Shoier M Badrawy T \nSacrococcygeal teratoma: a neonatal surgical problem . Ann Pediatr Surg \n2006 ; 2 :106 –111 .\n3 \nHedrick HL Flake AW Crombleholme TM \nSacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome . J Pediatr Surg \n2004 ; 39 :430 –438 .15017565 \n4 \nUsui N Kitano Y Sago H \nOutcomes of prenatally diagnosed sacrococcygeal teratomas: the results of a Japanese nationwide survey . J Pediatr Surg \n2012 ; 47 :441 –447 .22424335 \n5 \nBenachi A Durin L Maurer SV \nPrenatally diagnosed sacrococcygeal teratoma: a prognostic classification . J Pediatr Surg \n2006 ; 41 :1517 –1521 .16952584 \n6 \nWesterburg B Feldstein VA Sandberg PL \nSonographic prognostic factors in fetuses with sacrococcygeal teratoma . J Pediatr Surg \n2000 ; 35 :322 –325 .10693688 \n7 \nColeman A Shaaban A Keswani S \nSacrococcygeal teratoma growth rate predicts adverse outcomes . J Pediatr Surg \n2014 ; 49 :985 –989 .24888848 \n8 \nBenachi A Durinb L Maurerc SV \nPrenatally diagnosed sacrococcygeal teratoma: a prognostic classification . J Pediatr Surg \n2006 ; 41 :1517 –1521 .16952584 \n9 \nHambraeus M Arnbjornsson E Borjesson A \nSacrococcygeal teratoma: a population-based study of incidence and prenatal prognostic factors . J Pediatr Surg \n2016 ; 51 :481 –485 .26454470 \n10 \nDehner LP \nFinegold M Benington JL \nGonadal and extragonadal germ cell neoplasms: teratomas in childhood . Pathology of Neoplasia in Children and Adults . Philadelphia, PA : WB Saunders ; 1986 \n282 –312 .\n11 \nO’Connor DM Norris HJ \nThe influence of grade on outcome of stage I immature (malignant) teratomas and the reproducibility of grading . Int J Gynae Pathol \n1994 ; 13 :283 –289 .\n12 \nSchropp KP Lobe TE Rao B \nSacrococcygeal teratoma: the experience of four decades . J Pediatr Surg \n1992 ; 27 :1075 –1079 .1403540 \n13 \nBacker A Madern GC Hakvoort-Cammel FG \nStudy of the factors associated with recurrence in children with sacrococcygeal teratoma . J Pediatr Surg \n2006 ; 41 :173 –181 .16410129 \n14 \nDerikx JP Backer A van de Schoot L \nFactors associated with recurrence and metastasis in sacrococcygeal teratoma . Br J Surg \n2006 ; 93 :1543 –1548 .17058315 \n15 \nSchneider D Wessalowski R Calaminus G \nTreatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96 . J Clin Oncol \n2001 ; 19 :1951 –1960 .11283127 \n16 \nBilik R Shandling B Pope M \nMalignant benign neonatal sacrococcygeal teratoma . J Pediatr Surg \n1993 ; 28 :1158 –1160 .7508500 \n17 \nGobel U Calaminus G Engert J \nTeratomas in infancy and childhood . Med Pediatr Oncol \n1998 ; 31 :8 –15 .9607423 \n18 \nLo Curto M D’ Angelo P Cecchetto G \nMature and immature teratomas: results of the first paediatric Italian study . Pediatr Surg Int \n2007 ; 23 :315 –322 .17333214 \n19 \nDe Backer A Madern GC Hakvoort-Cammel FG \nStudy of the factors associated with recurrence in children with sacrococcygeal teratoma . J Pediatr Surg \n2006 ; 41 :173 –181 .[discussion 173–181] .16410129 \n20 \nMann JR Gray ES Thornton C \nMature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience . J Clin Oncol \n2008 ; 26 :3590 –3597 .18541896\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "95(43)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000970:Antineoplastic Agents; D003937:Diagnosis, Differential; D005260:Female; D005333:Fetus; D005865:Gestational Age; D006801:Humans; D006849:Hydrocephalus; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D010386:Pelvic Neoplasms; D011247:Pregnancy; D013724:Teratoma; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e5244",
"pmc": null,
"pmid": "27787388",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "7508500;26454470;7814189;22424335;17058315;24888848;18541896;17333214;15017565;1403540;16952584;23845611;11283127;9607423;16410129;10693688",
"title": "Hydrocephalus secondary to chemotherapy in a case of prenatally diagnosed giant immature grade 3 sacrococcygeal teratoma: A case report and literature review.",
"title_normalized": "hydrocephalus secondary to chemotherapy in a case of prenatally diagnosed giant immature grade 3 sacrococcygeal teratoma a case report and literature review"
} | [
{
"companynumb": "RO-FRESENIUS KABI-FK201701457",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.",
"affiliations": "University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.;University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.;University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.;Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;Taunton and Somerset NHS Foundation Trust, Taunton, United Kingdom.;Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom.;Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.;Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.;University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom.;University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom.;Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, United Kingdom.;Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.;Great Western Hospitals NHS Foundation Trust, Swindon, United Kingdom.;Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.;Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.;Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.;University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom.;Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom.;University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.;Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.;Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom.;Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, United Kingdom.;Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom.",
"authors": "McCulloch|Rory|R|0000-0003-0090-7174;Lewis|David|D|;Crosbie|Nicola|N|;Eyre|Toby A|TA|0000-0002-6631-9749;Bolam|Simon|S|;Arasaretnam|Anita|A|;Creasey|Thomas|T|;Goradia|Harshita|H|;McMillan|Annabel|A|0000-0003-0624-165X;Dawi|Safia|S|;Harrison|Samuel|S|;Miles|Oliver|O|;Robinson|Andrew|A|;Dutton|David|D|0000-0002-5629-4920;Wilson|Matthew R|MR|0000-0001-5423-3270;McKay|Pam|P|0000-0002-3959-9730;Follows|George|G|;Phillips|Neil|N|;Patmore|Russell|R|;Lambert|Jonathan|J|;Bishton|Mark|M|;Osborne|Wendy|W|;Johnston|Rosalynd|R|;Kirkwood|Amy A|AA|;Rule|Simon|S|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D003561:Cytarabine; C551803:ibrutinib; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "193(2)",
"journal": "British journal of haematology",
"keywords": "clinical aspects; ibrutinib; mantle cell lymphoma; post-ibrutinib outcomes",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D003561:Cytarabine; D018450:Disease Progression; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010880:Piperidines; D000077982:Progression-Free Survival; D047428:Protein Kinase Inhibitors; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D013222:State Medicine; D006113:United Kingdom; D028761:Withholding Treatment",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "290-298",
"pmc": null,
"pmid": "33620106",
"pubdate": "2021-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients.",
"title_normalized": "ibrutinib for mantle cell lymphoma at first relapse a united kingdom real world analysis of outcomes in 211 patients"
} | [
{
"companynumb": "GB-ABBVIE-20K-167-3245008-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo show the feasibility of using different unobtrusive activity-sensing technologies to provide objective behavioral markers of persons with dementia (PwD).\n\n\nMETHODS\nMonitored the behaviors of two PwD living in memory care unit using the Oregon Center for Aging & Technology (ORCATECH) platform, and the behaviors of two PwD living in assisted living facility using the Emerald device.\n\n\nMETHODS\nA memory care unit in Portland, Oregon and an assisted living facility in Framingham, Massachusetts.\n\n\nMETHODS\nA 63-year-old male with Alzheimer's disease (AD), and an 80-year-old female with frontotemporal dementia, both lived in a memory care unit in Portland, Oregon. An 89-year-old woman with a diagnosis of AD, and an 85-year-old woman with a diagnosis of major neurocognitive disorder, Alzheimer's type with behavioral symptoms, both resided at an assisted living facility in Framingham, Massachusetts.\n\n\nMETHODS\nThese include: sleep quality measured by the bed pressure mat; number of transitions between spaces and dwell times in different spaces measured by the motion sensors; activity levels measured by the wearable actigraphy device; and couch usage and limb movements measured by the Emerald device.\n\n\nRESULTS\nNumber of transitions between spaces can identify the patient's episodes of agitation; activity levels correlate well with the patient's excessive level of agitation and lack of movement when the patient received potentially inappropriate medication and neared the end of life; couch usage can detect the patient's increased level of apathy; and periodic limb movements can help detect risperidone-induced side effects. This is the first demonstration that the ORCATECH platform and the Emerald device can measure such activities.\n\n\nCONCLUSIONS\nThe use of technologies for monitoring behaviors of PwD can provide more objective and intensive measurements of PwD behaviors.",
"affiliations": "Department of Neurology, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR; Oregon Center for Aging & Technology, Oregon Health & Science University (W-TMA-Y, LM, ZB, JK), Portland, OR; NIA-Layton Aging & Alzheimer's Disease Center, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR. Electronic address: auyeungm@ohsu.edu.;Oregon Center for Aging & Technology, Oregon Health & Science University (W-TMA-Y, LM, ZB, JK), Portland, OR; School of Nursing, Oregon Health & Science University (LM), Portland, OR.;Department of Neurology, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR; Oregon Center for Aging & Technology, Oregon Health & Science University (W-TMA-Y, LM, ZB, JK), Portland, OR; NIA-Layton Aging & Alzheimer's Disease Center, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR.;McLean Hospital (RM, HVC, IVV), Belmont, MA.;McLean Hospital (RM, HVC, IVV), Belmont, MA.;Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (ZK, DK), Cambridge, MA.;Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (ZK, DK), Cambridge, MA.;Department of Neurology, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR; Oregon Center for Aging & Technology, Oregon Health & Science University (W-TMA-Y, LM, ZB, JK), Portland, OR; NIA-Layton Aging & Alzheimer's Disease Center, Oregon Health & Science University (W-TMA-Y, ZB, JK), Portland, OR.;McLean Hospital (RM, HVC, IVV), Belmont, MA; Harvard Medical School (IVV), Boston, MA.",
"authors": "Au-Yeung|Wan-Tai M|WM|;Miller|Lyndsey|L|;Beattie|Zachary|Z|;May|Rose|R|;Cray|Hailey V|HV|;Kabelac|Zachary|Z|;Katabi|Dina|D|;Kaye|Jeffrey|J|;Vahia|Ipsit V|IV|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jagp.2021.04.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-7481",
"issue": null,
"journal": "The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry",
"keywords": "Alzheimer's disease; Unobtrusive activity-sensing technology; agitation; apathy; behavioral and psychological symptoms; end-of-life; late-stage dementia; potentially inappropriate medication; technology",
"medline_ta": "Am J Geriatr Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "9309609",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34039534",
"pubdate": "2021-04-22",
"publication_types": "D016428:Journal Article",
"references": "18585647;30102277;29487556;25962476;23877083;25731881;32245677;9154580;25452601;11180484;23511664;11739063;28074409;30525266;24443644;29282768;32864417;19932989;22067732;28429641;32295567;19965096;20403790;16503315;32116687;27066526;23611363;11589923;14564127;27624397;22586419",
"title": "Monitoring Behaviors of Patients With Late-Stage Dementia Using Passive Environmental Sensing Approaches: A Case Series.",
"title_normalized": "monitoring behaviors of patients with late stage dementia using passive environmental sensing approaches a case series"
} | [
{
"companynumb": "US-ORGANON-O2112USA002647",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND AND OBJECTIVE: INTP5 has been developed as a pegfilgrastim biosimilar. Single-dose, crossover study compared the pharmacokinetics and pharmacodynamics (PK/PD) of INTP5 (pegfilgrastim biosimilar) with reference pegfilgrastim (Neulasta®, pegfilgrastim-ref) and a multiple-dose, parallel-group study compared the immunogenicity of INTP5 with pegfilgrastim-ref in healthy subjects as part of a complete clinical development plan.\n\n\nMETHODS\nIn the PK/PD study, subjects received a single subcutaneous 6 mg dose of INTP5 and pegfilgrastim-ref (N = 142) separated by a 6-week washout period. The primary endpoints were area under the serum concentration-time curve measured from time zero to infinity (AUC0-∞) and maximum measured serum concentration (Cmax) of pegfilgrastim and area under the absolute neutrophil count (ANC) versus time curve from time zero to t (AUEC0-t) and maximum measured ANC (Emax) of baseline non-adjusted ANCs. In the immunogenicity study, subjects received two 6 mg doses of INTP5 (N = 100) or pegfilgrastim-ref (N = 100) separated by 21 days. The primary endpoints were incidence of anti-drug antibodies (ADAs) in the two treatment groups.\n\n\nRESULTS\nThe primary PK endpoints [AUC0-∞ (90% CI 108.59-123.11) and Cmax (106.24-118.99)] and the primary PD endpoints [AUEC0-t (99.07-102.32) and Emax (100.24-104.25)] met the acceptance criteria of 80-125%. The incidence of ADAs was 10.6% in the INTP5 arm and 9.0% in the pegfilgrastim-ref arm. The 90% CI for risk difference of the ADA incidence between INTP5 and pegfilgrastim-ref was 1.64% (- 5.40 to 8.68) and was within the 10% margin. No neutralizing antibodies were reported. Immunogenicity did not impact PK/PD parameters and subjects with aberrant PK/PD/safety did not show immunogenicity concerns. Incidence of adverse events (AEs) was similar with INTP5 and pegfilgrastim-ref in both studies. The most common AEs were musculoskeletal pain and headache.\n\n\nCONCLUSIONS\nINTP5 showed PK/PD equivalence with pegfilgrastim-ref following a single dose, no clinically meaningful difference in the immune response following multiple doses, and a comparable safety profile.",
"affiliations": "Intas Pharmaceuticals Ltd. (Biopharma), Plot No: 423/P/A, Sarkhej-Bavla Highway, Moraiya, Sanand, Ahmedabad, Gujarat, 382213, India.;Lambda Therapeutic Research Ltd., Lambda House, Plot No. 38, Survey No. 388, Near Silver Oak Club, S. G. Highway, Gota, Ahmedabad, Gujarat, 382481, India.;Lambda Therapeutic Research Ltd., Lambda House, Plot No. 38, Survey No. 388, Near Silver Oak Club, S. G. Highway, Gota, Ahmedabad, Gujarat, 382481, India.;Lambda Therapeutic Research Ltd., Lambda House, Plot No. 38, Survey No. 388, Near Silver Oak Club, S. G. Highway, Gota, Ahmedabad, Gujarat, 382481, India.;Intas Pharmaceuticals Ltd. (Biopharma), Plot No: 423/P/A, Sarkhej-Bavla Highway, Moraiya, Sanand, Ahmedabad, Gujarat, 382213, India. vinu_jose@intaspharma.com.",
"authors": "Singh|Inderjeet|I|;Attrey|Anshul|A|;Garg|Adarsh|A|;Patel|Ronak|R|;Jose|Vinu|V|http://orcid.org/0000-0001-6164-0632",
"chemical_list": "D059451:Biosimilar Pharmaceuticals; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-020-00987-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "41(1)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D059451:Biosimilar Pharmaceuticals; D018592:Cross-Over Studies; D005260:Female; D000069585:Filgrastim; D006261:Headache; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D059352:Musculoskeletal Pain; D009504:Neutrophils; D011092:Polyethylene Glycols; D013810:Therapeutic Equivalency; D055815:Young Adult",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "29-42",
"pmc": null,
"pmid": "33236287",
"pubdate": "2021-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "25491042;26598744;26858339;32524499",
"title": "Single-Dose Pharmacokinetics, Pharmacodynamics and Immunogenicity, and Multiple-Dose Immunogenicity of INTP5 (Pegfilgrastim Biosimilar) Versus Reference Pegfilgrastim in Healthy Subjects.",
"title_normalized": "single dose pharmacokinetics pharmacodynamics and immunogenicity and multiple dose immunogenicity of intp5 pegfilgrastim biosimilar versus reference pegfilgrastim in healthy subjects"
} | [
{
"companynumb": "IN-AMGEN-INDSP2020198336",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFor its numerous abilities including sedation, we have been using thalidomide (TH) as the 'last therapeutic option' in patients with advanced gliomas. We noticed that a small subgroup, i.e. patients with secondary glioblastoma (GBM, whose GBM has evolved over several months or years from a less malignant glioma), survived for prolonged periods. Therefore, we retrospectively evaluated the outcomes of patients with secondary GBM treated with TH at our centre.\n\n\nMETHODS\nStarting in the year 2000, we have studied 23 patients (13 females, 10 males, with a median age of 31.5 years) with secondary GBM who have received palliative treatment with TH 100 mg at bedtime. All patients had previously undergone radiotherapy and received at least 1 and up to 5 regimens of chemotherapy.\n\n\nRESULTS\nThe median duration of TH administration was 4.0 months (range 0.8-32). The median duration of overall survival after the start of TH therapy was 18.3 months (range 0.8-57). Eleven patients with secondary GBM survived longer than 1 year. Symptomatic improvement was most prominent in the restoration of a normal sleep pattern.\n\n\nCONCLUSIONS\nThe palliative effects of TH, especially the normalization of a sleep pattern, were highly valued by patients and families. The prolongation of survival of patients with secondary GBM has not been reported previously.",
"affiliations": null,
"authors": "Hassler|Marco Ronald|MR|;Sax|Cornelia|C|;Flechl|Birgit|B|;Ackerl|Michael|M|;Preusser|Matthias|M|;Hainfellner|Johannes Andreas|JA|;Woehrer|Adelheid|A|;Dieckmann|Karin Ute|KU|;Rössler|Karl|K|;Prayer|Daniela|D|;Marosi|Christine|C|",
"chemical_list": "D000970:Antineoplastic Agents; D013792:Thalidomide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000368903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "88(3)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D005260:Female; D005909:Glioblastoma; D005910:Glioma; D006801:Humans; D008297:Male; D010166:Palliative Care; D012189:Retrospective Studies; D012894:Sleep Stages; D016019:Survival Analysis; D013792:Thalidomide; D055815:Young Adult",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "173-9",
"pmc": null,
"pmid": "25427949",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thalidomide as palliative treatment in patients with advanced secondary glioblastoma.",
"title_normalized": "thalidomide as palliative treatment in patients with advanced secondary glioblastoma"
} | [
{
"companynumb": "AT-CELGENE-009-20785-13101301",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo describe the prevalence, clinical characteristics and risk factors of opportunistic infection (OI) in a cohort of patients with inflammatory myopathies, and compare mortality rates between those with and without OIs.\n\n\nMETHODS\nIn total, 204 patients from our myositis cohort were reviewed to identify patients who had experienced an OI during the period 1986-2014. The patients' clinical characteristics, treatments received, and outcomes were systematically recorded. Disease activity at the OI diagnosis and the cumulative doses of immunosuppressive drugs were analyzed, as well as the specific pathogens involved and affected organs.\n\n\nRESULTS\nThe prevalence of OI in the total cohort was 6.4%: viruses, 44.4% (varicella-zoster virus, cytomegalovirus); bacteria, 22.2% (Salmonella sp., Mycobacterium tuberculosis, M. chelonae); fungi, 16.7% (Candida albicans, Pneumocystis jirovecii); and parasites, 16.7% (Toxoplasmosis gondii, Leishmania spp.). Lung and skin/soft tissues were the organs most commonly affected (27.8%). Overall, 55.6% of OIs developed during the first year after the myositis diagnosis and OI was significantly associated with administration of high-dose glucocorticoids (P = 0.0148). Fever at onset of myositis (P = 0.0317), biological therapy (P < 0.001) and sequential administration of four or more immunosuppressive agents during myositis evolution (P = 0.0032) were significantly associated with OI. All-cause mortality in the OI group was 3.69 deaths per 100 patients/year versus 3.40 in the remainder of the cohort (P = 0.996).\n\n\nCONCLUSIONS\nThe prevalence of OI was 6.4% in our myositis cohort, higher than the rest of the inpatients of our hospital (1.7%; P < 0.01). High-dose glucocorticoids at disease onset and severe immunosuppression are the main factors implicated.",
"affiliations": "Internal Medicine Department, Autonomous University of Barcelona, Barcelona, Spain.;Department of Infectious Diseases, Vall d'Hebron General Hospital, Barcelona, Spain.;Department of Pneumology, Vall d'Hebron General Hospital, Barcelona, Spain.;Department of Rheumatology, Vall d'Hebron General Hospital, Barcelona, Spain.;Internal Medicine Department, Autonomous University of Barcelona, Barcelona, Spain.;Internal Medicine Department, Autonomous University of Barcelona, Barcelona, Spain.;Department of Epidemiology and Preventive Medicine, Vall d'Hebron General Hospital, Barcelona, Spain.;Internal Medicine Department, Autonomous University of Barcelona, Barcelona, Spain.",
"authors": "Redondo-Benito|Ada|A|;Curran|Adrian|A|;Villar-Gomez|Ana|A|;Trallero-Araguas|Ernesto|E|;Fernández-Codina|Andreu|A|;Pinal-Fernandez|Iago|I|;Rodrigo-Pendás|Jose Ángel|JÁ|;Selva-O'Callaghan|Albert|A|http://orcid.org/0000-0003-2823-9761",
"chemical_list": "D001688:Biological Products; D005938:Glucocorticoids; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "21(2)",
"journal": "International journal of rheumatic diseases",
"keywords": "autoimmune diseases; infections; myositis",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000328:Adult; D001424:Bacterial Infections; D001688:Biological Products; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009220:Myositis; D009894:Opportunistic Infections; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D013030:Spain; D013997:Time Factors; D014777:Virus Diseases",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "487-496",
"pmc": null,
"pmid": "29314762",
"pubdate": "2018-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Opportunistic infections in patients with idiopathic inflammatory myopathies.",
"title_normalized": "opportunistic infections in patients with idiopathic inflammatory myopathies"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-293995",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Because patients with abdominal solid organ transplants (SOTs) are at increased risk of polymicrobial intraabdominal infections (IAIs) following transplantation, the objective of this study was to compare the effectiveness and adverse event profile of tigecycline with those of other broad-spectrum therapies for polymicrobial IAIs in this population.\n\n\n\nRetrospective cohort study.\n\n\n\nLarge academic medical center with multiple outpatient clinics.\n\n\n\nA total of 81 adult SOT recipients were included who were treated for confirmed or suspected polymicrobial IAIs from 2007-2012. Of these patients, 27 received tigecycline and 54 received comparator therapy with a broad-spectrum β-lactam (e.g., piperacillin-tazobactam, cefepime, or meropenem) with or without glycopeptide or lipopeptide gram-positive therapy (vancomycin or daptomycin) (comparator group). Patients in the comparator group were matched to tigecycline-treated patients based on transplant type (kidney, combined kidney-pancreas, combined kidney-liver, or solitary pancreas) in a 1:2 ratio (tigecycline-to-other broad-spectrum antibiotics).\n\n\n\nData on patient demographics, comorbidities, and clinical variables were collected and compared by using bivariate analyses. Clinical outcomes-clinical cure, improvement or failure, and disease recurrence-as well as death within 1 year were analyzed by bivariate analyses and logistic regression. Clinical cure was lower in the tigecycline group versus the comparator group (40.7% vs 72.2%, p=0.008), but cure combined with improvement was similar between the two groups (85.2% vs 88.9%, p=0.724). Multiple logistic regression analysis showed that treatment with comparator antibiotics increased the odds of cure (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.15-12.27) and reduced the odds of treatment failure (OR 0.59, 95% CI 0.07-4.55) and death within 1 year (OR 0.79, 95% CI 0.22-2.86); however, patients receiving comparator antibiotics were more likely to have disease recurrence (OR 1.45, 95% CI 0.33-6.36). Patients receiving tigecycline experienced a higher rate of adverse events than those receiving comparator antibiotics (29.6% vs 9.3%, p=0.026).\n\n\n\nPatients receiving tigecycline were less likely to achieve optimal clinical outcomes and had more adverse events. Alternative regimens should be selected over tigecycline for the treatment of polymicrobial IAIs in abdominal SOT recipients until additional studies are completed to examine its role in this population.",
"affiliations": "Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.;Division of Infectious Diseases, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.;Division of Infectious Diseases, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.",
"authors": "Liebenstein|Tyler|T|;Schulz|Lucas T|LT|;Viesselmann|Chris|C|;Bingen|Emma|E|;Musuuza|Jackson|J|;Safdar|Nasia|N|;Rose|Warren E|WE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1883",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "37(2)",
"journal": "Pharmacotherapy",
"keywords": "broad-spectrum therapy; glycylcycline; outcomes; polymicrobial infections; transplant",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D015331:Cohort Studies; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D016377:Organ Transplantation; D012008:Recurrence; D012189:Retrospective Studies; D000078304:Tigecycline; D066027:Transplant Recipients",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "151-158",
"pmc": null,
"pmid": "27983753",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Effectiveness and Safety of Tigecycline Compared with Other Broad-Spectrum Antimicrobials in Abdominal Solid Organ Transplant Recipients with Polymicrobial Intraabdominal Infections.",
"title_normalized": "effectiveness and safety of tigecycline compared with other broad spectrum antimicrobials in abdominal solid organ transplant recipients with polymicrobial intraabdominal infections"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-041016",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
... |
{
"abstract": "Background: The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods: Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. Results: A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort 26 patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. Conclusion: The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen 'cytokine storm' of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.",
"affiliations": "Dermatology Department, University of Rome \"Tor Vergata\" , Rome, Italy.;Dermatology Department, University of Rome \"Tor Vergata\" , Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, Dermatologia, Dipartimento Scienze Mediche e Chirurgiche , Rome, Italy.;Medical Sciences Department, Dermatologic Clinic, University of Turin , Turin, Italy.;Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II , Naples, Italy.;Section of Dermatology and Venereology, Department of Medicine, University of Verona , Verona, Italy.;Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan, Italy.;Department of Medico-Surgical Sciences and Biotechnologies, Dermatology Unit \"Daniele Innocenzi\" Sapienza University of Rome - Polo Pontino , Rome, Italy.;Dermatologic Unit, Department of Specialized Medicine, AOU Policlinico di Modena , Modena, Italy.;Clinica Dermatologica DiSSal Università di Genova, Ospedale-Policlinico San Martino IRCCS Genova , Italy.;Dermatology Unit - Department of Medicine DIMED, University of Padova , Padova, Italy.;Dermatology Division, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna , Bologna, Italy.;Dermatology Unit, University of Campania Luigi Vanvitelli , Naples, Italy.;Section of Dermatology, Department of Medical Sciences and Public Health, University of Cagliari , Cagliari, Italy.;Dermatology Section, Department of Medicine, University of Perugia , Perugia, Italy.;Dermatology Clinic, University of Catania , Catania, Italy.;Department of Biomedical Science and Human Oncology, Unit of Dermatology, University of Bari , Bari, Italy.;Department of Dermatology, ASST Spedali Civili of Brescia, University of Brescia , Brescia, Italy.;Section of Dermatology, Department of Health Promotion, Maternal-Infant, Internal Medicine and Specialization, University of Palermo , Palermo, Italy.;Department of Medicine and Surgery, Section of Dermatology, University of Parma , Parma, Italy.;Dermatology Unit, Department of Medical, Surgical and Neurosciences, University of Siena , Siena, Italy.;Department of Medicine and Aging Science, Dermatologic Clinic, G. D'Annunzio University , Chieti, Italy.;Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila , L'Aquila, Italy.;Department of Biomedical, Surgical and Dental Sciences, Clinical Dermatology, IRCCS Galeazzi Orthopaedic Institute, University of Milan , Milan, Italy.;Department of Health Science, Dermatologic Clinic, University of Eastern Piedmont , Novara, Italy.;Dermatology Unit, Department of Health Sciences, Università Magna Graecia , Catanzaro, Italy.;Department of Dermatology, 'Sapienza' University of Rome , Rome, Italy.;Dermatology Unit, ASST Papa Giovanni XXIII Hospital , Bergamo, Italy.;Dermatology, Department of Clinical and Experimental Medicine, University of Messina , Messina, Italy.;Division of Dermatology, Santa Chiara Hospital , Trento, Italy.;Dermatology Clinic, Department of Health Sciences, University of Florence , Florence, Italy.;Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of the Marche Region , Ancona, Italy.;Unit of Dermatological Diseases, ASST Sette Laghi, Ospedale di Circolo , Varese, Italy.;Department of Dermatology, University of Trieste , Trieste, Italy.;Dermatology Department, University of Rome \"Tor Vergata\" , Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, Dermatologia, Dipartimento Scienze Mediche e Chirurgiche , Rome, Italy.",
"authors": "Talamonti|Marina|M|0000-0002-3070-4071;Galluzzo|Marco|M|0000-0002-3424-5175;Chiricozzi|Andrea|A|0000-0002-6739-0387;Quaglino|Pietro|P|;Fabbrocini|Gabriella|G|;Gisondi|Paolo|P|;Marzano|Angelo Valerio|AV|;Potenza|Concetta|C|;Conti|Andrea|A|;Parodi|Aurora|A|;Piaserico|Stefano|S|;Bardazzi|Federico|F|;Argenziano|Giuseppe|G|;Rongioletti|Franco|F|;Stingeni|Luca|L|;Micali|Giuseppe|G|;Loconsole|Francesco|F|;Rossi|Maria Teresa|MT|;Bongiorno|Maria Rita|MR|;Feliciani|Claudio|C|;Rubegni|Pietro|P|;Amerio|Paolo|P|;Fargnoli|Maria Concetta|MC|;Pigatto|Paolo|P|;Savoia|Paola|P|;Nisticò|Steven Paul|SP|;Giustini|Sandra|S|;Carugno|Andrea|A|0000-0002-8231-2205;Cannavo'|Serafinella Patrizia|SP|;Rech|Giulia|G|;Prignano|Francesca|F|;Offidani|Annamaria|A|;Lombardo|Maurizio|M|;Zalaudek|Iris|I|;Bianchi|Luca|L|0000-0001-8697-6896;Peris|Ketty|K|",
"chemical_list": "D001688:Biological Products; C515500:IL23R protein, human; D020381:Interleukin-17; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1080/14712598.2021.1853698",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1471-2598",
"issue": "21(2)",
"journal": "Expert opinion on biological therapy",
"keywords": "COVID-19; biological therapy; dermatology; psoriasis; sars-CoV-2",
"medline_ta": "Expert Opin Biol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001688:Biological Products; D001691:Biological Therapy; D000086382:COVID-19; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D020381:Interleukin-17; D007558:Italy; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011565:Psoriasis; D018123:Receptors, Interleukin; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101125414",
"other_id": null,
"pages": "271-277",
"pmc": null,
"pmid": "33216643",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Characteristic of chronic plaque psoriasis patients treated with biologics in Italy during the COVID-19 Pandemic: Risk analysis from the PSO-BIO-COVID observational study.",
"title_normalized": "characteristic of chronic plaque psoriasis patients treated with biologics in italy during the covid 19 pandemic risk analysis from the pso bio covid observational study"
} | [
{
"companynumb": "IT-CELLTRION INC.-2021IT018935",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 6-month-old boy was brought to the ophthalmology outpatient clinic of our hospital by his parents with the suspicion of esotropia of his left eye. He was able to follow the objects, pupillary light reactions were normal, orthophoric in primary position with corneal light reflex (Hirschberg) test, ductions and versions were normal in all gaze positions. One drop of tropicamide (1%) was instilled in both eyes of the infant for cycloplegic retinoscopy and fundus examinations. After 10 min, anaphylaxis, respiratory and circulatory failure developed. He was immediately examined by the pediatrician, and emergency code was announced. At the 5th min of treatment, he regained consciousness, his respiratory and circulatory symptoms started to improve, and blood pressure returned to normal. In this case report, we aim to point out that tropicamide may rarely lead to life-threatening complications.",
"affiliations": "Department of Ophthalmology, Başkent University Zübeyde Hanım Hospital, İzmir, Turkey.;Department of Pediatry, Başkent University Zübeyde Hanım Hospital, İzmir, Turkey.",
"authors": "Sefi-Yurdakul|Nazife|N|;Sancakli|Özlem|Ö|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1319-4534.325779",
"fulltext": "\n==== Front\nSaudi J Ophthalmol\nSaudi J Ophthalmol\nSJO\nSaudi Journal of Ophthalmology\n1319-4534\n2542-6680\nWolters Kluwer - Medknow India\n\nSJO-35-71\n10.4103/1319-4534.325779\nCase Report\nTropicamide and anaphylaxis: A case report\nSefi-Yurdakul Nazife\nSancakli Özlem 1\nDepartment of Ophthalmology, Başkent University Zübeyde Hanım Hospital, İzmir, Turkey\n1 Department of Pediatry, Başkent University Zübeyde Hanım Hospital, İzmir, Turkey\nAddress for correspondence: Prof. Nazife Sefi-Yurdakul, Halk Sokak, No. 26 Sahilevleri, 35320 Narlıdere, İzmir, Turkey. E-mail: nsefi@yahoo.com\nJan-Mar 2021\n09 9 2021\n35 1 7172\n30 9 2019\n20 10 2020\n17 11 2020\nCopyright: © 2021 Saudi Journal of Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nA 6-month-old boy was brought to the ophthalmology outpatient clinic of our hospital by his parents with the suspicion of esotropia of his left eye. He was able to follow the objects, pupillary light reactions were normal, orthophoric in primary position with corneal light reflex (Hirschberg) test, ductions and versions were normal in all gaze positions. One drop of tropicamide (1%) was instilled in both eyes of the infant for cycloplegic retinoscopy and fundus examinations. After 10 min, anaphylaxis, respiratory and circulatory failure developed. He was immediately examined by the pediatrician, and emergency code was announced. At the 5th min of treatment, he regained consciousness, his respiratory and circulatory symptoms started to improve, and blood pressure returned to normal. In this case report, we aim to point out that tropicamide may rarely lead to life-threatening complications\n\nTropicamide\ncycloplegia\nanaphylaxis\n==== Body\npmcINTRODUCTION\n\nAnticholinergic-parasympathicolytic agents cause accommodation paralysis and pupillary dilatation through ciliary muscle paralysis along with sphincter pupillae effect. Cyclopentolate 0.5%–1% and tropicamide 0.5%–1% are the most commonly used agents for that purpose. These eye drops may pass to the systemic circulation through conjunctiva and nasolacrimal canal, and eventually toxic effects may occur.[1] Anaphylactic reaction, psychosis, hallucination, paralytic ileus, circulatory and respiratory failure are the main adverse effects reported so far.[12345] In this case report, we aim to point out that tropicamide (1%) instilled for cycloplegic refraction and fundus examination may rarely lead to life-threatening complications.\n\nCASE REPORT\n\nA 6-month-old boy was brought to the ophthalmology outpatient clinic of our hospital by his parents for a control examination due to suspected esotropia of the left eye. He had orthophoria in primary position in the corneal light reflex (Hirschberg) test, ductions and versions were normal in all gaze positions. He could follow objects and had pupillary light reactions normal. One drop of tropicamide (1%) in standard volume was instilled in both eyes of the infant without punctual occlusion to perform cycloplegic retinoscopy, optical media, and fundus examination. After 10 min, the baby displayed a serious distress along with cries. He was immediately examined by the pediatrician on urticaria that appeared on the face and spread to the neck and trunk, persistent nausea and retching, respectively. He was observed to have cardiac pulse: 120/R and respiration rate: 30/min, and administered intramuscular injection of 0.6 mg/kg dexamethasone and ½ ampoule pheniramine maleate due to drug allergy.\n\nEmergency code was announced in the observation room, due to hypotension, deterioration of the peripheral circulation, prolongation of capillary refill time, along with cyanosis and clouding of consciousness. Anaphylaxis was considered and 0.01 mg/kg adrenaline was administered intramuscularly. Oxygen was delivered through a mask at a rate of 5 ml/min. Vascular access was established and 20 ml/kg bolus infusion of saline was initiated. At the 5th min of treatment, he regained consciousness, circulatory symptoms improved, and blood pressure returned to normal. Urticaria plaques regressed within 1 h. He was monitored for 24 h with regard to biphasic anaphylaxis and discharged with full recovery. Further control was recommended in outpatient settings.\n\nDISCUSSION\n\nCyclopentolate and tropicamide used to provide cycloplegia and pupillary dilatation in the assessment of refractive errors and fundus examination, are synthetic anticholinergic agents. Undesirable side effects of these agents may appear at a rate of 10%, as a result of their systemic absorption from transconjunctival or nasolacrimal tract following their instillation into the eye.[1] In their prospective study, comparing double dose of cyclopentolate (1%) and one dose of cyclopentolate (1%) followed by one dose of tropicamide (1%) in the pediatric population, van Minderhout et al.[2] determined that side effects related to anticholinergic agents were more common in children using a double dose of cyclopentolate. Their observations also suggested a possible correlation with younger age and/or lower body mass index. Similarly, Pooniya and Pandey[3] reported that overdose use of topical cyclopentolate can lead to systemic toxicity such as behavioral alterations, visual hallucinations, and difficulty in walking. Adverse effects may occur during infancy and childhood as a result of prolonged half-lives of the drugs, due to the immaturity of their metabolic systems and organs. For this reason, it is recommended that ocular examinations requiring cyclopentolate (1%), a single dose should be performed in hospital setting or at least in the environments where vital functions can be monitored and if necessary, combined with tropicamide in small children with a low body mass index.[2]\n\nAmong mydriatic eye drops, tropicamide is reported as one of the safest agents in infants.[6] However, Wahl[7] reported a child with an anaphylactic shock reaction following instillation of 0.5% tropicamide. Similarly, in the study comparing micro-drops with standard-volume drops, Elibol et al.[4] showed that even tropicamide (0.5%) used in the standard volumes leads to a serious increase in systemic blood pressure as in cyclopentolate and phenylephrine. They suggest that adverse effects can be prevented by reducing the volume. Agrawal et al.[5] also observed cardiopulmonary arrest developed in a 6-week-old infant after using standard volume of tropicamide (1%) and phenylephrine (2.5%), and where vital functions improved after resuscitation. Alpay et al.[8] recommended 0.5% dose of tropicamide combine with phenylephrine (2.5%) in infants.\n\nSupportive treatment is primarily applied when side effects of topical anticholinergic agents occur. Physostigmine, which is the specific antidote of anticholinergic drugs and an anticholinesterase inhibitor, can be used in those cases with no response. Our patient recovered in a short time, responding to supportive treatment.\n\nIn conclusion, it should be kept in mind that there may be side effects related to topical drug use in pediatric cases. Smaller-volume drops (microdrop) should be used to reduce side effects, the dose and the number of drops should be clearly explained to the health workers, and pressure should be applied to the puncta and canaliculi to reduce the passage through nasolacrimal channels. It is also appropriate to obtain written informed consent forms from patients' parents, explaining the likelihood of side effects.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained allappropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in thejournal. The patients understand that their names and initial s will not be published and due efforts will bemade to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Tayman C Mete E Catal F Akca H Anaphylactic reaction due to cyclopentolate in a 4-year-old child J Investig Allergol Clin Immunol 2010 20 347 8\n2 van Minderhout HM Joosse MV Grootendorst DC Schalij-Delfos NE Adverse reactions following routine anticholinergic eye drops in a paediatric population: An observational cohort study BMJ Open 2015 5 e008798\n3 Pooniya V Pandey N Systemic toxicity of topical cyclopentolate eyedrops in a child Eye (Lond) 2012 26 1391 2 22814809\n4 Elibol O Alçelik T Yüksel N Caglar Y The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants Acta Ophthalmol Scand 1997 75 178 80 9197568\n5 Agrawal Y Parti S Kalavakunta JK Gupta V Retinopathy of prematurity screening leading to cardiopulmonary arrest: fatal complication of a benign procedure BMJ Case Rep 2016 cr2016216594\n6 Oğüt MS Bozkurt N Ozek E Birgen H Kazokoğlú H Oğüt M Effects and side effects of mydriatic eyedrops in neonates Eur J Ophthalmol 1996 6 192 6 8823596\n7 Wahl JW Systemic reaction to tropicamide Arch Ophthalmol 1969 82 320 1 5806055\n8 Alpay A Canturk Ugurbas S Aydemir C Efficiency and safety of phenylephrine and tropicamide used in premature retinopathy: A prospective observational study BMC Pediatr 2019 19 415 31690284\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1319-4534",
"issue": "35(1)",
"journal": "Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society",
"keywords": "Tropicamide; anaphylaxis; cycloplegia",
"medline_ta": "Saudi J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9425601",
"other_id": null,
"pages": "71-72",
"pmc": null,
"pmid": "34667937",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "8823596;5806055;9197568;27469387;20815313;26700273;22814809;31690284",
"title": "Tropicamide and anaphylaxis: A case report.",
"title_normalized": "tropicamide and anaphylaxis a case report"
} | [
{
"companynumb": "ALC2021TR005491",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TROPICAMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Herpes simplex virus (HSV) hepatitis is an uncommon cause of liver failure, but may have a dramatic outcome. We herein present a case report of a liver graft infection by HSV-1 associated with liver failure and encephalitis. A complete hospital chart review of the case and a literature search were undertaken. Literature review suggests that herpes simplex acute liver failure is rare and associated with a poor prognosis, even with early treatment. Novel diagnostic and preventive approaches need to be instituted.",
"affiliations": "Hepatology Service, Department of Medicine, Saint-Luc Hospital, CHUM, University of Montreal, Montreal, Quebec, Canada.",
"authors": "Côté-Daigneault|J|J|;Carrier|F M|FM|;Toledano|K|K|;Wartelle-Bladu|C|C|;Willems|B|B|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12178",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "acute liver failure; hepatitis; herpes simplex; liver transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D020803:Encephalitis, Herpes Simplex; D017809:Fatal Outcome; D006525:Hepatitis, Viral, Human; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D019737:Transplants",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "130-4",
"pmc": null,
"pmid": "24383552",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Herpes simplex hepatitis after liver transplantation: case report and literature review.",
"title_normalized": "herpes simplex hepatitis after liver transplantation case report and literature review"
} | [
{
"companynumb": "PHHY2015CA044211",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"dru... |
{
"abstract": "Complete or partial resistance to prednisone and calcineurin inhibitors in children with idiopathic nephrotic syndrome often leads to end-stage renal disease. The aim of the study was to report the outcome of patients with multidrug-resistant nephrotic syndrome treated with an association of immunoglobulin immunoadsorption, intravenous immunoglobulins and B-cell depletion.\n\n\n\nAt treatment initiation, patients received ten sessions of immunoglobulin immunoadsorption and intravenous immunoglobulins in two weeks followed by one rituximab in case of remission.\n\n\n\nA remission of proteinuria was obtained in nine out of 14 patients at the end of the initial phase and in two additional patients after an extended period. The remission was stable in three patients and after additional IgIA and heavy immunosuppression in six. Two patients that initially responded relapsed after IgIA withdrawal and remained with an uncontrolled disease at last follow-up. Three patients did not respond to the treatment including two who were found to have a genetic podocytopathy.\n\n\n\nPatients with multidrug-resistant idiopathic nephrotic syndrome can be successfully led into remission by IgIA prior to reaching end-stage renal disease. However, IgIA does not suppress the need for heavy additional immunosuppression to control INS in most cases.",
"affiliations": "Pediatric Nephrology Unit, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.;Pediatric Nephrology Unit, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.;Pediatric Nephrology Unit, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.;Laboratory of Pathology, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.;Pediatric Nephrology Unit, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.;Pediatric Nephrology Unit, Hôpital Robert Debré, APHP, Sorbonne Paris Cité University, Paris, France.",
"authors": "Nattes|Elodie|E|;Karaa|Danièle|D|;Dehoux|Laurène|L|;Peuchmaur|Michel|M|;Kwon|Theresa|T|;Deschênes|Georges|G|0000-0002-5158-2915",
"chemical_list": "D007136:Immunoglobulins",
"country": "Norway",
"delete": false,
"doi": "10.1111/apa.14582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "108(4)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": "Antibody; B cell; Intravenous immunoglobulin G; Proteinuria; Rituximab",
"medline_ta": "Acta Paediatr",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007223:Infant; D008297:Male; D009404:Nephrotic Syndrome; D010956:Plasmapheresis; D011507:Proteinuria; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "757-762",
"pmc": null,
"pmid": "30230027",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Remission of proteinuria in multidrug-resistant idiopathic nephrotic syndrome following immunoglobulin immunoadsorption.",
"title_normalized": "remission of proteinuria in multidrug resistant idiopathic nephrotic syndrome following immunoglobulin immunoadsorption"
} | [
{
"companynumb": "FR-ROCHE-2217325",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Natural killer (NK) cells exhibit strong cytotoxic activity against tumor cells without prior sensitization, and have the potential to exert antibody-dependent cellular cytotoxicity (ADCC). In this clinical trial, we examined the safety and efficacy of the use of NK cells, generated using a novel expansion system, in combination with IgG1 antibodies for the treatment of advanced gastric or colorectal cancers. Treatment consisted of trastuzumab- or cetuximab-based chemotherapy, plus adoptive NK cell therapy. For administration of expanded NK cells, dose escalation with a sequential 3 + 3 design was performed in three steps, at doses of 0.5 × 109 , 1.0 × 109 , and 2.0 × 109 cells/injection (N = 9). After 3 days of IgG1 antibody administration, patients were infused with expanded NK cells three times at triweekly intervals. NK cell populations expanded with our system were confirmed as being enriched in NK cells (median 92.9%) with high expression of NKG2D (97.6%) and CD16 (69.6%). The combination therapy was very well tolerated with no severe adverse events. Among six evaluable patients, four presented stable disease (SD) and two presented progressive disease. Of the four SD patients, three showed an overall decrease in tumor size after combination therapy. Immune monitoring suggested that combination therapy enhanced whole blood IFN-γ production and reduced peripheral regulatory T cells (Tregs). In conclusion, this phase I trial provides evidence of good tolerability, induction of Th1 immune responses, and preliminary anti-tumor activity for this combination therapy, in patients with advanced gastric and colorectal cancer that have received previous therapy.",
"affiliations": "Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;CDM Center, Takara Bio Inc., Kusatsu, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;CDM Center, Takara Bio Inc., Kusatsu, Japan.;CDM Center, Takara Bio Inc., Kusatsu, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Basic Research, Louis Pasteur Center for Medical Research, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Ishikawa|Takeshi|T|0000-0002-5770-9710;Okayama|Tetsuya|T|;Sakamoto|Naoyuki|N|0000-0001-5215-3621;Ideno|Mitsuko|M|;Oka|Kaname|K|;Enoki|Tatsuji|T|;Mineno|Junichi|J|;Yoshida|Naohisa|N|;Katada|Kazuhiro|K|;Kamada|Kazuhiro|K|;Uchiyama|Kazuhiko|K|;Handa|Osamu|O|;Takagi|Tomohisa|T|;Konishi|Hideyuki|H|;Kokura|Satoshi|S|;Uno|Kazuko|K|;Naito|Yuji|Y|;Itoh|Yoshito|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D000068878:Trastuzumab; D000068818:Cetuximab",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.31285",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "142(12)",
"journal": "International journal of cancer",
"keywords": "adoptive NK therapy; antibody-dependent cellular cytotoxicity (ADCC); cetuximab; trastuzumab",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "2599-2609",
"pmc": null,
"pmid": "29388200",
"pubdate": "2018-06-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer.",
"title_normalized": "phase i clinical trial of adoptive transfer of expanded natural killer cells in combination with igg1 antibody in patients with gastric or colorectal cancer"
} | [
{
"companynumb": "JP-ROCHE-2124672",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "In the USA and other countries, oocyte donation is gaining increasing importance. Although sufficient data exist on procedure-associated short-term risks for oocyte donors, such as ovarian hyperstimulation syndrome, long-term follow-up studies of egg donors are lacking and their health risks are unknown. The lack of information may be misleadingly interpreted as lack of risk. Long-term hormone replacement therapy is recognized as a risk factor for breast cancer; the breast cancer risk of ovarian stimulation for egg donors is unknown but is a possibility. This commentary describes five individual cases of egg donors who developed breast cancer (four out of five women in their 30s) despite negative genetic testing results. Additionally, we summarize available studies of breast cancer in infertile women who experienced IVF. We emphasize the need to create egg donor registries that will facilitate long-term studies on egg donors. Until this information is available, we call for more realistic explanations to egg donors about the lack of knowledge of long-term risks as well as more transparent informed consent documents.",
"affiliations": "Professional Boundaries, Inc, 3052 N Palomino Park Loop, Tucson, AZ 85712, USA. Electronic address: jennifer@jenniferschneider.com.;Center for Bioethics and Culture, 3380 Vincent Road, Pleasant Hill, CA 94523, USA.;Donor Sibling Registry, P.O. Box 1571, Nederland, CO 80466, USA.",
"authors": "Schneider|Jennifer|J|;Lahl|Jennifer|J|;Kramer|Wendy|W|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.rbmo.2017.02.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1472-6483",
"issue": "34(5)",
"journal": "Reproductive biomedicine online",
"keywords": "Breast cancer; Egg donors; Informed consent; Long-term risks; Ovarian stimulation",
"medline_ta": "Reprod Biomed Online",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007258:Informed Consent; D010062:Ovulation Induction; D055815:Young Adult",
"nlm_unique_id": "101122473",
"other_id": null,
"pages": "480-485",
"pmc": null,
"pmid": "28473127",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term breast cancer risk following ovarian stimulation in young egg donors: a call for follow-up, research and informed consent.",
"title_normalized": "long term breast cancer risk following ovarian stimulation in young egg donors a call for follow up research and informed consent"
} | [
{
"companynumb": "US-009507513-1705USA010152",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FOLLITROPIN"
},
"drugadditional": null,
... |
{
"abstract": "We discuss a case of severe respiratory depression in a child, with ultrarapid CYP2D6 genotype and obstructive sleep apnea syndrome, after taking tramadol for pain relief related to a day-case tonsillectomy.",
"affiliations": "Department of Anesthesiology and Pediatric Critical Care, and gilles.orliaguet@nck.aphp.fr.;Department of Anesthesiology and Pediatric Critical Care, and.;Pediatric Otolaryngology Department, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, Assistance Publique des Hôpitaux de Paris, Paris, France;;Pediatric Otolaryngology Department, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, Assistance Publique des Hôpitaux de Paris, Paris, France;;Department of Biochemistry, Pharmacogenetics and Molecular Oncology Unit, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 1147, Paris, France; and.;Department of Toxicology and Genopathy, University of Lille Nord de France, Lille, France.;Pediatric Otolaryngology Department, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, Assistance Publique des Hôpitaux de Paris, Paris, France;",
"authors": "Orliaguet|Gilles|G|;Hamza|Jamil|J|;Couloigner|Vincent|V|;Denoyelle|Françoise|F|;Loriot|Marie-Anne|MA|;Broly|Franck|F|;Garabedian|Erea Noel|EN|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2014-2673",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "135(3)",
"journal": "Pediatrics",
"keywords": "respiratory depression; tramadol; ultrarapid CYP2D6",
"medline_ta": "Pediatrics",
"mesh_terms": "D000701:Analgesics, Opioid; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6; D005838:Genotype; D006801:Humans; D008297:Male; D010149:Pain, Postoperative; D012131:Respiratory Insufficiency; D014068:Tonsillectomy; D014147:Tramadol",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e753-5",
"pmc": null,
"pmid": "25647677",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol.",
"title_normalized": "a case of respiratory depression in a child with ultrarapid cyp2d6 metabolism after tramadol"
} | [
{
"companynumb": "FR-ACTAVIS-2015-09860",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"... |
{
"abstract": "Currently, data that supports the clinical benefit of agents targeting the epidermal growth factor receptor (EGFR) in the therapy of squamous cell carcinoma (SCC) histologic version of the lung cancer (LC) is insufficient. In the following report we present the case of a patient treated with erlotinib for SCC NSCLC. At the time of initiation, there were no available guidelines recommendations regarding the EGFR status in for initiation of EGFR tyrosine kinase inhibitors (TKIs) therapy for NSCLC, thus the sample was never tested for the EGFR mutational status. Not widely used in the treatment of SCC, EGFR-TKIs remain a valid therapeutic option in selected groups of patients.",
"affiliations": "Emergency County Hospital of Slatina, Romania.;Emergency County Hospital of Alexandria, Romania.;Department of Biochemistry, University of Medicine and Pharmacy of Craiova, Romania.;Emergency County Hospital of Slatina, Romania.",
"authors": "Vatu|Bogdan Ionel|BI|;Cristian|TuŢĂ|T|;Artene|Stefan|S|;Stiuca|Adelina|A|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.12865/CHSJ.46.03.13",
"fulltext": "\n==== Front\nCurr Health Sci J\nCurr Health Sci J\nCHSJ\nCurrent Health Sciences Journal\n2067-0656 2069-4032 Medical University Publishing House Craiova \n\n2020.3.13\n10.12865/CHSJ.46.03.13\nCase Report\nLong Term Survivor with Erlotinib in Metastatic Lung Cancer-Squamous Cell Carcinoma Subtype\nVATU BOGDAN IONEL 1 CRISTIAN TUŢĂ 2 ARTENE STEFAN 3 STIUCA ADELINA 1 1 Emergency County Hospital of Slatina, Romania\n2 Emergency County Hospital of Alexandria, Romania\n3 Department of Biochemistry, University of Medicine and Pharmacy of Craiova, Romania\nCorresponding Author: Bogdan Ionel Vatu,\nEmergency County Hospital of SlatinaRomaniabogdan.vatu@yahoo.com\nJul-Sep 2020 \n30 9 2020 \n46 3 300 304\n23 7 2020 20 9 2020 Copyright © 2014, Medical University Publishing House Craiova2014This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.Currently, data that supports the clinical benefit of agents targeting the epidermal growth factor receptor (EGFR) in the therapy of squamous cell carcinoma (SCC) histologic version of the lung cancer (LC) is insufficient. In the following report we present the case of a patient treated with erlotinib for SCC NSCLC. At the time of initiation, there were no available guidelines recommendations regarding the EGFR status in for initiation of EGFR tyrosine kinase inhibitors (TKIs) therapy for NSCLC, thus the sample was never tested for the EGFR mutational status. Not widely used in the treatment of SCC, EGFR-TKIs remain a valid therapeutic option in selected groups of patients.\n\nNon-small cell lung cancerTKIEGFREGFR-TKIserlotinibtargeted therapy\n==== Body\nIntroduction\nLC has been regarded as the number two cause of death worldwide and in the United States of America (USA) LC is responsible for the majority of cancer related deaths both in males and females [1].\n\nAccording to the World Health Organization (WHO), in the European Union (EU) about 20 percent of total deaths are attributed to cancer, LC being the most prevalent and the leading cause of death amongst cancer patients [1].\n\nNSCLC represents 80% of all LC and SCC subtype accounts for about 25% of NSCLC. The vast majority of patients with NSCLC are diagnosed in an advanced or metastatic stage, with survival being 6 months from the time of diagnosis till death [2].\n\nUp until a few years ago, chemotherapy was the only viable treatment option for patients with SCC LC. The advent of targeted therapy some twenty years ago has paved the road for very promising therapeutic options for an ever-growing number of cancers. Particularly, in lung cancer, the EGFR‐TKIs are currently being used to treat NSCLC that harbor EGFR mutations as a first line setting in advanced and metastatic disease [3].\n\nEGFR‐TKIs have presented a clear improvement in the treatment of NSCLC in terms of progression free survival (PFS) and an improvement in quality of life (QoL) when compared to chemotherapy [4,5].\n\nUnfortunately, while EGFR‐TKIs have demonstrated a clear effect in a subgroup of adenocarcinoma patients harboring a specific mutation, no clear benefit has been observed for those with the SCC subtype. However, a few case reports have noted a benefit for patients with the SCC subtype after receiving EGFR TKIs [6].\n\nAccording to the latest guidelines, EGFR mutation status testing is an integral part of standard care in LC. The American Association for Clinical Oncology (ASCO), The European Association for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) publish guidelines regarding EGFR status testing in patients with SCC LC [3].\n\nAccording to ASCO, all NSCLC cases should be included in the testing for EGFR mutational status, if they are eligible for first‐line therapy with an EGFR‐TKI [7].\n\nIn Europe, the ESMO has reached a consensus which recommends that all patients who are never/former light smokers and those with non squamous cell should be tested for the EGFR mutation [8].\n\nThe NCCN guidelines strongly recommend that all never smokers, patients with small biopsy specimens, or those with mixed histology should have the EGFR mutation investigated via immunohistochemistry if they have been previously diagnosed with the SCC subtype [3].\n\nAs a conclusion, ASCO encourages EGFR mutation testing for all SCC cases when the patients are candidates for EGFR‐TKIs therapy while ESMO/NCCN guidelines recommend EGFR testing for several clearly defined situations [3,7,8].\n\nMore interestingly, in the past decade, a number of studies have highlighted that the incidence of EGFR mutations in SCC samples was between 3.9%‐17.2%, which is higher than expected [9,10,11].\n\nErlotinib is a first generation TKI used for the treatment of locally advanced or metastatic NSCLC and for therapy of patients diagnosed with pancreatic cancer in locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine [12,13].\n\nIt was approved following the results of phase III BR.21 study, since 2004 by the Food and Drug Administration (FDA) in the second and third line setting for locally advanced and metastatic NSCLC treatment regardless of EGFR mutational status [14].\n\nSince 2004, multiple studies have shown that erlotinib has a higher clinical benefit in the subpopulation of patients with NSCLC that had non-SCC histology, who were females and never smoked.\n\nCase Study\nIn this study we present the case of a 67 year old man, diagnosed 11 years ago (July 2009) with stage IV NSCLC, former heavy smoker, with a SCC tumor histology who was treated for nine years with erlotinib in the second line setting, following relapse after first line chemotherapy with a platinum doublet. The patient signed the informed consent granting access to the information presented in this article strictly for scientific purposes only.\n\nThe patient was first admitted in the “Bagdasar Arseni” Emergency Hospital in Bucharest, Romania in July 2009 for headaches, dizziness and aphasia. He lived in an urban home and had a medical history of asthma and chronic obstructive broncho pneumopathy.\n\nThe neurological exam performed at admittance discovered that the patient was unable to walk or stand up, presented a hemiparesis of the right upper limb, right nasolabial fold flattening and aphasia.\n\nThe computer tomography (CT) (Figure 1) and magnetic resonance imaging (MRI) brain scans showed a left parietal brain lesion about 10mm in its greatest diameter.\n\nFigure 1 Left parietal brain lesion, (lateral and transversal view), 2009\n\nChest X-ray shows a tumor in the right inferior lung lobe. Abdominal ultrasound shows no pathological finds. Chest CT scan confirmed the tumour in the right inferior lung lobe. Cardiology and ophthalmology exams showed no abnormalities.\n\nThe initial blood count, liver and renal functions showed modified values in fibrinogen (FiB): 538mg% and Erytrocyte sedimentation rate (ESR): 40mm/hour.\n\nBronchoscopy was negative. The forced vital capacity (FVC), FEV (forced expiration ventilation) and diffusing capacity of carbon monoxide (DLCO) showed a mild respiratory restrictive obstruction.\n\nFive days later the patient receives gamma knife radiosurgery for the brain lesion, a total of 0.9Gy over a tumoral volume of 1,6 cubic centimeters tissue mass being delivered. He then undergoes surgery and the right inferior lung lobe is removed together with mediastinal lymph node dissection.\n\nThe histopathological examination of the sample presented the following results: A 13/7/5cm lobectomy piece with a 6cm diameter tumor with pleural invasion and massive necrosis. The microscopic evaluation described a poorly differentiated epidermoid squamous carcinoma with clear invasion of the visceral pleura. No lymph node invasion was detected. The post-intervention stage was pT2pN0M1. No immunohistochemistry was performed at the time.\n\nFollowing the multidisciplinary team (MDT) evaluation the diagnosis of stage IV (M1BRA) right inferior lobe NSCLC is established.\n\nOn the 21st of November 2009 the patient begins first line chemotherapy with cisplatin and gemcitabine administered at a 21 days interval for a total of nine cycles, until 24th of June 2010.\n\nThe chest and abdominal CT scan evaluation performed six months after chemotherapy, shows pretracheal and laterotracheal lymph node enlargement (under 10mm largest diameter) and blood tests show an elevated gamma glutamyl transferase of 69.6U/L. We considered progressive disease after first line chemotherapy and started second line treatment with EGFR TKI-erlotinib. This decision was taken based on clinical experience as there were no clear guideline indications for TKIs therapy in NSCLC, based on the immunohistochemical analysis of driver mutations.\n\nIn December 2010 the patient started second line therapy with erlotinib 150mg daily continued to this day.\n\nCT scans of the chest (Figure 2a) and brain MRI (Figure 3), abdominal US and blood tests, performed at a 6 month interval show no evidence of progressive disease. There is a residual left parietal lesion described in every CT scan since gamma knife surgery and post-surgery right lobe scarring (Figure 2b).\n\nFigure 2 Thorax - transversal view, 2011 with no signs of local disease (a) and residual right lobe scarring (b).\n\nFigure 3 Brain section transversal view, left parietal lesion post Gamma Knife treatment, 2014\n\nDiscussion\nNSCLC that has spread to other parts of the body is often hard to treat. The 5-year survival rate for stage IVA NSCLC is about 10%, and for stage IVB the 5-year survival rate is less than 1% [15].\n\nSCC is responsible for almost a quarter of all lung cancer cases, second only to adenocarcinomas.\n\nIt has several particular traits which make its diagnosis and treatment different from other LC types.\n\nFirst and foremost, its’ usually appears from cells belonging to the central respiratory airways, making it the most likely subtype to cause an obstructive respiratory syndrome [16].\n\nSCC is strongly linked to a personal history of long-term tobacco consumption which contains a large number of DNA-altering toxins.\n\nAs such, it was strongly expected that SCC would present a plethora of mutations and other types of genetic alterations with targeting potential.\n\nParadoxically, no mainstay driver mutation has been identified in the case of SCC. EGFR, which has been strongly linked to the development and evolution of adenocarcinomas has presented a meager influence in the genesis of SCC.\n\nHowever, there are several clinical trials which suggest that anti-EGFR treatment might be a valuable option for the treatment of SSC.\n\nA multicenter phase III trial from 23 countries analyzed the effect of Afatinib vs. Erlotinib for second line treatment of stage IIIB and IV non-resecable SCC.\n\nThe study showed markedly improved OS and PFS for the patients who received Afatinib underscoring that even though the earlier generations of anti-EGFR TKIs presented favorable results in only a select number of cases the newer molecules might play a larger role [17].\n\nAnother study showed that the anti-EGF antibody necitumumab alongside gemcitabine was superior to the standard cisplatin-gemcitabine doublet in the treatment of EGFR-expressing SCC patients, in terms of both OS and PFS.\n\nThe safety profile for both gemcitabine and necitumumab and necitumumab as maintenance therapy was more favorable when compared to the combined chemotherapy regimen which is known to have multiple adverse effects [18].\n\nIn our case, when the targeted treatment was initiated, there were no guidelines for EGFR mutational status testing and EGFR-TKIs could be prescribed as part of the treatment panel strategy of NSCLC regardless of histopathological type or EGFR.\n\nOur patient benefited from erlotinib as a second line option following progression after first line platinum doublet.\n\nIt is worth mentioning that in this case we did not have an accurate description on the number of lymp nodes resected at the time of surgery.\n\nThe number of lymph nodes were not assessed prior to surgery through Endoscopic Ultrasound (EUS) or Endobronchial Ultrasound (EBUS).\n\nBiopsy from the brain lesion was not obtained because the MDT panel decidet the risk-benefit ratio was unacceptable for the patient at that moment.\n\nIn this case there is a disease free interval of 97 months, last CT scan, performed in May 2019 showing the same left parietal residual lesion as before and right lung post-surgery scarring.\n\nConclusions\nThe presented case, underlines that even in SCC of the lung where ESMO and NCCN guidelines are specific with EGFR testing, EGFR-TKIs may play a role in the treatment of certain patients and EGFR mutational status should be part of the initial panel of explorations for every NSCLC patient diagnosed.\n\nConflict of interests\nNone to declare.\n\nAcknowledgments\nBogdan-Ionel Vatu and Cristian Tuta share equal contributions to this work.\n\nList of abbreviations\nEGFREpidermal growth factor receptor\n\nTKITyrosine Kinase Inhibitor\n\nLCLung Cancer\n\nNSCLCNon-small cell lung cancer\n\nSCCSquamous Cell Carcinoma\n\nASCOAmerican Association for Clinical Oncology\n\nESMOEuropean Association for Medical Oncology\n\nNCCNNational Comprehensive Cancer Network\n\nFDAFood and Drug Administration\n\nPFSprogression free survival\n\nQoLquality of life\n\nUSAUnited States of America\n\nWHOWorld Health Organization\n\nCTcomputer tomography\n\nMRImagnetic resonance imaging\n\nMDTmultidisciplinary team\n\nFVCforced vital capacity\n\nFEVforced expiration ventilation\n\nDLCOdiffusing capacity of carbon monoxide\n\nEUSEndoscopic Ultrasound\n==== Refs\nReferences\n1 The L GLOBOCAN 2018: counting the toll of cancer Lancet 2018 392 10152 985 985 30264708 \n2 Torre LA Siegel RL Jemal A Lung Cancer Statistics Advances in experimental medicine and biology 2016 893 1 19 26667336 \n3 Ettinger DS Wood DE Aggarwal C Aisner DL Akerley W Bauman JR Bharat A Bruno DS Chang JY Chirieac LR D'Amico TA Dilling TJ Dobelbower M Gettinger S Govindan R Gubens MA Hennon M Horn L Lackner RP Lanuti M Leal TA Lin J Loo BW Martins RG Otterson GA Patel SP Reckamp KL Riely GJ Schild SE Shapiro TA Stevenson J Swanson SJ Tauer KW Yang SC Gregory K Ocn Hughes M NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020 Journal of the National Comprehensive Cancer Network: JNCCN 2019 17 12 1464 1472 31805526 \n4 Planchard D Boyer MJ Lee JS Dechaphunkul A Cheema PK Takahashi T Gray JE Tiseo M Ramalingam SS Todd A McKeown A Rukazenkov Y Ohe Y Postprogression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-mutated Advanced Non-Small Cell Lung Cancer Clinical cancer research: an official journal of the American Association for Cancer Research 2019 25 7 2058 2063 30659024 \n5 Greenhalgh J Dwan K Boland A Bates V Vecchio F Dundar Y Jain P Green JA First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer The Cochrane database of systematic reviews 2016 5 CD010383 CD010383 27223332 \n6 Zhang Y Chen HM Liu YM Peng F Yu M Wang WY Xu H Wang YS Lu Y Significant benefits of osimertinib in treating acquired resistance to first-generation EGFR-TKIs in lung squamous cell cancer: A case report World journal of clinical cases 2019 7 10 1221 1229 31183356 \n7 Keedy VL Temin S Somerfield MR Beasley MB Johnson DH McShane LM Milton DT Strawn JR Wakelee HA Giaccone G American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011 29 15 2121 2127 21482992 \n8 Planchard D Popat S Kerr K Novello S Smit EF Faivre-Finn C Mok TS Reck M Van Schil PE Hellmann MD Peters S Committee EG Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Annals of oncology: official journal of the European Society for Medical Oncology 2018 29 Suppl 4 iv192 iv237 \n9 Wang R Zhang Y Pan Y Li Y Hu H Cai D Li H Ye T Luo X Zhang Y Li B Shen L Sun Y Chen H Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients Oncotarget 2015 6 33 34300 34308 26486077 \n10 Zhang Q Zhu L Zhang J Epidermal growth factor receptor gene mutation status in pure squamous-cell lung cancer in Chinese patients BMC cancer 2015 15 88 88 25886585 \n11 Han B Tjulandin S Hagiwara K Normanno N Wulandari L Laktionov K Hudoyo A He Y Zhang YP Wang MZ Liu CY Ratcliffe M McCormack R Reck M EGFR mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: The IGNITE study Lung cancer 2017 113 37 44 29110846 \n12 Yang Z Hackshaw A Feng Q Fu X Zhang Y Mao C Tang J Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis International journal of cancer 2017 140 12 2805 2819 28295308 \n13 Tseng JS Yang TY Chen KC Hsu KH Chen HY Chang GC Retrospective study of erlotinib in patients with advanced squamous lung cancer Lung cancer 2012 77 1 128 133 22420950 \n14 Zhu CQ da Cunha Santos G Ding K Sakurada A Cutz JC Liu N Zhang T Marrano P Whitehead M Squire JA Kamel-Reid S Seymour L Shepherd FA Tsao MS National Cancer Institute of Canada Clinical Trials Group Study BR Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21 Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2008 26 26 4268 4275 18626007 \n15 Ferlay J Colombet M Soerjomataram I Mathers C Parkin DM Pineros M Znaor A Bray F Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods International journal of cancer 2019 144 8 1941 1953 30350310 \n16 Hirsh V New developments in the treatment of advanced squamous cell lung cancer: focus on afatinib OncoTargets and therapy 2017 10 2513 2526 28546756 \n17 Soria JC Felip E Cobo M Lu S Syrigos K Lee KH Goker E Georgoulias V Li W Isla D Guclu SZ Morabito A Min YJ Ardizzoni A Gadgeel SM Wang B Chand VK Goss GD Investigators LU-L Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial The Lancet Oncology 2015 16 8 897 907 26156651 \n18 Ciuleanu T Socinski MA Obasaju C Luft AV Szczesna A Szafranski W Ramlau R Balint B Molinier O Depenbrock H Nanda S Paz-Ares L Thatcher N Efficacy and Safety of Necitumumab Continuation Therapy in the Phase III SQUIRE Study of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer Clinical lung cancer 2018 19 2 130 138 e132 29158123\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "46(3)",
"journal": "Current health sciences journal",
"keywords": "EGFR; EGFR-TKIs; Non-small cell lung cancer; TKI; erlotinib; targeted therapy",
"medline_ta": "Curr Health Sci J",
"mesh_terms": null,
"nlm_unique_id": "101597164",
"other_id": null,
"pages": "300-304",
"pmc": null,
"pmid": "33304633",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25886585;22420950;26486077;26667336;30285222;21482992;30659024;31183356;26156651;27223332;31805526;29158123;28295308;18626007;29110846;30350310;30264708;28546756",
"title": "Long Term Survivor with Erlotinib in Metastatic Lung Cancer-Squamous Cell Carcinoma Subtype.",
"title_normalized": "long term survivor with erlotinib in metastatic lung cancer squamous cell carcinoma subtype"
} | [
{
"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-269148",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "Restless legs syndrome (RLS) is a neuro-sensorimotor disorder affecting 2-4% of adults. It is characterized by intense urges to move the legs, associated with unpleasant sensory disturbances in the legs occurring at rest and manifests mostly in the evening and night, relieved by movement. Diagnosis is primarily based on clinical presentation and the consensus criteria for the diagnosis have been established. Antipsychotics, the dopamine antagonists, have been reported to induce RLS. Dopamine agonists, the effective first-line treatment of RLS, carry the risk of inducing or worsening psychosis. Many nondopaminergic agents including antiepileptic medications have also been used in the treatment of primary RLS. In this report we describe clozapine-induced RLS in two patients with schizophrenia and its successful treatment with gabapentin, a nondopaminergic agent. In addition, we have reviewed the available literature on clozapine-induced RLS and its management.",
"affiliations": "Department of Psychiatry, National Institute of Mental Health and Neurosciences, New Kabini Hostel Complex, Hosur road, Bangalore, Karnataka 560029, India.;The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.",
"authors": "Kumar|Vijaya|V|;Venkatasubramanian|Ganesan|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2045125316672133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-1253",
"issue": "7(1)",
"journal": "Therapeutic advances in psychopharmacology",
"keywords": "antipsychotics; clozapine; gabapentin; restless legs syndrome",
"medline_ta": "Ther Adv Psychopharmacol",
"mesh_terms": null,
"nlm_unique_id": "101555693",
"other_id": null,
"pages": "42-47",
"pmc": null,
"pmid": "28101323",
"pubdate": "2017-01",
"publication_types": "D016454:Review; D016428:Journal Article",
"references": "25023924;20535374;23331473;17459547;26329430;24874697;24813045;10221640;24892899;17224721;2015836;19464949;23361623;23686071;19690226;14592341;23859128;7249508;26215616;23131889;22099638;24824748;25300012;14592342;21777043",
"title": "Gabapentin treatment in clozapine-induced restless legs syndrome: two cases and a review of the literature.",
"title_normalized": "gabapentin treatment in clozapine induced restless legs syndrome two cases and a review of the literature"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1006852",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Herein we present a patient that underwent a liver transplant due to primary biliary cholangitis (PBC) and after 9 years developed multiple myeloma. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection. The patient recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. Lenalidomide-associated allograft rejection has been reported in other organs. However, this is the first case report of liver rejection induced by lenalidomide.",
"affiliations": "Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Division of gastroenterology and hepatology, Mayo Clinic, Rochester, MN, USA.;Pathology Department, Mayo Clinic Rochester, MN, USA.;Division of Hematology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Vaxman|Iuliana|I|https://orcid.org/0000-0002-8390-064X;Eaton|John|J|;Lee|Hee Eun|HE|;Gertz|Morie A|MA|https://orcid.org/0000-0002-3853-5196",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8894922",
"fulltext": "\n==== Front\nCase Rep Transplant\nCase Rep Transplant\nCRIT\nCase Reports in Transplantation\n2090-6943 2090-6951 Hindawi \n\n10.1155/2020/8894922\nCase Report\nAcute Liver Rejection in a Multiple Myeloma Patient Treated with Lenalidomide\nhttps://orcid.org/0000-0002-8390-064XVaxman Iuliana \n1\n\n2\n\n3\n Eaton John \n4\n Lee Hee Eun \n5\n https://orcid.org/0000-0002-3853-5196Gertz Morie A. gertz.morie@mayo.edu\n1\n \n1Division of Hematology, Mayo Clinic, Rochester, MN, USA\n\n2Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center Petah-Tikva, Israel\n\n3Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel\n\n4Division of gastroenterology and hepatology, Mayo Clinic, Rochester, MN, USA\n\n5Pathology Department, Mayo Clinic Rochester, MN, USA\nAcademic Editor: Ryszard Grenda\n\n\n2020 \n12 12 2020 \n2020 889492223 7 2020 2 12 2020 5 12 2020 Copyright © 2020 Iuliana Vaxman et al.2020This 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.Herein we present a patient that underwent a liver transplant due to primary biliary cholangitis (PBC) and after 9 years developed multiple myeloma. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection. The patient recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. Lenalidomide-associated allograft rejection has been reported in other organs. However, this is the first case report of liver rejection induced by lenalidomide.\n\nInternational Waldenstrom FoundationCA186781-04Amyloidosis Foundation\n==== Body\n1. Introduction\nLenalidomide has immunomodulatory, antiangiogenic, and antineoplastic characteristics and is used for the treatment of multiple myeloma (MM) [1, 2] and other hematological malignancies [3–5]. Acute cellular rejection secondary to lenalidomide has been described following kidney [6, 7] and cardiac transplantation [8–10]. This is the first case report of liver rejection induced by lenalidomide.\n\n2. Case Presentation\nA 65-year-old Caucasian female with a past medical history significant for infantile polio, which resulted in lower motor neuron damaged in her left leg with atrophy and weakness, was seen at Mayo Clinic. The patient was diagnosed with primary biliary cholangitis (PBC) in May 2010 and underwent a living donor liver transplant in 2011. At the first week posttransplant, she had a biopsy-proven mild acute cellular rejection and was treated with 2 doses of high dose-methylprednisolone. The patient maintained normal liver tests thereafter.\n\nIn January 2020, she presented with anemia (hemoglobin 10 g/dL). Bone marrow biopsy showed 65% plasma cells, lambda light chain restricted, and fluorescence in situ hybridization (FISH) indicated a plasma cell clone with a 1q duplication, monosomy 13, and monosomy 14. In addition, a tetraploid subclone was observed in 20% of the nuclei. Epstein-barr virus hybridization was not performed so it is uncertain whether myeloma is a variant of posttransplant lymphoproliferative disorder (PTLD). The diagnostic workup included WBC 2.9 × 109/L (N = 3.4‐9.6), platelet count 128 × 109/L (N = 157‐371), calcium 9.9 mg/dL (N = 8.8‐10.2), creatinine 0.73 mg/dL (N = 0.59‐1.04), albumin 3.8 g/dL (N = 3.5‐5), and beta 2 microglobulin 3.5 μg/mL (N = 1.2‐2.7). M spike 0.1 g/dL type lambda, IgG 982 mg/dL (N = 767‐1590), IgA 33 mg/dL (N = 61‐356), and IgM 47 mg/dL (N = 37‐286). Serum lambda 290 mg/dL (N = 0.57‐2.63), serum kappa 1.23 mg/dL (N = 0.33‐1.94), and kappa to lambda ratio was 0.003 (N = 0.26‐1.65). Her 24-hour urine protein was 50 mg, and no monoclonal protein was seen. CT skeletal survey was negative for lytic lesions. Liver tests were normal. Multiple myeloma (MM) was diagnosed. At MM diagnosis, AST was 31 U/L (N = 8‐43), ALT was 23 (N = 7‐45), ALP was 69 U/L (N = 35‐104), and bilirubin was 0.47 (N = 0‐1.2).\n\nImmunosuppression following liver transplant consisted of mycophenolate mofetil 500 mg twice daily and tacrolimus 0.5 mg twice daily. When MM was diagnosed, mycophenolate mofetil was stopped due to cytopenias and the need for myeloma directed therapy. The patient started bortezomib 1.3 mg/m2 once weekly, lenalidomide 25 mg 21/28 days, and dexamethasone 40 mg once weekly (VRd). After the first 2 weeks of therapy, in cycle 1, she had a rise in AST to 365 U/L (N = 8‐43), ALT to 386 (N = 7‐45), and ALP to 253 U/L (N = 35‐104). Bilirubin was elevated to at 3.3 mg/dL (N = 0‐1.2) and 1.4 mg/dL direct. VRd treatment was discontinued. Preceding the rise in liver tests, her tacrolimus trough was 4.0 ng/mL.\n\nA liver biopsy was performed and revealed the following findings: (i) mild to moderate portal inflammation with plasma cells and eosinophils and necroinflammatory foci in the lobular parenchyma, (ii) focal interface activity, (iii) endotheliitis in the portal tracts and hepatic vein branches, (iv) focal cholangitis with biliary epithelial injury and granulomatous inflammation, and (v) trichome stain was negative for fibrosis. This was felt to represent recurrent PBC with mild acute cellular rejection. In addition, the prominent interface and lobular inflammatory activity raised the possibility of a minor component of superimposed drug-induced liver injury or concurrent autoimmune hepatitis.\n\nShe was started on 1000 mg IV methylprednisolone, mycophenolate mofetil was resumed at 250 mg twice daily, and tacrolimus was raised to 1 mg twice daily. Treatment with ursodeoxycholic acid 15 mg/kg/day was started. A second biopsy was done a week after the first one which showed improving but persistent features of acute cellular rejection. No significant interface or lobular inflammatory activity was seen on the biopsy which may be due to the prior methyl prednisone treatment. Features of recurrent PBC were not visualized on this biopsy which may be related to the patchy nature of PBC (Figure 1).\n\nThe patient received a total of 3 doses of methylprednisolone 1000 mg (days 1, 3, and 5). Liver enzyme was normalized within a month, and MM treatment was resumed which included bortezomib 1.3 mg/m2 once weekly, cyclophosphamide 500 mg once weekly, and dexamethasone (VCd). Pre bone marrow transplant, the patient achieved a very good partial response (VGPR) as evidenced by serum lambda light chain reduction of more than 90%. Liver enzymes remain normal.\n\n3. Discussion\nWe present a patient that underwent a liver transplant due to PBC and after 9 years developed MM. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection and ultimately recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. While the cessation of mycophenolate mofetil in this case may have been a contributing factor, lenalidomide-associated allograft rejection has been reported in other organs and is important for clinicians to be aware of.\n\nWhile acute cellular rejection secondary to lenalidomide and other immunomodulatory treatments (IMiDs) has not previously been reported after liver transplant, it has been described following kidney [6, 7] and cardiac transplantation [8–10]. Hence, the possibility of IMiD-induced rejection may not be organ specific. Indeed, a heart rejection 40 days after pomalidomide initiation was reported [9]. In all case reports, organ rejection occurred early in the courses of lenalidomide treatment, always in the first 2 months from IMiD treatment initiation. In most of the reported cases, organ function improved after antirejection treatment.\n\nLenalidomide is used in the treatment of MM [1], light chain amyloidosis [5], mantle cell lymphoma [11], deletion 5q myelodysplastic syndrome [4], diffuse large B cell lymphoma [12], and chronic lymphocytic leukemia [3].\n\nThe underlying mechanism leading to rejection is unclear. IMiDs activate the cereblon complex which degrades IKZF3, a repressor of interleukin 2 (IL-2). This causes an increase in IL-2, leading to the recruitment of CD4+ cells and natural killer cells, which may cause an immune rejection of the solid organ. IMiDs also induce T cell activation by stimulating CD28, which works via nuclear factor kappa B [13].\n\nIt is interesting to note that there are reports about lenalidomide causing graft versus host disease (GVHD) after autologous [14] and allogeneic [15] stem cell transplantations. In a prospective trial, 9 out of 24 patients treated with lenalidomide after allogeneic transplantation developed GVHD, and the median time was 22 days. An increased risk of autoimmune disease in MM patients treated with IMiDs was reported in a retrospective trial, most cases early after treatment initiation [16].\n\n4. Conclusion\nTransplantation physicians and hematologists should be aware of the potential risk of organ rejection associated with immunomodulatory drugs such as lenalidomide. Patients who are receiving IMiDs (thalidomide, lenalidomide, or pomalidomide) who have previously undergone a transplant should have their allograft function monitored closely.\n\nAcknowledgments\nThis study was funded by the Amyloidosis Foundation and International Waldenstrom Foundation NCI SPORE MM SPORE 5P50 CA186781-04.\n\nData Availability\nThis is a case report. References from PUBMED are included in the manuscript.\n\nConflicts of Interest\nDr. Gertz reports personal fees from Ionis/Akcea, personal fees from Alnylam, personal fees from Prothena, personal fees from Janssen, grants and personal fees from Spectrum, personal fees from Annexon, personal fees from Appellis, personal fees from Amgen, personal fees from Medscape, personal fees from Physicians Education Resource, personal fees for Data Safety Monitoring board from Abbvie and Celgene, personal fees from Research to Practice, workforce training Sanofi, speaker fees from Teva, speaker fees from Johnson and Johnson, speaker fees from Medscape, and speaker fees from DAVA oncology; Advisory Board for Pharmacyclics Advisory Board for Proclara; Development of educational materials for i3Health.Royalties from Springer Publishing, Stock Options Aurora Bio.\n\nFigure 1 The liver biopsy shows venous endotheliitis which is one of the diagnostic features of acute cellular rejection (hematoxylin and eosin stain, original magnification ×200).\n==== Refs\n1 Durie B. G. M. Hoering A. Sexton R. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT) Blood Cancer Journal 2020 10 5 p. 53 10.1038/s41408-020-0311-8 32393732 \n2 Goldschmidt H. Mai E. K. Dürig J. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial Leukemia 2020 34 7 1853 1865 10.1038/s41375-020-0724-1 32034285 \n3 Chen C. I. Paul H. Snitzler S. A phase 2 study of lenalidomide and dexamethasone in previously untreated patients with chronic lymphocytic leukemia (CLL) Leukemia & Lymphoma 2019 60 4 980 989 10.1080/10428194.2018.1508669 2-s2.0-85054361890 30277089 \n4 Arcioni F. Roncadori A. Di Battista V. Lenalidomide treatment of myelodysplastic syndromes with chromosome 5q deletion: results from the National Registry of the Italian Drug Agency European Journal of Haematology 2018 101 1 78 85 10.1111/ejh.13067 2-s2.0-85047456290 29569278 \n5 Cohen O. C. Sharpley F. Gillmore J. D. Use of ixazomib, lenalidomide and dexamethasone in patients with relapsed amyloid light-chain amyloidosis British Journal of Haematology 2020 189 4 643 649 10.1111/bjh.16401 31984481 \n6 Walavalkar V. Adey D. B. Laszik Z. G. Jen K. Y. Severe renal allograft rejection resulting from lenalidomide therapy for multiple myeloma: case report Transplantation Proceedings 2018 50 3 873 876 10.1016/j.transproceed.2018.01.014 2-s2.0-85045388373 29661456 \n7 Lum E. L. Huang E. Bunnapradist S. Pham T. Danovitch G. Acute kidney allograft rejection precipitated by lenalidomide treatment for multiple myeloma American Journal of Kidney Diseases 2017 69 5 701 704 10.1053/j.ajkd.2016.11.024 2-s2.0-85012940181 28189378 \n8 Meyers D. E. Adu-Gyamfi B. Segura A. M. Fatal cardiac and renal allograft rejection with lenalidomide therapy for light-chain amyloidosis American Journal of Transplantation 2013 13 10 2730 2733 10.1111/ajt.12391 2-s2.0-84884905611 23914832 \n9 Qualls D. A. Lewis G. D. Sanchorawala V. Staron A. Orthotopic heart transplant rejection in association with immunomodulatory therapy for AL amyloidosis: a case series and review of the literature American Journal of Transplantation 2019 19 11 3185 3190 10.1111/ajt.15499 2-s2.0-85068651794 31207062 \n10 Xie L. Jozwik B. Weeks P. Treatment of multiple myeloma in a heart transplant recipient Progress in Transplantation 2017 27 1 65 68 10.1177/1526924816679842 2-s2.0-85016216055 27885144 \n11 Witzig T. E. Luigi Zinzani P. Habermann T. M. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma American Journal of Hematology 2017 92 10 E575 E583 10.1002/ajh.24854 2-s2.0-85028774352 28699256 \n12 Salles G. Duell J. González Barca E. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study The Lancet Oncology 2020 21 7 978 988 10.1016/S1470-2045(20)30225-4 32511983 \n13 LeBlanc R. Hideshima T. Catley L. P. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway Blood 2004 103 5 1787 1790 10.1182/blood-2003-02-0361 2-s2.0-10744231369 14512311 \n14 Hammami M. B. Talkin R. Al-Taee A. M. Schoen M. W. Goyal S. D. Lai J. P. Autologous graft-versus-host disease of the gastrointestinal tract in patients with multiple myeloma and hematopoietic stem cell transplantation Gastroenterology Research 2018 11 1 52 57 10.14740/gr925w 29511407 \n15 Sockel K. Bornhaeuser M. Mischak-Weissinger E. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial Haematologica 2012 97 9 e34 e35 10.3324/haematol.2012.067629 2-s2.0-84865838005 22952334 \n16 Montefusco V. Galli M. Spina F. Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide Leukemia & Lymphoma 2014 55 9 2032 2037 10.3109/10428194.2014.914203 2-s2.0-84906052553 24730540\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6951",
"issue": "2020()",
"journal": "Case reports in transplantation",
"keywords": null,
"medline_ta": "Case Rep Transplant",
"mesh_terms": null,
"nlm_unique_id": "101591863",
"other_id": null,
"pages": "8894922",
"pmc": null,
"pmid": "33381347",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "14512311;29511407;29569278;32393732;28189378;32511983;30277089;31984481;23914832;32034285;22952334;28699256;29661456;27885144;31207062;24730540",
"title": "Acute Liver Rejection in a Multiple Myeloma Patient Treated with Lenalidomide.",
"title_normalized": "acute liver rejection in a multiple myeloma patient treated with lenalidomide"
} | [
{
"companynumb": "US-CELGENEUS-USA-20210100581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,... |
{
"abstract": "GABAA receptors are ligand-gated anion channels that are important regulators of neuronal inhibition. Mutations in several genes encoding receptor subunits have been identified in patients with various types of epilepsy, ranging from mild febrile seizures to severe epileptic encephalopathy. Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay. Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K) and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L). Patients with the GABRA2 and GABRB3 variants also presented with severe epilepsy and developmental delay. We evaluated the effects of the GABRA5, GABRA2 and GABRB3 missense variants on receptor function using whole-cell patch-clamp recordings from human embryonic kidney 293T cells expressing appropriate α, β and γ subunits. The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization. The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were tonically open, even in the absence of GABA. Receptors containing the GABRB3 p.P301L variant were less sensitive to GABA and produced less GABA-evoked current. These results provide the first functional evidence that de novo variants in the GABRA5 and GABRA2 genes contribute to early-onset epilepsy and developmental delay, and demonstrate that epilepsy can result from reduced neuronal inhibition via a wide range of alterations in GABAA receptor function.",
"affiliations": "Department of Human Genetics, Emory University, Atlanta, Georgia, 30322, USA.;Departments of Anesthesiology and Pharmacology, Emory University, Atlanta, Georgia, 30322, USA.;Department for Pediatric Metabolic Medicine and Neurology, University Children's Hospital, Heidelberg, 69120, Germany.;Departments of Pediatrics and Neurology, School of Medicine, Oregon Health & Sciences University, Portland, Oregon, 97239, USA.;Department of Human Genetics, Emory University, Atlanta, Georgia, 30322, USA.;Departments of Anesthesiology and Pharmacology, Emory University, Atlanta, Georgia, 30322, USA.;Department of Human Genetics, Emory University, Atlanta, Georgia, 30322, USA.",
"authors": "Butler|Kameryn M|KM|;Moody|Olivia A|OA|;Schuler|Elisabeth|E|;Coryell|Jason|J|;Alexander|John J|JJ|;Jenkins|Andrew|A|;Escayg|Andrew|A|",
"chemical_list": "C484841:GABRA2 protein, human; C527986:GABRA5 protein, human; C546273:GABRB3 protein, human; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid",
"country": "England",
"delete": false,
"doi": "10.1093/brain/awy171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-8950",
"issue": "141(8)",
"journal": "Brain : a journal of neurology",
"keywords": null,
"medline_ta": "Brain",
"mesh_terms": "D002648:Child; D002658:Developmental Disabilities; D004831:Epilepsies, Myoclonic; D004827:Epilepsy; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0372537",
"other_id": null,
"pages": "2392-2405",
"pmc": null,
"pmid": "29961870",
"pubdate": "2018-08-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24550784;16835366;27367160;29053855;23934111;24623842;19553237;24065890;14993607;28440033;28053010;18079559;27768696;29100083;26918889;17725516;25124326;24909990;17715197;27521439;20854673;10991923;10397372;25904555;11326274;9930699;20066485;27622563;27490490;18760291;25087078;17339270;9846630;20007704;28223510;11326275;28717674;11395011;27864268;27789573;15950776;1331359;11992121;25156961;12921352;23086956;29422393",
"title": "De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.",
"title_normalized": "de novo variants in gabra2 and gabra5 alter receptor function and contribute to early onset epilepsy"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08501",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
... |
{
"abstract": "OBJECTIVE\nTo analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years.\n\n\nMETHODS\nWe collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12).\n\n\nRESULTS\nPatients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12.\n\n\nCONCLUSIONS\nOur findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.",
"affiliations": "Department of Medicine, Centre for Liver Disease, Buon Consiglio-Fatebenefratelli Hospital, Via Manzoni 220, 80123, Naples, Italy. antonio.ascione@paginemediche.it.;Liver Unit, AORN Cardarelli, Naples, Italy.;Italian Medicines Agency (AIFA), Rome, Italy.;Italian Medicines Agency (AIFA), Rome, Italy.;Italian Medicines Agency (AIFA), Rome, Italy.;Department of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy.;Division of Infectious Diseases, AO Niguarda Ca' Granda Hospital, Milan, Italy.;III U.O.C. P.O. Cotugno, AORN Ospedali dei Colli, Naples, Italy.;Infectious Diseases Unit, AORN Caserta, Caserta, Italy.;Humanitas University and IRCCS Clinical Institute Humanitas, Rozzano, Milan, Italy.;Infectious Disease, Cotugno Hospital, AORN Ospedali dei Colli, Naples, Italy.;Gastroenterology Unit, Department of Internal Medicine, AOU Policlinico of Modena, Modena, Italy.;UO Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Hospital Maggiore Policlinico of Milan, Milan, Italy.;Interdepartmental Centre for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Unit of Infectious Diseases and Hepatology, AOU of Parma, Parma, Italy.;Department of Medicine, Centre for Liver Disease, Buon Consiglio-Fatebenefratelli Hospital, Via Manzoni 220, 80123, Naples, Italy.;Internal Medicine, Gastroenterology and Hepatology, Agostino Gemelli Hospital, Rome, Italy.;Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Department of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy.",
"authors": "Ascione|Antonio|A|http://orcid.org/0000-0003-2040-8380;De Luca|Massimo|M|;Melazzini|Mario|M|;Montilla|Simona|S|;Trotta|Maria Paola|MP|;Petta|Salvatore|S|;Puoti|Massimo|M|;Sangiovanni|Vincenzo|V|;Messina|Vincenzo|V|;Bruno|Savino|S|;Izzi|Antonio|A|;Villa|Erica|E|;Aghemo|Alessio|A|;Zignego|Anna Linda|AL|;Orlandini|Alessandra|A|;Fontanella|Luca|L|;Gasbarrini|Antonio|A|;Marzioni|Marco|M|;Giannini|Edoardo G|EG|;Craxì|Antonio|A|;|||",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1157-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "46(5)",
"journal": "Infection",
"keywords": "Cirrhosis; Dasabuvir; Elderly; Ombitasvir; Paritaprevir",
"medline_ta": "Infection",
"mesh_terms": "D015081:2-Naphthylamine; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D047028:Macrocyclic Compounds; D008297:Male; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "607-615",
"pmc": null,
"pmid": "29808463",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "27482173;27549000;27667367;24795200;21185796;26476290;1966702;28497758;1380021;20497143;28183063;26170136;12405251;28195877;24725237;27976461;17370330;15714480;24818763;28111883",
"title": "Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis.",
"title_normalized": "safety and efficacy of ombitasvir paritaprevir ritonavir dasabuvir plus ribavirin in patients over 65 years with hcv genotype 1 cirrhosis"
} | [
{
"companynumb": "IT-KADMON PHARMACEUTICALS, LLC-KAD201806-000380",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to develop an automated causality assessment algorithm to identify drug-induced liver injury.\n\n\nMETHODS\nThe Roussel Uclaf Causality Assessment Method (RUCAM) is an algorithm for determining the causal association between a drug and liver injury. In collaboration with hepatology experts, definitions were developed for the RUCAM criteria to operationalize an electronic RUCAM (eRUCAM). The eRUCAM was tested in a population of patients taking 14 drugs with a characteristic phenotype for liver injury. Quality assurance for programming specifications involved comparisons between scores generated by the eRUCAM, for probable and highly probable cases, and expert manual RUCAM (n = 20). Concordance between eRUCAM and manual RUCAM subscores and total score was tested using the Wilcoxon signed rank test.\n\n\nRESULTS\nCausality scores were the same for 6 of 20 patients (30%) by manual and eRUCAM algorithms. Analysis of subscores revealed ≥80% concordance between manual and eRUCAM for five of the seven criteria. In general, the total scores tended to be higher for the eRUCAM compared with the manual RUCAM. Programming issues were identified for criterion 5 'non-drug causes of liver injury' where significant differences existed between manual and eRUCAM scoring (p = 0.001). For criterion 5, identical scores occurred in 9 of 20 patients (45%), and manual review identified additional codes, timing criteria, and laboratory results for improving subsequent eRUCAM revisions.\n\n\nCONCLUSIONS\nThe eRUCAM had generally good concordance with manual RUCAM scoring. These preliminary findings suggest that the eRUCAM algorithm is feasible and could have application in clinical practice and drug safety surveillance.",
"affiliations": "Kaiser Permanente Southern California, Pharmacy Analytical Services, CA, USA.",
"authors": "Cheetham|T Craig|TC|;Lee|Janet|J|;Hunt|Christine M|CM|;Niu|Fang|F|;Reisinger|Steph|S|;Murray|Rich|R|;Powell|Greg|G|;Papay|Julie|J|",
"chemical_list": "D055553:Prescription Drugs",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3531",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "23(6)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "algorithm; automated; causality assessment; drug safety; drug-induced; liver injury; pharmacoepidemiology; risk assessment",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000465:Algorithms; D056486:Chemical and Drug Induced Liver Injury; D016208:Databases, Factual; D057286:Electronic Health Records; D006801:Humans; D010865:Pilot Projects; D055553:Prescription Drugs",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "601-8",
"pmc": null,
"pmid": "24920207",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An automated causality assessment algorithm to detect drug-induced liver injury in electronic medical record data.",
"title_normalized": "an automated causality assessment algorithm to detect drug induced liver injury in electronic medical record data"
} | [
{
"companynumb": "US-JNJFOC-20140616909",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDeferoxamine retinopathy is the informally designated term used to describe a characteristic pattern of outer retinal degeneration in iron-overloaded chronic anemia patients who are treated with deferoxamine. We hypothesize that insufficiently treated iron overloading and not only deferoxamine is the cause of the retinal degeneration. Our case report is based on exposure histories of two anemia patients and literature review.\n\n\nMETHODS\nBoth anemia patients presented with bilateral visual loss secondary to photoreceptor and retinal pigment epithelium degeneration. Chart review showed that visual loss came after a year-long slow, and rather monotonous rise in plasma ferritin concentrations, with no obvious relation to iron chelator exposure. In one patient, the onset of symptomatic visual loss came after a bout of fever followed by two additional febrile episodes, all accompanied by plasma ferritin spikes. Adjustment of iron chelation therapy did not improve visual function. Experimental studies clearly show that both systemic and intraocular exposure to iron ions can induce retinal degeneration.\n\n\nCONCLUSIONS\nThe available evidence indicates that retinal degeneration in chronic anemia patients treated by deferoxamine is cause by insufficient iron chelation, not by deferoxamine. The actual role of iron chelating agents may be to promote a long enough survival to allow the slow development of retinal siderosis.",
"affiliations": "Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark. mohamed.belmouhand@regionh.dk.;Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark.;Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark.;Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.;Department of Hematology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.;Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark.",
"authors": "Belmouhand|Mohamed|M|http://orcid.org/0000-0001-5855-4733;Eckmann-Hansen|Christina|C|;Ilginis|Tomas|T|;Leinøe|Eva Birgitte|EB|;Mortensen|Bo Kok|BK|;Larsen|Michael|M|",
"chemical_list": "D007502:Iron Chelating Agents; D003676:Deferoxamine",
"country": "England",
"delete": false,
"doi": "10.1186/s12886-021-02030-1",
"fulltext": "\n==== Front\nBMC Ophthalmol\nBMC Ophthalmol\nBMC Ophthalmology\n1471-2415\nBioMed Central London\n\n2030\n10.1186/s12886-021-02030-1\nCase Report\nIron overload and iron chelating agent exposure in anemia-associated outer retinal degeneration: a case report and review of the literature\nhttp://orcid.org/0000-0001-5855-4733\nBelmouhand Mohamed mohamed.belmouhand@regionh.dk\n\n12\nEckmann-Hansen Christina 12\nIlginis Tomas 1\nLeinøe Eva Birgitte 3\nMortensen Bo Kok 4\nLarsen Michael 12\n1 grid.475435.4 Department of Ophthalmology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark\n2 grid.5254.6 0000 0001 0674 042X Department of Clinical Medicine, Faculty of Healthy and Medical Science, University of Copenhagen, Copenhagen, Denmark\n3 grid.475435.4 Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark\n4 Department of Hematology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark\n13 7 2021\n13 7 2021\n2021\n21 2771 2 2021\n29 6 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\nDeferoxamine retinopathy is the informally designated term used to describe a characteristic pattern of outer retinal degeneration in iron-overloaded chronic anemia patients who are treated with deferoxamine. We hypothesize that insufficiently treated iron overloading and not only deferoxamine is the cause of the retinal degeneration. Our case report is based on exposure histories of two anemia patients and literature review.\n\nCase presentation\n\nBoth anemia patients presented with bilateral visual loss secondary to photoreceptor and retinal pigment epithelium degeneration. Chart review showed that visual loss came after a year-long slow, and rather monotonous rise in plasma ferritin concentrations, with no obvious relation to iron chelator exposure. In one patient, the onset of symptomatic visual loss came after a bout of fever followed by two additional febrile episodes, all accompanied by plasma ferritin spikes. Adjustment of iron chelation therapy did not improve visual function. Experimental studies clearly show that both systemic and intraocular exposure to iron ions can induce retinal degeneration.\n\nConclusion\n\nThe available evidence indicates that retinal degeneration in chronic anemia patients treated by deferoxamine is cause by insufficient iron chelation, not by deferoxamine. The actual role of iron chelating agents may be to promote a long enough survival to allow the slow development of retinal siderosis.\n\nKeywords\n\nAnemia\nIron chelation\nIron overload\nDeferoxamine\nRetinopathy\nCase report\nhttp://dx.doi.org/10.13039/501100005111 Rigshospitalet E-23334-02 Belmouhand Mohamed http://dx.doi.org/10.13039/501100005860 Helsefonden 19-B-0063 Belmouhand Mohamed http://dx.doi.org/10.13039/501100003035 Aase og Ejnar Danielsens Fond 18-10-0698 Belmouhand Mohamed http://dx.doi.org/10.13039/501100009898 Beckett-Fonden 19-2-3490 Belmouhand Mohamed http://dx.doi.org/10.13039/100007444 Einar Willumsen Foundation 500028 Belmouhand Mohamed P. Carl Petersens Fond19102 Belmouhand Mohamed http://dx.doi.org/10.13039/100010663 H2020 European Research Council 780989 Larsen Michael issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nThe iron content of the human body is regulated at the level of intestinal absorption. There is no regulated form of excretion in individuals with excessive iron store. This can lead to iron toxicity in patients with a chronic need for blood transfusions. If untreated, many patients with hematological disease will therefore die from heart and liver failure within 10 years [1]. To avoid fatal cardiac complications of hemosiderosis (systemic iron overload), individuals with chronic transfusion-treated anemia are therefore treated with an iron chelating agent.\n\nThe introduction of the iron chelating agent deferoxamine in 1968 was followed by a marked reduction in mortality from hemosiderosis. Subsequently, the term deferoxamine retinopathy was coined for a characteristic pigmented degeneration of the outer retina with annular visual defects and night blindness that was seen among chronic anemia patients treated with an iron chelating agent (e.g. deferoxamine) [2, 3]. Several studies, primarily case-reports, have suggested that iron chelators may cause retinopathy [3–7]. However, other studies have presented results that contradict this notion [8, 9], and the demonstration of a potential role of trace element imbalance in optic nerve degeneration further complicates the evaluation of visual loss in patients suffering from chronic anemia [10]. Finally, the potential role of iron in inducing retinal degeneration has received little attention in the context of chronic anemia management.\n\nHuman retinal pigment epithelium (RPE) cells contain transferrin receptors that enable endocytosis-mediated iron uptake from the choroid, and iron is known to be toxic to the retina, especially the RPE [11, 12]. The degenerative damage is believed to originate from iron-induced oxidative stress [12]. We therefore hypothesize that prolonged hemosiderosis plays a major role in the development of retinopathy in transfusion-dependent anemia patients, alone or in combination with iron chelating agents.\n\nThe aim of the study was to examine iron levels and deferoxamine treatment in two patients with chronic anemia before, during and after vision loss to more accurately determine the role of hemosiderosis in what is commonly called deferoxamine retinopathy. We have reviewed the evidence base of this nosological entity in the light of data from two patients with chronic anemia who consented to having their data published.\n\nCase presentation\n\nPatient 1\n\nA 72-year-old man presented with blurred vision in both eyes beginning 1 week earlier as a dark, partially transparent area in the center of both visual fields. The dark area gradually expanded and changed to a pericentral dark ring in both eyes. He had suffered from aplastic anemia for 4 years and received one blood transfusion per week for 8 months when he presented. He had also received five infusions of 301 mg antithymocyte globulin 1 month before the onset of visual loss (Fig. 1) and oral deferasirox beginning 4 months earlier. Deferasirox was discontinued after 1 month due to renal impairment and changed to deferoxamine infusion 1 month prior to visual loss. Past medical history included appendectomy (21 y), encephalitis (42 y), bilateral cataract surgery with pseudophakia (51 y) and curative treatment of prostate cancer (69 y). Best-corrected Snellen visual acuity (BCVA) was 0.6 in the right eye and 0.9 in the left eye, a serous detachment of the macula was found in both eyes and applanation tonometry was normal. Visual acuity deteriorated to 0.3 in both eyes 3 months later. A presumptive diagnosis of deferoxamine retinopathy prompted a switch to oral deferiprone, but visual acuity decreased to worse than 0.1 in both eyes over the following year. From half a year before presentation to half a year after presentation, plasma ferritin – a surrogate measure of iron stores – had ranged from 2000 to 7230 ng/mL (SI: 2000 to 7230 μg/L), reference range 15–320 ng/mL, with prominent peaks immediately before and after the onset of visual loss (Fig. 1). Patchy visual field sensitivity loss (Fig. 2) was seen corresponding to hyper- and hypofluorescent degeneration of the outer retina in both maculae (Fig. 3) and severely reduced cone photoreceptor density out 14 degrees from the foveola (Fig. 4). There were no other signs of hemosiderosis. Fig. 1 Timeline chart for patient 1 and 2 with relevant blood tests and drug exposure. Legend: Patient 1, timeline from 4 years after presentation with chronic anemia through half a year leading up to the onset of visual loss and 4 months thereafter, showing the exposure to cyclosporin, antithymocyte globulin, iron chelators (deferasirox, deferoxamine and deferiprone), thrombopoietin analog (eltrombopag), onset and persistence of visual loss, onset of fever and pulmonary edema, and plasma concentrations of ferritin, creatinine, c-reactive protein and hemoglobin. Additionally, the patient received blood transfusions throughout the period of observation. Patient 2, timeline from 3 years after the diagnosis of blood dyscrasia through 37 months of follow-up. Deferiprone was exchanges for deferoxamine due to deviating renal function and inefficiency. Additionally, the patient received blood transfusions throughout the period of observation. SI conversion factor: Ferritin, ng/mL ➔ μg/L, multiply by 1; creatinine, mg/dL ➔ μmol/L, multiply by 88.42; c-reactive protein, mg/dL ➔ mg/L, multiply by 10; and hemoglobin, g/dL ➔ mmol/L, multiply by 0.62\n\nFig. 2 Automated perimetry examination of patient 1 and 2. Legend: Automated perimetry, 30-2, (Octopus 900, Haag-Streit, Switzerland) in two patients, patient 1 above at presentation and patient 2 below at 2 years after presentation. MS, mean sensitivity; MD, mean defect; and sLV, square root of loss variance\n\nFig. 3 Optical coherence tomography and blue light fundus autofluorescence imaging of retinal defects. Legend: In patient 1 (A + B), a diffuse dotted blue light fundus autofluorescence of the right eye shows widespread defects in the whole macula (A). The corresponding horizontal transfoveal optical coherence tomography shows degeneration and irregularities in the outer retina (B). In patient 2 (C + D), a more localized defect is visible in the parafoveal region on blue light fundus autofluorescence (C). The optical coherence tomography shows the same outer retinal defects as in case 1 but temporally an intact outer retina is seen (D). In case 1 the images were acquired during initial visit, and in case 2 the images were acquired at follow-up 6 months after initial visit. Scans were acquired on Spectralis OCT2 (Heidelberg Engineering, Heidelberg, Germany)\n\nFig. 4 Adaptive optics fundus photography of photoreceptor mosaic. Legend: Patient 1 (A), patient 2 (B) and a healthy age-matched volunteer (C), spanning from the fovea (indicated by red circles) to a position 14 degrees temporal of the foveal center. Patient 1 is remarkable for having a transitional zone (white arrows) between injured granular retina on the foveal side and more normal retina on the temporal side. Patient 2 shows patchy absence or attenuation of the photoreceptor matrix. The healthy volunteer had a normal photoreceptor distribution. The images of patient 1 and 2 were recorded 5 and 4 months, respectively, after presentation. Acquired on RTX-1 (Imagine Eyes, Orly, France) on flood-illuminated adaptive optics fundus photography\n\nPatient 2\n\nA 70-year-old male erythropoiesis-deficient anemia patient with floaters, flashes and poor color vision was seen with BCVA 0.9 in the right eye and 1.0 in the left eye. He had previously been diagnosed with type 2 diabetes mellitus (57 y), hypertension (57 y), diabetic nephropathy (68 y) and myelodysplastic syndrome with ring sideroblasts (65 y). Blood transfusions had been administered from the past 2 years prior and was continued after the onset of visual symptoms. Deferiprone, administered until 8 months earlier, had been switched to deferoxamine due to renal impairment (Fig. 1). A tentative diagnosis of vitreous degeneration was made, but 6 months later BCVA had dropped to 0.2 in both eyes. The suspicion that deferoxamine was the cause prompted discontinuation of this drug without chelator substitution. One year later BCVA had increased to 0.8 in the right eye and 0.4 in the left eye. It then fell to 0.4 in both eyes when seen 55 months after presentation, when geographic atrophy was seen in the left macula. Over the 6 years up to his most recent visit, plasma ferritin had ranged from 1500 to 10,030 ng/mL, with a peak near the onset of visual loss (Fig. 1). Visual field sensitivity was moderately diffusely reduced (Fig. 2) and both maculae showed granular hyper- and hypoautofluorescence with corresponding photoreceptor and pigment epithelium atrophy (Figs. 3 and 4).\n\nDiscussion and conclusions\n\nThe outer retinal degeneration seen in our two patients fits the description of what is called deferoxamine retinopathy. It is remarkable, however, that neither case showed a clear temporal association between iron chelator exposure, disease duration or disease severity, and retinal degeneration. Remarkably, the onset of subjective visual loss occurred on the chronically rising slopes of plasma ferritin concentration curves that had exceeded the recommended maximum of 1000 ng/mL for years [13]. While this maximum has been set to safeguard the heart, there is insufficient data to estimate the level of ferritin that is safe for the retina. We did not observe any uniform pattern of changes in retinal function or structure and fluctuations in hemoglobin or c-reactive protein.\n\nCompeting with the notion that deferoxamine in itself should be retinotoxic [4, 14], there is evidence that iron overload can induce outer retinal degeneration by promoting the production of reactive oxygen species and an inherent increase in oxidative stress [12, 15]. Independent of the blood-retina barrier, human RPE cells have an abundance of transferrin receptors which permit endocytosis-mediated iron uptake from the choroid [11]. Of particular note, our patients’ ocular characteristics are comparable those seen in hemochromatosis [16], in experimental intraocular iron toxicity [17, 18] and in intraocular ferrous foreign body retention, where the functional deficit is partially reversible [19], as was the visual loss in our patient 2.\n\nThe mechanism or etiology of a possible deferoxamine-induced toxicity is not understood; however, it is plausible that deferoxamine affects iron mobilization locally in the retina and thereby causes atrophy. Furthermore, clinical cases of presumed deferoxamine retinopathy have all occurred in patients with iron overload during some period of their disease [3], and rabbits with intraocular iron foreign bodies are protected from retinal degeneration by deferoxamine [20]. Deferiprone, an oral iron chelator, was shown to protect against retinal degeneration induced by systemic iron overload in mice [21, 22]. While deferoxamine can depress the electroretinogram, the effect is transient and was observed in patients with concurrent hemosiderosis [3].\n\nPreclinical data from animal studies shows that iron overload can induce retinal damage [17, 23–25]. In addition, iron overload can also accelerate cell death in rats exposed to partial nerve head crush [26]. Knock-out of TIM2, the receptor for H-ferritin in Müller cells of the mouse retina, has led to iron overload and consequently production of reactive oxygen species and subsequent retinal degeneration [27]. Salvianic acid A, an extract from Chinese herbs, and Puerarin are agents used in alternative medicine that have been shown to ameliorate iron overload-induced toxicity in mice [28, 29]. The positive actions of these two drugs are believed to be through regulation of iron-handling proteins that possibly aid in iron chelation and attenuation of oxidative stress. These two drugs have not been tested in humans with hemosiderosis.\n\nFerroptosis, a recently described cell death mechanism that dependents on an abundant concentration of iron [30], may theoretically be involved in retinal damage by promoting retinal cell death in hemosiderosis. Thus, a study has found evidence that ferroptosis contributed to cell death in cultured human RPE cells exposed to iron overload, and that deferoxamine attenuated the rate of cell death [31].\n\nOnly a speculative case association with retinal degeneration has been reported for deferasirox and none for deferiprone, which are two alternative clinical iron chelating drugs [32]. Thus, the analysis of clinical cases may potentially be confounded by interaction between a reversible functional effect of deferoxamine and a more permanent effect of iron on the retina [3]. Notably, most clinical reports linking deferoxamine with retinal degeneration have not accounted for ferritin levels prior to, during or after vision loss. We therefore suspect that ferritin spikes or burst of cytokine release from disintegrating T-cells, as seen during antithymocyte therapy [33], may promote retinal degeneration, as may the natural accumulation of iron in the retina with aging [34]. Whether antithymocyte therapy or other unknown dysfunction in iron metabolism caused the retinal damage in our patient no. 1 to become irreversible can only be hypothesized.\n\nOur two cases expand OCT-based demonstrations of attenuation and irregularity of the photoreceptor and RPE layers in the macula [5, 14]. Cone photoreceptor counts in affected areas were about half of what is normal, with considerable focal variations confined to the area within the temporal vascular arcades.\n\nThe complexity of the typical clinical course in anemia limits the retrospective analysis of causality in retinopathy cases, of whom the ones with the highest iron load are the ones who received the most intensive chelation therapy. Although our two cases were highly valuable in understanding the complexity of chronic anemia and retinopathy, we cannot generalize or establish cause-effect relationships based on our findings.\n\nIn conclusion, retinal injury in iron-overload anemia should not unreservedly be attributed to iron chelation therapy. Insufficient iron chelation should be considered as an alternative etiology. Proactive eye examination, meticulous clinical documentation and awareness of the guideline upper plasma ferritin level of 1000 ng/mL may help enable rational analysis of cases and reduction of the incidence of retinal degeneration in chronic anemia patients.\n\nAbbreviations\n\nBCVA Best-corrected visual acuity\n\nRPE Retinal pigment epithelium\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nConcept and design: ML, CEH and MB. Acquisition, analysis or interpretation of data: All authors. Drafting of the manuscript: MB, CEH and ML. Critical revision of the manuscript for important intellectual content: TI, EL and BKM. Final approval of the manuscript: All authors.\n\nFunding\n\nThe study was supported by the European Union under H2020-EU.2.1.1. - ID 780989 (MERLIN); Rigshospitalet(grant E-23334-02); P. Carl Petersens Fond (grant 19102); Aase og Ejnar Danielsens Fond (grant 18-10-0698); Helsefonden (grant 19-B-0063); Beckett Fonden (grant 19-2-3490); and Einar Willumsens Mindelegat (grant 500028). None of the above-mentioned sources has had any role in the design, analysis or interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthics approval was not necessary for this case report.\n\nConsent for publication\n\nBoth study participants gave their oral and written informed consent for publication.\n\nCompeting interests\n\nML has consulted, spoken or been a trial investigator for Novartis, Chiesi, Allergan, Bayer, Alcon, AbbVie, Biogen, Novo Nordisk, Eli Lilly, Spark Therapeutics, Nightstar, Sanofi and Roche.\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. Borgna-Pignatti C Rugolotto S De Stefano P Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine Haematologica. 2004 89 10 1187 1193 15477202\n2. Viola F Barteselli G DellʼArti L Multimodal imaging in deferoxamine retinopathy Retina. 2014 34 7 1428 1438 10.1097/IAE.0000000000000073 24378427\n3. Davies SC Marcus RE Hungerford JL Miller MH Arden GB Huehns ER Ocular toxicity of high-dose intravenous desferrioxamine Lancet. 1983 2 8343 181 184 10.1016/s0140-6736(83)90170-8 6135026\n4. Di Nicola M Barteselli G Dell'Arti L Ratiglia R Viola F Functional and structural abnormalities in Deferoxamine retinopathy: a review of the literature Biomed Res Int 2015 2015 249617 249612 10.1155/2015/249617 26167477\n5. Van Bol L Alami A Benghiat FS Rasquin F Spectral domain optical coherence tomography findings in early deferoxamine maculopathy: report of two cases Retinal Cases and Brief Reports 2014 8 2 97 102 10.1097/ICB.0000000000000013 25372319\n6. Gelman R Kiss S Tsang SH Multimodal imaging in a case of deferoxamine-induced maculopathy Retin Cases Brief Rep 2014 8 4 306 309 10.1097/ICB.0000000000000059 25372534\n7. Georgakopoulos CD Tsapardoni F Kostopoulou EV Makri OE Pattern dystrophies in patients treated with deferoxamine: report of two cases and review of the literature BMC Ophthalmol 2018 18 1 246 10.1186/s12886-018-0911-2 30208862\n8. Nuzzi R Geronazzo G Tridico F Nuzzi A Caselgrandi P Piga AG Long-term effects of Iron chelating agents on ocular function in patients with thalassemia major Clin Ophthalmol 2021 15 2099 2109 10.2147/OPTH.S300974 34045846\n9. Bhoiwala DL Dunaief JL Retinal abnormalities in β-thalassemia major Surv Ophthalmol 2016 61 1 33 50 10.1016/j.survophthal.2015.08.005 26325202\n10. Kamińska A, Romano GL, Rejdak R, et al. Influence of Trace Elements on Neurodegenerative Diseases of The Eye-The Glaucoma Model. Int J Mol Sci. 2021;22(9). 10.3390/ijms22094323.\n11. Hunt RC Dewey A Davis AA Transferrin receptors on the surfaces of retinal pigment epithelial cells are associated with the cytoskeleton J Cell Sci 1989 92 Pt 4 655 666 10.1242/jcs.92.4.655 2600139\n12. He X Hahn P Iacovelli J Wong R King C Bhisitkul R Massaro-Giordano M Dunaief JL Iron homeostasis and toxicity in retinal degeneration Prog Retin Eye Res 2007 26 6 649 673 10.1016/j.preteyeres.2007.07.004 17921041\n13. Cappellini MDCA Eleftheriou A Guidelines for the clinical Management of Thalassaemia, 2nd revised edition. Thalassaemia International Federation 2008\n14. Wu CH, Yang CP, Lai CC, Wu WC, Chen YH Deferoxamine retinopathy: spectral domain-optical coherence tomography findings BMC Ophthalmol 2014;14:88. doi:10.1186/1471-2415-14-88, 1.\n15. Gnana-Prakasam JP Martin PM Smith SB Ganapathy V Expression and function of iron-regulatory proteins in retina IUBMB Life 2010 62 5 363 370 10.1002/iub.326 20408179\n16. Zerbib J Pierre-Kahn V Sikorav A Oubraham H Sayag D Lobstein F Massonnet-Castel S Haymann-Gawrilow P Souied EH Unusual retinopathy associated with hemochromatosis Retin Cases Brief Rep. 2015 9 2 190 194 10.1097/icb.0000000000000135 25767899\n17. Masciulli L Anderson DR Charles S Experimental ocular siderosis in the squirrel monkey Am J Ophthalmol 1972 74 4 638 661 10.1016/0002-9394(72)90826-4 4116414\n18. Declercq SS Meredith PC Rosenthal AR Experimental siderosis in the rabbit: correlation between electroretinography and histopathology Arch Ophthalmol 1977 95 6 1051 1058 10.1001/archopht.1977.04450060138014 869748\n19. Kannan NB Adenuga OO Rajan RP Ramasamy K Management of Ocular Siderosis: visual outcome and Electroretinographic changes J Ophthalmol 2016 2016 7272465 7272465 10.1155/2016/7272465 27073692\n20. Declercq SS Desferrioxamine in ocular siderosis: a long-term electrophysiological evaluation Br J Ophthalmol 1980 64 8 626 629 10.1136/bjo.64.8.626 7426580\n21. Hadziahmetovic M Song Y Wolkow N Iacovelli J Grieco S Lee J Lyubarsky A Pratico D Connelly J Spino M Harris ZL Dunaief JL The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration Invest Ophthalmol Vis Sci 2011 52 2 959 968 10.1167/iovs.10-6207 21051716\n22. Song D Zhao L Li Y Hadziahmetovic M Song Y Connelly J Spino M Dunaief JL The oral iron chelator deferiprone protects against systemic iron overload-induced retinal degeneration in hepcidin knockout mice Invest Ophthalmol Vis Sci 2014 55 7 4525 4532 10.1167/iovs.14-14568 24970260\n23. Hahn P Qian Y Dentchev T Chen L Beard J Harris ZL Dunaief JL Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration Proc Natl Acad Sci U S A 2004 101 38 13850 13855 10.1073/pnas.0405146101 15365174\n24. Chaudhary K Promsote W Ananth S Veeranan-Karmegam R Tawfik A Arjunan P Martin P Smith SB Thangaraju M Kisselev O Ganapathy V Gnana-Prakasam JP Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression Sci Rep 2018 8 1 3025 10.1038/s41598-018-21276-2 29445185\n25. Song D Dunaief JL Retinal iron homeostasis in health and disease Front Aging Neurosci 2013 5 24 10.3389/fnagi.2013.00024 23825457\n26. Thaler S Fiedorowicz M Rejdak R Choragiewicz TJ Sulejczak D Stopa P Zarnowski T Zrenner E Grieb P Schuettauf F Neuroprotective effects of tempol on retinal ganglion cells in a partial optic nerve crush rat model with and without iron load Exp Eye Res 2010 90 2 254 260 10.1016/j.exer.2009.10.013 19883642\n27. Valença A Mendes-Jorge L Bonet A Catita J Ramos D Jose-Cunilleras E Garcia M Carretero A Nacher V Navarro M Ruberte J TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown Exp Eye Res 2021 202 108292 10.1016/j.exer.2020.108292 33065090\n28. Song Q Zhang F Han X Yang Y Zhao Y Duan J Ameliorative effects and mechanisms of salvianic acid a on retinal iron overload in vivo and in vitro Exp Eye Res 2021 209 108642 10.1016/j.exer.2021.108642 34058232\n29. Song Q Zhao Y Li Q Han X Duan J Puerarin protects against iron overload-induced retinal injury through regulation of iron-handling proteins Biomed Pharmacother 2020 122 109690 10.1016/j.biopha.2019.109690 31786468\n30. Li J Cao F Yin H-L Ferroptosis: past, present and future Cell Death & Disease 2020 11 2 88 10.1038/s41419-020-2298-2 32015325\n31. Totsuka K Ueta T Uchida T Roggia MF Nakagawa S Vavvas DG Honjo M Aihara M Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells Exp Eye Res 2019 181 316 324 10.1016/j.exer.2018.08.019 30171859\n32. Walia HS Yan J Reversible retinopathy associated with oral deferasirox therapy BMJ Case Rep 2013 2013 bcr2013009205 10.1136/bcr-2013-009205 23867877\n33. Munch IC Traustason S Olgaard K Larsen M Acute macular neuroretinopathy in relation to anti-thymocyte globulin infusion Acta Ophthalmol 2012 90 4 e321 e322 10.1111/j.1755-3768.2011.02276.x 22008367\n34. Chen H Lukas TJ Du N Suyeoka G Neufeld AH Dysfunction of the retinal pigment epithelium with age: increased iron decreases phagocytosis and lysosomal activity Invest Ophthalmol Vis Sci 2009 50 4 1895 1902 10.1167/iovs.08-2850 19151392\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2415",
"issue": "21(1)",
"journal": "BMC ophthalmology",
"keywords": "Anemia; Case report; Deferoxamine; Iron chelation; Iron overload; Retinopathy",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D003676:Deferoxamine; D006801:Humans; D007502:Iron Chelating Agents; D019190:Iron Overload; D012162:Retinal Degeneration; D055213:Retinal Pigment Epithelium; D017086:beta-Thalassemia",
"nlm_unique_id": "100967802",
"other_id": null,
"pages": "277",
"pmc": null,
"pmid": "34256738",
"pubdate": "2021-07-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25372534;4116414;26325202;15477202;869748;27073692;21051716;33065090;23867877;25767899;29445185;34045846;22008367;6135026;19151392;17921041;30208862;23825457;26167477;25372319;31786468;30171859;19883642;24378427;2600139;33919241;20408179;24989140;24970260;34058232;15365174;32015325;7426580",
"title": "Iron overload and iron chelating agent exposure in anemia-associated outer retinal degeneration: a case report and review of the literature.",
"title_normalized": "iron overload and iron chelating agent exposure in anemia associated outer retinal degeneration a case report and review of the literature"
} | [
{
"companynumb": "DK-CHIESI-2021CHF03689",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEFERIPRONE"
},
"drugadditional": null,
... |
{
"abstract": "Baclofen is a medication used for tone management in cerebral palsy. Although it acts mainly at the spinal cord level, it can cause central nervous system adverse reactions at higher doses. Baclofen is mainly eliminated by renal excretion and there have been reports on adverse events when used in adults with renal impairment; however, there are no consensus guidelines as to the dose adjustments required due to renal impairment. The authors describe 2 children with acute kidney injury (AKI) and systemic side effects with initiation of oral baclofen, which was started for treatment of dystonia/spasticity in the recovery phase of their kidney injury. Following the initiation of the drug, they both had decreased level of consciousness and respiratory difficulties, which warranted discontinuation of the drug. These cases highlight the need for reduced initial dose, slow titration, and close monitoring when initiating baclofen treatment in children with AKI.",
"affiliations": "Sunny Hill Health Centre for Children, Vancouver, British Columbia, Canada.;Sunny Hill Health Centre for Children, Vancouver, British Columbia, Canada.;Sunny Hill Health Centre for Children, Vancouver, British Columbia, Canada.;Sunny Hill Health Centre for Children, Vancouver, British Columbia, Canada.;BC Children's Hospital, Vancouver, British Columbia, Canada.",
"authors": "Mishaal|Ram A|RA|https://orcid.org/0000-0002-0163-0106;Lanphear|Nancy E|NE|;Armarnik|Erez|E|;van Rensburg|Esias R|ER|;Matsell|Douglas G|DG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2329048X20937113",
"fulltext": "\n==== Front\nChild Neurol Open\nChild Neurol Open\nCNO\nspcno\nChild Neurology Open\n2329-048X SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2329048X20937113\n10.1177_2329048X20937113\nCase Report\nBaclofen Toxicity in Children With Acute Kidney Injury: Case Reports and Review of the Literature\nhttps://orcid.org/0000-0002-0163-0106Mishaal Ram A. MD123 Lanphear Nancy E. MD123 Armarnik Erez MD123 van Rensburg Esias R. MD123 Matsell Douglas G. MD23 \n1 Sunny Hill Health Centre for Children, Vancouver, British Columbia, Canada\n\n2 BC Children’s Hospital, Vancouver, British Columbia, Canada\n\n3 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada\nRam A. Mishaal, MD, Department of Pediatrics, University of British Columbia and Sunny Hill Health Centre for Children, 3644 Slocan St, Vancouver, British Columbia, Canada V5M 3H4. Email: ram.mishaal@cw.bc.ca\n24 6 2020 \nJan-Dec 2020 \n7 2329048X2093711309 4 2020 15 5 2020 27 5 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Baclofen is a medication used for tone management in cerebral palsy. Although it acts mainly at the spinal cord level, it can cause central nervous system adverse reactions at higher doses. Baclofen is mainly eliminated by renal excretion and there have been reports on adverse events when used in adults with renal impairment; however, there are no consensus guidelines as to the dose adjustments required due to renal impairment. The authors describe 2 children with acute kidney injury (AKI) and systemic side effects with initiation of oral baclofen, which was started for treatment of dystonia/spasticity in the recovery phase of their kidney injury. Following the initiation of the drug, they both had decreased level of consciousness and respiratory difficulties, which warranted discontinuation of the drug. These cases highlight the need for reduced initial dose, slow titration, and close monitoring when initiating baclofen treatment in children with AKI.\n\ntraumatic brain injuryrehabilitationdystoniachildrenspasticitykidney injurybaclofencover-dateJanuary-December 2020typesetterts3\n==== Body\nBaclofen is a medication used for tone management in adults and children. Although its exact mechanism of action is not fully known, it acts as a GABAb receptors agonist in the central nervous system (CNS), leading to neuronal inhibition and muscle relaxation.1 As a moderately lipophilic drug, baclofen penetrates the blood–brain barrier and can cause CNS adverse reactions at high doses.2,3 Baclofen is mainly eliminated by renal excretion,3,4 and there have been reports on adverse events when used in adults with renal impairment.5-7 Although there are suggestions to modify dose with chronic kidney disease (CKD),6,7 no consensus guidelines exist as to the dose adjustments required.\n\nTo the best of our knowledge, systemic baclofen adverse effects in children with renal dysfunction have not been previously described. The authors describe 2 children with acute kidney injury (AKI) and systemic side effects with baclofen initiation.\n\nCase Descriptions\nThe 2 children had an acute systemic disorder with severe AKI and CNS involvement, causing altered level of consciousness (LOC) and increased tone. Both children were started on oral baclofen for tone management in the recovery phase of their kidney injury, with an intention for gradual dose increase. Systemic responses warranted discontinuation of the drug.\n\nPatient 1\nA 2½-year-old boy with an unremarkable medical history was admitted with a diagnosis of hemolytic uremic syndrome and AKI (Figure 1). Rapid renal function decline warranted peritoneal dialysis (PD) at day 3 of admission.\n\nFigure 1. Patient 1 time line.\n\nConcurrently, he developed signs of brain injury, with a minimally conscious state, dystonia, and dysautonomia, with intermittent tachycardia and hypertension. Brain magnetic resonance imaging (MRI) at day 15 demonstrated extensive cerebral disease, with innumerable white matter and basal ganglia ischemic and hemorrhagic infarcts.\n\nAs renal function gradually improved, PD was stopped at approximately 3 weeks after admission. He was then started on oral baclofen to treat dystonia. At that time, he weighed 15.5 kg, serum creatinine was 54 µmol/L, and estimated glomerular filtration rate (eGFR) 64 mL/min/1.73 m2 (71% normal).\n\nBaclofen initial dose was 5 mg 3 times a day (tid). At that point, he has already been treated with gabapentin for 2 weeks.\n\nAfter the second dose of baclofen, he developed periodic breathing that resolved spontaneously. Two hours after his fourth dose, he developed bradypnea of 6 to 8 bpm and bradycardia. Blood pressure and O2 saturation were within normal limits. There was further decrease in his LOC, with no response to painful stimuli.\n\nBaclofen was discontinued, he received intravenous fluids but did not require ventilation or hemodynamic support. Within 12 hours, his hemodynamic, neurologic, and respiratory status were back to his baseline.\n\nTwo weeks later, low-dose baclofen was restarted (2.5 mg daily). The dose was gradually increased to a dose of 10 mg tid. There were no side effects noticed and there was an improvement in dystonic episodes frequency, severity, and length.\n\nPatient 2\nA 9-year-old, previously healthy girl, was admitted to hospital due to group A streptococcus toxic shock syndrome and severe AKI, requiring immediate continuous renal replacement therapy (CRRT; Figure 2). She was transitioned to overnight CRRT and daytime PD after approximately 3 weeks. She gradually regained renal function and dialysis was discontinued at approximately 5 weeks after admission.\n\nFigure 2. Patient 2 time line.\n\nAt admission, she presented with seizures and decreased LOC, which improved after 7 days. Brain MRI demonstrated left frontoparietal and right paracentral subdural hemorrhages, with sulcal Fluid-attenuated inversion recovery (FLAIR) hyperintensity.\n\nThree weeks into admission, while still on overnight CRRT, oral baclofen was started for generalized spasticity, at a dose of 2.5 mg twice daily. Two days later, she was also treated with pregabalin 25 mg daily for neuropathic pain. Neurologically, at this stage, she was opening her eyes spontaneously and to command and followed simple directions.\n\nOn the fourth day of baclofen treatment, after receiving a total of 8 doses (20 mg) and 2 doses (50 mg) of pregabalin, she developed generalized decreased tone with upper airway obstruction, increased work of breathing, and decreased LOC with no response to painful stimuli. She required nasopharyngeal airway insertion to protect her airway. Blood pressure and heart rate were slightly increased (150/105 mm Hg, and 90-150 bpm, respectively).\n\nThis episode started 2 and 12 hours after the last dose of baclofen and pregabalin, respectively, while still on intermittent dialysis (serum creatinine 82 µmol/L, eGFR 86 mL/min/1.73 m2).\n\nBoth medications were discontinued, and within 10 hours, her level of alertness, respiratory, and hemodynamic status returned to her baseline.\n\nDiscussion\nThe authors described 2 children treated with baclofen for hypertonia, who developed serious side effects due to their compromised kidney function. They both presented with severe AKI requiring renal replacement therapy and had respiratory and CNS depression after the initiation of baclofen. At the time of initiation and the described episodes, while both patients were recovering from their AKI, both still had evidence of kidney injury and decreased clearance.\n\nBaclofen is absorbed in the gastrointestinal system and peak serum concentrations are achieved approximately 2 hours postingestion.2-4 While about 15% of the drug undergoes liver metabolism, 65% to 85% is eliminated by renal excretion, with an elimination half-life of 2 to 4 hours.2-4 Hence, patients with decreased kidney function are at risk of toxicity.\n\nBaclofen toxicity has previously been described with overdose in adults8,9 and children,10-12 as well as in adults with renal dysfunction.5-7 The main adverse events described were CNS depression and decreased LOC, hypotonia, respiratory depression, bradycardia, hypertension, or hypotension. Some of these patients recovered spontaneously, while others required clearance of the drug by dialysis.\n\nThe suggested starting dose for baclofen in children is 5 mg tid with a titration to a maximum dose of 1.5 to 2 mg/kg/d or 80 mg daily.13,14 Although caution in patients with impaired renal function is suggested by the manufacturer,15 no consensus dose adjustments guidelines exist. Recently, 2 articles suggested an algorithm for dose modification in these cases. Vlavonou et al7 assessed oral baclofen pharmacokinetics in patients with CKD. They divided their cohort into 4 groups based on creatinine clearance: >80 mL/min, 50 to 80 mL/min (mild CKD), 30 to 50 mL/min (moderate CKD), and <30 mL/min (severe CKD). Based on their results, they suggested decreasing the total daily baclofen dose by 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD, respectively.\n\nBased on clinical experience and reports of neurotoxicity in patients with severe CKD on maintenance hemodialysis therapy taking low-dose baclofen, Wolf et al6 recommend avoiding baclofen in all patients with eGFR < 30 mL/min/1.73 m2, whether on renal replacement therapy or not. According to their algorithm for dose adjustments in CKD, the initial dose should be as follows: for eGFR ≥ 90 mL/min/1.73 m2, no adjustments; for eGFR 60 to 90 mL/min/1.73 m2, reduce dose by 1/3; for eGFR 30 to 60 mL/min/1.73 m2, reduce dose by 1/2; and for eGFR < 30mL/min/1.73 m2, avoid baclofen use.\n\nThese algorithms were created for patients with CKD and can differ from those for patients with acute and evolving kidney injury. In addition, baclofen dosing recommendations in children are based on body weight and extrapolated from adult dosing. The pharmacokinetics of baclofen in children can differ widely from that in adults.13,14 This suggests the need for future pharmacokinetic studies in children and in those with AKI.\n\nBaclofen was started for patient 1 described here, while his renal function was only mildly declined. As he had significant dystonia, the aim was to reach a therapeutic dose quickly. Since he was admitted in hospital and closely monitored, he was started on the full recommended initial dose,13,14 with the assumption that although it can cause some temporary sedation, there would not be significant hemodynamic side effects.\n\nPatient 2 was also treated with pregabalin at the time of the described episode. Although pregabalin can have contributed to this event, the last pregabalin dose was given 12 hours prior to the described episode. The episodes in both patients started 2 hours after the last dose of baclofen, which matches baclofen’s expected peak serum concentration time.2-4 Therefore, although other medications can have contributed to these events, it appears that baclofen played the key role.\n\nTo the best of our knowledge, this is the first report of systemic adverse effects in children treated with baclofen at therapeutic doses with renal dysfunction. As there are no data regarding suggested dose adjustments in the pediatric population with renal impairment, the authors suggest caution when initiating baclofen treatment in these cases, using a reduced initial dose and slowly titrating while monitoring for systemic side effects. Close monitoring in the appropriate health care setting should also be considered.\n\nAcknowledgments\nThe authors thank the children and their parents for consenting to publication of these case reports.\n\nAuthors Contributions: RM contributed to conception and design; acquisition, analysis, and interpretation; and drafted manuscript. NL contributed to conception; acquisition and interpretation; and critically revised manuscript. EA, EVR, and DM contributed to acquisition and critically revised manuscript. All authors gave final approval and agrees to be accountable for all aspects of work ensuring integrity and accuracy.\n\nDeclaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: Ram A. Mishaal, MD \nhttps://orcid.org/0000-0002-0163-0106\n\n\nEthical Approval: The children’s parents gave written informed consent that the cases could be published anonymously. The interventions described were part of the children’s treatment according to accepted practice. Hence, ethical approval from the regional committee for medical and health research ethics was not needed.\n==== Refs\nReferences\n1 \nAlbright AL \nBaclofen in the treatment of cerebral palsy\n. J Child Neurol . 1996 ;11 (3 ):77 –83\n.8881981 \n2 \nAnderson P Noher H Swahn CG \nPharmacokinetics in baclofen over dose\n. J Toxicol Clin Toxicol . 1984 ;22 (1 ):11 –20\n.6492227 \n3 \nFaigle JW Lieberle H \nThe chemistry and kinetics of Lioresal\n. Post Grad Med J . 1972 ;48 (suppl 5 ):9 –13\n.\n4 \nWuis EW Dirks MJ Termond EF , et al.\nPlasma and urinary excretion kinetics of oral baclofen in healthy subjects\n. Eur J Clin Pharmacol . 1989 ;37 (2 ):181 –184\n.2792173 \n5 \nSalim SA Thomas L Achanti A , et al.\nBaclofen-induced neurotoxicity in patients with compromised renal function: review\n. Int J Clin Pharmacol Ther . 2018 ;56 (10 ):467 –475\n.29974857 \n6 \nWolf E Kothari NR Roberts JK Sparks MA \nBaclofen toxicity in kidney disease\n. Am J Kidney Dis . 2018 ;71 (2 ):275 –280\n.28899601 \n7 \nVlavonou R Perreault MM Barrière O , et al.\nPharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations\n. J Clin Pharmacol . 2014 ;54 (5 ):584 –592\n.24414993 \n8 \nAnand JS Zając M Waldman W , et al.\nCorrelation between the single, high dose of ingested baclofen and clinical symptoms\n. Ann Agric Environ Med . 2017 ;24 (4 ):566 –569\n.29284225 \n9 \nKiel LB Hoegberg LC Jansen T , et al.\nA nationwide register-based survey of baclofen toxicity\n. Basic Clin Pharmacol Toxicol . 2015 ;116 (5 ):452 –456\n.25351863 \n10 \nCooke DE Glasstone MA \nBaclofen poisoning in children\n. Vet Hum Toxicol . 1994 ;36 (5 ):448 –450\n.7839572 \n11 \nChapple D Johnson D Connors R \nBaclofen overdose in two siblings\n. Pediatr Emerg Care . 2001 ;17 (2 ):110 –112\n.11334090 \n12 \nGholami N Alwasabi F Farnaghi F \nDrug-induced apnea in children admitted to Loghman Hakim Hospital, Tehran, Iran\n. Iran J Child Neurol . 2017 ;11 (3 ):15 –18\n.\n13 \nSanger TD \nHypertonia in children: how and when to treat\n. Curr Treat Options Neurol . 2005 ;7 (6 ):427 –439\n.16221366 \n14 \nHe Y Brunstrom-Hernandez JE Thio LL , et al.\nPopulation pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy\n. J Pediatr . 2014 ;164 (5 ):1181 –1188\n.24607242 \n15 \nBaclofen (tablet) [package insert] . Teva Pharmaceuticals USA, Inc ; 2018 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2329-048X",
"issue": "7()",
"journal": "Child neurology open",
"keywords": "baclofen; children; dystonia; kidney injury; rehabilitation; spasticity; traumatic brain injury",
"medline_ta": "Child Neurol Open",
"mesh_terms": null,
"nlm_unique_id": "101691975",
"other_id": null,
"pages": "2329048X20937113",
"pmc": null,
"pmid": "32637443",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "6492227;8881981;28899601;28883871;29974857;25351863;2792173;11334090;24414993;24607242;7839572;4668367;29284225;16221366",
"title": "Baclofen Toxicity in Children With Acute Kidney Injury: Case Reports and Review of the Literature.",
"title_normalized": "baclofen toxicity in children with acute kidney injury case reports and review of the literature"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-253593",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugad... |
{
"abstract": "A 10-year-old girl with attention-deficit hyperactivity disorder (ADHD) is diagnosed with hypertrophic cardiomyopathy. The stimulant medications used to control her ADHD pose possibly fatal risks to her cardiovascular health, so stimulant medication is stopped. Due to very poor quality of life off of medication, alternative therapies are used without improvement. The patient's caretakers decide that the benefits of stimulant medication outweigh the risks to the patient. The healthcare team clears the patient to be put back on stimulant medication with a signed waiver of liability by her caretakers.",
"affiliations": "Department of Pediatrics, Florida Atlantic University, Boca Raton, Florida, USA.;Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Pediatrics, Florida Atlantic University, Boca Raton, Florida, USA.",
"authors": "Senderey|Emily|E|;Sousa|John|J|;Stavitsky|Mark|M|",
"chemical_list": "D000697:Central Nervous System Stimulants",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; contraindications and precautions; drugs: psychiatry; ethics; medical management",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001289:Attention Deficit Disorder with Hyperactivity; D002312:Cardiomyopathy, Hypertrophic; D000697:Central Nervous System Stimulants; D002648:Child; D003657:Decision Making; D005260:Female; D006801:Humans; D011788:Quality of Life",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28978610",
"pubdate": "2017-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11265923;19057974;19617944",
"title": "Does quality of life outweigh the cardiovascular risks of stimulant medication in a child with ADHD and hypertrophic cardiomyopathy?",
"title_normalized": "does quality of life outweigh the cardiovascular risks of stimulant medication in a child with adhd and hypertrophic cardiomyopathy"
} | [
{
"companynumb": "US-JNJFOC-20171033738",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nPrescription opioid and heroin abuse has increased substantially in recent years. Enrolment on opioid agonist therapy programmes is consequently increasing as well. As a result of these trends, more patients who present with acute pain secondary to a malignancy are also on chronic methadone maintenance therapy (MMT) for substance abuse. This combination of diagnoses presents a pain management challenge for palliative care providers.\n\n\nOBJECTIVE\nThis paper aims to gather and review the available medical literature pertaining to the use of opioid analgesia in methadone-maintained patients.\n\n\nMETHODS\nThe authors searched PubMED, PsychINFO, EMBASE, Clinical Key, the Cochrane Library and CINAHL from their inception to May 2015 for relevant articles. All articles that discuss opioid therapy in adult patients on methadone maintenance for opioid addiction with cancer or advanced illness were included. Data were extracted and study quality was rated independently by the authors.\n\n\nRESULTS\nOur searches resulted in 680 hits. Of those, only 7 met inclusion criteria for the study. Most of the studies favoured the use of methadone either in scheduled divided doses every 4-8 hours or by continuous intravenous infusion. The overall strength of the evidence was poor, consisting mainly of case series, case reports and 1 single-centre retrospective cohort study lacking a comparison group.\n\n\nCONCLUSIONS\nTreating MMT-maintained patients with methadone for analgesia may be preferable to using other opioid analgesics. However, there are many systems barriers that may make this approach challenging and the evidence favouring methadone over other opioid analgesics is weak.",
"affiliations": "Hospice and Palliative Medicine, Montefiore Medical Center, Bronx, New York, USA.;Department of Family and Social Medicine, Palliative Care Service, Montefiore Medical Center, Bronx, New York, USA.",
"authors": "Taveros|Mel Clark|MC|;Chuang|Elizabeth J|EJ|http://orcid.org/0000-0002-2505-8159",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1136/bmjspcare-2016-001126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-435X",
"issue": "7(4)",
"journal": "BMJ supportive & palliative care",
"keywords": "Cancer; Methadone maintenance; Pain; opioid addiction; palliative care",
"medline_ta": "BMJ Support Palliat Care",
"mesh_terms": "D000701:Analgesics, Opioid; D006801:Humans; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D059408:Pain Management",
"nlm_unique_id": "101565123",
"other_id": null,
"pages": "383-389",
"pmc": null,
"pmid": "27566722",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Pain management strategies for patients on methadone maintenance therapy: a systematic review of the literature.",
"title_normalized": "pain management strategies for patients on methadone maintenance therapy a systematic review of the literature"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-US-ALKEM-2017-01124",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "Myoclonus is defined as involuntary muscle contractions that are self-limiting. The presentation can be diverse, and severe movements may cause significant alarm to both patient and practitioner, with the potential for inappropriate management. Although rare, myoclonus has been associated with intrathecal anaesthetics; however, the exact aetiology remains unclear. In this report, we present a case of delayed spinal myoclonus following the administration of intrathecal bupivacaine to a patient with a known history of restless legs syndrome. The aim of this report is to increase awareness of this rare complication and to contribute to the current body of literature in order that the pathophysiology and potential risk factors may be better understood.",
"affiliations": "Faculty of Medicine University of Toronto Toronto ON Canada.;Department of Anaesthesia and Pain Medicine Toronto Western Hospital University Health Network Toronto ON Canada.;Department of Anaesthesia and Pain Medicine Toronto Western Hospital University Health Network Toronto ON Canada.",
"authors": "Sieffien|W|W|;Peng|P|P|;Dinsmore|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/anr3.12113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2637-3726",
"issue": "9(1)",
"journal": "Anaesthesia reports",
"keywords": "seizure disorders; spinal anaesthesia: complications; spinal anaesthetics: transient neurological symptoms",
"medline_ta": "Anaesth Rep",
"mesh_terms": null,
"nlm_unique_id": "101759073",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "33898996",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30613902;12473756;16007657;8780319;3233864;19830168;26553594;17602048",
"title": "Spinal myoclonus following spinal anaesthesia in a patient with restless legs syndrome.",
"title_normalized": "spinal myoclonus following spinal anaesthesia in a patient with restless legs syndrome"
} | [
{
"companynumb": "CA-TEVA-2021-CA-1938270",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes.\nWe retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute.\nA total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean ± standard deviation age was 54 ± 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) regimen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus.\nPatients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxicity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxicities observed in the latter.",
"affiliations": "Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.;Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.",
"authors": "Bhadauria|Dharmendra|D|;Chellappan|Anand|A|;Kaul|Anupma|A|;Etta|Praveen|P|;Badri|Vinay|V|;Kumar Sharma|Raj|R|;Prasad|Narayan|N|;Gupta|Amit|A|;Jain|Manoj|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfx055",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfx055sfx055GlomerulonephritisIdiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary! Bhadauria Dharmendra 1Chellappan Anand 1Kaul Anupma 1Etta Praveen 1Badri Vinay 1Kumar Sharma Raj 1Prasad Narayan 1Gupta Amit 1Jain Manoj 21 Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India2 Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, IndiaCorrespondence and offprint requests to: Dharmendra Bhadauria; E-mail: drdharm1@rediffmail.com2 2018 18 7 2017 18 7 2017 11 1 46 50 08 11 2016 19 4 2017 © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.2017This 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\nProteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes.\n\nMethods\nWe retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute.\n\nResults\nA total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean ± standard deviation age was 54 ± 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) regimen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus.\n\nConclusion\nPatients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxicity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxicities observed in the latter.\n\ndiabetes mellitusmembranous nephropathynephrotic syndrome\n==== Body\nIntroduction\nMembranous nephropathy (MN) is a frequent cause of adult nephrotic syndrome, with a reported incidence of 5–10 cases per million population per year in Northern Europe [1]. Studies have reported an apparent reversal in the trend of the late 20th century with regard to the frequencies of focal segmental glomerulosclerosis and idiopathic membranous nephropathy (iMN) [2–4]. MN is emerging as the most common cause of adult nephrotic syndrome. In about one-third of patients with MN an underlying cause such as infection, hematological or solid organ malignancy, systemic autoimmune disease or the use of drugs such as nonsteroidal anti-inflammatory, penicillamine and intravenous gold can be identified [5]. In the remaining 70% of patients, the disease is regarded as primary or iMN.\n\nMembranous glomerulopathy is a common cause of primary glomerular disease in diabetics [6–8]. It can occur either as an isolated lesion or superimposed with diabetic nephropathy (DN). Nephrotic syndrome occurs late in the course of DN, indicating an advanced stage of glomerular damage [9]. Pathological changes in DN are characterized by mesangial expansion forming nodular glomerulosclerosis, thickening of glomerular basement membrane and arteriolar hyalinization, and in later stages global glomerulosclerosis and marked interstitial fibrosis. An expeditious onset of the nephrotic syndrome in diabetic patients may result from either an accelerated progression of DN or development of another primary glomerulopathy such as membranous, minimal change or IgA nephropathy [9]. Coexistence of diabetes and MN may pose both diagnostic and therapeutic challenges to the treating physician. Both DN and MN can present as proteinuric illnesses and may be indistinguishable. Steroids and other immunosuppressive drugs such as calcineurin inhibitors used to treat iMN may worsen glycemic control and exacerbate infections in diabetics. Despite the common occurrence of MN as a nondiabetic primary glomerular disease, there is a paucity of data on its natural history, management and outcome in diabetics. Hence we performed a retrospective analysis of the clinical profile, diagnostic and therapeutic difficulties encountered in treating this subset of iMN.\n\nMaterials and methods\nIn this retrospective observational study, we analyzed the data of all diabetics, evaluated for nondiabetic renal disease (NDRD) and found to have iMN, between January 2000 and June 2015. The study was carried out in a major tertiary care center situated in the northern part of India. The demographic profiles, details of illness and hospitalization, management and outcomes of the patients were retrieved from the electronic Hospital Information System.\n\nWe included all patients with diabetes mellitus (DM) with iMN and excluded patients with known secondary causes like infection with hepatitis B or C virus or HIV, known malignancy, positive antibodies to double-stranded DNA, or current treatment with gold or penicillamine.\n\nManagement protocol\nSupportive care was given to all patients with iMN with nephrotic syndrome including angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers to control proteinuria and to maintain blood pressure ≤130/80 mmHg (proteinuria < 1 g/day) or ≤125/75 mmHg (proteinuria > 1 g/day), statins for hyperlipidemia, dietary salt restriction and diuretics if edema was present.\n\nThe Modified Ponticelli (MP) regimen was started if the proteinuria was more than 4 g/day and more than 50% of the baseline value despite 6 months of supportive treatment, or if there was an unexplained >30% rise in the serum creatinine levels within 6–12 months of treatment initiation. The MP regimen included methyl prednisolone (1 g) given by parenteral route for three consecutive days, followed by oral prednisolone (0.5 mg/kg/day) for 27 days (Cycle A). Cycle A was followed by cyclophosphamide (2 mg/kg/day) orally for 1 month (Cycle B). Cycles A and B were continued at alternate months for three times each. The total duration of treatment was 6 months.\n\nIf there was no response within 4 months of starting of initial treatment, failure of MP regimen was considered and alternative therapy including macrolimus and steroids were started. Alternatives such as mycophenolate mofetil (MMF), rituximab and adrenocorticotropic hormone were considered if both tacrolimus and the MP regimen failed.\n\nDefinitions\nResponse: achievement of either complete remission or partial remission\n\nComplete remission (CR): a decrease of 24-h urinary protein excretion to at least 500 mg/day at least 1-month duration with plasma creatinine stable at <1.5 mg/dL.\n\n\nPartial remission (PR): a reduction in the rate of urinary protein excretion to between 0.5 and 2 g/day for at least 1-month duration with plasma creatinine stable at <1.5 mg/dL or decrease in proteinuria of >50% from baseline.\n\n\nTreatment failure/nonresponder: if there is no CR or PR within 4 months of starting of given treatment.\n\n\nRelapse: reappearance of proteinuria of >0.2 g/day in a patient who had either CR or PR. Renal failure: a persistent doubling of serum creatinine over the baseline values.\n\nResults\nA total of 134 patients with DM were evaluated during the study period and biopsied in suspicion of NDRD. Out of these 134 patients, 16 patients were found to have iMN in coexistence with DM. The duration of follow-up for MN ranged from 15 to 75 months.\n\nDemographic and clinical characteristics \nAll patients were male with a mean age of 54 ± 11.77 years (range: 23–69 years) (Table 1). All patients except one had Type 2 DM. Indications of kidney biopsy were rapid-onset proteinuria or massive proteinuria, or both. The mean ± standard deviation proteinuria was 9.4 g ± 2.85 g/day. Diabetic retinopathy (DR) was present in only four patients. Other complications of DM such as distal sensory polyneuropathy were present in five patients and coronary artery disease was present in 5 of 16 patients. Of the 16 patients, 11 were stratified as having high risk and 5 as an having intermediate risk for progression to end-stage renal disease. Renal histopathology was suggestive of pure MN in 12 of 16 patients while the remaining 4 had MN (Figure 1) in coexistence with DN.\nTable 1. Demographic and clinical characteristics of patients of iMN in coexistence with DM\n\nPatient no.\tAge (years)/ gender\tType of DM/ duration (years)\tIndication of kidney biopsy\tDR/other micro/macro vascular complication\tSAlb mg/dL/ UP (g/day)\tSCr (onset/last) (mg/dL)\tAnti PLA2R Ab\t Risk stratification of iMN\tRenal biopsy diagnosis\tFollow-up duration (months)\tTreatment\tOutcome at last follow-up\t\n1\t69/M\t2/18\t1\tDR−/CAD\t2.1/8.2\t0.9/1.5\tNA\tHigh\tMN + DN\t19\tMP→CNI→MMF\tRelapse\t\n2\t61/M\t2/10\t1\tDR+/PN/CAD\t1.9/7.5\t1.1/1.3\tNA\tIntermediate\tMN\t75\tMP\tPR\t\n3\t42/M\t2/6\t2\tDR−/None\t2.0/12.5\t1.0/1.2\tNA\tHigh\tMN\t29\tMP→CNI\tPR\t\n4\t62/M\t2/9\t1 + 2\tDR+/PN/CAD\t1.8/11.6\t1.2/1.4\tNA\tHigh\tMN\t33\tMP→CNI→MMF\tNR\t\n5\t45/M\t2/4\t1\tDR−/None\t2.3/8.5\t0.9/1.3\tNA\tHigh\tMN\t47\tMP→CNI→MMF\tPR\t\n6\t69/M\t2/13\t1\tDR−/None\t2.8/5.4\t1.1/1.2\tNA\tIntermediate\tMN + DN\t23\tMP→CNI→MMF\tCR\t\n7\t55/M\t2/11\t1 + 2\tDR+/PN/CAD\t2.3/10.4\t1.0/1.4\tNA\tHigh\tMN\t30\tMP→CNI→MMF\tNR\t\n8\t51/M\t2/9\t2\tDR−/None\t2.0/13.1\t1.2/1.6\tNA\tHigh\tMN\t18\tMP→CNI→MMF\tNR\t\n9\t48/M\t2/7\t1\tDR−/None\t3.0/4.9\t0.9/1.3\t109.96\tIntermediate\tMN\t20\tMP\tCR\t\n10\t56/M\t2/5\t2\tDR−/None\t2.0/12.1\t1.1/1.3\tNA\tHigh\tMN\t26\tMP→CNI→MMF\tCR\t\n11\t50/M\t2/4\t1 + 2\tDR−/None\t1.8/11.6\t1.2/1.4\tNA\tHigh\tMN\t29\tMP→CNI→MMF\tPR\t\n12\t23/M\t1/12\t1\tDR−/None\t2.9/6.0\t1.1/7\tNA\tIntermediate\tMN\t124\tMP→CNI→MMF\tESRD\t\n13\t67M\t2/19\t2\tDR−/PN\t2.1/13.0\t1.0/1.2\tNil\tHigh\tMN + DN\t24\tMP→CNI→MMF\tCR\t\n14\t57/M\t2/9\t1\tDR−/None\t2.8/5.9\t1.1/1.1\t106.48\tIntermediate\tMN\t16\tMP→CNI\tCR\t\n15\t61/M\t2/12\t1 + 2\tDR+/PN/CAD\t2.3/10.6\t1.2/1.0\tNA\tHigh\tMN + DN\t38\tMP→CNI→MMF\tPR\t\n16\t48/M\t2/4\t1\tDR−/None\t2.2/9.2\t1.2/1.3\t1.73\tHigh\tMN\t15\tMP→CNI\tCR\t\nUP: urinary protein; SAlb: serum albumin; SCr: serum creatinine; Anti PLA2R Ab: anti-phospholipase A2 receptor antibody; M: male; rapid-onset proteinuria = 1; massive proteinuria = 2; PN: distal sensory polyneuropathy; CAD: coronary artery disease; CNI: calcineurin inhibitors; ESRD: end-stage renal disease.\n\n\n\nFig. 1. Images from a case of case of MN with early DN. Periodic acidSchiff (A×20 and B×40) and silver stain (C×40) showing argyrophillic spikes (red arrow) and one nodule of exudative lesion (black and blue arrows) characteristic of diabetes.\n\nManagement and outcome \nAll patients (n = 16) with iMN were treated with the MP regimen after adequate supportive management (Figure 1 and Table 2). Of the 16 patients, only 3 (18%) patients had responded to the MP regimen and the remaining 13 (82%) patients were switched to tacrolimus and low-dose steroids. Persistent cytopenias and recurrent infections were contributory to poor tolerance and a switch in the regimen in two patients. One patient who relapsed after treatment with the MP regimen was treated subsequently with tacrolimus and low-dose steroids.\nTable 2. Response and adverse effects of different regimens used to treat patients with iMN in coexistence with DM\n\nRegimen\tResponders\tRelapse\tSwitch to other treatment (NR + IT + R)\tMean proteinuria before TT\tCytopenias\tInfections\tWorsening of diabetes\t\nMP regimen, N = 16\t3 (2 CR + 1 PR)\t1\t14 (11 + 2 + 1)\t9.40 ± 3.14 g/day\t6\t4\t7\t\nCNI, N = 14\t4 (2 CR + 2 PR)\t1\t11 (6 + 4 + 1)\t10.28 ± 2.81 g/day\t0\t2\t11\t\nMMF, N = 11\t7 (4 CR + 3 PR)\t1\t4 (3 + 0 + 1)\t8.92 ± 2.32 g/day\t2\t1\t0\t\nNR: nonresponder; IT: intolerant; R: relapse; TT: treatment; CNI: calcineurin inhibitors.\n\n\n\nOf the 14 patients who were treated with tacrolimus and low-dose steroids, only 4 patients (28.57%) had responded and the remaining 10 patients (71.43%) were switched to MMF and low-dose steroids. Of these 10 patients, 4 patients were unable to tolerate tacrolimus. They had a persistent worsening of diabetes even on insulin therapy. One patient developed ketosis during treatment with tacrolimus. One patient relapsed after treatment with tacrolimus and low-dose steroids and was treated subsequently with MMF and low-dose steroids.\n\nOf the 11 patients who were treated with MMF and low-dose steroid, 7 patients (63.63%) had responded to treatment. The remaining three (27.27%) nonresponders were managed with supportive treatment and planned for rituximab therapy but were lost to follow-up. One patient who relapsed after treatment with MMF and low-dose steroid was treated subsequently with supportive management.\n\nAdverse effects of treatment \nOf the 16 patients of iMN with coexisting DM, 5 patients (31.25%) developed treatment-related side effects significant enough to necessitate a regimen switch (Table 2). The most common cause of switch was worsening of diabetes (three patients) followed by cytopenias (one patient) and recurrent infections (one patient). Immunosuppression was not stopped in any patient treated with MMF owing to treatment-related toxicity.\n\nDiscussion\nTo the best of our knowledge, we report the largest data set in the literature to date on the clinical behavior and management of iMN in coexistence with DM. In this study, we have observed that patients with iMN in coexistence with DM responded poorly to the MP regimen, which is contrary to our logical belief. They had better response to MMF in comparison with the MP and tacrolimus-based regimen. Treatment-related toxicity was also seen less with MMF in comparison with the MP and tacrolimus-based regimen.\n\nThe incidence of these NDRDs varies between 18% and 80% among different studies based on the indication used for renal biopsy [10, 11]. MN is a common primary glomerular disease seen in diabetic patients [6–8]. Others include IgA nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis and minimal change disease [12].\n\nThe mean age of the patients in our cohort was 54 ± 11.77 years with a striking male predilection similar to the findings observed by Mami et al. [13]. The median duration of diabetes was 108 months (range: 48–228 months). The median duration of diabetes in the study done by Mami et al. was 71.4 months [13]. These findings are in accordance with the study done by Prakash et al., who concluded that NDRD is more common in patients with short duration of diabetes (<10 years duration) [14]. The indications for renal biopsy in our study included rapid-onset proteinuria in 50% of the patients, while the remaining had massive proteinuria or a combination of both. The mean ± standard deviation proteinuria was 9.4 ± 2.85 g/day. This is contrary to the findings of Mak et al., who showed that non-nephrotic range proteinuria is a predictor of NDRD. However, there were no cases of MN in their series [11]. DR was absent in 12 patients (75%) in our cohort. Four patients (25%) with DR had either iMN or a combination of iMN and DN. Prakash et al. showed that DR can be seen in 40% of the patients with non-DN either alone or in combination with DN [10]. Interestingly, among these four patients who had DR only one patient had DN and it was coexistent with iMN. Among the four patients who had features of DN in biopsy, only one had DR. These findings are consistent with the observation by Prakash et al., that, DR is a poor predictor of DN as DN can be present in 50% of the patients without DR [10]. Twelve patients (75%) had isolated MN and four patients (25%) had a combination of DN and MN. In the case series reported by Yoshikawa et al. features suggestive of diabetic glomerulosclerosis were seen in 12 of the 15 patients with MN [15].\n\nThe treatment of MN relies on immunosuppression in individuals who have not derived benefit from supportive therapy. Delaying immunosuppression in patients with iMN categorized as high risk could result in disease progression and may be associated with more frequent and severe adverse effects. There is no published literature examining the response to immunosuppressive medications in iMN patients with diabetes. Current knowledge of immunosuppression is derived from studies on isolated iMN. Alkylating agents with steroids are the most widely used initial immunosuppressive therapy for iMN. The response rate to MP regimen is as high as 93% [16]. However, in our study, only 18% of the patients responded to the MP regimen. Calcineurin inhibitors are used in patients who are unresponsive to other immunosuppressive medications, including alkylating agents, with response rates varying from 56% to 85% [17, 18]. The majority of CRs occur after 6 months of treatment and the number increases with the duration of therapy [17–19]. However, only 28.57% patients responded while similar percentages of patients were intolerant to the tacrolimus-based regimen. In contrast, however, 63.63% of the patients responded to MMF. Studies examining the role of MMF in the treatment of iMN have produced mixed results [20–22]. Two randomized controlled trials demonstrated a similar efficacy of MMF as compared to alkylating agents, with a response rate of ∼65% [20, 21]. A similar response rate to MMF was seen in our study. The reason for this poor response to alkylating agents and tacrolimus and a fair response to MMF remains elusive and needs further study. Adverse effects related to treatment were observed with all the regimens. However, adverse effects requiring treatment withdrawal were seen only with the MP regimen and tacrolimus, and not MMF. Worsening of the control of diabetes was the most common adverse effect and was more common in patients treated with tacrolimus.\n\nLimitations of our study include its retrospective nature and the relatively small number of patients. The major strength of our study is being largest dataset in the literature to date on clinical behavior and management of iMN in coexistence with DM.\n\nIn conclusion, our study presents a descriptive account of the clinical course, treatment outcomes and adverse effects of patients with iMN and diabetes. In this largest series of patients with iMN coexisting with DM, an unforeseen poor response to the MP regimen was observed. Treatment-related toxicity was also less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An a almost similar response was noted with the MMF and tacrolimus-based regimens. However, treatment-related toxicities leading to withdrawal of treatment were observed frequently in tacrolimus-based regimen.\n\nConflict of interest statement \nNone declared.\n==== Refs\nReferences\n1 \nMcQuarrie EP , Mackinnon B , Stewart GA \n; on behalf of the Scottish Renal Biopsy Registry Membranous nephropathy remains the commonest primary cause of nephrotic syndrome in a northern European Caucasian population . Nephrol Dial Transplant 2010 ; 25 : 1009 –1010 20037184 \n2 \nKraus MA , Punj S , Cimbaluk D \n\nResurgence of membranous nephropathy in African Americans in inner city Chicago . Clin Kidney J 2013 ; 6 : 373 –378 27293563 \n3 \nHanko JB , Mullan RN , O’Rourke DM \n\nThe changing pattern of adult primary glomerular disease . Nephrol Dial Transplant 2009 ; 24 : 3050 –3054 19487734 \n4 \nChanging Incidence of Glomerular Disease in Olmsted County, Minnesota: A 30-Year Renal Biopsy Study\nhttp://cjasn.asnjournals.org/content/1/3/483.abstract?ijkey=8efcff83b8b2fad114a7f50f2ca08be977106972&keytype2=tf_ipsecsha (26 September 2016, date last accessed)\n5 \nGlassock RJ. \nSecondary membranous glomerulonephritis . Nephrol Dial Transplant 1992 ; 7 : 64 –71 1337185 \n6 \nJin Kim Y , Hyung Kim Y , Dae Kim K \n\nNondiabetic kidney diseases in type 2 diabetic patients . Kidney Res Clin Pract 2013 ; 32 : 115 –120 26877926 \n7 \nNondiabetic Renal Disease in type 2 Diabetes Mellitus Patients: A Clinicopathological Study\nhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968638/#ref5 (26 September 2016, date last accessed)\n8 \nSoni SS , Gowrishankar S , Kishan AG \n\nNon diabetic renal disease in type 2 diabetes mellitus . Nephrology (Carlton) 2006 ; 11 : 533 –537 17199793 \n9 \nMogensen CE , Christensen CK , Vittinghus E. \nThe stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy . Diabetes 1983 ; 32 : 64 –78 6400670 \n10 \nPrakash J , Lodha M , Singh SK \n\nDiabetic retinopathy is a poor predictor of type of nephropathy in proteinuric type 2 diabetic patients . J Assoc Physicians India 2007 ; 55 : 412 –416 17879494 \n11 \nMak SK , Gwi E , Chan KW \n\nClinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus . Nephrol Dial Transplant 1997 ; 12 : 2588 –2591 9430856 \n12 \nRenal Outcomes and Clinical Course of Nondiabetic Renal Diseases in Patients with Type 2 Diabetes\nhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759762/ (2 October 2016, date last accessed)\n13 \nMami I , Harzallah A , Kaaroud H \n\nMP440 membranous glomerulonephritis in patients with type 2 diabetes . Nephrol Dial Transplant 2016 ; 31 (Suppl 1) : i486 \n14 \nPrakash J , Gupta T , Prakash S \n\nNon-diabetic renal disease in type 2 diabetes mellitus: Study of renal - retinal relationship . Indian J Nephrol 2015 ; 25 : 222 –228 26199473 \n15 \nYoshikawa Y , Truong LD , Mattioli CA \n\nMembranous glomerulonephritis in diabetic patients: a study of 15 cases and review of the literature . Mod Pathol 1990 ; 3 : 36 –42 2408036 \n16 \nPonticelli C , Altieri P , Scolari F \n\nA randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy . J Am Soc Nephrol 1998 ; 9 : 444 –450 9513907 \n17 \nChen M , Li H , Li X-Y \n\nTacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: a multicenter randomized controlled trial . Am J Med Sci 2010 ; 339 : 233 –238 20220333 \n18 \nPraga M , Barrio V , Juárez GF \n\nGrupo Español de Estudio de la Nefropatía Membranosa . \nTacrolimus monotherapy in membranous nephropathy: a randomized controlled trial . Kidney Int 2007 ; 71 : 924 –930 17377504 \n19 \nFritsche L , Budde K , Färber L \n\nTreatment of membranous glomerulopathy with cyclosporin A: how much patience is required? \nNephrol Dial Transplant \n1999 ; 14 : 1036 –1038 10328506 \n20 \nBranten AJ , du Buf-Vereijken PW , Vervloet M \n\nMycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide . Am J Kidney Dis 2007 ; 50 : 248 –256 17660026 \n21 \nChan TM , Lin AW , Tang SC \n\nProspective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome . Nephrology (Carlton) 2007 ; 12 : 576 –581 17995584 \n22 \nDussol B , Morange S , Burtey S \n\nMycophenolate mofetil monotherapy in membranous nephropathy: a 1-year randomized controlled trial . Am J Kidney Dis 2008 ; 52 : 699 –705 18585835\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "11(1)",
"journal": "Clinical kidney journal",
"keywords": "diabetes mellitus; membranous nephropathy; nephrotic syndrome",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "46-50",
"pmc": null,
"pmid": "29423200",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "9430856;17199793;20220333;20037184;9513907;18585835;26877926;17699249;17879494;1337185;27293563;2408036;6400670;17660026;17377504;26199473;17995584;10328506;19487734",
"title": "Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary!",
"title_normalized": "idiopathic membranous nephropathy in patients with diabetes mellitus a diagnostic and therapeutic quandary"
} | [
{
"companynumb": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2018-02512",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "OBJECTIVE\nSafety and tolerability assessment of initiating treatment with a once monthly long-acting injectable form of aripiprazole (aripiprazole once monthly) in patients stabilized on oral antipsychotics other than aripiprazole.\n\n\nMETHODS\nPatients with schizophrenia treated with oral atypical antipsychotics other than aripiprazole and with a history of aripiprazole tolerability were enrolled. Patients were stabilized per investigator's judgment for ≥14 days on oral atypical antipsychotics during screening. Patients then received one dose of aripiprazole once monthly (400 mg). Concomitant with aripiprazole once monthly, subjects received their current oral atypical antipsychotic for 14 ± 1 days at doses reduced to the mid/lower recommended dose range. Safety and tolerability were assessed for the 28-day treatment phase. For pharmacokinetic analyses, aripiprazole plasma concentrations were measured on Days 7, 14, and 28.\n\n\nRESULTS\nSixty patients were enrolled and initiated with aripiprazole once monthly while continuing treatment with oral olanzapine (n = 3), quetiapine (n = 28), risperidone (n = 24) or ziprasidone (n = 5). Duration of co-administered oral antipsychotic treatment varied, ranging from 0 to 15 days. Treatment was well tolerated. Frequently reported treatment-emergent adverse events (TEAEs) were injection-site pain and toothache (4/60 subjects each, 6.7%), followed by dystonia, fatigue, increased blood creatine phosphokinase, insomnia and restlessness (3/60 subjects each, 5.0%). Most TEAEs occurred in the first 8 days of co-administration irrespective of days of oral overlap. No clinically relevant mean changes from baseline were observed for laboratory values or fasting metabolic parameters. Psychotic symptoms remained stable. Aripiprazole plasma concentrations were similar to those observed following daily doses of oral aripiprazole.\n\n\nCONCLUSIONS\nThe adverse-event profile of patients receiving aripiprazole once monthly concomitant with oral atypical antipsychotics other than aripiprazole was consistent with previous reports of aripiprazole once monthly concomitant with oral aripiprazole. Adverse events were similar irrespective of prior atypical antipsychotic and duration of oral antipsychotic overlap, suggesting that patients can be safely switched from their existing oral antipsychotic to aripiprazole once monthly without requiring an intermediate stabilization phase with oral aripiprazole. Aspects of the study design (open-label trial and short duration) and patient population (predominantly male and of African-American ethnicity) may limit the generalizability of these findings.\n\n\nBACKGROUND\nSafety and Tolerability Trial of Aripiprazole IM Depot Treatment in Adult Subjects With Schizophrenia Stabilized on Oral Antipsychotics Other Than Aripiprazole. ID number: NCT01552772. Registry: clinicaltrials.gov.",
"affiliations": "Department of Psychiatry and Human Behavior, University of California , Irvine, CA , USA.",
"authors": "Potkin|Steven G|SG|;Raoufinia|Arash|A|;Mallikaarjun|Suresh|S|;Bricmont|Patricia|P|;Peters-Strickland|Timothy|T|;Kasper|William|W|;Baker|Ross A|RA|;Eramo|Anna|A|;Sanchez|Raymond|R|;McQuade|Robert|R|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1185/03007995.2013.821973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-7995",
"issue": "29(10)",
"journal": "Current medical research and opinion",
"keywords": null,
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D015363:Quinolones; D012307:Risk Factors; D012559:Schizophrenia; D012737:Sex Factors; D013997:Time Factors",
"nlm_unique_id": "0351014",
"other_id": null,
"pages": "1241-51",
"pmc": null,
"pmid": "23822566",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and tolerability of once monthly aripiprazole treatment initiation in adults with schizophrenia stabilized on selected atypical oral antipsychotics other than aripiprazole.",
"title_normalized": "safety and tolerability of once monthly aripiprazole treatment initiation in adults with schizophrenia stabilized on selected atypical oral antipsychotics other than aripiprazole"
} | [
{
"companynumb": "US-JNJFOC-20130915156",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "High dose insulin (HDI) therapy for cardiogenic shock from acute poisoning can be complicated by treatable hypoglycemia which persists following poisoning recovery. Glucose requirements post-HDI reflect supraphysiological insulin plasma concentration. A publication reported a patient treated with HDI with plasma insulin concentrations >1000 µU/mL and elimination half-life 10-18 h requiring intravenous glucose replacement for >5 days. We report two cases treated with HDI (Actrapid; soluble or regular insulin) with shorter elimination half-lives.\nA man ingesting diltiazem received HDI for approximately 60 h (maximum dose 10 U/kg/h) and supplemental intravenous dextrose for 44 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 6345 µU/mL and elimination half-life 5.5 h. A man ingesting propranolol received HDI for approximately 12 h (maximum dose 1.5 U/kg/h) and supplemental intravenous dextrose for 4 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 368 µU/mL and elimination half-life 2.2 h.\nMarkedly different insulin pharmacokinetics post-HDI is observed in two cases and a previously published report, and factors contributing to the interpatient differences are poorly defined. This pharmacokinetic variability impacts on the severity and duration of treatable hypoglycemia post-HDI. Analytical factors impacting on the measured plasma insulin concentrations include appropriate sample dilution and differing analytical specificity for the type of insulin.",
"affiliations": "Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.;Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.;Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.;St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.",
"authors": "Roberts|Darren M|DM|0000-0001-9101-7577;Hughes|Haddijatou K|HK|;Haber|Paul S|PS|0000-0001-8915-8872;Jones|Graham R D|GRD|0000-0001-9109-7255",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2021.1967372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": null,
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "HDI; HIET; Insulin; assay; diltiazem; inotrope; overdose; poisoning; propranolol; shock; toxicity",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": null,
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "34521309",
"pubdate": "2021-09-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Variability in insulin pharmacokinetics following high-dose insulin therapy.",
"title_normalized": "variability in insulin pharmacokinetics following high dose insulin therapy"
} | [
{
"companynumb": "AU-MYLANLABS-2021M1072596",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Occult hepatitis B infection consists of persistence of HBV genomes in hepatocytes,absence of serum HBsAg, low/undetectable serum HBVDNA. Reactivation of HBV infection may occur during immunosuppression, but few data are available in heart transplant.\n\n\n\nWe followed-up heart recipients with or without markers of previous HBV infection,evaluating prevalence of HBV markers, incidence of HBV reactivation and its virological and clinical features.\n\n\n\nHeart failure patients listed for heart transplant (2007-2013) were screened for current or past HBV infection. Transplanted patients with past HBV infection (anti-HBc+/±anti-HBs+/HBVDNA-) were followed up as cases, and an equal number of HBV negative patients as controls. Virological reactivation was detected by standard real-time and home-made highly sensitive PCR (surface/core HBVDNA regions). Clinical status and progression were assessed by liver histology, ultrasound or elastography.\n\n\n\n67 patients underwent heart transplant, including 4 (5.9%) HBsAg+ subjects. Cases were 11/67 (16.4%). During a median follow-up of 30 months, only one of these 11 patients presented viral reactivation (HBVDNA 209IU/mL) at month 22, and started antiviral treatment. Four other recipients showed virological events of uncertain significance (sensitive PCR-only intermittently positive). Clinical signs of liver disease were observed in only one case at the last follow-up. A nonsignificant difference in survival was observed between cases and all other heart recipients without prior HBV contact (death rate 5/11 vs 15/52, respectively; p=0.097).\n\n\n\nHBV genotypic reactivation in HBsAg-/anti-HBc+/HBVDNA- heart recipients is uncommon. Virological events of uncertain significance occur more frequently; their clinical impact seems to be negligible.",
"affiliations": "Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy. Electronic address: martina.vitrone@yahoo.it.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Units of Infectious & Transplant Medicine, Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Cardiac Surgery, AORN dei Colli, Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy; Units of Infectious & Transplant Medicine, Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.;Internal Medicine, University of Campania \"Luigi Vanvitelli\", Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy; Units of Infectious & Transplant Medicine, Monaldi Hospital, Piazzale Ettore Ruggieri snc, 80131, Naples, Italy.",
"authors": "Vitrone|Martina|M|;Iossa|Domenico|D|;Rinaldi|Luca|L|;Pafundi|Pia Clara|PC|;Molaro|Rosa|R|;Parrella|Antonio|A|;Andini|Roberto|R|;Ragone|Enrico|E|;Maiello|Ciro|C|;Zampino|Rosa|R|;Durante-Mangoni|Emanuele|E|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcv.2017.09.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "96()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Heart transplant; Hepatitis B reactivation; Occult hepatitis B infection (OBI); Virological event",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D016027:Heart Transplantation; D006509:Hepatitis B; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015994:Incidence; D008099:Liver; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D014775:Virus Activation",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "54-59",
"pmc": null,
"pmid": "28964958",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis B virus reactivation after heart transplant: Incidence and clinical impact.",
"title_normalized": "hepatitis b virus reactivation after heart transplant incidence and clinical impact"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1026017",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Plague is a re-emerging disease caused by the bacteria Yersinia pestis. Humans usually get the disease through the bite of an infected flea. Plague is a fulminant systemic disease, with pneumonic plague being the most lethal form. Late diagnosis is one of the main causes of mortality and spread of the disease, as it limits the effectiveness of control measures. We present the case of a 42-year-old male, who had previously traveled to an endemic plague area and then presented hyperpyrexia, hypotension, and inflammatory inguinal adenopathy. Despite the very characteristic clinical picture, nobody (before admission to our hospital) suspected plague. An effective combination of antibiotics and intensive treatment was initiated only on the fifth day of illness. The patient went into septic shock, respiratory failure, and death. Plague was confirmed by polymerase chain reaction (PCR). This case emphasizes the importance of having a high suspicion rate for plague.",
"affiliations": "Servicio de Medicina Interna, Hospital Regional Lambayeque, Chiclayo. Lambayeque, Perú.;Servicio de Infectologia, Hospital Regional Lambayeque, Chiclayo. Lambayeque, Perú.",
"authors": "Meregildo-Rodriguez|Edinson Dante|ED|;Villegas-Chiroque|Miguel|M|",
"chemical_list": null,
"country": "Peru",
"delete": false,
"doi": "10.17843/rpmesp.2019.363.4292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1726-4634",
"issue": "36(3)",
"journal": "Revista peruana de medicina experimental y salud publica",
"keywords": null,
"medline_ta": "Rev Peru Med Exp Salud Publica",
"mesh_terms": "D000328:Adult; D057210:Delayed Diagnosis; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D010930:Plague",
"nlm_unique_id": "101227566",
"other_id": null,
"pages": "515-519",
"pmc": null,
"pmid": "31800948",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapidly fatal septicemic plague secondary to undiagnosed primary bubonic plague: case report.",
"title_normalized": "rapidly fatal septicemic plague secondary to undiagnosed primary bubonic plague case report"
} | [
{
"companynumb": "PE-PFIZER INC-2019387804",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE HYCLATE"
},
"drugadditional": null... |
{
"abstract": "A 6-year-old girl with a history of chronic immunosuppression following small bowel and colon transplantation for tufting enteropathy presented with a diffuse, facial-predominant eruption composed of pink-to-skin-colored papules with central white dystrophic spicules. Histology from a punch biopsy and polymerase chain reaction (PCR) from plucked spicules confirmed a diagnosis of trichodysplasia spinulosa (TS). Additional molecular studies identified several strains of the trichodysplasia spinulosa-associated polyomavirus infecting multiple tissues of the patient, confirming the systemic nature of trichodysplasia spinulosa infections.",
"affiliations": "Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Dermatology, Howard University Hospital, Washington, District of Columbia.;Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas.;Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.;Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.;Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Dermatology, Children's National Medical Center, Washington, District of Columbia.",
"authors": "Chamseddin|Bahir H|BH|https://orcid.org/0000-0002-5729-3532;Tran|Bao Anh Patrick D|BAPD|;Lee|Eunice E|EE|;Pastrana|Diana V|DV|;Buck|Christopher B|CB|;Wang|Richard C|RC|;Kirkorian|Anna Yasmine|AY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13857",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "36(5)",
"journal": "Pediatric dermatology",
"keywords": "diagnosis; pediatric; trichodysplasia spinulosa; trichodysplasia spinulosa-associated polyomavirus",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D005260:Female; D006201:Hair Diseases; D006801:Humans; D011120:Polyomavirus; D027601:Polyomavirus Infections; D012878:Skin Neoplasms; D014412:Tumor Virus Infections",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "723-724",
"pmc": null,
"pmid": "31190328",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27990673;24315796;27578847;20686659;17696921",
"title": "Trichodysplasia spinulosa in a child: Identification of trichodysplasia spinulosa-associated polyomavirus in skin, serum, and urine.",
"title_normalized": "trichodysplasia spinulosa in a child identification of trichodysplasia spinulosa associated polyomavirus in skin serum and urine"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP011820",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nLocal antitumor efficacy and the outcome of neoadjuvant chemoradiotherapy (NACRT) with low-dose gemcitabine and wide irradiation area for borderline resectable and unresectable pancreatic cancer were evaluated.\n\n\nMETHODS\nThirty-four cases of borderline resectable and unresectable pancreatic cancer were recruited. Three-dimensional conformal radiotherapy to the pancreatic bed and the region scheduled for lymph node dissection was performed to a total dose of 50.4 Gy28 fractions with gemcitabine at a dose of 150 mg/m2 weekly. Clinical and pathological results were examined.\n\n\nRESULTS\nTwenty-seven patients (79.4%) completed the protocol. Grade 3/4 leucopenia (n=10), and grade 3 anorexia (n=1) occurred. Seven cases were excluded (two refused treatment; five had progressive disease), 20 underwent laparotomy, and 16 resected (47.1%) cases achieved R0 resection. Median survival time, and 3-year and 5-year survival rates were 39.0 months, and 56.3% and 28.1% in resected cases, respectively.\n\n\nCONCLUSIONS\nNACRT with low-dose gemcitabine and wide irradiation area achieved 100% R0 resection and acceptable prognosis.",
"affiliations": "Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan hkamachi@db3.so-net.ne.jp.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.",
"authors": "Kamachi|Hirofumi|H|;Tsuruga|Yousuke|Y|;Orimo|Tatsuya|T|;Wakayama|Kenji|K|;Shimada|Shingo|S|;Nagatsu|Akihisa|A|;Yokoo|Hideki|H|;Kamiyama|Toshiya|T|;Katoh|Norio|N|;Taketomi|Akinobu|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "32(5)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Neoadjuvant; R0 resection; chemoradiotherapy; gemcitabine; pancreatic cancer",
"medline_ta": "In Vivo",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "1183-1191",
"pmc": null,
"pmid": "30150442",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "23435609;17227978;22160780;27762654;17175452;28784865;10655437;26181261;24622063;11307091;20828979;23720019;25099441;16865597;24104372;25559415;12773980;22605518;15273542;19690548;27265347;18471707;22750974;28338509;21213060;28347525;19142173;29068800;23799421;27885480;8205542;22065318;16003309;22778019;1359851",
"title": "R0 Resection for Locally Advanced Pancreatic Cancer with Low-dose Gemcitabine with Wide Irradiation Area as Neoadjuvant Chemoradiotherapy.",
"title_normalized": "r0 resection for locally advanced pancreatic cancer with low dose gemcitabine with wide irradiation area as neoadjuvant chemoradiotherapy"
} | [
{
"companynumb": "JP-PFIZER INC-2018392127",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nBy inhibiting DNA repair, clofarabine (CLO) may augment cyclophosphamide (CY)-induced DNA damage and apoptosis. We performed a Phase I study for refractory and/or relapsed (R/R) leukemia in children to determine maximum-tolerated dose (MTD) of time-sequential CLO followed by CY.\n\n\nMETHODS\nThirteen patients with (R/R) ALL (n = 8) and AML (N = 5), median age 9 years (range: 2-12 years), were treated with escalating doses of CLO on days 1, 2, 3 and 8, 9, 10 and CY 200 mg/m(2) /day on days 0 and 1 then 400 mg/m(2) /day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20 mg/m(2) /day) and three patients at DL2 (CLO 30 mg/m(2) /day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2 hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2 hours after CLO followed by CY on day 1.\n\n\nRESULTS\nTwo patients at DL2 had dose-limiting toxicities (DLTs) that included hypotension with cardio-respiratory failure (1) and hepato-renal failure (1). Complete remission (CR) was achieved in 2/11 (18.2%) and partial remission (PR) in 2/11 (18.2%) for an overall response (OR) of 36.4%. The use of CLO before CY augmented CY-induced DNA damage in leukemic blasts compared to CY alone.\n\n\nCONCLUSIONS\nIn pediatric patients with R/R leukemia, 20 mg/m(2) /day is the MTD for CLO in timed sequential combination with CY. Increased DNA damage with the use of this combination suggests a mechanism for the sequential timing of these two chemotherapeutic agents.",
"affiliations": "Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting & Blaustein Cancer Research Building, Baltimore, MD 21231, USA.",
"authors": "Abd Elmoneim|Abeer|A|;Gore|Lia|L|;Ricklis|Rebecca M|RM|;Boklan|Jessica|J|;Cooper|Todd|T|;Narendran|Aru|A|;Rolla|Katherine|K|;Scott|Tammy|T|;Arceci|Robert J|RJ|",
"chemical_list": "D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24264",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "59(7)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000208:Acute Disease; D000227:Adenine Nucleotides; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001087:Arabinonucleosides; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003520:Cyclophosphamide; D004249:DNA Damage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia; D015470:Leukemia, Myeloid, Acute; D008297:Male; D020714:Maximum Tolerated Dose; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1252-8",
"pmc": null,
"pmid": "22887831",
"pubdate": "2012-12-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias.",
"title_normalized": "phase i dose escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias"
} | [
{
"companynumb": "US-SA-2014SA125002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "This article reviews the major contributions to our understanding of the rheumatic diseases. These include the first definite evidence of linkage between genes controlling the immune response and the major histocompatibility complex genotype; the recognition of the types and the role of the many crystals in arthritis; the application of sophisticated immunologic techniques to the understanding of the antinuclear autoantibodies; the recognition of a new disorder--Lyme arthritis; and the contributions of joint replacement and other surgeries, and the numerous drugs and procedures now available for treatment of patients.",
"affiliations": "Department of Internal Medicine, University of Cincinnati Medical Center, Ohio.",
"authors": "Mongey|A B|AB|;Hess|E V|EV|",
"chemical_list": "D000974:Antibodies, Antinuclear",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8389",
"issue": "26(6)",
"journal": "Radiologic clinics of North America",
"keywords": null,
"medline_ta": "Radiol Clin North Am",
"mesh_terms": "D000974:Antibodies, Antinuclear; D001168:Arthritis; D002805:Chondrocalcinosis; D006801:Humans; D012216:Rheumatic Diseases; D012219:Rheumatology; D013167:Spondylitis, Ankylosing",
"nlm_unique_id": "0123703",
"other_id": null,
"pages": "1157-64",
"pmc": null,
"pmid": "3051090",
"pubdate": "1988-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Advances in rheumatology.",
"title_normalized": "advances in rheumatology"
} | [
{
"companynumb": "BR-ABBVIE-18P-020-2538413-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "The landscape of acute lymphoblastic leukemia (ALL) has evolved significantly over the last few years. Identification of specific recurrent genetic alterations and of minimal residual disease (MRD) guides prognostic classification and management. Novel agents (eg, blinatumomab) have demonstrated encouraging results in relapsed/refractory (R/R) and MRD+ patients and are currently incorporated into upfront treatment in specific settings. Other new strategies include the incorporation of tyrosine kinase inhibitor-based therapy for patients with Philadelphia chromosome-like ALL and the use of DOT inhibitors and bcl-2/bcl-xl inhibitors in R/R disease. These innovations promise to improve management and outcome in this disease.",
"affiliations": "Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; and.;Levine Cancer Institute, Atrium Health, Charlotte, NC.",
"authors": "Advani|Anjali S|AS|;Copelan|Edward A|EA|",
"chemical_list": "D000970:Antineoplastic Agents; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase",
"country": "United States",
"delete": false,
"doi": "10.1182/hematology.2019000008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1520-4383",
"issue": "2019(1)",
"journal": "Hematology. American Society of Hematology. Education Program",
"keywords": null,
"medline_ta": "Hematology Am Soc Hematol Educ Program",
"mesh_terms": "D000970:Antineoplastic Agents; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008297:Male; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012307:Risk Factors",
"nlm_unique_id": "100890099",
"other_id": null,
"pages": "9-16",
"pmc": null,
"pmid": "31808877",
"pubdate": "2019-12-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29296758;28494052;25301704;25116331;17032921;30327352;28249141;28082340;11023499;29352703;18388178;30561755;30728140;27932787;30008477;29296813;28972016;19138562;27292104;27343252;18780832;16195338;25524800;10648387;27919910;19141862;27235138;25649768;24993360;21576633;27056999;27870571;26124497;30658992;27626518;30012635;22357140;30920645;17170120;20660823;30292743;27777238;30466746;25207766;19455460;29358182",
"title": "Navigating the nexus of MRD and novel agents in ALL.",
"title_normalized": "navigating the nexus of mrd and novel agents in all"
} | [
{
"companynumb": "US-AMGEN-USASP2019212167",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nSafety data on anti-tumor necrosis factor (anti-TNF) treatment during pregnancy are limited. We studied the risk of birth defects after anti-TNF treatment in early pregnancy.\n\n\nMETHODS\nWe collected data on 1,272,424 live-born infants identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. We determined the prevalence of birth defects among infants born to women with chronic inflammatory disease (inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis), with (n = 683) and without (n = 21,549) anti-TNF treatment during early pregnancy, and in the general population. We compared the risk of any major birth defect and birth defect by organ system for infants born to women with chronic inflammatory disease, with and without anti-TNF treatment. Risks were presented as odds ratios (ORs) with 95% confidence intervals (CIs). We adjusted for maternal age, parity, smoking, body mass index, multiple gestation, country, and chronic inflammatory diagnosis.\n\n\nRESULTS\nBirth defects were more prevalent among infants born to women with chronic inflammatory disease, regardless of anti-TNF treatment status, than in the general population (4.8% vs 4.2%). Birth defects occurred in 43 of the infants born to the 683 women who received anti-TNF treatment (6.3%), and 1019 of the infants born to women with chronic inflammatory disease (4.7%). The OR for any defect in women receiving anti-TNF therapy was 1.32 (95% CI, 0.93-1.82); the OR for a cardiovascular defect was 1.60 (95% CI, 0.93-2.58), and the OR for a urinary defect was 2.22 (95% CI, 0.86-4.71).\n\n\nCONCLUSIONS\nBased on an analysis of data from the health registries in Denmark and Sweden, women who received anti-TNF agents during pregnancy had a slightly (but not significantly) higher risk of having children with birth defects. Although larger studies are needed, the heterogeneity of the observed birth defects did not indicate a common etiology.",
"affiliations": "Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden. Electronic address: gabriella.broms@ki.se.;Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden.;Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden.;Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.;Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.;Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.;Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden; Department of Women and Children's Health, Karolinska Institutet, Stockholm, Sweden.;Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Bröms|Gabriella|G|;Granath|Fredrik|F|;Ekbom|Anders|A|;Hellgren|Karin|K|;Pedersen|Lars|L|;Sørensen|Henrik T|HT|;Stephansson|Olof|O|;Kieler|Helle|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "14(2)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Inflammatory Bowel Disease; Pregnancy; Rheumatoid Arthritis; TNF",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000293:Adolescent; D000328:Adult; D003718:Denmark; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D011247:Pregnancy; D011248:Pregnancy Complications; D015995:Prevalence; D018570:Risk Assessment; D013548:Sweden; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "234-41.e1-5",
"pmc": null,
"pmid": "26375613",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Low Risk of Birth Defects for Infants Whose Mothers Are Treated With Anti-Tumor Necrosis Factor Agents During Pregnancy.",
"title_normalized": "low risk of birth defects for infants whose mothers are treated with anti tumor necrosis factor agents during pregnancy"
} | [
{
"companynumb": "SE-UCBSA-2015031092",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": "3",
... |
{
"abstract": "Ventricular assist devices have been shown to be effective in advanced heart failure selected patients. They often have borderline end-organ function, what facilitates organ dysfunction. Liver failure is difficult to manage and leads to increased morbidity and mortality. We report a case of ductular cholestasis, an unusual cholestatic hepatic failure with untractable coagulopathy, developed during the use of a magnetic levitation centrifugal pump, implanted as a bridge to heart transplantation, in a patient with cardiogenic shock (as an end-stage disease of idiopathic dilated cardiomyopathy). We discussed the pathophysiology of this entity and the possible related factors, including the assist device. Preemptive interventions have been advocated as the primary way of treatment. Preoperative optimization of heart function and avoidance of visceral hypoperfusion and sepsis may play a major role.",
"affiliations": "Cardiovascular Intensive and Postoperative Care Unit (Intensive Care Unit), University Hospital 12 de Octubre, Madrid, Spain. albertomohedanomd@yahoo.es",
"authors": "Mohedano-Gómez|Alberto|A|;Pérez-Vela|José L|JL|;Renes-Carreño|Emilio|E|;De-Andrés|Carolina Ibarrola|CI|;Corres-Peiretti|María A|MA|;Arribas-López|Primitivo|P|;Gutierrez-Rodriguez|Julián|J|;Perales-Rodríguez-De-Viguri|Narciso|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1594.2009.00760.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-564X",
"issue": "34(2)",
"journal": "Artificial organs",
"keywords": null,
"medline_ta": "Artif Organs",
"mesh_terms": "D000328:Adult; D002311:Cardiomyopathy, Dilated; D002780:Cholestasis, Intrahepatic; D017809:Fatal Outcome; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008099:Liver; D008297:Male; D012770:Shock, Cardiogenic",
"nlm_unique_id": "7802778",
"other_id": null,
"pages": "149-52",
"pmc": null,
"pmid": "19817730",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ductular cholestasis, an unusual form of intrahepatic cholestasis, associated with cardiogenic shock and ventricular assist device.",
"title_normalized": "ductular cholestasis an unusual form of intrahepatic cholestasis associated with cardiogenic shock and ventricular assist device"
} | [
{
"companynumb": "ES-STADA-247026",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": "4",
"drugad... |
{
"abstract": "Relatively little data are available on how the response to the coronavirus disease 2019 (COVID-19) pandemic has affected treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. We aimed to determine the effect of COVID-19 countermeasures on treatment outcomes in this patient population.\n\n\n\nWe retrospectively analyzed data on patients treated for lymphoma or multiple myeloma in two tertiary hospitals in Seoul. Patients were divided into two groups: group 1 included patients who received chemotherapy between September and December 2019 (the control period), and group 2 included patients who received chemotherapy between September and December 2020 (the study period). Countermeasures to COVID-19 were applied to the patients in group 2. The countermeasures implemented included mask wearing and regular handwashing at home and in hospital; COVID-19 risk assessments on all hospital visitors; and pre-emptive COVID-19 screening for all newly hospitalized patients and their resident guardians.\n\n\n\nNo differences in treatment outcomes, including treatment response, incidence and duration of neutropenia or neutropenic fever, delays in chemotherapy, or number of deaths during chemotherapy, were observed between the g roups. None of the patients in group 2 tested positive for COVID-19, and there were no COVID-19-related deaths during the study period.\n\n\n\nCountermeasures to COVID-19 did not affect treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. Data on the effect of countermeasures to COVID-19 on treatment outcomes should continue to be analyzed to ensure that treatment outcomes are not adversely affected.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.",
"authors": "Kang|Ka-Won|KW|;Lee|Byung-Hyun|BH|;Jeon|Min Ji|MJ|;Yu|Eun Sang|ES|;Kim|Dae Sik|DS|;Lee|Se Ryeon|SR|;Sung|Hwa Jung|HJ|;Choi|Chul Won|CW|;Park|Yong|Y|;Kim|Byung Soo|BS|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3904/kjim.2021.186",
"fulltext": "\n==== Front\nKorean J Intern Med\nKorean J Intern Med\nThe Korean Journal of Internal Medicine\n1226-3303\n2005-6648\nKorean Association of Internal Medicine\n\n34666434\n10.3904/kjim.2021.186\nkjim-2021-186\nOriginal Article\nHemato-Oncology\nThe effect of the response to the coronavirus disease pandemic on treatment outcomes in patients with lymphoma and multiple myeloma\nKang Ka-Won\nLee Byung-Hyun\nJeon Min Ji\nYu Eun Sang\nKim Dae Sik\nLee Se Ryeon\nSung Hwa Jung\nChoi Chul Won\nPark Yong\nhttp://orcid.org/0000-0002-3657-8619\nKim Byung Soo\nDivision of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea\nCorrespondence to: Byung Soo Kim, M.D., Department of Internal Medicine, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea, Tel: +82-2-920-5690, Fax: +82-2-926-4534, E-mail: kbs0309@korea.ac.kr, https://orcid.org/0000-0002-3657-8619\n11 2021\n21 10 2021\n36 6 14591470\n13 4 2021\n7 5 2021\n10 5 2021\nCopyright © 2021 The Korean Association of Internal 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 noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground/Aims\n\nRelatively little data are available on how the response to the coronavirus disease 2019 (COVID-19) pandemic has affected treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. We aimed to determine the effect of COVID-19 countermeasures on treatment outcomes in this patient population.\n\nMethods\n\nWe retrospectively analyzed data on patients treated for lymphoma or multiple myeloma in two tertiary hospitals in Seoul. Patients were divided into two groups: group 1 included patients who received chemotherapy between September and December 2019 (the control period), and group 2 included patients who received chemotherapy between September and December 2020 (the study period). Countermeasures to COVID-19 were applied to the patients in group 2. The countermeasures implemented included mask wearing and regular handwashing at home and in hospital; COVID-19 risk assessments on all hospital visitors; and pre-emptive COVID-19 screening for all newly hospitalized patients and their resident guardians.\n\nResults\n\nNo differences in treatment outcomes, including treatment response, incidence and duration of neutropenia or neutropenic fever, delays in chemotherapy, or number of deaths during chemotherapy, were observed between the g roups. None of the patients in group 2 tested positive for COVID-19, and there were no COVID-19-related deaths during the study period.\n\nConclusions\n\nCountermeasures to COVID-19 did not affect treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. Data on the effect of countermeasures to COVID-19 on treatment outcomes should continue to be analyzed to ensure that treatment outcomes are not adversely affected.\n\nTreatment outcome\nLymphoma\nMultiple myeloma\nCoronavirus\n==== Body\npmcINTRODUCTION\n\nCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus transmitted via respiratory droplets (direct contact) and contaminated objects and airborne contagion (indirect contact) [1,2]. Although the mortality rate of COVID-19, at approximately 3%, is lower than that of SARS-CoV-1, at approximately 10%, or Middle East respiratory syndrome, at approximately 40%, it is far more contagious, infecting approximately 10 times more people [3]. As the number of patients with COVID-19 increases, the strain on medical resources locally and globally is reaching a level unprecedented in recent times. As various efforts to contain the spread of COVID-19, to produce vaccines against it, and to develop therapeutic agents to treat it are underway, the pressure on medical facilities remains challenging as the need to optimally treat patients with COVID-19 is added to the need to optimally treat patients with other diseases, including malignancies.\n\nPatients with malignancies are more likely to be infected by SARS-CoV-2 and are more likely to develop severe COVID-19 [4,5]. The mortality rate among patients with existing malignancies and COVID-19 can reach approximately 33% [6–10]. The risks of more severe disease and death tend to be higher in patients with hematologic malignancies [11,12], with the mortality rate reported to be as high as 62% [13,14]. Despite the challenges of COVID-19, chemotherapy for patients with hematologic malignancies cannot be delayed indefinitely. Countermeasures to prevent infection with SARS-CoV-2 are thus critical to ensure optimal treatment for both patients with COVID-19 and those with hematologic malignancies receiving chemotherapy.\n\nThis study aimed to analyze an example of countermeasures to COVID-19 and to evaluate the impact of these countermeasures on treatment processes and outcomes in patients who were hospitalized repeatedly and/or received outpatient treatment for lymphoma or multiple myeloma.\n\nMETHODS\n\nStudy design and patients\n\nThe study was approved by the appropriate Institutional Review Board (IRB) of Korea University Anam Hospital and Korea University Guro Hospital, and all data were fully anonymized (IRB No. 2020AN0559 and 2021GR0051). As this study was conducted using anonymous patient data, the requirement for informed consent was waived by the IRB.\n\nIn this non-interventional comparative cohort study, we retrospectively analyzed the data of patients who were consecutively enrolled in the Lymphoma and Myeloma Registry from September 2019 to December 2019 and from September 2020 to December 2020. Data from two tertiary hospitals affiliated with the Korea University Medical Center (Anam and Guro Hospitals) located in Seoul were used. The Anam and Guro Hospitals had a total of 1,048 and 1,075 beds and received approximately 3,665 and 3,985 outpatients daily, respectively, as of January 2021. Patients who met the following criteria were included: (1) a diagnosis of lymphoma or multiple myeloma according to the World Health Organization classification, and (2) provision of chemotherapy from September 2019 to December 2019 (the control period) or September 2020 to December 2020 (the study period).\n\nPatients were divided into two groups: group 1 included patients with lymphoma or multiple myeloma who received chemotherapy during the control period, and group 2 included patients with lymphoma or multiple myeloma who received chemotherapy during the study period. Countermeasures to COVID-19 were applied to group 2. Group 1 was included as a control group to account for seasonal viral infectious diseases, such as influenza, that may have occurred in patients treated at a similar time before the COVID-19 pandemic. Both groups were defined as patients with lymphoma or multiple myeloma who received chemotherapy within a limited period, and the clinical outcomes measured within the period were compared.\n\nCountermeasures to COVID-19 from September 2020 to December 2020\n\nThe South Korean government initiated active quarantine to control the COVID-19 pandemic in February 2020. With the continuation of the COVID-19 pandemic, the two tertiary hospitals in this study also initiated active responses to the COVID-19 pandemic that applied to patients, their guardians, and hospital workers from September 2020. The countermeasures that were implemented and included this study are listed in Table 1.\n\nPatients and their guardians were required to wear a mask, irrespective of whether they were indoors or outdoors at home or in a hospital, and to practice hand hygiene by washing their hands thoroughly with soap under running water. All patients and guardians who visited the hospital were permitted to enter only after confirming that they had no history of visiting any areas with COVID-19 outbreaks or foreign countries, no COVID-19-related symptoms, and no fever (temperature > 37.5°C). If one or more of the above conditions were not satisfied, they were not permitted to enter the hospital and were referred to an outdoor COVID-19 clinic or emergency department. All newly admitted patients and their resident guardians were confirmed to be negative for COVID-19 1 to 7 days before hospitalization. Hospitalized patients were prohibited from going out and were to avoid the use of lounges or restaurants in the hospital. When fever and respiratory symptoms occurred in patients or hospital workers, active consultation with the Department of Infectious Diseases to arrange for COVID-19 testing was undertaken. All COVID-19 tests were conducted at the outdoor COVID-19 clinic or emergency department, thoroughly separated from the existing laboratory. If emergency hospitalization was required, dedicated quarantine beds were used until the COVID-19 test result was confirmed. During this period, COVID-19 testing was conducted using a real-time PCR assay (Allplex™ 2019-nCoV Assay, Seegene, Seoul, Korea; or STANDARD M nCoV Real-Time Detection kit, SD biosensor, Suwon, Korea). All test results were recorded within 12 hours. Those who tested positive for COVID-19 were transferred to nationally designated COVID-19 hospitals or residential treatment centers.\n\nClinical endpoints\n\nThe primary endpoints were treatment outcomes under the countermeasures implemented during the COVID-19 pandemic. Treatment outcomes were evaluated as the result of the treatment response evaluation within the corresponding period for each group. If the treatment response evaluation was performed more than twice within the corresponding period for the group, it was summarized based on the best response. The treatment response evaluation for lymphoma and multiple myeloma was assessed according to the Lugano classification [15] and International Myeloma Working Group response criteria [16,17], respectively.\n\nThe secondary endpoints were the incidence and duration of neutropenia and neutropenic fever, delays in chemotherapy, mortality during chemotherapy, and the rate of positive COVID-19 results among the tested patients. To evaluate any adverse events, all events that occurred within the corresponding period in each group were counted. Neutropenia was defined as the absolute neutrophil counts (ANCs) < 1,000/μL after chemotherapy. Neutropenic fever and its duration was defined as the time period during which the following conditions were met: (1) development of fever after chemotherapy; (2) an ANC < 500/μL or an ANC < 1,000/μL with a predicted decline to ≤ 500/μL within the next 48 hours; and (3) a temperature of > 38.3°C once, or > 38.0°C sustained over a 1 hour period [18]. A delay in chemotherapy was defined as a delay of ≥ 3 days compared with the scheduled chemotherapy date.\n\nStatistical analyses\n\nMean values and standard deviations were reported for continuous variables, and percentages were reported for categorical values. Baseline characteristics were compared between the groups using the Mann–Whitney U test or chi-square test, according to the type of variable. Equivalence was concluded if the two-sided 90% confidence interval (CI) for the difference in clinical endpoints between the two groups was within the equivalence margin of ± 15% (two-one-sided t tests). In the existing equivalence comparison studies, the range of the equivalence margin was 10% to 20%, and a median value of 15% was determined in this study [19–22]. The median number of neutropenia or neutropenic fever episodes and their median durations were compared using the Mann–Whitney U test. IBM SPSS version 21.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. A p value < 0.05 was set as significant.\n\nRESULTS\n\nCOVID-19 pandemic status in South Korea during the study period\n\nBased on the national statistical data for 2019, the total area of South Korea is 100,401 km2, with a total population of 51,709,000 inhabitants. The total area of Seoul is 605 km2, accounting for only 0.6% of South Korea. However, 18.7% of the total population resides in Seoul, and the population density per km2 is 15,964 inhabitants, which is considerably higher than that in other regions and countries (Supplementary Fig. 1) [23–25]. As of January 1, 2021, the cumulative number of confirmed COVID-19 cases in South Korea was 61,769, of which 19,363 were reported in Seoul, accounting for 31.3% of the total number of confirmed cases (Supplementary Fig. 2) [26–28]. The number of newly reported COVID-19 cases and number of deaths from COVID-19 during the study period in Seoul are summarized in Supplementary Fig. 3 [26,27].\n\nPatient characteristics\n\nIn total, 202 patients with lymphoma and 174 patients with multiple myeloma were analyzed in this study (lymphoma, group 1 [n = 97], group 2 [n = 105]; multiple myeloma, group 1 [n = 91], group 2 [n = 83]). Baseline characteristics are summarized in Tables 2 and 3. There was no difference between the groups in the median number of inpatients and outpatients per month during each period (group 1, 158 patients [range, 156 to 161], group 2, 166.5 [range, 148 to171], p = 0.343; and group 1, 1,049 patients [range, 1,035 to 1,098], group 2, 1,176.5 patients [range, 1,045 to 1,324], p = 0.114, respectively).\n\nIn patients diagnosed with lymphoma, there was no difference between the two groups in terms of age, sex, lymphoma subtype, disease stage, extranodal involvement, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status score, International Prognostic Index score, and the proportion of patients receiving rituximab during chemotherapy. However, the rate of bone marrow involvement was higher in group 2 than in group 1 (group 1, 16/97 patients, 16.5%; group 2, 30/105 patients, 28.6%; p = 0.041).\n\nIn patients with multiple myeloma, the proportion of patients receiving pomalidomide during chemotherapy was higher in group 2 than in group 1 (group 1, 4/91 patients, 4.4%; group 2, 11/83 patients, 13.3%; p = 0.038). However, there was no difference between the two groups in terms of age, sex, type of multiple myeloma, International Stage System values, and the proportion of patients receiving bortezomib, carfilzomib, thalidomide, or lenalidomide during chemotherapy.\n\nTreatment outcomes and treatment-related adverse events\n\nAmong patients with lymphoma, 91 patients in group 1 (83.5%) and 91 patients in group 2 (86.7%) underwent response evaluation within the corresponding periods, and 54 patients in group 1 (55.7%) and 59 patients in group 2 (56.2%) achieved complete remission (Table 4). The 90% CIs for the estimate of the difference were within the equivalence margin (± 15%). In addition, the incidence of neutropenia (group 1, 62/97 patients, 63.9%; group 2, 68/105 patients, 64.8%), incidence of delays in chemotherapy (group 1, 8/97 patients, 8.2%; group 2, 8/105 patients, 7.6%), and number of deaths during chemotherapy (group 1, 9/97 patients, 9.3%; group 2, 4/105 patients, 3.8%) were similar between the two groups. Although the equivalence of the incidence of neutropenic fever was inconclusive, there was no difference between the two groups in the duration of neutropenia or neutropenic fever during chemotherapy (group 1, 2.4 [range, 1.0 to 23.0] vs. group 2, 2.4 [range, 1.0 to 45.0], p = 0.803; group 1, 4.0 [range, 1.0 to 15.0] vs. group 2, 4.3 [range, 2.0 to 11.0], p = 0.585, respectively). In group 1, the causes of delayed chemotherapy were as follows: infection (four cases: catheter-related bloodstream infection [CRBSI], intra-abdominal infection, candidemia, and neutropenic fever), cytopenia (two cases), and deterioration of the general condition (two cases). In group 2, the causes of delayed chemotherapy were as follows: infection (six cases: three cases of neutropenic fever, one case each of bacteremia, herpes zoster, and fungal arthritis), drug rash caused by chemotherapy (one case), and deterioration of the general condition (one case). In group 1, the causes of death were as follows: infection (five cases: two cases of neutropenic fever, two cases of pneumonia, and one case of bacteremia), bleeding at the cancer site (one case), tumor lysis syndrome (one case), and progression of lymphoma (two cases). In group 2, the cause of death was infection (four cases: two cases of pneumonia, and one case each of CRBSI and neutropenic fever).\n\nIn patients with multiple myeloma, 88 patients in group 1 (96.7%) and 82 patients in group 2 (98.8%) underwent response evaluation within the corresponding period, and 47 patients in group 1 (51.6%) and 43 patients in group 2 (42.9%) achieved complete remission or very good partial response (Table 5). The 90% CIs for the estimate of the difference were within the equivalence margin (± 15%). In addition, the incidence of neutropenia (group 1, 32/91 patients, 35.2%; group 2, 31/83 patients, 37.3%), incidence of neutropenic fever (group 1, 9/91 patients, 9.9%; group 2, 10/83 patients, 12.0%), incidence of delays in chemotherapy (group 1, 9/91 patients, 9.9%; group 2, 12/83 patients, 14.5%), and number of deaths during chemotherapy (group 1, 4/91 patients, 4.4%; group 2, 4/83 patients, 4.8%) were similar between the two groups. There were no differences between the two groups in the incidence and duration of neutropenia or neutropenic fever during chemotherapy (group 1, 1.3 [range, 1.0 to 29.0] vs. group 2, 1.3 [range, 1.0 to 22.0], p = 0.931; group 1, 2.0 [range, 1.0 to 3.0] vs. group 2, 2.8 [range, 1.0 to 5.5], p = 0.497, respectively). In group 1, the causes of delayed chemotherapy were as follows: infection (four cases: two cases of pneumonia, one case of urinary tract infection [UTI], and one case of infection of unknown origin) and deterioration of the general condition (five cases). In group 2, the causes of delayed chemotherapy were as follows: infection (five cases: three cases of pneumonia, one case of UTI, and one case of invasive aspergillosis) and deterioration of the general condition (four cases). In group 1, the causes of death were as follows: progression of multiple myeloma (two cases), intra-abdominal infection (one case), and underlying lung disease (one case). In group 2, the causes of death were progression of multiple myeloma (two cases) and infection (two cases: one case of UTI and one case of pneumonia).\n\nThere were no positive results for COVID-19 tests conducted according to the countermeasures implemented during the study period.\n\nDISCUSSION\n\nThe population density in Seoul, South Korea, was 15,964 per km2, and the cumulative number of confirmed cases and deaths related to COVID-19 were 19,363 and 182, respectively, as of January 1, 2021. Although the total number of confirmed COVID-19 cases was relatively small compared with those of other countries, this study was conducted in a situation where the risk of transmission of COVID-19 was expected to be high due to the high population density. In this study, no difference in treatment response, incidence and duration of neutropenia or neutropenic fever, delays in chemotherapy, and deaths during chemotherapy were observed between the control (group 1) and study groups (group 2) of patients with lymphoma or multiple myeloma who were hospitalized repeatedly and received outpatient treatment (Table 1 [26], Fig. 1). In addition, during the study period, none of the patients tested positive for COVID-19, and there were no deaths from COVID-19.\n\nDirect infection via expelled droplets and indirect infection via contact with virus-contaminated surfaces or objects are considered the main routes of transmission of SARS-CoV-2 [1,29]. Droplet transmission occurs when virus-laden droplets from an infected person are expelled during sneezing, coughing, or talking [30]. Exposure to an infected person at a distance of < 2 m for > 15 minutes increases the risk of droplet transmission, and in the case of symptomatic patients, droplet transmission can occur in a shorter time period [31]. In addition, expelled droplets can contaminate surrounding surfaces or objects. When these contaminated surfaces or objects are touched by another person who subsequently touches their eyes, nose, or mouth with their hands before washing them, SARS-CoV-2 infection can develop. The simplest ways to prevent droplet transmission of SARS-CoV-2 are to avoid visiting crowded places, to maintain social distancing, and to wear a mask covering the nose and mouth. In addition, to prevent indirect infection via contact with a virus-contaminated surface or object, it is recommended to refrain from touching your eyes, nose, or mouth with your hands and to wash your hands with soap under running water for at least 20 seconds [32].\n\nThe question remains, how should hospitals respond to situations such as the COVID-19 pandemic? For tertiary hospitals, guidance is needed to maintain the safety of patients already receiving treatment, along with appropriate responses to patients with COVID-19. In addition, countermeasures to minimize the depletion of the hospital workforce by ensuring safety are needed. Wearing a mask and washing hands are the most basic requirements for all patients, guardians, and hospital workers in hospitals. Based on data from the European Centers for Disease Control and Prevention, wearing a mask and handwashing resulted in significantly lower mortality and infection rates than did social distancing and handwashing [33]. Following countermeasures implemented in hospitals in Taiwan, establishing quarantine stations at the hospital entrance, screening for COVID-19-related risk factors and the presence of fever in all hospital visitors, and conducting training on wearing masks and handwashing may also be effective countermeasures to prevent hospital-acquired SARS-CoV-2 infection [34,35]. In this study, in addition to the standard countermeasures mentioned above, COVID-19 testing was performed in all patients requiring hospitalization and in their resident guardians, and hospitalization was only permitted once a negative result was obtained. Once admitted, leaving the premises was prohibited, and access to lounges or restaurants in the hospital was restricted. With the implementation of these countermeasures, there was no difference in treatment outcomes between patients with lymphoma or multiple myeloma who received chemotherapy before the COVID-19 pandemic and those who received chemotherapy during the COVID-19 pandemic. In addition, none of the patients tested positive for COVID-19, and there were no deaths from COVID-19 during the study period. To the best of our knowledge, there have been no studies on the treatment outcomes of patients with lymphoma or multiple myeloma who received chemotherapy in the social and medical context of the COVID-19 pandemic. This study may also be meaningful in that it presents countermeasures in an objective manner and offers learning that may be applied clinically should a similar situation occur post-COVID-19.\n\nThis study has some limitations. First, this was a retrospective study with a relatively small number of patients; thus, there were limitations intrinsic to the study design. Second, the analysis was performed using data from two tertiary hospitals. Additional studies from a wider variety of institutions and circumstances are needed to determine the appropriateness and effect of the countermeasures presented in this study. Third, the strategy presented in this study was limited in that COVID-19 testing was only routinely conducted in patients who required hospitalization and their resident guardians; however, outpatients, short-term visitors, and hospital workers were selectively tested according to their risk of exposure to COVID-19. In 50% to 80% of patients with COVID-19, there are no symptoms, and the transmission of COVID-19 can occur before symptoms develop [36–38], or even in the absence of symptoms [39–42]. If the population density, disease prevalence, or transmission rate is higher than that in this study, the countermeasures for asymptomatic patients should be modified. Finally, no positive COVID-19 results or deaths were reported among the enrolled patients with lymphoma or multiple myeloma in this study. This may be because the number of newly diagnosed patients with COVID-19 in Seoul was maintained at a level of < 500 per day, most likely due to the active COVID-19 quarantine measures implemented by the South Korean government. It may also be due to the countermeasures implemented by the hospital. However, conclusions on the effectiveness of the countermeasures that were implemented cannot be drawn from this study alone, and more studies in a variety of contexts are required to fully evaluate their efficacy and impact on treatment outcomes for patients with diseases other than COVID-19, particularly malignancies.\n\nIn conclusion, patients with lymphoma or multiple myeloma could receive chemotherapy during the COVID-19 pandemic without an adverse effect on treatment outcomes, and without infection-related adverse events, when appropriate countermeasures to COVID-19 were implemented. However, further studies are needed to determine the extent to which countermeasures can be applied, considering variations in population density, the prevalence and transmission rate of infectious diseases, and the characteristics of each institution. In addition, data on countermeasures to COVID-19 and the effects of these countermeasures should continue to be analyzed and shared to maintain optimal treatment outcomes for patients with existing diseases other than COVID-19 in the context of a shifting pandemic.\n\nKEY MESSAGE\n\n1. Patients with lymphoma or multiple myeloma could receive chemotherapy during the coronavirus disease 2019 (COVID-19) pandemic without an adverse effect on treatment outcomes, and without infection-related adverse events, when appropriate countermeasures to COVID-19 were implemented.\n\n2. Data on countermeasures to COVID-19 and the effects of these countermeasures should continue to be analyzed and shared to maintain optimal treatment outcomes for patients with existing diseases other than COVID-19 in the context of a shifting pandemic.\n\nAcknowledgments\n\nThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and Korea Infectious Diseases Clinical Trials Initiative, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HE21C0001).\n\nSupplementary Information\n\nFigure 1 Countermeasures to the coronavirus disease 2019 (COVID-19) pandemic and the results of this study.\n\nTable 1 Countermeasures to COVID-19 included in this study\n\nPatients and their guardians\tGeneral principles\n Patients and their guardians should wear a mask, indoors or outdoors (at home or in a hospital), and should not touch their eyes, nose, or mouth with unwashed hands. In addition, patients should practice hand hygiene by washing their hands thoroughly with soap under running water.\n Patients and their guardians should refrain from visiting crowded places and going outside and avoid contact with people who have fever or respiratory symptoms.\t\nHospital\tFor patients or visiting guardians\n All patients and visiting guardians are allowed to enter the hospital only after completing a questionnaire detailing any recent travel to foreign countries or areas where outbreaks of COVID-19 have occurred, as well as any COVID-19-related symptoms, and after confirming the absence of fever (temperature above 37.5°C).\n All patients newly admitted via emergency rooms, clinics, or other hospitals must be confirmed to be negative for COVID-19 1–7 days before their hospitalization.\n Resident guardians must also be confirmed to be negative for COVID-19 1–7 days before the patient’s hospitalization.\n Patients are prohibited from leaving the hospital during their hospitalization.\n Patients and their guardians should avoid unnecessary movement during hospitalization and should refrain from using lounges and restaurants in the hospital.\n Even if the COVID-19 test was negative before hospitalization, should patients or their guardians develop fever or respiratory symptoms during their hospitalization, the Department of Infectious Diseases should be consulted regarding the need for additional COVID-19 tests.\nFor hospital workers\n All hospital workers are required to follow quarantine regulations, such as wearing a mask and practicing hand hygiene at the hospital.\n When COVID-19-related symptoms occur, hospital workers must cease working and undergo prompt diagnostic testing.\n Unnecessary events or meetings inside and outside the institution are restricted, and if unavoidable, such events or meetings must be confirmed and approved by the department in charge of COVID-19 management. At least the following conditions must be met: (1) attendee list management; (2) sufficient space between seats to ensure physical distancing between all participants; (3) no meals in conference rooms; and (4) wearing of a mask while attending.\nFor those who test positive for COVID-19\n Those who test positive for COVID-19 are transferred to nationally designated COVID-19 hospitals or residential treatment centers.\t\nGovernment [26]a\tInfection prevention and control of foreign nationals\n Asymptomatic South Korean and foreign nationals on long-term visas are subject to self-quarantine of 14 days (Self-Quarantine Safety Protection App to be installed) and testing at a public health center within 3 days of arrival.\n Asymptomatic foreign nationals on short-term visas are subject to facility quarantine of 14 days (Self-Diagnosis App to be installed) and testing at a public health clinic within 14 days.\n If travelers exhibit fever or respiratory symptoms at entry screening, they are tested for COVID-19. South Korean or foreign nationals who test negative are placed under self-quarantine of 14 days (Self-Quarantine Safety Protection App to be installed) or are quarantined at a facility for 14 days (Self-Diagnosis App to be installed). Travelers who test positive for COVID-19 are transferred to nationally designated COVID-19 hospitals or residential treatment centers.\nPreventing the spread of the virus through epidemiological investigations and quarantine of contacts\n The central and local governments respond to COVID-19 cases by tracing the source of infection through prompt epidemiological investigations and quarantine of contacts.\n The contacts identified during the investigation are required to attend healthcare education, have their symptoms monitored, and remain in self-quarantine.\n Family members, housemates, and other contacts identified by epidemiological investigations on the patient’s travel and infection routes are subject to self-quarantine for the maximum incubation period (14 days) beginning from the day after the date of contact with a confirmed patient and should have their symptoms monitored.\n The Ministry of Interior and Safety and local governments thoroughly manage those under self-quarantine on a one-to-one basis.\t\na The contents have been summarized by extracting information provided on the official website of the Ministry of Health and Welfare of South Korea.\n\nTable 2 Baseline characteristics of patients with lymphoma\n\nBaseline characteristic\tGroup 1 (2019)\n(n = 97)\tGroup 2 (2020)\n(n = 105)\tp value\t\nAge, yr\t60 (13–90)\t65 (13–91)\t0.207\t\nSex ratio, male:female\t1.37\t1.39\t0.958\t\nNo. of hospitalizations\t4 (0–11)\t3 (0–10)\t0.355\t\nNewly diagnosed patients\t35 (36.1)\t26 (24.8)\t0.080\t\nChemotherapy line administered within the period\t\t\t0.231\t\n First line chemotherapy\t77 (79.4)\t68 (64.8)\t\t\n First and second line chemotherapy\t2 (2.1)\t4 (3.8)\t\t\n Second line chemotherapy\t10 (10.3)\t19 (18.1)\t\t\n Second and third line chemotherapy\t1 (1.0)\t3 (2.9)\t\t\n More than third line chemotherapy\t7 (7.2)\t11 (10.5)\t\t\nLymphoma subtype\t\t\t0.592\t\n Hodgkin lymphoma\t8 (8.2)\t8 (7.6)\t\t\n Diffuse large B-cell lymphoma\t49 (50.5)\t49 (46.7)\t\t\n Follicular lymphoma\t12 (17.1)\t18 (17.1)\t\t\n Marginal zone lymphoma\t5 (5.2)\t6 (5.7)\t\t\n Other B-cell lymphomas\t7 (7.2)\t13 (12·4)\t\t\n T-cell lymphoma\t16 (16.5)\t11 (10.5)\t\t\nDisease stage\t\t\t0.411\t\n Limited (stages I–II)\t30 (30.9)\t27 (25.7)\t\t\n Advanced (stages III–IV)\t67 (69.1)\t78 (74.3)\t\t\nExtranodal involvement\t57 (58.8)\t68 (64.8)\t0.380\t\nBone marrow involvement\t16 (16.5)\t30 (28.6)\t0.041\t\nLDH above the normal limit\t55 (56.7)\t63 (60.0)\t0.635\t\nECOG performance status score\t\t\t0.936\t\n 0–1\t95 (97.9)\t103 (98.1)\t\t\n 2–4\t2 (2.1)\t2 (1.9)\t\t\nIPI score\t\t\t0.276\t\n < 3\t60 (61.9)\t57 (54.3)\t\t\n ≥ 3\t37 (38.1)\t48 (45.7)\t\t\nChemotherapy including rituximab\t63 (64.9)\t72 (68.6)\t0.586\t\nCOVID-19 test, number\t-\t3 (0–7)\t-\t\nCOVID-19 test\t\n 0\t-\t13 (12.4)\t-\t\n 1–2\t-\t32 (30.5)\t-\t\n ≥ 3\t-\t60 (57.1)\t-\t\nValues are presented as median (range) or number (%).\n\nLDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; COVID-19, coronavirus disease 2019.\n\nTable 3 Baseline characteristics of patients with multiple myeloma\n\nBaseline characteristic\tGroup 1 (2019)\n(n = 91)\tGroup 2 (2020)\n(n = 83)\tp value\t\nAge, yr\t68 (42–89)\t69 (42–87)\t0.909\t\nSex ratio, male:female\t1.17\t1.31\t0.713\t\nNo. of hospitalizations\t3 (1–5)\t3 (1–5)\t0.197\t\nNewly diagnosed patients\t15 (16.5)\t9 (10.8)\t0.281\t\nChemotherapy line administered within the period\t\t\t0.369\t\n First line chemotherapy\t39 (42.9)\t35 (42.2)\t\t\n First and second line chemotherapy\t1 (1.1)\t3 (3.6)\t\t\n Second line chemotherapy\t26 (28.6)\t15 (18.1)\t\t\n Second and third line chemotherapy\t1 (1.1)\t1 (1.2)\t\t\n More than third line chemotherapy\t24 (26.4)\t29 (34.9)\t\t\nMonoclonal protein\t\t\t0.601\t\n IgG\t50 (54.9)\t46 (55.4)\t\t\n IgA\t21 (23.1)\t24 (28.9)\t\t\n IgM or IgD or IgE\t3 (3.3)\t1 (1.2)\t\t\n Light chain disease\t17 (18.7)\t12 (14.5)\t\t\nInternational Stage System\t\t\t0.065\t\n I\t26 (28.6)\t16 (19.3)\t\t\n II\t19 (20.9)\t30 (36.1)\t\t\n III\t46 (50.5)\t37 (44.6)\t\t\nChemotherapy including bortezomib\t34 (37.4)\t28 (33.7)\t0.618\t\nChemotherapy including carfilzomib\t25 (27.5)\t23 (27.7)\t0.972\t\nChemotherapy including thalidomide\t10 (11.0)\t8 (9.6)\t0.770\t\nChemotherapy including lenalidomide\t39 (42.9)\t40 (48.2)\t0.480\t\nChemotherapy including pomalidomide\t4 (4.4)\t11 (13.3)\t0.038\t\nCOVID-19 tests\t-\t3 (0–8)\t-\t\nCOVID-19 test\t\n 0\t-\t15 (18.1)\t-\t\n 1–2\t-\t16 (19.3)\t-\t\n ≥ 3\t-\t52 (62.7)\t-\t\nValues are presented as median (range) or number (%).\n\nIg, immunoglobulin; COVID-19, coronavirus disease 2019.\n\nTable 4 Treatment outcomes in patients with lymphoma\n\nTreatment outcome\tGroup 1 (2019)\n(n = 97)\t\tGroup 2 (2020)\n(n = 105)\t\nCR rate\t54 (55.7)\t\t59 (56.2)\t\n Difference estimate, %\t\t−0.5\t\t\n 90% CI, %\t\t−12.1 to 11.1\t\t\nIncidence of neutropenia\t62 (63.9)\t\t68 (64.8)\t\n Difference estimate, %\t\t0.8\t\t\n 90% CI, %\t\t−10.4 to 12.0\t\t\nIncidence of neutropenic fever\t27 (27.8)\t\t22 (21.0)\t\n Difference estimate, %\t\t−6.9\t\t\n 90% CI, %\t\t−16.9 to 3.2\t\t\nIncidence of delays in chemotherapy\t8 (8.2)\t\t8 (7.6)\t\n Difference estimate, %\t\t−0.6\t\t\n 90% CI, %\t\t−6.9 to 5.7\t\t\nDeaths within the study period\t9 (9.3)\t\t4 (3.8)\t\n Difference estimate, %\t\t−5.5\t\t\n 90% CI, %\t\t−11.3 to 0.3\t\t\nValues are presented as number (%).\n\nCR, complete remission; CI, confidence interval.\n\nTable 5 Treatment outcomes in patients with multiple myeloma\n\nTreatment outcome\tGroup 1 (2019)\n(n = 91)\t\tGroup 2 (2020)\n(n = 83)\t\nCR or VGPR rate\t47 (51.6)\t\t43 (42.9)\t\n Difference estimate, %\t\t−0.2\t\t\n 90% CI, %\t\t−12.8 to 12.5\t\t\nIncidence of neutropenia\t32 (35.2)\t\t31 (37.3)\t\n Difference estimate, %\t\t2.2\t\t\n 90% CI, %\t\t−9.9 to 14.3\t\t\nIncidence of neutropenic fever\t9 (9.9)\t\t10 (12.0)\t\n Difference estimate, %\t\t2.2\t\t\n 90% CI, %\t\t−5.7 to 10.0\t\t\nIncidence of delays in chemotherapy\t9 (9.9)\t\t12 (14.5)\t\n Difference estimate, %\t\t4.6\t\t\n 90% CI, %\t\t−3.6 to 12.8\t\t\nDeaths within the study period\t4 (4.4)\t\t4 (4.8)\t\n Difference estimate, %\t\t0.4\t\t\n 90% CI, %\t\t−4.9 to 5.7\t\t\nValues are presented as number (%).\n\nCR, complete remission; VGPR, very good partial response; CI, confidence interval.\n\nConflict of interest\n\nNo potential conflict of interest relevant to this article was reported.\n==== Refs\nREFERENCES\n\n1 Lotfi M Hamblin MR Rezaei N COVID-19: transmission, prevention, and potential therapeutic opportunities Clin Chim Acta 2020 508 254 266 32474009\n2 Shi Y Wang G Cai XP An overview of COVID-19 J Zhejiang Univ Sci B 2020 21 343 360 32425000\n3 Ahn DG Shin HJ Kim MH Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19) J Microbiol Biotechnol 2020 30 313 324 32238757\n4 Bakouny Z Hawley JE Choueiri TK COVID-19 and cancer: current challenges and perspectives Cancer Cell 2020 38 629 646 33049215\n5 Liang W Guan W Chen R Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol 2020 21 335 337 32066541\n6 Yang F Shi S Zhu J Shi J Dai K Chen X Clinical characteristics and outcomes of cancer patients with COVID-19 J Med Virol 2020 92 2067 2073 32369209\n7 Yu J Ouyang W Chua MLK Xie C SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China JAMA Oncol 2020 6 1108 1110 32211820\n8 Garassino MC Whisenant JG Huang LC COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study Lancet Oncol 2020 21 914 922 32539942\n9 Saini KS Tagliamento M Lambertini M Mortality in patients with cancer and coronavirus disease 2019: a systematic review and pooled analysis of 52 studies Eur J Cancer 2020 139 43 50 32971510\n10 Kuderer NM Choueiri TK Shah DP Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study Lancet 2020 395 1907 1918 32473681\n11 Westblade LF Brar G Pinheiro LC SARS-CoV-2 viral load predicts mortality in patients with and without cancer who are hospitalized with COVID-19 Cancer Cell 2020 38 661 671 32997958\n12 Williamson EJ Walker AJ Bhaskaran K Factors associated with COVID-19-related death using OpenSAFELY Nature 2020 584 430 436 32640463\n13 Vijenthira A Gong IY Fox TA Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients Blood 2020 136 2881 2892 33113551\n14 He W Chen L Chen L COVID-19 in persons with haematological cancers Leukemia 2020 34 1637 1645 32332856\n15 Cheson BD Fisher RI Barrington SF Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification J Clin Oncol 2014 32 3059 3068 25113753\n16 Kumar S Paiva B Anderson KC International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma Lancet Oncol 2016 17 e328 e346 27511158\n17 Durie BG Harousseau JL Miguel JS International uniform response criteria for multiple myeloma Leukemia 2006 20 1467 1473 16855634\n18 Baden LR Swaminathan S Angarone M Prevention and treatment of cancer-related infections, version 2.2016, NCCN Clinical Practice Guidelines in Oncology J Natl Compr Canc Netw 2016 14 882 913 27407129\n19 Tunes da Silva G Logan BR Klein JP Methods for equivalence and noninferiority testing Biol Blood Marrow Transplant 2009 15 1 Suppl 120 127 19147090\n20 Sharman JP Liberati AM Ishizawa K A randomized, double-blind, efficacy and safety study of PF-05280586 (a Rituximab Biosimilar) compared with rituximab reference product (MabThera) in subjects with previously untreated CD20-positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL) BioDrugs 2020 34 171 181 31820339\n21 Jurczak W Moreira I Kanakasetty GB Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study Lancet Haematol 2017 4 e350 e361 28712941\n22 Blackwell K Gligorov J Jacobs I Twelves C The global need for a trastuzumab biosimilar for patients with HER2-positive breast cancer Clin Breast Cancer 2018 18 95 113 29525430\n23 Statistical Geographic Information Service Thematic map [Internet] Daejeon (KR) SGIS 2021 [cited 2021 Sep 22]. Available from: https://sgis.kostat.go.kr/statexp/view/index\n24 Korean Statistical Information Service Population and population density by region [Internet] Daejeon (KR) KOSIS 2021 [cited 2021 Sep 22]. Available from: https://kosis.kr/index/index.do\n25 Statistics Korea Government Official Work Conference Population and population density by region [Internet] Daejeon (KR) Statistics Korea 2021 [cited 2021 Sep 22]. Available from: https://index.go.kr/main.do\n26 Korean Ministry of Health and Welfare COVID-19 response [Internet] Sejong (KR) MOHW 2021 [cited 2021 Sep 22]. Available from: http://ncov.mohw.go.kr\n27 Statistics Korea COVID-19 [Internet] Daejeon (KR) Statistics Korea 2021 [cited 2021 Sep 22]. Available from: https://kosis.kr/covid/covid_index.do\n28 Ministry of the Interior and Safety Census data [Internet] Sejong (KR) MOIS 2020 [cited 2021 Sep 22]. Available from: https://www.mois.go.kr\n29 Wiersinga WJ Rhodes A Cheng AC Peacock SJ Prescott HC Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review JAMA 2020 324 782 793 32648899\n30 Shiu EYC Leung NHL Cowling BJ Controversy around airborne versus droplet transmission of respiratory viruses: implication for infection prevention Curr Opin Infect Dis 2019 32 372 379 31259864\n31 Chu DK Akl EA Duda S Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis Lancet 2020 395 1973 1987 32497510\n32 Guner R Hasanoglu I Aktas F COVID-19: prevention and control measures in community Turk J Med Sci 2020 50 SI-1 571 577 32293835\n33 Hu LQ Wang J Huang A Wang D Wang J COVID-19 and improved prevention of hospital-acquired infection Br J Anaesth 2020 125 e318 e319 32534737\n34 Juang SF Chiang HC Tsai MJ Huang MK Integrated hospital quarantine system against COVID-19 Kaohsiung J Med Sci 2020 36 380 381 32282113\n35 Lee IK Wang CC Lin MC Kung CT Lan KC Lee CT Effective strategies to prevent coronavirus disease-2019 (COVID-19) outbreak in hospital J Hosp Infect 2020 105 102 103 32142886\n36 Mizumoto K Kagaya K Zarebski A Chowell G Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020 Euro Surveill 2020 25 2000180\n37 Sutton D Fuchs K D’Alton M Goffman D Universal screening for SARS-CoV-2 in women admitted for delivery N Engl J Med 2020 382 2163 2164 32283004\n38 Day M COVID-19: four fifths of cases are asymptomatic, China figures indicate BMJ 2020 369 m1375 32241884\n39 Bai Y Yao L Wei T Presumed asymptomatic carrier transmission of COVID-19 JAMA 2020 323 1406 1407 32083643\n40 Rothe C Schunk M Sothmann P Transmission of 2019-nCoV infection from an asymptomatic contact in Germany N Engl J Med 2020 382 970 971 32003551\n41 Tong ZD Tang A Li KF Potential presymptomatic transmission of SARS-CoV-2, Zhejiang Province, China, 2020 Emerg Infect Dis 2020 26 1052 1054 32091386\n42 Ye F Xu S Rong Z Delivery of infection from asymptomatic carriers of COVID-19 in a familial cluster Int J Infect Dis 2020 94 133 138 32247826\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1226-3303",
"issue": "36(6)",
"journal": "The Korean journal of internal medicine",
"keywords": "Coronavirus; Lymphoma; Multiple myeloma; Treatment outcome",
"medline_ta": "Korean J Intern Med",
"mesh_terms": "D000086382:COVID-19; D006801:Humans; D008223:Lymphoma; D009101:Multiple Myeloma; D058873:Pandemics; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "8712418",
"other_id": null,
"pages": "1459-1470",
"pmc": null,
"pmid": "34666434",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32369209;28712941;32971510;31259864;27407129;33049215;32539942;32497510;27511158;32003551;32183930;32293835;32648899;19147090;32473681;32238757;25113753;32211820;32083643;31820339;32247826;32640463;32534737;32425000;32091386;32241884;32066541;16855634;32474009;32283004;32997958;32282113;32142886;32332856;33113551;29525430",
"title": "The effect of the response to the coronavirus disease pandemic on treatment outcomes in patients with lymphoma and multiple myeloma.",
"title_normalized": "the effect of the response to the coronavirus disease pandemic on treatment outcomes in patients with lymphoma and multiple myeloma"
} | [
{
"companynumb": "KR-AMGEN-KORSP2021207670",
"fulfillexpeditecriteria": "2",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "4",
... |
{
"abstract": "New onset refractory status epilepticus (NORSE) was defined by the International League Against Epilepsy as occurring in patients presenting without a prior diagnosis of epilepsy or other neurological disease, with seizures that persist beyond 24 h. There is still a need to develop new treatment strategies for NORSE, particularly for those patients who are least responsive to conventional medical therapies. We present a case of a young female patient without any medical history presenting with status epilepticus, which was refractory not only to anti-seizure medications and anesthetics, but also to conventional immunomodulatory therapies. After nine weeks of electroclinical seizure activity, the patient responded to two doses of tocilizumab.",
"affiliations": "Departments of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.;Departments of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.;Departments of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.;Departments of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.;Departments of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.;Pharmacotherapy and Pharmacy Services, University Health System, San Antonio, TX, United States.;Pharmacotherapy and Pharmacy Services, University Health System, San Antonio, TX, United States.;Departments of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.",
"authors": "Donnelly|Jonathan P|JP|;Kasatwar|Nidhi|N|;Hafeez|Shaheryar|S|;Seifi|Ali|A|;Gilbert|Andrea|A|;Barthol|Colleen|C|;Small|Clay|C|;Ákos Szabó|C|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ebr.2021.100431",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864\nElsevier\n\nS2589-9864(21)00005-8\n10.1016/j.ebr.2021.100431\n100431\nCase Report\nResolution of cryptogenic new onset refractory status epilepticus with tocilizumab\nDonnelly Jonathan P. a\nKasatwar Nidhi a\nHafeez Shaheryar b\nSeifi Ali b\nGilbert Andrea c\nBarthol Colleen d\nSmall Clay d\nÁkos Szabó C. szabo@uthscsa.edu\nae⁎\na Departments of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States\nb Departments of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States\nc Departments of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States\nd Pharmacotherapy and Pharmacy Services, University Health System, San Antonio, TX, United States\ne South Texas Comprehensive Epilepsy Center, University of Texas Health Science Center and University Health System, San Antonio, TX, United States\n⁎ Corresponding author at: Department of Neurology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-7883, United States. szabo@uthscsa.edu\n04 2 2021\n2021\n04 2 2021\n15 10043118 8 2020\n23 10 2020\n27 10 2020\n© 2021 The Authors\n2021\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• New onset refractory status epilepticus (NORSE) is a recently defined clinical entity.\n\n• No proven effective therapy for NORSE currently exists.\n\n• Proposed mechanisms include autoimmunity or inflammatory cascade within the brain leading to propagation of seizures.\n\n• Agents targeting the cytokines involved in this cascade are being investigated as potential treatments.\n\n• Tocilizumab, an IL-6 inhibitor, successfully treated our patient after nine weeks of refractory seizure activity.\n\nNew onset refractory status epilepticus (NORSE) was defined by the International League Against Epilepsy as occurring in patients presenting without a prior diagnosis of epilepsy or other neurological disease, with seizures that persist beyond 24 h. There is still a need to develop new treatment strategies for NORSE, particularly for those patients who are least responsive to conventional medical therapies. We present a case of a young female patient without any medical history presenting with status epilepticus, which was refractory not only to anti-seizure medications and anesthetics, but also to conventional immunomodulatory therapies. After nine weeks of electroclinical seizure activity, the patient responded to two doses of tocilizumab.\n\nKeywords\n\nStatus epilepticus\nRefractory\nInterleukin-6\nTocilizumab\n==== Body\n1 Introduction\n\nStatus epilepticus (SE) is a condition that has recently undergone much clinical scrutiny, with ongoing debate about its definition and diagnostic criteria that include other clinical terms, such as refractory and “super-refractory” status. Most recently, the International League Against Epilepsy (ILAE) proposed SE to be a condition resulting from either initiation of mechanisms leading to prolonged seizure activity and/or failure of mechanisms that terminate seizure activity [1]. Duration of seizure activity is central to these criteria, with 5 minutes being the most widely accepted period at which an individual is diagnosed with convulsive SE, and 30 minutes proposed as the time for “refractory,” at which point the risk of permanent neuronal injury becomes significant [1].\n\nWhile SE is commonly associated with an established diagnosis of epilepsy, there is growing recognition of SE presenting without a prior seizure history and, in some cases, with refractory or super-refractory SE. New Onset Refractory Status Epilepticus (NORSE) is diagnosed in people with SE lacking a previous diagnosis of epilepsy, any concomitant neurological disorder or structural abnormality, or toxic/metabolic disturbance [2]. NORSE is a rare condition, mostly affecting children and young adults [3]. Boys are more commonly affected than girls, but there is a female predominance in adults. NORSE may be preceded by fever or mental status changes, but patients typically present to the hospitals with status epilepticus, most commonly associated with focal motor seizures that may evolve to bilateral convulsive seizures, less frequently in the form of a nonconvulsive status epilepticus [4]. From a treatment perspective, NORSE may respond to anti-seizure medications with or without anesthetics, but as most patients develop super-refractory status, immunomodulatory therapies are often required [3]. The etiology is often unknown, but about 50% of cases appear to be autoimmune or inflammatory in nature [3], [4]. This has led to trials of immunosuppressant therapies, such as pulse steroids, intravenous immunoglobulin (IVIG), or plasmapheresis (PLEX), as well as immunomodulating agents, including rituximab, cyclophosphamide, or anakinra, with variable results [3], [4]. We present a case of a patient with cryptogenic NORSE, who failed conventional immunosuppressant and immunomodulating therapies, but who finally responded to tocilizumab.\n\n2 Case history\n\nA twelve-week timeline of diagnostic testing and therapeutic interventions during three consecutive hospitalizations is presented in Fig. 1. A 26-year-old woman was admitted first admitted to an outside hospital following repetitive convulsive seizures. She received lorazepam 2 mg intravenously then 5 mg of intranasal midazolam. She continued to have convulsive seizures without recovery of responsiveness, and while being loaded on levetiracetam and lacosamide, she was intubated and sedated. All of her EEG studies at the first hospital were daily 30-minute studies; her first study after initiation of treatment demonstrated continuous slowing, with recurrence of facial twitching associated with runs of periodic discharges at 1–4 Hz frequency on the second day, bilateral independent left and right hemispheric discharges on the third day, and generalized periodic discharges on the fourth day. She was transferred to a second hospital, where she underwent continuous scalp EEG monitoring, demonstrating predominantly left hemispheric discharges associated with right facial twitching, which frequently evolved into bilateral convulsive seizures. Magnetic resonance imaging (MRI) of her brain was normal and cerebrospinal (CSF) studies, including autoimmune panels, were unremarkable. Malignancy screening with thoracic, abdominal and pelvic CT revealed an ovarian cyst, which, after an oophorectomy, was determined to be histologically benign. Despite trial of multiple anti-seizure medications, including (PHT), phenobarbital (PB), valproic acid (VPA), and clobazam (CLB), and anesthetics, such as propofol, midazolam, ketamine and pentobarbital, her continuous video-EEG monitoring continued to show multifocal, bihemispheric epileptiform discharges with intermittent seizure activity. The frequency and of her seizures, and whether or not the seizures were clinically evident, was not clear from the available records. Immunotherapy was also initiated, including steroids, IVIG, PLEX and a single dose of rituximab, all without reported benefit. After an unsuccessful trial of hypothermic coma, the patient underwent three trials of electroconvulsive therapy (ECT), the third trial complicated by a cardiopulmonary arrest. After being in SE for six weeks, she was transferred to our institution.Fig. 1 MRI Brain, With and Without Contrast: small scattered foci of gradient susceptibility on T2* sequence noted in the gray-white matter junction throughout the right cerebral hemisphere (A, B) and left posterior parietal lobe (B). These are not visualized on FLAIR (C) or T1 post-contrast (D).\n\nOn arrival, continuous EEG monitoring confirmed nonconvulsive SE, characterized 2–3 Hz generalized periodic discharges (Fig. 2A). Her anti-seizure medication regimen consisted of CLB, VPA, LEV, PHT, LCM, and topiramate (TPM). Her EEG background was intermittently suppressed with propofol, pentobarbital, and ketamine (Fig. 2B). She underwent a repeated CSF examination, which did not reveal infection or inflammation (nucleated white blood cell count 12/mcL, red blood cell count 9000/mcL and protein 97 mg/dL), as well as repeat whole body CT to identify a potential neoplasm. A brain MRI demonstrated multiregional punctate microhemorrhages in the subcortical white matter, more diffusely over the right than left hemispheres, consistent with an ICU cerebral angiopathy (Fig. 3). Subtraction analysis of ictal and interictal single photon emission computerized tomography (SPECT) scans demonstrated bihemispheric, multiregional activations, best defined in the right frontal and left medial motor cortices. Based upon the multiregional findings which overlapped in the right frontal lobe, and an intermittent predominance of right hemispheric seizures, a right frontal brain biopsy was performed to identify an underlying etiology. The brain biopsy showed microglial activation and a subtle microvasculopathy characterized by thickened small vessels; reactive CD3 + T-lymphocytes and hemosiderin deposition were also noted within the perivascular spaces, indicating compromise of the blood brain barrier (Fig. 4). Her anti-seizure medication regimen was changed to include perampanel (PER), felbamate (FBM), and oxcarbazepine (OXC). She underwent a second round of PLEX and rituximab. Her EEG continued to demonstrate multifocal bihemispheric ictal patterns and interictal epileptic discharges. Decreases in pentobarbital levels resulted in return of repetitive myoclonus of the right foot, left face and hand, as well as recurrence of independent left or right focal motor seizures. Ketogenic diet and Epidiolex (CBD) were also attempted, but there was concern that neither these treatments could be sustained due to transaminitis and hyperammonemia.Fig. 2 A, B. Biopsy of frontal lobe cortex and subcortical white matter showed a subtle microvasculopathy characterized by fibrinoid thickening of small vessel walls, which were negative for amyloid on Congo red and Beta-amyloid immunostain (not shown) (H&E, A: 200×, B:400×). C. CD68 highlights activated microglia as well as macrophages and hemosiderin deposition in the perivascular spaces indicative of compromise of the blood brain barrier (CD68, 200×). D. Lymphocytes were limited to the perivascular spaces of small vessels with neither extension into the brain parenchyma nor infiltrating vessel walls (CD45, 400×). (Arrowhead: hemosiderin in perivascular spaces; *: lumen of small vessels; white arrow: activated microglia; black arrow: lymphocytes in perivascular spaces).\n\nFig. 3 Brain MRI Findings. MRI Brain with and without contrast: small scattered foci of gradient susceptibility on T2* sequence noted in the gray-white matter junction throughout the right cerebral hemisphere (Panels A, B) and left posterior parietal lobe (Panel B). These are not visualized on FLAIR (C) or T1 post-contrast (D).\n\nFig. 4 Histopathological Findings on Brain Biopsy. A and B: Biopsy of frontal lobe cortex and subcortical white matter showed a subtle microvasculopathy characterized by fibrinoid thickening of small vessel walls, which were negative for amyloid on Congo red and Beta-amyloid immunostain (not shown) (H&E, A: 200×, B:400×). Panel C: CD68 highlights activated microglia as well as macrophages and hemosiderin deposition in the perivascular spaces indicative of compromise of the blood brain barrier (CD68, 200x). Panel D: Lymphocytes were limited to the perivascular spaces of small vessels without extension into the brain parenchyma or infiltration of vessel walls (CD45, 400×). (Arrowhead: hemosiderin in perivascular spaces; *: lumen of small vessels; white arrow: activated microglia; black arrow: lymphocytes in perivascular spaces).\n\nAfter almost nine weeks of treatment for super-refractory SE, a trial of tocilizumab was considered after a literature search [5]. Tocilizumab 300 mg was administered intravenously, and, within 48 hours, the periodic epileptiform discharges resolved. Her focal seizures became clinically more discrete, occurring only 2–4 times per hour, and while anesthetics were weaned, the patient became arousable, even interactive. Due to her rapid recovery, a second dose was not repeated a week later as previously suggested [5]. She was extubated and she improved clinically the following three weeks. At that time, she suddenly exhibited evidence of psychomotor regression with an EEG demonstrating increased and repetitive focal ictal discharges involving either hemisphere. She received a second infusion of 300 mg tocilizumab, leading to the resolution of electroclinical changes, again within 48 h. Due to critical illness myopathy, the patient was discharged to an inpatient rehabilitation facility. Two months after discharge, her neurological examination demonstrated recovery of her cognitive and motor functioning, but with persistent mild cognitive impairment, mainly with short-term memory deficits, lower extremity weakness, and mild ataxia.\n\n3 Discussion\n\nOur patient was treated for super-refractory NORSE for nine weeks in three hospitals. She finally responded to tocilizumab within 48 hours of its administration on two separate occasions. Her case not only confirms the role of immunomodulatory agents in the treatment of NORSE, despite absence of clinical evidence pointing toward an immune-mediated mechanism, but also that the responses of super-refractory NORSE to immunomodulatory agents are variable, with a persistent need to better understand potential clinical markers that may predict a more favorable response to any particular agent. This case study also highlights histopathologic findings of antemortem brain tissue, thereby providing a rare glimpse into possible histopathological mechanisms underlying NORSE (Fig. 4).\n\nIn people presenting with SE, NORSE is a diagnosis of exclusion. Our patient presented with refractory SE, associated with bihemispheric and multiregional ictal and interictal epileptic discharges. She underwent several brain MRI scans and whole-body CT examinations, metabolic screening, as well as repeated CSF examinations to identify infectious or auto-immune etiologies, all of which were negative. She was treated pulse steroids, one round of IVIG, followed by two rounds of plasmapheresis and rituximab, respectively. On the verge of considering a trial of cyclophosphamide, we learned about a case series demonstrating the success of tocilizumab in patients who had failed other immunomodulatory and chemotherapies [5], and, as it was likely to be better tolerated than cyclophosphamide, we decided to administer tocilizumab. Furthermore, a repeat CSF examination demonstrating elevation of CSF cytokines, specifically of IL-6, could have provided further support for trying tocilizumab [5].\n\nTocilizumab therapy for patients with status epilepticus has been limited to case series and case reports [5], [6], [7], [8]. One prospective cohort study of seven adult patients with NORSE secondary autoimmune encephalitis was treated with two doses of tocilizumab (4 mg/kg) at least one week apart. They demonstrated cessation of status epilepticus in six patients with a median interval of 3 days from in its initiation. Earlier treatment correlated with better functional outcomes [5]. However, two patients experienced severe adverse events related to infection. It is possible that a using a single dose of tocilizumab may be just as efficacious with less compromise of the immune system. In another case series, two pediatric patients with refractory status epilepticus responded to tocilizumab with favorable functional outcomes, including an improved level of consciousness and recovery of language and motor skills [8].\n\nTocilizumab is an interleukin-6 (IL-6) receptor antagonist which was initially approved for the treatment of rheumatoid arthritis [9]. Tocilizumab has been used in the treatment of cytokine releasing syndrome, giant cell arteritis and various autoimmune disorders, most recently in patients with central nervous system autoimmune disorders, such as autoimmune encephalitis [4], [6], [10]. The role IL-6 in perpetuating status epilepticus is under investigation, but recent studies demonstrated that frequent, repetitive seizures activate an inflammatory cascade associated with a rise in IL-6 levels, leading to disruption of the blood–brain barrier and further inflammation, thereby sustaining seizure activity [11], [12]. As elevation of IL-6 may be evident even in the absence of abnormal cell counts or protein levels in the CSF [4], [13], measurement of serum or CSF cytokines, including IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12, as well as granulocyte–macrophage colony stimulating and tumor necrosis factors, may be used to direct immunomodulatory therapies and to evaluate their efficacy [4].\n\nIn summary, tocilizumab is a potentially effective immunomodulatory therapy for NORSE, even in absence of inflammatory markers in CSF or on brain MRI. Elevation of cytokines in the serum and CSF, and of IL-6 in particular, may encourage earlier intervention with tocilizumab.\n\n4 Study Ethics and patient consent\n\nThis study was performed in accordance with “The Code of Ethics of the World Medical Association”.\n\nEthical Statement\n\nFinancial disclosures\n\nJonathan Paul Donnelly reports no disclosures.\n\nNidhi Kasatwar reports no disclosures.\n\nShaheryar Hafeez reports no disclosures.\n\nAli Seifi reports no disclosures.\n\nAndrea Giblert reports no disclosures.\n\nColleen Barthol reports no disclosures.\n\nClay Small reports no disclosures.\n\nCharles Akos Szabo reports no disclosures.\n\nAuthor contributions\n\nJPD and NK designed and conceptualized the report, drafted, and revised the manuscript. SH, AS and CAS supervised the report design and revised the manuscript for intellectual content. AG provided pathology images and reports and edited the manuscript. CB and CS contributed to the pharmacological aspects of the case, report design and edited the manuscript. All authors have viewed the manuscript and agree to submit.\n\nThe authors confirm there is no identifiable patient information within this manuscript.\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==== Refs\nReferences\n\n1 Trinka E. Cock H. Hesdorffer D. Rossetti A.O. Scheffer I.E. Shinnar S. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus Epilepsia 56 10 2015 1515 1523 26336950\n2 Hirsch L.J. Gaspard N. van Baalen A. Nabbout R. Demeret S. Loddenkemper T. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions Epilepsia 59 4 2018 739 744 29399791\n3 Sculier C. Gaspard N. New onset refractory status epilepticus (NORSE) Seizure 68 2018 72 78 30482654\n4 Khajawa A.M. DeWolfe J.L. Miller D.W. Szaflarski J.P. New-onset refractory status epilepticus (NORSE) – The potential role for immunotherapy Epilepsy Behav 47 2015 17 23 26010959\n5 Jun J.S. Lee S.T. Kim R. Chu K. Lee S.K. Tocilizumab treatment for new onset refractory status epilepticus Ann Neurol 84 2018 940 945 30408233\n6 Lee W.J. Lee S.T. Moon J. Sunwoo J. Byun J. Lim J. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study Neurotherapeutics 13 4 2016 824 832 27215218\n7 Mazarati A.M. Cytokines: a link between fever and seizures Epilepsy Curr 5 5 2005 169 170 16175214\n8 Cantarin-Extremera V. Jimenez-Legido M. Duat-Rodriguez A. Garcia-Fernandez M. Ortiz-Cabrera N.V. Ruiz-Falco-Rojas M.L. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: experience in two patients J Neuroimmunol 340 2020 577142\n9 Sebba A. Tocilizumab: the first interleukin-6 receptor inhibitor Ann J Health-Syst Pharm 65 15 2008 1413 1418\n10 Erta M. Quintana A. Hidalgo J. Interleukin-6, a major cytokine in the central nervous system Int J Biol Sci 8 9 2016 1254 1266\n11 Vezzani A. French J. Bartfai T. Baram T.Z. The role of inflammation in epilepsy Nat Rev Neurol 7 1 2011 31 40 21135885\n12 Li G. Bauer S. Nowak M. Norwood B. Tackenberg B. Rosenow F. Cytokines and epilepsy Seizure 20 3 2011 249 256 21216630\n13 Peltola J. Palmio J. Korhonen L. Suhonen J. Miettinen A. Hurme M. Interleukin-6 and Interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic–clonic seizures Epilepsy Res 41 3 2000 205 211 10962211\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-9864",
"issue": "15()",
"journal": "Epilepsy & behavior reports",
"keywords": "Interleukin-6; Refractory; Status epilepticus; Tocilizumab",
"medline_ta": "Epilepsy Behav Rep",
"mesh_terms": null,
"nlm_unique_id": "101750909",
"other_id": null,
"pages": "100431",
"pmc": null,
"pmid": "33748736",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31935626;27215218;30408233;21216630;26010959;26336950;21135885;16175214;10962211;29399791;18653811;30482654;23136554",
"title": "Resolution of cryptogenic new onset refractory status epilepticus with tocilizumab.",
"title_normalized": "resolution of cryptogenic new onset refractory status epilepticus with tocilizumab"
} | [
{
"companynumb": "US-MYLANLABS-2022M1008232",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "Bupropion use to obtain nonmedical psychoactive effects has been reported. The objective was to determine the prevalence, characteristics, clinical effects, and outcomes of bupropion \"abuse.\"\n\n\n\nA 14-year retrospective review was conducted of single substance bupropion cases with \"intentional abuse\" as the coded reason for exposure in individuals 13 and older reported to the National Poison Data System. Data were evaluated for prevalence, demographics, clinical effect, route, final management site, and coded outcome.\n\n\n\nThere were 975 bupropion abuse cases, which accounted for 3.3% of single substance bupropion cases reported to US poison centers. The prevalence of abuse increased by 75%, from 2000 to 2012, declining slightly in 2013. The majority of cases were 13 to 29 years old (67.4%). The most frequent clinical effects were tachycardia (57.0%), seizures (33.5%), agitation/irritable (20.2%), hallucinations/delusions (14.0%), and tremor (13.1%). Most exposures were ingestions (745) followed by insufflation (166), parenteral (17), and other/unknown (17); 30 cases involved 2 routes. Seizure frequency was not significantly different between routes (P = 0.783) or exposure chronicity (P = 0.264). Final management sites were predominantly emergency department (36.9%) and admission to critical care unit (27.3%) or noncritical care unit (20.1%). Outcomes were major (11.4%), moderate (48.2%), minor (24.5%), and no effect (15.5%). There were 4 deaths.\n\n\n\nMost bupropion abuse occurs in adolescents and young adults. Tachycardia and seizures are common indicating the potential for serious effects. Seizures occur regardless of route. Providers should be aware of risk of bupropion abuse.",
"affiliations": "Maryland Poison Center, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, MD.",
"authors": "Stassinos|Gina L|GL|;Klein-Schwartz|Wendy|W|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000249",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "10(5)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016642:Bupropion; D003422:Critical Care; D018765:Dopamine Uptake Inhibitors; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D012640:Seizures; D019966:Substance-Related Disorders; D013610:Tachycardia; D055815:Young Adult",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "357-62",
"pmc": null,
"pmid": "27504927",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bupropion \"Abuse\" Reported to US Poison Centers.",
"title_normalized": "bupropion abuse reported to us poison centers"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US17706",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nKidney transplant (KT) recipients have a higher incidence of malignancy than the general population. Smooth muscle tumors (SMT), including leiomyosarcoma, are rare in kidney transplant recipients, and most cases are associated with Epstein-Barr virus (EBV) infection.\n\n\nMETHODS\nA 57-year-old man received a deceased donor kidney transplant at the age of 53 years, with 5 human leukocyte antigen (HLA) mismatches. Before the transplantation, the patient was IgG positive for EBV viral capsid antigen (VCA), negative for IgM EBV VCA, and also negative for IgG EBV nuclear antigen (EBNA), suggesting a prior EBV infection. He received immunosuppressive induction with basiliximab, and maintenance with tacrolimus, mycophenolate mofetil, and prednisolone. Two years after transplantation, he had an acute cellular rejection episode treated with methylprednisolone. An increased graft size was found 4 years after transplantation. A computed tomographic scan showed 3 solid tumors involving the renal graft with extension to the perinephric fat; no secondary localizations were found. A nephrectomy of the graft was performed. The histologic diagnosis was a high-grade leiomyosarcoma. In situ hybridization for EBV was negative. Nine months after nephrectomy, local recurrence was diagnosed. The surgical approach was unsuccessful, and the patient died after a brief period.\n\n\nCONCLUSIONS\nKidney leiomyosarcoma is a very rare clinical condition. Most of these neoplasms that arise in transplanted recipients are associated with EBV in tumor tissue. Only one case of renal graft leiomyosarcoma without EBV RNA in the tumor has been previously reported.",
"affiliations": "Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal. Electronic address: ivolaranjinha@gmail.com.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.;Department of Pathology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.;Department of Pathology, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.;Department of Pathology, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.;Department of General Surgery, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.;Department of General Surgery, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.;Department of General Surgery, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.;Renal Transplantation Department, Hospital de Santa Cruz, Lisboa, Portugal.",
"authors": "Laranjinha|I|I|;Matias|P|P|;Jorge|C|C|;Birne|R|R|;Weigert|A|A|;Adragão|T|T|;Bruges|M|M|;Cabrera|R A|RA|;Cassis|J|J|;Ramos|S|S|;Nogueira|A|A|;Godinho|J|J|;Messias|H|H|;Machado|D|D|",
"chemical_list": "D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; C041788:Epstein-Barr viral capsid antigen; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2016.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "48(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D006084:Graft Rejection; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D007890:Leiomyosarcoma; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients; D019737:Transplants",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2379-2383",
"pmc": null,
"pmid": "27742302",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kidney Graft Leiomyosarcoma: A Case Report.",
"title_normalized": "kidney graft leiomyosarcoma a case report"
} | [
{
"companynumb": "PT-ASTELLAS-2016US042171",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database.\n\n\n\nWe performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database.\n\n\n\nIn total, 75 questions about \"anti-cancer drugs and pregnancy\" received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies.\n\n\n\nPregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs.",
"affiliations": "Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale, Hôpital Lapeyronie, Montpellier, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Centre de Pharmacovigilance, CHU de Lille, France.;Centre Oscar-Lambret, Centre Régional de lutte contre le cancer, Lille, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Centre de Pharmacovigilance, CHU de Tours, France.;Centre de Pharmacovigilance, CHU de Lyon, France.;Centre de Pharmacovigilance, CHU de Lyon, France.;Centre Régional de Pharmacovigilance, Hôpital Saint-Vincent de Paul, Paris, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Régional de Pharmacovigilance, CHU de Toulouse, Université de Toulouse, Toulouse, France.",
"authors": "Danet|Chloé|C|;Araujo|Mélanie|M|;Bos-Thompson|Marie-Andrée|MA|;Portolan|Ghyslaine|G|;Gautier|Sophie|S|;Vanlemmens|Laurence|L|;Bonenfant|Sophie|S|;Jonville-Béra|Annie-Pierre|AP|;Cottin|Judith|J|;Vial|Thierry|T|;Bavoux|Françoise|F|;Montastruc|Jean-Louis|JL|0000-0001-6341-6001;Damase-Michel|Christine|C|;Benevent|Justine|J|;Bourgeois-Mondon|Isabelle|I|;Lacroix|Isabelle|I|0000-0001-7344-7282",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4689",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "27(12)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "cancer; chemotherapy; malformation; neonatal pathology; pharmacoepidemiology; pregnancy",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000970:Antineoplastic Agents; D016208:Databases, Factual; D005260:Female; D005602:France; D006801:Humans; D007231:Infant, Newborn; D008875:Middle Aged; D009369:Neoplasms; D060735:Pharmacovigilance; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D055815:Young Adult",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1302-1308",
"pmc": null,
"pmid": "30379378",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy outcomes in women exposed to cancer chemotherapy.",
"title_normalized": "pregnancy outcomes in women exposed to cancer chemotherapy"
} | [
{
"companynumb": "FR-JNJFOC-20181231070",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAtrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity, especially stroke and heart failure. There is also increasing awareness that atrial fibrillation is a major cause of embolic events which in 75% of cases are complicated by cerebrovascular accidents.\nA 50-year-old woman with mitral bioprosthesis under warfarin for nonvalvular atrial fibrillation was referred to our Coronary Intensive Care Unit due to acute myocardial infarction without evidence of significant coronary artery stenosis.\nCardiovascular examination showed an irregular pulse and a grade II diastolic murmur was audible at the apical area. The patient underwent coronary angiography showing absence of obstructive coronary artery disease. We decided to replace Warfarin with direct oral anticoagulants as anticoagulant therapy.\n\n\nMETHODS\nTransoesophageal echocardiography revealed a thrombus in left atrial appendage that was treated by replacing warfarin with an oral direct thrombin inhibitor.\n\n\nRESULTS\nAt 2-month follow-up, the therapy showed to be effective for thrombus resolution.\n\n\nCONCLUSIONS\nOur case demonstrated how AF has high risk of thromboembolic complications, not only in terms of stroke but also of myocardial infarction and death.The use of direct oral anticoagulants in AF patients with bioprosthetic heart valves is still debated due to an unclear definition of \"nonvalvular\" AF.",
"affiliations": "IRCCS Bonino Pulejo of Messina, Cardiology Unit.;Department of Clinical and Experimental Medicine, University of Messina, Cardiology Unit, Azienda Ospedaliera Universitaria \"Policlinico G. Martino\", Messina.;IRCCS Bonino Pulejo of Messina, Cardiology Unit.;Clinical Research, BIOTRONIK Italia, Vimodrone (MI), Italy.;IRCCS Bonino Pulejo of Messina, Cardiology Unit.;IRCCS Bonino Pulejo of Messina, Cardiology Unit.;IRCCS Bonino Pulejo of Messina, Cardiology Unit.;IRCCS Bonino Pulejo of Messina, Cardiology Unit.",
"authors": "D'Angelo|Myriam|M|0000-0003-4862-3832;Manganaro|Roberta|R|;Boretti|Ilaria|I|;Giacopelli|Daniele|D|;Cannavà|Gaetano|G|;Corallo|Francesco|F|;Bramanti|Placido|P|;Duca|Antonio|A|",
"chemical_list": "D065427:Factor Xa Inhibitors; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026137",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34114997\nMD-D-21-01166\n10.1097/MD.0000000000026137\n26137\n3400\nResearch Article\nClinical Case Report\nIntracardiac thrombus in a patient with mitral bioprosthesis and atrial fibrillation treated with direct oral anticoaugulant\nA case report\nhttp://orcid.org/0000-0003-4862-3832\nD’Angelo Myriam MD a∗\nManganaro Roberta MD b\nBoretti Ilaria MD a\nGiacopelli Daniele MD c\nCannavà Gaetano MD a\nCorallo Francesco Psy a\nBramanti Placido a\nDuca Antonio MD a\nSaranathan. Maya\na IRCCS Bonino Pulejo of Messina, Cardiology Unit\nb Department of Clinical and Experimental Medicine, University of Messina, Cardiology Unit, Azienda Ospedaliera Universitaria “Policlinico G. Martino”, Messina\nc Clinical Research, BIOTRONIK Italia, Vimodrone (MI), Italy.\n∗ Correspondence: Myriam D’Angelo, IRCCS Bonino Pulejo of Messina, Cardiology Unit, Viale Europa n. 45, Messina 98124, Italy (e-mail: myriam.dangelo@irrcsme.it).\n11 6 2021\n11 6 2021\n100 23 e2613725 2 2021\n26 4 2021\n11 5 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nAtrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity, especially stroke and heart failure. There is also increasing awareness that atrial fibrillation is a major cause of embolic events which in 75% of cases are complicated by cerebrovascular accidents.\n\nPatient concerns:\n\nA 50-year-old woman with mitral bioprosthesis under warfarin for nonvalvular atrial fibrillation was referred to our Coronary Intensive Care Unit due to acute myocardial infarction without evidence of significant coronary artery stenosis.\n\nDiagnoses:\n\nCardiovascular examination showed an irregular pulse and a grade II diastolic murmur was audible at the apical area. The patient underwent coronary angiography showing absence of obstructive coronary artery disease. We decided to replace Warfarin with direct oral anticoagulants as anticoagulant therapy.\n\nInterventions:\n\nTransoesophageal echocardiography revealed a thrombus in left atrial appendage that was treated by replacing warfarin with an oral direct thrombin inhibitor.\n\nOutcomes:\n\nAt 2-month follow-up, the therapy showed to be effective for thrombus resolution.\n\nLessons:\n\nOur case demonstrated how AF has high risk of thromboembolic complications, not only in terms of stroke but also of myocardial infarction and death.\n\nThe use of direct oral anticoagulants in AF patients with bioprosthetic heart valves is still debated due to an unclear definition of “nonvalvular” AF.\n\nKeywords\n\nanticoagulant\natrial fibrillation\nmitral bioprosthetic\nthrombosis\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nAtrial fibrillation (AF) is the most common cardiac arrhythmia[1] and is associated with increased morbidity, especially stroke, and heart failure, as well as increased mortality.[2] Oral anticoagulation with vitamin K antagonists (VKAs) or with direct oral anticoagulants (DOACs) is indicated for AF patients. Different studies compared DOACs with warfarin for prevention of stroke and systemic embolism in patients with nonvalvular AF. DOACs appeared to be safe and effective as a valid alternative to VKAs in patients with nonvalvular AF.[3–6] Current European Guidelines recommend preferring the DOACs over VKAs for stroke prevention in most patients with nonvalvular AF.[7] In patients with bioprosthetic heart valves (BHVs) and AF only VKAs are indicated in the first 3 months postoperatively.[8] After this initial period, there is no general consensus on the alternative use of DOACs due to the lack of prospective controlled studies. We describe the use of DOACs in a young woman with mitral bioprosthesis, initially treated with VKAs (Warfarin) for AF, who developed acute myocardial infarction (AMI) secondary to embolization from left atrial appendage thrombus.\n\n2 Case report\n\nWe report a case of a 50-year-old Caucasian woman presented with chest pain lasting several hours, associated with profuse sweating. She was admitted to our Coronary Intensive Care Unit with the diagnosis of acute AMI without ST-segment elevation.\n\nShe had a history of hypertension, dyslipidemia and diabetes mellitus. In 1988 the patient underwent valvuloplasty for a rheumatic mitral stenosis, while in 2011 the mitral valve was replaced with a biological prosthesis (25 mm Carpentier Edwards). Two months later, after an unsuccessful electrical cardioversion of AF, she had a vertebrobasilar stroke causing rigid-spastic tetraparesis and motor aphasia. From that episode, a strategy of rate control was chosen and anticoagulant therapy with VKAs (Warfarin) was started.\n\nOn admission to our department, physical examination revealed a body temperature of 36.5°C, oxygen saturation of 98% in ambient air, a heart rate of 80 beats/min, a blood pressure of 140/70 mm Hg. Cardiovascular examination showed an irregular pulse and a grade II diastolic murmur was audible at the apical area. Laboratory findings included a white blood cell count of 7300/L (normal range 4000–10,000/L), anemia (Hb 8.5 g/dL), troponin I 13.4 ng/mL, pro-Brain Natriuretic Peptide (NT-pro) 4232 pg/mL, international normalized ratio 2.12. Her CHA2DS2-VASc score was 6 and her HASBLED score was 4. The electrocardiogram confirmed AF, lateral T wave inversion and QT interval prolongation (QTc 0,50 seconds) as shown in Figure 1.\n\nFigure 1 On admission the electrocardiogram showed atrial fibrillation, lateral T wave inversion, and QT interval prolongation.\n\nTransthoracic echocardiography revealed a severe left ventricle (LV) systolic dysfunction with an ejection fraction of 30%, severe intra-atrial and intraventricular spontaneous echo-contrast effect and slightly increased transprothesic gradients (mean gradient 7 mm Hg at a heart rate of 85–90 beats/min). The patient underwent coronary angiography showing absence of obstructive coronary artery disease. In order to investigate a possible cardioembolic genesis of the AMI and to better evaluate mitral bioprosthesis function, a transesophageal echocardiography was performed. The left atrial appendage (LAA) was almost entirely occupied by thrombotic material, while mitral bioprosthesis was normal in functioning and morphology, as shown in Figure 2.\n\nFigure 2 Three-dimensional transesophageal echocardiography showing a left atrial appendage almost entirely occupied by thrombotic material.\n\nWe decided to replace Warfarin with DOACs (Dabigatran 150 mg twice daily) as anticoagulant therapy. In addition, during the hospitalization the patient developed third degree atrio-ventricular block that led to a dual-chamber implantable cardioverter defibrillator implant, for the concomitant presence of severe LV systolic dysfunction.\n\nAt 2 months follow up, we repeated the transesophageal echocardiography that showed resolution of all thrombotic material in the LAA with a mild spontaneous echocontrast effect and persistency of severe LV systolic dysfunction.\n\n3 Discussion\n\nTraditionally, VKAs, especially warfarin, have been the cornerstone for stroke prevention in all patients with AF. However, they have a narrow window of therapeutic benefit, a marked variation in their effect in several patients and a need to monitor their action on long-term coagulation. The DOACs overcame these limits and are now recommended in patients with nonvalvular AF. The use of DOAC in patients with AF and bioprostheses beyond 3-month postsurgery, however, is still debated.\n\nOur case demonstrated how AF has high risk of thromboembolic complications, not only in terms of stroke but also of AMI and death. The fear of hemorrhagic complications related to the use of anticoagulant therapy has been and continues to be an obstacle to the correct prescription of this therapy. The main consequence is the underutilization of the therapy with a consequent reduction protection of thromboembolic risk. In addition, an incorrect interpretation of the trials, combined with the exaggerated perception of hemorrhagic risk during treatment with DOAC, has led to the excessive (incorrect and dangerous) use of low doses of the drug. Our patient experienced a thromboembolic event under warfarin. Switching to DOAC showed resolution of thrombus in the LAA.\n\nAlthough BHVs are less thrombogenic than mechanical heart valves, patients with bioprosthesis and additional risk factors for embolism, such as AF, require life-long therapy with oral anticoagulation. Recently a study suggested that the risk of thromboembolic events in AF patients with bioprosthesis was similar to that of patients with nonvalvular AF without bioprosthesis. Old age and CHA2DS2-VASc score were independent predictors of stroke/systemic thromboembolic events (SEE) and oral anticoagulation was associated with a lower thromboembolic risk. These findings support the concept that patients with AF and BHVs can be assimilated, and therefore treated similarly, to those without significant valvular disease.[9]\n\nThe use of DOACs in AF patients with BHVs is still debated due to an unclear definition of “nonvalvular” AF. Recently, different new classifications have been proposed. Some authors proposed the term “MARM-AF” to define “Mechanical And Rheumatic Mitral valvular AF.”[10] The functional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) classification relies on the type of oral anticoagulation in patients with AF. The EHRA type 1 includes valvular heart disease that need therapy with only VKAs (moderate-severe mitral stenosis usually of rheumatic origin and mechanical prosthetic valve) while the EHRA type 2 identifies all the other valvular heart diseases in which both VKAs and DOAC can be used (mitral regurgitation, mitral valve repair, aortic stenosis, aortic regurgitation, tricuspid regurgitation, tricuspid stenosis, pulmonary regurgitation, bioprosthetic valve replacements and transaortic valve intervention).[11]\n\nAccording to the European Society of Cardiology Guidelines on AF, patients with AF and BHV or surgical valve repair are eligible to receive DOACs after 3 to 6 months from surgery.[8]\n\nThe 2018 European Heart Rhythm Association practical guide on the use of DOACs in patients with AF consider DOACs as a valid option in patients with BHVs and AF, except in case of bioprothesis implanted for rheumatic mitral stenosis.[12] In the latter case, in fact, patients usually have atria that remain large and severely diseased, so that VKA may be the preferred option over DOACs. Among the main studies about DOACs, only ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) and ENGAGE AF (effective anticoagulation with factor Xa next generation in atrial fibrillation) included patients with bioprosthesis or valve repair and AF. In a recent post hoc subgroup analysis they showed that there were no statistically significant interactions (odds) between patients treated with DOACs and those treated with warfarin in terms of stroke, major bleeding or all-cause mortality.\n\nIn particular, among 21,105 patients enrolled in the ENGAGE AF (effective anticoagulation with factor Xa next generation in atrial fibrillation), 191 had a previous bioprosthesis valve implantation. There were not significant differences between higher and lower dose of edoxaban vs warfarin in the rate of either stroke or SEE, while both doses of edoxaban were superior to Warfarin in primary net clinical outcome that included stroke/SEE, major bleeding and death.[13]\n\nSimilar results came from a post hoc analysis of the ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) that included 104 patients with a bioprosthetic valve (55 were randomized to apixaban and 49 to warfarin). It showed not significant differences between the 2 anticoagulants both in terms of efficacy and safety.[14]\n\nThe study DAWA (dabigatran vs warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively) randomized 27 patients: 15 patients received Dabigatran 110 mg twice daily and 12 patients warfarin at least 3 months after bioprosthesis replacement and with AF. The primary endpoint was the evidence of new intracardiac thrombus at 90 days while the secondary endpoint was incidence of myocardium infarction, stroke, valve thrombosis, or dense spontaneous echo contrast. The study was terminated early because of low enrolment rate but did not find significant differences between the 2 groups.[15]\n\nA recent retrospective study, conducted on 464 patients with nonvalvular AF and history of bioprosthetic heart valve replacement who received treatment with a DOAC (n = 211) or VKA (n = 253), showed that the use of DOACs was associated with improved net clinical benefit, thanks to a lower incidence of major bleeding and thromboembolic events compared with VKAs.[16]\n\nAlthough larger studies are needed to confirm safety and effectiveness of DOACs in patients with bioprosthesis and AF, their use in these patients is promising as shown in this case report.\n\nAuthor contributions\n\nConceptualization: Antonio Duca.\n\nInvestigation: Myriam D’Angelo.\n\nMethodology: Roberta Manganaro, Francesco Corallo.\n\nSupervision: Gaetano Cannava, Placido Bramanti.\n\nWriting – review & editing: Ilaria Boretti, Daniele Giacopelli.\n\nAbbreviations: AF = atrial fibrillation, AMI = myocardial infarction, BHVs = bioprosthetic heart valves, DOACs = direct oral anticoagulants, LV = left ventricle, VKAs = vitamin K antagonists.\n\nHow to cite this article: D’Angelo M, Manganaro R, Boretti I, Giacopelli D, Cannavà G, Corallo F, Bramanti P, Duca A. Intracardiac thrombus in a patient with mitral bioprosthesis and atrial fibrillation treated with direct oral anticoaugulant: a case report. Medicine. 2021;100:23(e26137).\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors have no funding and conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Fuster V Ryden LE Cannom DS . Acc/aha/esc 2006 guidelines for the management of patients with atrial fibrillation: a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European heart rhythm association and the heart rhythm society. Circulation 2006;114 :e257–354.16908781\n[2] Benjamin EJ Wolf PA D’Agostino RB . Impact of atrial fibrillation on the risk of death: the framingham heart study. Circulation 1998;98 :946–52.9737513\n[3] Ezekowitz MD Nagarakanti R Noack H . Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY (randomized evaluation of long-term anticoagulant therapy). Circulation 2016;134 :589–98.27496855\n[4] Breithardt G Baumgartner H Berkowitz SD . Clinical characteristics and outcomes with rivaroxaban vs warfarin in patients with nonvalvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J 2014;35 :3377–85.25148838\n[5] Avezum A Lopes RD Schulte PJ . Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial. Circulation 2015;132 :624–32.26106009\n[6] De Caterina R Renda G Carnicelli A . Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2017;69 :1372–82.28302288\n[7] Kirchhof P Benussi S Kotecha D . 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the task force for the management of atrial fibrillation of the European society of cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO). Eur Heart J 2016;37 :2893–962.27567408\n[8] Hein H Peter V Marco A . Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17 :1467–507.26324838\n[9] Raphael P Anne B-B Nicolas C . Oral anticoagulation, stroke and thromboembolism in patients with atrial fibrillation and valve bioprosthesis. Stroke and thromboembolism in patients with AF and biological valve prosthesis. J Am Coll Cardiol 2016;67 :343–4.26796401\n[10] De Caterina R John Camm A . Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial. Europace 2016;18 :06–11.\n[11] Lip GYH Collet JP de Caterina R Fauchier L Lane DA . ESC Antithrombotic therapy in atrial fibrillation associated with valvular heart disease EHRA CONSENSUS DOCUMENT. Europace 2017;19 :1757–8.29096024\n[12] Jan S Peter V Tatjana SP . The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39 :1330–93.29562325\n[13] Carnicelli AP De Caterina R Halperin JL . ENGAGE AF-TIMI 48 Investigators. Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves. Circulation 2017;135 :1273–5.28209729\n[14] Guimaraes PO Pokorney SD Lopes RD . Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: insights from the ARISTOTLE trial. Clin Cardiol 2019;42 :e568-e571.\n[15] Duraes AR de Souza Roriz P de Almeida Nunes B . Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: DAWA pilot study. Drugs R D 2016;16 :149–54.26892845\n[16] Russo V Carbone A Attena E . Clinical benefit of direct oral anticoagulants vs vitamin K antagonists in patients with atrial fibrillation and bioprosthetic heart valves. Clin Ther 2019;41 :2549–57.31735436\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(23)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D020517:Atrial Appendage; D001281:Atrial Fibrillation; D001705:Bioprosthesis; D057915:Drug Substitution; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D005260:Female; D006350:Heart Valve Prosthesis; D006801:Humans; D008875:Middle Aged; D008943:Mitral Valve; D013927:Thrombosis; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e26137",
"pmc": null,
"pmid": "34114997",
"pubdate": "2021-06-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intracardiac thrombus in a patient with mitral bioprosthesis and atrial fibrillation treated with direct oral anticoaugulant: A case report.",
"title_normalized": "intracardiac thrombus in a patient with mitral bioprosthesis and atrial fibrillation treated with direct oral anticoaugulant a case report"
} | [
{
"companynumb": "IT-IPCA LABORATORIES LIMITED-IPC-2021-IT-001334",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"d... |
{
"abstract": "BACKGROUND\nAnaphylactic shock during pregnancy is a rare but life-threatening event for both the mother and the newborn.\n\n\nMETHODS\nA 42-year-old woman, who was pregnant with twins, was scheduled for cesarean delivery under combined spinal and epidural anesthesia. An epidural catheter was placed uneventfully. After spinal anesthesia, the patient exhibited skin symptoms and severe hypotension. The patient was diagnosed with anaphylaxis, and subsequently, treatment was started. Fetal heart rate monitoring revealed sustained bradycardia, and it was decided to proceed with cesarean delivery. After delivery, the mother's vital signs recovered. Both infants were intubated due to birth asphyxia. Currently, the twins are 4 years old and exhibit no developmental problems. Clinical examination identified mepivacaine as the causative agent of anaphylaxis.\n\n\nCONCLUSIONS\nThis case report highlights that upon occurrence of anaphylaxis during pregnancy, maternal treatment and fetal assessment should be started immediately. Indication for immediate cesarean delivery should be considered and a definite identification of the causative factor pursued.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. r0908mk@jichi.ac.jp.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.;Department of Anesthesiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasak-shii, Kanagawa, 216-8511, Japan.;Intensive Care Unit, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi-shi, Gunma, 371-8511, Japan.;Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi-shi, Gunma, 371-8511, Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.",
"authors": "Takahashi|Miyuki|M|;Hotta|Kunihisa|K|;Inoue|Soichiro|S|;Takazawa|Tomonori|T|;Horiuchi|Tatsuo|T|;Igarashi|Takashi|T|;Takeuchi|Mamoru|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-019-0302-6",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 30210.1186/s40981-019-0302-6Case ReportMepivacaine-induced anaphylactic shock in a pregnant woman undergoing combined spinal and epidural anesthesia for cesarean delivery: a case report Takahashi Miyuki r0908mk@jichi.ac.jp 1Hotta Kunihisa 1Inoue Soichiro 2Takazawa Tomonori 3Horiuchi Tatsuo 4Igarashi Takashi 1Takeuchi Mamoru 11 0000000123090000grid.410804.9Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498 Japan 2 0000 0004 0372 3116grid.412764.2Department of Anesthesiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasak-shii, Kanagawa 216-8511 Japan 3 0000 0004 0595 7039grid.411887.3Intensive Care Unit, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi-shi, Gunma 371-8511 Japan 4 0000 0000 9269 4097grid.256642.1Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi-shi, Gunma 371-8511 Japan 19 12 2019 19 12 2019 12 2019 5 848 10 2019 28 11 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nAnaphylactic shock during pregnancy is a rare but life-threatening event for both the mother and the newborn.\n\nCase presentation\nA 42-year-old woman, who was pregnant with twins, was scheduled for cesarean delivery under combined spinal and epidural anesthesia. An epidural catheter was placed uneventfully. After spinal anesthesia, the patient exhibited skin symptoms and severe hypotension. The patient was diagnosed with anaphylaxis, and subsequently, treatment was started. Fetal heart rate monitoring revealed sustained bradycardia, and it was decided to proceed with cesarean delivery. After delivery, the mother’s vital signs recovered. Both infants were intubated due to birth asphyxia. Currently, the twins are 4 years old and exhibit no developmental problems. Clinical examination identified mepivacaine as the causative agent of anaphylaxis.\n\nConclusions\nThis case report highlights that upon occurrence of anaphylaxis during pregnancy, maternal treatment and fetal assessment should be started immediately. Indication for immediate cesarean delivery should be considered and a definite identification of the causative factor pursued.\n\nKeywords\nAnaphylaxisPregnancyCesarean deliverySpinal anesthesiaLocal anestheticMepivacaineBasophil activation testissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAnaphylactic shock during pregnancy is a rare but life-threatening event for both the mother and the newborn. The estimated incidence is 1.6 to 3.8 cases per 100,000 maternities, which is much lower than that in other populations [1–3]. Since numerous drugs are contraindicated for pregnant women, the fewer opportunities for drug use may contribute to the low incidence of anaphylaxis during pregnancy. Antibiotics have been reported as the main causative agent of anaphylaxis during pregnancy, whereas local anesthetics have rarely been reported [1, 2].\n\nManaging anaphylactic shock during pregnancy is challenging, since the fetus’ condition and how it is affected by treatment must be considered. Upon occurrence of anaphylaxis during late pregnancy, the optimal timing for delivery and anesthetic management remain controversial. Emergency cesarean delivery may benefit the newborn but poses a risk for the mother, whose condition may be unstable [4]. Each patient’s clinical treatment strategy should therefore be determined based on anaphylaxis severity, maternal condition, and fetal status.\n\nHere, we report a case of anaphylaxis in a pregnant woman undergoing combined spinal and epidural anesthesia for cesarean delivery. Clinical examination identified mepivacaine as the causative agent.\n\nCase presentation\nA 42-year-old woman, who was pregnant with twins, was scheduled for cesarean section at 37 weeks of gestation under combined spinal and epidural anesthesia. The woman had atopic dermatitis but no past history of drug allergy. After arrival at the operating room, intravenous administration of hydroxyethylated starch was started. Combined spinal and epidural anesthesia was administered in the right lateral position, at the L3–L4 and the Th12–L1 interspaces, respectively. After local infiltration of 6 mL of preservative-free 1% mepivacaine, the epidural space was identified by loss of resistance to saline, and an epidural catheter was placed. An aspiration test was confirmed as negative, and a test dose of 1% mepivacaine (3 ml) was administered via the catheter. During spinal anesthesia, maternal blood pressure became unmeasurable with a noninvasive blood pressure monitor. Lumbar puncture was successfully performed, and 10 mg of 0.5% hyperbaric bupivacaine and 20 μg of fentanyl were intrathecally administered. After returning the patient to the supine position, her face was swollen, and she exhibited erythema all over the body. Maternal blood pressure and heart rate were 74/56 mmHg and 112 beats/min, respectively. The mother was diagnosed with anaphylaxis and immediately received infusion of Ringer’s solution with left uterine displacement. Intravenous phenylephrine was intermittently administered. Despite hemodynamic instability, the mother’s breathing remained stable at 98% of oxygen saturation on room air, and oxygen was administered via a face mask. Fetal heart rate monitoring revealed sustained fetal bradycardia of 80 beats/min. Maternal systolic blood pressure remained around 80–90 mmHg under repeated administration of phenylephrine and transfusion. Fetal bradycardia was not recovered. After confirming the sensory block level of Th4, it was decided to proceed with cesarean delivery. The infants were delivered 17 and 18 min after anaphylaxis onset, both without spontaneous respiration, and were intubated and transferred to the neonatal intensive care unit. At 1 and 5 min, the apgar scores were 2 and 4 for the first infant and 2 and 5 for the second infant, respectively. Analysis of the umbilical artery blood revealed a pH of 6.842 for the first infant and 6.775 for the second infant. After delivery, the mother’s vital signs were recovered and remained stable. A two-phase allergic reaction was prevented through administration of 500 mg of methylprednisolone. After surgery, the mother was continuously monitored in the maternity ward, and her clinical course remained uneventful, being discharged 6 days after surgery. The first infant was extubated 2 days after birth and discharged 13 days after birth, whereas the second infant required further examination and treatment after having seizures. He was discharged with an oral anticonvulsant 16 days after birth, after which he remained seizure-free. The anticonvulsant was discontinued at 6 months of age. Currently, the twins are 4 years old and exhibit no developmental problems.\n\nWe suggested the patient to be examined to determine the causative agent of anaphylaxis. The patient agreed to be subjected to the basophil activation test (BAT), but not the skin test. The BAT was performed 9 months after the operation for mepivacaine and hydroxyethylated starch, providing a positive result to mepivacaine (Fig 1). The patient was then suggested once more to undergo the skin test to confirm the accuracy of the BAT results and to investigate cross-reactivity with other local anesthetics. The skin prick test was performed 10 months after the operation, for latex, hydroxyethylated starch, procaine, lidocaine, bupivacaine, and mepivacaine, providing a positive reaction to both lidocaine and mepivacaine (Fig 2).\nFig. 1 Basophil activation test. Flow cytometric analysis of basophils expressing CD203c. a The patient’s mepivacaine-induced CD203c upregulation. b Hydroxyethylated starch did not induce CD203c upregulation\n\n\nFig. 2 Skin prick test. NS saline, La latex, H hydroxyethylated starch, P procaine, L lidocaine, B bupivacaine, M mepivacaine. Positive reaction to lidocaine and mepivacaine\n\n\n\nDiscussion\nThe present case describes anaphylaxis in a pregnant woman who underwent combined spinal and epidural anesthesia for cesarean delivery. The immediate diagnosis, treatment, and cesarean delivery may have led to the good outcomes achieved for both the mother and the newborns.\n\nWhen treating anaphylaxis during late pregnancy, besides comprehensive treatment, care should be taken to evaluate the fetal condition and to decide the best delivery timing. Primary management of anaphylaxis includes immediate withdrawal of antigen administration, seeking help, airway maintenance, aggressive fluid resuscitation, and adrenaline administration. Examining serum tryptase and histamine levels is useful for diagnosing anaphylaxis. Additionally, obstetric management may involve left uterine displacement and fetal monitoring. Maternal hypotension immediately affects the placental circulation and fetal status. However, the American College of Obstetricians and Gynecologists indicates that, during anaphylaxis, a stable maternal hemodynamic status does not ensure adequate placental perfusion and fetal oxygenation, whereas normal fetal heart rate variability reassures fetal status [5]. Previous studies recommend that emergency cesarean delivery should be considered in cases of persistent maternal hemodynamic instability, despite resuscitation [4, 6]. In the present case, monitoring fetal heart rate was the key for the decision to perform a cesarean delivery. Although the good outcomes were achieved, fetal bradycardia was not recovered by phenylephrine. Administration of adrenaline for anaphylaxis may have increased cardiac output and systemic vascular resistance, resulting in improved uteroplacental perfusion [7].\n\nAmong previous case reports of anaphylactic labor, 46% resulted in adverse fetal neurologic outcomes [8–13]. In such cases, the anaphylactic parturients either had a delayed cesarean delivery [8, 9, 13] or did not receive sufficient adrenaline to manage severe hypotension [11]. The fetal neurologic outcome was much better in cases of anaphylaxis occurring during cesarean delivery, which can be attributed to a short duration of fetal cerebral ischemia [4]. The benefits of emergency cesarean delivery for anaphylactic patients refractory to medical treatment need to be balanced against the risks of surgery in pregnant women with an unstable general condition. If the time of gestation is less than 32 weeks, the risks of neonatal morbidity and mortality should also be considered. Anaphylaxis-related cardiovascular disturbance can be enhanced in pregnant patients by inferior vena cava compression. Moreover, neuraxial anesthesia blocks the sympathetic nerve, often causing hypotension. For anaphylaxis occurring during cesarean delivery, maternal morbidity due to severe complications was reported in 20% of cases [4]. In the present case, anaphylaxis occurred during the intrapartum period, and the immediate cesarean delivery exerted a beneficial impact both on the mother and the infants.\n\nIdentifying the causative agent of anaphylaxis is essential to prevent allergic reactions. Agents, or known as allergens, administered immediately before an event, are often determined as culprit allergens without subsequent examinations. Had we not pursued the cause of the allergic reaction, we might have mistakenly assumed that the hydroxyethylated starch was the allergen, since anesthetic allergies have rarely been reported. Therefore, it should be kept in mind that the suspected agent may not be the true causative agent, and incorrect speculation may place the patient at risk of further exposure to the true allergen or cause unnecessary avoidance of harmless effective drugs.\n\nThe skin prick test is the gold standard to determine the cause of anaphylaxis, although it carries the risk of immediate hypersensitivity reactions. On the other hand, the BAT is an in vitro examination, which poses no risk of anaphylactic reactions. The BAT is based on the upregulation of granule-derived markers expressed at the basophil membrane upon ex vivo activation by the suspected agent. It recently became widely accepted as an additional and reliable tool, with high sensitivity and specificity to identify the causative agent of immediate drug hypersensitivity [14–17]. Further studies are required to evaluate the usefulness of this tool as a diagnostic approach of anaphylaxis, although diagnostic precision can be improved by combining multiple methods, such as the skin test and the BAT. In the present case, positive reactions to mepivacaine in both the BAT and skin prick test would support the reliability of BAT as a diagnostic tool.\n\nIn summary, the present case highlights that, upon anaphylaxis during pregnancy, maternal treatment and fetal heart rate monitoring should be started immediately. If the maternal hemodynamic status does not recover or if persistent non-reassuring fetal heart rate patterns are observed, immediate cesarean delivery should be considered, especially at the intrapartum period. Moreover, pursuing a definite diagnosis of the culprit allergen is beneficial for patients to prevent allergic reactions.\n\nAbbreviations\nBATBasophil activation test\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank Enago (https://www.enago.jp) for the English language review.\n\nAuthor’s contributions\nMT and TI participated in the anesthetic management. SI, TT, and TH supported to make a clinical diagnosis. MK drafted the manuscript. KH and MT supervised the manuscript drafting. All authors read and approved the final manuscript.\n\nFunding\nNot applicable\n\nAvailability of data and materials\nNot applicable\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. McCall SJ Bunch KJ Brocklehurst P D’Arcy R Hinshaw K Kurinczuk JJ The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study BJOG. 2018 125 1340 1341 10.1111/1471-0528.15302 \n2. Mccall SJ, Kurinczuk JJ, Knight M. Anaphylaxis in pregnancy in the United States: risk factors and temporal trends using national routinely collected data. J Allergy Clin Immunol Pract. 2019;S2213-2198(19)30455-6.\n3. Harper NJN Cook TM Garcez T Lucas DN Thomas M Kemp H Kong KL Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project(NAP6) Br J Anaesth. 2018 121 172 188 10.1016/j.bja.2018.04.015 29935569 \n4. Hepner DL Castells M Mouton-Faivre C Dewachter P Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review Anesth Analg. 2013 117 1357 1367 10.1213/ANE.0b013e3182a706c7 24257386 \n5. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin No.106: Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol. 2009;114:192–202.\n6. Adriaensens I Vercauteren M Soetens F Janssen L Leysens J Ebo D Allergic reactions during labour analgesia and caesarean section anaesthesia Int J Obstet Anesth. 2013 22 231 242 10.1016/j.ijoa.2013.04.010 23711758 \n7. Riley ET Editorial I Spinal anaesthesia for caesarean delively: keep the pressure and don’t spare the vasoconstrictors Br J Anaesth. 2004 92 459 461 10.1093/bja/aeh084 15013956 \n8. Chaudhuri K Gonzales J Jesurun CA Ambat MT Mandal-Chaudhuri S Anaphylactic shock in pregnancy: a case study and review of the literature Int J Obstet Anesth. 2008 17 350 357 10.1016/j.ijoa.2008.05.002 18691872 \n9. Shingai Y Nakagawa K Kato T Fujioka T Matsumoto T Severe allergy in a pregnant woman after vaginal examination with a latex glove Gynecol Obstet Invest. 2002 54 183 184 10.1159/000067888 12571444 \n10. Kaneko K Maruta H Severe anaphylactoid reaction to ranitidine in a parturient with subsequent fetal distress J Anesth. 2003 17 199 200 10.1007/s00540-003-0178-4 12911210 \n11. Berardi A Rossi K Cavalleri F Simoni A Aguzzoli L Maternal anaphylaxis and fetal brain damage after intrapartum chemoprophylaxis J Perinat Med 2004 32 375 377 10.1515/JPM.2004.070 15346827 \n12. Sheikh J Intrapartum anaphylaxis to penicillin in a woman with rheumatoid arthritis who had no prior penicillin allergy Ann Allergy Asthma Immunoll. 2007 99 287 289 10.1016/S1081-1206(10)60667-9 \n13. Khan R Anastasakis E Kadir RA Anaphylactic reaction to ceftriaxone in labour. An emerging complication J Obstet Gynaecol. 2008 28 751 753 10.1080/01443610802260595 19065378 \n14. Horiuchi T Yokohama A Orihara M Tomita Y Tomioka A Usefulness of basophil activation tests for diagnosis of sugammadex-induced anaphylaxis Anesth Analg. 2018 126 1509 1516 10.1213/ANE.0000000000002879 29517573 \n15. Ebo DG Faber M Elst J Van Gasse AL Birdts CH In vitro diagnosis of immediate drug hypersensitivity during anesthesia: a review of the literature J Allergy Clin Immunol Pract. 2018 6 1176 1184 10.1016/j.jaip.2018.01.004 29454709 \n16. Takazawa T Sabato V Ebo DG In vitro diagnostic tests for perioperative hypersensitivity, a narrative review: potential, limitations, and perspectives Br J Anaesth. 2019 123 e117 e125 10.1016/j.bja.2019.01.002 30915999 \n17. Dewachter P Chollet-Martin S Mouton-Faivre C de Chaisemartin L Nicaise-Roland P Comparison of basophil activation test and skin testing performances in NMBA allergy J Allergy Clin Immunol Pract 2018 6 1681 1689 10.1016/j.jaip.2017.12.037 29477296\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "5(1)",
"journal": "JA clinical reports",
"keywords": "Anaphylaxis; Basophil activation test; Cesarean delivery; Local anesthetic; Mepivacaine; Pregnancy; Spinal anesthesia",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "84",
"pmc": null,
"pmid": "32026066",
"pubdate": "2019-12-19",
"publication_types": "D016428:Journal Article",
"references": "15346827;29952063;29517573;31102701;19546798;17910335;29477296;15013956;23711758;12571444;18691872;19065378;12911210;29935569;24257386;29454709;30915999",
"title": "Mepivacaine-induced anaphylactic shock in a pregnant woman undergoing combined spinal and epidural anesthesia for cesarean delivery: a case report.",
"title_normalized": "mepivacaine induced anaphylactic shock in a pregnant woman undergoing combined spinal and epidural anesthesia for cesarean delivery a case report"
} | [
{
"companynumb": "JP-DENTSPLY-2020SCDP000015",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEPIVACAINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "Varicella zoster reactivation (\"shingles\" or \"herpes zoster\") usually presents as a self-limiting, unilateral, dermatomal vesicular rash in older adults. We present the case of a 73 year-old woman with unilateral brachial plexopathy, an unusual but debilitating complication of shingles. Despite treatment with intravenous acyclovir and immunoglobulin she had a marked residual motor paresis that required an upper limb rehabilitation program after discharge.",
"affiliations": "St. Vincents Hospital, Dublin, Ireland.;Departments of Medicine for the Older Person, St. Columcilles Hospital, Dublin, Ireland.;Departments of Neurology, St. Vincent's University Hospital, Dublin, Ireland.;Clinical Neurophysiology, St. Vincent's University Hospital, Dublin, Ireland.;Departments of Medicine for the Older Person, St. Columcilles Hospital, Dublin, Ireland.",
"authors": "McFeely|Aoife|A|;Doyle|Rachael|R|;O'Riordan|Sean|S|;Connolly|Sean|S|;O'Dwyer|Clodagh|C|",
"chemical_list": "D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afab055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "50(3)",
"journal": "Age and ageing",
"keywords": "herpes zoster; older people; plexopathy; radiculopathy; shingles",
"medline_ta": "Age Ageing",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D020516:Brachial Plexus Neuropathies; D005260:Female; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "1001-1003",
"pmc": null,
"pmid": "33765117",
"pubdate": "2021-05-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe brachial plexopathy secondary to shingles (herpes zoster).",
"title_normalized": "severe brachial plexopathy secondary to shingles herpes zoster"
} | [
{
"companynumb": "IE-TOLMAR, INC.-21IE026450",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": null,
... |
{
"abstract": "Encephalopathy is a common side effect of ifosfamide, occurring in up to 30% of patients. Although self-resolving in most cases, death secondary to severe encephalopathy has been reported. Methylene blue and thiamine have been occasionally successful as treatment. We report a case of an 11-year-old girl with relapsed neuroblastoma who developed grade 4 ifosfamide-induced encephalopathy. She showed no initial response to methylene blue and thiamine. She remained neurologically impaired and continuous veno-venous hemodiafiltration was started, with rapid resolution of encephalopathy. This is the first report of continuous veno-venous hemodiafiltration use for suspected ifosfamide-induced encephalopathy in the pediatric population.",
"affiliations": "*Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles †Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA.",
"authors": "Yeo|Kee Kiat|KK|;HaDuong|Josephine H|JH|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008751:Methylene Blue; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000527",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "38(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001927:Brain Diseases; D002648:Child; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007069:Ifosfamide; D008751:Methylene Blue; D009447:Neuroblastoma",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "489-90",
"pmc": null,
"pmid": "26907647",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Use of Continuous Veno-Venous Hemodiafiltration in the Management of Ifosfamide-induced Encephalopathy: A Case Report.",
"title_normalized": "the use of continuous veno venous hemodiafiltration in the management of ifosfamide induced encephalopathy a case report"
} | [
{
"companynumb": "US-BAXTER-2017BAX022755",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPOTECAN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "The patient was a 71-year-old man referred to our department because of asymptomatic gross hematuria. Detailed examination led to a diagnosis of bilateral ureteral cancer and prostate cancer. Total nephroureterectomy was performed for bilateral ureteral cancers on separate occasions, while prostate cancer was managed with hormone therapy. Because multiple bladder tumors were found by cystoscopy conducted after 3 months, total cystectomy was performed. Neither distant metastasis nor local recurrence had developed, 2 years later, when the patient visited our department again because of glans enlargement and received a diagnosis of penile cancer. Partial penectomy was performed, and a 1-cm indurated nodule was found in the skin of the hypogastric region during surgery and treated by simultaneous wedge-shaped excision. Histopathologically, the lesions were urothelial carcinomas. Multiple metastatic foci occurred in the skin postoperatively centering on the hypogastric region, growing rapidly and accompanied by bleeding and exudate causing a bad odor. Topical application of Mohs paste resulted in dramatic improvement of the pain and exudate, which thereby improved the patient's quality of life (QOL) to a level enabling discontinuation of narcotic drug therapy for cancer-related pain. Thereafter, hepatic metastasis was found and chemotherapy with gemcitabine and paclitaxel was administered. The patient did not respond to this chemotherapy and died of cancer 3 months later. Cutaneous metastasis of urothelial carcinoma, which is a very rare condition, is often managed with palliative therapy due to the lack of response to anticancer chemotherapy. In such cases, the use of Mohs paste appears to be of great value for maintaining the patient's QOL which otherwise might deteriorate markedly.",
"affiliations": "Department of Urology, National Hospital Organization Higashi-Hiroshima Medical Center.;Department of Urology, National Hospital Organization Higashi-Hiroshima Medical Center.",
"authors": "Masumoto|Hiroshi|H|;Fujiwara|Seiji|S|",
"chemical_list": "D002712:Chlorides; C583017:Mohs' paste; D017967:Zinc Compounds",
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.108.41",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "108(1)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "Cutaneous metastasis; Mohs paste; Urotherial carcinoma",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D002712:Chlorides; D015653:Cystectomy; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009378:Neoplasms, Multiple Primary; D000074682:Nephroureterectomy; D010166:Palliative Care; D010412:Penile Neoplasms; D010413:Penis; D011471:Prostatic Neoplasms; D011788:Quality of Life; D012878:Skin Neoplasms; D016896:Treatment Outcome; D014516:Ureteral Neoplasms; D001749:Urinary Bladder Neoplasms; D017967:Zinc Compounds",
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "41-44",
"pmc": null,
"pmid": "29367508",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CUTANEOUS METASTASIS OF UROTHERIAL CARCINOMA FOR WHICH MOHS PASTE WAS USEFUL: A CASE REPORT.",
"title_normalized": "cutaneous metastasis of urotherial carcinoma for which mohs paste was useful a case report"
} | [
{
"companynumb": "JP-ACCORD-063271",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "Up to 30% of patients with classical Hodgkin lymphoma (cHL) are not responsive to frontline therapy or relapse after primary treatment. In these cases, autologous hematopoietic stem cell transplantation (AHSCT) is the standard of care. The combination of brentuximab vedotin and bendamustine (BV + B) is an effective salvage regimen in this challenging subpopulation. This nationwide multicenter study investigated the real-world efficacy and safety of the BV + B regimen as a bridge to AHSCT in patients with primary refractory or relapsed cHL. A total of 41 cHL patients underwent AHSCT after receiving at least 1 cycle of BV + B (with brentuximab vedotin given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m2 on days 1-2 every 4 weeks). After a median of 3 (1-6) cycles of BV + B, the objective response rate was 78%, with 29 (70.7%) patients achieving complete remission. Twelve (29.3%) patients relapsed after AHSCT, 2 (4.9%) of them died, while 2 (4.9%) patients are lost to follow-up. After a median of 17 months of follow-up, the estimated 2-year overall- and progression-free survival after AHSCT was 93 and 62%, respectively. Features of advanced disease at recurrence (p = 0.038) and the presence of stage IV cHL at relapse (p = 0.024) are strong predictor markers of unfavorable outcomes. Twenty-four (58.5%) patients experienced adverse events of any grade, while no grade IV toxicities were reported. BV + B is an effective salvage option with a manageable toxicity profile in cHL. The real-world safety and efficacy of this combination are similar to the observations made on the study population.",
"affiliations": "Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary.;Division of Hematology, 2nd Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.;Division of Hematology, 2nd Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.;Division of Hematology, 1st Department of Internal Medicine, Faculty of Medicine, University of Pécs, Pecs, Hungary.;Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary. miltenyi.zsofia@med.unideb.hu.",
"authors": "Pinczés|László Imre|LI|https://orcid.org/0000-0003-0453-1709;Szabó|Roxána|R|;Illés|Árpád|Á|;Földeák|Dóra|D|;Piukovics|Klára|K|;Szomor|Árpád|Á|;Gopcsa|László|L|;Miltényi|Zsófia|Z|http://orcid.org/0000-0003-3507-9997",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000074322:Antineoplastic Agents, Immunological; D000079963:Brentuximab Vedotin; D000069461:Bendamustine Hydrochloride",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04204-1",
"fulltext": "\n==== Front\nAnn Hematol\nAnn. Hematol\nAnnals of Hematology\n0939-5555 1432-0584 Springer Berlin Heidelberg Berlin/Heidelberg \n\n32748163\n4204\n10.1007/s00277-020-04204-1\nOriginal Article\nReal-world efficacy of brentuximab vedotin plus bendamustine as a bridge to autologous hematopoietic stem cell transplantation in primary refractory or relapsed classical Hodgkin lymphoma\nhttps://orcid.org/0000-0003-0453-1709Pinczés László Imre 12 Szabó Roxána 1 Illés Árpád 12 Földeák Dóra 3 Piukovics Klára 3 Szomor Árpád 4 Gopcsa László 5 http://orcid.org/0000-0003-3507-9997Miltényi Zsófia miltenyi.zsofia@med.unideb.hu 12 1 grid.7122.60000 0001 1088 8582Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032 Hungary \n2 grid.7122.60000 0001 1088 8582Doctoral School of Clinical Medicine, University of Debrecen, Debrecen, Hungary \n3 grid.9008.10000 0001 1016 9625Division of Hematology, 2nd Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary \n4 grid.9679.10000 0001 0663 9479Division of Hematology, 1st Department of Internal Medicine, Faculty of Medicine, University of Pécs, Pecs, Hungary \n5 Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Budapest, Hungary \n3 8 2020 \n3 8 2020 \n2020 \n99 10 2385 2392\n27 1 2020 27 7 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Up to 30% of patients with classical Hodgkin lymphoma (cHL) are not responsive to frontline therapy or relapse after primary treatment. In these cases, autologous hematopoietic stem cell transplantation (AHSCT) is the standard of care. The combination of brentuximab vedotin and bendamustine (BV + B) is an effective salvage regimen in this challenging subpopulation. This nationwide multicenter study investigated the real-world efficacy and safety of the BV + B regimen as a bridge to AHSCT in patients with primary refractory or relapsed cHL. A total of 41 cHL patients underwent AHSCT after receiving at least 1 cycle of BV + B (with brentuximab vedotin given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m2 on days 1–2 every 4 weeks). After a median of 3 (1–6) cycles of BV + B, the objective response rate was 78%, with 29 (70.7%) patients achieving complete remission. Twelve (29.3%) patients relapsed after AHSCT, 2 (4.9%) of them died, while 2 (4.9%) patients are lost to follow-up. After a median of 17 months of follow-up, the estimated 2-year overall- and progression-free survival after AHSCT was 93 and 62%, respectively. Features of advanced disease at recurrence (p = 0.038) and the presence of stage IV cHL at relapse (p = 0.024) are strong predictor markers of unfavorable outcomes. Twenty-four (58.5%) patients experienced adverse events of any grade, while no grade IV toxicities were reported. BV + B is an effective salvage option with a manageable toxicity profile in cHL. The real-world safety and efficacy of this combination are similar to the observations made on the study population.\n\nKeywords\nHodgkin lymphomaAutologous hematopoietic stem cell transplantationBrentuximab vedotinBendamustineSurvivalUniversity of DebrecenOpen access funding provided by University of Debrecen.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nWith the new risk- and response-adapted treatment modalities, classical Hodgkin lymphoma (cHL) became a highly curable hematologic malignancy, with 80–90% of patients achieving long-term remission after standard first-line therapy [1, 2]. However, 20–30% of cHL patients have primary refractory disease or will experience recurrence. In these patients, an autologous hematopoietic stem cell transplantation (AHSCT) is the standard of care, despite the 50% relapse rate after transplantation in cHL [3]. Several prognostic factors associated with an increased risk of relapse following AHSCT include primary refractory cHL, stage IV disease at relapse, extranodal involvement, presence of B symptoms, and less than a complete remission (CR) to salvage therapy before AHSCT [4]. Achievement of CR by positron emission tomography/computed tomography (PET/CT) before AHSCT is a strong predictor for a favorable outcome [5–9].\n\nComplete remission rates before AHSCT with conventional salvage chemotherapy regimens, such as DHAP (cisplatin, cytarabine, and dexamethasone), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), IGEV (ifosfamide, gemcitabine, etoposide, and vinblastine), BeGEV (bendamustine, gemcitabine, and vinorelbine), and ICE (ifosfamide, carboplatin, and etoposide) vary from 17 to 76% [5, 6, 9–11]. In recent years, novel therapies (brentuximab vedotin, anti-programmed cell death-1 (PD-1) inhibitors) became available to help improve transplant outcomes and also survival rate of patients relapsing after AHSCT.\n\nOne of the novel combination therapies is brentuximab vedotin (BV) plus bendamustine (BV + B). BV is an antibody-drug conjugate, which consists of an anti-CD30 chimeric monoclonal antibody and the microtubule-disrupting agent, monomethyl auristatin E. Bendamustine is a bifunctional molecule containing the alkylating agent nitrogen mustard and the purine analog fludarabine, causing intra- and inter-strand cross-links between DNA bases resulting in cell death. In heavily pretreated cHL patients, BV used as monotherapy resulted in CR rates and overall response rates (ORR) of 27–35 and 72–75%, respectively [12–14]. CR and OR rates associated with single-agent bendamustine therapy were 33 and 53% [15]. The combination of these two agents is outstanding in a practical way. The increased proportion of patients achieving CR (43–74%), reduced toxicity burden compared with standard platinum-based salvage protocols, nonoverlapping toxicities of the combined agents, and the opportunity to treat patients in the outpatient setting highlight BV + B regimen, compared with other BV-based therapies [10, 16–18].\n\nAccording to the European Medicines Agency (EMA), brentuximab vedotin is indicated for the treatment of adult cHL patients with relapsed or refractory cHL after AHSCT or following at least two prior therapies when AHSCT or multiagent chemotherapy is not a treatment option or for cHL patients at increased risk of relapse or progression following AHSCT [19]. Therefore, in everyday practice, brentuximab vedotin can be used as a second salvage therapy for relapsed or refractory cHL patients as a sole agent, or even in combination.\n\nThe purpose of this study was to evaluate the safety and efficacy of the BV + B combination therapy as a bridge to transplantation in relapsed or refractory cHL patients who previously received two or more multiagent chemotherapy regimens.\n\nMethods\nStudy design and participants\nWe retrospectively analyzed the demographic data and clinical features of cHL patients receiving BV + B salvage therapy before AHSCT, between January 01, 2016, and December 31, 2018, treated at the four national transplant centers: the University of Debrecen (Debrecen, Hungary), the University of Pecs (Pecs, Hungary), the University of Szeged (Szeged, Hungary), and the Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases (Budapest, Hungary). Patients were treated according to the evidence- and consensus-based practice guidelines of the Hungarian Society of Hematology and Transfusion (Fig. 1) [20].Fig. 1 Practice guideline of the Hungarian Society of Hematology and Transfusion for the treatment of primary refractory or relapsed classical Hodgkin lymphoma. Abbreviations: PET, positron emission tomography; AHSCT, autologous hematopoietic stem cell transplantation\n\n\n\nEligible patients were aged 18 years or older and had a histologically confirmed diagnosis of classical cHL. Patients must have had relapsed or refractory disease following standard first-line polychemotherapy. We included patients who received at least one cycle of BV + B regimen in guideline-based dose. No exclusion criteria were determined regarding marrow and other organ function, Eastern Cooperative Oncology Group (ECOG) performance status, or a total number of previous therapies received.\n\nAll patients provided written informed consent during enrollment. Local research ethics committees of all participating centers approved the study, which was done according to the Declaration of Helsinki.\n\nProcedures and assessment\nRelapsed or refractory cHL patients received at least 2 cycles of a standard salvage chemotherapy regimen before the administration of BV + B combination therapy. Patients received 1 to 6 cycles of BV + B with a dose of 1.8 mg/kg brentuximab vedotin intravenously on day 1 and 90 mg/m2 of bendamustine intravenously on each of days 1 and 2 of a 21-day cycle. AHSCTs were performed with BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen.\n\nResponse to the salvage therapies was assessed using the 2016 Refinement of the Lugano Classification Lymphoma Response Criteria [21]. Failure after at least one standard salvage chemotherapy regimen made relapsed or refractory cHL patients eligible for BV + B therapy. A dedicated PET/CT scan was performed after cycle 2 of BV + B combination therapy, and later as it was deemed necessary. PET-negative patients (Deauville score 1–3) underwent AHSCT at any time after cycle 2, while PET-positive (Deauville score 4–5) patients were administered further antitumor therapy.\n\nStem cell mobilization and collection and also the administration of standard supporting treatment were performed according to institutional guidelines. Adverse events (AE) were monitored at every visit throughout treatment and follow-up.\n\nOutcomes\nOur analysis focuses on the CR and OR rates of relapsed or refractory cHL patients treated with BV + B combination therapy before AHSCT. Treatment response rates were also evaluated regarding PET/CT status according to the Lugano Classification. The overall survival (OS) was calculated from the day of AHSCT to the last follow-up visit or death. Progression-free survival (PFS) was defined as the time from AHSCT to disease progression, to relapse, or to death. Statistical analysis was performed via Fisher’s exact test, and survival data were calculated using the Kaplan-Meier method, with the SPSS 25.0 software.\n\nResults\nPatient characteristics and treatment\nDuring the 3-year observational period, 41 cHL patients with relapsed or refractory cHL underwent AHSCT after receiving BV + B salvage therapy (Table 1). The majority (61%) of patients had nodular sclerosing cHL, and a marked male predominance was present. Thirty-two (78%) patients had an advanced-stage disease at initial diagnosis. All patients had received ABVD as frontline therapy, in accordance with the national guidelines. Twenty-eight (68.3%) patients had primary refractory disease. At relapse, 23 (56%) patients had stage III–IV disease, while 8 (19.5%) of them had extranodal involvement.Table 1 Patient characteristics\n\n\tPatients\t%\t\nMen\t25\t61%\t\nWomen\t16\t39%\t\nHistological subtypes\t\nMC\t6\t14.6%\t\nNS\t25\t61%\t\nLR\t5\t12.2%\t\nLD\t1\t2.4%\t\nND\t4\t9.8%\t\nStage at the diagnosis\t\nII\t8\t19.5%\t\nIII\t11\t26.8%\t\nIV\t21\t51.2%\t\nRefractory\t28\t68.3%\t\nRelapse ≤ 12 months\t9\t22%\t\nRelapse > 12 months\t4\t9.7%\t\nStage at relapse\t\nI\t1\t2.4%\t\nII\t16\t39%\t\nIII\t9\t22%\t\nIV\t14\t34.1%\t\nExtranodal involvement\t8\t19.50%\t\nB symptoms\t15\t36.60%\t\nNumber of salvage therapies\t\n2\t24\t58.5%\t\n≥ 3\t17\t41.5%\t\nPET − (before AHSCT)\t29\t70.7%\t\nPET + (before AHSCT)\t12\t22%\t\nRelapse after AHSCT\t12\t29.3%\t\nAlive\t37\t90.2%\t\nDead\t2\t4.9%\t\nLost to follow-up\t2\t4.9%\t\nMC mixed cellularity, NS nodular sclerosing, LR lymphocyte rich, LD lymphocyte depleted, ND not defined, PET positron emission tomography, AHSCT autologous hematopoietic stem cell transplantation\n\n\n\nThe median number of prior salvage therapies preceding BV + B was 3 (range 1–6). Twenty (48.8%) patients received DHAP, while 4 (9.8%) patients received ifosfamide-based first salvage regimen. Seventeen (41.5%) patients received two or more salvage therapies before BV + B, including DHAP, ESHAP, IGEV, and PD-1 inhibitor. Patients received a median of 3 (range 1–6) cycles of BV + B. The last salvage regimen before AHSCT was BV + B.\n\nTreatment response and long-term follow-up\nOf the 41 evaluable patients, 29 (70.7%) achieved CR with BV + B therapy before AHSCT. The ORR was 92.6% overall, with 9 (21.9%) patients having partial remission (PR). Twenty-nine (70.8%) patients were PET-negative, and 12 (29.2%) patients were PET-positive before AHSCT. Of the 14 patients with stage IV disease at cHL progression or relapse, the CR and ORR rates were 64.3 and 85.7%, respectively.\n\nTwelve (29.2%) patients relapsed after AHSCT, including 8 (19.5%) patients who underwent AHSCT with PET-negative cHL. With a median follow-up of 17 (range 2–40) months, 37 patients are alive, two patients died, and two have been lost to follow-up. One patient died of disease progression and one of septic shock. None of the deaths were considered treatment-related. The median 2-year OS and PFS were 93 and 62%, respectively (Fig. 2). Compared with patients with stage I–II cHL at relapse, patients with advanced disease features at recurrence had an inferior outcome (p = 0.038) (Fig. 3). Also, the presence of stage IV cHL at relapse is a strong predictor marker of unfavorable outcome (p = 0.024) (Fig. 4). It is noteworthy that the survival curves reach a plateau before 18 months of follow-up. No association was found between outcome and any of the following features: age, sex, B symptoms, or histological subtype. Also, patients who achieved PET negativity before AHSCT had no survival benefit compared with the PET-positive group.Fig. 2 Median 2-year overall- and progression-free survival for all patients. Abbreviation: Tx, transplantation\n\nFig. 3 Median 2-year overall- and progression-free survival according to disease stage at recurrence (stage I–II vs. stage III–IV). Abbreviation: Tx, transplantation\n\nFig. 4 Median 2-year overall- and progression-free survival according to disease stage at recurrence (stage I–III vs. stage IV). Abbreviation: Tx, transplantation\n\n\n\nThirty-seven patients who underwent AHSCT were at increased risk of relapse or progression, based on the EMA indication criteria. However, only 15 patients received additional, posttransplant BV monotherapy. Eleven of the 12 PET-positive patients were candidates for single-agent BV after AHSCT, but only two of them were treated. Also, 13 of the 26 available patients received BV maintenance in the PET-negative group.\n\nAdverse events\nA total of 24 (58.5%) patients experienced treatment-related adverse events (AE) of any grade (Table 2). The most common toxicities were neutropenia (17%), peripheral neuropathy (12.2%), and infusion-related reactions (IRR) with fever, chills, flushing, or pruritus (12.2%). No cases of anaphylaxis were recorded. There were no grade 4 toxicities, and only a total of 3 (7.3%) patients experienced grade 3 toxicities. Serious AEs were neutropenia in 2 (4.8%) patients and peripheral neuropathy in 1 (2.4%) patient. One patient discontinued bendamustine due to severe, treatment-related neutropenia. Patients did not receive prophylactic corticosteroids or growth factor support routinely.Table 2 Summary of treatment-related adverse events\n\nAdverse events\tPatients\t%\t\nNeutropenia\t7\t17%\t\nPeripheral neuropathy\t5\t12.2%\t\nInfusion-related reaction\t5\t12.2%\t\nBronchitis, pneumonia\t2\t4.9%\t\nGI\t2\t4.9%\t\nRash\t1\t2.4%\t\nCMV infection\t1\t2.4%\t\nHerpes zoster infection\t1\t2.4%\t\nCMV cytomegalovirus, GI gastrointestinal\n\n\n\nDiscussion\nTo date, three prior phase 1–2 studies and a retrospective analysis evaluated the combination of BV and bendamustine in relapsed or refractory cHL patients. BV + B regimen showed marked activity in a heavily pretreated population of patients. LaCasce et al. reported on 55 cHL patients who relapsed after first-line chemotherapy and were treated with BV + B within a multicenter, phase 2 trial [16]. The overall response and CR rates were 92.5 and 73.6%, respectively. Those 40 patients, who proceeded to AHSCT, had improved OR (95%) and CR (85%) rates, with a 2-year OS of 94.9% and a 2-year PFS of 69.8%. More than half (56.4%) of this patient population experienced grade 3–4 AEs, with lymphopenia, rash, and hypotension occurring most frequently. The incidence of an infusion-related reaction, defined as fever, chills, dyspnea, flushing, nausea, pruritus, hypotension, or the combination of these, was 60%, which is more than single-agent brentuximab vedotin or bendamustine caused alone (12–15%) [22, 23]. Peripheral neuropathy occurred in 54.4% of the evaluable patients. O’Connor et al. treated 37 patients with an ORR of 78% in a phase 2 study population [17]. Forty-three percent of these patients achieved a complete response, while the 2-year OS and PFS were 80 and 62%, respectively. The most common grade 3–4 AEs were neutropenia (35%) and lung infection (14%). Broccoli et al. also observed high remission rates (ORR 80%, CR 75%) and promising 3-year OS and PFS (88.1 and 67.3%, respectively) with BV + B in 40 cHL patients, who inadequately responded to standard induction [18]. Martineau et al. administered BV + B combination to 80 heavily pretreated, relapsed, or refractory cHL patients. They reported a CR in 49 (65%) of 76 patients evaluable for efficacy, with an estimated 2-year OS and PFS of 88.5 and 64%, respectively. Patients eligible to AHSCT had an improved posttransplant CR rate (81%), compared with patients in the group without AHSCT (49%). The most frequent (> 30%) toxicities were hematological and infectious [24].\n\nOur results are similar to these data in terms of response rates, estimated survival, and toxicities (Table 3). Seemingly, cHL patients who do not respond to one or more traditional chemotherapy regimens could be effectively treated with BV + B salvage therapy and consolidated by AHSCT. However, it is important to note that, according to the national regulations on BV indication, we used BV + B combination as second salvage therapy. Notably, the majority of post-AHSCT relapses occur in the first year after transplantation. Around 18 months, the Kaplan-Meier PFS survival curve for all patients began to plateau and extended to 38 months for the longest survival follow-up.Table 3 Observations with brentuximab vedotin plus bendamustine combination in primary refractory or relapsed classical Hodgkin lymphoma\n\nAuthors\tReference no.\tNo. of patients\tORR (%)\tCR (%)\t2-year PFS (%)\t\nLaCasce et al.\t16\t55\t92.5\t73.6\t62.6\t\nO’Connor et al.\t17\t37\t78.0\t43.0\t62.0\t\nBroccoli et al.\t18\t40\t80.0\t75.0\t67.3\t\nMartineau et al.\t24\t80\tn/a\t65.0\t64.0\t\nPinczés et al.\t–\t41\t92.7\t70.8\t62.0\t\net al. et alia, no. number, ORR overall response rate, CR complete remission, PFS progression-free survival, n/a not available\n\n\n\nAchievement of a negative PET/CT scan before AHSCT had no impact on PFS, which may be due to the low number of patients included in the analysis. Also, because of the expanse in therapeutic options, all cHL patients are transplanted in the deepest achievable metabolic remission. Positive PET/CT results predominantly represent localized or non-widespread disease activity. In these cases, a high-dose conditioning regimen before AHSCT or posttransplant consolidation therapy can also be curative.\n\nThe impact of BV maintenance therapy for patients with high risk for relapse after AHSCT is challenging to assess. According to the AETHERA trial, high-risk patients are the ones with primary refractory HL, relapsed HL with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. While most patients were candidates according to this criteria, only 38% of them received BV consolidation, and there was no difference in either PFS or OS compared with low-risk cHL patients. The lack of proven survival benefit may also be the result of BV administration before AHSCT, as it provides better survival rates used as salvage therapy than conventional chemotherapy regimens. However, based on the results of the AETHERA study, consolidation treatment with BV is strongly recommended, as it significantly improved PFS compared with the placebo arm (5-year PFS of 59% vs. 41%, respectively) [25]. The low proportion of BV maintenance among the high-risk patients of this analysis is due to drug availability issues.\n\nIn relapsed or refractory cHL patients, several standard salvage chemotherapy regimens (ICE, DHAP, ESHAP) and checkpoint inhibitors (nivolumab, pembrolizumab) were complemented with BV in early-phase studies, resulting in OR and CR rates ranging from 68 to 100% and 34–100%, respectively [11, 26]. Also, bendamustine-based BeGEV regimen reached OR and CR rates comparable with those achieved with BV + B combination and is considered a feasible candidate for first salvage in primary refractory or relapsed cHL. However, the possibility arises that the effectiveness of a subsequent treatment with BV + B would be impaired in BeGEV-resistant patients. Along with the achievement of a durable disease control and the favorable safety profile, the main advantage of the BV + B regimen, compared with the combinations mentioned above, is the benefit of the administration in the outpatient setting, resulting in the improvement of quality of life.\n\nHowever, the results of this study suggest that patients with advanced stages, particularly with stage IV cHL at relapse, have inferior outcomes compared with relapsed or refractory cHL patients with early-stage cHL at recurrence. These patients might be appropriate candidates for BV combined with traditional chemotherapy regimens (e.g., augmented ICE) or other novel therapies (e.g., nivolumab) to achieve significantly improved PFS.\n\nPotential limitations of our analysis include the retrospective nature of data collection, limiting the ability to determine cause and effect. Also, due to the relatively low number of patients receiving consolidation, we were not able to assess the impact of BV maintenance therapy. However, we believe that the inclusion of patients from all age groups with no regard to co-morbidities represents real-world experience and can be considered the main strength of the current report.\n\nThe treatment paradigm of relapsed and refractory cHL has changed with the availability of BV and checkpoint inhibitors. With the successful introduction of these novel agents into salvage therapy, there will be another shift in treatment, with these agents being incorporated into first-line regimens in the future. Also, the indication of radiation therapy has already been significantly reduced. The use of the BV + B regimen as a bridge to AHSCT in relapsed or refractory cHL patients can be an outstanding example of this process. BV + B is a promising, highly active salvage option with a manageable toxicity profile and a potential for long-term disease control. Complemented by AHSCT, BV + B regimen has the potential to considerably improve the outcome of cHL patients progressing after first-line therapy. The comparison of BV + B with other salvage regimens demands prospective analysis.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors acknowledge the clinicians and nurses at associated transplant centers who treated the patients and also the patients who participated in this study.\n\nCode availability\nNot applicable.\n\nAuthors’ contributions\nZs.M., Á.I., and L.I.P. designed the analysis, interpreted the data, and wrote the initial draft of the manuscript. R.Sz., D.F., K.P., Á.Sz., and L.G. collected the data and performed the analyses of the data. All authors read and approved the final manuscript.\n\nFunding Information\nOpen access funding provided by University of Debrecen.\n\nData availability\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthics approval\nApproval was obtained from the ethics committees of all participating centers. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.\n\nConsent to participate\nInformed consent was obtained from all individual participants included in the study.\n\nConsent for publication\nNot applicable.\n==== Refs\nReferences\n1. Bonadonna G Bonfante V Viviani S di Russo A Villani F Valagussa P ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results J Clin Oncol 2004 22 2835 2841 10.1200/JCO.2004.12.170 15199092 \n2. Engert A Diehl V Franklin J Lohri A Dörken B Ludwig WD Koch P Hänel M Pfreundschuh M Wilhelm M Trümper L Aulitzky WE Bentz M Rummel M Sezer O Müller-Hermelink HK Hasenclever D Löffler M Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study J Clin Oncol 2009 27 4548 4554 10.1200/JCO.2008.19.8820 19704068 \n3. Majhail NS Weisdorf DJ Defor TE Miller JS McGlave PB Slungaard A Arora M Ramsay NKC Orchard PJ MacMillan ML Burns LJ Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma Biol Blood Marrow Transplant 2006 12 1065 1072 10.1016/j.bbmt.2006.06.006 17084370 \n4. Sureda A Constans M Iriondo A Arranz R Caballero MD Vidal MJ Petit J López A Lahuerta JJ Carreras E García-Conde J García-Laraña J Cabrera R Jarque I Carrera D García-Ruiz JC Pascual MJ Rifón J Moraleda JM Pérez-Equiza K Albó C Díaz-Mediavilla J Torres A Torres P Besalduch J Marín J Mateos MV Fernández-Rañada JM Sierra J Conde E Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse Ann Oncol 2005 16 625 633 10.1093/annonc/mdi119 15737986 \n5. Moskowitz CH Matasar MJ Zelenetz AD Nimer SD Gerecitano J Hamlin P Horwitz S Moskowitz AJ Noy A Palomba L Perales MA Portlock C Straus D Maragulia JC Schoder H Yahalom J Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma Blood 2012 119 1665 1670 10.1182/blood-2011-10-388058 22184409 \n6. Moskowitz CH Nimer SD Zelenetz AD Trippett T Hedrick EE Filippa DA Louie D Gonzales M Walits J Coady-Lyons N Qin J Frank R Bertino JR Goy A Noy A O'Brien JP Straus D Portlock CS Yahalom J A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model Blood 2001 97 616 623 10.1182/blood.V97.3.616 11157476 \n7. Moskowitz AJ Yahalom J Kewalramani T Maragulia JC Vanak JM Zelenetz AD Moskowitz CH Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma Blood 2010 116 4934 4937 10.1182/blood-2010-05-282756 20733154 \n8. Josting A Rudolph C Reiser M Mapara M Sieber M Kirchner HH Dörken B Hossfeld DK Diehl V Engert A Participating Centers Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease Ann Oncol 2002 13 1628 1635 10.1093/annonc/mdf221 12377653 \n9. Bartlett NL Niedzwiecki D Johnson JL Friedberg JW Johnson KB van Besien K Zelenetz AD Cheson BD Canellos GP Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804 Ann Oncol 2007 18 1071 1079 10.1093/annonc/mdm090 17426059 \n10. Vitolo U Chiappella A Salvage regimens for Hodgkin’s lymphoma in the brentuximab vedotin era Lancet Oncol 2018 19 162 163 10.1016/S1470-2045(17)30913-0 29276023 \n11. Santoro A Mazza R Pulsoni A Re A Bonfichi M Zilioli VR Salvi F Merli F Anastasia A Luminari S Annechini G Gotti M Peli A Liberati AM di Renzo N Castagna L Giordano L Carlo-Stella C Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: final results of a multicenter phase II study J Clin Oncol 2016 34 3293 3299 10.1200/JCO.2016.66.4466 27382096 \n12. Younes A Gopal AK Smith SE Ansell SM Rosenblatt JD Savage KJ Ramchandren R Bartlett NL Cheson BD de Vos S Forero-Torres A Moskowitz CH Connors JM Engert A Larsen EK Kennedy DA Sievers EL Chen R Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma J Clin Oncol 2012 30 2183 2189 10.1200/JCO.2011.38.0410 22454421 \n13. Chen R Gopal AK Smith SE Ansell SM Rosenblatt JD Savage KJ Connors JM Engert A Larsen EK Huebner D Fong A Younes A Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma Blood 2016 128 1562 1566 10.1182/blood-2016-02-699850 27432875 \n14. Gopal AK Chen R Smith SE Ansell SM Rosenblatt JD Savage KJ Connors JM Engert A Larsen EK Chi X Sievers EL Younes A Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma Blood 2015 125 1236 1243 10.1182/blood-2014-08-595801 25533035 \n15. Moskowitz AJ Hamlin PA Perales MA Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma J Clin Oncol 2013 31 456 460 10.1200/JCO.2012.45.3308 23248254 \n16. LaCasce AS Gregory Bociek R Sawas A Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma Blood 2018 132 40 48 10.1182/blood-2017-11-815183 29703778 \n17. O’Connor OA Lue JK Sawas A Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin’s lymphoma: an international, multicentre, single-arm, phase 1–2 trial Lancet Oncol 2018 19 257 266 10.1016/S1470-2045(17)30912-9 29276022 \n18. Broccoli A Argnani L Botto B First salvage treatment with bendamustine and brentuximab vedotin in Hodgkin lymphoma: a phase 2 study of the Fondazione Italiana Linfomi Blood Cancer J 2019 9 100 10.1038/s41408-019-0265-x 31827067 \n19. European Medicines Agency (2020) Adcetris. European Medicines Agency website. https://www.ema.europa.eu/en/medicines/human/EPAR/adcetris. Accessed 26 Jan 2020\n20. Illés Á Molnár Z Miltényi Z Novelties in the management of Hodgkin lymphoma Klin Onkol 2016 3 185 193 \n21. Cheson BD Ansell S Schwartz L Gordon LI Advani R Jacene HA Hoos A Barrington SF Armand P Refinement of the Lugano classification lymphoma response criteria in the era of immunomodulatory therapy Blood 2016 128 2489 2496 10.1182/blood-2016-05-718528 27574190 \n22. Seattle Genetics Inc. (2020) ADCETRIS® (brentuximab vedotin) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125388_S056S078lbl.pdf. Accessed 26 Jan 2020\n23. Kahl BS Bartlett NL Leonard JP Chen L Ganjoo K Williams ME Czuczman MS Robinson KS Joyce R van der Jagt RH Cheson BD Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study Cancer 2010 116 106 114 10.1002/cncr.24714 19890959 \n24. Martineau D Sauvezie M Oberic L Brentuximab-vedotin + bendamustine: a highly effective salvage treatment in refractory/relapsed patients with Hodgkin lymphoma HemaSphere 2018 2 53 10.1097/01.hs9.0000547978.61156.2d \n25. Moskowitz CH Walewski J Nademanee A Masszi T Agura E Holowiecki J Abidi MH Chen AI Stiff P Viviani S Bachanova V Sureda A McClendon T Lee C Lisano J Sweetenham J Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse Blood 2018 132 2639 2642 10.1182/blood-2018-07-861641 30266774 \n26. Herrera AF Moskowitz AJ Bartlett NL Vose JM Ramchandren R Feldman TA LaCasce AS Ansell SM Moskowitz CH Fenton K Ogden CA Taft D Zhang Q Kato K Campbell M Advani RH Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma Blood 2018 131 1183 1194 10.1182/blood-2017-10-811224 29229594\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "99(10)",
"journal": "Annals of hematology",
"keywords": "Autologous hematopoietic stem cell transplantation; Bendamustine; Brentuximab vedotin; Hodgkin lymphoma; Survival",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D000079963:Brentuximab Vedotin; D003131:Combined Modality Therapy; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009503:Neutropenia; D010523:Peripheral Nervous System Diseases; D049268:Positron-Emission Tomography; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D016879:Salvage Therapy; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2385-2392",
"pmc": null,
"pmid": "32748163",
"pubdate": "2020-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "15199092;19704068;17084370;15737986;22184409;11157476;20733154;12377653;17426059;27382096;22454421;27432875;25533035;23248254;29703778;29276022;31827067;27574190;19890959;30266774;29229594",
"title": "Real-world efficacy of brentuximab vedotin plus bendamustine as a bridge to autologous hematopoietic stem cell transplantation in primary refractory or relapsed classical Hodgkin lymphoma.",
"title_normalized": "real world efficacy of brentuximab vedotin plus bendamustine as a bridge to autologous hematopoietic stem cell transplantation in primary refractory or relapsed classical hodgkin lymphoma"
} | [
{
"companynumb": "HU-SEATTLE GENETICS-2020SGN05058",
"fulfillexpeditecriteria": "2",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": "3"... |
{
"abstract": "A woman in her forties with asthma and COPD was admitted to a general medical floor with respiratory symptoms, body aches, and anosmia. Reverse transcription polymerase chain reaction detected severe acute respiratory syndrome coronavirus-2. Admission labs, including biomarkers of the systemic immunological dysfunction seen in many cases of coronavirus disease 2019 (COVID-19), were within normal ranges. On the second day of admission, she developed neck and back pain that was constant, burning in quality, and exacerbated by light touch and heat. Wearing clothing caused pain and interfered with her sleep. The area was tender to light finger stroke. The patient was given acetaminophen, NSAIDs, and opioids with no relief of pain. However, gabapentin was effective. At follow-up 1 month later, her symptoms were improved and still relieved by gabapentin. Neuropathic pain was seen in over 2% of COVID-19 patients in one observational study. The pain seen in our case was bilateral, involved an area innervated by multiple levels of spinal nerves, and was limited to the back. While it is rare, a significant number of COVID-19 patients are afflicted by neuropathic pain, and our case illustrates that gabapentin may be effective.",
"affiliations": "Department of Internal Medicine, Montefiore Wakefield Campus, 600 East 233rd Street, Bronx, NY, 10466, USA.;Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, 111 E 210th Street, Bronx, NY, 10467, USA. nelson7@gmail.com.;Department of Internal Medicine, Montefiore Wakefield Campus, 600 East 233rd Street, Bronx, NY, 10466, USA.",
"authors": "Aksan|Feyzullah|F|;Nelson|Eric Andrew|EA|0000-0003-3348-1499;Swedish|Kristin A|KA|",
"chemical_list": "D000700:Analgesics; D000082:Acetaminophen; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-020-00887-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": "26(5)",
"journal": "Journal of neurovirology",
"keywords": "COVID-19; Gabapentin; Neuralgia; Neuropathic pain; SARS-CoV-2",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000082:Acetaminophen; D000700:Analgesics; D000080445:Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome; D001416:Back Pain; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008875:Middle Aged; D019547:Neck Pain; D000857:Olfaction Disorders; D010146:Pain; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "800-801",
"pmc": null,
"pmid": "32779108",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31861926;32369429;19714266;32329222;32275288;28832395",
"title": "A COVID-19 patient with intense burning pain.",
"title_normalized": "a covid 19 patient with intense burning pain"
} | [
{
"companynumb": "US-NUVO PHARMACEUTICALS INC-2096337",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"drugadditional": nul... |
{
"abstract": "A 36-year-old African American with a medical history of nonanesthesia-related malignant hyperthermia (MH) who was taking chronic oral dantrolene therapy presented with right upper quadrant pain for a laparoscopic cholecystectomy. A multidisciplinary perioperative plan was implemented with the goal of avoiding triggering an MH episode or rhabdomyolysis. He developed a postoperative left brachial vein thrombus of unclear etiology, possibly related to dantrolene administration or his underlying susceptibility to MH.",
"affiliations": "From the Departments of Anesthesia and Perioperative Medicine.;Surgery, Medical University of South Carolina, Charleston, South Carolina.;From the Departments of Anesthesia and Perioperative Medicine.;Department of Anesthesiology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina.;Surgery, Medical University of South Carolina, Charleston, South Carolina.;From the Departments of Anesthesia and Perioperative Medicine.;From the Departments of Anesthesia and Perioperative Medicine.",
"authors": "Nelson|Emily P|EP|;Dorlon|Margaret E|ME|;Szabo|Tamas A|TA|;Trollinger|Jonathan B|JB|;Johnson-Mann|Crystal|C|;Broderick|Gearin|G|;Warters|Robert D|RD|",
"chemical_list": "D009125:Muscle Relaxants, Central; D003620:Dantrolene",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "11(5)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D017081:Cholecystectomy, Laparoscopic; D003620:Dantrolene; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia; D009125:Muscle Relaxants, Central; D012206:Rhabdomyolysis; D020246:Venous Thrombosis",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "137-139",
"pmc": null,
"pmid": "29608462",
"pubdate": "2018-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of a Patient With a History of Nonanesthesia-Related Malignant Hyperthermia Undergoing Laparoscopic Cholecystectomy: A Case Report.",
"title_normalized": "management of a patient with a history of nonanesthesia related malignant hyperthermia undergoing laparoscopic cholecystectomy a case report"
} | [
{
"companynumb": "US-MYLANLABS-2019M1010449",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DANTROLENE SODIUM"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo report the case of a patient, who in the context of an anti-Parkinsonian therapy, developed addiction to apomorphine.\n\n\nMETHODS\nClinical case description.\n\n\nRESULTS\nApomorphine is a dopaminergic agonist that acts directly on D2 receptors. It has been used in alcoholism, male sexual dysfunction and with diagnostic and therapeutic purposes in Parkinson's disease (PD).\n\n\nCONCLUSIONS\nThe present work describes the case of a woman with PD who developed a loss of control over the consumption of apomorphine that resulted in a significant impairment of her functioning. PD patients with high frequency develop different psychiatric symptoms. Conversely, anti-Parkinsonian drugs also generate psychiatric symptoms that can be experienced by the patient as pleasant sensations ('alerting', 'awakening', 'activating', hypomania and hypersexuality). In spite of this, addiction to these drugs in patients with PD is a very rare phenomenon. Currently, the prescription of apomorphine has been extended to patients with erectile dysfunction, which may increase the prevalence of addiction cases or of severe psychiatric symptoms.",
"affiliations": "Hospital Clínico de la Universidad de Chile, Santiago, Chile. sdiaz@redclinicauchile.cl",
"authors": "Téllez|Carlos|C|;Bustamante|M Leonor|ML|;Toro|Pablo|P|;Venegas|Pablo|P|",
"chemical_list": "D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D001058:Apomorphine",
"country": "England",
"delete": false,
"doi": "10.1111/j.1360-0443.2006.01580.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0965-2140",
"issue": "101(11)",
"journal": "Addiction (Abingdon, England)",
"keywords": null,
"medline_ta": "Addiction",
"mesh_terms": "D000978:Antiparkinson Agents; D001058:Apomorphine; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D008875:Middle Aged; D009021:Morphine Dependence; D010300:Parkinson Disease",
"nlm_unique_id": "9304118",
"other_id": null,
"pages": "1662-5",
"pmc": null,
"pmid": "17034447",
"pubdate": "2006-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Addiction to apomorphine: a clinical case-centred discussion.",
"title_normalized": "addiction to apomorphine a clinical case centred discussion"
} | [
{
"companynumb": "CL-US WORLDMEDS, LLC-STA_00019278",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "APOMORPHINE HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "A male aged 44 years presented to the emergency department with a 1-week history of intermittent right-sided abdominal pain radiating to the midline. Examination demonstrated a tender right upper quadrant with voluntary guarding and a low grade fever. One week previously, he had been admitted to hospital after an isolated, self-terminating seizure secondary to an deliberate venlafaxine overdose. His upper abdominal symptoms started immediately postseizure but at the time were attributed to musculoskeletal chest pain by the discharging team. Acute cholecystitis was suspected, but liver function tests, amylase and an erect chest radiograph were unremarkable.The abdominal pain responded well to morphine, permitting a thorough reassessment of the patient, which revealed midthoracic spine tenderness, previously undetected. Prior to this, the patient had not complained of any back pain. A CT scan confirmed a burst fracture of T8 requiring urgent transfer to the local spinal unit for posterior stabilisation.",
"affiliations": "Emergency Medicine, Torbay and South Devon NHS Foundation Trust, Torquay, UK.;Emergency Medicine, Torbay and South Devon NHS Foundation Trust, Torquay, UK.;Emergency Medicine, Torbay and South Devon NHS Foundation Trust, Torquay, UK.",
"authors": "Smith|Radford Arran James|RAJ|;Poland|Nigel|N|;Cope|Simon|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Epilepsy and seizures; General surgery; Orthopaedics; Trauma",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000006:Abdomen, Acute; D000328:Adult; D001863:Bone Screws; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D012640:Seizures; D016103:Spinal Fractures; D013904:Thoracic Vertebrae; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28500130",
"pubdate": "2017-05-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11471412;13130623;23198223;4270321;8153811",
"title": "A seizure-induced T8 burst fracture re-presenting as an acute abdomen.",
"title_normalized": "a seizure induced t8 burst fracture re presenting as an acute abdomen"
} | [
{
"companynumb": "GB-TEVA-781251ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": null,... |
{
"abstract": "Neurotoxicity after intra-arterial administration of cisplatin, alone or in combination with other chemotherapeutic agents, is not yet well-documented. In our experience with 63 previously untreated patients with head and neck cancer, we observed four patients with cranial nerve impairment ipsilateral to the cannulated artery. The first patient has already been reported, whereas the other three are the subject of the present report. Overall, all three patients developed cranial peripheral palsy a few days after the end of intra-arterial cisplatin and after a median total dose of 200 mg (range, 160-250). The nerves involved were the 12th in the first patient, the seventh in the second, and the ninth, tenth, 11th, and 12th in the third patient. Complete recovery of the palsy was noted only in the first patient. The patient reported previously had developed a cranial nerve palsy involving the ninth, tenth, 11th, and 12th nerves of the right side. The low incidence of this toxicity (6.3% in our experience) and the very high objective remission rate achieved by the intra-arterial administration of cisplatin justify the continuation of such an approach to obtain the maximum tumor regression and to research the individual predisposing factors.",
"affiliations": null,
"authors": "Frustaci|S|S|;Barzan|L|L|;Comoretto|R|R|;Tumolo|S|S|;Lo Re|G|G|;Monfardini|S|S|",
"chemical_list": "D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-5960",
"issue": "71(3)",
"journal": "Cancer treatment reports",
"keywords": null,
"medline_ta": "Cancer Treat Rep",
"mesh_terms": "D000368:Aged; D002945:Cisplatin; D003389:Cranial Nerve Diseases; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7607107",
"other_id": null,
"pages": "257-9",
"pmc": null,
"pmid": "3815392",
"pubdate": "1987-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Local neurotoxicity after intra-arterial cisplatin in head and neck cancer.",
"title_normalized": "local neurotoxicity after intra arterial cisplatin in head and neck cancer"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1013818",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nMacroglossia has been reported in patients undergoing posterior fossa neurosurgical procedures and is thought to be as a result of venous engorgement from intubation or mechanical positioning during these prolonged procedures.\n\n\nMETHODS\nWe report three patients who developed macroglossia and dysautonomia of central neurogenic origin following brainstem injury.\n\n\nRESULTS\nThe three patients developed macroglossia and dysautonomia with wide hemodynamic fluctuations in the setting of posterior fossa injury of the lower brainstem structures, necessitating tracheostomy placement. Macroglossia was managed with dexamethasone and there was complete resolution of dysautonomia while treated with beta-blockers and gabapentin.\n\n\nCONCLUSIONS\nNeurointensivists should be aware of macroglossia with dysautonomia complicating brainstem injury, which may have perilous consequences in the setting of cerebral edema or intracranial hypertension.",
"affiliations": "Division of Neurocritical Care, Department of Neurology, Ochsner Medical Center, New Orleans, LA, USA, iiwuchuk@tulane.edu.",
"authors": "Iwuchukwu|Ifeanyi|I|;Ardelt|Agnieszka|A|;Cueva|Wilson|W|;Reshi|Rwoof|R|;Goldenberg|Fernando|F|;Frank|Jeffrey|J|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000588:Amines; D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1007/s12028-013-9901-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1541-6933",
"issue": "20(1)",
"journal": "Neurocritical care",
"keywords": null,
"medline_ta": "Neurocrit Care",
"mesh_terms": "D000293:Adolescent; D000319:Adrenergic beta-Antagonists; D000368:Aged; D000588:Amines; D000893:Anti-Inflammatory Agents; D001930:Brain Injuries; D001933:Brain Stem; D002121:Calcium Channel Blockers; D003388:Cranial Fossa, Posterior; D003509:Cyclohexanecarboxylic Acids; D003907:Dexamethasone; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008260:Macroglossia; D008297:Male; D008875:Middle Aged; D054969:Primary Dysautonomias; D014139:Tracheostomy; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "101156086",
"other_id": null,
"pages": "106-10",
"pmc": null,
"pmid": "24002892",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "13762360;17143247;22103631;17858337;9438617;7911281;18338269;17968518;10575027;13201968;7890977;3400847;7264186;8218090;4812721;17435191;16992213;18410507",
"title": "Macroglossia associated with brainstem injury.",
"title_normalized": "macroglossia associated with brainstem injury"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK016710",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"dru... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.